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1
Chow, Lai-man, and 周勵文. "Folate receptor alpha and reduced folate carrier in endometrialcancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B45153188.
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Amanna, Karen Ruggio. "Folate status and milk folate concentration in lactating women." Thesis, This resource online, 1996. http://scholar.lib.vt.edu/theses/available/etd-11182008-063632/.
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Tsang, Hiu-may, and 曾嬈媚. "Folate receptor alpha and reduced folate carrier in ovarian cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2010. http://hub.hku.hk/bib/B4467059X.
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Scurachio, Regina Spricigo. "Fotodegradação de folatos sensibilizados por flavinas." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/75/75132/tde-17032011-155300/.
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O ácido fólico, a forma mais estável entre os folatos, é indicado como forma de prevenção sendo encontrado em forma de suplementação medicamentosa e alimentos fortificados, como leite e derivados. O folato pode reagir com a riboflavina singlete excitada, 1kq = 4,8·1010 L·mol-1·s-1, como determinado por desativação da fluorescência do estado estacionário, e com a riboflavina triplete excitada, com uma reação um pouco mais lenta, 3kq= 4,8·108 L·mol-1·s-1, como determinado por fotólise de pulso de laser e espectroscopia de absorção de transientes verificando-se que ambos os processos são competitivos e próximos ao limite de difusão. A preferência cinética de um a outro depende da matriz alimentar. O rendimento quântico para solução de riboflavina e de folato preparado em solvente aquoso e deuterado e em meio anaeróbico e aeróbico mostrou a prevalência do mecanismo fotoreacional do Tipo I. A voltametria cíclica apresentou um processo irreversível anódico de dois elétrons para o ácido fólico (E= 1,14 V vs. NHE). Os principais produtos da fotodegradação do folato sensibilizado pela riboflavina foram identificados por LC-IT-MS/MS como: 6-carboxipterina,p-aminobenzoil-L-ácido glutâmico e oxaziridina derivada do ácido fólico, como confirmando a desativação química do estado triplete excitado da riboflavina por transferência de elétrons com subseqüente clivagem oxidativa entre N(10) e C(9) no ácido fólico.Folic acid, the most stable among folate, is recommended as prevention and it is found in supplementation and fortified foods such as milk and dairy products. The folate can react with singlet-excited state of riboflavin, 1kq= 4.8·1010 L·mol-1·s-1, as determined by steady-state fluorescence quenching, and with triplet-excited state of riboflavin in a slower reaction with 3kq= 4.8·108 L·mol-1·s-1, as determined by laser flash photolysis and transient absorption spectroscopy, verifying that both the processes are competitive and they are near limited diffusion. The kinetic preference depends on the matrix food. The quantum yield for the solution of riboflavin and folate prepared in aqueous and deuterated solvents and in anaerobic and aerobic medium showed the prevalence of the mechanism Type I. The cyclic voltammetry showed an irreversible two-electron anodic process for folate (E = 1.14 V vs. NHE). The main products of folate photodegradation sensitized by riboflavin were identified by LC-IT-MS/MS as: pterin-6-carboxylic acid, p-aminobenzoyl-L-glutamic acid and oxaziridine derivative of folic acid, as confirming chemical quenching of the triplet-excited state of riboflavin by electron transfer with subsequent oxidative cleavage between N(10) and C(9) in folic acid.
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Lawrence, Scott Alan. "The Mechanism of Mitochondrial Folate Transport by the Mitochondrial Folate Transporter." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/2066.
