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Sample records for folic acid antagonists

  1. Folic Acid

    MedlinePLUS

    ... get enough folic acid each day? What foods contain folic acid? Can I get enough folic acid ... their doctors. Some doctors prescribe prenatal vitamins that contain higher amounts of folic acid. You are breastfeeding. ...

  2. Folic Acid

    MedlinePLUS

    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 ...

  3. Folic Acid

    MedlinePLUS

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

  4. Folic acid

    MedlinePLUS

    ... appear to have a lower risk of developing Alzheimer’s disease than people who consume less folic acid. Preventing re-blockage of blood vessels after angioplasty. There is inconsistent evidence on the ...

  5. Folic Acid and Pregnancy

    MedlinePLUS

    ... Kids Deal With Bullies Pregnant? What to Expect Folic Acid and Pregnancy KidsHealth > Parents > Pregnancy & Newborn Center > Your ... especially before conception and during early pregnancy . About Folic Acid Folic acid, sometimes called folate, is a B ...

  6. Facts about Folic Acid

    MedlinePLUS

    ... Us Information For... Media Policy Makers Facts About Folic Acid Language: English Español (Spanish) Recommend on Facebook Tweet ... defects of the baby's brain and spine. About folic acid Folic acid is a B vitamin. Our bodies ...

  7. Folic acid - test

    MedlinePLUS

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

  8. Folic Acid Quiz

    MedlinePLUS

    ... Partners About Us Information For... Media Policy Makers Folic Acid Quiz Language: English Español (Spanish) Recommend on Facebook ... CORRECT button beside the question. Good Luck! 1. Folic acid is: A a B vitamin B a form ...

  9. Circulating folic acid in plasma: relation to folic acid fortification

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The implementation of folic acid fortification in the United States has resulted in unprecedented amounts of this synthetic form of folate in the American diet. Folic acid in circulation may be a useful measure of physiologic exposure to synthetic folic acid, and there is a potential for elevated co...

  10. Folic Acid Questions and Answers

    MedlinePLUS

    ... or planning to get pregnant to start taking folic acid? A : Birth defects of the brain and spine ( ... month. Is it too late to start taking folic acid? A: The CDC recommends women to take 400 ...

  11. Folic Acid Helps Prevent Neural Tube Defects

    MedlinePLUS

    ... What's this? Submit Button Past Emails CDC Features Folic Acid Helps Prevent Neural Tube Defects Language: English Español ( ... every day before and during pregnancy. What Is Folic Acid? Folic acid is a B vitamin. Our bodies ...

  12. Photogenotoxicity of folic acid.

    PubMed

    Butzbach, Kathrin; Epe, Bernd

    2013-12-01

    Folic acid (FA), also named vitamin B9, is an essential cofactor for the synthesis of DNA bases and other biomolecules after bioactivation by dihydrofolate reductase (DHFR). FA is photoreactive and has been shown to generate DNA modifications when irradiated with UVA (360 nm) in the presence of DNA under cell-free conditions. To investigate the relevance of this reaction for cells and tissues, we irradiated three different cell lines (KB nasopharyngeal carcinoma cells, HaCaT keratinocytes, and a melanoma cell line) in the presence of FA and quantified cytotoxicity and DNA damage generation. The results indicate that FA is phototoxic and photogenotoxic by two different mechanisms. First, extracellular photodecomposition of FA gives rise to the generation of H2O2, which causes mostly DNA strand breaks. If this is prevented, e.g., by the presence of catalase, DNA damage generated by intracellular FA becomes evident. The damage spectrum in this case consists predominantly of oxidatively generated purine modifications sensitive to the repair glycosylase Fpg, as characteristic for type I photoreactions, and is associated with the formation of micronuclei. In KB cells, the DNA damage is strongly enhanced after pretreatment with the DHFR inhibitor methotrexate, which prevents the loss of the chromophore associated with the intracellular reduction of FA by DHFR. The results indicate that FA is photoreactive in cells and gives rise to nuclear DNA damage under irradiation. PMID:23973753

  13. Folic acid and birth defect prevention

    MedlinePLUS

    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 ...

  14. Getting folic acid nutrition right

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The two articles in this issue of the journal provide some definitive answers to questions relating to folic acid exposure and folate nutritional status of the US population in the post-fortification era, and, by implication, pose other questions. Most convincingly, these reports, which are based la...

  15. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Folic acid test system. 862.1295 Section 862.1295....1295 Folic acid test system. (a) Identification. A folic acid test system is a device intended to measure the vitamin folic acid in plasma and serum. Folic acid measurements are used in the diagnosis...

  16. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Folic acid test system. 862.1295 Section 862.1295....1295 Folic acid test system. (a) Identification. A folic acid test system is a device intended to measure the vitamin folic acid in plasma and serum. Folic acid measurements are used in the diagnosis...

  17. Folic acid in diet

    MedlinePLUS

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

  18. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...acid test system is a device intended to 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...

  19. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...acid test system is a device intended to 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...

  20. 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 ...

  1. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Folic acid (folacin). 172.345 Section 172.345 Food... Special Dietary and Nutritional Additives § 172.345 Folic acid (folacin). Folic acid (CAS Reg. No....

  2. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Folic acid (folacin). 172.345 Section 172.345 Food... Special Dietary and Nutritional Additives § 172.345 Folic acid (folacin). Folic acid (CAS Reg. No....

  3. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Folic acid (folacin). 172.345 Section 172.345 Food... Special Dietary and Nutritional Additives § 172.345 Folic acid (folacin). Folic acid (CAS Reg. No....

  4. Neural Tube Defects, Folic Acid and Methylation

    PubMed Central

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

    2013-01-01

    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

  5. Contemporary Issues Surrounding Folic Acid Fortification Initiatives

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

    Dugbaza, Jacinta; Cunningham, Judy

    2012-01-01

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

  7. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... following prescribed conditions: (a) Folic acid is the chemical N- amino]benzoyl]-L-glutamic acid. (b) Folic... incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies are available from the... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Folic acid (folacin). 172.345 Section 172.345...

  8. Will mandatory folic acid fortification prevent or promote cancer?

    PubMed

    Kim, Young-In

    2004-11-01

    An overwhelming body of evidence for a protective effect of periconceptional folic acid supplementation against neural tube defects (NTDs) led to mandatory folic acid fortification in the United States. The effectiveness of folic acid fortification in improving folate status has already been shown to be quite striking, with a dramatic increase in blood measurements of folate in the United States. Preliminary reports also suggest a significant reduction ( approximately 15-50%) in NTDs in the United States. The success of folic acid fortification in improving folate status and in reducing NTD rates is truly a public health triumph and provides a paradigm of collaboration between science and public health policy. Although folic acid is generally regarded as safe, there continues to be concern that folic acid fortification may have adverse effects in subpopulation groups not originally targeted for fortification. In this regard, an emerging body of evidence suggests that folic acid supplementation may enhance the development and progression of already existing, undiagnosed premalignant and malignant lesions. Over the past few years, the US population has been exposed to a significant increase in folate intake, for which essentially no data on safety exist. The potential cancer-promoting effect of folic acid supplementation needs to be considered in carefully monitoring the long-term effect of folic acid fortification on the vast majority of the US population, who are not at risk of NTDs. PMID:15531657

  9. Folic Acid Determination Using Electrochemical Sensors

    PubMed Central

    Mirmoghtadaie, Leila; Shamaeizadeh, Nahal; Mirzanasiri, Nooshin

    2015-01-01

    Folic acid (FA) is a water soluble vitamin that exists in many natural species. The lack of FA causes some deficiencies in the human body, so finding a simple and sensitive method for determining the FA is important. One of the modern techniques which overcome the disadvantages of conventional determination methods is the sensors. Possibility of miniaturization, the development of microfabricated electrochemical (EC) sensors has resulted in high sensitivity, portability, improved performance and spatial resolution, low power consumption, and the opportunity for integration with other technologies made Micro-Electrical-Mechanical Systems-based EC sensors suitable to identify low concentration analytes and microorganisms in a variety of mediums. PMID:26605021

  10. A survey of folic acid use in primigravid women.

    PubMed

    Wilton, Diane C; Foureur, Maralyn J

    2010-06-01

    A convenience sample of 320 consecutive primigravid women attending the antenatal clinic of a large Sydney tertiary referral hospital were invited to take part in a survey of folic acid use in pregnancy. The aim of the survey was to determine the number of primigravid women who commenced taking folic acid supplementation at least 1 month prior to conception. In addition the survey sought information on women's source of knowledge about the need for folic acid in pregnancy and whether their pregnancy was planned or unplanned. 295 women qualified to be included in the survey. While 88.1% of women took folic acid at some time prior to and/or during the first trimester, only 23.4% were found to have taken folic acid at least 1 month prior to conception. Of women with a planned birth only 34.5% commenced folic acid prior to conception. This survey adds further weight to the decision of the Australian Government to mandate for fortification of bread-making flour with folic acid, due to commence in September 2009. However, even with folic acid fortified food, health professionals need to continue to advise women to take supplements prior to conception and for at least 12 weeks into their pregnancy to prevent neural tube defects. PMID:19828392

  11. Avidity Mechanism of Dendrimer–Folic Acid Conjugates

    PubMed Central

    2015-01-01

    Multivalent conjugation of folic acid has been employed to target cells overexpressing folate receptors. Such polymer conjugates have been previously demonstrated to have high avidity to folate binding protein. However, the lack of a monovalent folic acid–polymer material has prevented a full binding analysis of these conjugates, as multivalent binding mechanisms and polymer-mass mechanisms are convoluted in samples with broad distributions of folic acid-to-dendrimer ratios. In this work, the synthesis of a monovalent folic acid–dendrimer conjugate allowed the elucidation of the mechanism for increased binding between the folic acid–polymer conjugate and a folate binding protein surface. The increased avidity is due to a folate-keyed interaction between the dendrimer and protein surfaces that fits into the general framework of slow-onset, tight-binding mechanisms of ligand/protein interactions. PMID:24725205

  12. Folic acid prevented cognitive impairment in experimental pneumococcal meningitis.

    PubMed

    Barichello, Tatiana; Generoso, Jaqueline S; Simões, Lutiana R; Steckert, Amanda V; Moreira, Ana Paula; Dominguini, Diogo; Ferrari, Pâmela; Gubert, Carolina; Kapczinski, Flávio; Jornada, Luciano K; Danielski, Lucineia G; Petronilho, Fabricia; Budni, Josiane; Quevedo, João

    2015-05-01

    Streptococcus pneumoniae is a common cause of bacterial meningitis, with a high mortality rate and neurological sequelae. In contrast, folic acid plays an important role in neuroplasticity and the preservation of neuronal integrity. In the present study, we evaluated the influence of folic acid on memory, oxidative damage, enzymatic defence, and brain-derived neurotrophic factor (BDNF) expression in experimental pneumococcal meningitis. In animals that received folic acid at a dose of 10 or 50 mg, there was a reduction in both crossing and rearing during an open-field task compared with the training session, demonstrating habituation memory. During a step-down inhibitory avoidance task, there was a difference between the training and the test sessions, demonstrating aversive memory. In the hippocampus, BDNF expression decreased in the meningitis group; however, adjuvant treatment with 10 mg of folic acid increased BDNF expression, decreased lipid peroxidation, protein carbonylation, nitrate/nitrite levels, and myeloperoxidase activity and increased superoxide dismutase activity. In frontal cortex adjuvant treatment with 10 mg of folic acid decreased lipid peroxidation and protein carbonylation. There is substantial interest in the role of folic acid and related pathways in nervous system function and in folic acid's potential therapeutic effects. Here, adjuvant treatment with vitamin B9 prevented memory impairment in experimental pneumococcal meningitis. PMID:25233798

  13. The neurology of folic acid deficiency.

    PubMed

    Reynolds, E H

    2014-01-01

    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

  14. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

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

  15. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

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

  16. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

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

  17. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    .../federal-register/cfr/ibr-locations.html. (c) Folic acid may be added to foods subject to a standard of... 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain copies from the United States Pharmacopeial... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Folic acid (folacin). 172.345 Section 172.345...

  18. Benefits and risks of folic acid to the nervous system

    PubMed Central

    Reynolds, E

    2002-01-01

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

  19. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Folic acid test system. 862.1295 Section 862.1295 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  20. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Folic acid test system. 862.1295 Section 862.1295 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  1. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Folic acid test system. 862.1295 Section 862.1295 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  2. 21 CFR 862.1295 - Folic acid test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Folic acid test system. 862.1295 Section 862.1295 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  3. [Disturbances of folic acid and homocysteine metabolism in alcohol abuse].

    PubMed

    Cylwik, Bogdan; Chrostek, Lech

    2011-04-01

    Chronic alcohol abuse leads to malnutrition, and thus to the deficiency of many nutrients, including vitamins and trace elements. Most often comes to the deficiency of all vitamins, however because the clinical implications, the most important is folic acid (vitamin B9) deficiency. Biochemical effect of folate deficiency is elevated homocysteine concentration in the blood, named "cholesterol of XXI. century". In the paper, the folate and homocysteine metabolism in alcohol abuse was discussed. Mechanisms of alcohol action on folate homeostasis in the human body have been indicated. Chronic alcohol consumption leads to deficiency of this vitamin due to their dietary inadequacy, intestinal malabsorption, decreased hepatic uptake and increased body excretion, mainly via urine. The decreased concentration of serum folic acid may occur in 80% of alcoholics. The cause of elevated concentrations of homocysteine in the serum of alcohol abusers is also a deficiency of vitamins involved such as vitamin B12 and pyridoxal phosphate. Disturbance of folic acid and homocysteine metabolism in alcohol abusers can lead to serious clinical consequences. Folic acid deficiency leads inter alia to macrocytic and megaloblastic anemia and neurological disorders. Megaloblastic anemia occurs in about half of alcohol abusers with chronic liver diseases. In turn, high level of homocysteine in blood is associated with an inreased risk of cardiovascular diseases. Hyperhomocysteinemia is an independent risk factor that favors the occurrence of acute coronary syndromes in patients with coronary heart disease. PMID:21595178

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

    ERIC Educational Resources Information Center

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

    2007-01-01

    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.…

  5. Role of Folic Acid on Symptoms of Chronic Arsenic Toxicity

    PubMed Central

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

    2014-01-01

    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

  6. Prevention of spina bifida: folic acid intake during pregnancy in Gulu district, northern Uganda

    PubMed Central

    Bannink, Femke; Larok, Rita; Kirabira, Peter; Bauwens, Lieven; van Hove, Geert

    2015-01-01

    Introduction The intake of folic acid before conception and during the first trimester of pregnancy can prevent spina bifida. This paper describes folic acid intake in women in Gulu district in northern Uganda. Methods Structured interviews were held with 394 women attending antenatal care (ANC), 15 mothers of children with spina bifida, and 35 health workers in 2012 and 2013. SPSS16 was used for data analysis. Results 1/4 mothers of children with spina bifida took folic acid during late pregnancy, none preconception. None had knowledge about folic acid and spina bifida prevention. 33.5% of women attending ANC had ever heard about spina bifida, 1% knew folic acid intake can prevent spina bifida. 42.4% took folic acid supplements in late pregnancy, 8.1% during the first trimester, none preconception. All women said to have eaten food rich in folic acid. None were aware about fortified foods. 7% of health workers understood the importance of early folic acid intake. All health workers recommended folic acid intake to women attending ANC. 20% of the health workers and 25% of the women said folic acid supplements are not always available. Conclusion Folic acid intake is limited in northern Uganda. This is attributed to limited education and understanding of women and health workers about the importance of early folic acid intake, late presentation of women at ANC, poor supply chain and dilapidated health services caused by war and poverty. A combination of food fortification, sensitization of health workers, women, and improving folic acid supply is recommended. PMID:26090048

  7. Folic acid conjugated ferritins as photosensitizer carriers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Zhen, Zipeng; Tang, Wei; Zhang, Weizhong; Xie, Jin

    2015-06-01

    We coupled folic acid as a tumour targeting ligand to the surface of ferritins and loaded them with ZnF16Pc. The resulting nanoconjugates can efficiently hone in on 4T1 tumours in vivo, and, with photoirradiation, leading to suppressed tumour growth and tumour metastasis.We coupled folic acid as a tumour targeting ligand to the surface of ferritins and loaded them with ZnF16Pc. The resulting nanoconjugates can efficiently hone in on 4T1 tumours in vivo, and, with photoirradiation, leading to suppressed tumour growth and tumour metastasis. Electronic supplementary information (ESI) available: Details of experiments and ex vivo imaging results. See DOI: 10.1039/c5nr01833a

  8. Detection of folic acid protein in human serum using reduced graphene oxide electrodes modified by folic-acid.

    PubMed

    He, Lijie; Wang, Qian; Mandler, Daniel; Li, Musen; Boukherroub, Rabah; Szunerits, Sabine

    2016-01-15

    The detection of disease markers is considered an important step for early diagnosis of cancer. We design in this work a novel electrochemical sensing platform for the sensitive and selective detection of folic acid protein (FP). The platform is fabricated by electrophoretic deposition (EPD) of reduced graphene oxide (rGO) onto a gold electrode and post-functionalization of rGO with folic acid. Upon FP binding, a significant current decrease can be measured using differential pulse voltammetry (DPV). Using this scheme, a detection limit of 1pM is achieved. Importantly, the method also allows the detection of FP in serum being thus an appealing approach for the sensitive detection of biomarkers in clinical samples. PMID:26342582

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

    SciTech Connect

    Zorn, N.E.; Smith, J.T. )

    1990-01-01

    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.

  10. 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...

  11. Achieving a public health recommendation for preventing neural tube defects with folic acid.

    PubMed Central

    Werler, M M; Louik, C; Mitchell, A A

    1999-01-01

    OBJECTIVES: This study examined 3 approaches to achieving the public health recommendation that all women of child-bearing age ingest 0.40 mg of folic acid per day to reduce the occurrence of neural tube defects (NTDs). METHODS: A total of 1136 mothers of infants with major malformations from the Boston and Philadelphia areas, whose pregnancies began from 1993 to 1995, were interviewed within 6 months of delivery about vitamin supplementation, dietary intakes, and other factors. RESULTS: Seventy-one percent of the 1136 women in the study did not take folic acid--containing supplements daily before conception, but the proportion decreased over the years of the study. Women not taking supplements consumed an average of 0.25 mg of naturally occurring folates daily. On the basis of dietary intakes reported by women not taking folic acid supplements, a simulation of cereal grain fortification with folic acid at the level required by the US Food and Drug Administration showed that an average of only 0.13 mg of folic acid would be ingested daily. CONCLUSIONS: With consumption of folic acid only through dietary intake, sizeable portions of the childbearing population would receive less than the level of folic acid recommended for preventing NTDs. Even with food fortification, women of childbearing age should be advised to take folic acid--containing supplements on a daily basis. PMID:10553381

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

    ERIC Educational Resources Information Center

    deRosset, Leslie; Mullenix, Amy; Zhang, Lei

    2009-01-01

    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…

  13. 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...

  14. Association of low potassium diet and folic acid deficiency in patients with CKD

    PubMed Central

    Hassan, Kamal

    2015-01-01

    Background Most of the folic acid sources are rich also in potassium. Patients with chronic kidney disease (CKD) usually receive a low potassium diet. We investigated the possibility of an association between low potassium diet and folic acid deficiency. Methods In total, 128 CKD patients participated in this cross-sectional study. Sixty-four patients with CKD grades 1 and 2 were on an unrestricted potassium diet when enrolled in the study, and 64 patients with CKD grades 3 and 4 had received instructions to restrict their intake of potassium at least 6 months before enrollment in the study. Subjects were evaluated for daily intake of folic acid (DIFA), daily intake of potassium (DIK), and serum folic acid levels (SFA). Results DIFA correlated with the estimated glomerular filtration rate, the DIK, and the SFA (P<0.001). SFA correlated with the estimated glomerular filtration rate (P<0.001). Mean DIFA and mean SFA were lower among patients with CKD grades 3 and 4 than among those with CKD grades 1 and 2 (P<0.001). The mean DIFA in patients with folic acid deficiency was lower than that in those with SFA ?7.1 nmol/L (P<0.001). There was lower SFA and threefold greater frequency of folic acid deficiency among patients with CKD grades 3 and 4 who had received instructions to restrict their intake of potassium than among patients with CKD grades 1 and 2 who were on an unrestricted potassium diet. Conclusion A potassium-restricted diet offered to patients with CKD grades 3 and 4 may be associated with folic acid deficiency. Serum levels of folic acid should be investigated before starting potassium restriction in patients with CKD grades 3 and 4, in order to identify individuals with folic acid deficiency or with marginal serum levels who should receive folic acid replacement therapy. PMID:26056461

  15. Folic acid fortification of grain: an economic analysis.

    PubMed Central

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

    1995-01-01

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

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

    PubMed

    Ding, Xuzhe; Yao, Ping

    2013-07-01

    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

  17. L-FOLINIC ACID VERSUS FOLIC ACID FOR THE TREATMENT OF HYPERHOMOCYSTEINEMIA IN HEMODIALYSIS PATIENTS

    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...

  18. [Neural tube defects and folic acid: a historical overview of a highly successful preventive intervention].

    PubMed

    Vásquez, Adriana Ordoñez; Suarez-Obando, Fernando

    2015-12-01

    This article gives a broad overview of part of the historical evolution of medical knowledge about neural tube defects (NTD) and the discovery of vitamin B9 or folic acid, as well as some relevant research events that, over the course of several centuries, defined the relationships between the understanding of central nervous system embryology, the discovery of the vitamin, the correlation between folic acid and cell proliferation and lastly the development of preventive measures for this type of defects. This narrative allows us to examine historically relevant concepts underlying clinical actions with a populational impact that prevent NTDs via folic acid consumption prior to conception. PMID:25650704

  19. A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Evidence from observational studies suggests that inadequate folate status enhances colorectal carcinogenesis, but results from some randomized trials do not support this hypothesis. Objective: To assess the effect of folic acid supplementation on recurrent colorectal adenoma, we conduc...

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

    PubMed Central

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

    2013-01-01

    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

  1. [The effect of folic acid fortification on the reduction of neural tube defects].

    PubMed

    Santos, Leonor Maria Pacheco; Pereira, Michelle Zanon

    2007-01-01

    Neural tube defects are congenital malformations that occur during initial fetal development, leading to anencephaly and spina bifida; folic acid deficiency is the most important risk factor identified to date. Brazil has one of the world's highest neural tube defect rates. Food consumption surveys among pregnant Brazilian women showed a high rate of inadequate folic acid intake (< 0.6 mg/day). In 2004, the National Health Surveillance Agency (ANVISA) mandated the fortification of corn meal and wheat flour with folic acid (0.15 mg/100g). The National Family Budget Survey estimated the average amount of bread/flour products available in households as 106.1g/day (contributing with 0.16 mg folic acid/day). However, while in the South of the country the supply was 144 g/day, in the North and Central West it barely reached 70 g/day. Folic acid food fortification is mandatory in some 40 countries, but only four have assessed this strategy. The existing studies have all shown a significant impact, ranging from 19 to 78%. Folic acid fortification is an undeniably important intervention for primary prevention, and neural tube defects can now be considered a preventable epidemic. PMID:17187100

  2. Development of electrochemical folic acid sensor based on hydroxyapatite nanoparticles

    NASA Astrophysics Data System (ADS)

    Kanchana, P.; Sekar, C.

    2015-02-01

    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.

  3. Photoinactivation of tyrosinase sensitized by folic acid photoproducts.

    PubMed

    Laura Dántola, M; Zurbano, Beatriz N; Thomas, Andrés H

    2015-08-01

    Tyrosinase catalyzes in mammals the first and rate-limiting step in the biosynthesis of the melanin, the main pigment of the skin. Pterins, heterocyclic compounds able to photoinduce oxidation of biomolecules, accumulate in the skin of patients suffering from vitiligo, where there is a lack of melanin. Folic acid (PteGlu) is a conjugated pterin widespread in biological systems. Aqueous solutions of tyrosinase were exposed to UV-A irradiation (350nm) in the presence of PteGlu and its photoproducts (6-formylpterin and 6-carboxypterin). The reactions were followed by UV-Vis spectrophotometry, enzyme activity measurement, fluorescence spectroscopy and HPLC. In this work, we present data that demonstrate unequivocally that solutions of tyrosinase exposed to UV-A irradiation in the presence of PteGlu, undergo enzyme inactivation. However, PteGlu itself causes a negligible effect on the activity of the enzyme. In contrast, PteGlu photoproducts are efficient photosensitizers. The tyrosinase inactivation involves two different pathways: (i) a photosensitization process and (ii) the oxidation of the enzyme by the hydrogen peroxide produced during the photooxidation of PteGlu and its photoproduct. The former pathway affects both the active site and the tryptophan residues, whereas the latter affects only the active site. The biological implications of the results are discussed. PMID:26086354

  4. Oral folic acid supplementation decreases palate and/or lip cleft occurrence in Pug and Chihuahua puppies and elevates folic acid blood levels in pregnant bitches.

    PubMed

    Domos?awska, A; Jurczak, A; Janowski, T

    2013-01-01

    The aim of this study was to compare the frequency of the occurrence of lip and/or palate cleft (CL/CP) in new-borns of two breeds, Pugs and Chihuahuas, and to measure the folic acid blood levels in bitches during gestations both with and without folic acid oral supplementation. Bitches of 13 Pugs and 17 Chihuahuas with CL/CP cases were used in the study. In trial 1, the animals of the experimental group (n=25) were given additional folic acid from the onset of heat till the 40th day of gestation. The females of the control group (n=12) were fed a traditional diet. From all the animals blood was collected at the onset of heat, 14 days later and on the 30th day of the gestation to estimate folic acid concentration. In trial 2, the prevalence of CP/CL cases in litters from pregnancies before and after supplementation was compared. The percentage of puppies with CL/CP after supplementation decreased in both Pugs and Chihuahua puppies (10.86% and 15.78% vs. 4.76% and 4.8% respectively). On Day 0, the concentrations of folic acid were at a low physiological level (around 8 ng/ml) in all the animals. In bitches of the experimental group the blood level of folic acid on day 14th and 30th of the treatment showed an increase in both breeds (13.65 +/- 4.27 ng/ml in Pugs, 10.79 +/- 2.84 ng/ml in Chihuahuas, and 14.94 +/- 3.22 ng/ml in Pugs, 12.95 +/- 3.58 in Chihuahuas, respectively) while in the control group, this level decreased with time of gestation both in Pugs and in Chihuahuas (around 6 ng/ml). Folic acid supplementation seems to be a simple, effective preventive method to reduce the risk of CL/CP, especially in the predisposed breeds. PMID:23691573

  5. Characterization of ZnO nanoparticles grown in presence of Folic acid template

    PubMed Central

    2012-01-01

    Background ZnO nanoparticles (grown in the template of folic acid) are biologically useful, luminescent material. It can be used for multifunctional purposes, e.g., as biosensor, bioimaging, targeted drug delivery and as growth promoting medicine. Methods Sol–gel chemical method was used to develop the uniform ZnO nanoparticles, in a folic acid template at room temperature and pH?~?7.5. Agglomeration of the particles was prevented due to surface charge density of folic acid in the medium. ZnO nanoparticle was further characterized by different physical methods. Results Nanocrystalline, wurtzite ZnO particles thus prepared show interesting structural as well as band gap properties due to capping with folic acid. Conclusions A rapid, easy and chemical preparative method for the growth of ZnO nanoparticles with important surface physical properties is discussed. Emphatically, after capping with folic acid, its photoluminescence properties are in the visible region. Therefore, the same can be used for monitoring local environmental properties of biosystems. PMID:22788841

  6. Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha.

    PubMed

    Hansen, Mariann F; Greibe, Eva; Skovbjerg, Signe; Rohde, Sarah; Kristensen, Anders C M; Jensen, Trine R; Stentoft, Charlotte; Kjær, Karina H; Kronborg, Camilla S; Martensen, Pia M

    2015-07-01

    The signal transducer and activator of transcription 3 (STAT3) is a well-described pro-oncogene found constitutively activated in several cancer types. Folates are B vitamins that, when taken up by cells through the Reduced Folate Carrier (RFC), are essential for normal cell growth and replication. Many cancer cells overexpress a glycophosphatidylinositol (GPI)-anchored Folate Receptor ? (FR?). The function of FR? in cancer cells is still poorly described, and it has been suggested that transport of folate is not its primary function in these cells. We show here that folic acid and folinic acid can activate STAT3 through FR? in a Janus Kinase (JAK)-dependent manner, and we demonstrate that gp130 functions as a transducing receptor for this signalling. Moreover, folic acid can promote dose dependent cell proliferation in FR?-positive HeLa cells, but not in FR?-negative HEK293 cells. After folic acid treatment of HeLa cells, up-regulation of the STAT3 responsive genes Cyclin A2 and Vascular Endothelial Growth Factor (VEGF) were verified by qRT-PCR. The identification of this FR?-STAT3 signal transduction pathway activated by folic and folinic acid contributes to the understanding of the involvement of folic acid in preventing neural tube defects as well as in tumour growth. Previously, the role of folates in these diseases has been attributed to their roles as one-carbon unit donors following endocytosis into the cell. Our finding that folic acid can activate STAT3 via FR? adds complexity to the established roles of B9 vitamins in cancer and neural tube defects. PMID:25841994

  7. Intestinal absorption, liver uptake, and excretion of /sup 3/H-folic acid in folic acid-deficient, alcohol-consuming nonhuman primates

    SciTech Connect

    Blocker, D.E.; Thenen, S.W.

    1987-09-01

    Nonhuman primates fed folic acid-deficient diets +/- 30% kcal ethanol were used to determine alcohol effects on megaloblastic anemia development and folate bioavailability. Lower hemoglobin (Hb) and red blood cell (RBC) counts and higher mean corpuscular volume (MCV) occurred after 13 wk in alcohol-fed monkeys, later in controls. Plasma, RBC, and liver folate declined and urinary formiminoglutamic acid (FIGLU) was elevated in both groups with FIGLU increasing more among alcohol-fed monkeys at 38 wk. After 40 wk, the bioavailability of oral /sup 3/H-folic acid was investigated and showed increased fecal and reduced urinary tritium excretion in alcohol-fed monkeys compared with controls while plasma uptake and liver and whole body tritium retention were similar in both groups. These observations demonstrate that chronic alcohol consumption impairs folate coenzymes, accelerates appearance of hematologic indices of megaloblastic anemia, and causes possible malabsorption of enterohepatically circulated folates in folate deficiency even when other essential nutrients are provided.

  8. Folic acid and human reproduction—ten important issues for clinicians

    PubMed Central

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

    2011-01-01

    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

  9. Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials

    PubMed Central

    Qin, Tingting; Du, Mulong; Du, Haina; Shu, Yongqian; Wang, Meilin; Zhu, Lingjun

    2015-01-01

    Numerous studies have investigated the effects of folic acid supplementation on colorectal cancer risk, but conflicting results were reported. We herein performed a meta-analysis based on relevant studies to reach a more definitive conclusion. The PubMed and Embase databases were searched for quality randomized controlled trials (RCTs) published before October 2014. Eight articles met the inclusion criteria and were subsequently analyzed. The results suggested that folic acid treatment was not associated with colorectal cancer risk in the total population (relative risk [RR]?=?1.00, 95% confidence interval [CI]?=?0.82–1.22, P?=?0.974). Moreover, no statistical effect was identified in further subgroup analyses stratified by ethnicity, gender, body mass index (BMI) and potential confounding factors. No significant heterogeneity or publication bias was observed. In conclusion, our meta-analysis demonstrated that folic acid supplementation had no effect on colorectal cancer risk. However, this finding must be validated by further large studies. PMID:26131763

  10. Folic acid supplements and colorectal cancer risk: meta-analysis of randomized controlled trials

    NASA Astrophysics Data System (ADS)

    Qin, Tingting; Du, Mulong; Du, Haina; Shu, Yongqian; Wang, Meilin; Zhu, Lingjun

    2015-07-01

    Numerous studies have investigated the effects of folic acid supplementation on colorectal cancer risk, but conflicting results were reported. We herein performed a meta-analysis based on relevant studies to reach a more definitive conclusion. The PubMed and Embase databases were searched for quality randomized controlled trials (RCTs) published before October 2014. Eight articles met the inclusion criteria and were subsequently analyzed. The results suggested that folic acid treatment was not associated with colorectal cancer risk in the total population (relative risk [RR]?=?1.00, 95% confidence interval [CI]?=?0.82-1.22, P?=?0.974). Moreover, no statistical effect was identified in further subgroup analyses stratified by ethnicity, gender, body mass index (BMI) and potential confounding factors. No significant heterogeneity or publication bias was observed. In conclusion, our meta-analysis demonstrated that folic acid supplementation had no effect on colorectal cancer risk. However, this finding must be validated by further large studies.

  11. Impact of multiple micronutrient vs. iron - folic acid supplements on maternal anemia and micronutrient status in pregnancy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background. Multiple micronutrient (MMN) supplements could increase hemoglobin and improve micronutrient status of pregnant women more than iron ± folic acid supplements alone. Objective. To compare the effects of MMN vs. iron ± folic acid supplements on hemoglobin and micronutrient status of pregn...

  12. Folic acid protects against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1

    PubMed Central

    Ma, Yan; Zhang, Chen; Gao, Xiao-Bo; Luo, Hai-Yan; Chen, Yang; Li, Hui-hua; Ma, Xu; Lu, Cai-Ling

    2015-01-01

    As a nutritional factor, folic acid can prevent cardiac and neural defects during embryo development. Our previous study showed that arsenic impairs embryo development by down-regulating Dvr1/GDF1 expression in zebrafish. Here, we investigated whether folic acid could protect against arsenic-mediated embryo toxicity. We found that folic acid supplementation increases hatching and survival rates, decreases malformation rate and ameliorates abnormal cardiac and neural development of zebrafish embryos exposed to arsenite. Both real-time PCR analysis and whole in-mount hybridization showed that folic acid significantly rescued the decrease in Dvr1 expression caused by arsenite. Subsequently, our data demonstrated that arsenite significantly decreased cell viability and GDF1 mRNA and protein levels in HEK293ET cells, while folic acid reversed these effects. Folic acid attenuated the increase in subcellular reactive oxygen species (ROS) levels and oxidative adaptor p66Shc protein expression in parallel with the changes in GDF1 expression and cell viability. P66Shc knockdown significantly inhibited the production of ROS and the down-regulation of GDF1 induced by arsenite. Our data demonstrated that folic acid supplementation protected against arsenic-mediated embryo toxicity by up-regulating the expression of Dvr1/GDF1, and folic acid enhanced the expression of GDF1 by decreasing p66Shc expression and subcellular ROS levels. PMID:26537450

  13. Prevention of neural tube defects with folic acid: The Chinese experience

    PubMed Central

    Ren, Ai-Guo

    2015-01-01

    Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system that are caused by the closure failure of the embryonic neural tube by the 28th day of conception. Anencephaly and spina bifida are the two major subtypes. Fetuses with anencephaly are often stillborn or electively aborted due to prenatal diagnosis, or they die shortly after birth. Most infants with spina bifida are live-born and, with proper surgical treatment, can survive into adulthood. However, these children often have life-long physical disabilities. China has one of the highest prevalence of NTDs in the world. Inadequate dietary folate intake is believed to be the main cause of the cluster. Unlike many other countries that use staple fortification with folic acid as the public health strategy to prevent NTDs, the Chinese government provides all women who have a rural household registration and who plan to become pregnant with folic acid supplements, free of charge, through a nation-wide program started in 2009. Two to three years after the initiation of the program, the folic acid supplementation rate increased to 85% in the areas of the highest NTD prevalence. The mean plasma folate level of women during early and mid-pregnancy doubled the level before the program was introduced. However, most women began taking folic acid supplements when they knew that they were pregnant. This is too late for the protection of the embryonic neural tube. In a post-program survey of the women who reported folic acid supplementation, less than a quarter of the women began taking supplements prior to pregnancy, indicating that the remaining three quarters of the fetuses remained unprotected during the time of neural tube formation. Therefore, staple food fortification with folic acid should be considered as a priority in the prevention of NTDs. PMID:26261765

  14. Prevention of neural tube defects with folic acid: The Chinese experience.

    PubMed

    Ren, Ai-Guo

    2015-08-01

    Neural tube defects (NTDs) are a group of congenital malformations of the central nervous system that are caused by the closure failure of the embryonic neural tube by the 28(th) day of conception. Anencephaly and spina bifida are the two major subtypes. Fetuses with anencephaly are often stillborn or electively aborted due to prenatal diagnosis, or they die shortly after birth. Most infants with spina bifida are live-born and, with proper surgical treatment, can survive into adulthood. However, these children often have life-long physical disabilities. China has one of the highest prevalence of NTDs in the world. Inadequate dietary folate intake is believed to be the main cause of the cluster. Unlike many other countries that use staple fortification with folic acid as the public health strategy to prevent NTDs, the Chinese government provides all women who have a rural household registration and who plan to become pregnant with folic acid supplements, free of charge, through a nation-wide program started in 2009. Two to three years after the initiation of the program, the folic acid supplementation rate increased to 85% in the areas of the highest NTD prevalence. The mean plasma folate level of women during early and mid-pregnancy doubled the level before the program was introduced. However, most women began taking folic acid supplements when they knew that they were pregnant. This is too late for the protection of the embryonic neural tube. In a post-program survey of the women who reported folic acid supplementation, less than a quarter of the women began taking supplements prior to pregnancy, indicating that the remaining three quarters of the fetuses remained unprotected during the time of neural tube formation. Therefore, staple food fortification with folic acid should be considered as a priority in the prevention of NTDs. PMID:26261765

  15. Folic Acid Inhibits Amyloid ?-Peptide Production through Modulating DNA Methyltransferase Activity in N2a-APP Cells

    PubMed Central

    Li, Wen; Jiang, Mingyue; Zhao, Shijing; Liu, Huan; Zhang, Xumei; Wilson, John X.; Huang, Guowei

    2015-01-01

    Alzheimer’s disease (AD) is a common neurodegenerative disease resulting in progressive dementia, and is a principal cause of dementia among older adults. Folate acts through one-carbon metabolism to support the methylation of multiple substrates. We hypothesized that folic acid supplementation modulates DNA methyltransferase (DNMT) activity and may alter amyloid ?-peptide (A?) production in AD. Mouse Neuro-2a cells expressing human APP695 were incubated with folic acid (2.8–40 ?mol/L), and with or without zebularine (the DNMT inhibitor). DNMT activity, cell viability, A? and DNMTs expression were then examined. The results showed that folic acid stimulated DNMT gene and protein expression, and DNMT activity. Furthermore, folic acid decreased A? protein production, whereas inhibition of DNMT activity by zebularine increased A? production. The results indicate that folic acid induces methylation potential-dependent DNMT enzymes, thereby attenuating A? production. PMID:26492244

  16. Synthesis and 188Re radiolabelling of dendrimer polyamide amine (PAMAM) folic acid conjugate.

    PubMed

    Cui, Wei; Zhang, Yuanqing; Xu, Xiaoping; Shen, Yu-Mei

    2012-07-01

    Folic acid receptors (FR) are usually over expressed in many cancer cells and are considered as potential targeted therapy agent. Generation of five polyamido amine (PAMAM) dendrimer folic acid conjugate was synthesised and radiolabelled with (188)Re, furthermore the in vitro/in vivo stability was evaluated accordingly. The labelling yield of the conjugate G5-FA-DTPA-(188)Re was 67.1% and its radiochemical purity exceeded 95%. The conjugate also showed high in vitro stability and potential value for further structure modifications and evaluations. PMID:22548334

  17. Combined iron and folic acid supplementation with or without zinc reduces time to walking unassisted among Zanzibari infants 5-11 months old

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Iron and zinc deficiencies have been associated with delayed motor development in nutritionally at-risk children, albeit inconsistently. In this community-based, randomized double-blind trial, iron+folic acid (FeFA) (12.5 mg Fe + 50 'g folic acid), zinc (Zn) (10 mg), and iron+folic acid+zinc (FeFA+Z...

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

    SciTech Connect

    Dawson, Jennifer E.; Raymond, Angela M.; Winn, Louise M. . E-mail: winnl@biology.queensu.ca

    2006-03-01

    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.

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

    PubMed

    Rosenberg, Irwin H

    2012-01-01

    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

  20. MASS SPECTRAL DETERMINATIONS OF THE FOLIC ACID CONTENT OF FORTIFIED BREADS FROM CHILE

    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 ...

  1. 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...

  2. 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...

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

    PubMed

    Garcia, Josel; Datol-Barrett, Eva; Dizon, Maynilad

    2005-12-01

    After participating in a pilot project under a government-industry partnership to promote the adoption of weekly iron-folic acid supplementation among women of reproductive age in the Philippines in 1998, United Laboratories (UNILAB), the Philippines' largest private pharmaceutical company, decided in April 2002 to launch a weekly iron-folic acid supplement for pregnant and non-pregnant women under the brand name Femina. The business objective set for the Femina brand was to build the category of preventive iron-folic acid supplements in line with the Philippine Department of Health's advocacy on weekly supplementation as an alternate to daily dosing to reduce the prevalence of anemia in the country. The brand was supported with an integrated mix of traditional advertising media with complementary direct-to-consumer educational programs that aimed to create awareness of iron-deficiency anemia, its causes and effects, and the role of weekly intake of iron-folic acid in preventing the condition. Aggressive marketing support for 1 year was successful in creating awareness among the target women. Significant lessons derived from consumers identified opportunity areas that can be further addressed in developing advocacy programs on weekly iron supplementation implemented on a nationwide scale in the future. PMID:16466091

  4. UNMETABOLIZED FOLIC ACID IN PLASMA IS ASSOCIATED WITH REDUCED NATURAL KILLER CELL CYTOTOXICITY AMONG POSTMENOPAUSAL WOMEN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the USA and elsewhere have an unprecedented high FA intake. We evaluated dietary and su...

  5. Pros and cons of increasing folic acid and vitamin B12 intake by fortification

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There is no doubt that folic acid fortification can be effective for reducing the incidence of neural tube defects (NTDs). The degree of efficacy depends on both the level of folate depletion and other, yet to be fully characterized, genetic and/or environmental factors. This article summarizes brie...

  6. Effects of folic acid plus levothyroxine on serum homocysteine level in hypothyroidism

    PubMed Central

    Ziaee, Amir; Hajibagher Tehrani, Nader; Hosseinkhani, Zahra; Kazemifar, Amir; Javadi, Amir; Karimzadeh, Toktam

    2012-01-01

    Background: Rise in serum homocysteine level may be associated with higher prevalence of cardiovascular diseases in hypothyroidism. Levothyroxine can partly diminish serum homocysteine level. Folic acid participates in homocysteine metabolic cycle in the human body. The effect of concomitant administration of folic acid and levothyroxine on serum homocysteine level was evaluated in the present study. Methods: Sixty patients with hypothyroidism participated in this double-blinded clinical trial study. They were divided into two equal groups; Group A received oral levothyroxine 50-100 µg daily. Group B took oral folic acid 1 mg on a daily basis in addition to levothyroxine with similar schedule to group A. The patients were followed up for two months. The serum homocysteine levels of these two groups were measured before and after the study. This study was registered in Iranian Registry of clinical trial (IRCT number: 201112077723N1). Results: Mean serum homocysteine level fell from 11.5±4.2 to 9.9±3.5 µmol/lit and from 11.2±3.1 to 6.9±1.9 µmol/lit in group A and B, respectively (p<0.001). The mean reduction in serum homocysteine levels were 1.6±1.2 µmol/lit and 4.3±1.4 µmol/lit in group A and B, respectively (p<0.001). Conclusion: Levothyroxine can decrease serum homocysteine level partly; still its combination with folic acid empowers the effect. Combination therapy declines serum homocysteine level more successfully. PMID:24358436

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

    ERIC Educational Resources Information Center

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

    2010-01-01

    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…

  8. CHINESE STUDY OF THE EFFECTIVENESS OF FOLIC ACID IN A COMMUNITY INTERVENTION

    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...

  9. 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...

  10. Public health significance of supplementation or fortification of grain products with folic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The need for supplemental folate can be traced to the initial phase of the discovery of this vitamin as a micronutrient for the prevention of pregnancy related anemia. In the post discovery era, folic acid was used primarily to prevent deficiency as manifested by low blood folate levels and megalob...

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

    PubMed Central

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

    2011-01-01

    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 brain injury induced by rapid axial head rotation without impact. One group of injured (Inj) animals received folic acid (Fol; 80 ?g/kg) by intraperitoneal (IP) injection 15 min following injury, and then daily for 6 days (Inj + Fol; n = 7). The second group of injured animals received an IP injection of saline (Sal) at the same time points (Inj + Sal; n = 8). Two uninjured (Uninj) control groups (Uninj + Fol, n = 8; Uninj + Sal, n = 7) were intubated, anesthetized and received folic acid (80 ?g/kg) or saline by IP injection at the same time points as the injured animals following a sham procedure. Animals underwent neurobehavioral and cognitive testing on days 1 and 4 following injury to assess behavior, memory, learning and problem solving. Serum folic acid and homocysteine levels were collected prior to injury and again before euthanasia. The piglets were euthanized 6 days following injury, and their brains were perfusion fixed for histological analysis. Folic acid levels were significantly higher in both Fol groups on day 6. Homocysteine levels were not affected by treatment. On day 1 following injury, the Inj + Fol group showed significantly more exploratory interest, and better motor function, learning and problem solving compared to the Inj + Sal group. Inj + Fol animals had a significantly lower cognitive composite dysfunction score compared to all other groups on day 1. These functional improvements were not seen on day 4 following injury. Axonal injury measured by ?-amyloid precursor protein staining 6 days after injury was not affected by treatment. These results suggest that folic acid may enhance early functional recovery in this piglet model of pediatric head injury. This is the first study to describe the application of complex functional testing to assess an intervention outcome in a swine model of TBI. PMID:21212637

  12. The effect of subchronic supplementation with folic acid on homocysteine induced seizures.

    PubMed

    Rasic-Markovic, A; Rankov-Petrovic, B; Hrncic, D; Krstic, D; Colovic, M; Macut, Dj; Djuric, D; Stanojlovic, Olivera

    2015-06-01

    Influence of folic acid on the CNS is still unclear. Folate has a neuroprotective effect, while on the other hand excess folate can exacerbate seizures in epileptics. The aim of the present study was to examine the effect of subchronic administration of folic acid on behavioural and electroencephalographic (EEG) characteristics of DL homocysteine thiolactone induced seizures in adult rats. The activity of Na?/K?-ATPase and Mg²?-ATPase in different brain regions was investigated. Adult male Wistar rats were divided into groups: 1. Controls (C, 0.9% NaCl); 2. DL homocysteine-thiolactone 8.0 mmol/kg (H); 3. Subchronic supplementation with folic acid 5 mg/kg for 7 days (F) and 4. Subchronic supplementation with F + single dose of H (FH). Seizure behaviour was assessed by incidence, latency, number and intensity of seizure episodes. Seizure severity was described by a descriptive scale with grades 0-4. For EEG recordings, three gold-plated recording electrodes were implanted into the skull. Subchronic supplementation with folic acid did not affect seizure incidence, median number of seizure episodes and severity in FH, comparison with H (p > 0.05). The majority of seizure episodes in all groups were of grade 2. There were no significant differences in lethal outcomes at 24 h upon H injection in the FH vs. H group. The activity of Na?/K?-ATPase and Mg²?-ATPase was significantly increased in almost all examined structures in the FH vs. H group. Subchronic folic acid administration did not exacerbate H induced seizures and completely recovered the activity of ATPases. PMID:26100305

  13. A Study of the Prevalence of Serum Vitamin B12 and Folic Acid Deficiency in Western Maharashtra

    PubMed Central

    Mahajan, Sanket K.; Aundhakar, Swati C.

    2015-01-01

    Context: This study summarizes the prevalence of vitamin B12 and folic acid deficiency in the population coming to tertiary care center in Western Maharashtra along with the main presenting symptom routinely misinterpreted in daily practice. Aims and Objectives: 1. To study the prevalence of vitamin B12 and folic acid deficiency in the population of western Maharashtra. 2. To correlate the symptoms with serum vitamin B12 and folic acid levels. Materials and Methods: The present study is a cross-sectional observation study carried out on patients from western Maharashtra seeking medical attention on outpatient and inpatient basis in the medicine department of a teaching institute in Karad. One-hundred patients were selected on basis of below mentioned symptoms viz. tingling and numbness in extremities, dizziness, unsteady gait, early tiredness, forgetfulness, proximal weakness, distal weakness, chronic headache, less interest in work, chronic loose stools, strict vegetarians, alcoholics, intake of medications like anti-tubercular treatment, surgery involving terminal ileum. Serum vitamin B12 and folic acid levels of these patients were observed. Deficiency of vitamin B12 and folic acid was studied in 4 groups: (a) Absolute vitamin B12 deficiency; (b) Absolute folic acid deficiency; (c) Borderline vitamin B12 deficiency; (d) Combined vitamin B12 and folic acid deficiency. Results: Of the 100 cases, 33% patients were vegetarian. Folic acid deficiency formed the major chunk of deficiency group. Six percent patients had neuropsychiatric manifestations. Depressive illness in 1% patients, dementia in 0% patients, forgetfulness in 1% patients, mania/hallucination in 0% patients each, and chronic headache in 1% patients. Neuropathy in form of loss of reflexes, decreased touch sensation was present in 9% patients. Posterior column involvement viz. Loss of joint position, vibration, positive Romberg's sign were present in 34% patients of vitamin B12 and folic acid deficiency. Conclusion: In a small study, it was found that megaloblastic anemia may have symptoms and signs referable to several systems including hematology, dermatology, gastrointestinal, neurology, and neuropsychiatry. PMID:25810991

  14. Knowledge and practices of pregnant women about folic acid in pregnancy in Abu Dhabi, United Arab Emirates.

    PubMed

    Al-Hossani, H; Abouzeid, H; Salah, M M; Farag, H M; Fawzy, E

    2010-04-01

    This study assessed the knowledge and practices about folic acid in pregnancy among pregnant women attending 2 main maternal and child health centres in Abu Dhabi. The majority of the 277 interviewed mothers (79.1%) had heard of folic acid and 46.6% had accurate knowledge about the role of folate in preventing neural tube defects. There were good practices regarding folate supplementation in the current pregnancy; most of the interviewed mothers took it daily and in the recommended dose. However, only a minority took it prior to pregnancy. Education, irrespective of age or parity, was the major factor determining better knowledge of folic acid in pregnancy. PMID:20795424

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

    SciTech Connect

    Nan, Alexandrina; Turcu, Rodica; Liebscher, Jürgen

    2013-11-13

    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.

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

    NASA Astrophysics Data System (ADS)

    Nan, Alexandrina; Turcu, Rodica; Liebscher, Jürgen

    2013-11-01

    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.

  17. Time dependent inhibition of xanthine oxidase in irradiated solutions of folic acid, aminopterin and methotrexate

    SciTech Connect

    Robinson, K.; Pilot, T.F.; Meany, J.E. )

    1990-01-01

    The xanthine oxidase catalyzed oxidation of hypoxanthine was followed by monitoring the formation of uric acid at 290 nm. Inhibition of xanthine oxidase occurs in aqueous solutions of folic acid methotrexate and aminopterin. These compounds are known to dissociate upon exposure to ultraviolet light resulting in the formation of their respective 6-formylpteridine derivatives. The relative rates of dissociation were monitored spectrophotometrically by determining the absorbance of their 2,4-dinitrophenylhydrazine derivatives at 500 nm. When aqueous solutions of folic acid, aminopterin and methotrexate were exposed to uv light, a direct correlation was observed between the concentrations of the 6-formylpteridine derivatives existing in solution and the ability of these solutions to inhibit xanthine oxidase. The relative potency of the respective photolysis products were estimated.

  18. Modeling fortification of corn masa flour with folic acid: the potential impact on exceeding the tolerable upper intake level for folic acid, NHANES 2001–2008

    PubMed Central

    Hamner, Heather C.; Tinker, Sarah C.; Berry, R.J.; Mulinare, Joe

    2013-01-01

    Background The Institute of Medicine set a tolerable upper intake level (UL) for usual daily total folic acid intake (1,000 µg). Less than 3% of US adults currently exceed the UL. Objective The objective of this study was to determine if folic acid fortification of corn masa flour would increase the percentage of the US population who exceed the UL. Design We used dietary intake data from NHANES 2001–2008 to estimate the percentage of adults and children who would exceed the UL if corn masa flour were fortified at 140 µg of folic acid/100 g. Results In 2001–2008, 2.5% of the US adult population (aged?19 years) exceeded the UL, which could increase to 2.6% if fortification of corn masa flour occurred. With corn masa flour fortification, percentage point increases were small and not statistically significant for US adults exceeding the UL regardless of supplement use, sex, race/ethnicity, or age. Children aged 1–8 years, specifically supplement users, were the most likely to exceed their age-specific UL. With fortification of corn masa flour, there were no statistically significant increases in the percentage of US children who were exceeding their age-specific UL, and the percentage point increases were small. Conclusions Our results suggest that fortification of corn masa flour would not significantly increase the percentage of individuals who would exceed the UL. Supplement use was the main factor related to exceeding the UL with or without fortification of corn masa flour and within all strata of sex, race/ethnicity, and age group. PMID:23316130

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

    MedlinePLUS

    Annals of Internal Medicine Summaries for Patients Folic Acid for the Prevention of Infant Neural Tube Defects: U.S. Preventive Services Task Force Recommendation Summaries for Patients are a service provided by Annals ...

  20. Folic acid and the prevention of neural tube defects: A survey of awareness among Latina women of childbearing age residing in southeast Michigan.

    PubMed

    Kannan, Srimathi; Menotti, Elaine; Scherer, Holly K; Dickinson, Jennifer; Larson, Kimberly

    2007-01-01

    Periconceptional intake of folic acid is known to reduce the risk for neural tube defects (NTDs). To inform southeast Michigan Latina women of childbearing age about the benefits of food and supplemental sources of the micronutrient in the prevention of NTDs, Spanish-English bilingual health educators carried out 20 education events in supermarkets and community organizations serving Latina women. One hundred and sixty Latina women ages 19 to 50 years indicated their current folic acid awareness and stated their future intentions regarding folic acid. Of 160 women surveyed, 114 (71%) had heard of folic acid, 84 (74%) knew that folic acid prevents birth defects, 63 (55%) knew the critical time to take folic acid, and 76 (67%) identified at least one source of folic acid. After participating in the education events, 136 women (85%) reported planning to eat more folate and/or folic acid-rich foods. Although general folic acid awareness is fairly high, health promotion efforts must be coordinated at community locations serving Latina women to share folic acid's specific protective effects in the prevention of NTDs, the critical timing of intake, and its food and supplement sources. PMID:16840767

  1. In vitro antioxidant activity and in vivo antifatigue effect of layered double hydroxide nanoparticles as delivery vehicles for folic acid.