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The mitochondrial folate transport protein (MFT) functions to transport folates into the mitochondrial matrix. The MFT is a member of a mitochondrial carrier family (MCF) of proteins that have a high degree of sequence and structural similarities, yet they transport vastly different substrates at high specificities. In this dissertation research, the folate-specific transport mechanism of the MFT was explored using experimental and computational techniques. MFT residues that differed from MCF consensus residues in conserved PxD/ExxK/R motifs and at a predicted substrate-binding site common to all MCF proteins were investigated. Site-directed mutagenesis of these anomalous residues in the MFT revealed that these residues were adapted for optimal folate transport, and that the MCF consensus residues at these positions were incompatible with folate transport. The structure of the MFT was predicted by homology modeling using the solved crystallographic structure of the ADP/ATP carrier as a template and this model was subjected to ~75 ns of molecular dynamics simulations. These simulations predicted a stepwise descent for the folate substrate into the MFT transport cavity and implicated several aromatic and basic residues in folate recognition and orientation. A predicted set of interactions at the base of the transport cavity between the MCF PxD/ExxK/R conserved motif residues did not appear static as previously hypothesized; these interactions appeared to be induced in the presence of the folate substrate. Therefore, we believe it is unlikely that these interactions form a barrier at the base of the transport cavity. We also investigated the role of the MFT in the compartmentalization of folate metabolism. Cell lines were created that could be induced with doxycycline to express either the cytosolic or mitochondrial isoform of the enzyme folylpoly-γ-glutamate synthetase (FPGS). The constructed cell lines were used to study the flux of folylpolyglutamates across the mitochondrial membrane. It appeared that cellular folylpolyglutamates are not transported across the mitochondrial membrane in either direction. We also demonstrated that many antifolates, including methotrexate and pemetrexed, impaired mitochondrial folate uptake. We believe that these folate analogs competitively inhibit the MFT and have purified the MFT protein for future analysis in reconstituted transport systems.
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Scott, D. A. "Folate metabolism in Leishmania." Thesis, University of Glasgow, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375461.
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Sharp, Linda. "Folate and genetic variation in folate metabolism in the aetiology of colorectal cancer." Thesis, University of Aberdeen, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430975.
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The aim of this thesis was to investigate the roles of folate and polymorphisms in folate metabolising genes in the aetiology of colorectal cancer. The objectives were to: (1) conduct systematic reviews of (a) folate and colorectal neoplasia and (b) polymorphic genes in the folate pathway and colorectal neoplasia; (2) undertake a case-control study of folate, polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and colorectal cancer in the north-east of Scotland; and (2) re-analyse the study data as if it were from a case-only study, comparing the results with those of the case-control analysis. The first systematic review concluded that there was considerable evidence that folate status modulates the risk of developing colon cancer, adenomatous polyps and, possibly, rectal cancer. The risk reduction in the highest compared to the lowest intake group, for colon cancer and adenomas, was in the region of 30-40%. The second systematic review considered polymorphisms in MTHFR, methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS) and thymidylate synthase (TS). Homozygosity for the MTHFR 677TT and 1298CC variants was associated with moderately reduced colorectal cancer risk in the majority of studies. There was evidence of gene-environment interaction; in four of five studies, the lowest cancer risk was in 677TT subjects who had higher folate levels (or a “high methyl diet”) while in three studies 677TT homozygotes with the highest alcohol intake had the highest cancer risk. The available evidence on MTHFR C677T and adenomatous polyps was inconclusive. A population-based case-control study of colorectal cancer was undertaken in Grampian health board area. Eligible cases were Grampian residents diagnosed with histologically confirmed primary colorectal cancer during September 1998-February 2000. The primary analysis focused on all colorectal cancer. Disease risk followed an inverted “U” pattern with increasing (total and dietary) folate intake. There was little evidence of relations between disease and intakes of total or dietary vitamin B12, vitamin B6 or riboflavin or of interactions between these factors and folate. There was a suggestion that protein intake was inversely related to colorectal cancer, which also drove the observation of a modestly increased risk with low, as compared to high, methyl intake (a combination of folate, protein and alcohol intake). A modest, non-significant, reduction in risk was found in those with the 677 TT, compared to the CC, genotype. For A1298C, a slight, non-significant, reduction in risk for homozygotes for the variant allele was found. Significant interactions between the two polymorphisms and total folate intake were observed, although the patterns of interaction were different for each variant and not entirely consistent with published studies.
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Ashfield-Watt, Pauline A. L. "Folate, homocysteine and cardiovascular disease : an investigation of dietary strategies to increase folate status." Thesis, Cardiff University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444123.
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Rudd, Michelle. "Folate : friend or foe? : an investigation into the opposing roles of folate in glioma." Thesis, University of Central Lancashire, 2017. http://clok.uclan.ac.uk/20737/.