    PubMed

    Qin, Lili; Wang, Wenrui; You, Songhui; Dong, Jingmei; Zhou, Yunhe; Wang, Jibing

    2014-01-01

    Folic acid antioxidants were successfully intercalated into layered double hydroxides (LDH) nanoparticles according to a previous method with minor modification. The resultant folic acid-LDH constructs were then characterized by X-ray powder diffraction and transmission electron microscopy. The in vitro antioxidant activities, cytotoxicity effect, and in vivo antifatigue were examined by a series of assays. The results showed that folic acid-LDH antioxidant system can scavenge 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radicals and chelate pro-oxidative Cu(2+). The in vitro cytotoxicity assays indicated that folic acid-LDH antioxidant system had no significant cytotoxic effect or obvious toxicity to normal cells. It also prolonged the forced swimming time of the mice by 32% and 51% compared to folic acid and control groups, respectively. It had an obvious effect on decreasing the blood urea nitrogen and blood lactic acid, while increasing muscle and hepatic glycogen levels. Therefore, folic acid-LDH might be used as a novel antioxidant and antifatigue nutritional supplement. PMID:25506219

  2. An investigation of folic acid-protein association sites and the effect of this association on folic acid self-assembly.

    PubMed

    Gupta, Rajat; Kalita, Prasanta; Patil, Omkar; Mohanty, Sanat

    2015-12-01

    The contribution of folic acid (FA)-tryptophan interactions to FA-protein association was investigated in the context of using FA as a drug carrier in protein delivery systems. Bovine serum albumin (BSA) and indolicidin were used as model proteins in the study. The FA-BSA complex was characterized by using the Bradford reagent to identify the impact of FA-BSA association on BSA-dye reagent interactions. UV-visible spectroscopic analysis of the FA-BSA mixture showed that the absorbance maximum of BSA-dye reagent occurred at 595 nm, even after the association of FA with BSA. This confirms that protonated amino acid groups of the protein are not involved in FA-BSA association. Moreover, molecular dynamics (MD) simulation confirmed the presence of an associative interaction between aromatic moieties in FA and tryptophan moieties in the indolicidin molecule, which disrupted FA self-assembly. An X-ray diffraction (XRD) study showed that there was limited disruption of FA self-assembly after the addition of BSA or tryptophan. This suggests that FA and BSA are compatible and associate with each other. Graphical Abstract Mechanism of folic acid and protein association. PMID:26560480

  3. Hepatoprotective role of vitamin B(12) and folic acid in arsenic intoxicated rats.

    PubMed

    Chattopadhyay, Sandip; Deb, Bimal; Maiti, Smarajit

    2012-01-01

    The present study elucidated the protective role of vitamin B(12) with folic acid against arsenic-induced hepatotoxicity in female rats. Ingestion of sodium-arsenite- contaminated water [0.4?ppm/100?g body weight (b.w.)/day] in combination with vitamin B(12) plus folic acid (0.07 and 4.0 ?g, respectively/100?g b.w./day) for 24 days to Wistar rats offered a significant protection against alone arsenic-induced distorted liver function, damaged histoarchitecture, elevated oxidative stress, and DNA fragmentation of hepatic tissues. Arsenic only exposure decreased hepatic superoxide dismutase (SOD), catalase activities, and the level of nonprotein-soluble thiol (NPSH), with a concomitant increase in thiobarbituric acid reactive substances (TBARS) and conjugated dienes (CDs) in the liver. Vitamin supplementation restrained the increase of TBARS and CDs by restoring catalase, SOD, and NPSH levels. Restricted generation of free radicals may be correlated to the protection of DNA stability and hepatic morphology. This study explains the decisive role of vitamin B(12) with folic acid to ameliorate arsenic-mediated liver injuries. PMID:21848401

  4. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid.

    PubMed

    Heseker, Helmut B; Mason, Joel B; Selhub, Jacob; Rosenberg, Irwin H; Jacques, Paul F

    2009-07-01

    Some countries have introduced mandatory folic acid fortification, whereas others support periconceptional supplementation of women in childbearing age. Several European countries are considering whether to adopt a fortification policy. Projections of the possible beneficial effects of increased folic acid intake assume that the measure will result in a considerable reduction in neural-tube defects (NTD) in the target population. Therefore, the objective of the present study is to evaluate the beneficial effects of different levels of folic acid administration on the prevalence of NTD. Countries with mandatory fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTD. This was also true for supplementation trials. However, the prevalence of NTD at birth declined to approximately five cases at birth per 10 000 births and seven to eight cases at birth or abortion per 10 000 births. This decline was independent of the amount of folic acid administered and apparently reveals a 'floor effect' for folic acid-preventable NTD. This clearly shows that not all cases of NTD are preventable by increasing the folate intake. The relative decline depends on the initial NTD rate. Countries with NTD prevalence close to the observed floor may have much smaller reductions in NTD rates with folic acid fortification. Additionally, potential adverse effects of fortification on other vulnerable population groups have to be seriously considered. Policy decisions concerning national mandatory fortification programmes must take into account realistically projected benefits as well as the evidence of risks to all vulnerable groups. PMID:19079944

  5. CDC Grand Rounds: additional opportunities to prevent neural tube defects with folic acid fortification.

    PubMed

    2010-08-13

    Neural tube defects (NTDs) are serious birth defects that result from the failure of the neural tube to close in the cranial region (anencephaly) or more caudally along the spine (spina bifida) by the 28th day of gestation. Infants born with anencephaly usually die within a few days of birth, and those with spina bifida have life-long disabilities with varying degrees of paralysis. Currently, identified risk factors for NTDs include a mother who previously had an NTD-affected pregnancy, maternal diabetes, obesity, hyperthermia, certain antiseizure medications, genetic variants, race/ethnicity, and nutrition (particularly folic acid insufficiency). In the United States, during 1995-1996, approximately 4,000 pregnancies were affected by an NTD. This number declined to 3,000 pregnancies in 1999-2000 after fortification of enriched cereal grain products with folic acid was mandated. Worldwide, in 1998, approximately 300,000 births were affected by an NTD. PMID:20703205

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

    PubMed

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

    2014-10-01

    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

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

    PubMed

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

    2013-10-01

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

  8. Targeted delivery of 5-fluorouracil to cholangiocarcinoma cells using folic acid as a targeting agent.

    PubMed

    Ngernyuang, Nipaporn; Seubwai, Wunchana; Daduang, Sakda; Boonsiri, Patcharee; Limpaiboon, Temduang; Daduang, Jureerut

    2016-03-01

    There are limits to the standard treatment for cholangiocarcinoma (CCA) including drug resistance and side effects. The objective of this study was to develop a new technique for carrying drugs by conjugation with gold nanoparticles and using folic acid as a targeting agent in order to increase drug sensitivity. Gold nanoparticles (AuNPs) were functionalized with 5-fluorouracil (5FU) and folic acid (FA) using polyethylene glycol (PEG) shell as a linker (AuNPs-PEG-5FU-FA). Its cytotoxicity was tested in CCA cell lines (M139 and M213) which express folic acid receptor (FA receptor). The results showed that AuNPs-PEG-5FU-FA increased the cytotoxic effects in the M139 and M213 cells by 4.76% and 7.95%, respectively compared to those treated with free 5FU+FA. It is found that the cytotoxicity of the AuNPs-PEG-5FU-FA correlates with FA receptor expression suggested the use of FA as a targeted therapy. The mechanism of cytotoxicity was mediated via mitochondrial apoptotic pathway as determined by apoptosis array. In conclusion, our findings shed some light on the use of gold nanoparticles for conjugation with potential compounds and FA as targeted therapy which contribute to the improvement of anti-cancer drug efficacy. In vivo study should be warranted for its effectiveness of stability, biosafety and side effect reduction. PMID:26706547

  9. Folic Acid Intake and Neural Tube Defects: Two Egyptian Centers Experience

    PubMed Central

    El-Shabrawi, Mortada H.; Kamal, Naglaa Mohamed; Elhusseini, Mona Abbas; Hussein, Laila; Abdallah, Enas Abdallah Ali; Ali, Yahia Zakaria Abdelalim; Azab, Ahmed Abelfattah; Salama, Mostafa Abdelazim; Kassab, Muna; Krawinkel, Michael

    2015-01-01

    Abstract Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex etiopathogenesis. Folic acid plays a pivotal role in their prevention. We aimed to identify the protective effect of folic acid intake against NTDs and its dependence on different socioeconomic and environmental factors in a cohort of mothers in Egypt. A cross-sectional study was carried over a period of 12 months on mothers who gave birth to babies with NTDs (group 1) and a control group with healthy offsprings (group 2). Both groups completed 2 questionnaires: food frequency questionnaire targeting the daily folate intake, and socioeconomic status and medical history questionnaire. Both groups of mothers received folate <800??g/day, recommended for pregnant women. A strong association was detected between NTDs and urban residency with medium educated mothers, with negative consanguinity, who had folate intake < 400??g daily, and who had their food long cooked. Each of these factors separately had a limited impact to cause NTDs, but when present together they did augment each other. Interestingly enough is the role of fava bean, cauliflower, spinach, and mango in predisposing of NTDs in the presence of the above-mentioned factors. The protective effect of folic acid intake against NTDs may depend on the synergism of different socioeconomic and environmental factors (which differ from country to another). In Egypt, females especially the medium-educated who live in urban areas should be well-informed with the value of folate intake in the periconceptional period. PMID:26376380

  10. Treatment of hyperhomocysteinemia with folic acid: effects on homocysteine levels, coagulation status, and oxidative stress markers.

    PubMed

    Mayer, Otto; Filipovský, Jan; Hromádka, Milan; Svobodová, Vlasta; Racek, Jaroslav; Mayer, Otto; Stehlík, Pavel; Trefil, Ladislav; Zárybnická, Marta

    2002-06-01

    The aim of the study was to determine whether folic acid treatment in subjects with homocysteinemia would change their coagulation and oxidative status. Thirty-three patients with peripheral vascular disease and 26 elderly subjects with no symptoms of atherosclerosis, all of whom had total homocysteine >20 microM, were treated with folic acid (5 or 10 mg) for 3 months. In the 33 patients with peripheral vascular disease, homocysteine levels decreased from a median of 26.7 microM at baseline to 20.0 microM (p < 0.0001), whereas in the 26 asymptomatic elderly subjects, homocysteine level decreased from 24.4 microM to 18.6 microM (p < 0.0001). Plasma fibrinogen decreased whereas plasminogen and anti-thrombin increased; the differences between pre- and posttreatment values were significant in both patients and healthy subjects. Oxidative status markers showed a shift toward lower oxidative stress. This effect was observed in both study groups. An association of the therapeutic effect with the genetic polymorphism of 5,10-methylenetetrahydrofolate reductase was not detected. Folic acid supplementation to hyperhomocysteinemic subjects resulted in a decrease in total blood homocysteine concentrations; moreover, there was a tendency to reverse the coagulation status and oxidative stress. PMID:12021579

  11. Unmetabolized Folic Acid in Prediagnostic Plasma and the Risk of Colorectal Cancer.

    PubMed

    Cho, Eunyoung; Zhang, Xuehong; Townsend, Mary K; Selhub, Jacob; Paul, Ligi; Rosner, Bernard; Fuchs, Charles S; Willett, Walter C; Giovannucci, Edward L

    2015-12-01

    Higher folate has been associated with a reduced colorectal cancer (CRC) risk, but excessive folate may promote tumor progression. The role of unmetabolized folic acid (UFA) from high folic acid consumption in carcinogenesis is largely unexplored. We evaluated prediagnostic plasma levels of UFA in relation to CRC risk in nested case-control studies (618 CRC case patients and 1207 matched control) with blood samples collected prior to folic acid fortification. UFA was detected in 21.4% of control UFA levels were not associated with CRC risk. Compared with undetectable levels, the multivariable relative risks (RRs) of CRC were 1.03 (95% confidence interval [CI] = 0.73 to 1.46) for less than 0.5 nmol/L and 1.12 (95% CI = 0.81 to 1.55) for 0.5 nmol/L or more (P trend = .32). A positive association between UFA levels and CRC risk was observed among men (RR = 1.57, 95% CI = 0.99 to 2.49 for ?0.5 nmol/L vs undetectable, P interaction = .04), and a positive association was also observed among those with the methylene-tetrahydrofolate reductase (MTHFR) CT/TT genotype (RR = 2.20, 95% CI = 1.22 to 3.94 for ?0.5 nmol/L vs undetectable, P interaction=0.02). In conclusion, prediagnostic plasma levels of UFA from the prefortification period were not associated with risk of CRC. PMID:26376686

  12. Folic Acid Intake and Neural Tube Defects: Two Egyptian Centers Experience.

    PubMed

    El-Shabrawi, Mortada H; Kamal, Naglaa Mohamed; Elhusseini, Mona Abbas; Hussein, Laila; Abdallah, Enas Abdallah Ali; Ali, Yahia Zakaria Abdelalim; Azab, Ahmed Abelfattah; Salama, Mostafa Abdelazim; Kassab, Muna; Krawinkel, Michael

    2015-09-01

    Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex etiopathogenesis. Folic acid plays a pivotal role in their prevention. We aimed to identify the protective effect of folic acid intake against NTDs and its dependence on different socioeconomic and environmental factors in a cohort of mothers in Egypt. A cross-sectional study was carried over a period of 12 months on mothers who gave birth to babies with NTDs (group 1) and a control group with healthy offsprings (group 2). Both groups completed 2 questionnaires: food frequency questionnaire targeting the daily folate intake, and socioeconomic status and medical history questionnaire. Both groups of mothers received folate <800??g/day, recommended for pregnant women. A strong association was detected between NTDs and urban residency with medium educated mothers, with negative consanguinity, who had folate intake < 400??g daily, and who had their food long cooked. Each of these factors separately had a limited impact to cause NTDs, but when present together they did augment each other. Interestingly enough is the role of fava bean, cauliflower, spinach, and mango in predisposing of NTDs in the presence of the above-mentioned factors. The protective effect of folic acid intake against NTDs may depend on the synergism of different socioeconomic and environmental factors (which differ from country to another). In Egypt, females especially the medium-educated who live in urban areas should be well-informed with the value of folate intake in the periconceptional period. PMID:26376380

  13. Folic acid supplementation improves microvascular function in older adults through nitric oxide-dependent mechanisms.

    PubMed

    Stanhewicz, Anna E; Alexander, Lacy M; Kenney, W Larry

    2015-07-01

    Older adults have reduced vascular endothelial function, evidenced by attenuated nitric oxide (NO)-dependent cutaneous vasodilatation. Folic acid and its metabolite, 5-methyltetrahydrofolate (5-MTHF), are reported to improve vessel function. We hypothesized that (i) local 5-MTHF administration and (ii) chronic folic acid supplementation would improve cutaneous microvascular function in ageing through NO-dependent mechanisms. There were two separate studies in which there were 11 young (Y: 22 ± 1 years) and 11 older (O: 71 ± 3 years) participants. In both studies, two intradermal microdialysis fibres were placed in the forearm skin for local delivery of lactated Ringer's solution with or without 5 mM 5-MTHF. Red cell flux was measured by laser-Doppler flowmetry. Cutaneous vascular conductance [CVC=red cell flux/mean arterial pressure] was normalized as percentage maximum CVC (%CVCmax) (28 mM sodium nitroprusside, local temperature 43°C). In study 1 after CVC plateaued during local heating, 20 mM NG-nitro-L-arginine methyl ester (L-NAME) was perfused at each site to quantify NO-dependent vasodilatation. The local heating plateau (%CVCmax: O = 82 ± 3 vs Y = 96 ± 1, P = 0.002) and NO-dependent vasodilatation (%CVCmax: O = 26 ± 6% vs Y = 49 ± 5, P = 0.03) were attenuated in older participants. 5-MTHF augmented the overall (%CVCmax = 91 ± 2, P = 0.03) and NO-dependent (%CVCmax = 43 ± 9%, P = 0.04) vasodilatation in older but not young participants. In study 2 the participants ingested folic acid (5 mg/day) or placebo for 6 weeks in a randomized, double-blind, crossover design. A rise in oral temperature of 1°C was induced using a water-perfused suit, body temperature was held and 20 mM L-NAME was perfused at each site. Older participants had attenuated reflex (%CVCmax: O = 31 ± 8 vs Y = 44 ± 5, P = 0.001) and NO-dependent (%CVCmax: O = 9 ± 2 vs Y = 21 ± 2, P = 0.003) vasodilatation. Folic acid increased CVC (%CVCmax = 47 ± 5%, P = 0.001) and NO-dependent vasodilatation (20 ± 3%, P = 0.003) in the older but not the young participants. Both local perfusion of 5-MTHF and supplementation with folic acid increase vasodilatation in ageing individuals through NO-dependent mechanisms. PMID:25748442

  14. Folic acid supplementation during high-fat diet feeding restores AMPK activation via an AMP-LKB1-dependent mechanism.

    PubMed

    Sid, Victoria; Wu, Nan; Sarna, Lindsei K; Siow, Yaw L; House, James D; O, Karmin

    2015-11-15

    AMPK is an endogenous energy sensor that regulates lipid and carbohydrate metabolism. Nonalcoholic fatty liver disease (NAFLD) is regarded as a hepatic manifestation of metabolic syndrome with impaired lipid and glucose metabolism and increased oxidative stress. Our recent study showed that folic acid supplementation attenuated hepatic oxidative stress and lipid accumulation in high-fat diet-fed mice. The aim of the present study was to investigate the effect of folic acid on hepatic AMPK during high-fat diet feeding and the mechanisms involved. Male C57BL/6J mice were fed a control diet (10% kcal fat), a high-fat diet (60% kcal fat), or a high-fat diet supplemented with folic acid (26 mg/kg diet) for 5 wk. Mice fed a high-fat diet exhibited hyperglycemia, hepatic cholesterol accumulation, and reduced hepatic AMPK phosphorylation. Folic acid supplementation restored AMPK phosphorylation (activation) and reduced blood glucose and hepatic cholesterol levels. Activation of AMPK by folic acid was mediated through an elevation of its allosteric activator AMP and activation of its upstream kinase, namely, liver kinase B1 (LKB1) in the liver. Consistent with in vivo findings, 5-methyltetrahydrofolate (bioactive form of folate) restored phosphorylation (activation) of both AMPK and LKB1 in palmitic acid-treated HepG2 cells. Activation of AMPK by folic acid might be responsible for AMPK-dependent phosphorylation of HMG-CoA reductase, leading to reduced hepatic cholesterol synthesis during high-fat diet feeding. These results suggest that folic acid supplementation may improve cholesterol and glucose metabolism by restoration of AMPK activation in the liver. PMID:26400185

  15. Synthesis of folic acid functionalized redox-responsive magnetic proteinous microcapsules for targeted drug delivery.

    PubMed

    Li, Zhanfeng; Liu, Songfeng; Wang, Shurong; Qiang, Linhui; Yang, Ting; Wang, Hongyan; Möhwald, Helmuth; Cui, Xuejun

    2015-07-15

    Folic acid (FA) functionalized magnetic bovine serum albumin (BSA) microcapsules (FA-MBMCs) were prepared by a facile sonochemical method, in which FA molecule was immobilized onto the outer walls of microcapsules as a targeting ligand and oleic acid (OA) modifying Fe3O4 magnetic nanoparticles (OA-Fe3O4 MNPs) were wrapped into the microcapsules. The obtained FA-MBMCs possessed a nice spherical morphology with the mean size of 1.4 ?m. FA-MBMCs also showed an excellent magnetic and molecular dual-targeted property. Besides, the reductant-triggered diffusion of coumarin 6 suggested superior drug controlled release of FA-MBMCs. PMID:25840270

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

    PubMed

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

    2015-01-16

    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

  17. Obstructive heart defects associated with candidate genes, maternal obesity, and folic acid supplementation.

    PubMed

    Tang, Xinyu; Cleves, Mario A; Nick, Todd G; Li, Ming; MacLeod, Stewart L; Erickson, Stephen W; Li, Jingyun; Shaw, Gary M; Mosley, Bridget S; Hobbs, Charlotte A

    2015-06-01

    Right-sided and left-sided obstructive heart defects (OHDs) are subtypes of congenital heart defects, in which the heart valves, arteries, or veins are abnormally narrow or blocked. Previous studies have suggested that the development of OHDs involved a complex interplay between genetic variants and maternal factors. Using the data from 569 OHD case families and 1,644 control families enrolled in the National Birth Defects Prevention Study (NBDPS) between 1997 and 2008, we conducted an analysis to investigate the genetic effects of 877 single nucleotide polymorphisms (SNPs) in 60 candidate genes for association with the risk of OHDs, and their interactions with maternal use of folic acid supplements, and pre-pregnancy obesity. Applying log-linear models based on the hybrid design, we identified a SNP in methylenetetrahydrofolate reductase (MTHFR) gene (C677T polymorphism) with a main genetic effect on the occurrence of OHDs. In addition, multiple SNPs in betaine-homocysteine methyltransferase (BHMT and BHMT2) were also identified to be associated with the occurrence of OHDs through significant main infant genetic effects and interaction effects with maternal use of folic acid supplements. We also identified multiple SNPs in glutamate-cysteine ligase, catalytic subunit (GCLC) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) that were associated with elevated risk of OHDs among obese women. Our findings suggested that the risk of OHDs was closely related to a combined effect of variations in genes in the folate, homocysteine, or glutathione/transsulfuration pathways, maternal use of folic acid supplements and pre-pregnancy obesity. PMID:25846410

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

    PubMed Central

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

    2013-01-01

    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

  19. Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia

    PubMed Central

    Regland, Björn; Forsmark, Sara; Halaouate, Lena; Matousek, Michael; Peilot, Birgitta; Zachrisson, Olof; Gottfries, Carl-Gerhard

    2015-01-01

    Background Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders. Objective To evaluate clinical data from patients with ME, with or without fibromyalgia, who had been on B12 injections at least once a week for six months and up to several years. Methods 38 patients were included in a cross-sectional survey. Based on a validated observer’s rating scale, they were divided into Good (n = 15) and Mild (n = 23) responders, and the two groups were compared from various clinical aspects. Results Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis. In addition to ME, the higher number of patients with fibromyalgia among Mild responders was bordering on significance (p<0.09). Good responders rated themselves as “very much” or “much” improved, while Mild responders rated “much” or “minimally” improved. Conclusions Dose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia. It’s important to be alert on co-existing thyroid dysfunction, and we suspect a risk of counteracting interference between B12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism. These issues should be considered when controlled trials for ME and fibromyalgia are to be designed. PMID:25902009

  20. SERS encoded nanoparticle heterodimers for the ultrasensitive detection of folic acid.

    PubMed

    Wu, Xiaoling; Chen, Xi; Gao, Fengli; Ma, Wei; Xu, Liguang; Kuang, Hua; Li, Aike; Xu, Chuanlai

    2016-01-15

    In this paper, gold–silver nanoparticle (AuNP–AgNP) heterodimers were assembled with highly yield as an active SERS substrate, based on antigen–antibody immunoreaction. The developed SERS sensor has successful achieved the ultrasensitive detection of folic acid (FA) with the limit of detection (LOD) as 0.86 pg/mL. And the linear range was from 0.005 ng/mL to 1 ng/mL. The results also demonstrated that this developed method showed high specificity and excellent recovery for the human serum samples, indicating its promising potential in bio-diagnosis and the environmental monitoring. PMID:26296240

  1. Fortification of corn masa flour with folic acid in the United States: an overview of the evidence.

    PubMed

    Hamner, Heather C; Tinker, Sarah C

    2014-04-01

    Corn masa flour, used to make products such as corn tortillas, is a staple food for Hispanic populations residing in the United States, particularly among Mexican Americans and Central Americans. Research has indicated that Hispanic women in the United States continue to be at a higher risk of having a neural tube defect-affected pregnancy than women of other races/ethnicities, even after the introduction of folic acid fortification of cereal grain products labeled as "enriched." Corn masa flour has, therefore, been suggested as a potential food vehicle for folic acid in the United States. This paper explores the potential impact that folic acid fortification of corn masa flour could have on the Hispanic population in the United States. PMID:24494975

  2. Impact of a folic acid-enriched diet on urinary tract function in mice treated with testosterone and estradiol.

    PubMed

    Keil, Kimberly P; Abler, Lisa L; Altmann, Helene M; Wang, Zunyi; Wang, Peiqing; Ricke, William A; Bjorling, Dale E; Vezina, Chad M

    2015-06-15

    Aging men are susceptible to developing lower urinary tract symptoms, but the underlying etiology is unknown and the influence of dietary and environmental factors on them is unclear. We tested whether a folic acid-enriched diet changed urinary tract physiology and biology in control male mice and male mice with urinary dysfunction induced by exogenous testosterone and estradiol (T+E2), which mimics changing hormone levels in aging humans. T+E2 treatment increased mouse urine output, time between voiding events, and bladder capacity and compliance. Consumption of a folic acid-enriched diet moderated these changes without decreasing prostate wet weight or threshold voiding pressure. One potential mechanism for these changes involves water balance. T+E2 treatment increases plasma concentrations of anti-diuretic hormone, which is offset at least in part by a folic acid-enriched diet. Another potential mechanism involves neural control of micturition. The folic acid-enriched diet, fed to T+E2-treated mice, increased voiding frequency in response to intravesicular capsaicin infusion and increased mRNA abundance of the capsaicin-sensitive cation channel transient receptor potential vanilloid subfamily member 1 (Trpv1) in L6 and S1 dorsal root ganglia (DRG) neurons. T+E2 treatment and a folic acid-enriched diet also modified DNA methylation, which is capable of altering gene expression. We found the enriched diet increased global DNA methylation in dorsal and ventral prostate and L6 and S1 DRG. Our results are consistent with folic acid acting to slow or reverse T+E2-mediated alteration in urinary function in part by normalizing water balance and enhancing or preserving afferent neuronal function. PMID:25855514

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

    PubMed Central

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

    2011-01-01

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

  4. FOLIC ACID METABOLISM IN ANTIFOLIC-RESISTANT MUTANTS OF STREPTOCOCCUS FAECALIS.

    PubMed

    JOHNSON, A H; HUTCHISON, D J

    1964-04-01

    Johnson, Alva H. (Sloan-Kettering Institute for Cancer Research, Rye, N.Y.), and Dorris J. Hutchison. Folic acid metabolism in antifolic-resistant mutants of Streptococcus faecalis. J. Bacteriol. 87:786-791. 1964.-Streptococcus faecalis ATCC 8043 and three of its mutants resistant to amethopterin were compared for their quantitative requirements for serine, purines, and thymine; for their quantitative requirements of folic acid (FA) for the synthesis de novo of serine, purines, and thymine; for the susceptibility to amethopterin of each pathway; and for the relative capacity of resting cells of each culture to synthesize N(5)-formyltetrahydrofolate (5-CHOFAH(4)) from FA and serine or FA and formate. The mutants were found to be both qualitatively and quantitatively different from one another and from the wild strain. The growth conditions, specifically the composition of the medium in which each mutant strain was selected, had a marked effect on the metabolic capacities of the mutants. The ability to synthesize serine, purines, and thymine, as observed from the FA requirements, directly reflected the level of resistance of each pathway to amethopterin. The resistant mutants were more efficient than the wild strain in the formation of 5-CHOFAH(4) from FA and formate and, furthermore, this formate activation paralleled their capacities in the synthesis de novo of serine. Alterations in purine and thymine biosyntheses were also observed. PMID:14137614

  5. Impact of iron and folic acid supplementation on oxidative stress during pregnancy.

    PubMed

    Lymperaki, E; Tsikopoulos, A; Makedou, K; Paliogianni, E; Kiriazi, L; Charisi, C; Vagdatli, E

    2015-11-01

    The aim of the study was to assess serum total antioxidant capacity (TAC) and the impact of supplements on oxidative stress (OS) during pregnancy. Fifty volunteer pregnant women (21-40 years old), in the 12 ± 2 weeks' and 38 ± 2 weeks' gestation of pregnancy (study group), and 25 non-pregnant healthy women (control group) were enrolled. All pregnant women were divided into two age groups (A1: < 35 years and A2: ? 35 years) and four groups according to supplementation (B1: iron, B2: folic acid, B3: both and B4: none). Antioxidant activity was assayed using the TAC kit (Cayman Chemical Co.). Level of statistical significance was p < 0.05. Serum TAC values in all pregnant women in the first trimester were significantly lower, as compared with those of the control group. Levels of TAC increased significantly in the third trimester of pregnancy, especially with folic acid or no supplementation. In conclusion, pregnancy is associated with OS, which is promoted by the administration of iron supplementation. PMID:25692315

  6. Simultaneous Derivative Spectrophotometric Analysis of Doxylamine Succinate, Pyridoxine Hydrochloride and Folic Acid in Combined Dosage Forms

    PubMed Central

    Pathak, A.; Rajput, S. J.

    2008-01-01

    Two UV spectrophotometric methods have been developed, based on first derivative spectrophotometry for simultaneous estimation of doxylamine succinate, pyridoxine hydrochloride, and folic acid in tablet formulations. In method I, the concentrations of these drugs were determined by using linear regression equation. Method II is also based on first derivative spectrophotometry however simultaneous equations (Vierdot's method) were derived on derivative spectra. The first derivative amplitudes at 270.0, 332.8 and 309.2 nm were utilized for simultaneous estimation of these drugs respectively by both methods. In both the methods, linearity was obtained in the concentration range 2.5-50 ?g/ml, 1-40 ?g/ml and 1-30 ?g/ml for doxylamine succinate, pyridoxine hydrochloride, and folic acid respectively. The developed methods show best results in terms of linearity, accuracy, precision, LOD, LOQ and ruggedness for standard laboratory mixtures of pure drugs and marketed formulations. The common excipients and additives did not interfere in their determinations. PMID:20046784

  7. Physiological Characteristics and Production of Folic Acid of Lactobacillus plantarum JA71 Isolated from Jeotgal, a Traditional Korean Fermented Seafood

    PubMed Central

    Lim, Sang-Dong

    2014-01-01

    Folic acid, one of the B group of vitamins, is an essential substance for maintaining the functions of the nervous system, and is also known to decrease the level of homocysteine in plasma. Homocysteine influences the lowering of the cognitive function in humans, and especially in elderly people. In order to determine the strains with a strong capacity to produce folic acid, 190 bacteria were isolated from various kinds of jeotgal and chungkuk-jang. In our test experiment, JA71 was found to contain 9.03?g/mL of folic acid after 24 h of incubation in an MRS broth. This showed that JA71 has the highest folic acid production ability compared to the other lactic acid bacteria that were isolated. JA71 was identified as Lactobacillus plantarum by the result of API carbohydrate fermentation pattern and 16s rDNA sequence. JA71 was investigated for its physiological characteristics. The optimum growth temperature of JA71 was 37?, and the cultures took 12 h to reach pH 4.4. JA71 proved more sensitive to bacitracin when compared with fifteen different antibiotics, and showed most resistance to neomycin and vancomycin. Moreover, it was comparatively tolerant of bile juice and acid, and displayed resistance to Escherichia coli, Salmonella Typhimurium, and Staphylococcus aureus with restraint rates of 60.4%, 96.7%, and 76.2%, respectively. These results demonstrate that JA71 could be an excellent strain for application to functional products.

  8. Folic acid

    MedlinePLUS

    ... with folate deficiency, including ulcerative colitis, liver disease, alcoholism, and kidney dialysis. Women who are pregnant or ... cancer in people with ulcerative colitis. Liver disease. Alcoholism. Weak bones (osteoporosis). Other conditions. More evidence is ...

  9. Folic Acid

    MedlinePLUS Videos and Cool Tools

    ... Fighting premature birth About us Annual report Our work Community impact Global programs Research Need help? Local ... Fighting premature birth About us Annual report Our work Community impact Global programs Research Need help? Local ...

  10. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this study was to evaluate the beneficial effects of different levels of folic acid administration on the prevalence of neural tube defects, with a concurrent assessment of other potential benefits or adverse effects. The evaluation was based on a systematic review of the published ...

  11. Will Increasing Folic Acid in Fortified Grain Products Further Reduce Neural Tube Defects without Causing Harm?: Consideration of the Evidence

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Will Increasing Folic Acid in Fortified Grain Products Further Reduce Neural Tube Defects without Causing Harm?: Consideration of the Evidence. In the January issue of this journal, Johnston (1) includes our group’s recent analysis of data from the 1999-2002 National Health and Nutrition Examination...

  12. DOSE-DEPENDENT EFFECTS OF FOLIC ACID ON BLOOD CONCENTRATIONS OF HOMOCYSTEINE: A META-ANALYSIS OF THE RANDOMIZED TRIALS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary supplementation with B vitamins that lower blood homocysteine concentrations is expected to reduce cardiovascular disease risk, but there has been uncertainty about the optimum regimen to use for this purpose. The objectives were to ascertain the lowest dose of folic acid associated with th...

  13. VITAMIN B6, B12 AND FOLIC ACID SUPPLEMENTATION AND COGNITIVE FUNCTION: A SYSTEMATIC REVIEW OF RANDOMIZED TRIALS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Despite their important role in cognitive function, the value of B vitamin supplementation is unknown. A systematic review of the effect of vitamins B6, B12, and folic acid supplementation on cognitive function was performed. Literature search conducted in MEDLINE with supplemental articles from re...

  14. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice12345

    PubMed Central

    Christensen, Karen E; Mikael, Leonie G; Leung, Kit-Yi; Lévesque, Nancy; Deng, Liyuan; Wu, Qing; Malysheva, Olga V; Best, Ana; Caudill, Marie A; Greene, Nicholas DE

    2015-01-01

    Background: Increased consumption of folic acid is prevalent, leading to concerns about negative consequences. The effects of folic acid on the liver, the primary organ for folate metabolism, are largely unknown. Methylenetetrahydrofolate reductase (MTHFR) provides methyl donors for S-adenosylmethionine (SAM) synthesis and methylation reactions. Objective: Our goal was to investigate the impact of high folic acid intake on liver disease and methyl metabolism. Design: Folic acid–supplemented diet (FASD, 10-fold higher than recommended) and control diet were fed to male Mthfr+/+ and Mthfr+/? mice for 6 mo to assess gene-nutrient interactions. Liver pathology, folate and choline metabolites, and gene expression in folate and lipid pathways were examined. Results: Liver and spleen weights were higher and hematologic profiles were altered in FASD-fed mice. Liver histology revealed unusually large, degenerating cells in FASD Mthfr+/? mice, consistent with nonalcoholic fatty liver disease. High folic acid inhibited MTHFR activity in vitro, and MTHFR protein was reduced in FASD-fed mice. 5-Methyltetrahydrofolate, SAM, and SAM/S-adenosylhomocysteine ratios were lower in FASD and Mthfr+/? livers. Choline metabolites, including phosphatidylcholine, were reduced due to genotype and/or diet in an attempt to restore methylation capacity through choline/betaine-dependent SAM synthesis. Expression changes in genes of one-carbon and lipid metabolism were particularly significant in FASD Mthfr+/? mice. The latter changes, which included higher nuclear sterol regulatory element-binding protein 1, higher Srepb2 messenger RNA (mRNA), lower farnesoid X receptor (Nr1h4) mRNA, and lower Cyp7a1 mRNA, would lead to greater lipogenesis and reduced cholesterol catabolism into bile. Conclusions: We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient. PMID:25733650

  15. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    NASA Astrophysics Data System (ADS)

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

    1993-06-01

    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.

  16. Folic acid supplementation in pregnancy and implications in health and disease

    PubMed Central

    2014-01-01

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

  17. Soft structure formation and cancer cell transport mechanisms of a folic acid-dipeptide conjugate.

    PubMed

    Kaur, Gagandeep; Shukla, Akansha; Sivakumar, Sri; Verma, Sandeep

    2015-03-01

    Folic acid (FA) is a low-molecular-weight micronutrient, which plays a critical role in the prevention of birth defects and cancers. It is also essential for biochemical pathways responsible for DNA synthesis and maintenance and for the generation of new red blood cells. Cellular trafficking of FA and folate is based on its high-affinity binding to cognate folate receptor, a protein commonly expressed in several human cancers. Thus, folate conjugates of drugs, plasmids, biosensors, contrast, and radiodiagnostic imaging agents have been used for assisted delivery in folate receptor-positive cancer cells, via endocytosis pathways. This report describes morphologies of soft structures from a fully characterized FA-dipeptide conjugate and detailed mechanistic studies of its cancer cell uptake, as tracked by the inherent fluorescence of the conjugate. PMID:25645907

  18. [Homocysteine, vitamin B-12, folic acid and the cognitive decline in the elderly].

    PubMed

    Smach, M A; Naffeti, S; Charfeddine, B; Ben Abdallah, J; Othmen, L B; Letaef, A; Limem, K

    2013-10-01

    Hyperhomocysteinemia is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained. Mild hyperhomocysteinemia, which is sometimes associated with a low plasma level of vitamin B9, B12 and folic acid, is responsible in the toxicity in neural cell by activating NMDA receptor. Indeed, even if vitamin supplementation has clearly proven its efficiency on lowering plasma levels of homocysteine, recent studies do not show any positive effect of vitamin therapy on cognitive function. The hypothesis that this therapy is inefficient has been recently reinforced by two randomized trials on the effects of vitamin supplementation. Several hypotheses still need to be explored: Mechanisms of homocysteine toxicity and that of total uselessness of vitamin supplementation; the possible need to complete the actual data with further, more powerful studies in order to prove the role of homocysteine in the development of neurodegenerative diseases and a clinical effect of vitamin therapy. PMID:22647793

  19. Development of ?-polyoxometalate-polypyrrole-Au nanoparticles modified sensor applied for detection of folic acid.

    PubMed

    Babakhanian, Arash; Kaki, Samineh; Ahmadi, Mahtab; Ehzari, Hosna; Pashabadi, Afshin

    2014-10-15

    In this work, electrochemically synthesized gold nanoparticles (AuNPs) and ?-polyoxometalate (?-POM) (K7PMO2W9O39 · H2O) were simultaneously doped into electropolymerized polypyrrole (PPy) film using the cyclic voltammetry (CV) technique. Scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and CVs were used to characterize the composite films. The PPy-?-POM-AuNPs modified gold (Au) electrode was used to determine folic acid (FA) using square-wave voltammetry (SWV). The modified electrode exhibited excellent electrocatalytic ability to the reduction of FA at 0.3 V (vs. SCE) with the electron transfer rate constant (ks) of 1.15 × 10(-19)s(-1). The common coexisting substances showed no interferences on the response of modified electrode to FA. The modified electrode indicated reproducible behavior and a high level stability during the experiments, making it particularly suitable for the analytical purposes. PMID:24800683

  20. Folic acid supplements and risk for oral clefts in the newborn: a population-based study.

    PubMed

    Gildestad, Trude; Bjørge, Tone; Vollset, Stein Emil; Klungsøyr, Kari; Nilsen, Roy Miodini; Haaland, Øystein Ariansen; Øyen, Nina

    2015-11-01

    Results from previous studies on maternal folic acid intake and infant oral clefts are inconclusive. The aim of the present study was to investigate the association between women's use of folic acid and/or multivitamin supplements and the risk for oral cleft in the newborn. We used data from the Medical Birth Registry of Norway based on all births in Norway from 1999 to 2013. A total of 528 220 women had 880 568 pregnancies, resulting in 896 674 live births and stillbirths, of which 1623 had oral clefts (isolated oral clefts, n 1311; non-isolated oral clefts, n 312). Altogether, 21·5 % of women were vitamin supplement users before pregnancy. The birth prevalence of oral clefts was 1·81/1000 live births and stillbirths. Relative risks (RR) were estimated with log-binomial regression. For pregnancies with maternal use of vitamins, the adjusted RR for clefts overall was 0·90 (95 % CI 0·79, 1·04). The adjusted RR for cleft palate only (n 586) was 0·84 (95 % CI 0·66, 1·06) and that for cleft lip with or without cleft palate (n 1037) was 0·94 (95 % CI 0·79, 1·13). Associations were stronger for cleft cases that occurred in combination with other malformations (adjusted RR 0·63; 95 % CI 0·45, 0·88), although vitamin supplements provided no protection against isolated clefts (adjusted RR 0·98; 95 % CI 0·84, 1·15). In conclusion, our study demonstrates no statistically significant association between vitamin use and isolated oral clefts. However, we found lower risk for oral clefts that occurred in combination with other malformations. PMID:26343883

  1. Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats.

    PubMed

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

    2011-01-01

    Potential adverse effects of excess maternal folic acid supplementation on a vegetarian population deficient in vitamin B(12) are poorly understood. We have previously shown in a rat model that maternal folic acid supplementation at marginal protein levels reduces brain omega-3 fatty acid levels in the adult offspring. We have also reported that reduced docosahexaenoic acid (DHA) levels may result in diversion of methyl groups towards DNA in the one carbon metabolic pathway ultimately resulting in DNA methylation. This study was designed to examine the effect of normal and excess folic acid in the absence and presence of vitamin B(12) deficiency on global methylation patterns in the placenta. Further, the effect of maternal omega 3 fatty acid supplementation on the above vitamin B(12) deficient diets was also examined. Our results suggest maternal folic acid supplementation in the absence of vitamin B(12) lowers plasma and placental DHA levels (p<0.05) and reduces global DNA methylation levels (p<0.05). When this group was supplemented with omega 3 fatty acids there was an increase in placental DHA levels and subsequently DNA methylation levels revert back to the levels of the control group. Our results suggest for the first time that DHA plays an important role in one carbon metabolism thereby influencing global DNA methylation in the placenta. PMID:21423696

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2014-04-01

    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

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

    PubMed Central

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

    2014-01-01

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

  5. Folic acid in combination with adult neural stem cells for the treatment of spinal cord injury in rats

    PubMed Central

    Zhang, Chen; Shen, Lin

    2015-01-01

    Purpose: To observe the therapeutic effect of folic acid in combination with adult neural stem cells on spinal cord injury and to investigate the possible mechanism. Methods: A total of 120 Wistar rats were randomly assigned to six groups: normal, model, sham-surgery, folic acid injection, adult neural stem cell transplantation, and combination (folic acid injection + adult neural stem cells transplantation) groups. Morphology of neural stem cells was observed by inverted microscopy. Expression of CD105, CD45, CD44, and CD29 were detected by flow cytometry; expression of neuron-specific enolase and glial fibrillary acidic protein were determined by immunofluorescence. Motor coordination and integration capabilities were assessed using BBB scores; Morphology of spinal cord tissues was observed by hematoxylin-eosin staining and 5-bromodeoxyuridine immunohistochemistry. GDNF, BDNF and NT-3 expression in spinal cord tissues were determined by ELISA; while expression of the apoptosis-related proteins BCL-2, Bax and caspase-3 was detected using western blotting. Results: Flow cytometry showed that the isolated cells were positive for CD44 and CD29 and negative for CD105 and CD45. Combination treatment significantly improved the behavior of model rats with spinal cord injury, attenuated inflammatory reaction of spinal cord tissues, restored injured nerve cells, and increased expression of GDNF, BDNF and NT-3 in spinal cord tissues, up regulated BCL-2 expression, and down regulated Bax and caspase-3 expression. Conclusions: Folic acid in combination with adult neural stem cells significantly improved nerve function and plays a key role in maintaining microenvironment homeostasis in the neurons of rats with spinal cord injury. PMID:26379837

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

    NASA Astrophysics Data System (ADS)

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

    2014-07-01

    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.

  7. Electrochemical determination of hydrochlorothiazide and folic acid in real samples using a modified graphene oxide sheet paste electrode.

    PubMed

    Beitollahi, Hadi; Hamzavi, Mozhdeh; Torkzadeh-Mahani, Masoud

    2015-07-01

    A new ferrocene-derivative compound, 2-chlorobenzoyl ferrocene, was synthesized and used to construct a modified graphene oxide sheet paste electrode. The electrooxidation of hydrochlorothiazide at the surface of the modified electrode was studied. Under optimized conditions, the square wave voltammetric (SWV) peak current of hydrochlorothiazide increased linearly with hydrochlorothiazide concentration in the range of 5.0 × 10(-8) to 2.0 × 10(-4) M and a detection limit of 20.0 nM was obtained for hydrochlorothiazide. The diffusion coefficient and kinetic parameters (such as electron transfer coefficient and the heterogeneous rate constant) for hydrochlorothiazide oxidation were also determined. The prepared modified electrode exhibits a very good resolution between the voltammetric peaks of hydrochlorothiazide and folic acid which makes it suitable for the detection of hydrochlorothiazide in the presence of folic acid in real samples. PMID:25953571

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

    PubMed Central

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

    2012-01-01

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

  9. Effect of losartan with folic acid on plasma homocysteine and vascular ultrastructural changes in spontaneously hypertensive rats

    PubMed Central

    Zhu, Lihe; Yu, Jiong; Jia, Baofu; Zhao, Feng; Tang, Mengmeng; Hu, Lufeng; Lin, Feiyan

    2015-01-01

    Elevated homocysteine (Hcy) is a high risk factor of hypertension due to its function in endothelial dysfunction. Its level in the blood is strongly influenced by folic acid. In order to investigate the effects of losartan with folic acid on plasma level of Hcy and vascular ultrastructural changes, thirty spontaneously hypertensive rats (SHR) involved and randomly divided into three groups (n=10): SHR-C group (control), SHR-L group (losartan 25 mg·kg-1·d-1), SHR-L+Y group (losartan 25 mg·kg-1·d-1 + folic acid 0.4 mg·kg-1·d-1). Another 10 Wistar Rats involved as WKY-C group for normal control. The level of plasma Hcy was measured dynamically by LS-MS, the vascular ultrastructural changes were analyzed by light and electron microscopy. Moreover, the thickness and area of aorta was measured. The results showed the Hcy levels in four groups were WKY-C 7.49 ± 1.95 ?mol/L; SHR-C 8.45 ± 1.90 ?mol/L; SHR-L 8.28 ± 2.11 ?mol/L; SHR-L+Y 7.53 ± 2.02 ?mol/L at 80 days. There was no significant change for plasma Hcy (P>0.05). The morphological change showed the subendothelial space didn’t increased significantly, the endothelial cells have a more smooth and intact cellular membrane in SHR-L+Y group. In conclusion, Losartan combined with folic acid could improve arterial endothelial structure in SHR which has no significant correlation with plasma Hcy. PMID:26722483

  10. Folic Acid and Creatine as Therapeutic Approaches to Lower Blood Arsenic: A Randomized Controlled Trial

    PubMed Central

    Peters, Brandilyn A.; Hall, Megan N.; Liu, Xinhua; Parvez, Faruque; Sanchez, Tiffany R.; van Geen, Alexander; Mey, Jacob L.; Siddique, Abu B.; Shahriar, Hasan; Uddin, Mohammad Nasir; Islam, Tariqul; Balac, Olgica; Ilievski, Vesna; Factor-Litvak, Pam; Graziano, Joseph H.

    2015-01-01

    Background The World Health Organization estimates that > 140 million people worldwide are exposed to arsenic (As)–contaminated drinking water. As undergoes biologic methylation, which facilitates renal As elimination. In folate-deficient individuals, this process is augmented by folic acid (FA) supplementation, thereby lowering blood As (bAs). Creatinine concentrations in urine are a robust predictor of As methylation patterns. Although the reasons for this are unclear, creatine synthesis is a major consumer of methyl donors, and this synthesis is down-regulated by dietary/supplemental creatine. Objectives Our aim was to determine whether 400 or 800 ?g FA and/or creatine supplementation lowers bAs in an As-exposed Bangladeshi population. Methods We conducted a clinical trial in which 622 participants were randomized to receive 400 ?g FA, 800 ?g FA, 3 g creatine, 3 g creatine+400 ?g FA, or placebo daily. All participants received an As-removal filter on enrollment, and were followed for 24 weeks. After the 12th week, half of the two FA groups were switched to placebo to evaluate post-treatment bAs patterns. Results Linear models with repeated measures indicated that the decline in ln(bAs) from baseline in the 800-?g FA group exceeded that of the placebo group (weeks 1–12: ?= –0.09, 95% CI: –0.18, –0.01; weeks 13–24: FA continued: ?= –0.12, 95% CI: –0.24, –0.00; FA switched to placebo: ?= –0.14, 95% CI: –0.26, –0.02). There was no rebound in bAs related to cessation of FA supplementation. Declines in bAs observed in the remaining treatment arms were not significantly different from those of the placebo group. Conclusions In this mixed folate-deficient/replete study population, 12- and 24-week treatment with 800 ?g (but not 400 ?g) FA lowered bAs to a greater extent than placebo; this was sustained 12 weeks after FA cessation. In future studies, we will evaluate whether FA and/or creatine altered As methylation profiles. Citation Peters BA, Hall MN, Liu X, Parvez F, Sanchez TR, van Geen A, Mey JL, Siddique AB, Shahriar H, Uddin MN, Islam T, Balac O, Ilievski V, Factor-Litvak P, Graziano JH, Gamble MV. 2015. Folic acid and creatine as therapeutic approaches to lower blood arsenic: a randomized controlled trial. Environ Health Perspect 123:1294–1301;?http://dx.doi.org/10.1289/ehp.1409396 PMID:25978852

  11. Dual nutraceutical nanohybrids of folic acid and calcium containing layered double hydroxides

    NASA Astrophysics Data System (ADS)

    Kim, Tae-Hyun; Oh, Jae-Min

    2016-01-01

    Dual nutraceutical nanohybrids consisting of organic nutrient, folic acid (FA), and mineral nutrient, calcium, were prepared based on layered double hydroxide (LDH) structure. Among various hybridization methods such as coprecipitation, ion exchange, solid phase reaction and exfoliation-reassembly, it was found that exfoliation-reassembly was the most effective in terms of intercalation of FA moiety between Ca-containing LDH layers. X-ray diffraction patterns and infrared spectra indicated that FA molecules were well stabilized in the interlayer space of LDHs through electrostatic interaction. From the atomic force and scanning electron microscopic studies, particle thickness of LDH was determined to be varied with tens, a few and again tens of nanometers in pristine, exfoliated and reassembled state, respectively, while preserving particle diameter. The result confirmed layer-by-layer hybrid structure of FA and LDHs was obtained by exfoliation-reassembly. Solid UV-vis spectra showed 2-dimensional molecular arrangement of FA moiety in hybrid, exhibiting slight red shift in n??* and ???* transition. The chemical formulae of FA intercalated Ca-containing LDH were determined to Ca1.30Al(OH)4.6FA0.74·3.33H2O and Ca1.53Fe(OH)5.06FA2.24·9.94H2O by inductively coupled plasma-atomic emission spectroscopy, high performance liquid chromatography and thermogravimetry, showing high nutraceutical content of FA and Ca.

  12. Voluntary fortification with folic acid in Spain: An updated food composition database.

    PubMed

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

    2016-02-15

    Folic acid (FA) is a key vitamin in the prevention of many diseases including neural tube defects. In Spain, only voluntary FA food fortification is allowed and there is a lack of compositional data to assess the contribution of these products to population's dietary folate intakes. Since 2007, our group has been compiling and updating a FA fortified food composition database. FA levels were obtained from retailers in Madrid and information provided by manufacturers. FA was also quantified by an affinity chromatography-HPLC method. In the present study we recorded 375 products. Our results show a high variability in the declared FA levels amongst different products, and food groups, which is also dependant on the commercial brand. FA overages are commonly added by manufacturers to some fortified products. FA content label claims are missing in 64% of products. This database is a useful tool to manage FA fortified foods data but it is necessary to continuously update it for the sound evaluation and monitoring of population's FA dietary intakes. PMID:26433301

  13. Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans.

    PubMed

    Rathor, Laxmi; Akhoon, Bashir Akhlaq; Pandey, Swapnil; Srivastava, Swati; Pandey, Rakesh

    2015-12-01

    Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments. PMID:26546011

  14. Encapsulation of Folic Acid in Zeolite Y for Controlled Release via Electric Field.

    PubMed

    Paradee, Nophawan; Sirivat, Anuvat

    2016-01-01

    Zeolite Y/alginate hydrogel was used as a drug carrier/matrix for an electrophoresis transdermal drug delivery system. Folic acid (FA) as a model drug was loaded into the zeolite Y/alginate hydrogel via an ion-exchange process. The effects of cross-linking ratio, Si/Al ratio, electric field strength, and electrode polarity were investigated with respect to the release mechanism and diffusion coefficient (D) of FA using a modified Franz-diffusion cell. The FA was released from the matrix through the diffusion-controlled mechanism or Fickian diffusion because the diffusion scaling exponent value of FA was close to the value of 0.5. The D increased with an increasing cross-linking ratio and Si/Al ratio due to the mesh-size-promoting and the aluminum-content effects. The electric field strength enhanced the D of FA from the anode-FA electroreplusion. In addition, the D of FA could be varied by the electro-attractive or electro-repulsive force between the positively charged FA and the charged electrode depending on whether cathode or anode was placed on the drug matrix. Thus, the fabricated zeolite/hydrogel is of great potential to be used in an electrically controlled transdermal drug delivery system where drug diffusion can be precisely activated and controlled at the time of application. PMID:26561875

  15. Binding of Folic Acid Induces Specific Self-Aggregation of Lactoferrin: Thermodynamic Characterization.

    PubMed

    Tavares, Guilherme M; Croguennec, Thomas; Lê, Sébastien; Lerideau, Olivia; Hamon, Pascaline; Carvalho, Antônio F; Bouhallab, Saïd

    2015-11-17

    In the study presented here, we investigated the interaction at pH 5.5 between folic acid (FA) and lactoferrin (LF), a positively charged protein. We found a binding constant Ka of 10(5) M(-1) and a high stoichiometry of 10 mol of FA/mol of LF. The size and charge of the complexes formed evolved during titration experiments. Increasing the ionic strength to 50 mM completely abolished the isothermal titration calorimetry (ITC) signal, suggesting the predominance of electrostatic interactions in the exothermic binding obtained. We developed a theoretical model that explains the complex triphasic ITC profile. Our results revealed a two-step mechanism: FA/LF interaction followed by self-association of the complexes thus formed. We suggest that 10 FA molecules bind to LF to form saturated reactive complexes (FA10/LF) that further self-associate into aggregates with a finite size of around 15 nm. There is thus a critical saturation degree of the protein, above which the self-association can take place. We present here the first results that provide comprehensive details of the thermodynamics of FA/LF complexation-association. Given the high stoichiometry, allowing a load of 55 mg of FA/g of LF, we suggest that FA/LF aggregates would be an effective vehicle for FA in fortified drinks. PMID:26488446

  16. Encapsulation of folic acid in different silica porous supports: A comparative study.

    PubMed

    Pérez-Esteve, Édgar; Ruiz-Rico, María; de la Torre, Cristina; Villaescusa, Luis A; Sancenón, Felix; Marcos, María D; Amorós, Pedro; Martínez-Máñez, Ramón; Barat, José Manuel

    2016-04-01

    Although folic acid is essential to numerous bodily functions, recent research indicates that a massive exposition to the vitamin could be a double-edged sword. In this study, the capacity of different caped mesoporous silica particles (i.e. Hollow Silica Shells, MCM-41, SBA-15 and UVM-7) to dose FA during its passage through the gastrointestinal tract has been evaluated. Results confirmed that the four capped materials were capable to hinder the delivery of FA at low pH (i.e. stomach) as well as able to deliver great amounts of the vitamin at neutral pH (i.e. intestine). Nevertheless, the encapsulation efficiency and the deliver kinetics differed among supports. While supports with large pore entrance exhibited an initial fast release, MCM-41, showed a sustained release along the time. This correlation between textural properties and release kinetics for each of the supports reveals the importance of a proper support selection as a strategy to control the delivery of active molecules. PMID:26593466

  17. Graphene decorated microelectrodes for simultaneous detection of ascorbic, dopamine, and folic acids by means of chemical vapor deposition

    NASA Astrophysics Data System (ADS)

    Namdar, N.; Hassanpour Amiri, M.; Dehghan Nayeri, F.; Gholizadeh, A.; Mohajerzadeh, S.

    2015-09-01

    In this paper, high quality and large area graphene layers were synthesized using thermal chemical vapour deposition on copper foil substrates. We use graphene incorporated electrodes to measure simultaneously ascorbic acid, dopamine and folic acid. Cyclic voltammetry and differential pulse voltammetry methods were used to evaluate electrochemical behaviour of the grown graphene layers. The graphene-modified electrode shows large electrochemical potential difference compared to bare gold electrodes with higher current responses. Also our fabricated electrodes configuration can be used easily for microfluidic analysis.

  18. Effects of prenatal and/or postnatal (maternal and/or child) folic acid supplementation on the mental performance of children.

    PubMed

    Skórka, Agata; Gieruszczak-Bia?ek, Dorota; Pie?cik, Ma?gorzata; Szajewska, Hania

    2012-01-01

    It has been suggested that a deficiency in folic acid during early, critical central nervous system development may result in persistent cognitive and behavioral effects. The purpose of this systematic review was to evaluate evidence regarding whether folic acid supplementation during pregnancy and early life influences mental performance outcomes in children. The following electronic databases were searched through December 2009 for studies relevant to mental performance and folic acid: MEDLINE, EMBASE and The Cochrane Library; additional references were obtained from reviewed articles. Only randomized controlled trials (RCTs) were included. Of 8 RCTs identified, only 2 met the inclusion criteria. Both studies involved periconceptional, multivitamin-containing, folic acid supplementation. Evidence from these 2 RCTs suggests that such supplementation does not affect the postnatal mental development of infants at a mean age of 11 mo, the developmental quotient (DQ) at 2 y of age, or the intelligence quotient (IQ) and Goodenough man drawing test quotient (DrQ) at 6 y of age. We conclude that the use of multivitamin-containing folic acid supplementation during pregnancy is associated with no benefit to the mental performance of children. These findings should be interpreted with caution due to the very limited number of studies included in this systemic review. PMID:22823344

  19. One-Pot Synthesis of Cu2 O/ZnO Nanoparticles at Present of Folic Acid to Improve UV-Protective Effect of Cotton Fabrics.

    PubMed

    Noorian, Seyyed Abbas; Hemmatinejad, Nahid; Bashari, Azadeh

    2015-01-01

    In this study, the effect of using folic acid on the in situ synthesis process of nanostructures has been investigated. Folic acid, as a biotemplate for synthesis of Cu2 O/ZnO, was used to improve the reducing and stabilizing the ability of cotton fabric and avoid agglomeration of the particles. Scanning electron microscopy images revealed that using folic acid caused the formation of particles with smaller sizes on the cotton fabric and X-ray diffraction confirmed the same crystalline pattern of nanoparticles in comparison with the previous synthesis process. The effect of using this biotemplate on different properties of treated fabrics including UV-protection effect, hydrophilicity, crease recovery angle, softness, thickness and mechanical properties has been evaluated. The folic acid had a great influence on UV-protection effect, in synthesis procedure, decreasing the droplet absorption time, bending length and improving the wrinkle resistance and mechanical properties. Interestingly, the higher tensile strength of the treated cotton fabrics proved the incorporation of nanoparticles into the cotton fibers. An in situ, green and rapid method can be provided by using folic acid for the synthesis of the nanostructures with controlled size. PMID:25580868

  20. Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.

    PubMed

    Burda, P; Kuster, A; Hjalmarson, O; Suormala, T; Bürer, C; Lutz, S; Roussey, G; Christa, L; Asin-Cayuela, J; Kollberg, G; Andersson, B A; Watkins, D; Rosenblatt, D S; Fowler, B; Holme, E; Froese, D S; Baumgartner, M R

    2015-09-01

    In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C?>?T, p.Thr296Ile) and a splice site mutation (c.1674G?>?A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C?>?T, p.Ser49Phe) and a premature stop mutation (c.673G?>?T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment. PMID:25633902

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

    PubMed

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

    2014-03-01

    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

  2. Awareness of folic acid use increases its consumption, and reduces the risk of spina bifida.

    PubMed

    Kondo, Atsuo; Morota, Nobuhito; Date, Hiroaki; Yoshifuji, Kazuhisa; Morishima, Toshibumi; Miyazato, Minoru; Shirane, Reizo; Sakai, Hideki; Pooh, Kyong Hon; Watanabe, Tomoyuki

    2015-07-14

    The majority of neural tube defects were believed to be folic acid (FA)-preventable in the 1990s. The Japanese government recommended women planning pregnancy to take FA supplements of 400 ?g/d in 2000, but the incidence of spina bifida has not decreased. We aimed to evaluate the OR of having an infant with spina bifida for women who periconceptionally took FA supplements and the association between an increase in supplement use and possible promoters for the increase. This is a case-control study which used 360 case women who gave birth to newborns afflicted with spina bifida, and 2333 control women who gave birth to healthy newborns during the first 12 years of this century. They were divided into two 6-year periods; from 2001 to 2006 and from 2007 to 2012. Logistic regression analyses were conducted to compute OR between cases and controls. The adjusted OR of having an infant with spina bifida for supplement users was 0.48 in the first period, and 0.53 in the second period. The proportion of women who periconceptionally consumed supplements significantly increased from 10 % in the first period to 30 % in the second period. Awareness of the preventive role of FA was a promoter for an increase in supplement use, and thus an FA campaign in high school seems rational and effective. The failure of the current public health policy is responsible for an epidemic of spina bifida. Mandatory food fortification with FA is urgent and long overdue in Japan. PMID:25999131

  3. BP, Cardiovascular Disease, and Death in the Folic Acid for Vascular Outcome Reduction in Transplantation Trial

    PubMed Central

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

    2014-01-01

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

  4. Photoinduced Electron Transfer in Folic Acid Investigated by Ultrafast Infrared Spectroscopy

    PubMed Central

    Li, Guifeng; Magana, Donny; Dyer, R. Brian

    2012-01-01

    Conformational control of excited-state intramolecular electron transfer (ET) in folic acid (FA) has been investigated using femtosecond time-resolved infrared (TRIR) spectroscopy. Ultrafast excited-state ET between the pterin and the 4-aminobenzoyl subunits of FA is observed for the anionic form (at pH 10.0). An ET lifetime of 2.5 ps is estimated from Marcus theory for FA in the “U” conformation, in close agreement with the observed lifetime of 2.0 ps. Return to the ground state through the reverse ET reaction happens almost as rapidly, within 5 ps, resulting in rapid quenching of the singlet excited state. In mixed water:dimethyl sulfoxide solvent, ET becomes more unfavorable as FA adopts a more open conformation, thereby increasing the effective donor–acceptor distance and reducing the coupling energy. In contrast, no ET is observed for the cationic form of FA at low pH (6.0). In this case, the initial singlet excited state is localized on the pterin moiety of FA, and the excited-state charge distribution evolves with time. The charge redistribution in the pterin that occurs with intersystem crossing to the triplet state is characterized by changes in the transient IR spectrum. The excited-state lifetime is much longer in the absence of an ET quenching pathway. These results provide new insight into the mechanism of photodegradation and toxicity of FA. Ultrafast intramolecular ET in closed conformations of FA rapidly quenches the excited state and prevents efficient triplet state formation. Thus, conformations of FA that allow ultrafast intra-ET and rapid quenching of the singlet excited state play a key role in inhibiting pathological pathways following photoexcitation of FA. PMID:22364409

  5. Antiinflammatory Activity of a Novel Folic Acid Targeted Conjugate of the mTOR Inhibitor Everolimus

    PubMed Central

    Lu, Yingjuan; Parker, Nikki; Kleindl, Paul J; Cross, Vicky A; Wollak, Kristin; Westrick, Elaine; Stinnette, Torian W; Gehrke, Mark A; Wang, Kevin; Santhapuram, Hari Krishna R; You, Fei; Hahn, Spencer J; Vaughn, Jeremy F; Klein, Patrick J; Vlahov, Iontcho R; Low, Philip S; Leamon, Christopher P

    2015-01-01

    Folate receptor (FR)-? has been identified as a promising target for antimacrophage and antiinflammatory therapies. In the present study, we investigated EC0565, a folic acid–derivative of everolimus, as a FR-specific inhibitor of the mammalian target of rapamycin (mTOR). Because of its amphiphilic nature, EC0565 was first evaluated for water solubility, critical micelle formation, stability in culture and FR-binding specificity. Using FR-expressing macrophages, the effect of EC0565 on mTOR signaling and cellular proliferation was studied. The pharmacokinetics, metabolism and bioavailability of EC0565 were studied in normal rats. The in vivo activity of EC0565 was assessed in rats with adjuvant arthritis, a “macrophage-rich” model with close resemblance to rheumatoid arthritis. EC0565 forms micellar aggregates in physiological buffers and demonstrates good water solubility as well as strong multivalent FR-binding capacity. EC0565 inhibited mTOR signaling in rat macrophages at nanomolar concentrations and induced G0/G1 cell cycle arrest in serum-starved RAW264.7 cells. Subcutaneously administered EC0565 in rats displayed good bioavailability and a relatively long half-life (~12 h). When given at 250 nmol/kg, EC0565 selectively inhibited proliferating cell nuclear antigen expression in thioglycollate-stimulated rat peritoneal cells. With limited dosing regimens, the antiarthritic activity of EC0565 was found superior to that of etanercept, everolimus and a nontargeted everolimus analog. The in vivo activity of EC0565 was also comparable to that of a folate-targeted aminopterin. Folate-targeted mTOR inhibition may be an effective way of suppressing activated macrophages in sites of inflammation, especially in nutrient-deprived conditions, such as in the arthritic joints. Further investigation and improvement upon the physical and biochemical properties of EC0565 are warranted. PMID:26181632

  6. Dietary folic acid protects against genotoxicity in the red blood cells of mice.

    PubMed

    MacFarlane, Amanda J; Behan, Nathalie A; Field, Martha S; Williams, Andrew; Stover, Patrick J; Yauk, Carole L

    2015-09-01

    Folate is an essential B vitamin required for the de novo synthesis of purines, thymidylate and methionine. Folate deficiency can lead to mutations and genome instability, and has been shown to exacerbate the genotoxic potential of environmental toxins. We hypothesized that a folic acid (FA) deficient diet would induce genotoxicity in mice as measured by the Pig-a mutant phenotype (CD24-) and micronuclei (MN) in reticulocytes (RET) and red blood cells/normochromatic erythrocytes (RBC/NCE). Male Balb/c mice were fed a FA deficient (0 mg/kg), control (2 mg/kg) or supplemented (6 mg/kg) diet from weaning for 18 wk. Mice fed the deficient diet had 70% lower liver folate (p < 0.001), 1.8 fold higher MN-RET (p < 0.001), and 1.5 fold higher MN-NCE (p < 0.001) than mice fed the control diet. RET(CD24-) and RBC(CD24-) frequencies were not different between mice fed the deficient and control diets. Compared to mice fed the FA supplemented diet, mice fed the deficient diet had 73% lower liver folate (p < 0.001), a 2.0 fold increase in MN-RET (p < 0.001), a 1.6 fold increase in MN-NCE (p < 0.001) and 3.8 fold increase in RBC(CD24-) frequency (p = 0.011). RET(CD24-) frequency did not differ between mice fed the deficient and supplemented diets. Our data suggest that FA adequacy protects against mutagenesis at the Pig-a locus and MN induction in the red blood cells of mice. PMID:26177356

  7. Inhibition of Carcinoma Cell Motility by Epoxyeicosatrienoic Acid (EET) Antagonists

    PubMed Central

    Nithipatikom, Kasem; Brody, Daniel M.; Tang, Alan T.; Manthati, Vijaya L.; Falck, John R.; Williams, Carol L.; Campbell, William B.

    2012-01-01

    Summary Cytochrome P450 (CYP) epoxygenases, CYP2C8, 2C9 and 2J2 mRNAs and proteins, were expressed in prostate carcinoma (PC-3, DU-145 and LNCaP) cells. 11,12-Epoxyeicosatrienoic acid (11,12-EET) was the major arachidonic acid metabolite in these cells. Blocking the EET synthesis by a selective CYP epoxygenase inhibitor (MS-PPOH) inhibited tonic (basal) invasion and migration (motility) while exogenously added EETs induced cell motility in a concentration-dependent manner. An EGFR kinase inhibitor (AG494) or a PI3 kinase inhibitor (LY294002) inhibited cell migration and reduced 11,12-EET-induced cell migration. Importantly, synthetic EET antagonists (14,15-EEZE, 14,15-EEZE-PEG and 14,15-EEZE-mSI) inhibited EET-induced cell invasion and migration. 11,12-EET induced cell stretching and myosin-actin microfilament formation as well as increased phosphorylation of EGFR and Akt (Ser473) while 14,15-EEZE inhibited these effects. These results suggest that EETs induce and EET antagonists inhibit cell motility, possibly by putative EET receptor-mediated EGFR and PI3K/Akt pathways, and suggest EET antagonists as potential therapeutic agents for prostate cancer. PMID:20804500

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

    PubMed

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

    2014-04-01

    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

  9. Folic acid-tethered Pep-1 peptide-conjugated liposomal nanocarrier for enhanced intracellular drug delivery to cancer cells: conformational characterization and in vitro cellular uptake evaluation

    PubMed Central

    Kang, Myung Joo; Park, Sang Han; Kang, Mean Hyung; Park, Min Jung; Choi, Young Wook

    2013-01-01

    Background A novel dual ligand–modified liposome, folic acid-tethered Pep-1 peptide-conjugated liposomal nanocarrier (FP-Lipo), was designed to overcome the nonselectivity of conventional penetrating peptide-tagged nanoparticulates and to provide the advantage of selective targeting of the folic acid receptor, which is frequently overexpressed on epithelial cancer cells. Methods FP-Lipo was prepared by a sequential process of formation of a maleimide-derivatized small unilamellar vesicle, postinsertion of distearoyl phosphatidyl ethanolamine-polyethylene glycol 2000–folate to the vesicle, and Pep-1 peptide conjugation via thiol-maleimide linkage. Conformational and physical characteristics of the FP-Lipo nanocarriers were investigated for the extent of Pep-1 peptide and folic acid on the surface, vesicle size, and zeta potential. In vitro cellular uptake behaviors of the novel carrier containing a fluorescein dextran isothiocyanate probe were examined by spectrophotometry or by confocal laser scanning microscopy. Results A novel nanocarrier bearing approximately 750 folate ligands and 100 penetrating peptides per vesicle was successfully prepared. The physical properties were as follows: 140 nm in size; 5 mV in zeta potential; less than 0.3 in polydispersity index. An in vitro cellular uptake study revealed that the FP-Lipo nanocarrier system exhibited more than twofold enhanced translocation into the folic acid receptor–positive HeLa cells compared with the single Pep-1 peptide–modified liposome. Meanwhile, its cellular association and internalization into the folic acid receptor–negative normal HaCaT cells was comparable with that of Pep-1 peptide–modified liposome. Conclusion An advanced dual ligand-modified liposome is potentially useful for the treatment of folic acid receptor–positive tumors with high translocation capability of the penetrating peptide–modified liposome. PMID:23515421

  10. Folic acid supplemented goat milk has beneficial effects on hepatic physiology, haematological status and antioxidant defence during chronic Fe repletion.

    PubMed

    Alférez, María J M; Rivas, Emilio; Díaz-Castro, Javier; Hijano, Silvia; Nestares, Teresa; Moreno, Miguel; Campos, Margarita S; Serrano-Reina, Jose A; López-Aliaga, Inmaculada

    2015-02-01

    The aim of the current study was to asses the effect of goat or cow milk-based diets, either normal or Fe-overloaded and folic acid supplement on some aspects of hepatic physiology, enzymatic antioxidant defence and lipid peroxidation in liver, brain and erythrocyte of control and anaemic rats after chronic Fe repletion. 160 male Wistar rats were placed on 40 d in two groups, a control group receiving normal-Fe diet and the Fe-deficient group receiving low Fe diet. Lately, the rats were fed with goat and cow milk-based diets during 30 d, with normal-Fe content or Fe-overload and either with normal folic or folic acid supplemented. Fe-overload increased plasma alanine transaminase and aspartate transaminase levels when cow milk was supplied. Dietary folate supplementation reduced plasma transaminases levels in animals fed goat milk with chronic Fe overload. A remarkable increase in the superoxide dismutase activity was observed in the animals fed cow milk. Dietary folate supplement lead to a decrease on the activity of this enzyme in all the tissues studied with both milk-based diets. A concomitant increment in catalase was also observed. The increase in lipid peroxidation products levels in rats fed cow milk with Fe-overload, suggest an imbalance in the functioning of the enzymatic antioxidant defence. In conclusion, dietary folate-supplemented goat milk reduces both plasma transaminases levels, suggesting a hepatoprotective effect and has beneficial effects in situation of Fe-overload, improving the antioxidant enzymes activities and reducing lipid peroxidation. PMID:25394837

  11. Congenital Anomalies in Children of Mothers Taking Antiepileptic Drugs with and without Periconceptional High Dose Folic Acid Use: A Population-Based Cohort Study

    PubMed Central

    Ban, Lu; Fleming, Kate M.; Doyle, Pat; Smeeth, Liam; Hubbard, Richard B.; Fiaschi, Linda; Tata, Laila J.

    2015-01-01

    Background Antenatal antiepileptic drug (AED) use has been found to be associated with increased major congenital anomaly (CA) risks. However whether such AED-associated risks were different according to periconceptional high dose (5mg daily) folic acid supplementation is still unclear. Methods We included 258,591 singleton live-born children of mothers aged 15-44 years in 1990-2013 from The Health Improvement Network, a large UK primary care database. We identified all major CAs according to the European Surveillance of Congenital Anomalies classification. Absolute risks and adjusted odds ratios (aOR) were calculated comparing children of mothers prescribed AEDs to those without such prescriptions, stratified by folic acid prescriptions around the time of conception (one month before conception to two months post-conception). Results CA risk was 476/10,000 in children of mothers with first trimester AEDs compared with 269/10,000 in those without AEDs equating to an aOR of 1.82, 95% confidence interval 1.30-2.56. The highest system-specific risks were for heart anomalies (198/10,000 and 79/10,000 respectively, aOR 2.49,1.47-4.21). Sodium valproate and lamotrigine were both associated with increased risks of any CA (aOR 2.63,1.46-4.74 and aOR 2.01,1.12-3.59 respectively) and system-specific risks. Stratification by folic acid supplementation did not show marked reductions in AED-associated risks (e.g. for CAs overall aOR 1.75, 1.01-3.03 in the high dose folic acid group and 1.94, 95%CI 1.21-3.13 in the low dose or no folic acid group); however, the majority of mothers taking AEDs only initiated high dose folic acid from the second month of pregnancy. Conclusions Children of mothers with AEDs in the first trimester of pregnancy have a 2-fold increased risk of major CA compared to those unexposed. We found no evidence that prescribed high dose folic acid supplementation reduced such AED-associated risks. Although statistical power was limited, prescribing of folic acid too late for it to be effective during the organogenic period or selective prescribing to those with more severe morbidity may explain these findings. PMID:26147467

  12. Characterization and comparative studies of zebrafish and human recombinant dihydrofolate reductases--inhibition by folic acid and polyphenols.

    PubMed

    Kao, Tseng-Ting; Wang, Kuan-Chieh; Chang, Wen-Ni; Lin, Chia-Ying; Chen, Bing-Hung; Wu, Hua-Lin; Shi, Guey-Yueh; Tsai, Jen-Ning; Fu, Tzu-Fun

    2008-03-01

    Dihydrofolate reductase (DHFR) catalyzes folic acid reduction and recycles dihydrofolate generated during dTMP biosynthesis to tetrahydrofolate. DHFR is the main target of methotrexate, the most widely used agent for antifolate therapy. Nevertheless, the emergence of methotrexate-resistance has greatly impeded the curative potential of this drug. Therefore, drugs with improved efficacy are still in demand, as well as an efficient in vitro assay system and animal model for antifolate drug discovery. The aim of this study is to evaluate the suitability of using zebrafish DHFR as an alternative assay system for antifolate drug discovery. The cDNAs encoding zebrafish and human DHFR were cloned, overexpressed, and purified. Similar structural and kinetic properties were revealed between zebrafish and human recombinant DHFRs. The susceptibilities of both enzymes to known DHFR inhibitors, including methotrexate and trimethoprim, and compounds with antifolate potential, such as polyphenols, are also comparable. In addition, the DHFR-mediated dihydrofolate reduction was significantly inhibited by its own substrate folic acid. An unexpected tissue-specific distribution of DHFR was observed with the highest level present in ova and brains of zebrafish. DHFR is also abundant in zebrafish embryos of early stages and decreased abruptly after 3 days postfertilization. The substantial resemblance between zebrafish and human DHFRs, as demonstrated in this study, provides compelling evidence supporting the use of zebrafish DHFR as an in vitro assay system for folate-related studies and drug discovery. PMID:18056255

  13. Folate-binding protein and the absorption of folic acid in the small intestine of the suckling rat

    SciTech Connect

    Mason, J.B.; Selhub, J.

    1988-09-01

    The folate in milk is largely bound to high-affinity folate-binding protein (FBP). With an in vivo intestinal loop technique, we examined the absorption of folic acid bound to FBP (FA-FBP) in the small intestine of the suckling rat. In contrast to unbound folic acid (FA), FA-FBP is absorbed more avidly in the ileum than in the jejunum (p less than 0.025) and its absorption is not inhibited by 1 mmol sulfasalazine/L. Folate-binding activities in the mucosa of the proximal (duodenum and jejunum combined) and distal (ileum) small intestine were also examined and found to be 0.32 and 1.31 pmol/mg protein, respectively (p less than 0.001). A 6-h fast produced a 42% decrease in folate-binding activity in the distal small intestine (p less than 0.01) but did not change activity in the proximal portion. Collectively, these observations suggest that FA-FBP is absorbed by a mechanism that is distinct from that responsible for the absorption of FA and that absorption does not require prior dissociation of the vitamin-binding protein complex.

  14. Folic acid intake by pregnant women from Vale do Jequitinhonha, Brazil, and the contribution of fortified foods.

    PubMed

    Rodrigues, Humberto Gabriel; Gubert, Muriel Bauermann; Santos, Leonor Maria Pacheco

    2015-03-01

    The folate deficiency can result in irreversible health damage, such as the neural tube defects. The aim of this article is to determine the folate intake of pregnant women in Vale do Jequitinhonha, Minas Gerais state, Brazil, one of the poorest regions in the world. A descriptive, cross-sectional study was done in 2013 with 492 pregnant women attending the basic health units run by the public health service (Sistema Único de Saúde, SUS) in 15 municipalities. A standard questionnaire was used to gather the data, which included socioeconomic indicators and a food frequency questionnaire. The data were analyzed and compared statistically based on prevalence ratios and 95% confidence intervals. The prevalence of inadequate folate intake was associated with some socioeconomic factors: it was higher amongst the low income and less educated women, in younger women and those who had fewer meals per day. The prevalence of inadequate folate intake in the diet was 94.7% when the contribution of food fortification was not considered, 49.2% taking into account fortified foods, and 17.1% considering food folate, fortified foods, and supplementation with folic acid. We conclude that fortifying foods with folic acid at the current levels reduces the inadequacy of folate intake in the diet, but not enough to assure safe levels and to meet the nutritional requirements of pregnant women in Brazil. PMID:26320303

  15. Folic acid deficiency impairs the gill health status associated with the NF-?B, MLCK and Nrf2 signaling pathways in the gills of young grass carp (Ctenopharyngodon idella).

    PubMed

    Shi, Lei; Feng, Lin; Jiang, Wei-Dan; Liu, Yang; Jiang, Jun; Wu, Pei; Zhao, Juan; Kuang, Sheng-Yao; Tang, Ling; Tang, Wu-Neng; Zhang, Yong-An; Zhou, Xiao-Qiu

    2015-11-01

    The aim of this study was to investigate the effect of dietary folic acid on fish growth, the immune and barrier functions of fish gills, and the potential mechanisms of these effects. Young grass carp (Ctenopharyngodon idella) were fed diets containing graded levels of folic acid at 0.10 (basal diet), 0.47, 1.03, 1.48, 1.88 and 3.12 mg kg(-1) diet for 8 weeks. The results showed that acid phosphatase and lysozyme activities and the complement component 3 content in fish gills decreased with folic acid deficiency (P < 0.05). Folic acid deficiency up-regulated liver-expressed antimicrobial peptide 1, interleukin 1?, interleukin 8, tumor necrosis factor ?, nuclear factor ?B p65, I?B kinase ? (IKK-?), IKK-? and IKK-? gene expression. Folic acid deficiency down-regulated interleukin 10, transforming growth factor ?, I?B and target of rapamycin gene expression in fish gills (P < 0.05). These results showed that limited folic acid decreased fish gill immune status. Furthermore, folic acid deficiency down-regulated claudin-b, claudin-c, claudin-3, occludin and zonula occludens 1 gene expression, whereas folic acid deficiency up-regulated claudin-12, claudin-15, myosin light chain kinase and p38 mitogen activated protein kinase gene expression in fish gills (P < 0.05). These results suggested that folic acid deficiency disrupted tight junction-mediated fish gill barrier function. Additionally, folic acid deficiency increased the content of reactive oxygen species, protein carbonyl and malondialdehyde (MDA); Mn superoxide dismutase activity and gene expression; and Kelch-like-ECH-associated protein 1a (Keap1a) and Keap1b gene expression (P < 0.05). Conversely, folic acid deficiency decreased Cu/Zn superoxide dismutase, catalase, glutathione peroxidase, glutathione s-transferases and glutathione reductase activities and gene expression as well as NF-E2-related factor 2 gene expression in fish gills (P < 0.05). All of these results indicated that folic acid deficiency impaired fish gill health status via regulating gene expression of cytokines, tight junction proteins, antioxidant enzymes, NF-?B p65, MLCK and Nrf2. Based on percent weight gain, LZ activity and MDA content in the gills, the dietary folic acid requirements for young grass carp were 1.60, 2.07 and 2.08 mg kg(-1), respectively. PMID:26381932

  16. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. T...

  17. 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...

  18. 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...

  19. The Role of Zinc and Iron-Folic Acid Supplementation on Early Child Temperament and Eating Behaviors in Rural Nepal: A Randomized Controlled Trial

    PubMed Central

    Surkan, Pamela J.; Charles, Mary Katherine; Katz, Joanne; Siegel, Emily H.; Khatry, Subarna K.; LeClerq, Steven C.; Stoltzfus, Rebecca J.; Tielsch, James M.

    2015-01-01

    Child eating behaviors play an important role in nutrient intake, ultimately affecting child growth and later outcomes in adulthood. The study assessed the effects of iron-folic acid and zinc supplementation on child temperament and child eating behaviors in rural Nepal. Children (N = 569) aged 4–17 months in Sarlahi district, southern Nepal were randomized to receive daily supplements of placebo, iron-folic acid, zinc, or zinc plus iron-folic acid and followed for approximately 1 year. At baseline and four follow-up visits mothers completed questionnaires including information on demographic characteristics and child temperament and eating behaviors. The main effects of zinc and iron-folic acid supplementation on temperament and eating behaviors were assessed through crude and adjusted differences in mean cumulative score changes between visits 1 and 5. The adjusted rate-of-change for these outcomes was modeled using generalized estimating equations. Mean changes in temperament scores and in eating behavior scores between visits 1 and 5 were not significant in either the zinc or non-zinc group. Children in the iron-folic acid group increased temperament scores by 0.37 points over 5 visits (95% CI 0.02, 0.7), which was not significant after adjustment. Neither the adjusted rate-of-change in temperament scores between zinc and non-zinc (? = ?0.03, 95% CI ?0.3, 0.2) or iron-folic acid and non-iron-folic acid (? = 0.08, 95% CI ?0.2, 0.3) were significantly different. Adjusted rate of change analysis showed no significant difference between zinc and non-zinc (? = ?0.14, 95% CI ?0.3, 0.04) or between iron and non-iron eating behavior scores (? = ?0.11, 95% CI ?0.3, 0.1). Only among children with iron-deficiency anemia at baseline was there a significant decrease in eating behavior score, indicating better eating behaviors, when supplemented with zinc (? = ?0.3, 95% CI ?0.6, ?0.01), Ultimately, this effect of zinc on eating behaviors was the only effect we observed after approximately one year of micronutrient supplementation. Trial Registration ClinicalTrials.gov NCT00109551 PMID:25821959

  20. Effects of intramuscular administration of folic acid and vitamin B12 on granulosa cells gene expression in postpartum dairy cows.

    PubMed

    Gagnon, A; Khan, D R; Sirard, M-A; Girard, C L; Laforest, J-P; Richard, F J

    2015-11-01

    The fertility of dairy cows is challenged during early lactation, and better nutritional strategies need to be developed to address this issue. Combined supplementation of folic acid and vitamin B12 improve energy metabolism in the dairy cow during early lactation. Therefore, the present study was undertaken to explore the effects of this supplement on gene expression in granulosa cells from the dominant follicle during the postpartum period. Multiparous Holstein cows received weekly intramuscular injection of 320 mg of folic acid and 10 mg of vitamin B12 (treated group) beginning 24 (standard deviation=4) d before calving until 56 d after calving, whereas the control group received saline. The urea plasma concentration was significantly decreased during the precalving period, and the concentration of both folate and vitamin B12 were increased in treated animals. Milk production and dry matter intake were not significantly different between the 2 groups. Plasma concentrations of folates and vitamin B12 were increased in treated animals. Daily dry matter intake was not significantly different between the 2 groups before [13.5 kg; standard error (SE)=0.5] and after (23.6 kg; SE=0.9) calving. Average energy-corrected milk tended to be greater in vitamin-treated cows, 39.7 (SE=1.4) and 38.1 (SE=1.3) kg/d for treated and control cows, respectively. After calving, average plasma concentration of ?-hydroxybutyrate tended to be lower in cows injected with the vitamin supplement, 0.47 (SE=0.04) versus 0.55 (SE=0.03) for treated and control cows, respectively. The ovarian follicle ?12 mm in diameter was collected by ovum pick-up after estrus synchronization. Recovered follicular fluid volumes were greater in the vitamin-treated group. A microarray platform was used to investigate the effect of treatment on gene expression of granulosa cells. Lower expression of genes involved in the cell cycle and higher expression of genes associated with granulosa cell differentiation before ovulation were observed. Selected candidate genes were analyzed by reverse transcription quantitative PCR. Although the effects of intramuscular injections of folic acid and vitamin B12 on lactational performance and metabolic status of animals were limited, ingenuity pathway analysis of gene expression in granulosa cells suggests a stimulation of cell differentiation in vitamin-treated cows, which may be the result of an increase in LH secretion. PMID:26298749

  1. Benefits of Docosahexaenoic Acid, Folic Acid, Vitamin D and Iodine on Foetal and Infant Brain Development and Function Following Maternal Supplementation during Pregnancy and Lactation

    PubMed Central

    Morse, Nancy L.

    2012-01-01

    Scientific literature is increasingly reporting on dietary deficiencies in many populations of some nutrients critical for foetal and infant brain development and function. Purpose: To highlight the potential benefits of maternal supplementation with docosahexaenoic acid (DHA) and other important complimentary nutrients, including vitamin D, folic acid and iodine during pregnancy and/or breast feeding for foetal and/or infant brain development and/or function. Methods: English language systematic reviews, meta-analyses, randomised controlled trials, cohort studies, cross-sectional and case-control studies were obtained through searches on MEDLINE and the Cochrane Register of Controlled Trials from January 2000 through to February 2012 and reference lists of retrieved articles. Reports were selected if they included benefits and harms of maternal supplementation of DHA, vitamin D, folic acid or iodine supplementation during pregnancy and/or lactation. Results: Maternal DHA intake during pregnancy and/or lactation can prolong high risk pregnancies, increase birth weight, head circumference and birth length, and can enhance visual acuity, hand and eye co-ordination, attention, problem solving and information processing. Vitamin D helps maintain pregnancy and promotes normal skeletal and brain development. Folic acid is necessary for normal foetal spine, brain and skull development. Iodine is essential for thyroid hormone production necessary for normal brain and nervous system development during gestation that impacts childhood function. Conclusion: Maternal supplementation within recommended safe intakes in populations with dietary deficiencies may prevent many brain and central nervous system malfunctions and even enhance brain development and function in their offspring. PMID:22852064

  2. Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1.

    PubMed

    Chrencik, Jill E; Roth, Christopher B; Terakado, Masahiko; Kurata, Haruto; Omi, Rie; Kihara, Yasuyuki; Warshaviak, Dora; Nakade, Shinji; Asmar-Rovira, Guillermo; Mileni, Mauro; Mizuno, Hirotaka; Griffith, Mark T; Rodgers, Caroline; Han, Gye Won; Velasquez, Jeffrey; Chun, Jerold; Stevens, Raymond C; Hanson, Michael A

    2015-06-18

    Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with at least six cognate G protein-coupled receptors. Herein, we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analyses. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease. PMID:26091040

  3. Gene delivery to tumor cells by cationic polymeric nanovectors coupled to folic acid and the cell-penetrating peptide octaarginine.

    PubMed

    Jiang, Qi-Ying; Lai, Li-Hua; Shen, Jie; Wang, Qing-Qing; Xu, Fu-Jian; Tang, Gu-Ping

    2011-10-01

    Target ligand folic acid (FA) and cell-penetrating peptide octaarginine (R8) were coupled with the gene vectors (PEI(600)-CyD, PC) composed of ?-cyclodextrin (?-CyD) and low-molecular-weight polyethylenimine (PEI, Mw 600) to form nanovectors for highly efficient gene delivery to tumor cells. The resultant ternary nanocomplexes of FA-PC/R8-PC/pDNA produced excellent gene transfaction abilities in the folate receptor (FR)-positive tumor cells in vitro and in vivo. The FR-mediated endocytosis and the R8-mediated transmembrane functionality together contributed to the high transfection levels. This study provides a promising means to produce gene nanovectors for in vivo applications. PMID:21715001

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

    PubMed

    Smitasiri, Suttilak; Solon, Florentino S

    2005-12-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-02-01

    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.

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

    PubMed

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

    2015-03-01

    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

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

    PubMed Central

    2011-01-01

    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

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

    PubMed Central

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

    2015-01-01

    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

  9. Reduced folic acid, vitamin B12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: implications for altered one-carbon metabolism.

    PubMed

    Kale, Anvita; Naphade, Nilesh; Sapkale, Swati; Kamaraju, Marellasv; Pillai, Anilkumar; Joshi, Sadhana; Mahadik, Sahebarao

    2010-01-30

    Abnormal one-carbon metabolism has long been suggested as one of the mechanisms for neuropathology and psychopathology of schizophrenia. Variable levels of components of one-carbon metabolism (folic acid and vitamin B12) and consequent altered levels of homocysteine and phospholipid docosahexaenoic acid (DHA) have been independently reported, mostly in medicated patients. This study examined the simultaneous levels of these key components of one-carbon metabolism and its consequences in unique, medication-naïve first-episode psychotic patients (FEP, n=31) and healthy controls (HC, n=48) matched for confounds such as race, diet and lifestyle to reduce the variability. Significantly lower levels of folate and vitamin B12 in plasma and folate in red blood cells were observed in FEP compared to HC. These reductions paralleled the significant increase in plasma homocysteine and cortisol levels. Significantly reduced levels of membrane DHA were also observed in FEP compared to HC. This study, using a unique cohort, provided a broader mechanism (disturbed folic acid-vitamin B12-DHA balance) of altered one-carbon metabolism and one of its key consequential components, an increased homocysteine level that together with cortisol, can contribute to the neuropathology of psychosis. These data may have important implications for the amelioration of psychopathology in schizophrenia. PMID:19969375

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

    PubMed Central

    Tielsch, James M; Khatry, Subarna K; Stoltzfus, Rebecca J; Katz, Joanne; LeClerq, Steven C; Adhikari, Ramesh; Mullany, Luke C; Shresta, Shardaram; Black, Robert E

    2008-01-01

    Summary Introduction Iron deficiency is widespread in the developing world and is especially common in young children who live on the Indian subcontinent. Supplementation with iron and folic acid alleviates severe anaemia and enhances neurodevelopment in deficient populations, but little is known about the risks of mortality and morbidity associated with supplementation. Methods We did a community-based, cluster-randomised, double-masked, placebo-controlled, 2• 2 factorial trial in children aged 1?36 months and residing in southern Nepal. We randomly assigned children daily oral supplementation to age 36 months with: iron (12·5 mg) and folic acid (50 • g; n=8337), zinc alone (10 mg), iron, folic acid, and zinc (n=9230), or placebo (n=8683); children aged 1?11 months received half the dose. Our primary outcome measure was all-cause mortality, and our secondary outcome measures included cause-specific mortality and incidence and severity of diarrhoea, dysentery, and acute respiratory illness. Analyses were by intention to treat. This study is registered at clinicaltrials.gov, number NCT00109551. Findings The iron and folic acid-containing groups of the study were stopped early in November, 2003, on the recommendation of the data and safety monitoring board; mortality in these groups did not differ from placebo and there was low power to detect positive or negative effects by the time enrolment was completed. We continued to enrol children to the placebo and zinc alone groups. 25 490 children participated and analyses are based on 29 097·3 person-years of follow-up. There was no difference in mortality between the groups who took iron and folic acid without or with zinc when compared with placebo (HR 1·03, 95% CI 0·78?1·37, and 1·00, 0·74?1·34, respectively). There were no significant differences in the attack rates for diarrhoea, dysentery, or respiratory infections between groups, although all the relative risks except one indicated modest, non-significant protective effects. Interpretation Daily supplementation of young children in southern Nepal with iron and folic acid with or without zinc has no effect on their risk of death, but might protect against diarrhoea, dysentery, and acute respiratory illness. PMID:16413878

  11. Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor

    PubMed Central

    Incerti, Matteo; Tognolini, Massimiliano; Russo, Simonetta; Pala, Daniele; Giorgio, Carmine; Hassan-Mohamed, Iftiin; Noberini, Roberta; Pasquale, Elena B.; Vicini, Paola; Piersanti, Silvia; Rivara, Silvia; Barocelli, Elisabetta; Mor, Marco; Lodola, Alessio

    2013-01-01

    The Eph receptor–ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5?)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different ?-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The L-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low ?M concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small molecule antagonists of the EphA2 receptor. PMID:23489211

  12. Comparative Transcriptome Analysis Reveals the Influence of Abscisic Acid on the Metabolism of Pigments, Ascorbic Acid and Folic Acid during Strawberry Fruit Ripening

    PubMed Central

    Luo, Zisheng; Mou, Wangshu; Mao, Linchun; Ying, Tiejin

    2015-01-01

    A comprehensive investigation of abscisic acid (ABA) biosynthesis and its influence on other important phytochemicals is critical for understanding the versatile roles that ABA plays during strawberry fruit ripening. Using RNA-seq technology, we sampled strawberry fruit in response to ABA or nordihydroguaiaretic acid (NDGA; an ABA biosynthesis blocker) treatment during ripening and assessed the expression changes of genes involved in the metabolism of pigments, ascorbic acid (AsA) and folic acid in the receptacles. The transcriptome analysis identified a lot of genes differentially expressed in response to ABA or NDGA treatment. In particular, genes in the anthocyanin biosynthesis pathway were actively regulated by ABA, with the exception of the gene encoding cinnamate 4-hydroxylase. Chlorophyll degradation was accelerated by ABA mainly owing to the higher expression of gene encoding pheide a oxygenase. The decrease of ?-carotene content was accelerated by ABA treatment and delayed by NDGA. A high negative correlation rate was found between ABA and ?-carotene content, indicating the importance of the requirement for ABA synthesis during fruit ripening. In addition, evaluation on the folate biosynthetic pathway indicate that ABA might have minor function in this nutrient’s biosynthesis process, however, it might be involved in its homeostasis. Surprisingly, though AsA content accumulated during fruit ripening, expressions of genes involved in its biosynthesis in the receptacles were significantly lower in ABA-treated fruits. This transcriptome analysis expands our understanding of ABA’s role in phytochemical metabolism during strawberry fruit ripening and the regulatory mechanisms of ABA on these pathways were discussed. Our study provides a wealth of genetic information in the metabolism pathways and may be helpful for molecular manipulation in the future. PMID:26053069

  13. Carbon dots on based folic acid coated with PAMAM dendrimer as platform for Pt(IV) detection.

    PubMed

    Campos, Bruno B; Oliva, María Moreno; Contreras-Cáceres, Rafael; Rodriguez-Castellón, Enrique; Jiménez-Jiménez, José; da Silva, Joaquim C G Esteves; Algarra, Manuel

    2016-03-01

    Carbon quantum dots (CQDs) coated with poly(amidoamine) (PAMAM-NH2) dendrimer are prepared from folic acid and phosphoric acid under a hydrothermal procedure. The obtained nanoparticles are successfully used as fluorescent sensor for Pt(IV) (in the form of chloroplatinate ion). CQDs possess many attractive features including uniform dispersion with average size about 13nm for unmodified particles and, ?30nm when they are coated with PAMAM-NH2 dendrimer. The synthesized nanoparticles have been characterized by elemental analysis, attenuated total reflectance (ATR), X-ray photoelectron (XPS) and Raman spectroscopies, transmission electron microscopy (TEM), dynamic light scattering (DLS), and steady-state and life-time fluorescence. CQDs are used as fluorescent sensor of Pt(IV) ion in aqueous media showing linear quenching effect of their fluorescence. The results obtained demonstrated a limit of detection of 657nM with an accuracy of the method of 0.13% (as RSD, n=10) and sensitivity of 78nM. Moreover, with the presence of other interference species, good results are obtained when applied in real samples from platinum nanoparticles synthesis. The dissolved platinum ions can be quantified in the range 6-96?M with an accuracy of 2.5%. PMID:26674232

  14. Methyltetrahydrofolate vs Folic Acid Supplementation in Idiopathic Recurrent Miscarriage with Respect to Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphisms: A Randomized Controlled Trial

    PubMed Central

    Hekmatdoost, Azita; Vahid, Farhad; Yari, Zahra; Sadeghi, Mohammadreza; Eini-Zinab, Hassan; Lakpour, Niknam; Arefi, Soheila

    2015-01-01

    Purpose To determine whether 5-methylenetetrahydrofolate (MTHF) is more effective than folic acid supplementation in treatment of recurrent abortion in different MTHFR gene C677T and A1298C polymorphisms. Methods A randomized, double blind, placebo-controlled trial conducted April 2011-September 2014 in recurrent abortion clinics in Tehran, Iran. The participants were women with three or more idiopathic recurrent abortion, aged 20 to 45 years. Two hundred and twenty eligible women who consented to participate were randomly assigned to receive either folic acid or 5-MTHF according to the stratified blocked randomization by age and the number of previous abortions. Participants took daily 1 mg 5-methylentetrahydrofolate or 1 mg folic acid from at least 8 weeks before conception to the 20th week of the pregnancy. The primary outcome was ongoing pregnancy rate at 20th week of pregnancy, and the secondary outcomes were serum folate and homocysteine at the baseline, after 8 weeks, and at the gestational age of 4, 8, 12, and 20 weeks, MTHFR gene C677T and A1298C polymorphisms. Results There was no significant difference in abortion rate between two groups. Serum folate increased significantly in both groups over time; these changes were significantly higher in the group receiving 5-MTHF than the group receiving folic acid (value = 2.39, p<00.1) and the result was the same by considering the time (value = 1.24, p<0.01). Plasma tHcys decreased significantly in both groups over time; however these changes were not significantly different between the groups (value = 0.01, p = 0.47). Conclusion The results do not support any beneficial effect of 5-MTHF vs. folate supplementation in women with recurrent abortion with any MTHFR C677T and/or A1298C polymorphism. Trial Registration ClinicalTrials.gov NCT01976676 PMID:26630680

  15. Vitamin B12 and Folic Acid Improve Gross Motor and Problem-Solving Skills in Young North Indian Children: A Randomized Placebo-Controlled Trial

    PubMed Central

    Kvestad, Ingrid; Taneja, Sunita; Kumar, Tivendra; Hysing, Mari; Refsum, Helga; Yajnik, Chittaranjan S.; Bhandari, Nita; Strand, Tor A.

    2015-01-01

    Objectives Deficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children. Methods In a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention. Results Compared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 ?mol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes. Conclusion Our findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children. Trial Registration ClinicalTrials.gov NCT00717730 PMID:26098427

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

    2014-01-01

    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

  18. An special epithelial staining agents: folic acid receptor-mediated diagnosis (FRD) effectively and conveniently screen patients with cervical cancer

    PubMed Central

    Lu, Meng-Han; Hu, Ling-Yun; Du, Xin-Xin; Yang, Min; Zhang, Wei-Yi; Huang, Ke; Li, Li-An; Jiang, Shu-Fang; Li, Ya-Li

    2015-01-01

    High-quality screening with cytology has markedly reduced mortality from cervical cancer. However, it needs experienced pathologists to review and make the final decisions. We have developed folic acid receptor-mediated diagnosis (FRD) kits to effectively and conveniently screen patients with cervical cancer. We conduct present study aim to assess clinical significances of FRD in screening cervical cancer. A total of 169 patients were enrolled at Chinese People’s liberation Army (PLA) general hospital. We compared diagnostic significances of FRD with thinprep cytology test (TCT). Meanwhile, colposcopy was also performed to confirm any lesion suspicious for cervical cancer. The sensitivity and specificity of FRD were 71.93% and 66.07% in diagnosis cervical cancer, respectively. Meanwhile, the positive predictive values (PPV), negative predictive values (NPV), Youden index were 51.90%, 82.22%, 0.38, respectively. On the other hand, the sensitivity and specificity of TCT in diagnosis cervical cancer were 73.68% and 61.61% respectively. PPV, NPV and Youden index for TCT were 49.41%, 82.14% and 0.35 respectively. Overall, FRD have high values of sensitivity, specificity and Youden index. However, this difference failed to statistical significance. FRD have comparable diagnostic significance with TCT. Therefore, FRD might serve as one effective method to screen cervical cancer. Especially for those patients living in remote regions of China, where cytology was unavailable. PMID:26221336

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

    NASA Astrophysics Data System (ADS)

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

    2013-04-01

    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).

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

    SciTech Connect

    Wu Xiayu; Liang Ziqing; Zou Tianning; Wang Xu

    2009-02-13

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

  1. Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy

    PubMed Central

    Li, Tianyuzi; Gendelman, Howard E; Zhang, Gang; Puligujja, Pavan; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson; Liu, Xin-Ming; Boska, Michael D

    2015-01-01

    Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory’s development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery. PMID:26082630

  2. Folic acid-conjugated fluorescent polymer for up-regulation folate receptor expression study via targeted imaging of tumor cells.

    PubMed

    Qiao, Juan; Dong, Ping; Mu, Xiaoyu; Qi, Li; Xiao, Ran

    2016-04-15

    Thoroughly investigation of folate receptor (FR) expression related to targeting drug delivery in tumor cells has been intensively pursued in recent years. Herein, a simple and versatile strategy for determination of FR expression based on targeted imaging of tumor cells with fluorescent nano-conjugates was developed. The fluorescent nano-conjugates were composed of poly 2-vinyl-4,4-dimethyl azlactone (PVDMA) as the linker, folic acid as the targeting unit and amino-Rhodamine B as the fluorescent ligand. Owing to possessing dimethyl azlactone groups in polymer framework, PVDMA could easily reacted with amines or alcohols, and form water soluble materials. Fluorescent imaging studies indicated that the prepared nano-conjugates could specifically target tumor cells and monitor the over expressing of FR. Moreover, the FR expression up-regulation in HeLa cells through medicines regulation has been further explored. This new protocol opens an effective way through synthesis and design of novel fluorescent nano-conjugates for FR expression investigation in tumor cells via targeted imaging, showing great potential in drug delivery mechanism study and cancer therapy. PMID:26606305

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

    PubMed Central

    2014-01-01

    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

  4. Magnetic resonance imaging of folic acid-coated magnetite nanoparticles reflects tissue biodistribution of long-acting antiretroviral therapy.

    PubMed

    Li, Tianyuzi; Gendelman, Howard E; Zhang, Gang; Puligujja, Pavan; McMillan, JoEllyn M; Bronich, Tatiana K; Edagwa, Benson; Liu, Xin-Ming; Boska, Michael D

    2015-01-01

    Regimen adherence, systemic toxicities, and limited drug penetrance to viral reservoirs are obstacles limiting the effectiveness of antiretroviral therapy (ART). Our laboratory's development of the monocyte-macrophage-targeted long-acting nanoformulated ART (nanoART) carriage provides a novel opportunity to simplify drug-dosing regimens. Progress has nonetheless been slowed by cumbersome, but required, pharmacokinetic (PK), pharmacodynamics, and biodistribution testing. To this end, we developed a small magnetite ART (SMART) nanoparticle platform to assess antiretroviral drug tissue biodistribution and PK using magnetic resonance imaging (MRI) scans. Herein, we have taken this technique a significant step further by determining nanoART PK with folic acid (FA) decorated magnetite (ultrasmall superparamagnetic iron oxide [USPIO]) particles and by using SMART particles. FA nanoparticles enhanced the entry and particle retention to the reticuloendothelial system over nondecorated polymers after systemic administration into mice. These data were seen by MRI testing and validated by comparison with SMART particles and direct evaluation of tissue drug levels after nanoART. The development of alendronate (ALN)-coated magnetite thus serves as a rapid initial screen for the ability of targeting ligands to enhance nanoparticle-antiretroviral drug biodistribution, underscoring the value of decorated magnetite particles as a theranostic tool for improved drug delivery. PMID:26082630

  5. Folic acid conjugated magnetic iron oxide nanoparticles for nondestructive separation and detection of ovarian cancer cells from whole blood.

    PubMed

    Liu, Wenting; Nie, Liju; Li, Fulai; Aguilar, Zoraida P; Xu, Hong; Xiong, Yonghua; Fu, Fen; Xu, Hengyi

    2015-12-15

    Because of the lack of early screening strategies, ovarian cancer is the most deadly cause of gynecologic malignancies. This paper describes an effective method for the separation and detection of ovarian cancer cells from female whole blood, using folic acid (FA) conjugated magnetic iron oxide nanoparticles (IO-FA nanoparticles). The IO nanoparticles were synthesized by thermal decomposition and then covalently conjugated with FA. The IO-FA nanoparticles were stably attached to the surface of ovarian cancer cells by coupling to the over-expressed folate receptor (FR), thereby making the cells magnetic. These "magnetic cells" were separated from the complex blood matrix without destruction under a magnetic field. The separation efficiency was as high as 61.3% when the abundance of spiked ovarian cancer SKOV3 cells was as low as 5 × 10(-5)%. We also successfully detected five (5) out of ten (10) metastatic ovarian cancer patients' whole blood. This study suggested the feasibility of early detecting of metastatic ovarian cancer cells, which may potentially improve the ovarian cancers patients' overall survival rate for clinical applications. PMID:26478922

  6. The Phosphorylation State of GSK3? Serine 9 Correlated to the Development of Valproic Acid-Associated Fetal Cardiac Teratogenicity, Fetal VPA Syndrome, Rescued by Folic Acid Administration.