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For individuals diagnosed with a glioma, survival rates have shown little improvement over the last 40 years due to the heterogeneity of tumours and the difficulty of specifically targeting the tumour whilst sparing surrounding healthy tissue. Altered gene methylation is often seen in glioma cells, but methylating agents such as folate, may reverse aberrant methylation. Folate treatment has shown a beneficial effect, reducing risk of certain cancers (colorectal, breast, squamous cell carcinoma) but other studies have shown detrimental results whereby proliferation of cancer increased (mammary, prostate). The aim of this thesis was to investigate the opposing roles of folate in glioma. The glioma cell lines 1321N1, U87 MG and non-cancerous glial SVGp12 cells were used for analysis. Cells were grown in folate deficient, folic or folinic acid supplemented media and compared to standard cell culture media. Cell viability, cell cycle and apoptosis analysis along with methylation status and protein expression of the genes of interest; PTEN, FOLR1, RFC, PCFT, and MTHFR were analysed to determine differences between cell lines following treatment. The investigation showed that folic and folinic acid behaved differently depending on concentration used and the cell lines treated. Folic acid at 5 µg/ml significantly increased cell viability and protein expression levels in the U87 MG and SVGp12 cell lines, whilst the folinic acid (35 µg/ml) resulted in significant decreased cell viability, increased apoptotic activity and down regulation of the folate transporters in the 1321N1, U87 MG and SVGp12 cell lines. Folate treatment did not significantly alter cell cycle phase. Altered methylation of genes specific for folate metabolism and transport did not explain the cytotoxic effects of folate in cell lines. In conclusion, the work presented here signifies that folinic acid rather than folic acid would be more suitable for glioma treatment. The effect of folinic acid treatment on glioma had not been previously studied, and the knowledge obtained here regarding the effects of folic and folinic acid treatment on folate transporter expression in glioma has advanced understanding.
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Díaz, de la Garza Rocío Isabel. "Folate engineering in tomato fruit." [Gainesville, Fla.] : University of Florida, 2006. http://purl.fcla.edu/fcla/etd/UFE0017287.
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Collin, Simon Michael. "Folate metabolism and prostate cancer." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.541606.
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Jones, Marc. "Folate binding protein : partial characterisation of bovine milk folate binding protein, includings its ligand binding /." [St. Lucia, Qld], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18263.pdf.
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Arkbåge, Karin. "Vitamin B₁₂, folate and folate-binding proteins in dairy products : analysis, process retention and bioavailability /." Uppsala : Dept. of Food Science, Swedish Univ. of Agricultural Sciences, 2003. http://epsilon.slu.se/a430.pdf.
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Ochong, Edwin Omondi. "Novel contributions to understanding the mechanism of folate transport and anti-folate resistance in Plasmodium falciparum." Thesis, University of Liverpool, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501706.
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The primary focus of the PhD thesis has exclusively been on studies on Plasmodium falciparum with a remit to build a clear understanding on some of the critical and relevant questions relating to folates transport and antifolates resistance. The direction of this work has been constructed on the following themes of interest; 1. The Influence of folate pathway substrates on the In Vitro activities of antifolate drugs. 2. Functional characterization of heterologously expressed putative folate transporters in the Xenopus laevis oocyte. 3. Transcriptional analysis of putative folate transporter genes.
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Anukul, Nampeung. "Genetic manipulation of folate in rice." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/12962/.