    PubMed

    Yu, Wei-Hsuan; Ho, Yi-Lwun; Huang, Po-Tsang; Chu, Shian-Ling; Tsai, Huai-Jen; Liou, Horng-Huei

    2016-01-01

    The effects of the phosphorylation state of the glycogen synthase kinase 3? involved in the cardiac myocytes (jelly-like cells) epithelial-mesenchymal transition-associated migration during heart-valve formation were examined through the valproic acid-induced cardiac teratogenicity of transgenic line A34 of Tg in a the Brachydanio rerio embryo model. Valproic acid is an effective anti-epileptic drug; however, when taken by pregnant women to treat epilepsy, it can produce cardiac developmental defects in fetuses. In this study, the role of glycogen synthase kinase 3? in valproic acid-induced cardiac teratogenicity was investigated. Transgenic line A34 of zebrafish embryos was used at 3 days postfertilization. The results show that 78 % (18/23) of the embryos treated with 0.10 mM valproic acid (group A) had incomplete chamber formation with normal looping and 22 % (5/23) had abnormal looping. Bradycardia was also found in comparison with control embryos (P < 0.001). For the embryos treated with 0.25 mM valproic acid (group B), 92 % (22/24) demonstrated chamber formation failure and looping abnormality. Pericardial effusion, noncontracting ventricles, and enlarged, slowly beating atriums were observed at 6 days postfertilization. Valproic acid inhibited phosphorylation of serine 9 in glycogen synthase kinase 3? in a dose-dependent manner. According to immunochemical staining results, valproic acid was shown to inhibit the mass migration and proliferation of cardiomyocytes in the development of the heart-valve region through inhibition of the GSK3? Ser 9 phosphorylation. Folic acid rescued the GSK3? Ser 9 phosphorylation and reversed the valproic acid-induced cardiac morphological, functional, and biochemical defects. PMID:25724324

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

    PubMed Central

    2011-01-01

    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

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

    PubMed

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

    2014-10-20

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

  9. Use of high doses of folic acid supplements in pregnant women in Spain: an INMA cohort study

    PubMed Central

    Navarrete-Muñoz, Eva María; Valera-Gran, Desirée; García de la Hera, Manoli; Gimenez-Monzo, Daniel; Morales, Eva; Julvez, Jordi; Riaño, Isolina; Tardón, Adonina; Ibarluzea, Jesus; Santa-Marina, Loreto; Murcia, Mario; Rebagliato, Marisa; Vioque, Jesus

    2015-01-01

    Objectives We examined the use of low (<400??g/day, including no use) and high folic acid supplement (FAS) dosages (?1000??g/day) among pregnant women in Spain, and explored factors associated with the use of these non-recommended dosages. Design Population-based cohort study. Setting Spain. Participants We analysed data from 2332 pregnant women of the INMA study, a prospective mother-child cohort study in Spain. Main outcome measures We assessed usual dietary folate and the use of FAS from preconception to the 3rd month (first period) and from the 4th to the 7th month (second period), using a validated food frequency questionnaire. We used multinomial logistic regression to estimate relative risk ratios (RRRs). Results Over a half of the women used low dosages of FAS in the first and second period while 29% and 17% took high dosages of FAS, respectively. In the first period, tobacco smoking (RRR=1.63), alcohol intake (RRR=1.40), multiparous (RRR=1.44), unplanned pregnancy (RRR=4.20) and previous spontaneous abortion (RRR=0.58, lower use of high FAS dosages among those with previous abortions) were significantly associated with low FAS dosages. Alcohol consumption (RRR=1.42), unplanned pregnancy (RRR=2.66) and previous spontaneous abortion (RRR=0.68) were associated with high dosage use. In the second period, only tobacco smoking was significantly associated with high FAS dosage use (RRR=0.67). Conclusions A high proportion of pregnant women did not reach the recommended dosages of FAS in periconception and a considerable proportion also used FAS dosages ?1000??g/day. Action should be planned by the Health Care System and health professionals to improve the appropriate periconceptional use of FAS, taking into consideration the associated factors. PMID:26603248

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

    PubMed

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

    2013-11-01

    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

  11. Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase

    PubMed Central

    Chalupsky, Karel; Kra?un, Damir; Kanchev, Ivan; Bertram, Katharina

    2015-01-01

    Abstract Aims: Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions. Results: In human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH. Innovation: FA-induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH. Conclusion: FA might serve as a novel therapeutic option combating PH. Antioxid. Redox Signal. 23, 1076–1091. PMID:26414244

  12. Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding

    PubMed Central

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

    2009-01-01

    Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. Methods: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007. Results: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. Recommendations: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations. PMID:19398680

  13. High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.

    PubMed

    Aarabi, Mahmoud; San Gabriel, Maria C; Chan, Donovan; Behan, Nathalie A; Caron, Maxime; Pastinen, Tomi; Bourque, Guillaume; MacFarlane, Amanda J; Zini, Armand; Trasler, Jacquetta

    2015-11-15

    Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR. PMID:26307085

  14. Elimination of Iron Deficiency Anemia and Soil Transmitted Helminth Infection: Evidence from a Fifty-four Month Iron-Folic Acid and De-worming Program

    PubMed Central

    Casey, Gerard J.; Montresor, Antonio; Cavalli-Sforza, Luca T.; Thu, Hoang; Phu, Luong B.; Tinh, Ta T.; Tien, Nong T.; Phuc, Tran Q.; Biggs, Beverley-Ann

    2013-01-01

    Background Intermittent iron-folic acid supplementation and regular de-worming are effective initiatives to reduce anemia, iron deficiency, iron deficiency anemia, and soil transmitted helminth infections in women of reproductive age. However, few studies have assessed the long-term effectiveness of population-based interventions delivered in resource-constrained settings. Methodology/Principal Findings The objectives were to evaluate the impact of weekly iron-folic acid supplementation and de-worming on mean hemoglobin and the prevalence of anaemia, iron deficiency, and soil transmitted helminth infection in a rural population of women in northern Vietnam and to identify predictive factors for hematological outcomes. A prospective cohort design was used to evaluate a population-based supplementation and deworming program over 54 months. The 389 participants were enrolled just prior to commencement of the intervention. After 54 months 76% (95% CI [68%, 84%]) were taking the iron-folic acid supplement and 95% (95% CI [93%, 98%]) had taken the most recently distributed deworming treatment. Mean hemoglobin rose from 122 g/L (95% CI [120, 124]) to 131 g/L (95% CI [128, 134]) and anemia prevalence fell from 38% (95% CI [31%, 45%]) to 18% (95% CI [12%, 23%]); however, results differed significantly between ethnic groups. Iron deficiency fell from 23% (95% CI [17%, 29%]) to 8% (95% CI [4%, 12%]), while the prevalence of iron deficiency anemia was reduced to 4% (95% CI [1%, 7%]). The prevalence of hookworm infection was reduced from 76% (95% CI [68%, 83%]) to 11% (95% CI [5%, 18%]). The level of moderate or heavy infestation of any soil-transmitted helminth was reduced to less than 1%. Conclusions/Significance Population-based interventions can efficiently and effectively reduce anemia and practically eliminate iron deficiency anemia and moderate to heavy soil transmitted helminth infections, maintaining them below the level of public health concern. PMID:23593517

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

    NASA Astrophysics Data System (ADS)

    Liu, Lili; Zhang, Xianwen; Chaudhuri, Jharna

    2014-09-01

    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.

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

    PubMed

    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

    2013-01-01

    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

  17. Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, ?-Cyclodextrin-Based Drug Complexes for Cancer Treatment

    PubMed Central

    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

    2013-01-01

    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 Ka 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

  18. Role of Hyperhomocysteinemia in the Regulation of Oxidative Stress and Inflammatory Responses in the Kidney: Protective Effect of Folic Acid Supplementation

    NASA Astrophysics Data System (ADS)

    Hwang, Sun-Young

    Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) level, is an independent risk factor for cardiovascular disease. Folic acid supplementation can effectively reduce blood Hcy levels. Recent studies have demonstrated that hyperhomocysteinemia is also associated with kidney disease. However, the underlying mechanisms remain unclear. The overall objective of the study was to investigate the biochemical and molecular mechanisms of Hcy-induced kidney injury and the effect of folic acid supplementation on Hcy-induced kidney injury. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 12 weeks. An elevation of serum total Hcy level was observed in hyperhomocysteinemic rats. Hyperhomocysteinemia-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation resulted in oxidative stress in the kidney. Reduction of oxidative stress by inhibiting superoxide anion production effectively ameliorated hyperhomocysteinemia-induced kidney injury. Inflammatory responses such as increased chemokine expression have been implicated as one of the mechanisms of kidney disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in kidney disease. Nuclear factor-kappa B (NF-kappaB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism responsible for such an effect in rat kidneys as well as in human kidney proximal tubular cells.

  19. Maternal Folic Acid Supplementation and the Risk of Congenital Heart Defects in Offspring: A Meta-Analysis of Epidemiological Observational Studies

    NASA Astrophysics Data System (ADS)

    Feng, Yu; Wang, Song; Chen, Runsen; Tong, Xing; Wu, Zeyu; Mo, Xuming

    2015-02-01

    Epidemiological studies have reported conflicting results regarding the association between maternal folic acid supplementation and the risk of congenital heart defects (CHDs). However, a meta-analysis of the association between maternal folic acid supplementation and CHDs in offspring has not been conducted. We searched the MEDLINE and EMBASE databases for articles cataloged between their inceptions and October 10, 2014 and identified relevant published studies that assessed the association between maternal folate supplementation and the risk of CHDs. Study-specific relative risk estimates were pooled using random-effects or fixed-effects models. Out of the 1,606 articles found in our initial literature searches, a total of 1 randomized controlled trial, 1 cohort study, and 16 case-control studies were included in our final meta-analysis. The overall results of this meta-analysis provide evidence that maternal folate supplementation is associated with a significantly decreased risk of CHDs (RR = 0.72, 95% CI: 0.63-0.82). Statistically significant heterogeneity was detected (Q = 82.48, P < 0.001, I2 = 79.4%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among the studies, and a Galbraith plot was generated to graphically assess the sources of heterogeneity. This meta-analysis provides a robust estimate of the positive association between maternal folate supplementation and a decreased risk of CHDs.

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

    PubMed Central

    2011-01-01

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

  1. Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 2.

    PubMed

    Grimstrup, Marie; Rist, Øystein; Receveur, Jean-Marie; Frimurer, Thomas M; Ulven, Trond; Mathiesen, Jesper M; Kostenis, Evi; Högberg, Thomas

    2010-02-01

    Structure-activity relationships have been established by exploring the eastern and western side of 5-thiazolyleacetic acids as CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonists. Benzhydryl motifs in the 2-position of the thiazole was found to be most advantageous. The 4-thiazole position should either carry 3- or 4-fluorophenyl rings or a 4-pyridyl suitably substituted in the flanking 2-position. Several compounds with single digit nanomolar binding affinity and full antagonistic efficacy for human CRTH2 receptor were obtained. The compound series display a good PK profile and selectivity over a large number of other targets. PMID:20022749

  2. The hepatic Igf2/H19 locus is not altered in 1-day old pups born to obese-prone Sprague-Dawley rats fed a low protein diet containing adequate folic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Gong et al. (Epigenetics, 2010) found, using diets low in folic acid, that compared to an 18% protein diet a 9% protein diet fed to pregnant Sprague-Dawley rats resulted in increased Igf2 and H19 gene expression in the liver of day 0 male offspring. In addition DNA methylation in the Imprinting Cont...

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

    PubMed Central

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

    2013-01-01

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

  4. Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome. Role of folic acid metabolism enzyme gene polymorphisms in Marfan syndrome.

    PubMed

    Benke, Kálmán; Ágg, Bence; Mátyás, Gábor; Szokolai, Viola; Harsányi, Gergely; Szilveszter, Bálint; Odler, Balázs; Pólos, Miklós; Maurovich-Horvat, Pál; Radovits, Tamás; Merkely, Béla; Nagy, Zsolt B; Szabolcs, Zoltán

    2015-10-01

    Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p<0.0001, p<0.0001, p=0.001 and p=0.003, respectively). Folate was lower in Group C2 than in Groups A, B, C1 and control subjects (p<0.0001, p=0.02, p<0.0001 and p<0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95% confidence interval [CI] 1.28-2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95%CI 1.30-4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta. PMID:26063524

  5. Fabrication and spectroscopic studies of folic acid-conjugated Fe3O4@Au core-shell for targeted drug delivery application.

    PubMed

    Karamipour, Sh; Sadjadi, M S; Farhadyar, N

    2015-09-01

    Gold coated magnetite core shell is a kind of nanoparticle that include magnetic iron oxide core with a thin layer nanogold. Fe3O4-gold core-shell nanostructure can be used in biomedical applications such as magnetic bioseparation, bioimaging, targeting drug delivery and cancer treatment. In this study, the synthesis and characterization of gold coated magnetite nanoparticles were discussed. Magnetite nanoparticles with an average size of 6 nm in diameter were synthesized by the chemical co-precipitation method and gold-coated Fe3O4 core-shell nanostructures were produced with an average size of 11.5 nm in diameter by reduction of Au(3+) with citrate ion in the presence of Fe3O4. Folate-conjugated gold coated magnetite nanoparticles were synthesized to targeting folate receptor that is overexpressed on the surface of cancerous cells. For this purpose, we used l-cysteine, as a bi-functional linker for attachment to gold surface and it was linked to the gold nanoparticles surface through its thiol group. Then, we conjugated amino-terminated nanoparticles to folic acid with an amide-linkage formation. These gold magnetic nanoparticles were characterized by various techniques such as X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrometer (FT-IR), UV-visible spectroscopy, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), dispersive analysis of X-ray (EDAX) and vibrating sample magnetometer (VSM) analysis. The magnetic and optical properties of Fe3O4 nanostructure were changed by gold coating and attachment of l-cysteine and folic acid to Fe3O4@Au nanoparticles. PMID:25879984

  6. Fabrication and spectroscopic studies of folic acid-conjugated Fe3O4@Au core-shell for targeted drug delivery application

    NASA Astrophysics Data System (ADS)

    Karamipour, Sh.; Sadjadi, M. S.; Farhadyar, N.

    2015-09-01

    Gold coated magnetite core shell is a kind of nanoparticle that include magnetic iron oxide core with a thin layer nanogold. Fe3O4-gold core-shell nanostructure can be used in biomedical applications such as magnetic bioseparation, bioimaging, targeting drug delivery and cancer treatment. In this study, the synthesis and characterization of gold coated magnetite nanoparticles were discussed. Magnetite nanoparticles with an average size of 6 nm in diameter were synthesized by the chemical co-precipitation method and gold-coated Fe3O4 core-shell nanostructures were produced with an average size of 11.5 nm in diameter by reduction of Au3+ with citrate ion in the presence of Fe3O4. Folate-conjugated gold coated magnetite nanoparticles were synthesized to targeting folate receptor that is overexpressed on the surface of cancerous cells. For this purpose, we used L-cysteine, as a bi-functional linker for attachment to gold surface and it was linked to the gold nanoparticles surface through its thiol group. Then, we conjugated amino-terminated nanoparticles to folic acid with an amide-linkage formation. These gold magnetic nanoparticles were characterized by various techniques such as X-ray powder diffraction (XRD) analysis, Fourier transform infrared spectrometer (FT-IR), UV-visible spectroscopy, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), dispersive analysis of X-ray (EDAX) and vibrating sample magnetometer (VSM) analysis. The magnetic and optical properties of Fe3O4 nanostructure were changed by gold coating and attachment of L-cysteine and folic acid to Fe3O4@Au nanoparticles.

  7. Antagonistic effects of ?-tocopherol and ursolic acid on model bacterial membranes.

    PubMed

    Broniatowski, Marcin; Flasi?ski, Micha?; H?c-Wydro, Katarzyna

    2015-10-01

    ?-tocopherol (Toc), the most active component of vitamin E can exert antagonistic effects disabling the therapy of cancers and bacterial infections. Such antagonisms were observed also between Toc and bioactive pentacyclic triterpenes (PT) exhibiting anticancer and antibacterial properties. Both Toc and PT are water-insoluble membrane active substances. Thus, our idea was to emulate their interactions with model Escherichia coli membranes. E. coli inner membranes were selected for the experiments because their lipid composition is quite simple and well characterized and the two main components are phosphatidylethanolamine and phosphatidylglycerol. As a model of E. coli membranes we applied Langmuir monolayers formed by the E. coli total extract of polar lipids (Etotal) as well as by the main lipid components: phosphatidylethanolamine (POPE) and phosphatidylglycerol (ECPG). The antagonistic effects of ursolic acid (Urs) and Toc were investigated with the application of ternary Langmuir monolayers formed by Urs, Toc and one of the phospholipids POPE or ECPG. Our studies indicated that the affinities of Urs and Toc towards the POPE molecule are comparable; whereas there are profound differences in the interactions of Urs and Toc with ECPG. Thus, the model experiments prove that in the case of E. coli membrane, the differences in the interactions between Urs and Toc with the anionic bacterial phosphatidylglycerol can be the key factor responsible for the antagonistic effects observed between PT and Toc in vivo. PMID:26003534

  8. N-Methyl-d-aspartate Receptor Antagonists Have Variable Affect in 3-Nitropropionic Acid Toxicity

    PubMed Central

    Carbery, Timothy; Geddes, James W.

    2013-01-01

    There is accumulating evidence that excitotoxicity and oxidative stress resulting from excessive activation of glutamate (N-methyl-d-aspartate) NMDA receptors are major participants in striatal degeneration associated with 3-nitropropionic acid (3NP) administration. Although excitotoxic and oxidative mechanisms are implicated in 3NP toxicity, there are conflicting reports as to whether NMDA receptor antagonists attenuate or exacerbate the 3NP-induced neurodegeneration. In the present study, we investigated the involvement of NMDA receptors in striatal degeneration, protein oxidation and motor impairment following systemic 3NP administration. We examined whether NMDA receptor antagonists, memantine and ifenprodil, influence the neurotoxicity of 3NP. The development of striatal lesion and protein oxidation following 3NP administration is delayed by memantine but not affected by ifenprodil. However, in behavioral experiments, memantine failed to improve and ifenprodil exacerbated the motor deficits associated with 3NP toxicity. Together, these findings suggest caution in the application of NMDA receptor antagonists as a neuroprotective agent in neurodegenerative disorders associated with metabolic impairment. PMID:18688711

  9. Transcriptomic insights into antagonistic effects of gibberellin and abscisic acid on petal growth in Gerbera hybrida

    PubMed Central

    Li, Lingfei; Zhang, Wenbin; Zhang, Lili; Li, Na; Peng, Jianzong; Wang, Yaqin; Zhong, Chunmei; Yang, Yuping; Sun, Shulan; Liang, Shan; Wang, Xiaojing

    2015-01-01

    Petal growth is central to floral morphogenesis, but the underlying genetic basis of petal growth regulation is yet to be elucidated. In this study, we found that the basal region of the ray floret petals of Gerbera hybrida was the most sensitive to treatment with the phytohormones gibberellin (GA) and abscisic acid (ABA), which regulate cell expansion during petal growth in an antagonistic manner. To screen for differentially expressed genes (DEGs) and key regulators with potentially important roles in petal growth regulation by GA or/and ABA, the RNA-seq technique was employed. Differences in global transcription in petals were observed in response to GA and ABA and target genes antagonistically regulated by the two hormones were identified. Moreover, we also identified the pathways associated with the regulation of petal growth after application of either GA or ABA. Genes relating to the antagonistic GA and ABA regulation of petal growth showed distinct patterns, with genes encoding transcription factors (TFs) being active during the early stage (2 h) of treatment, while genes from the “apoptosis” and “cell wall organization” categories were expressed at later stages (12 h). In summary, we present the first study of global expression patterns of hormone-regulated transcripts in G. hybrida petals; this dataset will be instrumental in revealing the genetic networks that govern petal morphogenesis and provides a new theoretical basis and novel gene resources for ornamental plant breeding. PMID:25852718

  10. Computational and functional analysis of the androgen receptor antagonist atraric acid and its derivatives.

    PubMed

    Papaioannou, Maria; Söderholm, Annu A; Hong, Wei; Dai, Yifan; Roediger, Julia; Roell, Daniela; Thiele, Marie; Nyrönen, Tommi H; Baniahmad, Aria

    2013-06-01

    Androgen receptor (AR) antagonists are important compounds for the treatment of prostate cancer (PCa). The atraric acid (AA), a natural compound, binds to the AR and acts as a specific AR antagonist. Interestingly, AA represents a novel chemical platform that could serve as a potential basis for new AR antagonists. Therefore, one objective of this study was to analyze the chemical/structural requirements for AR antagonism and to obtain predictions of where and how AA binds to the AR. Further, this study describes the chemical synthesis of 12 AA derivatives and their analysis using a combination of computational and functional assays. Functional analysis of AA derivatives indicated that none activated the AR. Both the para-hydroxyl group and the benzene ortho- and the meta-methyl groups of AA appeared to be essential to antagonize androgen-activated AR activity. Furthermore, extension of the hydrophobic side chain of AA led to slightly stronger AR antagonism. In silico data suggest that modifications to the basic AA structure change the hydrogen-bonding network with the AR ligand binding domain (LBD), so that the para-hydroxyl group of AA forms a hydrogen bond with the LBD, confirming the functional importance of this group for AR antagonism. Moreover, in silico modeling also suggested that the ortho- and meta- methyl groups of AA interact with hydrophobic residues of the ligand pocket of AR, which might explain their functional importance for antagonism. Thus, these studies identify the chemical groups of AA that play key roles in allowing the AA-based chemical platform to act as an AR antagonist. PMID:23194423

  11. Effects of pyrimidine antagonists on sialic acid regeneration in HL-60 cells.

    PubMed

    Hindenburg, A A; Taub, R N; Grant, S; Chang, G; Baker, M A

    1985-07-01

    Because alterations in cell membrane sialoglycoconjugates can affect the behavior of neoplastic cells, we investigated the effects of in vitro treatment with antimetabolites used in cancer therapy on the expression of membrane sialic acid in cultured HL-60 leukemic cells. In these studies, cells were incubated with Vibrio cholerae neuraminidase to remove surface sialic acid. Reappearance of membrane sialic acid during drug treatment was followed (a) by measuring changes in radioactive surface labeling of viable cells with sodium metaperiodate-sodium[3H]-borohydride, (b) by measuring the decline in accessible surface galactosyl receptor sites which occurred coincident with membrane sialic acid replacement, and (c) by measuring the incorporation of [3H]glucosamine into membrane-associated neuraminidase-labile sialic acid. We were especially interested in learning whether drugs that affect intracellular pools of cytidine triphosphate (CTP), an important nucleotide intermediate in sialylation reactions, could inhibit regeneration of membrane sialic acid. 3-Deazauridine, a competitive inhibitor of CTP synthetase, depleted CTP pools and curtailed surface membrane resialylation with little or no effect on synthesis of de novo sialic acid from precursor sugars. The addition of cytidine restored CTP pools and sialic acid regeneration. Acivicin, a glutamine antagonist, also depleted CTP pools and curtailed surface membrane resialylation. In addition, it retarded de novo synthesis of sialic acid. The addition of cytidine restored intracellular CTP pools and sialic acid regeneration. However, both cytidine and guanosine were required to restore sialic acid synthesis from precursor sugars. 1-beta-D-Arabinofuranosylcytosine, a competitive inhibitor of sialic acid synthetase and of sialyltransferase, inhibited both de novo sialic acid synthesis and membrane resialylation. Only the latter effect was reversed by the addition of exogenous cytidine. Hydroxyurea, an agent shown previously to inhibit glycoconjugate production in hamster fibroblasts, curtailed membrane resialylation and de novo synthesis of sialic acid without depleting CTP pools. Doxorubicin, at levels that caused marked arrest of cell proliferation, had no effect on sialic acid synthesis or expression on the membrane surface. These data suggest that antimetabolites, apart from their cytotoxic effects or effects on cellular growth, may directly inhibit the expression of membrane sialic acid.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3859365

  12. Adequately Diversified Dietary Intake and Iron and Folic Acid Supplementation during Pregnancy Is Associated with Reduced Occurrence of Symptoms Suggestive of Pre-Eclampsia or Eclampsia in Indian Women

    PubMed Central

    Agrawal, Sutapa; Fledderjohann, Jasmine; Vellakkal, Sukumar; Stuckler, David

    2015-01-01

    Background/Objective Pre-eclampsia or Eclampsia (PE or E) accounts for 25% of cases of maternal mortality worldwide. There is some evidence of a link to dietary factors, but few studies have explored this association in developing countries, where the majority of the burden falls. We examined the association between adequately diversified dietary intake, iron and folic acid supplementation during pregnancy and symptoms suggestive of PE or E in Indian women. Methods Cross-sectional data from India’s third National Family Health Survey (NFHS-3, 2005-06) was used for this study. Self-reported symptoms suggestive of PE or E during pregnancy were obtained from 39,657 women aged 15-49 years who had had a live birth in the five years preceding the survey. Multivariable logistic regression analysis was used to estimate the association between adequately diversified dietary intake, iron and folic acid supplementation during pregnancy and symptoms suggestive of PE or E after adjusting for maternal, health and lifestyle factors, and socio-demographic characteristics of the mother. Results In their most recent pregnancy, 1.2% (n=456) of the study sample experienced symptoms suggestive of PE or E. Mothers who consumed an adequately diversified diet were 34% less likely (OR: 0.66; 95% CI: 0.51-0.87) to report PE or E symptoms than mothers with inadequately diversified dietary intake. The likelihood of reporting PE or E symptoms was also 36% lower (OR: 0.64; 95% CI: 0.47-0.88) among those mothers who consumed iron and folic acid supplementation for at least 90 days during their last pregnancy. As a sensitivity analysis, we stratified our models sequentially by education, wealth, antenatal care visits, birth interval, and parity. Our results remained largely unchanged: both adequately diversified dietary intake and iron and folic acid supplementation during pregnancy were associated with a reduced occurrence of PE or E symptoms. Conclusion Having a adequately diversified dietary intake and iron and folic acid supplementation in pregnancy was associated with a reduced occurrence of symptoms suggestive of PE or E in Indian women. PMID:25785774

  13. A folic acid labelled carbon quantum dot-protoporphryin IX conjugate for use in folate receptor targeted two-photon excited photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Nicholas, Dean; Fowley, Colin; McHale, Anthony P.; Kamila, Sukanta; Sheng, Jason; Atchison, Jordan; Callan, John F.

    2015-03-01

    Folic acid (FA) has been used as a molecular targeting strategy to improve the specificity of a CQD-protoporphyrin IX (CQD-PPIX) conjugate to folate receptor positive (FR+) HeLa cells for use in two-photon excited Photodynamic Therapy (TPE-PDT). FA was covalently attached to the CQD-PPIX conjugate to form a FA-CQD-PPIX conjugate. The uptake of the FA-CQD-PPIX conjugate in FR+ HeLa cells was shown to be 7 times greater than the CQD-PPIX conjugate, while both conjugates showed a similar uptake in FR negative (FR-) HT-47 cells. TPE-PDT experiments, using HeLa cells as a target, revealed a 30% improved cytotoxicity for cells treated with the FA-CQD-PPIX conjugate and TPE compared to controls treated with the CQD-PPIX conjugate and TPE. Collectively, these results suggest the presence of FA can facilitate targeting of CQD-sensitiser conjugates to FR+ cells resulting in an improved PDT effect.

  14. Microarray Analysis Reveals Higher Gestational Folic Acid Alters Expression of Genes in the Cerebellum of Mice Offspring—A Pilot Study

    PubMed Central

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

    2015-01-01

    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

  15. Folic acid-conjugated, SERS-labeled silver nanotriangles for multimodal detection and targeted photothermal treatment on human ovarian cancer cells.

    PubMed

    Boca-Farcau, Sanda; Potara, Monica; Simon, Timea; Juhem, Aurelie; Baldeck, Patrice; Astilean, Simion

    2014-02-01

    The effectiveness of a therapeutic agent for cancer stands in its ability to reduce and eliminate tumors without harming the healthy tissue nearby. Nanoparticles peripherally conjugated with targeting moieties offer major improvements in therapeutics through site specificity. In this study we demonstrate this approach by targeting the folate receptor of NIH:OVCAR-3 human ovary cancer cell line. Herein we used silver nanotriangles which were biocompatibilized with chitosan (bio)polymer, labeled with para-aminothiophenol (pATP) Raman reporter molecule, and conjugated with folic acid. The nanoparticles conjugation and efficient labeling was investigated by localized surface plasmon resonance (LSPR), zeta potential, and surface-enhanced Raman scattering (SERS) measurements. Conjugated particles were proven to be highly stable in aqueous and cellular medium. The targeted uptake of conjugated nanoparticles by human ovary cancer cells was confirmed by dark field microscopy and scattering spectra of the particles inside cells. Comparative studies revealed specific internalization of the conjugated nanoparticles in comparison with similar bare nanoparticles. Moreover, the SERS identity of the particles was proven to be highly conserved inside cells. Targeted cancer cell treatment conducted by irradiating the nanoparticle-treated cells with a continuous wave-nearinfrared (cw-NIR) laser in resonance with their plasmonic band proved an efficient therapeutic response. By integrating the advantages of multimodal optical imaging and SERS detection with hyperthermia capabilities through site specificity, these nanoparticles can represent a real candidate for personalized medicine. PMID:24304361

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

    PubMed Central

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

    2011-01-01

    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

  17. 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

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

    2009-01-01

    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

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

    SciTech Connect

    Bhandari, Deepak; Kertesz, Vilmos; Van Berkel, Gary J

    2013-01-01

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

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

    PubMed Central

    JACOBSON, KENNETH A.; KIRK, KENNETH L.; PADGETT, WILLIAM L.; DALY, JOHN W.

    2012-01-01

    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

  20. Ibotenic acid analogues. Synthesis, molecular flexibility, and in vitro activity of agonists and antagonists at central glutamic acid receptors.

    PubMed

    Lauridsen, J; Honoré, T; Krogsgaard-Larsen, P

    1985-05-01

    The syntheses of (RS)-alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionic acid (9, ATPA), (alpha-RS, beta-RS)-alpha-amino-beta-methyl-3-hydroxy-5-isoxazolepropionic acid (8), (RS)-alpha-amino-3-hydroxy-5-isoxazolebutyric acid (15a), and (RS)-alpha-amino-3-hydroxy-5-isoxazolevaleric acid (15b) are described. The compounds were tested in vitro together with (RS)-alpha-amino-3-hydroxy-5-(bromomethyl)-4-isoxazolepropionic acid (ABPA) as inhibitors of the binding of radioactive-labeled (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to rat brain synaptic membranes. These data were compared with the earlier reported effects of the compounds on single neurons in the feline spinal cord obtained by microelectrophoretic techniques. The three compounds AMPA, ATPA, and ABPA are agonists at the class of receptors assumed to represent a subtype of physiological (S)-glutamic acid (Glu) receptors. Inhibition of [3H]AMPA binding by ATPA was 1 order of magnitude weaker than that of AMPA, in agreement with the relative potency of these compounds in vivo. ABPA proved to be equipotent with AMPA both as an inhibitor of AMPA binding and as a neuronal excitant. The compounds 8, 15a, and 15b have no effect as inhibitors of AMPA binding, in agreement with in vivo studies that have shown that 8 does not affect the firing of central neurons whereas 15a and 15b are antagonists at NMDA receptors, a subpopulation of excitatory receptors not affected by AMPA. Molecular mechanical calculations on AMPA, ATPA, and ABPA using the program MM2 showed that conformations of AMPA, ABPA, and especially ATPA by rotation of the amino acid side chain have energy barriers. A possible receptor-active conformation is suggested. PMID:2859375

  1. In vivo targeted magnetic resonance imaging and visualized photodynamic therapy in deep-tissue cancers using folic acid-functionalized superparamagnetic-upconversion nanocomposites

    NASA Astrophysics Data System (ADS)

    Zeng, Leyong; Luo, Lijia; Pan, Yuanwei; Luo, Song; Lu, Guangming; Wu, Aiguo

    2015-05-01

    Multifunctional nanoprobes used in magnetic resonance imaging (MRI) and photodynamic therapy (PDT) also have potential applications in diagnosis and visualized therapy of cancers, and hence it is important to investigate the active-targeting ability and in vivo reliability of these nanoprobes. In this work, folic acid (FA)-targeted, photosensitizer (PS)-loaded Fe3O4@NaYF4:Yb/Er (FA-NPs-PS) nanocomposites were synthesized for in vivo T2-weighted MRI and visualized PDT of cancers by modeling MCF-7 tumor-bearing nude mice. By measuring the upconversion luminescence (UCL) and fluorescence emission spectra, the as-prepared FA-NPs-PS nanocomposites showed near-infrared (NIR)-triggered PDT performance due to the production of a singlet oxygen species. Moreover, by tracing PS fluorescence in MCF-7, HeLa cells and in MCF-7 tumors, the FA-targeted nanocomposites demonstrated good targeting ability both in vitro and in vivo. Under the irradiation of a 980 nm laser, the viabilities of MCF-7 and HeLa cells incubated with FA-NPs-PS nanocomposites could decrease to about 18.4% and 30.7%, respectively, and the inhibition of MCF-7 tumors could reach about 94.9%. The transverse MR relaxivity of 63.79 mM-1 s-1 (r2 value) and in vivo MR imaging of MCF-7 tumors indicated an excellent T2-weighted MR performance. This work demonstrated that FA-targeted MRI/PDT nanoprobes are effective for in vivo diagnosis and visualized therapy of breast cancers.Multifunctional nanoprobes used in magnetic resonance imaging (MRI) and photodynamic therapy (PDT) also have potential applications in diagnosis and visualized therapy of cancers, and hence it is important to investigate the active-targeting ability and in vivo reliability of these nanoprobes. In this work, folic acid (FA)-targeted, photosensitizer (PS)-loaded Fe3O4@NaYF4:Yb/Er (FA-NPs-PS) nanocomposites were synthesized for in vivo T2-weighted MRI and visualized PDT of cancers by modeling MCF-7 tumor-bearing nude mice. By measuring the upconversion luminescence (UCL) and fluorescence emission spectra, the as-prepared FA-NPs-PS nanocomposites showed near-infrared (NIR)-triggered PDT performance due to the production of a singlet oxygen species. Moreover, by tracing PS fluorescence in MCF-7, HeLa cells and in MCF-7 tumors, the FA-targeted nanocomposites demonstrated good targeting ability both in vitro and in vivo. Under the irradiation of a 980 nm laser, the viabilities of MCF-7 and HeLa cells incubated with FA-NPs-PS nanocomposites could decrease to about 18.4% and 30.7%, respectively, and the inhibition of MCF-7 tumors could reach about 94.9%. The transverse MR relaxivity of 63.79 mM-1 s-1 (r2 value) and in vivo MR imaging of MCF-7 tumors indicated an excellent T2-weighted MR performance. This work demonstrated that FA-targeted MRI/PDT nanoprobes are effective for in vivo diagnosis and visualized therapy of breast cancers. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr01932j

  2. Folic Acid Supplementation during Pregnancy Induces Sex-Specific Changes in Methylation and Expression of Placental 11?-Hydroxysteroid Dehydrogenase 2 in Rats

    PubMed Central

    Penailillo, Reyna; Guajardo, Angelica; Llanos, Miguel; Hirsch, Sandra; Ronco, Ana Maria

    2015-01-01

    In the placenta, 11?-hydroxysteroid dehydrogenase type 2 (11?-HSD2) limits fetal glucocorticoid exposure and its inhibition has been associated to low birth weight. Its expression, encoded by the HSD11B2 gene is regulated by DNA methylation. We hypothesized that maternal diets supplemented with folic acid (FA) during pregnancy modify the expression of placental HSD11B2 through gene methylation. Wistar rats were fed with high (8 mg/kg) or normal low (1mg/kg, control) levels of FA during pregnancy. Concentrations of mRNA and protein in placentas were determined by qRT-PCR and Western blot respectively. Methylation in five CpG sites of the placental HSD11B2 promoter (?378 to ?275) was analyzed by bacterial cloning and subsequent sequencing. In the FA-supplemented group, mRNA and protein levels of 11?-HSD2 decreased by 58% and increased by 89%, respectively, only in placentas attached to males. In controls, most CpG sites were not methylated except for the CpG2 site which was 80% methylated. CpG2 methylation level increased under the FA treatment; however, only in placentas attached to females was this increase significant (113%). This change was not related to HSD11B2 expression. Fetal weight of females from FA- supplemented mothers was 6% higher than females from control mothers. In conclusion, this is the first study reporting that FA over supplementation during pregnancy modifies the placental HSD11B2 gene expression and methylation in a sex-dependent manner, suggesting that maternal diets with high content of FA can induce early sex-specific responses, which may lead to long-term consequences for the offspring. PMID:25793274

  3. Reversing of multidrug resistance breast cancer by co-delivery of P-gp siRNA and doxorubicin via folic acid-modified core-shell nanomicelles.

    PubMed

    Wu, Yang; Zhang, Yu; Zhang, Wei; Sun, Chunlong; Wu, Jianzhong; Tang, Jinhai

    2016-02-01

    Multidrug resistance (MDR) remains one of major limitation for the successful treatment of many cancers including breast cancer. Co-delivery of chemotherapeutic drugs and small interfering RNA (siRNA) has been developed because of its ability to generate synergistic anticancer effects via different mechanisms of action, to reverse MDR and increase the efficacy of chemotherapeutic drugs in cancer therapy. Herein, we employed a kind of efficient multifunctional tumor targeted nanomicelles (PECL3) for the co-delivery of hydrophobic anti-cancer drugs and siRNA. This kind of nanomicelles were constructed by folic acid (FA)-decorated PEG-b-(PCL-g-PEI)-b-PCL triblock copolymers, which were synthesized through "click chemistry" and "ring opening" polymerization. Driven by the "core-shell" structure and the electrostatic interaction, this triblock copolymer could efficiently encapsulate P-glycoprotein (P-gp) siRNA and doxorubicin (DOX). The obtained nanomicelles can prevent renal clearance, RNase degradation and aggregation in circulation. Compared to the non-specific delivery, these FA functionalized nanomicelles could efficiently deliver P-gp siRNA to reducing both P-gp expression levels and IC50 value of the DOX in DOX-resistant breast cancer cells (MCF-7/ADR). Additionally, in vivo results showed that DOX loaded PECL3 (D-PECL3) micelles could reduce toxicity of DOX on nontarget tissues and significantly inhibited MCF-7/ADR tumor growth through encapsulating DOX in the micelles and deliver them to target tumor region. Taken together, these results proof that PECL3 micelles could co-deliver siRNA and drug to inhibit MDR tumor growth. These results suggested that the co-delivery of DOX and siRNA in tumor-targeting nanomicelles could excite synergistic effect of gene therapy and chemotherapy, thus can efficiently reverse MDR cancer and kill the cancer cells. PMID:26655793

  4. Occurrence of cleft-palate and alteration of Tgf-?(3) expression and the mechanisms leading to palatal fusion in mice following dietary folic-acid deficiency.

    PubMed

    Maldonado, Estela; Murillo, Jorge; Barrio, Carmen; del Río, Aurora; Pérez-Miguelsanz, Juliana; López-Gordillo, Yamila; Partearroyo, Teresa; Paradas, Irene; Maestro, Carmen; Martínez-Sanz, Elena; Varela-Moreiras, Gregorio; Martínez-Álvarez, Concepción

    2011-01-01

    Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2-8 weeks' induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks' maternal FA deficiency caused complete CP in the fetuses although a 2 weeks' maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-?(3) (TGF-?(3)) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-?(3)null mutant mice, we investigated the presence of TGF-?(3) mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-?(3) expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-?(3) expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-?(3) to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-?(3) compensates this deficit in vitro. PMID:21293104

  5. Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial.

    PubMed

    Enneman, Anke W; Swart, Karin M A; van Wijngaarden, Janneke P; van Dijk, Suzanne C; Ham, Annelies C; Brouwer-Brolsma, Elske M; van der Zwaluw, Nikita L; Dhonukshe-Rutten, Rosalie A M; van der Cammen, Tischa J M; de Groot, Lisette C P G M; van Meurs, Joyce; Lips, Paul; Uitterlinden, André G; Zillikens, M Carola; van Schoor, Natasja M; van der Velde, Nathalie

    2015-05-01

    High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged ?65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p < 0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement. PMID:25712255

  6. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial

    PubMed Central

    2006-01-01

    BACKGROUND Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial – the Heart Outcomes Prevention Evaluation (HOPE)-2 study – is being conducted to evaluate this therapy in patients at high risk for CV events. OBJECTIVES To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke. METHODS A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005. RESULTS The patients’ baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention. PMID:16450017

  7. Ursodeoxycholic acid exerts farnesoid X receptor-antagonistic effects on bile acid and lipid metabolism in morbid obesity

    PubMed Central

    Mueller, Michaela; Thorell, Anders; Claudel, Thierry; Jha, Pooja; Koefeler, Harald; Lackner, Carolin; Hoesel, Bastian; Fauler, Guenter; Stojakovic, Tatjana; Einarsson, Curt; Marschall, Hanns-Ulrich; Trauner, Michael

    2015-01-01

    Background & Aims Bile acids (BAs) are major regulators of hepatic BA and lipid metabolism but their mechanisms of action in non-alcoholic fatty liver disease (NAFLD) are still poorly understood. Here we aimed to explore the molecular and biochemical mechanisms of ursodeoxycholic acid (UDCA) in modulating the cross-talk between liver and visceral white adipose tissue (vWAT) regarding BA and cholesterol metabolism and fatty acid/lipid partitioning in morbidly obese NAFLD patients. Methods In this randomized controlled pharmacodynamic study, we analyzed serum, liver and vWAT samples from 40 well-matched morbidly obese patients receiving UDCA (20 mg/kg/day) or no treatment three weeks prior to bariatric surgery. Results Short term UDCA administration stimulated BA synthesis by reducing circulating fibroblast growth factor 19 and farnesoid X receptor (FXR) activation, resulting in cholesterol 7?-hydroxylase induction mirrored by elevated C4 and 7?-hydroxycholesterol. Enhanced BA formation depleted hepatic and LDL-cholesterol with subsequent activation of the key enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl-CoA reductase. Blunted FXR anti-lipogenic effects induced lipogenic stearoyl-CoA desaturase (SCD) in the liver, thereby increasing hepatic triglyceride content. In addition, induced SCD activity in vWAT shifted vWAT lipid metabolism towards generation of less toxic and more lipogenic monounsaturated fatty acids such as oleic acid. Conclusion These data demonstrate that by exerting FXR-antagonistic effects, UDCA treatment in NAFLD patients strongly impacts on cholesterol and BA synthesis and induces neutral lipid accumulation in both liver and vWAT. PMID:25617503

  8. 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

    Lasry, Inbal; Berman, Bluma; Glaser, Fabian; Jansen, Gerrit; Assaraf, Yehuda G.

    2009-08-28

    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.

  9. Effects of folic acid supplementation to rations differing in the concentrate to roughage ratio on ruminal fermentation, nutrient flow at the duodenum, and on serum and milk variables of dairy cows.

    PubMed

    Ragaller, Veronika; Lebzien, Peter; Bigalke, Wiebke; Südekum, Karl-Heinz; Hüthera, Liane; Flachowsky, Gerhard

    2010-12-01

    The present study was undertaken to determine the effects of dietary folic acid (FOL) supplementation on ruminal fermentation, duodenal nutrient flow, serum and milk variables, and on B-vitamin concentration in serum. The study was divided into two experiments: in Exp. 1 the forage to concentrate (F:C) ratio of the diet (DM basis) was 34:66 (high concentrate, HC), while in Exp. 2 the F:C ratio was 66:34 (high forage, HF). In addition, the cows received 0 or 1 g FOL/d. In Exp. 1, two German Holstein cows equipped with cannulas in the dorsal sac of the rumen and in the proximal duodenum were dry and five were lactating (186 +/- 144 days in milk); in Exp. 2 four cows were dry and four were lactating (165 +/- 57 days in milk). In cows fed the HC diet, FOL supplementation decreased the ruminally-fermented organic matter. Thus, less energy was available for ruminal microorganisms, which resulted in a reduced microbial crude protein flow at the duodenum. Feeding the HF diet, FOL supplementation only increased the apparent ruminal digestibility of acid detergent fibre (ADF). With the HF diet, FOL had no influence on the serum levels of glucose, non-esterified fatty acids, beta-hydroxybutyrate, urea, thiamine, riboflavin, pyridoxal-5'-phosphate, pyridoxic acid, pyridoxal, pyridoxine, pyridoxamine, pantothenic acid, nicotinamide or nicotinic acid, whereas supplementing FOL to the HC diet lowered the serum glucose and riboflavin levels. In both experiments, the supplementation of FOL had no effects on milk composition. Folic acid supplementation to both diets increased the concentrations of serum 5-methyl-tetrahydrofolate. However, no beneficial effects to dairy cows were obvious. Therefore, to achieve certain results, studies with a higher number of non-fistulated cows would be necessary. PMID:21214021

  10. Liquid chromatography-tandem mass spectrometry evaluation of the pharmacokinetics of a diacid metabolite of norcantharidin loaded in folic acid-targeted liposomes in mice.

    PubMed

    Liu, Min-Chen; Ma, Xiao-Qiong; Xu, Yong; Peng, Li-Hua; Han, Min; Gao, Jian-Qing

    2016-02-01

    A previous study has reported diacid metabolite (DM) as the stable form of norcantharidin (NCTD), which is almost 100% metabolized to DM-NCTD. However, the unreliable pharmacokinetic characteristics of DM-NCTD could result in low bioavailability, hindering the clinical use of DM-NCTD in the treatment of diseases. A liposomal drug delivery system could overcome the shortcomings of DM-NCTD by improving the relative bioavailability (Fr), reducing drug toxicity, and increasing the therapeutic efficacy. However, there are no data concerning the pharmacokinetics of a DM-NCTD-loaded liposomal drug delivery system in animals, which is required for assessing its safety profile. Therefore, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of DM-NCTD in mouse plasma. Standard curves were linear (r=0.9966) over the range 10.0-1.00×10(4)ng/ml in mouse plasma with a lower limit of quantification (LLOQ) of 10ng/ml. This study successfully investigated the pharmacokinetics of DM-NCTD and DM-NCTD encapsulated in polyethylene glycol (PEG)-Liposomes (DM-NCTD/PEG-Liposome) or folic acid (FA)-PEG-Liposomes (DM-NCTD/FA-PEG-Liposome) in Kunming mice after a single intravenous dose of 2mg/kg. The plasma profile data of the three groups adhered to a two-compartment model. Compared with the DM-NCTD group, the Liposome groups had longer circulation times following intravenous administration in mice, and the Fr of DM-NCTD increased significantly (P<0.05). Furthermore, the area under the concentration-time curve (AUC) declined with an increase in the volume of distribution (Vd) from the PEG-Liposome to the FA-PEG-Liposome groups, which indicates a more efficient removal of the drug from the plasma of the FA-PEG-Liposome group. This result suggests a possible increased risk of DM-NCTD intoxication in normal tissues with FA-PEG-Liposomes. Based on this study, further investigation of the biodistribution of DM-NCTD/FA-PEG-Liposomes in healthy animals is warranted. In addition, the plausibility of formulating a safe DM-NCTD-loaded system without increasing toxicity against normal tissues needs to be determined. PMID:26658337

  11. Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid: community-based randomized clinical trial in Italy and the Netherlands

    PubMed Central

    2014-01-01

    Background In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear. Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open. The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae. Methods/Design This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information. We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis. Discussion The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes. Trial registration Italian trial: ClinicalTrials.gov Identifier: NCT01244347. Dutch trial: Dutch Trial Register ID: NTR3161. PMID:24884885

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

    PubMed

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

    2014-06-01

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

  13. Folic Acid: Data and Statistics

    MedlinePLUS

    ... had received a doctor's recommendation. Top of Page Economic Cost The annual medical care and surgical costs ... Collins JS, Green D, Dean JH, Stevenson RE. Economic evaluation of a neural tube defect recurrence prevention ...

  14. Gastric acid secretion stimulated by modified sham-feeding, and the effects of histamine H2-antagonist and anti-muscarinic agent in patients with duodenal ulcer.

    PubMed

    Ooi, S; Kaneko, E

    1989-10-01

    Patients with duodenal ulcer (DU) were classified into responders to H2-antagonist and non-responders in whom DU did not heal within 3 months with the antagonist. In these patients and healthy controls, a modified sham-feeding (MSF) test was performed to elucidate the pathogenesis of resistance to H2-antagonist. By MSF stimulation, gastric acid secretion significantly increased in all subjects. The mean acid output by MSF amounted to about 52 of the tetra-gastrin maximum in controls (12 cases), 46% in responders (12 cases) and 72% in non-responders (14 cases). The mean acid output in non-responders was significantly higher than in controls under baseline conditions, MSF and gastrin stimulations, but was higher than in responders during MSF stimulation. The effects of H2-antagonist (cimetidine 1mg/kg/h), anti-muscarinic agent (pirenzepine 0.3mg/kg/h), or both on the acid secretion were examined on non-responders (6 cases), responders (6 cases) and healthy controls (6 cases). The acid secretion stimulated by MSF was significantly inhibited by pirenzepine in responders and controls, but not in non-responders. With cimetidine, the acid output was significantly inhibited in all groups, but was still higher in non-responders than in controls and responders, indicating that the reduction of acid output by a H2-antagonist is significantly less in non-responders than in other groups. The combined use of pirenzepine and cimetidine almost completely inhibited the acid output in all groups. These data suggest that the vagal activity in non-responders to H2-antagonist is higher than in responders and healthy subjects, and H2-antagonist combined with anti-muscarinic agent is more effective in reducing the gastric acid secretion in non-responders. PMID:2572505

  15. In vitro and in vivo evaluation of an innocuous drug cocktail to improve the quality of folic acid targeted nuclear imaging in preclinical research.

    PubMed

    Müller, Cristina; Reber, Josefine; Schlup, Claudia; Leamon, Christopher P; Schibli, Roger

    2013-03-01

    Folate receptor (FR) targeting is an attractive strategy for nuclear imaging of cancer and activated macrophages through application of folic acid radioconjugates. However, significant renal accumulation of folate radioconjugates and hence exceedingly high emission of radiation from the kidneys may mask uptake of radioactivity at sites of interest such as small metastases in the abdominal region of animal models of ovarian cancer. Recently it was observed that the antifolate pemetrexed (PMX) reduces undesired renal uptake of radiofolates. A disadvantage of this strategy is the fact that pemetrexed is a chemotherapeutic agent which may have toxic side effects. The aims of this study were therefore to investigate whether the desired effect of PMX to reduce renal accumulation of folate radioconjugates would be maintained if it was applied as a cocktail together with its antidote, thymidine, and to explore whether thymidine was an effective rescue agent against PMX's related toxicity in vitro and in vivo. In vitro internalization of (67)Ga-EC0800 was investigated using FR-positive KB tumor cells and embryonic monkey MA104 kidney cells in the absence and presence of PMX alone and in combination with thymidine. Uptake of (67)Ga-EC0800 into KB cells was increased by coincubation of the cells with PMX. In contrast uptake of (67)Ga-EC0800 into MA104 cells was reduced under the same conditions. In both cell lines coincubation of thymidine did not change the results obtained with PMX. Biodistribution and SPECT/CT imaging studies of (67)Ga-EC0800 were performed with KB tumor bearing mice injected with PMX alone or with a cocktail of PMX and thymidine. The radiofolate's kidney uptake reducing effect of PMX in mice was maintained also if PMX was employed together with its antidote thymidine. The tumor uptake of (67)Ga-EC0800 remained unchanged independent of the administration of PMX or a combination of PMX and thymidine. The effect of thymidine to abrogate PMX-induced cytotoxicity was demonstrated in vitro with an MTT assay using KB and MA104 cells. Cell viability was reduced to 50% (KB cells) and 70% (MA104 cells) of untreated controls if PMX (5 ?M and 15 ?M, respectively) was coincubated. Addition of thymidine (10 ?M or 100 ?M) compensated PMX's toxic effects in a dose-dependent manner. The effect of thymidine was also investigated in non-tumor bearing mice treated with high-dosed PMX. Rescue of mice with side effects after the third and fourth cycles of PMX application (1 mg/mouse) was achieved by application of thymidine (20 mg/mouse) at five consecutive days starting the day of PMX injection. Application of PMX together with thymidine as a cocktail is effective to improve the tissue distribution of radiofolates while preventing pharmacological and potentially toxic side effects of the chemotherapeutic agent PMX. These findings open new perspectives for folate-based nuclear imaging in preclinical research potentially allowing longitudinal investigations and monitoring therapies in animal models of cancer and inflammatory diseases. PMID:23394590

  16. Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPAR? Antagonists.

    PubMed

    Asteian, Alice; Blayo, Anne-Laure; He, Yuanjun; Koenig, Marcel; Shin, Youseung; Kuruvilla, Dana S; Corzo, Cesar A; Cameron, Michael D; Lin, Li; Ruiz, Claudia; Khan, Susan; Kumar, Naresh; Busby, Scott; Marciano, David P; Garcia-Ordonez, Ruben D; Griffin, Patrick R; Kamenecka, Theodore M

    2015-09-10

    The thiazolidinediones (TZD) typified by rosiglitazone are the only approved therapeutics targeting PPAR? for the treatment of type-2 diabetes (T2DM). Unfortunately, despite robust insulin sensitizing properties, they are accompanied by a number of severe side effects including congestive heart failure, edema, weight gain, and osteoporosis. We recently identified PPAR? antagonists that bind reversibly with high affinity but do not induce transactivation of the receptor, yet they act as insulin sensitizers in mouse models of diabetes (SR1664).1 This Letter details our synthetic exploration around this novel series of PPAR? antagonists based on an N-biphenylmethylindole scaffold. Structure-activity relationship studies led to the identification of compound 46 as a high affinity PPAR? antagonist that exhibits antidiabetic properties following oral administration in diet-induced obese mice. PMID:26396687

  17. 20-125Iodo-14,15-Epoxyeicosa-5(Z)-enoic Acid: a High-Affinity Radioligand Used to Characterize the Epoxyeicosatrienoic Acid Antagonist Binding Site

    PubMed Central

    Chen, Yuenmu; Falck, John R.; Tuniki, Venugopal R.

    2009-01-01

    Epoxyeicosatrienoic acids (EETs) are endothelium-derived metabolites of arachidonic acid. They relax vascular smooth muscle by membrane hyperpolarization. These actions are inhibited by the EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EE5ZE). We synthesized 20-125iodo-14,15-EE5ZE (20-125I-14,15-EE5ZE), a radiolabeled EET antagonist, and characterized its binding to cell membranes. 14,15-EET (10?9-10?5M) caused a concentration-related relaxation of the preconstricted bovine coronary artery and phosphorylation of p38 in U937 cells that were inhibited by 20-125I-14,15-EE5ZE. Specific 20-125I-14,15-EE5ZE binding to U937 cell membranes reached equilibrium within 5 min and remained unchanged for 30 min. The binding was saturable and reversible, and it exhibited KD and Bmax values of 1.11 ± 0.13 nM and 1.13 ± 0.04 pmol/mg protein, respectively. Guanosine 5?-O-(3-thio)triphosphate (10 ?M) did not change the binding, indicating antagonist binding of the ligand. Various EETs and EET analogs (10?10-10?5M) competed for 20-125I-14,15-EE5ZE binding with an order of potency of 11,12-EET = 14,15-EET > 8,9-EET = 14,15-EE5ZE > 15-hydroxyeicosatetraenoic acid = 14,15-dihydroxyeicosatrienoic acid. 8,9-Dihydroxyeicosatrienoic acid and 11-hydroxyeicosatetraenoic acid did not compete for binding. The soluble and microsomal epoxide hydrolase inhibitors (1-cyclohexyl-3-dodecyl-urea, elaidamide, and 12-hydroxyl-elaidamide) and cytochrome P450 inhibitors (sulfaphenazole and proadifen) did not compete for the binding. However, two cytochrome P450 inhibitors, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) and miconazole competed for binding with Ki of 1558 and 315 nM, respectively. Miconazole and MS-PPOH, but not proadifen, inhibited 14,15-EET-induced relaxations. These findings define an EET antagonist's binding site and support the presence of an EET receptor. The inhibition of binding by some cytochrome P450 inhibitors suggests an alternative mechanism of action for these drugs and could lead to new drug candidates that target the EET binding sites. PMID:19762546

  18. Interactions between ?-tocopherol and rosmarinic acid and its alkyl esters in emulsions: synergistic, additive, or antagonistic effect?

    PubMed

    Panya, Atikorn; Kittipongpittaya, Ketinun; Laguerre, Mickaël; Bayrasy, Christelle; Lecomte, Jérôme; Villeneuve, Pierre; McClements, D Julian; Decker, Eric A

    2012-10-17

    Many antioxidants can interact to produce synergistic interactions that can more effectively inhibit lipid oxidation in foods. Esterification of rosmarinic acid produces a variety of compounds with different antioxidant activity due to differences in polarity and thus differences in partitioning in oil, water, and interfacial regions of oil-in-water emulsions (O/W). Therefore, rosmarinic acid and rosmarinate esters provide an interesting tool to study the ability of antioxidant to interact in O/W emulsions. In O/W emulsions, rosmarinic acid (R0) exhibited the strongest synergistic interaction with ?-tocopherol while butyl (R4) and dodecyl (R12) rosmarinate esters exhibited small synergistic interaction and eicosyl rosmarinate esters (R20) exhibited slightly antagonistic interaction. Fluorescence quenching and electron paramagnetic resonance (EPR) studies showed that water-soluble rosmarinic acid (R0) exhibited more interactions with ?-tocopherol than any of the tested esters (R4, R12, R20). This was also confirmed in O/W emulsions where R0 altered the formation of ?-tocopherol quinone and ?-tocopherol increased the formation of caffeic acid from R0. This formation of caffeic acid was proposed to be responsible for the synergistic activity of R0 and ?-tocopherol since the formation of an additional antioxidant could further increase the oxidative stability of the emulsion. PMID:22988974

  19. 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

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

    2013-01-01

    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

  20. Cannabiorci- and 8-chlorocannabiorcichromenic acid as fungal antagonists from Cylindrocarpon olidum.

    PubMed

    Quaghebeur, K; Coosemans, J; Toppet, S; Compernolle, F

    1994-09-01

    Cannabiorcichromenic acid and 8-chlorocannabiorcichromenic acid [8-chloro-5-hydroxy-2,7-dimethyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran -6- carboxylic acid] were identified as active components in cultures of Cylindrocarpon olidum which antagonized various other fungi. Experiments performed with the purified acids confirmed the antifungal activity; in addition, they revealed that the acids had antibiotic properties towards gram-positive bacteria and were toxic to nematodes. PMID:7765609

  1. Non-equivalence of Key Positively Charged Residues of the Free Fatty Acid 2 Receptor in the Recognition and Function of Agonist Versus Antagonist Ligands.

    PubMed

    Sergeev, Eugenia; Hansen, Anders Højgaard; Pandey, Sunil K; MacKenzie, Amanda E; Hudson, Brian D; Ulven, Trond; Milligan, Graeme

    2016-01-01

    Short chain fatty acids (SCFAs) are produced in the gut by bacterial fermentation of poorly digested carbohydrates. A key mediator of their actions is the G protein-coupled free fatty acid 2 (FFA2) receptor, and this has been suggested as a therapeutic target for the treatment of both metabolic and inflammatory diseases. However, a lack of understanding of the molecular determinants dictating how ligands bind to this receptor has hindered development. We have developed a novel radiolabeled FFA2 antagonist to probe ligand binding to FFA2, and in combination with mutagenesis and molecular modeling studies, we define how agonist and antagonist ligands interact with the receptor. Although both agonist and antagonist ligands contain negatively charged carboxylates that interact with two key positively charged arginine residues in transmembrane domains V and VII of FFA2, there are clear differences in how these interactions occur. Specifically, although agonists require interaction with both arginine residues to bind the receptor, antagonists require an interaction with only one of the two. Moreover, different chemical series of antagonist interact preferentially with different arginine residues. A homology model capable of rationalizing these observations was developed and provides a tool that will be invaluable for identifying improved FFA2 agonists and antagonists to further define function and therapeutic opportunities of this receptor. PMID:26518871

  2. Discovery of 2-[5-(4-Fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic Acid (SX-517): Noncompetitive Boronic Acid Antagonist of CXCR1 and CXCR2

    PubMed Central

    2015-01-01

    The G protein-coupled chemokine receptors CXCR1 and CXCR2 play key roles in inflammatory diseases and carcinogenesis. In inflammation, they activate and recruit polymorphonuclear cells (PMNs) through binding of the chemokines CXCL1 (CXCR1) and CXCL8 (CXCR1 and CXCR2). Structure–activity studies that examined the effect of a novel series of S-substituted 6-mercapto-N-phenyl-nicotinamides on CXCL1-stimulated Ca2+ flux in whole human PMNs led to the discovery of 2-[5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanylmethyl]phenylboronic acid (SX-517), a potent noncompetitive boronic acid CXCR1/2 antagonist. SX-517 inhibited CXCL1-induced Ca2+ flux (IC50 = 38 nM) in human PMNs but had no effect on the Ca2+ flux induced by C5a, fMLF, or PAF. In recombinant HEK293 cells that stably expressed CXCR2, SX-517 antagonized CXCL8-induced [35S]GTP?S binding (IC50 = 60 nM) and ERK1/2 phosphorylation. Inhibition was noncompetitive, with SX-517 unable to compete the binding of [125I]-CXCL8 to CXCR2 membranes. SX-517 (0.2 mg/kg iv) significantly inhibited inflammation in an in vivo murine model. SX-517 is the first reported boronic acid chemokine antagonist and represents a novel pharmacophore for CXCR1/2 antagonism. PMID:25254640

  3. The SnRK2-APC/CTE regulatory module mediates the antagonistic action of gibberellic acid and abscisic acid pathways

    PubMed Central

    Lin, Qibing; Wu, Fuqing; Sheng, Peike; Zhang, Zhe; Zhang, Xin; Guo, Xiuping; Wang, Jiulin; Cheng, Zhijun; Wang, Jie; Wang, Haiyang; Wan, Jianmin

    2015-01-01

    Abscisic acid (ABA) and gibberellic acid (GA) antagonistically regulate many developmental processes and responses to biotic or abiotic stresses in higher plants. However, the molecular mechanism underlying this antagonism is still poorly understood. Here, we show that loss-of-function mutation in rice Tiller Enhancer (TE), an activator of the APC/CTE complex, causes hypersensitivity and hyposensitivity to ABA and GA, respectively. We find that TE physically interacts with ABA receptor OsPYL/RCARs and promotes their degradation by the proteasome. Genetic analysis also shows OsPYL/RCARs act downstream of TE in mediating ABA responses. Conversely, ABA inhibits APC/CTE activity by phosphorylating TE through activating the SNF1-related protein kinases (SnRK2s), which may interrupt the interaction between TE and OsPYL/RCARs and subsequently stabilize OsPYL/RCARs. In contrast, GA can reduce the level of SnRK2s and may promote APC/CTE-mediated degradation of OsPYL/RCARs. Thus, we propose that the SnRK2-APC/CTE regulatory module represents a regulatory hub underlying the antagonistic action of GA and ABA in plants. PMID:26272249

  4. Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

    PubMed

    Harden, Cynthia L; Pennell, Page B; Koppel, Barbara S; Hovinga, Collin A; Gidal, Barry; Meador, Kimford J; Hopp, Jennifer; Ting, Tricia Y; Hauser, W A; Thurman, David; Kaplan, Peter W; Robinson, Julian N; French, Jacqueline A; Wiebe, Samuel; Wilner, Andrew N; Vazquez, Blanca; Holmes, Lewis; Krumholz, Allan; Finnell, Richard; Shafer, Patricia O; Le Guen, Claire L

    2009-05-01

    A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations. PMID:19507305

  5. Antagonistic Characteristics Against Food-borne Pathogenic Bacteria of Lactic Acid Bacteria and Bifidobacteria Isolated from Feces of Healthy Thai Infants

    PubMed Central

    Uraipan, Supansa; Hongpattarakere, Tipparat

    2015-01-01

    Background: Food-borne pathogens are among the most significant problems in maintaining the health of people. Many probiotics have been widely reported to alleviate and protect against gastrointestinal infections through antibacterial secretion. However, the majority of them cannot always play antagonistic roles under gut conditions. Probiotic bacteria of human origin must possess other protective mechanisms to survive, out-compete intestinal flora and to successfully establish in their new host at a significant level. Objectives: Probiotic characteristics of Lactic Acid Bacteria (LAB) and bifidobacteria isolated from the feces of Thai infants were primarily investigated in terms of gastric acid and bile resistances, antibacterial activity and mucin adhesion ability. Antagonistic interaction through secretion of antibacterial compounds and competitive exclusion against food-borne pathogens were also evaluated. Materials and Methods: Culturable LAB and bifidobacteria were isolated from feces of Thai infants. Their ability to withstand gastric acid and bile were then evaluated. Acid and bile salt tolerant LAB and bifidobacteria were identified. They were then further assessed according to their antagonistic interactions through antibacterial secretion, mucin adhesion and competitive mucin adhesion against various food-borne pathogenic bacteria. Results: Gastric acid and bile tolerant LAB and bifidobacteria isolated from healthy infant feces were identified and selected according to their antagonistic interaction against various food-borne pathogenic bacteria. These antagonistic probiotics included four strains of Lactobacillus rhamnosus, two strains of L. casei, five strains of L. plantarum, two strains of Bifidobacterium longum subsp. longum and three strains of B. bifidum. All strains of the selected LAB inhibited all pathogenic bacteria tested through antibacterial secretion, while bifidobacteria showed high level of competitive exclusion against the pathogenic bacteria. Conclusions: These human-derived LAB and bifidobacteria exhibited different mechanisms involved in pathogenic inhibition. Therefore a combination of these probiotic strains could be a great promise and possibility for the development of probiotic products to effectively prevent and control food-borne infection in humans. PMID:26301060

  6. Reversal of multidrug resistance in MCF-7/Adr cells by codelivery of doxorubicin and BCL2 siRNA using a folic acid-conjugated polyethylenimine hydroxypropyl-?-cyclodextrin nanocarrier

    PubMed Central

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

    2015-01-01

    Systemic administration of chemotherapy for cancer often faces drug resistance, limiting its applications in cancer therapy. In this study, we developed a simple multifunctional nanocarrier based on polyethylenimine (PEI) to codeliver doxorubicin (DOX) and BCL2 small interfering RNA (siRNA) for overcoming multidrug resistance (MDR) and enhancing apoptosis in MCF-7/Adr cancer cells by combining chemotherapy and RNA interference (RNAi) therapy. The low-molecular-weight branch PEI was used to conjugate hydroxypropyl-?-cyclodextrin (HP-?-CD) and folic acid (FA), forming the codelivery nanocarrier (FA-HP-?-CD-PEI) to encapsulate DOX with the cavity HP-?-CD and bind siRNA with the positive charge of PEI for tumor-targeting codelivering drugs. The drug-loaded nanocomplexes (FA-HP-?-CD-PEI/DOX/siRNA) showed uniform size distribution, high cellular uptake, and significant gene suppression of BCL2, displaying the potential of overcoming MDR for enhancing the effect of anticancer drugs. Furthermore, the nanocomplexes achieved significant cell apoptosis through a mechanism of downregulating the antiapoptotic protein BCL2, resulted in improving therapeutic efficacy of the coadministered DOX by tumor targeting and RNA interference. Our study indicated that combined RNAi therapy and chemotherapy using our functional codelivery nanocarrier could overcome MDR and enhance apoptosis in MDR cancer cells for a potential application in treating MDR cancers. PMID:25960653

  7. Electrocatalytic boost up of epinephrine and its simultaneous resolution in the presence of serotonin and folic acid at poly(serine)/multi-walled carbon nanotubes composite modified electrode: A voltammetric study.

    PubMed

    Narayana, P V; Madhusudana Reddy, T; Gopal, P; Mohan Reddy, M; Ramakrishna Naidu, G

    2015-11-01

    The present paper describes the new strategy for the development of nanosensor based on dropcasting of multi-walled carbon nanotubes (MWCNTs) followed by electropolymerization of serine (ser) onto the glassy carbon electrode (GCE). The developed nanocomposite sensor was abbreviated as poly(ser)/MWCNTs/GCE and was characterized by using electrochemical impedance spectroscopy (EIS) technique. The EIS results confirmed the fast electron transfer rate at the surface of poly(ser)/MWCNTs/GCE. The proposed sensor exhibited good catalytic activity towards the sensing of epinephrine (EP) individually and simultaneously in the presence of serotonin (5-HT) and folic acid (FA) in 0.1M phosphate buffer solution (PBS) at pH7.0. The limit of detection (LOD) and limit of quantification (LOQ) of EP was found to be 6×10(-7)M and 2×10(-6)M respectively. The fabricated sensor showed excellent precision and accuracy with a relative standard deviation (RSD) of 4.86%. The proposed composite sensor was effectively applied towards the determination of EP in human blood serum and pharmaceutical injection sample. PMID:26249565

  8. Nanoparticle-encapsulated P2X? receptor antagonist in a pH-sensitive polymer as a potential local drug delivery system to acidic inflammatory environments.

    PubMed

    Lee, Sun-Mi; Cho, Joong-Heui; Lee, So-Deok; Kim, Yong-Chul

    2015-10-01

    We have developed nanoparticles of anti-inflammatory P2X7 receptor antagonist encapsulated in a pH-sensitive polymer, poly(tetrahydropyran-2-yl methacrylate) (poly(THPMA)), as a potential local drug delivery system to target to acidic inflammatory environments, in which P2X7 receptors are implicated in the pathology of inflammation via the activation of immune cells. The nanoparticles were prepared using single emulsion methods, also their size and shape were confirmed by microscopy and spectroscopy, etc. The profiles of the pH-dependent degradation, release of antagonist and biological activities were investigated. The nanoparticles that encapsulated the 3,5-dichloropyridine derivative (2) with poly(THPMA), were observed to be more slowly cleaved than the blank nanoparticles. Moreover, the free P2X7 receptor antagonists potently inhibited the receptor activation, whereas the nanoparticles of the 3,5-dichloropyridine derivative (2) encapsulated poly(THPMA) exhibited much lower P2X7 antagonistic activity through sustained encapsulation. Thus, the nanoparticles of the 3,5-dichloropyridine derivative (2) encapsulated poly(THPMA) may be utilized to develop a pH-sensitive local drug delivery system for controlled release of anti-inflammatory therapeutics in acidic physiological environments. PMID:26303894

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

    PubMed

    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

    2014-12-11

    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

  10. Tailored-CuO-nanowire decorated with folic acid mediated coupling of the mitochondrial-ROS generation and miR425-PTEN axis in furnishing potent anti-cancer activity in human triple negative breast carcinoma cells.

    PubMed

    Ahir, Manisha; Bhattacharya, Saurav; Karmakar, Soumendu; Mukhopadhyay, Ayan; Mukherjee, Sudeshna; Ghosh, Swatilekha; Chattopadhyay, Sreya; Patra, Prasun; Adhikary, Arghya

    2016-01-01

    Metal oxide nanoparticles are the forthcoming anti-tumor therapeutics and provide a versatile platform in the development of therapeutic approaches for drug-resistant cancers such as triple negative breast cancer (TNBC). Copper oxide nanoparticles have been characterized as anti-cancer agents but its toxicity has been a matter of concern. Herein, we have developed a targeted CuO Nanowire fabricated with Folic acid (CuO-Nw-FA) that enables enhanced cellular uptake in TNBC cells without imparting significant toxicity in normal cellular system. In the present study, we enumerated that CuO-Nw-FA caused mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, CuO-Nw-FA mediated cytosolic retardation of NF-?B favoured inactivation of miR-425 and henceforth activated PTEN to induce apoptosis in TNBC cells. Simultaneously, CuO-Nw-FA also restricted the in-vitro cell migration through the miR-425/PTEN axis via pFAK. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of CuO-Nw-FA. Additionally, the accumulations of nanoparticles in tumor as well as different organs in mice were examined by in-vivo biodistribution and ex-vivo optical imaging studies. Thus our results cumulatively propose that CuO-Nw-FA cross-talks two distinct signalling pathways to induce apoptosis and retard migration in TNBC cells and raises the possibility for the use of CuO-Nw-FA as a potent anti-tumor agent. PMID:26520043

  11. Folic acid inhibits COLO-205 colon cancer cell proliferation through activating the FR?/c-SRC/ERK1/2/NF?B/TP53 pathway: in vitro and in vivo studies

    PubMed Central

    Kuo, Chun-Ting; Chang, Chieh; Lee, Wen-Sen

    2015-01-01

    To investigate the molecular mechanism underlying folic acid (FA)-induced anti-colon caner activity, we showed that FA caused G0/G1 arrest in COLO-205. FA activated the proto-oncogene tyrosine-protein kinase Src (c-SRC)-mediated signaling pathway to enhance nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF?B) nuclear translocation and binding onto the tumor protein p53 (TP53) gene promoter, and up-regulated expressions of TP53, cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). Knock-down of TP53 abolished FA-induced increases in the levels of CDKN1A and CDKN1B protein and G0/G1 arrest in COLO-205. Knock-down of folate receptor alpha (FR?) abolished FA-induced activations in the c-SRC-mediated pathway and increases in the levels of CDKN1A, CDKN1B and TP53 protein. These data suggest that FA inhibited COLO-205 proliferation through activating the FR?/c-SRC/mitogen-activated protein kinase 3/1 (ERK1/2)/NF?B/TP53 pathway-mediated up-regulations of CDKN1A and CDKN1B protein. In vivo studies demonstrated that daily i.p. injections of FA led to profound regression of the COLO-205 tumors and prolong the lifespan. In these tumors, the levels of CDKN1A, CDKN1B and TP53 protein were increased and von willebrand factor (VWF) protein levels were decreased. These findings suggest that FA inhibits COLO-205 colon cancer growth through anti-cancer cell proliferation and anti-angiogenesis. PMID:26056802

  12. Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis.

    PubMed

    Scott, Jill M; Baccei, Christopher; Bain, Gretchen; Broadhead, Alex; Evans, Jilly F; Fagan, Patrick; Hutchinson, John H; King, Christopher; Lorrain, Daniel S; Lee, Catherine; Prasit, Peppi; Prodanovich, Pat; Santini, Angelina; Stearns, Brian A

    2011-11-01

    Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing. PMID:21958540

  13. Regulation of aromatic L-amino acid decarboxylase in rat striatal synaptosomes: effects of dopamine receptor agonists and antagonists.

    PubMed Central

    Zhu, M. Y.; Juorio, A. V.; Paterson, I. A.; Boulton, A. A.

    1994-01-01

    1. In this study we investigated the effects of dopamine receptor agonists and antagonists on rat striatal synaptosomal aromatic L-amino acid decarboxylase (AADC) activity. 2. The results show that 10(-5)-10(-7) M cis-flupenthixol increased the striatal synaptosomal AADC activity (by 25% to 57%) in a time-dependent manner. SCH 23390 and remoxipride alone had little or no effect on striatal synaptosomal AADC activity, but in combination they increased AADC activity by 20%, suggesting that the increases in striatal synaptosomal AADC activity occurred only after blockade of both dopamine D1 and D2 receptors. 3. Treatment with (+)-amphetamine and (+/-)-2-(N-phenylethyl-N-propyl)amino-5- hydroxytetralin hydrochloride ((+/-)-PPHT) produced a reduction of striatal synaptosomal AADC activity in a concentration- and time-dependent manner. SKF 38393 and (-)-quinpirole, however, exhibited no effect on striatal synaptosomal AADC activity, suggesting that only the mixed dopamine receptor agonists can reduce the AADC activity. Incubation with apomorphine at a concentration of 10(-4) M inhibited the AADC activity by 74% and this inhibition cannot be antagonized by SCH 23390, remoxipride or cis-flupenthixol, suggesting that apomorphine-induced inhibition of striatal synaptosomal AADC activity was not mediated by dopamine receptors. 4. cis-Flupenthixol can reverse the reduction of AADC activity induced by (+)-amphetamine and (+/-)-PPHT. The inhibition of AADC activity elicited by (+/-)-PPHT also can be reversed by SCH 23390 and remoxipride. 5. The inhibition of striatal synaptosomal AADC activity induced by (+/-)-PPHT is calcium-dependent and protein kinase C may play a role in the regulation of striatal AADC activity.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7913379

  14. Amide derivatives of 9,11-seco-estra-1,3,5(10)-trien-11-oic acid as modified orally active estrogen agonists with moderate antagonistic activity.

    PubMed

    Negi, Arvind Singh; Chaturvedi, Devdutt; Gupta, Atul; Ray, S; Dwivedy, Anila; Singh, M M

    2005-01-01

    Synthesis of amide derivatives of 9,11-seco-estra-1,3,5(10)-trien-11-oic acid containing alkyl and aromatic amine residues has been carried out with an aim to prepare orally active estrogen antagonists. Modification of the estradiol molecule in the form of C-seco-amide derivatives has led to their high oral absorption. Compounds 7 an n-propyl amide, 8 an n-butyl amide, and 16 a p-anisidyl amide of C-seco-estrane showed significant estrogen antagonistic activity (>20%), while, the majority of compounds possessed high estrogen agonistic activity on oral administration at 10mg/kg dose in rats. PMID:15582419

  15. 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

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

    2014-01-01

    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

  16. Effects of TAK-480, a novel tachykinin NK(2)-receptor antagonist, on visceral hypersensitivity in rabbits and ricinoleic acid-induced defecation in guinea pigs.

    PubMed

    Tanaka, Takahiro; Tanaka, Akiko; Nakamura, Akihiro; Matsushita, Kozo; Imanishi, Akio; Matsumoto-Okano, Shiho; Inatomi, Nobuhiro; Miura, Kasei; Toyoda, Masao; Mizojiri, Gaku; Tsukimi, Yasuhiro

    2012-01-01

    TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK(2)-receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK(2) receptors with a marked species difference and a 10,000-fold selectivity versus NK(1) and NK(3) receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK(2) receptor-selective agonist beta-Ala(8)-NKA(4-10) (?A-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT(3)-receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid-induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as ?A-NKA in an isolated human colon. In conclusion, the novel NK(2)-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK(2) receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients. PMID:22893394

  17. Spina Bifida and Folic Acid Awareness

    ERIC Educational Resources Information Center

    Exceptional Parent, 2007

    2007-01-01

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

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

    PubMed Central

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

    2012-01-01

    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

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

    PubMed Central

    2015-01-01

    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

  20. Identification of novel amino acid derived CCK-2R antagonists as potential antiulcer agent: homology modeling, design, synthesis, and pharmacology.

    PubMed

    Gupta, Amit K; Varshney, Kanika; Singh, Neetu; Mishra, Vaibhav; Saxena, Mridula; Palit, Gautam; Saxena, Anil K

    2013-01-28

    The present study revisited the three-dimensional (3D) homology model of CCK-2R using human A(2a) adenosine receptor and the resolved NMR based structure of the third extracellular loop of the CCK-2R as templates. Further in order to identify novel antiulcer agents, rational designing have been performed utilizing the substructure of a well-known CCK-2R antagonist benzotript as a lead molecule and submitted to the combined docking and simulation studies. This led to the understanding of the essential structure requirement as well as variation of binding mode among conformational isomers of small molecule CCK-2R antagonists. In the next step, preparation of each configurational isomer of these molecules was carried out and submitted for their in vitro activity followed by in vivo screening into antiulcer rat model. The biological screening of these compounds has not only validated the developed homology model of CCK-2R but also led to the identification of highly potent CCK-2R antagonist 6a as an orally active and safe candidate molecule having better antiulcer properties than the well-known drug benzotript. PMID:23240656

  1. P2X7 receptor antagonists protect against N-methyl-d-aspartic acid-induced neuronal injury in the rat retina.

    PubMed

    Sakamoto, Kenji; Endo, Kanako; Suzuki, Taishi; Fujimura, Kyosuke; Kurauchi, Yuki; Mori, Asami; Nakahara, Tsutomu; Ishii, Kunio

    2015-06-01

    Activation of N-methyl-d-aspartic acid (NMDA) receptors followed by a large Ca(2+) influx is thought to be a mechanism of glaucoma-induced neuronal cell death. It is possible that damage-associated molecular patterns leak from injured cells, such as adenosine triphosphate, causing retinal ganglion cell death in glaucoma. In the present study, we histologically investigated whether antagonists of the P2X7 receptor protected against NMDA-induced retinal injury in the rat in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal injection of NMDA. We used A438079 (3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine) and brilliant blue G as P2X7 receptor antagonists. Upon morphometric evaluation 7 days after an intravitreal injection (200 nmol/eye), NMDA-induced cell loss was apparent in the ganglion cell layer. Intravitreal A438079 (50 pmol/eye) simultaneously injected with NMDA and intraperitoneal brilliant blue G (50 mg/kg) administered just before the NMDA injection as well as 24 and 48h after significantly reduced cell loss. In addition, A438079 decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells 12h after NMDA injection. P2X7 receptors were immunolocalized in the ganglion cell layer and the inner and outer plexiform layers, whereas the immunopositive P2X7 receptor signal was not detected on the Iba1-positive microglial cells that infiltrated the retina 12h after NMDA injection. The present study shows that stimulation of the P2X7 receptor is involved in NMDA-induced histological damage in the rat retina in vivo. P2X7 receptor antagonists may be effective in preventing retinal diseases caused by glutamate excitotoxicity, such as glaucoma and retinal artery occlusion. PMID:25796199

  2. Toxic Identification and Evaluation of Androgen Receptor Antagonistic Activities in Acid-Treated Liver Extracts of High-Trophic Level Wild Animals from Japan.

    PubMed

    Misaki, Kentaro; Suzuki, Go; Tue, Nguyen Minh; Takahashi, Shin; Someya, Masayuki; Takigami, Hidetaka; Tajima, Yuko; Yamada, Tadasu K; Amano, Masao; Isobe, Tomohiko; Tanabe, Shinsuke

    2015-10-01

    Sulfuric acid-treated liver extracts of representative high-trophic level Japanese animals were analyzed by toxic identification and evaluation (TIE) with chemically activated luciferase expression (CALUX) and chemical analysis to elucidate androgen receptor (AR) antagonistic activities and potential contributions of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). The activities were detected in striped dolphins (n = 5), Stejneger's beaked whales (n = 6), golden eagle (n = 1), and Steller's sea eagle (n = 1) with CALUX-flutamide equivalents (FluEQs) as follow: 38 (20-52), 47 (21-96), 5.0, and 80 ?g FluEQ/g-lipid, respectively. The AR antagonism was detected in limited number of specimens at lower levels for finless porpoise, raccoon dog, and common cormorant. Theoretical activities (Theo-FluEQs) were calculated using the concentration of OCPs and PCBs and their IC25-based relative potency (REP) values. These total contribution to CALUX-FluEQ was 126%, 84%, 53%, 55%, and 44% for striped dolphin, Steller's sea eagle, Stejneger's beaked whale, finless porpoise, and golden eagle, respectively, and the main contributor was p,p'-DDE. However, most of the activities for raccoon dog (7.6%) and common cormorant (17%) could not be explained by OCPs and PCBs. This suggests other unknown compounds could function as AR antagonists in these terrestrial species. PMID:26321157

  3. Boronic acid-containing CXCR1/2 antagonists: Optimization of metabolic stability, in vivo evaluation, and a proposed receptor binding model.

    PubMed

    Maeda, Dean Y; Peck, Angela M; Schuler, Aaron D; Quinn, Mark T; Kirpotina, Liliya N; Wicomb, Winston N; Auten, Richard L; Gundla, Rambabu; Zebala, John A

    2015-06-01

    Blockade of undesired neutrophil migration to sites of inflammation remains an area of substantial pharmaceutical interest. To effect this blockade, a validated therapeutic target is antagonism of the chemokine receptor CXCR2. Herein we report the discovery of 6-(2-boronic acid-5-trifluoromethoxy-benzylsulfanyl)-N-(4-fluoro-phenyl)-nicotinamide 6, an antagonist with activity at both CXCR1 and CXCR2 receptors (IC50 values 31 and 21 nM, respectively). Compound 6 exhibited potent inhibition of neutrophil influx in a rat model of pulmonary inflammation, and is hypothesized to interact with a unique intracellular binding site on CXCR2. Compound 6 (SX-576) is undergoing further investigation as a potential therapy for pulmonary inflammation. PMID:25933594

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

    PubMed

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

    2013-01-01

    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

  5. Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.

    PubMed

    McDonald, Iain M; Black, James W; Buck, Ildiko M; Dunstone, David J; Griffin, Eric P; Harper, Elaine A; Hull, Robert A D; Kalindjian, S Barret; Lilley, Elliot J; Linney, Ian D; Pether, Michael J; Roberts, Sonia P; Shaxted, Mark E; Spencer, John; Steel, Katherine I M; Sykes, David A; Walker, Martin K; Watt, Gillian F; Wright, Laurence; Wright, Paul T; Xun, Wei

    2007-06-28

    Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration. PMID:17536796

  6. 2-Amino-7-phosphonoheptanoic acid, a selective N-methyl-D-aspartate antagonist, blocks swim-induced elevation of cerebellar cyclic guanosine monophosphate.

    PubMed

    McCaslin, P P; Morgan, W W

    1986-11-19

    In order to explore how rapidly locomotor activity induces an elevation in cerebellar cyclic guanosine monophosphate (cGMP) content, Sprague-Dawley rats, pretrained to swim a 2.5-m course, were required to swim from one to 5 laps representing from 7 to 40s of strenuous activity. Immediately after completing the swimming task, each animal was killed by microwave irradiation and the cerebellum was collected for subsequent determination of the cGMP content. There was no difference in the cerebellar cGMP content between rats swimming one lap, i.e. for 7 s, and control rats that did not swim. However, there was a linear increase in the cGMP over control values from 1.8- to 2.4-fold in rats swimming 3 and 5 times, respectively. The first significant elevation of the cerebellar cGMP was seen at 24 s (3 laps). To determine if acidic amino acid pathways were involved in this elevation, a low dosage of a selective NMDA antagonist, 2-amino-7-phosphonoheptanoic acid (APH) was injected intracerebroventricularly 4 min before having rats swim 4 laps. This low dosage of APH, which alone had no effect on the cerebellar cGMP content, completely blocked the swim-induced elevation of this parameter. These data provide the first report of how quickly locomotor activity elevates the cerebellar cGMP content and further suggest that an NMDA receptor-mediated pathway is involved in the activity-induced elevation of this parameter. PMID:3026565

  7. Relationship between the 19 base pair deletion polymorphism in DHFR and unmetabolized folic and in plasma and RBC folate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: A 19 base pair (bp) deletion allele of dihydrofolate reductase (DHFR), an enzyme that makes folic acid metabolically active and reduces dihydrofolate to tetrahydrofolate to stimulate folate turnover, has been implicated in folate related health outcomes. Objective: Examine the effect ...

  8. Calcitonin gene-related peptide analogues with aza and indolizidinone amino acid residues reveal conformational requirements for antagonist activity at the human calcitonin gene-related peptide 1 receptor.

    PubMed

    Boeglin, Damien; Hamdan, Fadi F; Melendez, Rosa E; Cluzeau, Jérôme; Laperriere, Andre; Héroux, Madeleine; Bouvier, Michel; Lubell, William D

    2007-03-22

    Calcitonin gene-related peptide antagonists have potential for the treatment and prevention of disease states such as non-insulin-dependent diabetes mellitus, migraine headache, pain, and inflammation. To gain insight into the spatial requirements for CGRP antagonism, three strategies were employed to restrict the conformation of the potent undecapeptide antagonist, [D31,P34,F35]CGRP27-37. First, aza-amino acid scanning was performed, and ten aza-peptide analogues were synthesized and examined for biological activity. Second, (3S,6S,9S)-2-oxo-3-amino-indolizidin-2-one amino acid (I2aa) and (2S,6S,8S)-9-oxo-8-amino-indolizidin-9-one amino acid (I9aa) both were introduced at positions 31-32, 32-33, 33-34, and 34-35, regions of the backbone expected to adopt turns. Finally, the conformation of the backbone and side-chain of the C-terminal residue, Phe35-Ala36-Phe37-NH2, was explored employing (2S,4R,6R,8S)-9-oxo-8-amino-4-phenyl-indolizidin-9-one amino acid (4-Ph-I9aa) as a constrained phenylalanine mimic. The structure-activity relationships exhibited by our 26 analogues illustrate conformational requirements important for designing CGRP antagonists and highlight the importance of beta-turns centered at Gly33-Pro34 for potency. PMID:17319653

  9. Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine

    PubMed Central

    Parsons, E; Cowen, LG; McTavish, SF; Cowen, PJ; Harmer, CJ

    2012-01-01

    There is growing interest in the role of the glutamatergic system both in depression and as a novel target for treatments. Preclinical studies suggested that the non-competitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine might have antidepressant properties, but a randomised controlled trial failed to support this. A healthy volunteer model of emotional processing was used to assess the neuropsychological profile of action of memantine. Healthy volunteers (n=32) were randomised to receive a single dose of memantine (10 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory, dot-probe and emotion-potentiated startle tasks, as well as working and verbal memory. Memantine treated volunteers showed an increased emotion-potentiated startle, and a reduced bias for negative items in emotional recognition memory. There were no effects of the drug on any other aspect of emotional or non-emotional information processing. These results suggest that a single dose of memantine produces an early anxiogenic response in the emotion-potentiated startle similar to that seen following a single dose of the selective serotonin reuptake inhibitor, citalopram. However, the overall profile of effects is more limited than that which might be expected in response to a conventional antidepressant. PMID:22596208

  10. Zhankuic Acid A Isolated from Taiwanofungus camphoratus Is a Novel Selective TLR4/MD-2 Antagonist with Anti-Inflammatory Properties

    PubMed Central

    Chen, Yu-Fon; Shiau, Ai-Li; Wang, Sheng-Hung; Yang, Jai-Sing; Chang, Sue-Joan

    2014-01-01

    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

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

    PubMed Central

    2014-01-01

    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

  12. Platelet-activating factor antagonists.

    PubMed

    Negro Alvarez, J M; Miralles López, J C; Ortiz Martínez, J L; Abellán Alemán, A; Rubio del Barrio, R

    1997-01-01

    Platelet-activating factor (PAF), identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, exhibits potent proinflammatory properties. PAF is produced by numerous cell types, including endothelial cells, neutrophils, monocytes, macrophages, basophils, eosinophils and mastocytes. Since the discovery and identification of the chemical structure of PAF, a large variety of specific PAF-receptor antagonists, both natural and synthetic compounds, have been described. Intensive research has been conducted and development programs set up by more 25 pharmaceutical companies world-wide, studying the therapeutic interest of more than 50 PAF-receptors antagonists in various pathophysiological conditions. Medline (1966-1996), Embase (Excerpta Medica; 1974-1996), and other biomedical and drug directory databases were searched to identify English-language articles (basic science, clinical trial research, and review articles) and abstracts of conference proceedings on PAF receptor antagonists and related terms. The most important PAF receptor antagonists are reviewed with their effectiveness in various experimental tests. Fundamentally, PAF antagonists may be divided in two groups: natural and synthetic compounds. Natural (Ginkgolides, Kadsurenone, Chantancin, Phomactin, Swietemohonin A, Prehispalone, THC-7-oic acid, Aglafoline, FR 900452, PCA 4248 and SCH 37370), and synthetic antagonists (CV-3988, CV-6209, SRI 63-072, SRI 63-441, UR-10324, UR-11353, E-5880, CL 184005, 6-Mono and Bis-aryl phosphate antagonists, TCV-309, Ro-74719, WEB 2086, Y 24180, BN 50726, BN 50727, BN 50730, BN 50739, Ro 24-4736, Ro 24-0238, RP 55778, RP 59227, RP 66681, YM 264, YM 461, SM 10661, SR 27417, UK 74505, BB 182, BB 823, BB 654, SDZ 64-412, SDZ 65-123, L 652731, L 659898, L 668750, L 671284, L680573, L 680574, CIS 19, ABT-299 and Pinusolide) have a great variability in their chemical structure that might have importance in their different pharmacological profile. The great majority of these drugs are under development, and only a few have undergone clinical trials. PMID:9395010

  13. Indication of acid suppression therapy and predictors for the prophylactic use of protonpump inhibitors vs. histamine-2 receptor antagonists in a Malaysian tertiary hospital

    PubMed Central

    Oh, Ai L.; Tan, Andrew G.; Phan, Hui S.; Lee, Basil C.; Jumaat, Nafisah; Chew, Soo P.; Wong, Siok H.; Ting, Shee H.; Subramaniam, Theebaa

    2015-01-01

    Background: Proton-pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA) are common acid suppressants used in gastrointestinal disorders. The trend of usage in Malaysia has changed from predominantly H2RA to PPI from 2007 to 2008, 3.46 versus 2.87 and 2.99 versus 3.24 DDD (Defined Daily Dose)/1000 population/day respectively. This raises concerns as PPI overutilization amounts to higher cost expenditure and are associated with various untoward consequences such as Clostridium difficile-associated diarrhea, pneumonia, and osteoporosis. Objectives: To evaluate the indication of acid suppression therapy (AST) and to look for predictors associated with the prophylactic use of PPI as compared to H2RA. Methods: Data collection was conducted via a standardized surveillance form over a 2-month period in the general medical wards of Sarawak General Hospital. All patients who received at least one dose of PPI or H2RA in any dosage form were included in the study. Appropriateness of prophylaxis was determined using current available guidelines. Selected risk factors were analysed using simple logistic regression to look for predictors associated with the choice of PPI in prophylactic AST. Results: Out of 212 cases in the present cohort, about three quarters (75.5%, n=160) of acid suppressants were given as prophylaxis. Over half of these did not have appropriate indications for prophylactic AST (58.1%, n=93). Among all cases given prophylactic AST, 75.0% (n=120) of them were given PPI. Renal insufficiency was identified as the only predictor associated with the use of prophylactic PPI in preference to H2RA (OR=2.86, 95%CI 1.21:6.72, p=0.011). Conclusion: Inappropriate prophylactic AST is a major concern and may even be underestimated due to the lack of appropriate guidelines. More data is required to guide the selection between PPI and H2RA, specifically the more cost-effective use of H2RA in patients with lower gastrointestinal risk or in whom PPI has no clear advantage. PMID:26445624

  14. Discovery of substituted-2,4-dimethyl-(naphthalene-4-carbonyl)amino-benzoic acid as potent and selective EP4 antagonists.

    PubMed

    Blanco, Maria-Jesus; Vetman, Tatiana; Chandrasekhar, Srinivasan; Fisher, Matthew J; Harvey, Anita; Mudra, Daniel; Wang, Xu-Shan; Yu, Xiao-Peng; Schiffler, Matthew A; Warshawsky, Alan M

    2016-01-01

    A novel series of EP4 antagonists, based on a quinoline scaffold, has been discovered. Medicinal chemistry efforts to optimize the potency of the initial hit are described. A highly potent compound in a clinically relevant human whole blood assay was identified. Selectivity and pharmacokinetic profiles of this compound are discussed. PMID:26608552

  15. Rational discovery of novel nuclear hormone receptor antagonists

    NASA Astrophysics Data System (ADS)

    Schapira, Matthieu; Raaka, Bruce M.; Samuels, Herbert H.; Abagyan, Ruben

    2000-02-01

    Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor- by using information derived from antagonist-bound estrogen receptor-? and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

  16. The antagonistic strain Bacillus subtilis UMAF6639 also confers protection to melon plants against cucurbit powdery mildew by activation of jasmonate-and salicylic acid-dependent defence responses

    PubMed Central

    García-Gutiérrez, Laura; Zeriouh, Houda; Romero, Diego; Cubero, Jaime; Vicente, Antonio; Pérez-García, Alejandro

    2013-01-01

    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

  17. The antagonistic strain Bacillus subtilis?UMAF6639 also confers protection to melon plants against cucurbit powdery mildew by activation of jasmonate- and salicylic acid-dependent defence responses.

    PubMed

    García-Gutiérrez, Laura; Zeriouh, Houda; Romero, Diego; Cubero, Jaime; de Vicente, Antonio; Pérez-García, Alejandro

    2013-05-01

    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

  18. Investigation on bile acid receptor regulators. Discovery of cholanoic acid derivatives with dual G-protein coupled bile acid receptor 1 (GPBAR1) antagonistic and farnesoid X receptor (FXR) modulatory activity.

    PubMed

    Sepe, Valentina; Renga, Barbara; Festa, Carmen; Finamore, Claudia; Masullo, Dario; Carino, Adriana; Cipriani, Sabrina; Distrutti, Eleonora; Fiorucci, Stefano; Zampella, Angela

    2016-01-01

    Bile acids, the end products of cholesterol metabolism, activate multiple mechanisms through the interaction with membrane G-protein coupled receptors including the bile acid receptor GPBAR1 and nuclear receptors such as the bile acid sensor, farnesoid X receptor (FXR). Even if dual FXR/GPBAR1 agonists are largely considered a novel opportunity in the treatment of several liver and metabolic diseases, selective targeting of one of these receptors represents an attractive therapeutic approach for a wide range of disorders in which dual modulation is associated to severe side effects. In the present study we have investigated around the structure of LCA generating a small library of cholane derivatives, endowed with dual FXR agonism/GPBAR1 antagonism. To the best of our knowledge, this is the first report of bile acid derivatives able to antagonize GPBAR1. PMID:26607331

  19. 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.

    PubMed

    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

    2002-12-19

    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

  20. Activation of hippocampal BDNF signaling is involved in the antidepressant-like effect of the NMDA receptor antagonist 7-chlorokynurenic acid.

    PubMed

    Li, Cheng-Fu; Chen, Xue-Mei; Chen, Shao-Mei; Mu, Rong-Hao; Liu, Bin-Bin; Luo, Liu; Liu, Xiao-Long; Geng, Di; Liu, Qing; Yi, Li-Tao

    2016-01-01

    Previous studies showed that acute 7-chlorokynurenic acid treatment produced a rapid antidepressant-like action in depression-like animal models. However, the underlying mechanism involved in neurotrophin system about 7-chlorokynurenic acid is unclear. Our present study aimed to verify whether chronic 7-chlorokynurenic acid treatment produced an antidepressant-like effect through the activation of brain-derived neurotrophic factor (BDNF) signaling in mice exposed to chronic unpredictable mild stress (CUMS). In addition, we performed an oral toxicological evaluation of chronic 7-chlorokynurenic acid administration in mice. The results showed that a two-week administration with 7-chlorokynurenic acid reversed the decreased sucrose preference and prolonged first feeding latency. In addition, 7-chlorokynurenic acid significantly reversed the CUMS-induced down-regulation of BDNF, p-ERK, p-Akt, PSD-95, synapsin I and cell proliferation in the hippocampus. In contrast, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), blocked the antidepressant-like effect and the improvement of 7-chlorokynurenic acid. Furthermore, we found that 7-chlorokynurenic acid did not produce any toxicological effect in mice. In conclusion, our findings suggest that the antidepressant-like effect of 7-chlorokynurenic acid may be mediated, at least in part, by activating BDNF signaling in the hippocampus. PMID:26562663

  1. A novel antagonist, phenylbenzene omega-phosphono-alpha-amino acid, for strychnine-sensitive glycine receptors in the rat spinal cord.

    PubMed Central

    Saitoh, T; Ishida, M; Maruyama, M; Shinozaki, H

    1994-01-01

    1. 3-[2'-Phosphonomethyl[1,1'-biphenyl]-3-yl]alanine (PMBA) is a novel glycine antagonist at strychnine-sensitive receptors. The chemical structure of PMBA, possessing both a glycine moiety and a phosphono group, is quite different from that of strychnine. 2. In the spinal motoneurone of newborn rats, glycine (100 microM-1 mM) induced depolarizing responses in a concentration-dependent manner. PMBA effectively inhibited depolarizing responses to glycine and other agonists, such as taurine and beta-alanine. The dose-response curves for glycine were shifted to the right in an almost parallel manner (pA2 value: 5.30 +/- 0.23, n = 5) by PMBA which was about 60 times less potent than strychnine (pA2 value: 7.08 +/- 0.21, n = 5) as a glycine antagonist. 3. PMBA (1-100 microM) did not interact with modulatory glycine sites on N-methyl-D-aspartate (NMDA) receptors, which suggests a high selectivity of PMBA for strychnine-sensitive glycine receptors. At considerably high concentrations (0.1 mM-1 mM), PMBA depressed responses to GABA (pA2 value: 3.57 +/- 0.24, n = 3). 4. PMBA inhibited the binding of [3H]-strychnine to synaptosomes from adult rat spinal cords; the IC50 values of PMBA, glycine and strychnine were 8 +/- 2, 9 +/- 3 and 0.08 +/- 0.04 microM, respectively (n = 5) for [3H]-strychnine (4.8 nM). 5. PMBA is a central excitant drug with relatively high potency and selectivity and should be useful as a pharmacological probe for analysing the mechanisms underlying physiological functions of glycine receptors. PMID:7812607

  2. Mesoporous Silica with Site-Isolated Amine and Phosphotungstic Acid Groups: A Solid Catalyst with Tunable Antagonistic Functions for One-Pot Tandem Reactions

    SciTech Connect

    Shiju N. R.; Syed K.; Alberts A.; Brown D. and Rothenberg G.

    2011-09-15

    A bifunctional solid catalyst is prepared by combining acid and base functions on mesoporous silica supports. The co-existence of these functions is shown by a two-step reaction sequence in one pot. Excellent product yields, which cannot be obtained by separated acid and base functions in one pot, show the validity of our concept.

  3. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) FOOD ADDITIVES...DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Special Dietary and Nutritional...the Federal Food, Drug, and Cosmetic Act (the act) when the...

  4. 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 ...

  5. 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...

  6. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...serving if the food is a meal-replacement that is represented for use once per day; or (2) Two hundred µg per serving if the food is a meal-replacement that is...for use more than once per day. [61 FR 8807,...

  7. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...serving if the food is a meal-replacement that is represented for use once per day; or (2) Two hundred µg per serving if the food is a meal-replacement that is...for use more than once per day. [61 FR 8807,...

  8. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...serving if the food is a meal-replacement that is represented for use once per day; or (2) Two hundred µg per serving if the food is a meal-replacement that is...for use more than once per day. [61 FR 8807,...

  9. 21 CFR 172.345 - Folic acid (folacin).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...serving if the food is a meal-replacement that is represented for use once per day; or (2) Two hundred µg per serving if the food is a meal-replacement that is...for use more than once per day. [61 FR 8807,...

  10. Ago-Antagonistic Systems

    NASA Astrophysics Data System (ADS)

    Bernard-Weil, Élie

    Today, bio-medical sciences and human sciences in general are demanding some new epistemological paradigms, in the same manner that quantum physics began to proceed to a renewal of this kind eighteen years ago. Such paradigms seem to be connected with systems science, and especially a special branch of it, called agonistic-antagonistic systemics (AAS), combining co-operativity and conflict between two poles. AAS is under the necessity of considering, at the same time, both sides of whatever phenomenon—which may appear as contradictory, opposite or only different—and, finally, of taking into account the unity to which both sides belong. The dynamics study of the behavior of these couples, or of the so-called agonistic-antagonistic networks, allows to better understand the occurrence of amazing phenomena, as well as to consider special types of control, when agonistic antagonistic unbalances have occurred.

  11. 3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a Selective Antagonist of Sphingosine-1-phospahte Receptor Subtype 1, Enhances AMD3100-stimulated Mobilization of Hematopoietic Stem Progenitor Cells in Animals.

    PubMed

    Liu, Jingjing; Zhao, Jiawei; Lee, Jen-Fu; Gartung, Allison; Jawadi, Hiba; Zhang, Wenliang; Lominadze, David; Lee, Menq-Jer

    2013-12-01

    Sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, regulates various physiological functions. We observed that the S1P receptor subtype 1 (S1P1), a high affinity G-protein coupled receptor of S1P, is the major S1P receptor expressed in the Kit(+)/Sca-1(+)/Lin(-) (KSL) hematopoietic stem progenitor cells (HSPCs, KSL-HSPCs). In this study, we investigate function of S1P1 receptors in the regulation of HSPC mobilization in animals. Treatment with SEW2871, a specific agonist of S1P1, had no effect on KSL-HSPC mobilization. In addition, mice pretreated with SEW2871 followed by AMD3100, a well-known activator of KSL-HSPC mobilization by antagonizing the stromal-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) signaling axis, did not enhance the AMD3100-induced KSL-HSPC mobilization. In contrast, pretreatment of (R)-3-amino-4-(3-hexylphenylamino)-4-oxobutyl phosphonic acid (W146), a selective antagonist of S1P1, significantly augments AMD3100-induced KSL-HSPC mobilization into peripheral blood. The inactive enantiomer W140 was incapable of enhancing the AMD3100-induced KSL-HSPC mobilization. Moreover, treatment with selective antagonists for S1P2 and S1P3 had no effects on AMD3100-mediated KSL-HSPC mobilization. Collectively, our data suggest that S1P/S1P1 signaling regulates the SDF-1/CXCR4-mediated retention of KSL-HSPCs in bone marrow microenvironment. PMID:25383272

  12. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  13. 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

    Simon, M.F.; Chap, H.; Braquet, P.; Douste-Blazy, L.

    1987-02-15

    /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.

  14. N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 blocks non-opioid stress-induced analgesia. II. Comparison across three swim-stress paradigms in selectively bred mice.

    PubMed

    Marek, P; Mogil, J S; Sternberg, W F; Panocka, I; Liebeskind, J C

    1992-04-24

    The effects of the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 (dizocilpine, 0.075 mg/kg, i.p.) on swim-stress-induced analgesia (SSIA) were studied in control (C) mice and in mice selectively bred for high (HA) or low (LA) SSIA. In three consecutive experiments, animals were subjected to forced swimming at water temperature of 20 degrees C, 32 degrees C and 15 degrees C and the resulting analgesia (hot-plate test) was found to be mixed opioid/non-opioid, opioid and non-opioid, respectively, as a function of the degree of antagonism by naloxone (10 mg/kg, i.p.). The major finding of this study is that MK-801 attenuated 15 degrees C SSIA, against which naloxone was ineffective, but had no effect on 32 degrees C SSIA, which naloxone blocked completely. A combination of naloxone and MK-801 significantly attenuated 20 degrees C SSIA in C and HA mice and in HA mice this attenuation was significantly larger than that produced by either drug alone. Morphine analgesia (10 mg/kg, i.p.) was unaffected by MK-801. It is concluded that low doses of MK-801 selectively block non-opioid mechanisms of SSIA. PMID:1387334

  15. LXR antagonists induce ABCD2 expression.

    PubMed

    Gondcaille, Catherine; Genin, Emmanuelle C; Lopez, Tatiana E; Dias, Alexandre M M; Geillon, Flore; Andreoletti, Pierre; Cherkaoui-Malki, Mustapha; Nury, Thomas; Lizard, Gérard; Weinhofer, Isabelle; Berger, Johannes; Kase, Eili T; Trompier, Doriane; Savary, Stéphane

    2014-02-01

    X-linked adrenoleukodystrophy (X-ALD) is a rare neurodegenerative disorder characterized by the accumulation of very-long-chain fatty acids resulting from a beta-oxidation defect. Oxidative stress and inflammation are also key components of the pathogenesis. X-ALD is caused by mutations in the ABCDI gene, which encodes for a peroxisomal half ABC transporter predicted to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their beta-oxidation. Two homologous peroxisomal ABC transporters, ABCD2 and ABCD3 have been proven to compensate for ABCD1 deficiency when overexpressed. Pharmacological induction of these target genes could therefore represent an alternative therapy for X-ALD patients. Since LXR activation was shown to repress ABCD2 expression, we investigated the effects of LXR antagonists in different cell lines. Cells were treated with GSK(17) (a LXR antagonist recently discovered from the GlaxoSmithKline compound collection), 22(S)-hydroxycholesterol (22S-HC, another LXR antagonist) and 22R-HC (an endogenous LXR agonist). We observed up-regulation of ABCD2,ABCD3 and CTNNB1 (the gene encoding for beta-catenin, which was recently demonstrated to induce ABCD2 expression) in human HepG2 hepatoma cells and in X-ALD skin fibroblasts treated with LXR antagonists. Interestingly, induction in X-ALD fibroblasts was concomitant with a decrease in oxidative stress. Rats treated with 22S-HC showed hepatic induction of the 3 genes of interest. In human, we show by multiple tissue expression array that expression of ABCD2 appears to be inversely correlated with NR1H3 (LXRalpha) expression. Altogether, antagonists of LXR that are currently developed in the context of dyslipidemia may find another indication with X-ALD. PMID:24239766

  16. Retinoic acid receptor antagonist BMS453 inhibits the growth of normal and malignant breast cells without activating RAR-dependent gene expression.

    PubMed

    Yang, L; Munoz-Medellin, D; Kim, H T; Ostrowski, J; Reczek, P; Brown, P H

    1999-08-01

    To elucidate the role of RAR-dependent gene transcription in inhibiting breast cell growth, we have investigated the ability of retinoids to suppress growth of normal, immortal, and malignant breast cells. We compared the ability of all trans retinoic acid (atRA) to activate retinoid receptors in normal, immortal, and malignant breast cells, with its ability to inhibit the growth of these cells. Our studies demonstrate that normal breast cells are more sensitive to the growth inhibitory effect of atRA than are immortal nonmalignant breast cells and breast cancer cells. atRA activated RAR-dependent gene transcription in both atRA-sensitive and -resistant breast cells as determined by transfection of a RARE-containing reporter gene. These results demonstrate that activation of RAR-dependent gene transcription by atRA is not sufficient to inhibit growth in atRA-resistant breast cancer cells. To determine whether activation of RAR-dependent gene transcription by atRA is necessary for growth inhibition, we tested the growth suppressive effect of a retinoid (BMS453) which binds RAR receptors and transrepresses AP-1 but does not activate RAR-dependent gene expression. This retinoid inhibited the growth of normal breast cells (HMEC and 184) and T47D breast cancer cells. Breast cancer cells which were resistant to atRA, were also resistant to BMS453. Normal human breast cells were most sensitive to the anti-proliferative effects of BMS453. These results indicate that in some breast cells RAR-dependent transactivation is not necessary for retinoids to inhibit growth. Instead, retinoids may suppress growth by inhibiting transcription factors such as AP-1 through transcription factor crosstalk. PMID:10573118

  17. Biomolecular recognition of antagonists by ?7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure-activity relationships studies.

    PubMed

    Peng, Wei; Ding, Fei

    2015-08-30

    As the key constituent of ligand-gated ion channels in the central nervous system, nicotinic acetylcholine receptors (nAChRs) and neurodegenerative diseases are strongly coupled in the human species. In recently years the developments of selective agonists by using nAChRs as the drug target have made a large progress, but the studies of selective antagonists are severely lacked. Currently these antagonists rest mainly on the extraction of partly natural products from some animals and plants; however, the production of these crude substances is quite restricted, and artificial synthesis of nAChR antagonists is still one of the completely new research fields. In the context of this manuscript, our primary objective was to comprehensively analyze the recognition patterns and the critical interaction descriptors between target ?7 nAChR and a series of the novel compounds with potentially antagonistic activity by means of virtual screening, molecular docking and molecular dynamics simulation, and meanwhile these recognition reactions were also compared with the biointeraction of ?7 nAChR with a commercially natural antagonist - methyllycaconitine. The results suggested clearly that there are relatively obvious differences of molecular structures between synthetic antagonists and methyllycaconitine, while the two systems have similar recognition modes on the whole. The interaction energy and the crucially noncovalent forces of the ?7 nAChR-antagonists are ascertained according to the method of Molecular Mechanics/Generalized Born Surface Area. Several amino acid residues, such as B/Tyr-93, B/Lys-143, B/Trp-147, B/Tyr-188, B/Tyr-195, A/Trp-55 and A/Leu-118 played a major role in the ?7 nAChR-antagonist recognition processes, in particular, residues B/Tyr-93, B/Trp-147 and B/Tyr-188 are the most important. These outcomes tally satisfactorily with the discussions of amino acid mutations. Based on the explorations of three-dimensional quantitative structure-activity relationships, the structure-antagonistic activity relationships of antagonists and the characteristics of ?7 nAChR-ligand recognitions were received a reasonable summary as well. These attempts emerged herein would not only provide helpful guidance for the design of ?7 nAChR antagonists, but shed new light on the subsequent researches in antagonistic mechanism. PMID:25963024

  18. L-[alphaS, 5S]-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (NSC-163501): a new amino acid antibiotic with the properties of an antagonist of L-glutamine.

    PubMed

    Jayaram, H N; Cooney, D A; Ryan, J A; Neil, G; Dion, R L; Bono, V H

    1975-01-01

    L-[alphaS,5S]-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (NSC-163501), an antibiotic elaborated by Streptomyces sviceus, has been shown to be a powerful inhibitor of many mammalian and bacterial reactions involving the transfer of nitrogen from the gamma-carboxamide of L-glutamine. Thus, the utilization of L-glutamine for the synthesis of carbamyl phosphate, L-asparagine, guanosine-5'-monophosphate, cytidine-5'-triphosphate, N-formylglycinamidine ribonucleotide, NAD, glucosamine-6-phosphate, and anthranilic acid is strongly or totally inhibited by a concentration of NSC-163501 of 1 X 10(-3) M. L-Glutamate synthetase of Escherichia coli is only modestly inhibited and 5-phosphoribosylamine synthesis in fetal rat liver is comparatively refractory to inhibition. NSC-163501 treatment of L1210 cells growing in a low L-glutamine culture medium produced arrest in G or early S phase. Of the amino acids tested, only L-glutamine antagonized such growth inhibition. PMID:1147

  19. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice.