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Folate malnutrition is a major problem in many countries around the world especially in Asia and Africa. Stable foods such as rice contain very low amounts of folate. White rice which is the most popular form for human consumption contains less than 80 µg folate per 100 g. Given that it forms a major part of the South East Asian diet, rice represents an important target for enhancing folate levels. The objectives of this thesis is study the mechanisms that regulate total folate levels in rice grains and attempt to enhance and stabilise folate in rice endosperm. Three main strategies were adopted. First, the natural variation of folate biosynthesis gene expression was probed using RT- qPCR. Second, functional genomic approaches were used to manipulate the activity of rice folylpolyglutamate synthetase (FPGS), the enzyme which adds glutamate residues to folate. Third, genetic engineering was used to express FPGS enzymes and mammalian folate binding proteins in rice endosperm. RT-qPCR revealed that the variation in folate biosynthesis transcript abundance was closely correlated with total folate levels among rice varieties. High transcript abundance of all folate biosynthesis genes was associated with high total folate levels in Moroberekan rice mature seed. Comparative genomic studies revealed that rice FPGS is encoded by two distinct genes, FPGS Os03g02030 and FPGS Os10g35940. Transcript abundance of FPGS Os03g02030 appeared higher than that of FPGS Os10g35940 in seed, whilst, transcript abundance of FPGS Os10g35940 was higher in leaf. To determine the function of the FPGS Os03g02030 gene in rice seed, a TDNA knock out line was characterised. Disrupting Os03g02030 gene expression resulted in delayed seed maturation and decreased mono- and polyglutamylated folate pools in mutant seed. RT-qPCR detected an increase in the transcript abundance of folate biosynthesis genes in seed of the knock out plant, whereas the folate deglutamylating enzyme y-glutamyl hydrolase (GGH) mRNA level was reduced. A potential feedback mechanism to maintain folate abundance during rice development was uncovered through the alternative functional FPGS Os10g35940 activity and reduction of folate breakdown. Protein-bound folate forms are better protected from oxidative degradation resulting in greater folate stability (Suh et al. 2001). Two rice FPGS and mammalian folate binding proteins was successfully introduced into rice endosperm using Agrobacterium based transformation in an attempt to retain and stabilise folate pool within rice endosperm. Analysis in terms of folate abundance and bioavailability will form part of future studies.
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Robson, Claire. "Biochemical probes for folate-metabolising enzymes." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240965.
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McKillop, Derek John. "Stability and bioavailablity of food folate." Thesis, University of Ulster, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274093.
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Elnakat, Hala. "Regulation of Folate Receptor Raft Recycling." University of Toledo Health Science Campus / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=mco1174569209.
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McEligot, Archana Jaiswal. "Relationships between smoking, homocysteine and folate /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3029638.
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Hersey, Sarah Koltenbah. "The effect of folate intake and extended lactation on material serum, red cell and milk folate status." Virtual Press, 1997. http://liblink.bsu.edu/uhtbin/catkey/1041901.
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Maternal folate intake and levels of folate in milk, serum and red cells were assessed in 57 healthy, lactating women, ages 22-38 years, throughout early (0-6 months) and later (7-23 months) lactation. Average maternal folate intake from diet alone was 212 µg/day or 78.5% RDA (1989) and mean total folate intake from diet and supplements was 314% RDA (878 µg/day) at 0-6 months and 238% RDA (620 µg/day) at >6 months. Human milk folate was sufficient to meet the RDA (1989) for infants. Milk folate was not related to maternal folate intake, maternal serum or red cell folate and was unaffected by extended lactation (7-23 months), perhaps at the expense of maternal folate stores. Compared with early lactation, serum folate decreased (p=0.0004) and red cell folate tended to decrease (p=0.08) in later lactation and were both increased by folate supplementation (p < 0.001).Level of folic acid supplementation appeared to predict red cell folate concentration. An average of 884 µg supplemental folate/day was associated with red cell folate levels >400 ng/mL, which have previously been reported as optimal for prevention of folateresponsive neural tube defects. The addition of an 880 µg/day folic acid supplement to the diet of lactating women may raise red cell folate concentrations of lactating women to protective levels.Department of Family and Consumer Sciences
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Shinohara, Elvira Maria Guerra. "Prevalência de anemia em gestantes de primeira consulta em centros de saúde do estado no Subdistrito de Paz do Butantã, Município de São Paulo." Universidade de São Paulo, 1989. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-27032008-142216/.