    PubMed

    Li, Ning; Zhang, Limin; An, Yanpeng; Zhang, Lulu; Song, Yipeng; Wang, Yulan; Tang, Huiru

    2015-03-01

    Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4. PMID:25669961

  20. Species-specific lipophilicity of morphine antagonists.

    PubMed

    Mazák, Károly; Hosztafi, Sándor; Noszál, Béla

    2015-10-12

    Complete sets of microscopic acid-base and partition equilibrium constants were experimentally determined for therapeutically important morphine derivatives, including the widely used antagonists naloxone and naltrexone. The acid-base microequilibria were characterized by combining pH-potentiometry and deductive methods using synthesized auxiliary compounds. Microscopic protonation equilibria show that approximately three times as many zwitterionic microspecies than non-charged ones exist in oxymorphone and naltrexone solutions. On the other hand, the non-charged microspecies is the dominant one in the case of naloxone, although its concentration is only 1.34 times higher than that of its zwitterionic protonation isomer. Partition coefficients of the individual microspecies were determined by a combination of experimentally measured distribution constants and deductive methods. The contribution ratio of the non-charged versus zwitterionic species to the overall lipophilicity is quantified and depicted in terms of species-specific lipophilicities over the entire pH range for each compound. Our lipophilicity values allowed the molecular interpretation of the classical pharmacologic observation that naloxone has a faster onset for antagonist activity, and a concomitant shorter duration of action. PMID:26122463

  1. Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists III: the role of a hydrogen-bond acceptor in long receptor residence times.

    PubMed

    Alonso, Juan Antonio; Andrés, Miriam; Bravo, Mónica; Buil, Maria Antonia; Calbet, Marta; Castro, Jordi; Eastwood, Paul R; Esteve, Cristina; Ferrer, Manel; Forns, Pilar; Gómez, Elena; González, Jacob; Lozoya, Estrella; Mir, Marta; Moreno, Imma; Petit, Silvia; Roberts, Richard S; Sevilla, Sara; Vidal, Bernat; Vidal, Laura; Vilaseca, Pere

    2014-11-01

    The correct positioning and orientation of an hydrogen bond acceptor (HBA) in the tail portion of the biaryl series of CRTh2 antagonists is a requirement for long receptor residence time. The HBA in combination with a small steric substituent in the core section (R(core) ? H) gives access to compounds with dissociation half-lives of ? 24h. PMID:25437506

  2. Cytotoxic mechanisms of glutamine antagonists in mouse L1210 leukemia.

    PubMed

    Lyons, S D; Sant, M E; Christopherson, R I

    1990-07-01

    The glutamine antagonists, acivicin (NSC 163501), azaserine (NSC 742), and 6-diazo-5-oxo-L-norleucine (DON) (NSC 7365), are potent inhibitors of many glutamine-dependent amidotransferases in vitro. Experiments performed with mouse L1210 leukemia growing in culture show that each antagonist has different sites of inhibition in nucleotide biosynthesis. Acivicin is a potent inhibitor of CTP and GMP synthetases and partially inhibits N-formylglycineamidine ribotide (FGAM) synthetase of purine biosynthesis. DON inhibits FGAM synthetase, CTP synthetase, and glucosamine-6-phosphate isomerase. Azaserine inhibits FGAM synthetase and glucosamine-6-phosphate isomerase. Large accumulations of FGAR and its di- and triphosphate derivatives were observed for all three antagonists which could interfere with the biosynthesis of nucleic acids, providing another mechanism of cytotoxicity. Acivicin, azaserine, and DON are not potent inhibitors of carbamyl phosphate synthetase II (glutamine-hydrolyzing) and amidophosphoribosyltransferase in leukemia cells growing in culture although there are reports of such inhibitions in vitro. Blockade of de novo purine biosynthesis by these three antagonists results in a "complementary stimulation" of de novo pyrimidine biosynthesis. PMID:2358467

  3. Endothelin Receptors and Their Antagonists???

    PubMed Central

    Maguire, Janet J.; Davenport, Anthony P.

    2015-01-01

    Summary All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein–coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ETA receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ETB. The renal vascular endothelium only expresses the ETB subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ETB in in the nephron to reduce salt and water re-absorption. In contrast, ETA predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ETA (BQ123, TAK-044) and ETB (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ETA/ETB antagonists or display ETA selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease. PMID:25966344

  4. Endothelin receptors and their antagonists.

    PubMed

    Maguire, Janet J; Davenport, Anthony P

    2015-03-01

    All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease. PMID:25966344

  5. A new alcohol antagonist: Phaclofen

    SciTech Connect

    Allan, A.M. ); Harris, R.A. )

    1989-01-01

    The ability of the GABA{sub B} receptor antagonist, phaclofen to alter behavioral effects of ethanol was evaluated by loss of righting reflex (sleep time), motor incoordination (bar holding), spontaneous locomotion (open field activity) and hypothermia. Pretreatment with phaclofen significantly decreased the effects of ethanol on motor incoordination, locomotor activity and hypothermia. However, phaclofen had no effect on either pentobarbital- or diazepam-induced motor incoordination. Phaclofen slightly increased the ED{sub 50} for loss of the righting reflex but did not alter either the duration of reflex loss produced by ethanol or blood ethanol levels at awakening. Our results suggest phaclofen is rapidly inactivated resulting in difficulty in observing antagonism of long duration ethanol effects. These findings suggest that the GABA{sub B} system may play a role in mediating several important actions of ethanol.

  6. Alpha 2 agonists and antagonists.

    PubMed

    Paddleford, R R; Harvey, R C

    1999-05-01

    The alpha 2 agonists can produce reliable dose-dependent sedation and analgesia in most species. Nevertheless, they can also produce significant physiological adverse side effects depending on dose, rate, route of administration, and the concurrent use of other CNS depressants. For this reason, it may be best to use a low dose of an alpha 2 agonist as a preanesthetic agent. The alpha 2 agonists are best suited for young, healthy, exercise-tolerant patients. The combining of low doses of alpha 2, opioid, and benzodiazepine agonists results in a synergistic CNS depressant response while minimizing the undesirable side effects of these three classes of drugs. Each group of drugs has specific antagonists available for their reversal, thus allowing veterinarians to reverse one or more of the agonists depending on the desired response. This may represent a significant advantage to the use of low-dose alpha 2 agonists in combination with opioids and benzodiazepines. PMID:10332820

  7. Long-acting muscarinic antagonists.

    PubMed

    Melani, Andrea S

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting ??-agonists, eventually in fixed dose combinations. Long-acting ??-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients. PMID:26109098

  8. The discriminative stimulus effects of N-methyl-D-aspartate glycine-site ligands in NMDA antagonist-trained rats.

    TOXLINE Toxicology Bibliographic Information

    Nicholson KL; Balster RL

    2009-04-01

    RATIONALE: Many N-methyl-D-aspartate (NMDA) antagonists produce phencyclidine (PCP)-like side effects that limit their clinical utility. NMDA glycine-site antagonists may be less likely to produce these effects than other site-selective NMDA antagonists.OBJECTIVES: The objective of the study is to compare the discriminative stimulus effects of novel NMDA glycine-site drugs to those of channel blocking and competitive NMDA antagonists.MATERIALS AND METHODS: Drug discrimination studies were performed in separate groups of rats trained with saline vs. PCP (2 mg/kg i.p.) or the competitive antagonist NPC 17742 (4 mg/kg i.p.) using a standard two-lever operant conditioning procedure under an FR32.RESULTS: Neither the partial glycine-site agonists aminocyclopropane carboxylic acid methyl ester and (+)-HA-966 nor the antagonists L701,324; MDL 100,458; MDL 100,748; MDL 103,371; MDL 104,472; MDL 105,519; MRZ 2/571; MRZ 2/576; and ACEA 0762 produced >50% PCP-lever selection, though all were tested over a sufficient dose range to produce response rate decreasing effects. All of the antagonists, except MDL 100,458 and MDL 100,748, were also tested for NPC 17742-like effects, producing somewhat more variable results than in PCP-trained rats. ACEA-0762 produced full substitution for NPC 17742, whereas MDL 105,519 produced no substitution. The remaining compounds engendered between 20% and 80% drug-lever selection.CONCLUSION: These results provide evidence that NMDA glycine-site partial agonists and antagonists generally do not produce discriminative stimulus effects similar to those of representative NMDA channel blockers or competitive antagonists. This suggests that these NMDA glycine-site antagonists should be less likely to produce the undesirable behavioral side effects seen in clinical trials with many other NMDA antagonists.

  9. Effects of the Metabotropic Glutamate Receptor Antagonist MCPG on Phosphoinositide Turnover and Synaptic Plasticity in

    E-print Network

    Bear, Mark

    Effects of the Metabotropic Glutamate Receptor Antagonist MCPG on Phosphoinositide Turnover- servation that the developmental decline in glutamate-stimulated PI turnover is well correlated-aminocyclopentane-1,3-dicarboxylic acid, it fails to block PI turnover and changes in spike adaptation stimulated

  10. 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

    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.

    2013-01-01

    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

  11. Small molecule antagonist of leukocyte function associated antigen-1 (LFA-1): structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521).

    PubMed

    Watterson, Scott H; Xiao, Zili; Dodd, Dharmpal S; Tortolani, David R; Vaccaro, Wayne; Potin, Dominique; Launay, Michele; Stetsko, Dawn K; Skala, Stacey; Davis, Patric M; Lee, Deborah; Yang, Xiaoxia; McIntyre, Kim W; Balimane, Praveen; Patel, Karishma; Yang, Zheng; Marathe, Punit; Kadiyala, Pathanjali; Tebben, Andrew J; Sheriff, Steven; Chang, Chiehying Y; Ziemba, Theresa; Zhang, Huiping; Chen, Bang-Chi; DelMonte, Albert J; Aranibar, Nelly; McKinnon, Murray; Barrish, Joel C; Suchard, Suzanne J; Murali Dhar, T G

    2010-05-13

    Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials. PMID:20405922

  12. Antagonistic competition moderates virulence in Bacillus thuringiensis

    E-print Network

    Obbard, Darren

    LETTER Antagonistic competition moderates virulence in Bacillus thuringiensis Jennie Garbutt,1 competitiveness arises from faster growth. However, diverse modes of parasite competition (resource, mixed infections were less virulent than single-strain infections, and between-strain competition tended

  13. The evolution of sexually antagonistic phenotypes.

    PubMed

    Perry, Jennifer C; Rowe, Locke

    2015-06-01

    Sexual conflict occurs whenever there is sexually antagonistic selection on shared traits. When shared traits result from interactions (e.g., mating rate) and have a different genetic basis in each sex (i.e., interlocus conflict), then sex-specific traits that shift the value of these interaction traits toward the sex-specific optimum will be favored. Male traits can be favored that increase the fitness of their male bearers, but decrease the fitness of interacting females. Likewise, female traits that reduce the costs of interacting with harmful males may simultaneously impose costs on males. If the evolution of these antagonistic traits changes the nature of selection acting on the opposite sex, interesting coevolutionary dynamics will result. Here we examine three current issues in the study of sexually antagonistic interactions: the female side of sexual conflict, the ecological context of sexual conflict, and the strength of evidence for sexually antagonistic coevolution. PMID:26032715

  14. Complications of TNF-? antagonists and iron homeostasis

    EPA Science Inventory

    TNF-? is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-? antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  15. Folic acid content in thermostabilized and freeze-dried space shuttle foods

    NASA Technical Reports Server (NTRS)

    Lane, H. W.; Nillen, J. L.; Kloeris, V. L.

    1995-01-01

    This study was designed to determine whether freeze-dried and thermostabilized foods on a space shuttle contain adequate folate and to investigate any effects of freeze-drying on folacin. Frozen vegetables were analyzed after three states of processing: thawed; cooked; and rehydrated. Thermostabilized items were analyzed as supplied with no further processing. Measurable folate decreased in some freeze-dried vegetables and increased in others. Folacin content of thermostabilized food items was comparable with published values. We concluded that although the folacin content of some freeze-dried foods was low, adequate folate is available from the shuttle menu to meet RDA guidelines.

  16. AMPHOTERICIN B- AND FOLIC ACID-INDUCED NEPHROPATHIES IN DEVELOPING RATS

    EPA Science Inventory

    The kidneys of newborn rats, which are both morphologically and physiologically immature, have been shown to be relatively insensitive to the nephrotoxic effects of several chemicals. To examine the specificity of these age-related differences, pups received either 20 mg/kg of Am...

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

    E-print Network

    Doctor, Vasant Manilal

    1953-01-01

    Thirty 10-wk-old, Rambouillet wethers were used to evaluate the effect of confinement in metabolism stalls on cortisol and specific and non-specific immune function. All lambs were habituated to human contact and maintained in an outside lot...

  18. Molecular basis for selectivity of high affinity peptide antagonists for the gastrin-releasing peptide receptor.

    PubMed

    Tokita, K; Katsuno, T; Hocart, S J; Coy, D H; Llinares, M; Martinez, J; Jensen, R T

    2001-09-28

    Few gastrointestinal hormones/neurotransmitters have high affinity peptide receptor antagonists, and little is known about the molecular basis of their selectivity or affinity. The receptor mediating the action of the mammalian bombesin (Bn) peptide, gastrin-releasing peptide receptor (GRPR), is an exception, because numerous classes of peptide antagonists are described. To investigate the molecular basis for their high affinity for the GRPR, two classes of peptide antagonists, a statine analogue, JMV594 ([d-Phe(6),Stat(13)]Bn(6-14)), and a pseudopeptide analogue, JMV641 (d-Phe-Gln-Trp-Ala-Val-Gly-His-Leupsi(CHOH-CH(2))-(CH(2))(2)-CH(3)), were studied. Each had high affinity for the GRPR and >3,000-fold selectivity for GRPR over the closely related neuromedin B receptor (NMBR). To investigate the basis for this, we used a chimeric receptor approach to make both GRPR loss of affinity and NMBR gain of affinity chimeras and a site-directed mutagenesis approach. Chimeric or mutated receptors were transiently expressed in Balb/c 3T3. Only substitution of the fourth extracellular (EC) domain of the GRPR by the comparable NMBR domain markedly decreased the affinity for both antagonists. Substituting the fourth EC domain of NMBR into the GRPR resulted in a 300-fold gain in affinity for JMV594 and an 11-fold gain for JMV641. Each of the 11 amino acid differences between the GRPR and NMBR in this domain were exchanged. The substitutions of Thr(297) in GRPR by Pro from the comparable position in NMBR, Phe(302) by Met, and Ser(305) by Thr decreased the affinity of each antagonist. Simultaneous replacement of Thr(297), Phe(302), and Ser(305) in GRPR by the three comparable NMBR amino acids caused a 500-fold decrease in affinity for both antagonists. Replacing the comparable three amino acids in NMBR by those from GRPR caused a gain in affinity for each antagonist. Receptor modeling showed that each of these three amino acids faced inward and was within 5 A of the putative binding pocket. These results demonstrate that differences in the fourth EC domain of the mammalian Bn receptors are responsible for the selectivity of these two peptide antagonists. They demonstrate that Thr(297), Phe(302), and Ser(305) of the fourth EC domain of GRPR are the critical residues for determining GRPR selectivity and suggest that both receptor-ligand cation-pi interactions and hydrogen bonding are important for their high affinity interaction. PMID:11463790

  19. 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 ...

  20. DETERMINATION OF 5-METHYLTETRAHYDROFOLIC ACID IN HUMAN SERUM BY STABLE-ISOTOPE DILUTION HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This report describes a stable isotope liquid chromatography-mass spectrometry (LC-MS) method that was developed for the quantitative determination of 5-methyltetrahydrofolic acid (5-MTHFA) and folic acid in a variety of citrus juices. Folates were extracted from juices and the polyglutamyl side ch...

  1. Therapeutic efficacy of dimercaptosuccinic acid and thiamine/ascorbic acid on lead intoxication in rats

    SciTech Connect

    Tandon, S.K.; Flora, S.J.S. )

    1989-11-01

    Thiamine, folic acid, pyridoxine and ascorbic acid either individually or in combination have been proven to be effective in reducing the toxic manifestations of lead and in enhancing the antidotal efficacy of CaNa{sub 2}EDTA. In a recent report from the authors' laboratory, it was observed that given combination of thiamine and ascorbic acid with thiol chelators improved the ability of the animals to excrete lead thereby reducing body lead burden. In view of the beneficial effect of these two vitamins, it was considered of interest to evaluate their potential to modify the prophylactic action of DMS in lead intoxication in rat after repeated administration.

  2. Antagonistic formation motion of cooperative agents

    NASA Astrophysics Data System (ADS)

    Lu, Wan-Ting; Dai, Ming-Xiang; Xue, Fang-Zheng

    2015-02-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonistic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all of the agents make an antagonistic formation motion in a distributed manner. It is shown that all of the agents can be spontaneously divided into several groups and that agents in the same group collaborate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results. Project supported by the National Natural Science Foundation of China (Grant Nos. 61203080 and 61473051) and the Natural Science Foundation of Chongqing City (Grant No. CSTC 2011BB0081).

  3. 3D pharmacophore models for thromboxane A(2) receptor antagonists.

    PubMed

    Wei, Jing; Liu, Yixi; Wang, Songqing

    2009-10-01

    Thromboxane A(2) (TXA(2)) is an endogenous arachidonic acid derivative closely correlated to thrombosis and other cardiovascular diseases. The action of TXA(2) can be effectively inhibited with TXA(2) receptor antagonists (TXRAs). Previous studies have attempted to describe the interactions between the TXA(2) receptor and its ligands, but their conclusions are still controversial. In this study, ligand-based computational drug design is used as a new and effective way to investigate the structure-activity relationship of TXRAs. Three-dimensional pharmacophore models of TXRAs were built with HypoGenRefine and HipHop modules in CATALYST software. The optimal HypoGenRefine model was developed on the basis of 25 TXRAs. It consists of two hydrophobic groups, one aromatic ring, one hydrogen-bond acceptor and four excluded volumes. The optimal HipHop model contains two hydrophobic groups and two hydrogen-bond acceptors. These models describe the key structure-activity relationship of TXRAs, can predict their activities, and can thus be used to design novel antagonists. PMID:19263096

  4. Electrophysiological studies on the specificity of the cholecystokinin antagonist proglumide.

    PubMed

    Chiodo, L A; Freeman, A S; Bunney, B S

    1987-05-01

    Recent evidence suggests that the glutaramic acid derivative proglumide (PROG) is a selective antagonist of cholecystokinin (CCK) in the rat CNS. The extent of this selectivity has now been characterized in more detail. Iontophoretic or intravenous (i.v.) administration of PROG was ineffective against the excitatory effect of iontophoretically applied neurotensin on midbrain dopamine (DA) cells, the excitatory effect of substance P and the inhibitory effect of Met-enkephalin on prefrontal cortical neurons, and the inhibitory effect of histamine on neurons of the sensorimotor cortex. In contrast, PROG blocked the excitatory effect of the C-terminal octapeptide of CCK in all 3 areas. Furthermore, iontophoretic PROG diminished, whereas CCK enhanced the inhibitory effect of similarly applied DA and GABA on DA cells. PROG pretreatment (1 mg/kg, i.v.) reduced the inhibitory potency and maximum effect of i.v. apomorphine (APO) on A9 DA neurons, while the inhibitory potency of APO was enhanced by i.v. CCK. Pretreatment with PROG plus CCK resulted in APO effects which were no different from those after PROG alone. Chronic treatment with PROG (1 mg/kg, p.o., 21 days) resulted in a return to normal of DA cell APO sensitivity. Combined, these findings suggest that PROG may be a relatively selective CCK antagonist, that the functional effect of dendritically released DA may be influenced by endogenously released CCK, and that tolerance may develop to the effects of chronic CCK receptor blockade. PMID:3036308

  5. Antagonistic Control Thomas Lipp and Stephen Boyd

    E-print Network

    and therefore deserving of the 1 #12;most protection. Knowing how quickly a catastrophic event can occur post the best input and state trajectory. The antagonistic control problem is simply the problem of maximizing trajectory. We let p be the optimal value of (2), i.e., the

  6. Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation.

    PubMed

    Shiraishi, M; Kato, K; Terao, S; Ashida, Y; Terashita, Z; Kito, G

    1989-09-01

    A new series of omega-phenyl-omega-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (+/- )-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA2 value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10(-7) M). Compound 4d displaced the binding of [3H]U-46619 to guinea pig platelets (IC50 = 7.4 x 10(-9) M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD4-, PAF-, or IgG1-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA2 receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD2-, PGF2 alpha-, and 11-epi-PGF2 alpha-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity. PMID:2769691

  7. Antagonist-elicited cannabis withdrawal in humans.

    PubMed

    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

    2011-10-01

    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

  8. 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...

  9. Antitussive effects of Ca2+ channel antagonists.

    PubMed

    Kamei, J; Kasuya, Y

    1992-02-25

    The effects of Ca2+ channel antagonists on the capsaicin-induced cough reflex in guinea pigs were studied. Intraperitoneal injection of nifedipine, verapamil and flunarizine in doses that ranged from 0.3 to 3.0 mg/kg decreased the number of coughs in a dose-dependent manner. These Ca2+ channel antagonists exhibited antitussive effects in the following order of potency: flunarizine = verapamil greater than nifedipine. Pretreatment with a low dose of nifedipine (0.3 mg/kg), which by itself had no significant effect on the number of coughs, markedly increased the antitussive effects of morphine, dihydrocodeine and dextromethorphan. These data suggest that Ca2+ channels play an important role in the regulation of the cough reflex. PMID:1555640

  10. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  11. NMDA Receptor Antagonists for Treatment of Depression

    PubMed Central

    Ates-Alagoz, Zeynep; Adejare, Adeboye

    2013-01-01

    Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery. PMID:24276119

  12. Antagonistic Regulation of Arabidopsis Growth by Brassinosteroids and Abiotic Stresses

    PubMed Central

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

    2014-01-01

    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

  13. Modulation of suicidal erythrocyte cation channels by an AMPA antagonist

    PubMed Central

    Föller, Michael; Mahmud, Hasan; Gu, Shuchen; Kucherenko, Yuliya; Gehring, Eva-Maria; Shumilina, Ekaterina; Floride, Elisa; Sprengel, Rolf; Lang, Florian

    2009-01-01

    In neurons alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are heteromeric cation channels composed of different sub-units, including GluA1-GluA4. When expressed without GluA2, AMPA receptors function as Ca2+-permeable cation channels. In erythrocytes, activation of Ca2+-permeable cation channels triggers suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with subsequent exposure of phosphatidylserine at the cell surface. Activators of the channels and thus eryptosis include removal of extracellular Cl? (replaced by gluconate) and energy depletion (removal of glucose). The present study explored whether GluA1 is expressed in human erythrocytes and whether pharmacological AMPA receptor inhibition modifies Ca2+ entry and suicidal death of human erythrocytes. GluA1 protein abundance was determined by confocal microscopy, phosphatidylserine exposure was estimated from annexin V binding, cell volume from forward scatter in FACS analysis, cytosolic Ca2+ concentration from Fluo3 fluorescence and channel activity by whole-cell patch-clamp recordings. As a result, GluA1 is indeed expressed in the erythrocyte cell membrane. The AMPA receptor antagonist NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide) inhibited the cation channels following Cl? removal and the eryptosis following Cl? removal or energy depletion. The present study reveals a novel action of AMPA receptor antagonists and raises the possibility that GluA1 or a pharmacologically related protein participates in the regulation of Ca2+ entry into and suicidal death of human erythrocytes. PMID:19320779

  14. How Is Anemia Treated?

    MedlinePLUS

    ... such as soy-based beverages and vegetarian burgers Folic Acid Folic acid (folate) is a form of vitamin B that's found in foods. Your body needs folic acid to make and maintain new cells. Folic acid ...

  15. Identification and characterisation of a prototype for a new class of competitive PPAR? antagonists.

    PubMed

    Knape, Tilo; Flesch, Daniel; Kuchler, Laura; Sha, Lisa K; Giegerich, Annika K; Labocha, Sandra; Ferreirós, Nerea; Schmid, Tobias; Wurglics, Mario; Schubert-Zsilavecz, Manfred; Proschak, Eugen; Brüne, Bernhard; Parnham, Michael J; von Knethen, Andreas

    2015-05-15

    Understanding of the physiological role of peroxisome proliferator-activated receptor gamma (PPAR?) offers new opportunities for the treatment of cancers, immune disorders and inflammatory diseases. In contrast to PPAR? agonists, few PPAR? antagonists have been studied, though they do exert immunomodulatory effects. Currently, no therapeutically useful PPAR? antagonist is commercially available. The aim of this study was to identify and kinetically characterise a new competitive PPAR? antagonist for therapeutic use. A PPAR?-dependent transactivation assay was used to kinetically characterise (E)-2-(5-((4-methoxy-2-(trifluoromethyl)quinolin-6-yl)methoxy)-2-((4-(trifluoromethyl)benzyl)oxy)-benzylidene)-hexanoic acid (MTTB) in kidney, T and monocytic cell lines. Cytotoxic effects were analysed and intracellular accumulation of MTTB was assessed by tandem mass spectrometry (LC-MS/MS). Potential interactions of MTTB with the PPAR? protein were suggested by molecular docking analysis. In contrast to non-competitive, irreversible inhibition caused by 2-chloro-5-nitrobenzanilide (GW9662), MTTB exhibited competitive antagonism against rosiglitazone in HEK293T and Jurkat T cells, with IC50 values in HEK293T cells of 4.3µM and 1.6µM, using the PPAR? ligand binding domain (PPAR?-LBD) and the full PPAR? protein, respectively. In all cell lines used, however, MTTB showed much higher intracellular accumulation than GW9662. MTTB alone exhibited weak partial agonistic effects and low cytotoxicity. Molecular docking of MTTB with the PPAR?-LBD supported direct interaction with the nuclear receptor. MTTB is a promising prototype for a new class of competitive PPAR? antagonists. It has weak partial agonistic and clear competitive antagonistic characteristics associated with rapid cellular uptake. Compared to commercially available PPAR? modulators, this offers the possibility of dose regulation of PPAR? and immune responses. PMID:25746464

  16. Enhancement of Antiviral Immunity by Small Molecule Antagonist of Suppressor of Cytokine Signaling

    PubMed Central

    Ahmed, Chulbul M. I.; Dabelic, Rea; Martin, James P.; Jager, Lindsey D.; Haider, S. Mohammad; Johnson, Howard M.

    2011-01-01

    Suppressors of cytokine signaling (SOCSs) are negative regulators of both innate and adaptive immunity via inhibition of signaling by cytokines such as type I and type II IFNs. We have developed a small peptide antagonist of SOCS-1 that corresponds to the activation loop of JAK2. SOCS-1 inhibits both type I and type II IFN activities by binding to the kinase activation loop via the kinase inhibitory region of the SOCS. The antagonist, pJAK2(1001–1013), inhibited the replication of vaccinia virus and encephalomyocarditis virus in cell culture, suggesting that it possesses broad antiviral activity. In addition, pJAK2(1001–1013) protected mice against lethal vaccinia and encephalomyocarditis virus infection. pJAK2(1001–1013) increased the intracellular level of the constitutive IFN-?, which may play a role in the antagonist antiviral effect at the cellular level. Ab neutralization suggests that constitutive IFN-? may act intracellularly, consistent with recent findings on IFN-? intracellular signaling. pJAK2(1001–1013) also synergizes with IFNs as per IFN-? mimetic to exert a multiplicative antiviral effect at the level of transcription, the cell, and protection of mice against lethal viral infection. pJAK2(1001–1013) binds to the kinase inhibitory region of both SOCS-1 and SOCS-3 and blocks their inhibitory effects on the IFN-? activation site promoter. In addition to a direct antiviral effect and synergism with IFN, the SOCS antagonist also exhibits adjuvant effects on humoral and cellular immunity as well as an enhancement of polyinosinic-polycytidylic acid activation of TLR3. The SOCS antagonist thus presents a novel and effective approach to enhancement of host defense against viruses. PMID:20543109

  17. Antagonistic functional duality of cancer genes.

    PubMed

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

    2013-10-25

    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

  18. Habit, prejudice, power and politics: issues in the conversion of H2-receptor antagonists to over-the-counter use.

    PubMed Central

    Hunt, R H

    1996-01-01

    H2-receptor antagonists have been widely prescribed in the last 20 years and are considered to rank among the safest drugs known. In several countries they have been switched to over-the-counter (OTC) status, and a similar move is under consideration in Canada. Some concerns have been raised as to the effectiveness of these drugs in the treatment of dyspepsia and heartburn, their safety when taken for self-diagnosed symptoms, and the potential for their use to delay diagnosis or mask serious disease. The author presents evidence to support the use of OTC H2-receptor antagonists in the treatment of dyspepsia. He argues that the safety record of these drugs is reassuring and that they are unlikely to mask gastric cancer. Finally, he describes the appropriate place of OTC H2-receptor antagonists in the overall management of acid-related disorders. PMID:8542566

  19. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  20. Antagonism of histamine-activated adenylate cyclase in brain by D-lysergic acid diethylamide.

    PubMed Central

    Green, J P; Johnson, C L; Weinstein, H; Maayani, S

    1977-01-01

    D-Lysergic acid diethylamide and D-2-bromolysergic acid diethylamide are competitive antagonists of the histamine activation of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); E.C. 4.6.1.1] in broken cell preparations of the hippocampus and cortex of guinea pig brain. The adenylate cyclase is linked to the histamine H2-receptor. Both D-lysergic acid diethylamide and D-2-bromolysergic acid diethylamide show topological congruency with potent H2-antagonists. D-2-Bromolysergic acid diethylamide is 10 times more potent as an H2-antagonist than cimetidine, which has been the most potent H2-antagonist reported, and D-lysergic acid diethylamide is about equipotent to cimetidine. Blockade of H2-receptors could contribute to the behavioral effects of D-2-bromolysergic acid diethylamide and D-lysergic acid diethylamide. Images PMID:23536

  1. Regulation of the adrenoleukodystrophy-related gene (ABCD2): focus on oxysterols and LXR antagonists.

    PubMed

    Trompier, Doriane; Gondcaille, Catherine; Lizard, Gérard; Savary, Stéphane

    2014-04-11

    The regulation of the ABCD2 gene is recognized as a possible therapeutic target for X-linked adrenoleukodystrophy, a rare neurodegenerative disease caused by mutations in the ABCD1 gene. Up-regulation of ABCD2 expression has indeed been demonstrated to compensate for ABCD1 deficiency, restoring peroxisomal ?-oxidation of very-long-chain fatty acids. Besides the known inducers of the ABCD2 gene (phenylbutyrate and histone deacetylase inhibitors, fibrates, dehydroepiandrosterone, thyroid hormone and thyromimetics), this review will focus on LXR antagonists and 22S-hydroxycholesterol, recently described as inducers of ABCD2 expression. Several LXR antagonists have been identified and their possible indication for neurodegenerative disorders will be discussed. PMID:24480443

  2. The antiinflammatory activity of topically applied novel calcium-channel antagonists.

    PubMed

    De Vries, G W; McLaughlin, A; Wenzel, M B; Perez, J; Harcourt, D; Lee, G; Garst, M; Wheeler, L A

    1995-04-01

    The antiinflammatory activities of two novel calcium-channel antagonists, AGN 190742 and AGN 190744, were evaluated in murine models of cutaneous inflammation. These 2(5H)-furanone ring compounds block both depolarization-dependent Ca2+ entry and receptor-mediated responses in GH3 cells. Topical application of AGN 190742 or AGN 190744 inhibits neutrophil infiltration and epidermal hyperplasia induced by repeated treatment of mouse skin with phorbol ester. AGN 190744 also is active in an arachidonic acid model of acute inflammation. These data suggest that topical application of calcium-channel antagonists can inhibit cutaneous inflammatory responses and that AGN 190742 and/or AGN 190744 may serve as useful pharmacological probes for examining these responses in vivo. PMID:7601508

  3. History of the 'geste antagoniste' sign in cervical dystonia.

    PubMed

    Poisson, A; Krack, P; Thobois, S; Loiraud, C; Serra, G; Vial, C; Broussolle, E

    2012-08-01

    The geste antagoniste is a voluntary maneuver that temporarily reduces the severity of dystonic posture or movements. It is a classical feature of focal and particularly cervical dystonia. However, the precise historical aspects of geste antagoniste still remain obscure. The goals of this review were (1) to clarify the origin of the geste antagoniste sign; (2) to identify the factors that led to its diffusion in the international literature; (3) to follow the evolution of that term across the twentieth century. We used medical and neurological French, German and English literature of the late nineteenth and early twentieth centuries, and the PubMed database by entering the terms geste antagoniste, antagonistic gesture and sensory trick. The geste antagoniste sign is a legacy of the Paris Neurological School of the end of the nineteenth century. The term was introduced by Meige and Feindel in their 1902 book on tics, written in the vein of their master, Brissaud, who first described this sign in 1893. The almost immediate translations of this book by Giese into German and Kinnier Wilson into English contributed to the rapid spreading of the term geste antagoniste, which is still in use worldwide today. The term antagonistic gesture is the translation proposed by Kinnier Wilson, which also led to the use of the term geste antagonistique. The geste antagoniste sign has long been considered a solid argument for the psychogenic origins of dystonia until the 1980s when Marsden made strong arguments for its organic nature. PMID:22234840

  4. Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

    PubMed

    Michinaga, Shotaro; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Koyama, Yutaka

    2014-01-01

    Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults. PMID:25000290

  5. Amelioration of Cold Injury-Induced Cortical Brain Edema Formation by Selective Endothelin ETB Receptor Antagonists in Mice

    PubMed Central

    Michinaga, Shotaro; Nagase, Marina; Matsuyama, Emi; Yamanaka, Daisuke; Seno, Naoki; Fuka, Mayu; Yamamoto, Yui; Koyama, Yutaka

    2014-01-01

    Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults. PMID:25000290

  6. Therapeutic perspectives for melatonin agonists and antagonists.

    PubMed

    Delagrange, P; Atkinson, J; Boutin, J A; Casteilla, L; Lesieur, D; Misslin, R; Pellissier, S; Pénicaud, L; Renard, P

    2003-04-01

    Melatonin is a neurohormone synthesized in the pineal gland during the dark period in all species, including humans. The diversity and differences in melatonin receptor distribution in the brain and extracerebral organs suggest multiple functional roles for melatonin. Administration of melatonin agonists reduces neophobia and treatment with a melatonin antagonist during the dark period reverses the anxiolytic-like effect of endogenous melatonin. Chronic treatment with agonists prevents various perturbations induced by chronic mild stress. Melatonin in vivo directly constricts cerebral arterioles in rats and decreases the lower limit of cerebral blood flow autoregulation, suggesting that melatonin may diminish the risk of hypoperfusion-induced cerebral ischemia. At the extracerebral level, melatonin regulates intestinal motility in rats. The intestinal postprandial motor response is shorter in the dark phase than in the light phase and this reduction is reversed in animals pretreated with a melatonin antagonist. Moreover, melatonin reduces the duration of cholecystokinin excitomotor effect. Endogenous melatonin may modulate intestinal motility to coordinate intestinal functions such as digestion and transit and control the metabolism of the animal. An adipocyte melatonin binding site may also participate in this control. Melatonin is involved in a wide range of physiological functions. The question remains as to whether evolution, adaptation and diurnal life have modified the physiological role of melatonin in humans. Moreover, the functional role of each of the receptor subtypes has to be characterized to design selective ligands to treat specific diseases. PMID:12622848

  7. Beta-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe peptides results in highly potent delta opioid antagonists.

    PubMed

    Tóth, Géza; Ioja, Eniko; Tömböly, Csaba; Ballet, Steven; Tourwé, Dirk; Péter, Antal; Martinek, Tamás; Chung, Nga N; Schiller, Peter W; Benyhe, Sándor; Borsodi, Anna

    2007-01-25

    The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic:1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2',6'-dimethyltyrosine) and a new unnatural amino acid, beta-MeCha (beta-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar delta antagonist activity and mu agonist or antagonist properties depending on the configuration of the beta-MeCha residue. The most promising analog, H-Dmt-Tic-(2S,3S)-beta-MeCha-Phe-OH was a very selective delta antagonist both in the mouse vas deferens (MVD) assay (Ke = 0.241 +/- 0.05 nM) and in radioligand binding assay (K i delta = 0.48 +/- 0.05 nM, K i mu/K i delta = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-beta-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial mu agonist/delta antagonists in the guinea pig ileum and MVD assays. Our results constitute further examples of the influence of Dmt and beta-methyl substitution as well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPP related peptides. Some of these compounds represent valuable pharmacological tools for opioid research. PMID:17228874

  8. Novel dominant negative Smad antagonists to TGFbeta signaling.

    PubMed

    Ho, Joanne; Chen, Hui; Lebrun, Jean-Jacques

    2007-07-01

    We previously identified a critical serine/threonine residue within the linker domain of Smad2/3, phosphorylated by the kinase GRK2 which plays a critical role in regulating Smad signaling. To define the mechanism by which GRK2-mediated phosphorylation modifies Smad2/3 behavior at the molecular level, we generated mutant Smads where the GRK2 phosphorylation site was replaced with an aspartic acid (D) to mimic the properties of a phospho-residue or an alanine (A) as a control. Interestingly, overexpression of either the D or A mutant inhibits TGFbeta signaling, but through two distinct mechanisms. The D mutant is properly localized and released from the plasma membrane upon ligand stimulation, but fails to interact with the type I receptor kinase. The A mutant properly interacts with and is phosphorylated by the type I receptor, translocates to the nucleus and homodimerizes with wild-type R-Smads, but it fails to form a heterocomplex with Smad4. As a result, both mutants act as antagonists of endogenous TGFbeta signaling through divergent mechanisms. The D mutant acts by blocking endogenous R-Smads phosphorylation and the A mutant acts by preventing endogenous R-Smad/Smad4 heterocomplexes. Thus, mutation of the GRK2 phosphorylation site within the Smad generates dominant negative Smads that efficiently inhibit TGFbeta responses. PMID:17360157

  9. A TRPA1 antagonist reverts oxaliplatin-induced neuropathic pain.

    PubMed

    Nativi, Cristina; Gualdani, Roberta; Dragoni, Elisa; Di Cesare Mannelli, Lorenzo; Sostegni, Silvia; Norcini, Martina; Gabrielli, Gabriele; la Marca, Giancarlo; Richichi, Barbara; Francesconi, Oscar; Moncelli, Maria Rosa; Ghelardini, Carla; Roelens, Stefano

    2013-01-01

    Neuropathic pain (NeP) is generally considered an intractable problem, which becomes compelling in clinical practice when caused by highly effective chemotherapeutics, such as in the treatment of cancer with oxaliplatin (OXA) and related drugs. In the present work we describe a structurally new compound, ADM_09, which proved to effectively revert OXA-induced NeP in vivo in rats without eliciting the commonly observed negative side-effects. ADM_09 does not modify normal behavior in rats, does not show any toxicity toward astrocyte cell cultures, nor any significant cardiotoxicity. Patch-clamp recordings demonstrated that ADM_09 is an effective antagonist of the nociceptive sensor channel TRPA1, which persistently blocks mouse as well as human variants of TRPA1. A dual-binding mode of action has been proposed for ADM_09, in which a synergic combination of calcium-mediated binding of the carnosine residue and disulphide-bridge-forming of the lipoic acid residue accounts for the observed persistent blocking activity toward the TRPA1 channel. PMID:23774285

  10. Identification and determination of selected histamine antagonists by densitometric method.

    PubMed

    Czerwi?ska, Krystyna; Wyszomirska, Elzbieta; Mazurek, Aleksander P

    2013-01-01

    The conditions for identification were determined for four histamine antagonists: clemastine fumarate, loratadine, cetirizine dihydrochloride and desloratadine by TLC (thin-layer chromatography) method. The selected chromatographic conditions were used to develop a densitometric method for the content determination of the histamine antagonists in medicinal products and substances. The statistical data showed adequate accuracy and precision of the developed methods. PMID:23610955

  11. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  12. Microbial antagonists of Verticillium dahliae colonize cotton root system

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Verticillium wilt remains one of the most severe diseases affecting cotton production in Uzbekistan. We are investigating microbial antagonist to control this pathogen. To this end, we have identified several antagonists of Verticillium dahliae (Bacillus sp. 234, Bacillus sp. 3, Streptomyces roseofl...

  13. Mutually-Antagonistic Interactions in Baseball Networks

    E-print Network

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  14. Mutually-antagonistic interactions in baseball networks

    NASA Astrophysics Data System (ADS)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  15. Evaluation of amino acids, B vitamins and butylated hydroxyanisole as protective agents against pyrrolizidine alkaloid toxicity in rats.

    PubMed

    Garrett, B J; Cheeke, P R

    1984-01-01

    Supplementation of the diets of rats with branched chain amino acids (BCAA: leucine, isoleucine, valine) did not alter their susceptibility to chronic poisoning by tansy ragwort (Senecio jacobaea), which contains hepatotoxic pyrrolizidine alkaloids (PA). Phenobarbital in the diet, which alters liver microsomal enzyme activity, also did not alter susceptibility to PA poisoning. A combination of butylated hydroxyanisole (BHA), cysteine and BCAA did increase (P less than .05) survival time of rats fed tansy ragwort. Dietary BHA and cysteine increased the survival time of rats injected with the PA monocrotaline, with evidence that addition of vitamin B12 and folic acid improved the effectiveness of this treatment. In a chronic feeding trial with tansy ragwort, a combination of BHA and cysteine increased (P less than .05) the survival times of rats, showing protective activity against PA poisoning. A mixture of B-complex vitamins, or vitamin B12-folic acid, was not effective in improving the response. PMID:6421791

  16. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  17. A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.

    PubMed

    DeVita, R J; Walsh, T F; Young, J R; Jiang, J; Ujjainwalla, F; Toupence, R B; Parikh, M; Huang, S X; Fair, J A; Goulet, M T; Wyvratt, M J; Lo, J L; Ren, N; Yudkovitz, J B; Yang, Y T; Cheng, K; Cui, J; Mount, G; Rohrer, S P; Schaeffer, J M; Rhodes, L; Drisko, J E; McGowan, E; MacIntyre, D E; Vincent, S; Carlin, J R; Cameron, J; Smith, R G

    2001-03-15

    Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates. PMID:11300873

  18. Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin.

    PubMed

    Joshi, Anand A; Murray, Thomas F; Aldrich, Jane V

    2015-11-25

    The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr(1)-cyclo(d-Asp(5),Dap(8))]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-activity relationships of this peptide. The synthesis of selected analogues required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N-terminal modifications, the N-phenethyl and N-cyclopropylmethyl substitutions resulted in analogues with the highest KOR affinities. Pharmacological results for the alanine-substituted analogues indicated that Phe(4) and Arg(6), but interestingly not the Tyr(1) phenol, are important for zyklophin's KOR affinity and that Arg(7) was important for KOR antagonist activity. In the GTP?S assay, while all of the cyclic analogues exhibited negligible KOR efficacy, the N-cyclopropylmethyl-Tyr(1) and N-benzyl-Phe(1) analogues were 28- and 11-fold more potent KOR antagonists, respectively, than zyklophin. PMID:26491810

  19. Further studies regarding the structure activity relationships of beta-adrenoceptor antagonists.

    PubMed

    Bagwell, E E; Williams, E M

    1973-08-01

    1. The ortho (M66,527) and para (M66,368) analogues of 1-t-butylamino-3-(methoxyphenoxy)-2-propanol and para substituted tertiary butylphenoxy-1-N-isopropylamine-3 propanol-2 oxalate acid (L8429) were tested in dogs for their beta-adrenoceptor blocking activity.2. M66,527, which contains a methoxy group in the ortho position of the benzene ring, was found to be comparable to propranolol in blocking cardiac and peripheral vascular responses to isoprenaline. Like propranolol, M66,527 was more potent on peripheral receptors.3. Transference of the methoxy group to the para position (M66,368) reduced the overall potency; however, this compound was found to be relatively cardioselective in that it was 2 to 3.6 times more active in blocking cardiac responses to isoprenaline.4. The cardioselective properties of the short chain para methoxy substituent were less than those reported for compounds with longer para substitutions (i.e. practolol, para oxprenolol and para alprenolol).5. L8429, with a tertiary butyl group in the para position, was a weak beta-adrenoceptor antagonist without cardioselective properties. A longer, less bulky n-butyl group may provide for a more potent and selective antagonist.6. The results support the view that the size and site of the substituent on the benzene ring may be of importance in determining the cardioselective potency of beta-adrenoceptor antagonists. PMID:4150921

  20. (?) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor ?

    PubMed Central

    2015-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor ?. Follow-up experimental results show that lignans (?) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor ?. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

  1. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    SciTech Connect

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  2. Fine Tuning of a Type 1 Interferon Antagonist

    PubMed Central

    Urin, Victoria; Levin, Doron; Sharma, Nanaocha; Harari, Daniel; Schreiber, Gideon

    2015-01-01

    Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition. PMID:26158644

  3. Antagonistic neural networks underlying differentiated leadership roles

    PubMed Central

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  4. The renal effects of mineralocorticoid receptor antagonists.

    PubMed

    Bianchi, Stefano; Batini, Valentina; Bigazzi, Roberto

    2015-12-01

    Beyond its well known classic effects on renal water and electrolytes metabolism, an increasing amount of experimental and clinical evidence suggests that aldosterone contributes to the pathogenesis and progression of kidney disease. The binding of aldosterone on epithelial and non-epithelial cells of the kidney induces many deleterious effects, such as podocyte apoptosis and injury, mesangial cell proliferation and deformability and tubulointerstitial inflammation, finally resulting in glomerular fibrosis and sclerosis. Moreover, aldosterone acting by fast non-genomic mechanisms, may induce other potential deleterious effects on kidney function and structure. Indeed, many experimental studies have shown that aldosterone participates to the progression of kidney disease through hemodynamic and direct cellular actions and that antagonists of aldosterone may retard the progression of kidney disease, independently of effects on blood pressure. Therefore, blockade of the aldosterone pathway may prove to be a beneficial therapy for kidney disease. In this brief review we summarize the reported data that support an independent role of aldosterone in inducing kidney damage both in human and experimental models, and interventional studies that highlight how strategies aimed to antagonize its action may favorably modify the progressive decline of renal function in patient with kidney disease and in patients with extrarenal disease frequently associated with kidney function impairment. PMID:26049733

  5. Antagonistic interactions among coral-associated bacteria.

    PubMed

    Rypien, Krystal L; Ward, Jessica R; Azam, Farooq

    2010-01-01

    Reef-building corals are comprised of close associations between the coral animal, symbiotic zooxanthellae, and a diversity of associated microbes (including Bacteria, Archaea and Fungi). Together, these comprise the coral holobiont - a paradigm that emphasizes the potential contributions of each component to the overall function and health of the coral. Little is known about the ecology of the coral-associated microbial community and its hypothesized role in coral health. We explored bacteria-bacteria antagonism among 67 bacterial isolates from the scleractinian coral Montastrea annularis at two temperatures using Burkholder agar diffusion assays. A majority of isolates exhibited inhibitory activity (69.6% of isolates at 25 degrees C, 52.2% at 31 degrees C), with members of the gamma-proteobacteria (Vibrionales and Alteromonadales) being especially antagonistic. Elevated temperatures generally reduced levels of antagonism, although the effects were complex. Several potential pathogens were observed in the microbial community of apparently healthy corals, and 11.6% of isolates were able to inhibit the growth of the coral pathogen Vibrio shiloi at 25 degrees C. Overall, this study demonstrates that antagonism could be a structuring force in coral-associated microbial communities and may contribute to pathogenesis as well as disease resistance. PMID:19691500

  6. Eprosartan mesylate, an angiotensin II receptor antagonist

    PubMed Central

    Qian, Jing-Jing; Hu, Xiu-Rong; Gu, Jianming; Wu, Su-Xiang

    2011-01-01

    The title compound, eprosartan mesylate {systematic name: 2-butyl-1-(4-carb­oxy­benz­yl)-5-[(E)-2-carb­oxy-3-(thio­phen-2-yl)prop-1-en­yl]-1H-imidazol-3-ium methane­sulfonate}, C23H25N2O4S+·CH3O3S?, one of the angiotensin II-receptor antagonists, is effective in regulating hypertension, induced or exacerbated by angiotensin II, and in the treatment of congestive heart failure, renal failure and glaucoma. In the eprosartan residue, which appears in this crystal in the cationic imidazolium form, the benzene ring plane is almost orthogonal to that of the imidazole ring, making a dihedral angle of 87.89?(2)°. The thio­phene ring forms dihedral angles of 66.54?(2) and 67.12?(2)° with the benzene and imidazole rings, respectively. The imidazolium NH group and the H atom of the aromatic carboxyl group participate in hydrogen bonds with the the O atoms of the anion, thus forming centrosymmetric aggregates made up of two cations and two anions each. The second carboxyl group further links the above-mentioned aggregates through a conventional centrosymmetric hydrogen-bonding motif into infinite chains along [011]. PMID:21754064

  7. Antagonistic neural networks underlying differentiated leadership roles.

    PubMed

    Boyatzis, Richard E; Rochford, Kylie; Jack, Anthony I

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks - the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  8. Folic acid-functionalized up-conversion nanoparticles: toxicity studies in vivo and in vitro and targeted imaging applications

    NASA Astrophysics Data System (ADS)

    Sun, Lining; Wei, Zuwu; Chen, Haige; Liu, Jinliang; Guo, Jianjian; Cao, Ming; Wen, Tieqiao; Shi, Liyi

    2014-07-01

    Folate receptors (FRs) are overexpressed on a variety of human cancer cells and tissues, including cancers of the breast, ovaries, endometrium, and brain. This over-expression of FRs can be used to target folate-linked imaging specifically to FR-expressing tumors. Fluorescence is emerging as a powerful new modality for molecular imaging in both the diagnosis and treatment of disease. Combining innovative molecular biology and chemistry, we prepared three kinds of folate-targeted up-conversion nanoparticles as imaging agents (UCNC-FA: UCNC-Er-FA, UCNC-Tm-FA, and UCNC-Er,Tm-FA). In vivo and in vitro toxicity studies showed that these nanoparticles have both good biocompatibility and low toxicity. Moreover, the up-conversion luminescence imaging indicated that they have good targeting to HeLa cells and can therefore serve as potential fluorescent contrast agents.Folate receptors (FRs) are overexpressed on a variety of human cancer cells and tissues, including cancers of the breast, ovaries, endometrium, and brain. This over-expression of FRs can be used to target folate-linked imaging specifically to FR-expressing tumors. Fluorescence is emerging as a powerful new modality for molecular imaging in both the diagnosis and treatment of disease. Combining innovative molecular biology and chemistry, we prepared three kinds of folate-targeted up-conversion nanoparticles as imaging agents (UCNC-FA: UCNC-Er-FA, UCNC-Tm-FA, and UCNC-Er,Tm-FA). In vivo and in vitro toxicity studies showed that these nanoparticles have both good biocompatibility and low toxicity. Moreover, the up-conversion luminescence imaging indicated that they have good targeting to HeLa cells and can therefore serve as potential fluorescent contrast agents. Electronic supplementary information (ESI) available: Up-conversion luminescence spectra of UCNC-Er and UCNC-Er-FA, UCNC-Tm and UCNC-Tm-FA. Confocal luminescence imaging data collected as a series along the Z optical axis. See DOI: 10.1039/c4nr02312a

  9. Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The incidence of unilateral retinoblastoma varies globally, suggesting possible environmental contributors to disease incidence. Maternal intake of naturally occurring folate from vegetables during pregnancy is associated inversely with the risk of retinoblastoma in offspring. The authors used a ca...

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

    PubMed

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

    2015-02-01

    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. PMID:25384423

  11. Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.

    PubMed

    Chen, Chen; Tucci, Fabio C; Jiang, Wanlong; Tran, Joe A; Fleck, Beth A; Hoare, Sam R; Wen, Jenny; Chen, Takung; Johns, Michael; Markison, Stacy; Foster, Alan C; Marinkovic, Dragan; Chen, Caroline W; Arellano, Melissa; Harman, John; Saunders, John; Bozigian, Haig; Marks, Daniel

    2008-05-15

    A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia. PMID:18417348

  12. Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.

    TOXLINE Toxicology Bibliographic Information

    Chen C; Tucci FC; Jiang W; Tran JA; Fleck BA; Hoare SR; Wen J; Chen T; Johns M; Markison S; Foster AC; Marinkovic D; Chen CW; Arellano M; Harman J; Saunders J; Bozigian H; Marks D

    2008-05-15

    A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.

  13. GnRH receptor antagonists for prostate cancer.

    PubMed

    Patrick, Emily; Whitson, Melissa; Smith, Amy; Parnell, Jamin; Thomas, Suzanne E; Blankenship, Clint C

    2013-07-01

    GnRH receptor antagonists can reduce testosterone levels without the adverse reactions caused by other drugs used to treat prostate cancer. These drugs also offer hope for prolonged control of metastasis. PMID:23923287

  14. Peristaltic Locomotion with Antagonistic Actuators in Soft Robotics

    E-print Network

    Seok, Sangok

    This paper presents a soft robotic platform that exhibits peristaltic locomotion. The design principle is based on the unique antagonistic arrangement of radial/circular and longitudinal muscle groups of Oligochaeta. ...

  15. Stilbenes as ?-selective, non-nitrogenous opioid receptor antagonists.

    PubMed

    Hartung, Alyssa M; Beutler, John A; Navarro, Hernán A; Wiemer, David F; Neighbors, Jeffrey D

    2014-02-28

    The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the ? receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the ? receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid receptor antagonists that are required for activity. PMID:24456556

  16. Stilbenes as ?-Selective, Non-nitrogenous Opioid Receptor Antagonists

    PubMed Central

    2015-01-01

    The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the ? receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the ? receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid receptor antagonists that are required for activity. PMID:24456556

  17. Identification of M-CSF agonists and antagonists

    DOEpatents

    Pandit, Jayvardhan (Mystic, CT); Jancarik, Jarmila (Walnut Creek, CA); Kim, Sung-Hou (Moraga, CA); Koths, Kirston (El Cerrito, CA); Halenbeck, Robert (San Rafael, CA); Fear, Anna Lisa (Oakland, CA); Taylor, Eric (Oakland, CA); Yamamoto, Ralph (Martinez, CA); Bohm, Andrew (Armonk, NY)

    2000-02-15

    The present invention is directed to methods for crystallizing macrophage colony stimulating factor. The present invention is also directed to methods for designing and producing M-CSF agonists and antagonists using information derived from the crystallographic structure of M-CSF. The invention is also directed to methods for screening M-CSF agonists and antagonists. In addition, the present invention is directed to an isolated, purified, soluble and functional M-CSF receptor.