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Foram estudadas 363 gestantes de primeira consulta, que não faziam uso de medicamentos que continham ferro, ácido fólico, vitamina B12 ou associação destes, na ocasião da coleta do material, em Centros de Saúde do Estado, no Subdistrito de Paz do Butantã, município de São Paulo. A prevalência de anemia (concentração de hemoglobina inferior a 11,6 g/dl) foi de 12,4%. As médias das concentrações de hemoglobina e as prevalências de anemia, segundo o trimestre de gestação, foram respectivamente: 13,47 g/dl e 3,57% no primeiro, 12,47 g/dl e 20,86% no segundo e 12,25 g/dl e 32,14% no terceiro trimestre. Não encontramos diferença. estatisticamente significativa entre as médias das concentrações de hemoglobina e entre as prevalências de anemia nas gestantes primigestas e multigestas. O mesmo aconteceu com as médias e as prevalências das gestantes multigestas com intervalo do último parto até dois anos e maior que dois anos. Na amostra estudada, encontramos maior prevalência de anemia naquelas gestantes que pertenciam às famílias que tinham renda per capita até 0,5 SMPC (salário mínimo per capita). As prevalências de verminose e de ancilostomídeos nas 300 gestantes foram respectivamente: 64,7% e 14,0%. Nas gestantes anêmicas foram respectivamente: 73,7% e 7,9%. Nas gestantes anêmicas, a prevalência de deficiência de ferro foi de 42,2% (concentração de ferro sérico <50 µg/dl) ou 46,7% (saturação da transferrina <15% ou 40,0% (concentração de ferro sérico <50 µg/dl e saturação de transferrina <15%). A prevalência de deficiência de ácido fólico foi 44,4%. A prevalência de deficiência de ferro e ácido fólico foi de 17,8%. Não encontramos deficiência de vitamina B
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Hussien, M. "Folate status, genetic damage and breast cancer." Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269044.
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Abilgos, Ramos Riza. "Folate profiling in wild and transgenic rice." Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/12870/.
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Quantitative profiling of mono- and polyglutamyl folates in rice was achieved using the microbiological assay (MA) and a newly developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method. MA was used to screen 51 rice cultivars for their total folate content and LC-MS/MS was employed to measure naturally occurring mono- and polyglutamated forms of the vitamin in wild type, FPGS Os03g02030 knockout and transgenic lines with overexpressed FPGS genes and with folate binding protein from cow’s milk (cFBP) and rat’s liver (GNMT). Natural variation among rice cultivars in terms of total folate content was measured using MA screening and the validated LC-MS/MS technique of simultaneous profiling of mono- and polyglutamated folates through MeOHAA/PO4 extraction revealed that the naturally-occurring species in wild type rice are 5-CH3-H4PteGlu, 5/10-CHO-H4PteGlu, 5-CH3-H4PteGlu4, 5-CH3-H4PteGlu5 and 5/10-CHO-PteGlu5. There was a general decrease in these folate forms in the FPGS Os03g02030 knockout rice line while a dramatic increase was observed in overexpressed FPGS, cFBP and GNMT compared to Nipponbare in terms of 5-CH3-H4PteGlu4, 5/10-CHO-H4Pteglu5, 5-CH3-H4PteGlu6, and 5/10-CHO-H4Pteglu6 levels, resulting in a 2.5 to 8.8-fold increase in the total folate pool in the unpolished grains of rice. This study looked at the role of the two FPGS genes (Os03g02030 and Os10g35940) found in rice and the possible effect of introducing folate binding proteins (cFBP and GNMT) in terms of the overall folate profile in rice which can be exploited in breeding programmes designed to enhance folate content in staple crops like rice.
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Ordakowski, Amy L. "Folate Status and Supplementation in the Horse." Diss., Virginia Tech, 2001. http://hdl.handle.net/10919/28568.
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A series of studies were conducted to evaluate effects of lactation, exercise, and anti-folate drugs on folate status in the horse, and the bioavailability of supplement and feed folate in the horse. In the first study, mares and foals had adequate plasma folate, RBC folate, and plasma homocysteine concentrations during 6 mo of lactation and growth. Therefore, mares and foals maintained on quality grass/legume pastures and offered a pasture supplement did not require additional folate supplementation to maintain folate status during lactation and growth. In the second study, 25 mg of oral folic acid (FA) supplemented 5 times/wk to 11 mature horses engaged in routine submaximal exercise did not improve folate status, submaximal athletic performance, or combat the increase in oxidative stress during the 12 wk supplementation period compared to 11 horses not given supplemental folate. The common practice of supplementing horses with oral FA in vitamin supplements appears to be of little benefit to horses engaged in routine submaximal exercise. In the third study, daily oral administration of pyrimethamine (PYR) and sulfadiazine (SDZ) for 9 wk followed by 6 wk of coadministration of either Peptidoglycan or FA was associated with a decline in folate status resulting in moderate hyperhomocysteinemia, but not clinical signs of anemia. Peptidoglycan as a source of formylated folate and FA were not effective in improving folate status in horses coadministered PYR and SDZ, two anti-folate drugs commonly administered in equine veterinary practice. The last study assessed the bioavailability of oral and i.v. 5-methyltetrahydrofolate (5-mTHF), 5-formyltetrahydrofolate (5-fTHF), or FA, and the bioavailability of folate from concentrates fed to horses. The minimum efficiency of absorption for supplemental FA was 11 %. The low bioavailability of FA indicates a need for further research on the potential benefits of alternative sources of folate, including 5-fTHF, on increasing folate status in the horse.Ph. D.
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Sudimack, Moseley Jennifer Jo. "Targeted drug delivery via the folate receptor /." The Ohio State University, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=osu1486459267519529.
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Andrews, Shannon. "FOLATE CONJUGATED DENDRIMERS FOR TARGETED ANTICANCER THERAPY." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3497.
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Anticancer therapeutics are often limited to suboptimal doses due to their lack of selectivity for tumor cells and resultant damage to healthy tissue. These limitations motivated researchers to develop tumor-specific delivery systems for improved therapeutic efficacy and reduced unintended cytotoxicity. Polyamidoamine dendrimers offer an ideal platform for designing targeted therapeutics with tunable characteristics that optimize pharmacokinetic behavior and targeting specificity. Ligand conjugation to dendrimer provides the biochemical interaction necessary to activate tumor-specific receptors for receptor-mediated endocytosis and effective internalization of polyplexes. Tumor-specific receptors overexpressed in carcinomas, like folate receptor-alpha (FOLRα), are targeted by ligand-conjugated dendrimer to allow enhanced internalization of dendrimer and its therapeutic cargo. We examined the cellular trafficking dynamics and potential of folate-conjugated dendrimer for nucleic acid delivery in vitro. Results show folate-conjugation to G4 PAMAM dendrimer (G4FA) confers enhanced uptake in FOLRα-positive tumor cells. Cells internalize G4FA in a receptor-dependent manner with specificity for FOLRα-positive tumor cells.
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Moradi, Emilia. "Folate-mediated macromolecule delivery across the epithelium." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/27899/.
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Folate uses the natural endocytosis pathway via the folate receptor (FR) to enter the cells. Folate conjugation to small or macromolecular therapeutics has hence been exploited for intracellular delivery to, particularly, cancerous cells. This work reports on the expression and functionality of FR in polarised cell monolayer models of respiratory and gastrointestinal mucosa with the view to assess its potential for delivery of folate-modified macromolecular therapeutics either intracellularly or across the epithelium. Four cell lines representing bronchial and intestinal epithelium; cancer-derived intestinal Caco-2 and bronchial cell line Calu-3, and noncancerous intestinal and bronchial cell lines IEC-6 and HBEC were cultured on permeable membranes to produce polarised monolayers. Expression of FR was confirmed by RT-PCR and Western blot analysis for all the tested cell types and shown to be dependent on culturing time. The functionality of the receptor for endocytosis was demonstrated by a model macromolecular folate conjugate (fluorescent ovalbumin-folate (OVA-FA)), whereby significantly higher cellular uptake of the folate-conjugate, relative to non-folate control, was clearly demonstrated. Importantly the data showed that the expressed folate receptor was capable of mediating transport