  18. Celiprolol, a potent cardioselective beta 1-adrenoceptor antagonist with mild alpha 2-adrenoceptor antagonist properties.

    PubMed

    Wolf, P S; Pruss, T P; Rand, M J; Smith, R D; Mann, W S; Romano, D V

    1985-12-01

    Celiprolol is a cardioselective beta-adrenoceptor antagonist, with interesting propranolol-insensitive cardiostimulatory, vasodilatory and bronchodilatory effects. Recent reports suggest that mild alpha 2-adrenoceptor antagonism may contribute to these effects. The present investigation further explored the alpha 2 effects of celiprolol. In isolated electrically-stimulated rat atria celiprolol (1.0 and 10 mumol/l) significantly increased the release of [3H]-norepinephrine, consistent with the blockade of pre-junctional alpha 2-adrenoceptors. Evidence for post-synaptic alpha 2-adrenoceptor antagonist activity was obtained in studies of the effects of celiprolol on the pressor response to clonidine and either phenylephrine or methoxamine in perfused hind-limbs of dogs (pretreated with mecamylamine and propranolol) and pithed rats. In the dog, celiprolol (10 mg/kg) significantly inhibited the vasoconstrictor response of clonidine while in the rat higher doses were required (> or = 12.5 mg/kg). Celiprolol did not affect the pressor response induced by alpha 1-agonists. We conclude that celiprolol possesses a mild alpha 2-adrenoceptor blocking action which may contribute to its unconventional profile. PMID:2908816

  19. Anthropomorphic finger antagonistically actuated by SMA plates.

    PubMed

    Engeberg, Erik D; Dilibal, Savas; Vatani, Morteza; Choi, Jae-Won; Lavery, John

    2015-10-01

    Most robotic applications that contain shape memory alloy (SMA) actuators use the SMA in a linear or spring shape. In contrast, a novel robotic finger was designed in this paper using SMA plates that were thermomechanically trained to take the shape of a flexed human finger when Joule heated. This flexor actuator was placed in parallel with an extensor actuator that was designed to straighten when Joule heated. Thus, alternately heating and cooling the flexor and extensor actuators caused the finger to flex and extend. Three different NiTi based SMA plates were evaluated for their ability to apply forces to a rigid and compliant object. The best of these three SMAs was able to apply a maximum fingertip force of 9.01N on average. A 3D CAD model of a human finger was used to create a solid model for the mold of the finger covering skin. Using a 3D printer, inner and outer molds were fabricated to house the actuators and a position sensor, which were assembled using a multi-stage casting process. Next, a nonlinear antagonistic controller was developed using an outer position control loop with two inner MOSFET current control loops. Sine and square wave tracking experiments demonstrated minimal errors within the operational bounds of the finger. The ability of the finger to recover from unexpected disturbances was also shown along with the frequency response up to 7 rad s(-1). The closed loop bandwidth of the system was 6.4 rad s(-1) when operated intermittently and 1.8 rad s(-1) when operated continuously. PMID:26292164

  20. CXCR3 antagonist VUF10085 binds to an intrahelical site distinct from that of the broad spectrum antagonist TAK–779

    PubMed Central

    Nedjai, Belinda; Viney, Jonathan M; Li, Hubert; Hull, Caroline; Anderson, Caroline A; Horie, Tomoki; Horuk, Richard; Vaidehi, Nagarajan; Pease, James E

    2015-01-01

    Background and Purpose The chemokine receptor CXCR3 is implicated in a variety of clinically important diseases, notably rheumatoid arthritis and atherosclerosis. Consequently, antagonists of CXCR3 are of therapeutic interest. In this study, we set out to characterize binding sites of the specific low MW CXCR3 antagonist VUF10085 and the broad spectrum antagonist TAK-779 which blocks CXCR3 along with CCR2 and CCR5. Experimental Approach Molecular modelling of CXCR3, followed by virtual ligand docking, highlighted several CXCR3 residues likely to contact either antagonist, notably a conserved aspartate in helix 2 (Asp-1122:63), which was postulated to interact with the quaternary nitrogen of TAK-779. Validation of modelling was carried out by site-directed mutagenesis of CXCR3, followed by assays of cell surface expression, ligand binding and receptor activation. Key Results Mutation of Asn-1323.33, Phe-207 and Tyr-2716.51 within CXCR3 severely impaired both ligand binding and chemotactic responses, suggesting that these residues are critical for maintenance of a functional CXCR3 conformation. Contrary to our hypothesis, mutation of Asp-1122:63 had no observable effects on TAK-779 activity, but clearly decreased the antagonist potency of VUF 10085. Likewise, mutations of Phe-1313.32, Ile-2796.59 and Tyr-3087.43 were well tolerated and were critical for the antagonist activity of VUF 10085 but not for that of TAK-779. Conclusions and Implications This more detailed definition of a binding pocket within CXCR3 for low MW antagonists should facilitate the rational design of newer CXCR3 antagonists, with obvious clinical potential. PMID:25425280

  1. REGULATION OF BENEFICIAL TRAITS IN ANTAGONISTIC BACTERIA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The phz operon of Pseudomonas fluorescens 2-79, which produces the antibiotic phenazine-1-carboxylic acid (PCA), is preceded by phzR and phzI, a pair of quorum-sensing members of the luxR-luxI gene family. Quantitative analyses showed that strain 2-79 produces six acyl-homoserine lactone (HSL) signa...

  2. Effects of 5-hydroxytryptamine agonists and antagonists on the responses of rat spinal motoneurones to raphe obscurus stimulation.

    PubMed Central

    Roberts, M. H.; Davies, M.; Girdlestone, D.; Foster, G. A.

    1988-01-01

    1. The excitability of lumbar spinal motoneurones was studied in halothane-anaesthetized rats by recording with microelectrodes the amplitude of the population spike evoked antidromically by stimulation of the cut ventral roots. 2. Electrical stimulation of the nucleus raphe obscurus for 1 min at 20 Hz increased the population spike amplitude and, as shown by intracellular recording, depolarized motoneurones. This response could be mimicked by microinjection of DL-homocysteic acid into raphe obscurus but the response was not present in animals pretreated with the 5-hydroxytryptamine (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). 3. Microiontophoretically applied 5-HT had very similar effects on the extracellularly recorded population spike to those caused by stimulation of the raphe obscurus. These responses to 5-HT were larger in 5,7-DHT-pretreated animals. 4. The effects of 5-HT were potently mimicked by iontophoretically applied 5-carboxamidotryptamine but 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was without effect. 5. Antagonists were applied by microiontophoresis and also by intravenous injection. Ketanserin, the selective 5-HT2 antagonist, did not antagonize the effects of 5-HT. Neither did the 5-HT3-receptor antagonist MDL 72222 or the selective 5-HT1 binding ligand cyanopindolol. 6. The non-selective 5-HT1/5-HT2-receptor antagonist methysergide was an effective antagonist of both the effects of 5-HT and the response to raphe obscurus stimulation. Methysergide did not reduce the excitatory effects of noradrenaline. 7. It is concluded that 5-HT application and stimulation of raphe obscurus increase the excitability of motoneurones by an action on a 5-HT1-like receptor which appears to be different from the 5-HT1A-and the 5-HT1B-binding sites characterized by others. PMID:3228671

  3. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

    PubMed Central

    Broussolle, Emmanuel; Laurencin, Chloé; Bernard, Emilien; Thobois, Stéphane; Danaila, Teodor; Krack, Paul

    2015-01-01

    Background Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. Results In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin. Discussion Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia. PMID:26417535

  4. Dopamine Receptor Antagonists as New Mode-of-Action Insecticide Leads for Control of Aedes and Culex Mosquito Vectors

    PubMed Central

    Nuss, Andrew B.; Ejendal, Karin F. K.; Doyle, Trevor B.; Meyer, Jason M.; Lang, Emma G.; Watts, Val J.; Hill, Catherine A.

    2015-01-01

    Background New mode-of-action insecticides are sought to provide continued control of pesticide resistant arthropod vectors of neglected tropical diseases (NTDs). We previously identified antagonists of the AaDOP2 D1-like dopamine receptor (DAR) from the yellow fever mosquito, Aedes aegypti, with toxicity to Ae. aegypti larvae as leads for novel insecticides. To extend DAR-based insecticide discovery, we evaluated the molecular and pharmacological characteristics of an orthologous DAR target, CqDOP2, from Culex quinquefasciatus, the vector of lymphatic filariasis and West Nile virus. Methods/Results CqDOP2 has 94.7% amino acid identity to AaDOP2 and 28.3% identity to the human D1-like DAR, hD1. CqDOP2 and AaDOP2 exhibited similar pharmacological responses to biogenic amines and DAR antagonists in cell-based assays. The antagonists amitriptyline, amperozide, asenapine, chlorpromazine and doxepin were between 35 to 227-fold more selective at inhibiting the response of CqDOP2 and AaDOP2 in comparison to hD1. Antagonists were toxic to both C. quinquefasciatus and Ae. aegypti larvae, with LC50 values ranging from 41 to 208 ?M 72 h post-exposure. Orthologous DOP2 receptors identified from the African malaria mosquito, Anopheles gambiae, the sand fly, Phlebotomus papatasi and the tsetse fly, Glossina morsitans, had high sequence similarity to CqDOP2 and AaDOP2. Conclusions DAR antagonists represent a putative new insecticide class with activity against C. quinquefasciatus and Ae. aegypti, the two most important mosquito vectors of NTDs. There has been limited change in the sequence and pharmacological properties of the DOP2 DARs of these species since divergence of the tribes Culicini and Aedini. We identified antagonists selective for mosquito versus human DARs and observed a correlation between DAR pharmacology and the in vivo larval toxicity of antagonists. These data demonstrate that sequence similarity can be predictive of target potential. On this basis, we propose expanded insecticide discovery around orthologous DOP2 targets from additional dipteran vectors. PMID:25793586

  5. Statistical interaction model for exchangeability of food folates in rat growth bioassay.

    PubMed

    Müller, H G; Facer, M R; Bills, N D; Clifford, A J

    1996-10-01

    The comparative value of several sources of dietary folate in promoting growth of folate-depleted rats was determined in a folate depletion-repletion rat growth bioassay. Folate-depleted rats were fed an amino acid-based diet supplemented with 11 different concentrations of folate (227, 272, 317, 363, 408, 454, 499, 544, 590, 635 and 680 nmol/kg) from each of 12 different sources of folate (folic acid, fried beef liver, cooked pinto beans individually, or as 1/3, 1/1, or 3/1 combinations of folate from the folic acid/beans, folic acid/beef liver and beans/beef liver) for a total of 132 treatments. Growth response to folic acid and bean folate was linear, whereas that to beef liver folate was distinctly nonlinear, beef liver folate being more potent at lower dietary concentrations but less potent at higher concentrations compared with folic acid and bean folate. Folic acid and bean folate were equivalent to and exchangeable with one another in promoting growth. Beef liver folate and folic acid/bean folate had an interactive effect in promoting growth. The nature of the interaction was antagonistic in that the presence of folic acid and/or bean folate reduced the efficacy of beef liver folate and vice versa. Beef liver folate is not exchangeable with either folic acid or bean folate. We conclude that food folates generally are not exchangeable and do interact adversely. A statistical interaction model that predicted the growth-promoting effect of several sources of dietary folate was developed and validated. PMID:8857521

  6. A novel leptin antagonist peptide inhibits breast cancer growth in vitro and in vivo

    PubMed Central

    Catalano, Stefania; Leggio, Antonella; Barone, Ines; De Marco, Rosaria; Gelsomino, Luca; Campana, Antonella; Malivindi, Rocco; Panza, Salvatore; Giordano, Cinzia; Liguori, Alessia; Bonofiglio, Daniela; Liguori, Angelo; Andò, Sebastiano

    2015-01-01

    The role of the obesity cytokine leptin in breast cancer progression has raised interest in interfering with leptin's actions as a valuable therapeutic strategy. Leptin interacts with its receptor through three different binding sites: I–III. Site I is crucial for the formation of an active leptin–leptin receptor complex and in its subsequent activation. Amino acids 39-42 (Leu-Asp-Phe-Ile- LDFI) were shown to contribute to leptin binding site I and their mutations in alanine resulted in muteins acting as typical antagonists. We synthesized a small peptide based on the wild-type sequence of leptin binding site I (LDFI) and evaluated its efficacy in antagonizing leptin actions in breast cancer using in vitro and in vivo experimental models. The peptide LDFI abolished the leptin-induced anchorage-dependent and -independent growth as well as the migration of ER?-positive (MCF-7) and -negative (SKBR3) breast cancer cells. These results were well correlated with a reduction in the phosphorylation levels of leptin downstream effectors, as JAK2/STAT3/AKT/MAPK. Importantly, the peptide LDFI reversed the leptin-mediated up-regulation of its gene expression, as an additional mechanism able to enhance the peptide antagonistic activity. The described effects were specific for leptin signalling, since the developed peptide was not able to antagonize the other growth factors' actions on signalling activation, proliferation and migration. Finally, we showed that the LDFI pegylated peptide markedly reduced breast tumour growth in xenograft models. The unmodified peptide LDFI acting as a full leptin antagonist could become an attractive option for breast cancer treatment, especially in obese women. PMID:25721149

  7. Selection for biocontrol bacteria antagonistic toward Rosellinia necatrix by enrichment of competitive avocado root tip colonizers.

    PubMed

    Pliego, Clara; Cazorla, Francisco Manuel; González-Sánchez, María Angeles; Pérez-Jiménez, Rosa María; de Vicente, Antonio; Ramos, Cayo

    2007-06-01

    Biological control of soil-borne pathogens is frequently based on the application of antagonistic microorganisms selected solely for their ability to produce in vitro antifungal factors. The aim of this work was to select bacteria that efficiently colonize the roots of avocado plants and display antagonism towards Rosellinia necatrix, the causal agent of avocado white root rot. A high frequency of antagonistic strains (ten isolates, 24.4%) was obtained using a novel procedure based on the selection of competitive avocado root tip colonizers. Amplification and sequencing of the 16S rRNA gene, in combination with biochemical characterization, showed that eight and two of the selected isolates belonged to the genera Pseudomonas and Stenotrophomonas, respectively. Characterization of antifungal compounds produced by the antagonistic strains showed variable production of exoenzymes and HCN. Only one of these strains, Pseudomonas sp. AVO94, produced a compound that could be related to antifungal antibiotics. All of the ten selected strains showed twitching motility, a cell movement involved in competitive colonization of root tips. Production of N-acyl-homoserine lactones and indole-3-acetic acid was also reported for some of these isolates. Resistance to several bacterial antibiotics was tested, and three strains showing resistance to only one of them were selected for biocontrol assays. The three selected strains persisted in the rhizosphere of avocado plants at levels considered crucial for efficient biocontrol, 10(5)-10(6) colony forming units/g of root; two of them, Pseudomonas putida AVO102 and Pseudomonas pseudoalcaligenes AVO110, demonstrated significant protection of avocado plants against white root rot. PMID:17467245

  8. Modulation of Glutamate Transport and Receptor Binding by Glutamate Receptor Antagonists in EAE Rat Brain

    PubMed Central

    Sulkowski, Grzegorz; D?browska-Bouta, Beata; Sali?ska, El?bieta; Stru?y?ska, Lidia

    2014-01-01

    The etiology of multiple sclerosis (MS) is currently unknown. However, one potential mechanism involved in the disease may be excitotoxicity. The elevation of glutamate in cerebrospinal fluid, as well as changes in the expression of glutamate receptors (iGluRs and mGluRs) and excitatory amino acid transporters (EAATs), have been observed in the brains of MS patients and animals subjected to experimental autoimmune encephalomyelitis (EAE), which is the predominant animal model used to investigate the pathophysiology of MS. In the present paper, the effects of glutamatergic receptor antagonists, including amantadine, memantine, LY 367583, and MPEP, on glutamate transport, the expression of mRNA of glutamate transporters (EAATs), the kinetic parameters of ligand binding to N-methyl-D-aspartate (NMDA) receptors, and the morphology of nerve endings in EAE rat brains were investigated. The extracellular level of glutamate in the brain is primarily regulated by astrocytic glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Excess glutamate is taken up from the synaptic space and metabolized by astrocytes. Thus, the extracellular level of glutamate decreases, which protects neurons from excitotoxicity. Our investigations showed changes in the expression of EAAT mRNA, glutamate transport (uptake and release) by synaptosomal and glial plasmalemmal vesicle fractions, and ligand binding to NMDA receptors; these effects were partially reversed after the treatment of EAE rats with the NMDA antagonists amantadine and memantine. The antagonists of group I metabotropic glutamate receptors (mGluRs), including LY 367385 and MPEP, did not exert any effect on the examined parameters. These results suggest that disturbances in these mechanisms may play a role in the processes associated with glutamate excitotoxicity and the progressive brain damage in EAE. PMID:25426719

  9. NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice

    SciTech Connect

    Dekundy, Andrzej . E-mail: andrzej.dekundy@merz.de; Kaminski, Rafal M.; Zielinska, Elzbieta; Turski, Waldemar A.

    2007-03-15

    Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures.

  10. Discovery and development of orexin receptor antagonists as therapeutics for insomnia

    PubMed Central

    Winrow, CJ; Renger, JJ

    2014-01-01

    Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for insomnia primarily target ?-aminobutyric acid-A (GABA-A) receptor signalling and include benzodiazepines and GABA-A receptor modulators. These drugs are used to address this sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance therapy. Forward and reverse genetic approaches in animals have implicated orexin signalling (also referred to as hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the orexin receptors (single or dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual orexin receptors, while a number of DORAs have progressed to clinical development as pharmaceutical candidates for insomnia. The DORA almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with insomnia but its development was halted. SB-649868 and suvorexant have demonstrated efficacy and tolerability in Phase II and III trials respectively. Furthermore, suvorexant is currently under review by the Food and Drug Administration for the treatment of insomnia. Based on the publication of recent non-clinical and clinical data, orexin receptor antagonists potentially represent a targeted, effective and well-tolerated new class of medications for insomnia. Linked ArticlesThis article is part of a themed section on Orexin Receptors. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-2 PMID:23731216

  11. TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes.

    PubMed

    Lu, Zhongyang; Zhang, Xiaoming; Li, Yanchun; Lopes-Virella, Maria F; Huang, Yan

    2015-11-01

    Although a large number of studies have well documented a key role of toll-like receptor (TLR)4 in atherosclerosis, it remains undetermined if TLR4 antagonist attenuates atherogenesis in mouse model for type 2 diabetes. In this study, we induced type 2 diabetes in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice by high-fat diet (HFD). At 8 weeks old, 20 mice were fed HFD and 20 mice fed regular chow (RC) for 24 weeks. In the last 10 weeks, half HFD-fed mice and half RC-fed mice were treated with Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist. After the treatment, atherosclerotic lesions in aortas were analyzed. Results showed that the HFD significantly increased bodyweight, glucose, lipids including total cholesterol, triglycerides and free fatty acids, and insulin resistance, indicating that the HFD induced type 2 diabetes in LDLR(-/-) mice. Results also showed that Rs-LPS had no effect on HFD-increased metabolic parameters in both nondiabetic and diabetic mice. Lipid staining of aortas and histological analysis of cross-sections of aortic roots showed that diabetes increased atherosclerotic lesions, but Rs-LPS attenuated atherogenesis in diabetic mice. Furthermore, immunohistochemical studies showed that Rs-LPS reduced infiltration of monocytes/macrophages and expression of interleukin (IL)-6 and matrix metalloproteinase-9 in atherosclerotic lesions of diabetic mice. Finally, the antagonistic effect of Rs-LPS on TLR4 was demonstrated by our in vitro studies showing that Rs-LPS inhibited IL-6 secretion from macrophages and endothelial cells stimulated by LPS or LPS plus saturated fatty acid palmitate. Taken together, our study demonstrated that TLR4 antagonist was capable of attenuating vascular inflammation and atherogenesis in mice with HFD-induced type 2 diabetes. PMID:26162692

  12. Neutralization of staphylococcal enterotoxin B by an aptamer antagonist.

    PubMed

    Wang, Kaiyu; Gan, Longjie; Jiang, Li; Zhang, Xianhui; Yang, Xiangyue; Chen, Min; Lan, Xiaopeng

    2015-04-01

    Staphylococcal enterotoxin B (SEB) is a major virulence factor for staphylococcal toxic shock syndrome (TSS). SEB activates a large subset of the T lymphocytic population, releasing proinflammatory cytokines. Blocking SEB-initiated toxicity may be an effective strategy for treating TSS. Using a process known as systematic evolution of ligands by exponential enrichment (SELEX), we identified an aptamer that can antagonize SEB with nanomolar binding affinity (Kd = 64 nM). The aptamer antagonist effectively inhibits SEB-mediated proliferation and cytokine secretion in human peripheral blood mononuclear cells. Moreover, a PEGylated aptamer antagonist significantly reduced mortality in a "double-hit" mouse model of SEB-induced TSS, established via sensitization with d-galactosamine followed by SEB challenge. Therefore, our novel aptamer antagonist may offer potential therapeutic efficacy against SEB-mediated TSS. PMID:25624325

  13. Neutralization of Staphylococcal Enterotoxin B by an Aptamer Antagonist

    PubMed Central

    Wang, Kaiyu; Gan, Longjie; Jiang, Li; Zhang, Xianhui; Yang, Xiangyue; Chen, Min

    2015-01-01

    Staphylococcal enterotoxin B (SEB) is a major virulence factor for staphylococcal toxic shock syndrome (TSS). SEB activates a large subset of the T lymphocytic population, releasing proinflammatory cytokines. Blocking SEB-initiated toxicity may be an effective strategy for treating TSS. Using a process known as systematic evolution of ligands by exponential enrichment (SELEX), we identified an aptamer that can antagonize SEB with nanomolar binding affinity (Kd = 64 nM). The aptamer antagonist effectively inhibits SEB-mediated proliferation and cytokine secretion in human peripheral blood mononuclear cells. Moreover, a PEGylated aptamer antagonist significantly reduced mortality in a “double-hit” mouse model of SEB-induced TSS, established via sensitization with d-galactosamine followed by SEB challenge. Therefore, our novel aptamer antagonist may offer potential therapeutic efficacy against SEB-mediated TSS. PMID:25624325

  14. Discovery of cannabinoid-1 receptor antagonists by virtual screening.

    PubMed

    Lee, Gil Nam; Kim, Kwang Rok; Ahn, Sung-Hoon; Bae, Myung Ae; Kang, Nam Sook

    2010-09-01

    In this work, we tried to find a new scaffold for a CB1 receptor antagonist using virtual screening. We first analyzed structural features for the known cannabinoid-1 receptor antagonists and, then, we built pharmacophore models using the HipHop concept and carried out a docking study based on our homology CB1 receptor 3D structure. The most active compound, including thiazole-4-one moiety, showed an activity value of 125 nM IC(50), with a good PK profile. PMID:20667724

  15. Oxytocin antagonists for the management of preterm birth: a review.

    PubMed

    Usta, Ihab M; Khalil, Ali; Nassar, Anwar H

    2011-06-01

    Preterm birth, the leading cause of neonatal morbidity and mortality, is estimated at incidence of 12.7% of all births, which has not decreased over the last four decades despite intensive antenatal care programs aimed at high-risk groups, the widespread use of tocolytics, and a series of other preventive and therapeutic interventions. Oxytocin antagonists, namely atosiban, represent an appealing choice that seems to be effective with apparently fewer side effects than the traditional tocolytics. This article reviews the available literature on the pharmacokinetics, mode of administration, and clinical utility of oxytocin antagonists for acute and maintenance tocolysis with special emphasis on its safety profile. PMID:21170825

  16. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

    SciTech Connect

    Zuercher, William J.; Buckholz?, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M.

    2010-08-12

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  17. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

    SciTech Connect

    Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya

    2012-03-15

    The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

  18. Intrathecal neurosteroids and a neurosteroid antagonist: effects on inflammation-evoked thermal hyperalgesia and tactile allodynia.

    PubMed

    Svensson, Elin; Persson, Josefin; Fitzsimmons, Bethany; Yaksh, Tony L

    2013-08-26

    Neurosteroids regulate neuronal excitability though binding sites associated with the ionotropic ?-aminobutyric acid (GABAA) receptor. We sought to characterize the spinal analgesic actions in rats of two 5?-reduced neurosteroids, allopregnanolone and alphaxalone, on nociceptive processing and to determine whether a putative neurosteroid antagonist attenuates this effect: (3?,5?)-17-phenylandrost-16-en-3-ol (17PA). Intrathecal (IT) injection of allopregnanolone (1-30 ?g/10 ?L in 20% cyclodextrin) delivered through lumbar catheters produced a dose-dependent analgesia in rats as measured by thermal thresholds in the ipsilateral (inflamed by intraplantar carrageenan) and in the contralateral (un-inflamed paws). Similar observations were made with alphaxalone (30-60 ?g in 20% cyclodextrin). Effective doses were not associated with suppressive effects on pinnae, blink or placing and stepping reflex. Effects of allopregnanolone (30 ?g) on the normal and hyperalgesic paw were completely prevented by IT 17PA (30 ?g). Reversal by IT 17PA of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing. These results suggest that a spinal neurosteroid-binding site with which 17PA interacts may regulate spinal nociceptive processing in normal and inflamed tissue. PMID:23707652

  19. Aspartic acid

    MedlinePLUS

    Aspartic acid is a nonessential amino acids . Amino acids are building blocks of proteins. "Nonessential" means that our ... this amino acid from the food we eat. Aspartic acid is also called asparaginic acid. Aspartic acid helps ...

  20. Actions of picrodendrin antagonists on dieldrin-sensitive and -resistant Drosophila GABA receptors.

    PubMed Central

    Hosie, A. M.; Ozoe, Y.; Koike, K.; Ohmoto, T.; Nikaido, T.; Sattelle, D. B.

    1996-01-01

    1. A series of terpenoid compounds, recently isolated from Picrodendron baccatum, share a picrotoxane skeleton with picrotoxinin, an antagonist of ionotropic GABA receptors. Referred to as picrodendrins, they inhibit the binding of [35S]-tert-butylbicyclophosphorothionate (TBPS) to rat GABAA receptors. Hitherto, their effects on GABA receptors have not been investigated electrophysiologically. Under two-electrode voltage-clamp, the actions of picrodendrins and related terpenoids have been assayed on homooligomeric GABA receptors formed by the expression of a Drosophila GABA receptor subunit (RDLac) in Xenopus oocytes. 2. All the terpenoids tested, dose-dependently antagonized currents induced by 30 microM (EC50) GABA. 3. Tutin and its analogues (dihydrotutin and isohyenanchin) differ in the structure of their axial C4 substituents. Of these compounds, tutin, which bears an isopropenyl group at this carbon atom, was the most potent antagonist of RDLac homo-oligomers, whereas isohyenanchin, which bears a hydroxyisopropyl group, was the least potent antagonist tested. 4. Picrodendrins differ mainly in the structure of their C9 substituents. The IC50s of picrodendrins ranged from 17 +/- 1.3 nM (picrodendrin-Q) to 1006 +/- 1.3 nM (picrodendrin-O). As such, the most potent picrodendrins (Q, A and B) were approximately equipotent with picrotoxinin as antagonists of RDLac homo-oligomers. 5. Certain picrodendrin compounds effected a use-dependent blockade of RDLac homo-oligomers. Such a biphasic block was not observed with tutin analogues. 6. Picrotoxin-resistant RDLacA3025 homo-oligomers, which have a single amino acid substitution (A302S) in the 2nd transmembrane region, were markedly less sensitive to picrodendrin-O than the wild-type, dieldrin-sensitive, homo-oligomers. 7. The relative potency of tutin analogues demonstrates that the structure-activity relationship of the C4 substituent of picrotoxane-based compounds is conserved in vertebrates and insects. However, the relative order of potency of picrodendrins on RDLac homo-oligomers is distinctly different from that observed in previous radioligand binding studies performed on vertebrate GABAA receptors. As picrodendrin compounds differ in the structure of their C9 substituents, these data suggest that the optimal convulsant pharmacophores of vertebrate GABAA receptors and RDLac homo-oligomers differ with respect to this substituent. PMID:8982503

  1. A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques

    PubMed Central

    Peluffo, M.C.; Stanley, J.; Braeuer, N.; Rotgeri, A.; Fritzemeier, K.-H.; Fuhrmann, U.; Buchmann, B.; Adevai, T.; Murphy, M.J.; Zelinski, M.B.; Lindenthal, B.; Hennebold, J.D.; Stouffer, R.L.

    2014-01-01

    STUDY QUESTION Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? SUMMARY ANSWER This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. WHAT IS KNOWN ALREADY The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus–oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. STUDY DESIGN, SIZE, DURATION First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3–4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus–oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3–4 animals/treatment; ?3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. PARTICIPANTS/MATERIALS, SETTING, METHODS Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests and blood lipid profiles. MAIN RESULTS AND THE ROLE OF CHANCE Several mRNAs encoding proteins involved in PGE2 synthesis, metabolism and signaling increase (P < 0.05) in the periovulatory follicle after administration of an ovulatory hCG bolus. PGE2 signaling through PTGER2 induces cumulus cell expansion and production of hyaluronic acid, which are critical events for fertilization. Moreover, chronic administration of a selective PTGER2 antagonist resulted in a significant (P < 0.05 versus vehicle-treated controls) contraceptive effect without altering steroid hormone patterns or menstrual cyclicity during a 5-months contraceptive trial. Fertility recovered as early as 1 month after ending treatment. LIMITATIONS, REASONS FOR CAUTION This is a proof-of-concept study in a non-human primate model. Further investigations are warranted to elucidate the mechanism(s) of PTGER2 antagonist action in the primate ovary. Although PTGER2 antagonist treatment did not produce any obvious undesirable effects, improvements in the mode of administration, as well as the efficacy of these compounds, are necessary to consider such a contraceptive for women. WIDER IMPLICATIONS OF THE FINDINGS Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity. Even though hormonal contraceptives are effective for women, concerns remain regarding their side-effects and long-term use because of the widespread actions of such steroidal products in many tissues. Moreover, some women cannot take hormones for medical reasons. Thus, development of non-hormonal contraceptives for women is warranted. STUDY FUNDING/COMPETING INTEREST(S) Supported by Bayer HealthCare Pharmaceuticals, The Eunice Kennedy Shriver NICHD Contraceptive Development and Research Center (U54 HD055744), NIH Office of the Director (Oregon National Primate Research Center P51 OD011092), and a Lalor Foundation Postd

  2. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    SciTech Connect

    Li, Qun-Yi; Zhang, Meng; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai ; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; MPI Research, Mattawan, MI ; Wang, Ming-Wei; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  3. Approaches to the rational design of selective melanocortin receptor antagonists

    PubMed Central

    Hruby, Victor J; Cai, Minying; Nyberg, Joel; Muthu, Dhanasekaran

    2015-01-01

    Introduction When establishing the physiological roles of specific receptors in normal and disease states, it is critical to have selective antagonist ligands for each receptor in a receptor system with several subtypes. The melanocortin receptors have five subtypes referred to as the melanocortin 1 receptor, melanocortin 2 receptor, melanocortin 3 receptor, melanocortin 4 receptor and melanocortin 5 receptor, and they are of critical importance for many aspects of human health and disease. Areas covered This article reviews the current efforts to design selective antagonistic ligands for the five human melanocortin receptors summarizing the currently published orthosteric and allosteric antagonists for each of these receptors. Expert opinion Though there has been progress, there are still few drugs available that address the many significant biological activities and diseases that are associated with these receptors, which is possibly due to the lack of receptor selectivity that these designed ligands are currently showing. The authors believe that further studies into the antagonists’ 3D conformational and topographical properties in addition to future mutagenesis studies will provide greater insight into these ligands which could play a role in the treatment of various diseases in the future. PMID:22646078

  4. Antagonistic peptide technology for functional dissection of CLE peptides revisited

    PubMed Central

    Czyzewicz, Nathan; Wildhagen, Mari; Cattaneo, Pietro; Stahl, Yvonne; Pinto, Karine Gustavo; Aalen, Reidunn B.; Butenko, Melinka A.; Simon, Rüdiger; Hardtke, Christian S.; De Smet, Ive

    2015-01-01

    In the Arabidopsis thaliana genome, over 1000 putative genes encoding small, presumably secreted, signalling peptides can be recognized. However, a major obstacle in identifying the function of genes encoding small signalling peptides is the limited number of available loss-of-function mutants. To overcome this, a promising new tool, antagonistic peptide technology, was recently developed. Here, this antagonistic peptide technology was tested on selected CLE peptides and the related IDA peptide and its usefulness in the context of studies of peptide function discussed. Based on the analyses, it was concluded that the antagonistic peptide approach is not the ultimate means to overcome redundancy or lack of loss-of-function lines. However, information collected using antagonistic peptide approaches (in the broad sense) can be very useful, but these approaches do not work in all cases and require a deep insight on the interaction between the ligand and its receptor to be successful. This, as well as peptide ligand structure considerations, should be taken into account before ordering a wide range of synthetic peptide variants and/or generating transgenic plants. PMID:26136270

  5. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    PubMed

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic. PMID:11554551

  6. Retention and Outcome in a Narcotic Antagonist Treatment Program.

    ERIC Educational Resources Information Center

    Capone, Thomas; And Others

    1986-01-01

    Patients in an outpatient narcotic antagonist treatment program were followed through their course of treatment. Those who remained longer were found to enter treatment with more stable employment records and less recent opiate use. They also appeared more successful at termination, with better vocational stability, less extraneous drug use, and…

  7. Medium-Induced Antagonistic Behavior in Staphylococcus Aureus.

    ERIC Educational Resources Information Center

    Benathen, Isaiah A.

    1992-01-01

    Antagonism is the production of substances by microorganisms that inhibit or prevent the growth of other bacteria. This paper demonstrates the antagonistic behavior of gram-positive coccus on the B. subtilis and Enterococcus faecalis gram-positive microorganisms, showing that the process of antagonism is sometimes dependent on the nutritional…

  8. The Effect of Antagonist Muscle Sensory Input on Force Regulation

    PubMed Central

    Onushko, Tanya; Schmit, Brian D.; Hyngstrom, Allison

    2015-01-01

    The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years), healthy subjects performed constant isometric knee flexion contractions (agonist) at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback) during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%), subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40%) between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical) are likely involved. PMID:26186590

  9. Antagonistic gene transcripts regulate adaptation to new growth environments

    E-print Network

    Tsimring, Lev S.

    Antagonistic gene transcripts regulate adaptation to new growth environments Bridget L for review July 15, 2011) Cells have evolved complex regulatory networks that reorganize gene expression that affect various levels of gene expression. Here, we examine the con- sequences of enhanced m

  10. Polyphloretin phosphate (PPP) antagonists of prostaglandin action also inhibit prostaglandin biosynthesis in-vitro.

    PubMed

    Curtis-Prior, P B; Oblin, A R; Bennett, A; Parkinson, N A; Orloff, A M

    1990-09-01

    Several polyphloretin phosphate (PPP) fractions (low mol. wt LC1259; high mol. wt LC1261; crude mixture, LC101) were confirmed in their established property as antagonists of the pharmacological actions of prostaglandins in a preparation of guinea-pig isolated ileum stimulated by prostaglandin (PG)E2. Further samples of the same material were then compared in-vitro with indomethacin in their ability to inhibit prostaglandin biosynthesis from arachidonic acid by a microsomal enzyme preparation. All three PPP fractions potently inhibited prostaglandin generation, with the rank order of potency LC1259 = LC101 = indomethacin greater than LC1261. The oral LD50 in mice was 25 mg kg-1 for indomethacin and greater than 1 g kg-1 for LC101. PPP fractions (especially LC101) may therefore have therapeutic potential as anti-inflammatory agents. PMID:1981908

  11. Overview of the safety profile of the H2-receptor antagonists.

    PubMed

    Hansten, P D

    1990-11-01

    Reports of adverse drug reactions due to histamine H2-receptor antagonists (H2RAs) are rare considering their wide usage. Cimetidine produces central nervous system and endocrine toxicities more often than other H2RAs. Drug-drug interactions are of potentially greater concern with H2RAs, especially because the critically ill patient routinely receives many drugs. H2RAs may alter the absorption, metabolism, or renal excretion of concurrently administered drugs. Gastrointestinal absorption of drugs, such as ketoconazole, that dissolve poorly in the absence of adequate acid may be reduced. Inhibition of hepatic oxidative drug metabolism of agents such as warfarin, theophylline, and phenytoin, is primarily a problem with cimetidine. Adverse effects will be seen in predisposed individuals and the time course will depend on the pharmacokinetics of the object drug. The other H2RAs are less likely to inhibit drug metabolism and affect renal clearance of procainamide than is cimetidine. PMID:1980183

  12. HPS4/SABRE regulates plant responses to phosphate starvation through antagonistic interaction with ethylene signalling

    PubMed Central

    Yu, Hailan; Luo, Nan; Sun, Lichao; Liu, Dong

    2012-01-01

    The phytohormone ethylene plays important roles in regulating plant responses to phosphate (Pi) starvation. To date, however, no molecular components have been identified that interact with ethylene signalling in regulating such responses. In this work, an Arabidopsis mutant, hps4, was characterized that exhibits enhanced responses to Pi starvation, including increased inhibition of primary root growth, enhanced expression of Pi starvation-induced genes, and overproduction of root-associated acid phosphatases. Molecular cloning indicated that hps4 is a new allele of SABRE, which was previously identified as an important regulator of cell expansion in Arabidopsis. HPS4/SABRE antagonistically interacts with ethylene signalling to regulate plant responses to Pi starvation. Furthermore, it is shown that Pi-starved hps4 mutants accumulate more auxin in their root tips than the wild type, which may explain the increased inhibition of their primary root growth when grown under Pi deficiency. PMID:22615140

  13. Plant monocultures produce more antagonistic soil Streptomyces communities than high-diversity plant communities

    E-print Network

    Thomas, David D.

    bacteria, the Streptomyces possess particularly strong antagonistic activities and inhibit diverse plant the potential of soil Streptomyces to antagonize plant pathogens, using an in vitro plate assay with indicatorPlant monocultures produce more antagonistic soil Streptomyces communities than high

  14. Discovery of a novel series of nonacidic benzofuran EP1 receptor antagonists.

    PubMed

    Allan, Amanda C; Billinton, Andy; Brown, Susan H; Chowdhury, Anita; Eatherton, Andrew J; Fieldhouse, Charlotte; Giblin, Gerard M P; Goldsmith, Paul; Hall, Adrian; Hurst, David N; Naylor, Alan; Rawlings, D Anthony; Sime, Mairi; Scoccitti, Tiziana; Theobald, Pamela J

    2011-07-15

    We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain. PMID:21676612

  15. Effect of combined leukotriene D(4) and thromboxane A(2) receptor antagonist on mediator-controlled resistance in guinea pigs.

    PubMed

    Arakida, Y; Ohga, K; Okada, Y; Morio, H; Suwa, K; Yokota, M; Yamada, T

    2000-09-01

    The effects of YM158 (3-[(4-tert-butylthiazol-2-yl)methoxy]-5'-[3-(4-chlorobenzenesu lfonyl )propyl]-2'-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate), a new dual antagonist for leukotriene D(4) and thromboxane A(2) receptors, on antigen-induced increases in airway resistance were investigated in mediator-controlled novel asthmatic models using actively sensitized guinea pigs. While the predominant mediator was thromboxane A(2), complete inhibition of cyclooxygenase induced mediation by cysteinyl-leukotrienes. About 1-mg/kg indomethacin induced a state where both mediators participated equally. YM158 inhibited increases in resistance whether only one or both mediators were involved. When leukotriene D(4) and thromboxane A(2) equally participated, ED(50) values for 4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4 H-1-benzo pyran hemihydrate (pranlukast; 3.9 mg/kg) and 7-(3,5,6-trimethyl-1, 4-benzoquinon-2-yl)-7-phenylheptanoic acid (seratrodast; 2.1 mg/kg) were similar to that for YM158 (8.3 mg/kg), although those effects on the corresponding mediator-induced reaction were 10 times stronger than those of YM158. Additionally, the maximum inhibition of YM158 was stronger than those of either single receptor antagonist. In conclusion, YM158 has a potentially greater efficacy in wider types of experimental asthmatic models than single receptor antagonists. PMID:10969159

  16. Synthesis and thromboxane A2/prostaglandin H2 receptor antagonistic activity of phenol derivatives.

    PubMed

    Fukumoto, S; Shiraishi, M; Terashita, Z; Ashida, Y; Inada, Y

    1992-06-12

    Consideration of possible structural similarities between thromboxane A2 and the hydroquinone form of (R)-(+)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7- phenylheptanoic acid (R-(+)-AA-2414) led to the development of a new series of thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor antagonists, namely 7-(4-fluorophenyl)-7-(2-hydroxyphenyl)heptanoic acids (I). These compounds were found to be potent TXA2/PGH2 receptor antagonists. Compounds having either a carbonyl or a hydroxymethyl group at the para-position of the phenolic hydroxy group exhibited most potent activities in this series. Compounds 14, 15, 18, and 26 inhibited the specific binding of [3H]U-46619 to guinea pig platelet membranes (IC50 = 4.4, 80, 32, and 13 nM, respectively), and also inhibited U-46619-induced human platelet aggregation (IC50 = 310, 69, 79, and 78 nM, respectively). Comparison of the UV spectra of the compounds with a carbonyl group at the para-position of phenolic hydroxy group revealed that the activity tended to increase in accordance with a decrease in the torsional angle between the carbonyl group and the phenol ring. These results suggested that the spacial location of the carbonyl and hydroxymethyl oxygen are important for significant increase in activity and that the carbonyl and hydroxymethyl oxygen at the para-position of the phenolic hydroxy group might interact with one of the TXA2/PGH2 receptor sites. PMID:1535377

  17. Pathologic crossroads: cardio–vascular diseases, periodontal diseases and calcium antagonists

    PubMed Central

    Popescu, E; Angelescu, G

    2011-01-01

    RationaleDuring the last decennium t a more focused attention has been directed to the presence of chronic inflammation in cardiovascular diseases (CVD), but mainly to the high impact that this one has in generating and fastening the atherosclerotic process. ObjectiveTo highlight the causal relationship between periodontal diseases (PD) and CVD. One of the most important chronic inflammations, present in the modern societies in the vast majority of the population, is represented by the periodontal diseases (PD). Both types of diseases are characterized by a high and continuously increasing prevalence. It is now clear that they share some common risk factors, but it would be of great interest, not only for a scientific purpose, but also from a possible health benefit, as PD can be prevented and treated efficiently, to prove that there is a causal link between these two pathologies. MethodsWe will present a review of the actual data concerning their relationship DiscussionThe study of this causal relationship is made more difficult due to the increased utilization, due to the guides' recommendations of the calcium antagonists (CA) in treating CVD. Abreviations: AE = adverse effect; AMI = acute myocardial infarction; CA = calcium antagonists; CHD = coronary heart disease; COI = chronic oral infection; CsA = cyclosporine A; CVD = cardio-vascular diseases; DM = diabetes mellitus; DNA = deoxyribonucleic acid; GH = gingival hypertrophy; GO = gingival overgrowth; hs-CRP = high-sensitivity C reactive protein; IL = interleukine; ICAM = intracellular adhesion molecule; JE/MCP–1 = macrophage chemotactic protein; LPS– lipopolisaccharides; MIP–2 = macrophage inflammatory protein–2; MMP = matrix metalloproteinases; mRNA = messenger–ribonucleic acid; NOS = nitric oxide synthase; PAI–1 = plasminogen activator inhibitor–1; PD = periodontal diseases; TIMP = tissue inhibitor of metalloproteinase; TNF = tumor necrosis factor; USA = United States of America; UFC = units forming cultures; WHO= World Health Organization. PMID:21505569

  18. Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists.

    PubMed

    DeVita, R J; Goulet, M T; Wyvratt, M J; Fisher, M H; Lo, J L; Yang, Y T; Cheng, K; Smith, R G

    1999-09-01

    Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+/-)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Amdt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency. PMID:10498221

  19. Adenosine Deaminase Acts as a Natural Antagonist for Dipeptidyl Peptidase 4-Mediated Entry of the Middle East Respiratory Syndrome Coronavirus

    PubMed Central

    Raj, V. Stalin; Smits, Saskia L.; Provacia, Lisette B.; van den Brand, Judith M. A.; Wiersma, Lidewij; Ouwendijk, Werner J. D.; Bestebroer, Theo M.; Spronken, Monique I.; van Amerongen, Geert; Rottier, Peter J. M.; Fouchier, Ron A. M.; Bosch, Berend Jan; Osterhaus, Albert D.M.E.

    2014-01-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) replicates in cells of different species using dipeptidyl peptidase 4 (DPP4) as a functional receptor. Here we show the resistance of ferrets to MERS-CoV infection and inability of ferret DDP4 to bind MERS-CoV. Site-directed mutagenesis of amino acids variable in ferret DPP4 thus revealed the functional human DPP4 virus binding site. Adenosine deaminase (ADA), a DPP4 binding protein, competed for virus binding, acting as a natural antagonist for MERS-CoV infection. PMID:24257613

  20. Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

    SciTech Connect

    Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr. )

    1991-04-01

    The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative {sup 14}C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions.

  1. Acid Safety Checklist Acid Storage

    E-print Network

    Acid Safety Checklist Acid Storage Acids stored separately from bases, organic acids, flammables stored in separate secondary containment from bases, flammables Acid waste container correctly labeled, water reactives Acids stored in secondary containment Eyewash and shower immediately available Spill kit

  2. Antitussive agents as N-methylaspartate antagonists: further studies.

    PubMed

    Church, J; Jones, M G; Davies, S N; Lodge, D

    1989-06-01

    The relative potencies of ketamine and the morphinan derivatives dextrorphan, dextromethorphan, and levorphanol as antagonists of the excitatory actions of N-methylaspartate on rat spinal neurones in vivo were examined, both following their microelectrophoretic administration and, with the exception of levorphanol, after intravenous injection. Applied microelectrophoretically, dextrorphan was a more potent N-methylaspartate antagonist than ketamine, levorphanol, or dextromethorphan. After systemic administration, however, dextrorphan was rather less potent than ketamine in this respect, whereas dextromethorphan remained less potent than either ketamine or dextrorphan. Noscapine, an antitussive that lacks anticonvulsant activity, failed to reduce selectively responses to N-methylaspartate as did papaverine, an isoquinoline structurally related to noscapine, and triprolidine, an antihistamine commonly found in proprietary cough medicines. The results are discussed with particular reference to the potential of the compounds tested as anticonvulsant and neuroprotective agents in vivo. PMID:2673498

  3. Antagonistic Coevolution of Marine Planktonic Viruses and Their Hosts

    NASA Astrophysics Data System (ADS)

    Martiny, Jennifer B. H.; Riemann, Lasse; Marston, Marcia F.; Middelboe, Mathias

    2014-01-01

    The potential for antagonistic coevolution between marine viruses and their (primarily bacterial) hosts is well documented, but our understanding of the consequences of this rapid evolution is in its infancy. Acquisition of resistance against co-occurring viruses and the subsequent evolution of virus host range in response have implications for bacterial mortality rates as well as for community composition and diversity. Drawing on examples from a range of environments, we consider the potential dynamics, underlying genetic mechanisms and fitness costs, and ecological impacts of virus-host coevolution in marine waters. Given that much of our knowledge is derived from laboratory experiments, we also discuss potential challenges and approaches in scaling up to diverse, complex networks of virus-host interactions. Finally, we note that a variety of novel approaches for characterizing virus-host interactions offer new hope for a mechanistic understanding of antagonistic coevolution in marine plankton.

  4. Potent CXCR4 Antagonists Containing Amidine Type Peptide Bond Isosteres

    PubMed Central

    2011-01-01

    A series of FC131 [cyclo(-d-Tyr-Arg-Arg-Nal-Gly-)] analogues containing amidine type peptide bond isosteres were synthesized as selective CXC chemokine receptor type 4 (CXCR4) antagonists. An isosteric amidine substructure was constructed by a macrocyclization process using nitrile oxide-mediated C?N bond formation. All of the amidine-containing FC131 analogues exhibited potent SDF-1 binding inhibition to CXCR4. The Nal-Gly-substituted analogue was characterized as one of the most potent cyclic pentapeptide-based CXCR4 antagonists reported to date. The improved activity against human immunodeficiency virus (HIV) type-1 X4 strains suggested that addition of another basic amidine group to the peptide backbone effectively increases the selective binding of the peptides to CXCR4 receptor. PMID:24900333

  5. Percolation on networks with antagonistic and dependent interactions

    NASA Astrophysics Data System (ADS)

    Kotnis, Bhushan; Kuri, Joy

    2015-03-01

    Drawing inspiration from real world interacting systems, we study a system consisting of two networks that exhibit antagonistic and dependent interactions. By antagonistic and dependent interactions we mean that a proportion of functional nodes in a network cause failure of nodes in the other, while failure of nodes in the other results in failure of links in the first. In contrast to interdependent networks, which can exhibit first-order phase transitions, we find that the phase transitions in such networks are continuous. Our analysis shows that, compared to an isolated network, the system is more robust against random attacks. Surprisingly, we observe a region in the parameter space where the giant connected components of both networks start oscillating. Furthermore, we find that for Erd?s-Rényi and scale-free networks the system oscillates only when the dependence and antagonism between the two networks are very high. We believe that this study can further our understanding of real world interacting systems.

  6. Lead optimization studies of cinnamic amide EP2 antagonists.

    PubMed

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (?10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID:24773616

  7. Effects of dopamine receptor antagonists on sucrose consumption and preference.

    PubMed

    Muscat, R; Willner, P

    1989-01-01

    Effects of the dopamine D2 receptor antagonist sulpiride and the D1 antagonist SCH-23390 were examined, in rats, in two-bottle preference tests (sucrose versus water) and in single-bottle tests, at different sucrose concentrations. Both drugs decreased sucrose intake in single bottle tests, at low sucrose concentrations, but had no effect at high concentrations; reducing drive level had exactly the opposite pattern of effects. In two-bottle tests, both drugs reduced preference for the weakest sucrose concentration (0.7%) but increased preference for the strongest concentration (34%). The effects of antagonizing either subtype of DA receptor appear to be similar to those of reducing the concentration of sucrose. PMID:2506610

  8. In Vitro and In Vivo Plant Growth Promoting Activities and DNA Fingerprinting of Antagonistic Endophytic Actinomycetes Associates with Medicinal Plants

    PubMed Central

    Passari, Ajit Kumar; Mishra, Vineet Kumar; Gupta, Vijai Kumar; Yadav, Mukesh Kumar; Saikia, Ratul; Singh, Bhim Pratap

    2015-01-01

    Endophytic actinomycetes have shown unique plant growth promoting as well as antagonistic activity against fungal phytopathogens. In the present study forty-two endophytic actinomycetes recovered from medicinal plants were evaluated for their antagonistic potential and plant growth-promoting abilities. Twenty-two isolates which showed the inhibitory activity against at least one pathogen were subsequently tested for their plant-growth promoting activities and were compared genotypically using DNA based fingerprinting, including enterobacterial repetitive intergenic consensus (ERIC) and BOX repetitive elements. Genetic relatedness based on both ERIC and BOX-PCR generates specific patterns corresponding to particular genotypes. Exponentially grown antagonistic isolates were used to evaluate phosphate solubilization, siderophores, HCN, ammonia, chitinase, indole-3-acetic acid production, as well as antifungal activities. Out of 22 isolates, the amount of indole-3-acetic acid (IAA) ranging between 10–32 ?g/ml was produced by 20 isolates and all isolates were positive for ammonia production ranging between 5.2 to 54 mg/ml. Among 22 isolates tested, the amount of hydroxamate-type siderophores were produced by 16 isolates ranging between 5.2 to 36.4 ?g/ml, while catechols-type siderophores produced by 5 isolates ranging from 3.2 to 5.4 ?g/ml. Fourteen isolates showed the solubilisation of inorganic phosphorous ranging from 3.2 to 32.6 mg/100ml. Chitinase and HCN production was shown by 19 and 15 different isolates, respectively. In addition, genes of indole acetic acid (iaaM) and chitinase (chiC) were successively amplified from 20 and 19 isolates respectively. The two potential strains Streptomyces sp. (BPSAC34) and Leifsonia xyli (BPSAC24) were tested in vivo and improved a range of growth parameters in chilli (Capsicum annuum L.) under greenhouse conditions. This study is the first published report that actinomycetes can be isolated as endophytes from within these plants and were shown to have antagonistic and plant growth promoting abilities. These results clearly suggest the possibility of using endophytic actinomycetes as bioinoculant for plant growth promotion, nutrient mobilization or as biocontrol agent against fungal phytopathogens for sustainable agriculture. PMID:26422789

  9. In Vitro and In Vivo Plant Growth Promoting Activities and DNA Fingerprinting of Antagonistic Endophytic Actinomycetes Associates with Medicinal Plants.

    PubMed

    Passari, Ajit Kumar; Mishra, Vineet Kumar; Gupta, Vijai Kumar; Yadav, Mukesh Kumar; Saikia, Ratul; Singh, Bhim Pratap

    2015-01-01

    Endophytic actinomycetes have shown unique plant growth promoting as well as antagonistic activity against fungal phytopathogens. In the present study forty-two endophytic actinomycetes recovered from medicinal plants were evaluated for their antagonistic potential and plant growth-promoting abilities. Twenty-two isolates which showed the inhibitory activity against at least one pathogen were subsequently tested for their plant-growth promoting activities and were compared genotypically using DNA based fingerprinting, including enterobacterial repetitive intergenic consensus (ERIC) and BOX repetitive elements. Genetic relatedness based on both ERIC and BOX-PCR generates specific patterns corresponding to particular genotypes. Exponentially grown antagonistic isolates were used to evaluate phosphate solubilization, siderophores, HCN, ammonia, chitinase, indole-3-acetic acid production, as well as antifungal activities. Out of 22 isolates, the amount of indole-3-acetic acid (IAA) ranging between 10-32 ?g/ml was produced by 20 isolates and all isolates were positive for ammonia production ranging between 5.2 to 54 mg/ml. Among 22 isolates tested, the amount of hydroxamate-type siderophores were produced by 16 isolates ranging between 5.2 to 36.4 ?g/ml, while catechols-type siderophores produced by 5 isolates ranging from 3.2 to 5.4 ?g/ml. Fourteen isolates showed the solubilisation of inorganic phosphorous ranging from 3.2 to 32.6 mg/100ml. Chitinase and HCN production was shown by 19 and 15 different isolates, respectively. In addition, genes of indole acetic acid (iaaM) and chitinase (chiC) were successively amplified from 20 and 19 isolates respectively. The two potential strains Streptomyces sp. (BPSAC34) and Leifsonia xyli (BPSAC24) were tested in vivo and improved a range of growth parameters in chilli (Capsicum annuum L.) under greenhouse conditions. This study is the first published report that actinomycetes can be isolated as endophytes from within these plants and were shown to have antagonistic and plant growth promoting abilities. These results clearly suggest the possibility of using endophytic actinomycetes as bioinoculant for plant growth promotion, nutrient mobilization or as biocontrol agent against fungal phytopathogens for sustainable agriculture. PMID:26422789

  10. Neurokinin-1 Receptor Antagonists in Preventing Postoperative Nausea and Vomiting

    PubMed Central

    Liu, Meng; Zhang, Hao; Du, Bo-Xiang; Xu, Feng-Ying; Zou, Zui; Sui, Bo; Shi, Xue-Yin

    2015-01-01

    Abstract Newly developed neurokinin-1 receptor (NK-1R) antagonists have been recently tried in the prevention of postoperative nausea and vomiting (PONV). This systematic review and meta-analysis was conducted to explore whether NK-1R antagonists were effective in preventing PONV. The PRISMA statement guidelines were followed. Randomized clinical trials (RCTs) that tested the preventive effects of NK-1R antagonists on PONV were identified by searching EMBASE, CINAHL, PubMed, and the Cochrane Library databases followed by screening. Data extraction was performed using a predefined form and trial quality was assessed using a modified Jadad scale. The primary outcome measure was the incidence of PONV. Meta-analysis was performed for studies using similar interventions. Network meta-analysis (NMA) was conducted to compare the anti-vomiting effects of placebo, ondansetron, and aprepitant at different doses. Fourteen RCTs were included. Meta-analysis found that 80?mg of aprepitant could reduce the incidences of nausea (3 RCTs with 224 patients, pooled risk ratio (RR)?=?0.60, 95% confidence interval (CI)?=?0.47 to 0.75), and vomiting (3 RCTs with 224 patients, pooled RR?=?0.13, 95% CI?=?0.04 to 0.37) compared with placebo. Neither 40?mg (3 RCTs with 1171 patients, RR?=?0.47, 95% CI?=?0.37 to 0.60) nor 125?mg (2 RCTs with 1058 patients, RR?=?0.32, 95% CI?=?0.13 to 0.78) of aprepitant showed superiority over 4?mg of ondansetron in preventing postoperative vomiting. NMA did not find a dose-dependent effect of aprepitant on preventing postoperative vomiting. Limited data suggested that NK-1R antagonists, especially aprepitant were effective in preventing PONV compared with placebo. More large-sampled high-quality RCTs are needed. PMID:25984662

  11. Effects of dihydropyridine calcium antagonists on rat midbrain dopaminergic neurones.

    PubMed Central

    Mercuri, N B; Bonci, A; Calabresi, P; Stratta, F; Stefani, A; Bernardi, G

    1994-01-01

    1. The effects of the dihydropyridine calcium channel antagonists, nifedepine and nimodipine (300 nM-30 microM) were tested in vitro on intracellularly recorded dopaminergic neurones in the rat ventral mesencephalon. 2. Bath applied nifedipine and nimodipine inhibited in a concentration-dependent manner the spontaneous firing discharge of the action potentials, whereas, the dihydropyridine calcium channel agonist, Bay K 8644 increased the firing rate. 3. Pacemaker oscillations and bursts of action potentials were produced by loading the cells with caesium. Nifedipine and nimodipine reduced the rate and the duration of the caesium-induced membrane oscillations and decreased the number of action potentials in a burst. During the blockade of potassium currents the dopaminergic neurones often developed a prolonged (100-800 ms) afterdepolarization that was also inhibited by dihydropyridines. 4. The spontaneous discharge of calcium spikes was also inhibited by both dihydropyridine calcium antagonists. The apparent input resistance and the level of membrane potential were not affected by the dihydropyridine calcium antagonists. 5. If the action potential duration was less than 150 ms the shape of the spike was not clearly influenced by both calcium antagonists. However, when the duration of the action potential was longer than 150-200 ms due to the intracellular injection of caesium ions plus the extracellular application of tetraethylammonium (10-50 mM), both nifedipine and nimodipine reversibly shortened the plateau potential. 6. It is suggested that nifedipine and nimodipine depress the rhythmic and bursting activity of the dopaminergic cells and shorten the calcium action potential by blocking dihydropyridine-sensitive high-threshold calcium currents. PMID:7858874

  12. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    PubMed

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain. PMID:22939234

  13. Structural and Dynamical Insight into PPAR? Antagonism: In Silico Study of the Ligand-Receptor Interactions of Non-Covalent Antagonists

    PubMed Central

    Fratev, Filip; Tsakovska, Ivanka; Al Sharif, Merilin; Mihaylova, Elina; Pajeva, Ilza

    2015-01-01

    The structural and dynamical properties of the peroxisome proliferator-activated receptor ? (PPAR?) nuclear receptor have been broadly studied in its agonist state but little is known about the key features required for the receptor antagonistic activity. Here we report a series of molecular dynamics (MD) simulations in combination with free energy estimation of the recently discovered class of non-covalent PPAR? antagonists. Their binding modes and dynamical behavior are described in details. Two key interactions have been detected within the cavity between helices H3, H11 and the activation helix H12, as well as with H12. The strength of the ligand-amino acid residues interactions has been analyzed in relation to the specificity of the ligand dynamical and antagonistic features. According to our results, the PPAR? activation helix does not undergo dramatic conformational changes, as seen in other nuclear receptors, but rather perturbations that occur through a significant ligand-induced reshaping of the ligand-receptor and the receptor-coactivator binding pockets. The H12 residue Tyr473 and the charge clamp residue Glu471 play a central role for the receptor transformations. Our results also demonstrate that MD can be a helpful tool for the compound phenotype characterization (full agonists, partial agonists or antagonists) when insufficient experimental data are available. PMID:26184155

  14. Non-genetic inheritance and the patterns of antagonistic coevolution

    PubMed Central

    2012-01-01

    Background Antagonistic species interactions can lead to coevolutionary genotype or phenotype frequency oscillations, with important implications for ecological and evolutionary processes. However, direct empirical evidence of such oscillations is rare. The rarity of observations is generally attributed to inherent difficulties of ecological and evolutionary long-term studies, to weak or absent interaction between species, or to the absence of negative frequency-dependence. Results Here, we show that another factor – non-genetic inheritance, mediated for example by epigenetic mechanisms – can completely eliminate oscillations in the presence of such negative frequency dependence, even if only a small fraction of offspring are affected. We analytically derive the threshold value of this fraction at which the dynamics change from oscillatory to stable, and investigate how selection, mutation and generation times differences between the two species affect the threshold value. These results strongly suggest that the lack of phenotype frequency oscillations should not be attributed to the lack of strong interactions between antagonistic species. Conclusions Given increasing evidence of non-genetic effects on the outcomes of antagonistic species interactions, we suggest that these effects should be incorporated into ecological and evolutionary models of interacting species. PMID:22720868

  15. Affinity and selectivity of beta-adrenoceptor antagonists in vitro

    SciTech Connect

    Wellstein, A.; Palm, D.; Belz, G.G.

    1986-01-01

    The potency order of the catecholamines (-)-isoprenaline (Iso), (-)-noradrenaline (NA), and (-)-adrenaline (Adr) in competition for radiolabelled sites is used for their pharmacological classification. It is shown that the radioligand /sup 3/H-CGP 12177 exclusively labels beta 1-adrenoceptors in rat salivary gland membranes (Iso greater than NA greater than Adr), and beta 2-adrenoceptors in rat reticulocytes (Iso greater than Adr greater than or equal to NA). These models are then used to derive the subtype-selectivity of the classical beta-adrenoceptor antagonists (+/-)-propranolol (prop; twofold beta 2-selective) and (+/-)-atenolol (aten; 35-fold beta 1-selective), as well as of the newer antagonists (+/-)-betaxolol and (+/-)-bisoprolol (betax and biso; 35-fold and 75-fold beta 1-selective, respectively). The ligand with the highest selectivity is ICI 118,551 (ICI), with a 300-fold beta 2-subtype selectivity. For comparison with antagonistic effects in humans at given plasma concentrations, the equilibrium dissociation constants of the ligands are measured in the presence of native human plasma and yield values for the relative selectively labelled subtype in the mean (Ki-values in nmol/l): prop: 20, aten: 250, biso: 24, betax: 23, and ICI: 2.5.

  16. Does intergenerational social mobility affect antagonistic attitudes towards ethnic minorities?

    PubMed

    Tolsma, Jochem; de Graaf, Nan Dirk; Quillian, Lincoln

    2009-06-01

    Up till now, no study satisfactorily addressed the effect of social mobility on antagonistic attitudes toward ethnic minorities. In this contribution, we investigate the effect of educational and class intergenerational mobility on ethnic stereotypes, ethnic threat, and opposition to ethnic intermarriage by using diagonal mobility models. We test several hypotheses derived from ethnic competition theory and socialization theory with data from the Social and Cultural Developments in The Netherlands surveys (SOCON, waves 1995, 2000, and 2005) and The Netherlands Kinship and Panel Study (NKPS, wave 2002). We find that the relative influence of social origin and social destination depends on the specific origin and destination combination. If one moves to a more tolerant social destination position, the influence of the social origin position is negligible. If on the other hand, one is socially mobile to a less tolerant social position, the impact of the origin on antagonistic attitudes is substantial and may even exceed the impact of the destination category. This confirms our hypothesis that adaptation to more tolerant norms is easier than adaptation to less tolerant norms. We find only meagre evidence for the hypothesis that downward mobility leads to frustration and consequently to more antagonistic attitudes. PMID:19489819

  17. Tumor necrosis factor-? antagonists: Side effects and their management.

    PubMed

    Dogra, Sunil; Khullar, Geeti

    2013-07-01

    As elevated levels of tumor necrosis factor-alpha (TNF-?) are associated with disease severity in psoriasis and psoriatic arthritis, TNF-? antagonists are being used to treat moderate to severe disease in patients who have contraindications, fail to respond or develop side effects to conventional systemic therapies. It is of utmost importance to be well versed with the possible adverse effects and contraindications of TNF-? antagonists so that they can be used effectively and safely. Many of their adverse effects have been well studied in patients of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) and may not be completely applicable in psoriasis. This is because patients with RA and IBD are on multiple immunosuppressants while those with psoriasis are mostly receiving single systemic therapy and often have comorbidities that distinguish them from those with RA or IBD. Also, some of the side effects are still controversial and debated. Long-term prospective randomized controlled studies are needed to better understand the associated risk in patients of psoriasis. Baseline screening and periodic monitoring during treatment can reduce and help in early identification and appropriate management of the adverse outcomes. This article reviews the side effects known to be associated with TNF-? antagonists, their pathomechanisms and management guidelines. Some of the common side effects include infusion and injection site reactions, infections particularly reactivation of tuberculosis, autoantibody formation and drug induced lupus erythematosus, liver function abnormalities, hematological, and solid organ malignancies. PMID:23974693

  18. Interactions between adenosine and dopamine receptor antagonists with different selectivity profiles: Effects on locomotor activity.

    PubMed

    Collins, Lyndsey E; Galtieri, Daniel J; Collins, Patricia; Jones, Shawnet K; Port, Russell G; Paul, Nicholas E; Hockemeyer, Jörg; Müller, Christa E; Salamone, John D

    2010-08-25

    Forebrain dopamine (DA) is a critical component of the brain circuitry regulating behavioral activation. Adenosine A(2A) antagonists reverse many of the behavioral effects of DA antagonists, and A(2A) receptors are co-localized with D(2) receptors on striatal medium spiny neurons. The present work was undertaken to determine if the ability of an A(2A) antagonist, a non-selective adenosine antagonist, or an A(1) antagonist to reverse the locomotor effects of DA blockade in rats differed depending upon whether D(1) or D(2) family receptors were being antagonized. The adenosine antagonists MSX-3, caffeine, DPCPX and CPT were studied for their ability to reverse the locomotor suppression induced by the D(1) antagonist SCH 39166 (ecopipam) and the D(2) antagonist eticlopride. The D(1) and D(2) antagonists suppressed locomotion in all experiments. The adenosine A(2A) receptor antagonist MSX-3 (0.5-2.0 mg/kg IP) significantly reversed the suppression of locomotion induced by eticlopride. The non-selective adenosine antagonist caffeine (5.0-20.0 mg/kg IP) also reversed the effect of eticlopride, though the effect was not as robust as that seen with MSX-3. The adenosine A(1) antagonists DPCPX (0.375-1.5 mg/kg) and CPT (3.0-12.0 mg/kg IP) were unable to reverse the locomotor impairment elicited by eticlopride. Furthermore, the attenuation of locomotion induced by the D(1) antagonist could only be reversed by the highest dose of MSX-3, but not by caffeine, DPCPX or CPT. DA and adenosine receptor antagonists interact in the regulation of locomotor activation, but the nature of this interaction appears to depend upon the receptor selectivity profiles of the specific drugs being tested. PMID:20211657

  19. Why Take a Prenatal Supplement?

    MedlinePLUS

    ... need from food. This is especially true for folic acid and iron : During pregnancy, mothers need to consume ... as well as those of their growing baby. Folic Acid: Folic acid, also called folate, is a B ...

  20. Pregnancy Quiz

    MedlinePLUS

    ... is dangerous for pregnant women. True or False? Folic acid is important during pregnancy and pregnant women need ... to get pregnant should get 400 micrograms of folic acid per day. Folic acid helps a baby's spine ...

  1. How Are Thalassemias Treated?

    MedlinePLUS

    ... the stomach), vomiting, diarrhea, joint pain, and tiredness. Folic Acid Supplements Folic acid is a B vitamin that helps build healthy red blood cells. Your doctor may recommend folic acid supplements in addition to treatment with blood transfusions ...

  2. Cleft Lip and Cleft Palate

    MedlinePLUS

    ... passed from parents to children. Not getting enough folic acid before pregnancy. Folic acid is a vitamin that can help protect your ... pregnancy, take a multivitamin with 400 micrograms of folic acid in it every day. During pregnancy, take a ...

  3. Oral mineralocorticoid antagonists for recalcitrant central serous chorioretinopathy

    PubMed Central

    Chin, Eric K; Almeida, David RP; Roybal, C Nathaniel; Niles, Philip I; Gehrs, Karen M; Sohn, Elliott H; Boldt, H Culver; Russell, Stephen R; Folk, James C

    2015-01-01

    Purpose To evaluate the effect and tolerance of oral mineralocorticoid antagonists, eplerenone and/or spironolactone, in recalcitrant central serous chorioretinopathy. Methods Retrospective consecutive observational case series. Primary outcome measures included central macular thickness (CMT, ?m), macular volume (MV, mm3), Snellen visual acuity, and prior treatment failures. Secondary outcomes included duration of treatment, treatment dosage, and systemic side effects. Results A total of 120 patients with central serous chorioretinopathy were reviewed, of which 29 patients were treated with one or more mineralocorticoid antagonists. The average age of patients was 58.4 years. Sixteen patients (69.6%) were recalcitrant to other interventions prior to treatment with oral mineralocorticoid antagonists, with an average washout period of 15.3 months. The average duration of mineralocorticoid antagonist treatment was 3.9±2.3 months. Twelve patients (52.2%) showed decreased CMT and MV, six patients (26.1%) had increase in both, and five patients (21.7%) had negligible changes. The mean decrease in CMT of all patients was 42.4 ?m (range, ?136 to 255 ?m): 100.7 ?m among treatment-naïve patients, and 16.9 ?m among recalcitrant patients. The mean decrease in MV of all patients was 0.20 mm3 (range, ?2.33 to 2.90 mm3): 0.6 mm3 among treatment-naïve patients, and 0.0 mm3 among recalcitrant patients. Median visual acuity at the start of therapy was 20/30 (range, 20/20–20/250), and at final follow-up it was 20/40 (range, 20/20–20/125). Nine patients (39.1%) experienced systemic side effects, of which three patients (13.0%) were unable to continue therapy. Conclusion Mineralocorticoid antagonist treatment had a positive treatment effect in half of our patients. The decrease in CMT and MV was much less in the recalcitrant group compared to the treatment-naïve group. An improvement in vision was seen only in the treatment-naïve group. Systemic side effects, even at low doses, may limit its usage in some patients. PMID:26316684

  4. Endothelin@25 – new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12

    PubMed Central

    Maguire, J J; Davenport, A P

    2014-01-01

    Since the discovery of endothelin (ET)-1 in 1988, the main components of the signalling pathway have become established, comprising three structurally similar endogenous 21-amino acid peptides, ET-1, ET-2 and ET-3, that activate two GPCRs, ETA and ETB. Our aim in this review is to highlight the recent progress in ET research. The ET-like domain peptide, corresponding to prepro-ET-193–166, has been proposed to be co-synthesized and released with ET-1, to modulate the actions of the peptide. ET-1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long-lasting action. To date, the major therapeutic strategy to block the unwanted actions of ET in disease, principally in pulmonary arterial hypertension, has been to use antagonists that are selective for the ETA receptor (ambrisentan) or that block both receptor subtypes (bosentan). Macitentan represents the next generation of antagonists, being more potent than bosentan, with longer receptor occupancy and it is converted to an active metabolite; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy. A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET-converting enzyme and neutral endopeptidase such as SLV306 (daglutril). A third strategy based on activating the ETB receptor, has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti-tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions. Finally, we discuss biased signalling, epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research. PMID:25131455

  5. Dihydroergocryptine: a pseudo-irreversible alpha-adrenergic antagonist in the guinea pig vas deferens

    SciTech Connect

    Wilberding, C.A.; Marks, B.H.

    1981-03-01

    The ergot alkaloid, dihydroergocryptine, exhibits some of the characteristics of a competitive alpha-adrenergic antagonist. Dihydroergocryptine physiological antagonism is surmountable by high concentrations of alpha-adrenergic agonists and (/sup 3/H)-dihydroergocryptine readily binds and dissociates from crude membranes with the characteristics expected of an alpha-adrenoreceptor ligand. However, during physiological studies, dihydroergocryptine antagonism is not readily reversible by washing. To explain this apparently paradoxical behavior of dihydroergocryptine, the characteristic of (/sup 3/H)-dihydroergocryptine accumulation and efflux in the guinea pig vas deferens were studied. Vas deferens segments accumulated 0.99 pmol (/sup 3/H)-dihydroergocryptine/mg protein. Most of the radioligand was extractable by acid-ethanol. About 5-6% of the radioligand remained bound to extracted tissue residues and appeared to be associated with crude membrane fractions prepared from vas deferens segments. Kinetic analysis of (/sup 3/H)-dihydroergocryptine efflux from vas deferens segments indicated the presence of three compartments of radioligand in this tissue. A large compartment of (/sup 3/H)-dihydroergocryptine emptied slowly and may represent radioligand accumulated into the intracellular space. (/sup 3/H)-Dihydroergocryptine also was released from a compartment which exhibited the size and kinetics characteristic of alpha-adrenoreceptor sites on guinea pig vas deferens crude membranes. A small compartment of (/sup 3/H)-dihydroergocryptine was nonexchangeable and nonextractable by acid-ethanol; this nonextractable radioligand may be bound covalently to membrane sites and/or other tissue components.

  6. Solid-phase synthesis of neurokinin A antagonists. Comparison of the Boc and Fmoc methods.

    PubMed

    Rovero, P; Quartara, L; Fabbri, G

    1991-02-01

    During the preparation of the NK-2 selective tachykinin antagonist MEN 10208 (Thr-Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Arg-NH2) and its analogs by the solid-phase method employing the Boc strategy routinely used in our laboratory, we encountered difficulties in the coupling of hydrophobic amino acids D-Trp and Val. To study the coupling problems several syntheses of MEN 10208 and analogs were carried out with different activation strategies. These syntheses yielded considerable amounts of deletion sequences even though a negative Kaiser test was obtained after each coupling. Inaccessibility of the free amino group of the growing peptide due to steric hindrance of the hydrophobic residues during coupling, and for the ninhydrin complex during the Kaiser test, may account, at least in part, for the unsatisfactory synthetics results and for the false-negative ninhydrin tests. Repetition of each synthesis with the Fmoc strategy on a newly developed DOD resin for peptide amides using the DCC/HOBt chemistry gave superior results in terms of the yield and purity of the crude peptides. Therefore, the Fmoc strategy appears to offer advantages over the Boc method for the preparation of these peptides containing hydrophobic amino acids. PMID:1850390

  7. Agonistic and Antagonistic Interactions between Chlorhexidine and Other Endodontic Agents: A Critical Review

    PubMed Central

    Mohammadi, Zahed; Giardino, Luciano; Palazzi, Flavio; Asgary, Saeed

    2015-01-01

    Root canal irrigants play a significant role in elimination of the microorganisms, tissue remnants, and removal of the debris and smear layer. No single solution is able to fulfill all these actions completely; therefore, a combination of irrigants may be required. The aim of this investigation was to review the agonistic and antagonistic interactions between chlorhexidine (CHX) and other irrigants and medicaments. An English-limited Medline search was performed for articles published from 2002 to 2014. The searched keywords included: chlorhexidine AND sodium hypochlorite/ethylenediaminetetraacetic acid/calcium hydroxide/mineral trioxide aggregate. Subsequently, a hand search was carried out on the references of result articles to find more matching papers. Findings showed that the combination of CHX and sodium hypochlorite (NaOCl) causes color changes and the formation of a neutral and insoluble precipitate; CHX forms a salt with ethylenediaminetetraacetic acid (EDTA). In addition, it has been demonstrated that the alkalinity of calcium hydroxide (CH) remained unchanged after mixing with CHX. Furthermore, mixing CHX with CH may enhance its antimicrobial activity; also mixing mineral trioxide aggregate (MTA) powder with CHX increases its antimicrobial activity but this may negatively affect its mechanical properties. PMID:25598802

  8. Synthesis of p-aminophenyl aryl H-phosphinic acids and esters via cross-coupling reactions: elaboration to phosphinic acid pseudopeptide analogues of pteroyl glutamic acid and related antifolates.

    PubMed

    Yang, Yonghong; Coward, James K

    2007-07-20

    The synthesis of suitably protected p-aminophenyl H-phosphinic acids and esters from the corresponding para-substituted aryl halides has been accomplished via the Pd-catalyzed cross-coupling reaction of anilinium hypophosphite, either in the absence or presence of a tetraalkyl orthosilicate, to provide the free H-phosphinic acid or the corresponding ester, respectively. Subsequent conjugate addition of either a PIII species or phosphorus anion, generated in situ from either the free H-phosphinic acid or ester, to a 2-methylene glutaric acid ester provided the aryl phosphinic acid analogue of p-aminobenzoyl glutamic acid. Alkylation of these suitably protected p-aminophenyl phosphinic acid esters with a 6-(bromomethyl)pteridine or the corresponding (bromomethyl)pyridopyrmidine, followed by hydrolytic removal of protecting groups, provided the target aryl phosphinic acid analogues of folic acid and related antifolates. Alternatively, for the synthesis of the folate or 5-deazafolate analogues on a slightly larger scale, reductive amination with either N2-acetyl or N2-pivaloyl-6-formylpterin or the corresponding formylpyridopyrmidine and the same suitably protected p-aminophenyl phosphinic acid esters, followed by removal of protecting groups, is preferred. In the course of this research, it was observed that the nucleophilicity of both the aniline nitrogen and various PIII species derived from p-aminophenyl phosphinic acid derivatives is significantly reduced compared to that of the unsubstituted counterpart. PMID:17602593

  9. A selective cysteinyl leukotriene receptor 2 antagonist blocks myocardial ischemia/reperfusion injury and vascular permeability in mice.

    PubMed

    Ni, Nathan C; Yan, Dong; Ballantyne, Laurel L; Barajas-Espinosa, Alma; St Amand, Tim; Pratt, Derek A; Funk, Colin D

    2011-12-01

    Cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators that predominantly exert their effects by binding to cysteinyl leukotriene receptors of the G protein-coupled receptor family. CysLT receptor 2 (CysLT(2)R), expressed in endothelial cells of some vascular beds, has been implicated in a variety of cardiovascular functions. Endothelium-specific overexpression of human CysLT(2)R in transgenic mice (hEC-CysLT(2)R) greatly increases myocardial infarction damage. Investigation of this receptor, however, has been hindered by the lack of selective pharmacological antagonists. Here, we describe the characterization of 3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-phenoxybutoxy)phenyl)-propoxy)benzoic acid (BayCysLT(2)) and explore the selective effects of this compound in attenuating myocardial ischemia/reperfusion damage and vascular leakage. Using a recently developed ?-galactosidase-?-arrestin complementation assay for CysLT(2)R activity (Mol Pharmacol 79:270-278, 2011), we determined BayCysLT(2) to be ?20-fold more potent than the nonselective dual CysLT receptor 1 (CysLT(1)R)/CysLT(2)R antagonist 4-(((1R,2E,4E,6Z,9Z)-1-((1S)-4-carboxy-1-hydroxybutyl)-2,4,6,9-pentadecatetraen-1-yl)thio)benzoic acid (Bay-u9773) (IC(50) 274 nM versus 4.6 ?M, respectively). Intracellular calcium mobilization in response to cysteinyl leukotriene administration showed that BayCysLT(2) was >500-fold more selective for CysLT(2)R compared with CysLT(1)R. Intraperitoneal injection of BayCysLT(2) in mice significantly attenuated leukotriene D(4)-induced Evans blue dye leakage in the murine ear vasculature. BayCysLT(2) administration either before or after ischemia/reperfusion attenuated the aforementioned increased myocardial infarction damage in hEC-CysLT(2)R mice. Finally, decreased neutrophil infiltration and leukocyte adhesion molecule mRNA expression were observed in mice treated with antagonist compared with untreated controls. In conclusion, we present the characterization of a potent and selective antagonist for CysLT(2)R that is useful for discerning biological activities of this receptor. PMID:21903747

  10. The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats

    PubMed Central

    Iemolo, Attilio; Narayan, Aditi R.; Kwak, Jina; Momaney, Duncan

    2012-01-01

    Rationale Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice. Objectives Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice. Methods Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755. Results Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition. Conclusions NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low-impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used. PMID:23104264

  11. Nkd1 Functions as a Passive Antagonist of Wnt Signaling

    PubMed Central

    Angonin, Diane; Van Raay, Terence J.

    2013-01-01

    Wnt signaling is involved in many aspects of development and in the homeostasis of stem cells. Its importance is underscored by the fact that misregulation of Wnt signaling has been implicated in numerous diseases, especially colorectal cancer. However, how Wnt signaling regulates itself is not well understood. There are several Wnt negative feedback regulators, which are active antagonists of Wnt signaling, but one feedback regulator, Nkd1, has reduced activity compared to other antagonists, yet is still a negative feedback regulator. Here we describe our efforts to understand the role of Nkd1 using Wnt signaling compromised zebrafish mutant lines. In several of these lines, Nkd1 function was not any more active than it was in wild type embryos. However, we found that Nkd1’s ability to antagonize canonical Wnt/?-catenin signaling was enhanced in the Wnt/Planar Cell Polarity mutants silberblick (slb/wnt11) and trilobite (tri/vangl2). While slb and tri mutants do not display alterations in canonical Wnt signaling, we found that they are hypersensitive to it. Overexpression of the canonical Wnt/?-catenin ligand Wnt8a in slb or tri mutants resulted in dorsalized embryos, with tri mutants being much more sensitive to Wnt8a than slb mutants. Furthermore, the hyperdorsalization caused by Wnt8a in tri could be rescued by Nkd1. These results suggest that Nkd1 functions as a passive antagonist of Wnt signaling, functioning only when homeostatic levels of Wnt signaling have been breached or when Wnt signaling becomes destabilized. PMID:24009776

  12. Nkd1 functions as a passive antagonist of Wnt signaling.

    PubMed

    Angonin, Diane; Van Raay, Terence J

    2013-01-01

    Wnt signaling is involved in many aspects of development and in the homeostasis of stem cells. Its importance is underscored by the fact that misregulation of Wnt signaling has been implicated in numerous diseases, especially colorectal cancer. However, how Wnt signaling regulates itself is not well understood. There are several Wnt negative feedback regulators, which are active antagonists of Wnt signaling, but one feedback regulator, Nkd1, has reduced activity compared to other antagonists, yet is still a negative feedback regulator. Here we describe our efforts to understand the role of Nkd1 using Wnt signaling compromised zebrafish mutant lines. In several of these lines, Nkd1 function was not any more active than it was in wild type embryos. However, we found that Nkd1's ability to antagonize canonical Wnt/?-catenin signaling was enhanced in the Wnt/Planar Cell Polarity mutants silberblick (slb/wnt11) and trilobite (tri/vangl2). While slb and tri mutants do not display alterations in canonical Wnt signaling, we found that they are hypersensitive to it. Overexpression of the canonical Wnt/?-catenin ligand Wnt8a in slb or tri mutants resulted in dorsalized embryos, with tri mutants being much more sensitive to Wnt8a than slb mutants. Furthermore, the hyperdorsalization caused by Wnt8a in tri could be rescued by Nkd1. These results suggest that Nkd1 functions as a passive antagonist of Wnt signaling, functioning only when homeostatic levels of Wnt signaling have been breached or when Wnt signaling becomes destabilized. PMID:24009776

  13. Behavioral approach to nondyskinetic dopamine antagonists: identification of seroquel.

    PubMed

    Warawa, E J; Migler, B M; Ohnmacht, C J; Needles, A L; Gatos, G C; McLaren, F M; Nelson, C L; Kirkland, K M

    2001-02-01

    A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-induced climbing and antagonism of apomorphine-induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-sensitized Cebus monkeys. Initial examination of a few close cogeners of 1 enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-substituted analogues of 6-(piperazin-1-yl)-11H-dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepines and -oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-substituted analogues were found to be good apomorphine antagonists but all were dyskinetic. PMID:11462978

  14. Virtual High-Throughput Screening To Identify Novel Activin Antagonists

    PubMed Central

    Zhu, Jie; Mishra, Rama K.; Schiltz, Gary E.; Makanji, Yogeshwar; Scheidt, Karl A.; Mazar, Andrew P.; Woodruff, Teresa K.

    2015-01-01

    Activin belongs to the TGF? superfamily, which is associated with several disease conditions, including cancer-related cachexia, preterm labor with delivery, and osteoporosis. Targeting activin and its related signaling pathways holds promise as a therapeutic approach to these diseases. A small-molecule ligand-binding groove was identified in the interface between the two activin ?A subunits and was used for a virtual high-throughput in silico screening of the ZINC database to identify hits. Thirty-nine compounds without significant toxicity were tested in two well-established activin assays: FSH? transcription and HepG2 cell apoptosis. This screening workflow resulted in two lead compounds: NUCC-474 and NUCC-555. These potential activin antagonists were then shown to inhibit activin A-mediated cell proliferation in ex vivo ovary cultures. In vivo testing showed that our most potent compound (NUCC-555) caused a dose-dependent decrease in FSH levels in ovariectomized mice. The Blitz competition binding assay confirmed target binding of NUCC-555 to the activin A:ActRII that disrupts the activin A:ActRII complex’s binding with ALK4-ECD-Fc in a dose-dependent manner. The NUCC-555 also specifically binds to activin A compared with other TGF? superfamily member myostatin (GDF8). These data demonstrate a new in silico-based strategy for identifying small-molecule activin antagonists. Our approach is the first to identify a first-in-class small-molecule antagonist of activin binding to ALK4, which opens a completely new approach to inhibiting the activity of TGF? receptor superfamily members. in addition, the lead compound can serve as a starting point for lead optimization toward the goal of a compound that may be effective in activin-mediated diseases. PMID:26098096

  15. Central actions of a novel and selective dopamine antagonist

    SciTech Connect

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D/sub 1/ class, which is linked to the stimulation of adenylate cyclase-activity, and the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ class which is not. There is much evidence suggesting that it is the D/sub 2/ dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D/sub 1/ class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of (/sup 3/H)-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D/sub 1/ receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for (/sup 3/H)-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D/sub 1/ receptors and (/sup 3/H)-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D/sub 1/ dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated.

  16. [Hyponatraemia, antagonists of the antidiuretic hormone and cardiac failure].

    PubMed

    de Groote, P

    2006-03-01

    Hyponatraemia is a common clinical finding in cardiac failure, complicating the management of these patients. Vasopressin plays a fundamental role in the physiopathology of the hyponatraemia of cardiac failure and binds to two distinct specific receptors, receptor V1a and V2. The V2 receptors, situated in the renal collecting duct, control the resorbtion of free water. The V1a receptors, present everywhere, are responsible for the vasoconstrictive effect of vasopressin. Specific antagonists of vasopressin receptors are being evaluated in pathologies associated with hyponatraemia. The preliminary results in patients with cardiac failure are encouraging and mortality studies are underway. PMID:16618024

  17. Discovery of dopamine D? receptor antagonists with planar chirality.

    PubMed

    Sanna, Fabrizio; Ortner, Birgit; Hübner, Harald; Löber, Stefan; Tschammer, Nuska; Gmeiner, Peter

    2013-04-01

    Employing the D4 selective phenylpiperazine 2 as a lead compound, planar chiral analogs with paracyclophane substructure were synthesized and evaluated for their ability to bind and activate dopamine receptors. The study revealed that the introduction of a [2.2]paracyclophane moiety is tolerated by dopamine receptors of the D2 family. Subtype selectivity for D4 and ligand efficacy depend on the absolute configuration of the test compounds. Whereas the achiral single-layered lead 2 and the double-layered paracyclophane (R)-3 showed partial agonist properties, the enantiomer (S)-3 behaved as a neutral antagonist. PMID:23428965

  18. VCP and PSMF1: Antagonistic regulators of proteasome activity.

    PubMed

    Clemen, Christoph S; Marko, Marija; Strucksberg, Karl-Heinz; Behrens, Juliane; Wittig, Ilka; Gärtner, Linda; Winter, Lilli; Chevessier, Frederic; Matthias, Jan; Türk, Matthias; Tangavelou, Karthikeyan; Schütz, Johanna; Arhzaouy, Khalid; Klopffleisch, Karsten; Hanisch, Franz-Georg; Rottbauer, Wolfgang; Blümcke, Ingmar; Just, Steffen; Eichinger, Ludwig; Hofmann, Andreas; Schröder, Rolf

    2015-08-01

    Protein turnover and quality control by the proteasome is of paramount importance for cell homeostasis. Dysfunction of the proteasome is associated with aging processes and human diseases such as neurodegeneration, cardiomyopathy, and cancer. The regulation, i.e. activation and inhibition of this fundamentally important protein degradation system, is still widely unexplored. We demonstrate here that the evolutionarily highly conserved type II triple-A ATPase VCP and the proteasome inhibitor PSMF1/PI31 interact directly, and antagonistically regulate proteasomal activity. Our data provide novel insights into the regulation of proteasomal activity. PMID:26086101

  19. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    PubMed

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter. PMID:26585147

  20. Structure-Guided Rescaffolding of Selective Antagonists of BCL-XL

    PubMed Central

    2014-01-01

    Because of the promise of BCL-2 antagonists in combating chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), interest in additional selective antagonists of antiapoptotic proteins has grown. Beginning with a series of selective, potent BCL-XL antagonists containing an undesirable hydrazone functionality, in silico design and X-ray crystallography were utilized to develop alternative scaffolds that retained the selectivity and potency of the starting compounds. PMID:24944740

  1. The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus.

    PubMed

    Guzman-Perez, Angel; Pfefferkorn, Jeffrey A; Lee, Esther C Y; Stevens, Benjamin D; Aspnes, Gary E; Bian, Jianwei; Didiuk, Mary T; Filipski, Kevin J; Moore, Dianna; Perreault, Christian; Sammons, Matthew F; Tu, Meihua; Brown, Janice; Atkinson, Karen; Litchfield, John; Tan, Beijing; Samas, Brian; Zavadoski, William J; Salatto, Christopher T; Treadway, Judith

    2013-05-15

    A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation. PMID:23562063

  2. The 5-HT2A receptor antagonist M100907 is more effective in counteracting NMDA antagonist- than dopamine agonist-induced hyperactivity in mice.

    PubMed

    Carlsson, M L; Martin, P; Nilsson, M; Sorensen, S M; Carlsson, A; Waters, S; Waters, N

    1999-01-01

    The purpose of the present study was to compare the effectiveness of the selective 5-HT2A antagonist M100907 in different psychosis models. The classical neuroleptic haloperidol was used as reference compound. Two hyperdopaminergia and two hypoglutamatergia mouse models were used. Hyperdopaminergia was produced by the DA releaser d-amphetamine or the DA uptake inhibitor GBR 12909. Hypoglutamatergia was produced by the un-competitive NMDA receptor antagonist MK-801 or the competitive NMDA receptor antagonist D-CPPene. M100907 was found to counteract the locomotor stimulant effects of the NMDA receptor antagonists MK-801 and D-CPPene, but spontaneous locomotion, d-amphetamine- and GBR-12909-induced hyperactivity were not significantly affected. Haloperidol, on the other hand, antagonized both NMDA antagonist- and DA agonist-induced hyperactivity, as well as spontaneous locomotion in the highest dose used. Based on the present and previous results we draw the conclusion that 5-HT2A receptor antagonists are particularly effective against behavioural anomalies resulting from hypoglutamatergia of various origins. The clinical implications of our results and conclusions would be that a 5-HT2A receptor antagonist, due to i a the low side effect liability, could be the preferable treatment strategy in various disorders associated with hypoglutamatergia; such conditions might include schizophrenia, childhood autism and dementia disorders. PMID:10226932

  3. Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior

    PubMed Central

    Sink, K. S.; Vemuri, V. K.; Olszewska, T.; Makriyannis, A.

    2013-01-01

    Rationale Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission. Objective To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased. Results Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05–0.2 mg/kg) or the D2 antagonist eticlopride (0.025–0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0–16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0–8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake. Conclusions These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission. PMID:18004546

  4. Effect of antagonistic yeast XL-1 on resistance-associated enzyme activities in postharvest cantaloupe.

    PubMed

    Shan, C-H; Chen, W; Zhang, H; Tang, F-X; Tong, J-M

    2014-01-01

    The effect of the antagonistic yeast XL-1 on resistance-associated enzyme activities in postharvest cantaloupe was studied by inoculating the antagonistic yeast XL-1. Cantaloupes were sterilized, dried in air, and soaked in antagonistic yeast treatment liquid for 30 s. After drying in air, the cantaloupe was stored at room temperature (2°-5°C). The activities of resistance-associated enzymes in cantaloupe like polyphenol oxidase, ?-1,3-glucanase, peroxidase, and superoxide dismutase were measured every 7 days. Our results indicated that the antagonistic yeast XL-1 significantly improved the activity of ?-1,3-glucanase and chitinase to promote the disease resistance of postharvest cantaloupe. PMID:25158252

  5. Antagonistic action of AA-2414 on thromboxane A2/prostaglandin endoperoxide receptor in platelets and blood vessels.

    PubMed

    Imura, Y; Terashita, Z; Shibouta, Y; Inada, Y; Nishikawa, K

    1990-01-01

    AA-2414, (+/-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoi c acid, inhibited the aggregation of guinea pig platelets induced by a prostaglandin endoperoxide (PGH2) analogue, U-44069 and the specific binding of another analogue, [3H]U-46619 to washed guinea pig platelets with IC50 values of 3.1 x 10(-7) and 8.2 x 10(-9) M, respectively. AA-2414 competitively inhibited the contraction of rabbit aorta and pig coronary arteries induced by U-44069 with pA2 values of 8.3 and 9.0, respectively. AA-2414 also inhibited the contraction of rabbit aorta induced by PGF2 alpha (pA2: 7.8) and the contraction of pig coronary arteries induced by PGF2 alpha, PGD2 and 9 alpha,11 beta-PGF2 with pA2 values of 7.8, 8.6 and 7.8, respectively. But, AA-2414 had no effect on the antiaggregatory effect of PGD2 on the aggregation of guinea pig platelets. In experiments with guinea pigs ex vivo, AA-2414 (0.1-1 mg/kg, p.o.) dose-dependently inhibited the platelet aggregation induced by U-44069; the inhibition at a dose of 1 mg/kg was 100% at 1 hr and was 89% even at 24 hr after the administration. The thromboxane (TX) A2/PGH2 receptor antagonistic action of AA-2414 was stereospecific. These results show that AA-2414 is a potent, orally active and long acting TXA2/PGH2 receptor antagonist. In addition, AA-2414 has PGF2 alpha, PGD2 and 9 alpha,11 beta-PGF2 antagonistic effects. PMID:2137886

  6. Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer.

    PubMed

    Gourni, Eleni; Del Pozzo, Luigi; Kheirallah, Emilie; Smerling, Christiane; Waser, Beatrice; Reubi, Jean-Claude; Paterson, Brett M; Donnelly, Paul S; Meyer, Philipp T; Maecke, Helmut R

    2015-08-01

    The gastrin-releasing peptide receptor (GRPr) is an important molecular target for the visualization and therapy of tumors and can be targeted with radiolabeled bombesin derivatives. The present study aims to develop statine-based bombesin receptor antagonists suitable for labeling with 64Cu for imaging by positron emission tomography (PET). The potent GRPr antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was conjugated to the sarcophagine (3,6,10,13,16,19-hexaazabicyclo[6.6.6] icosane=Sar) derivative 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar) via PEG4 (LE1) and PEG2 (LE2) spacers and radiolabeled with 64Cu2+ with >95% yield and specific activities of about 100 MBq/nmol. Both Cu(II) conjugates have high affinity for GRPr (IC50: natCu-LE1, 1.4±0.1 nM; natCu-LE2, 3.8±0.6 nM). The antagonistic properties of both conjugates were confirmed by Ca2+-flux measurements. Biodistribution studies of Cu-64-LE1 exhibited specific targeting of the tumor (19.6±4.7% IA/g at 1 h p.i.) and GRPr-positive organs. Biodistribution and PET images at 4 and 24 h postinjection showed increasing tumor-to-background ratios with time. This was illustrated by the acquisition of PET images showing high tumor-to-normal tissue contrast. This study demonstrates the high affinity of the MeCOSar-PEGx-bombesin conjugates to GRPr. The stability of 64Cu complexes of MeCOSar, the long half-life of 64Cu, and the suitable biodistribution profile of the 64Cu-labeled peptides lead to PET images of high contrast suitable for potential translation into the clinic. PMID:26132879

  7. Pharmacological lineage analysis revealed the binding affinity of broad-spectrum substance P antagonists to receptors for gonadotropin-releasing peptide.

    PubMed

    Arai, Kazune; Kashiwazaki, Aki; Fujiwara, Yoko; Tsuchiya, Hiroyoshi; Sakai, Nobuya; Shibata, Katsushi; Koshimizu, Taka-aki

    2015-02-15

    A group of synthetic substance P (SP) antagonists, such as [Arg(6),D-Trp(7,9),N(Me)Phe(8)]-substance P(6-11) and [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance P, bind to a range of distinct G-protein-coupled receptor (GPCR) family members, including V1a vasopressin receptors, and they competitively inhibit agonist binding. This extended accessibility enabled us to identify a GPCR subset with a partially conserved binding site structure. By combining pharmacological data and amino acid sequence homology matrices, a pharmacological lineage of GPCRs that are sensitive to these two SP antagonists was constructed. We found that sensitivity to the SP antagonists was not limited to the Gq-protein-coupled V1a and V1b receptors; Gs-coupled V2 receptors and oxytocin receptors, which couple with both Gq and Gi, also demonstrated sensitivity. Unexpectedly, a dendrogram based on the amino acid sequences of 222 known GPCRs showed that a group of receptors sensitive to the SP antagonists are located in close proximity to vasopressin/oxytocin receptors. Gonadotropin-releasing peptide receptors, located near the vasopressin receptors in the dendrogram, were also sensitive to the SP analogs, whereas ?1B adrenergic receptors, located more distantly from the vasopressin receptors, were not sensitive. Our finding suggests that pharmacological lineage analysis is useful in selecting subsets of candidate receptors that contain a conserved binding site for a ligand with broad-spectrum binding abilities. The knowledge that the binding site of the two broad-spectrum SP analogs partially overlaps with that of distinct peptide agonists is valuable for understanding the specificity/broadness of peptide ligands. PMID:25592317

  8. Amino acids

    MedlinePLUS

    Amino acids are organic compounds that combine to form proteins . Amino acids and proteins are the building blocks of life. When proteins are digested or broken down, amino acids are left. The human body uses amino acids ...

  9. Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis

    PubMed Central

    Renga, Barbara; Mencarelli, Andrea; D'Amore, Claudio; Cipriani, Sabrina; D'Auria, Maria Valeria; Sepe, Valentina; Chini, Maria Giovanna; Monti, Maria Chiara; Bifulco, Giuseppe; Zampella, Angela; Fiorucci, Stefano

    2012-01-01

    Background The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OST?, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis. PMID:22291955

  10. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    SciTech Connect

    Yu, Hui; Department of Laboratory Medicine, The Affiliated Tenth People's Hospital, Tongji University, Shanghai 200072 ; Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi; Wang, Zhanli; Liang, Huaping

    2010-11-05

    Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  11. Leukotriene synthesis inhibitors versus antagonists: the pros and cons.

    PubMed

    Steinke, John W; Culp, Jeffrey A

    2007-05-01

    It has been recognized for many years that leukotrienes play an important role in mediating various effects of the allergic reaction. Recent evidence has shown that they play a role in other diseases. Leukotrienes can be separated into the fairly well-characterized cysteinyl leukotrienes and the less well-characterized leukotriene B(4). Effects of the leukotrienes are mediated through receptors that are expressed on a variety of cell types and can be modulated based on the inflammatory environment present. The pharmaceutical industry has long been interested in blocking leukotriene action. As such, two approaches have been developed that led to drugs approved for treating allergic disease. The most widely used class is the cysteinyl type 1 receptor antagonists, which block binding of the cysteinyl leukotrienes to the cell. The second class is an inhibitor of the 5-lipoxygenase enzyme that prevents synthesis of both the cysteinyl leukotrienes and leukotriene B(4). This review focuses on the role that leukotrienes play in various diseases, with the emphasis on allergic diseases, and considers the rationale for choosing either a leukotriene antagonist or synthesis inhibitor as a treatment option. PMID:17437683

  12. CCR9 Antagonists in the Treatment of Ulcerative Colitis

    PubMed Central

    Bekker, Pirow; Ebsworth, Karen; Walters, Matthew J.; Berahovich, Robert D.; Ertl, Linda S.; Charvat, Trevor T.; Punna, Sreenivas; Powers, Jay P.; Campbell, James J.; Sullivan, Timothy J.; Jaen, Juan C.; Schall, Thomas J.

    2015-01-01

    While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a?/? mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a?/? mice. In the mdr1a?/? mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation. PMID:26457007

  13. Safety profile of mineralocorticoid receptor antagonists: Spironolactone and eplerenone.

    PubMed

    Lainscak, Mitja; Pelliccia, Francesco; Rosano, Giuseppe; Vitale, Cristiana; Schiariti, Michele; Greco, Cesare; Speziale, Giuseppe; Gaudio, Carlo

    2015-12-01

    Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more mineralocorticoid receptor-specific. From a marginal role as a potassium-sparing diuretic, spironolactone has been shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure. Also, spironolactone is safe and protective in arterial hypertension, particularly in patients with so-called resistant hypertension. Eplerenone is the second oral aldosterone antagonist available for the treatment of arterial hypertension and heart failure. Treatment with eplerenone has been associated with decreased blood pressure and improved survival for patients with heart failure and reduced left ventricular ejection fraction. Due to the selectivity of eplerenone for the aldosterone receptor, severe adverse effects such as gynecomastia and vaginal bleeding seem to be less likely in patients who take eplerenone than in those who take spironolactone. The most common and potentially dangerous side effect of spironolactone--hyperkalemia--is also observed with eplerenone but the findings from clinical trials do not indicate more hyperkalemia induced drug withdrawals. Treatment with eplerenone should be initiated at a dosage of 25mg once daily and titrated to a target dosage of 50mg once daily preferably within 4 weeks. Serum potassium levels and renal function should be assessed prior to initiating eplerenone therapy, and periodic monitoring is recommended, especially in patients at high risk of developing hyperkalemia. PMID:26404748

  14. Human homosexuality: a paradigmatic arena for sexually antagonistic selection?

    PubMed

    Camperio Ciani, Andrea; Battaglia, Umberto; Zanzotto, Giovanni

    2015-04-01

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. PMID:25635045

  15. Antagonist models for treating persons with substance use disorders.

    PubMed

    Woody, George E

    2014-10-01

    This paper provides an overview on the status of antagonist models for treating patients with substance use disorders. It begins with an overview describing the ambivalence about stopping or not stopping substance use and how antagonist approaches, combined with psychosocial treatment, are aimed to address it. It then goes on to review data on disulfiram and acamprosate treatment of alcohol dependence and naltrexone treatment of opioid and alcohol dependence. The superior results achieved by extended release formulations are emphasized. The mixed findings on naltrexone treatment for amphetamine dependence are presented and the chapter ends with a brief review of vaccine development for treatment of substance use disorders. Overall conclusions are that the strongest treatment effects are with extended release naltrexone with opioid dependence. Disulfiram treatment of alcohol dependence also has strong effects but is not widely used due to low levels of patient acceptance and concerns about its potential for serious adverse events. Less robust but clinically meaningful effects are seen with naltrexone or acamprosate treatment of alcohol dependence. Vaccines are a very interesting and promising new development but many challenges and hurdles must be overcome before they are ready for clinical use. PMID:25182514

  16. Intralocus sexual conflict for fitness: sexually antagonistic alleles for testosterone

    PubMed Central

    Mills, Suzanne C.; Koskela, Esa; Mappes, Tapio

    2012-01-01

    Intralocus sexual conflict occurs when a trait encoded by the same genetic locus in the two sexes has different optima in males and females. Such conflict is widespread across taxa, however, the shared phenotypic traits that mediate the conflict are largely unknown. We examined whether the sex hormone, testosterone (T), that controls sexual differentiation, contributes to sexually antagonistic fitness variation in the bank vole, Myodes glareolus. We compared (opposite-sex) sibling reproductive fitness in the bank vole after creating divergent selection lines for T. This study shows that selection for T was differentially associated with son versus daughter reproductive success, causing a negative correlation in fitness between full siblings. Our results demonstrate the presence of intralocus sexual conflict for fitness in this small mammal and that sexually antagonistic selection is acting on T. We also found a negative correlation in fitness between parents and their opposite-sex progeny (e.g. father–daughter), highlighting a dilemma for females, as the indirect genetic benefits of selecting reproductively successful males (high T) are lost with daughters. We discuss mechanisms that may mitigate this disparity between progeny quality. PMID:22171083

  17. Polypeptide having an amino acid replaced with N-benzylglycine

    DOEpatents

    Mitchell, Alexander R. (Livermore, CA); Young, Janis D. (Los Angeles, CA)

    1996-01-01

    The present invention relates to one or more polypeptides having useful biological activity in a mammal, which comprise: a polypeptide related to bradykinin of four to ten amino acid residues wherein one or more specific amino acids in the polypeptide chain are replaced with achiral N-benzylglycine. These polypeptide analogues have useful potent agonist or antagonist pharmacological properties depending upon the structure. A preferred polypeptide is (N-benzylglycine.sup.7)-bradykinin.

  18. Behaviorally active doses of the CB1 receptor antagonist SR 141716A increase brain serotonin and dopamine levels and turnover.

    PubMed

    Darmani, N A; Janoyan, J J; Kumar, N; Crim, J L

    2003-07-01

    Large doses (10-40 mg/kg) of the selective cannabinoid CB(1) receptor antagonist, SR 141716A, produce the head-twitch response (HTR) and scratching in rodents and vomiting in the least shrew (Cryptotis parva). Agents that increase brain serotonin (5-HT) levels induce the HTR in rodents, whereas enhancements in either brain 5-HT or dopamine concentrations can lead to production of emesis in vomiting species. The present study was undertaken to demonstrate whether large doses of SR 141716A can (1) induce the HTR and scratching in the least shrew and (2) cause concurrent biochemical changes in brain 5-HT and dopamine concentrations. SR 141716A (0, 1, 5, 10, 20 and 40 mg/kg i.p.) administration induced the HTR, scratching and vomiting. The HTR effect was bell shaped with a maximum frequency occurring at the 20 mg/kg SR 141716A dose, whereas the scratching and vomiting behaviors displayed dose-dependent effects. The selective 5-HT(2A/C) receptor antagonist, SR 46349B (0, 0.1, 0.25, 1, 3 and 6 mg/kg i.p.), differentially attenuated all SR 141716A (20 mg/kg)-induced behaviors because the HTR was relatively more potently and completely blocked. In the shrew forebrain, SR 141716A (20 and 40 mg/kg ip) caused dose- and time-dependent increases in the levels of 5-HT and dopamine and the concentrations of their major metabolites [5-hydroxyindole acetic acid (5-HIAA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA)] and the turnover of both monoamines. Although the effects of SR 141716A on brainstem concentrations of both monoamines and their metabolites were not always consistent, the CB(1) antagonist did increase the turnover of both 5-HT and dopamine. The present findings suggest that the mechanism and the neurochemical substrate for SR 141716A-induced HTR and scratching behaviors is enhancement of 5-HT release, whereas increased release of 5-HT and dopamine probably contributes to the production of emesis. PMID:12957219

  19. Tetrafibricin, a novel non-peptide fibrinogen receptor antagonist, induces conformational changes in glycoprotein IIb/IIIa.

    PubMed Central

    Satoh, T; Kouns, W C; Yamashita, Y; Kamiyama, T; Steiner, B

    1994-01-01

    Arg-Gly-Asp (RGD) is an amino acid sequence in fibrinogen recognized by platelet glycoprotein (GP) IIb/IIIa. Recently, it was found that RGD peptide binding to GPIIb/IIIa leads to conformational changes in the complex that are associated with the acquisition of high-affinity fibrinogen-binding function. In this study, we found that tetrafibricin, a novel non-peptidic GPIIb/IIIa antagonist, induced similar conformational changes in GPIIb/IIIa as did RGD peptides. Tetrafibricin increased the binding of purified inactive GPIIb/IIIa to immobilized pl-80, a monoclonal antibody that preferentially recognizes ligand-occupied GPIIb/IIIa. Exposure of the pl-80 epitope by tetrafibricin was also observed on resting human platelets by flow cytometry. On intact platelets, the conformational changes transformed GPIIb/IIIa into a high-affinity receptor for fibrinogen and triggered subsequent platelet aggregation. Tetrafibricin is the first non-peptidic GPIIb/IIIa antagonist reported that has the capacity to induce conformational changes in GPIIb/IIIa. PMID:7519850

  20. Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition.

    PubMed

    Uslaner, Jason M; Tye, Spencer J; Eddins, Donnie M; Wang, Xiaohai; Fox, Steven V; Savitz, Alan T; Binns, Jacquelyn; Cannon, Christopher E; Garson, Susan L; Yao, Lihang; Hodgson, Robert; Stevens, Joanne; Bowlby, Mark R; Tannenbaum, Pamela L; Brunner, Joseph; Mcdonald, Terrence P; Gotter, Anthony L; Kuduk, Scott D; Coleman, Paul J; Winrow, Christopher J; Renger, John J

    2013-04-01

    Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are ?-aminobutyric acid type A (GABAA)-positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound's minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use. PMID:23552372