of the macromolecular folate conjugate across (transcytosis) the cells in the polarised monolayers. Preliminary studies led to investigation of the folate mediated uptake and transport of folate modified nanoparticles (NPs). It was shown that folate modified NPs traversed the Calu-3 layers and studies characterizing this transport indicated folate involvement in this process. Adsorption of OVA-FA on the surface of NPs was seen to promote their cellular uptake and transport across the cell layers. To examine the mechanism of cellular uptake and transport of folate modified nanoparticles, various endocytic inhibitors were employed. The study demonstrated an involvement of the caveolar pathway in internalization of folate modified nanoparticles; as judged from a significant reduction of internalization in filipin (inhibitor of caveolar pathway) treated cells. Moreover, the work also showed evidence of transport of folate-modified nanoparticles via the caveolar pathway, since translocation of nanoparticles across the cell monolayer was absent when this path was inhibited. Disruption of actin filament and microtubules caused no difference in cellular uptake of NPs but increased the transcytosis of folate modified NPs. Confocal microscopy, Transmission Electron Microscopy (TEM), Total Internal Reflection Microscopy (TIRM) and Total Internal Reflection Florescence microscopy (TIRFM) were used to confirm and visualize quantitative data. This study also investigated the effects of surface ligand distribution pattern (ligand clustering and density) on the internalization of nanoparticles by Calu-3 cells cultured as polarised layers. The density of the displayed ligand was manipulated by controlling the conjugation level of folate-ovalbumin, while ligand clustering was achieved by co-adsorption of varying mixtures of folate-ovalbumin conjugate (at different ligand density levels) and unconjugated ovalbumin. Increasing ligand density on the nanoparticle surface resulted in increased internalization of modified nanoparticles by the cells, up to a saturation level. Surface ligand density also affected the cellular uptake pathway; from predominantly clathrin to predominantly caveolae-mediated as the ligand density was increased. It was further demonstrated that surface clustering of the folate ligand enhanced cellular internalization of nanoparticles, relative to its dispersed surface distribution.
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Surdhar, Mohinderjeet S. "Folate metabolism in the female weanling rat." Thesis, Aston University, 1987. http://publications.aston.ac.uk/14503/.
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The metabolism of a mixture of [2-14C] and [3',5',7,9-3H] folic acid was studied in female weanling rats. Intact folates and folate catabolites were excreted in the urine. Folate polyglutamates were found in the tissues. Rats treated with the oestrogen diethylstilbestrol and 17 -ethynyloestradiol exhibited marked changes in the metabolic handling of folic acid and folate catabolism was greatly increased compared to controls. Allopurinol treatment gave greater label retention in the gut, with a substantial increase in catabolism compared to normals. A dose response relationship was illustrated between allopurinol dose and folate catabolism. After lead acetate dosing there was little radioactivity in the urine and tissues over 72h and more radioactivity was retained in the faeces compared to normals. Excretion of intact folates was depressed, especially 5MeTHF and 10CHOTHF. A tenfold increase in both lead and folic acid dosage resulted in an even further decrease of radioactivity in the tissues and urine over 72h. Excretion in the faeces was further elevated. Ferrous sulphate administration resulted in increased catabolism. The retention of radioactivity in the liver, kidney and gut was greatly reduced. A new method of folate analysis; Sephadex LH-20 was introduced. In vitro superoxide anion formation was illustrated using an allopurinol/xanthine oxidase system. Histological studies were employed to qualitatively and quantitatively illustrate the oxidative status in livers and brains of allopurinol and ferrous sulphate dosed rats. Increased dose related formazan deposition was observed when livers of pretreated animals were incubated with nitroblue tetrazolium. Formazan deposition was reduced in pretreated animals also treated with the anti-oxidants vitamin E, mannitol or 4-hydroxy-methyl-4,6-ditertiary-butylphenol. A possible route of folate catabolism is scission by a non-enzymic oxidation involving active oxygen species.
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McNulty, Breige. "Folate status during pregnancy - implications for dietary recommendations for folate and related B-vitamins in women of reproductive age." Thesis, University of Ulster, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.529578.
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Colapinto, Cynthia. "Examining the Folate Status of Canadians: An Analysis of the Canadian Health Measures Survey to Assess and Guide Folate Policies." Thesis, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/26103.
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Canada fortifies certain products with folic acid and has periconceptional supplementation guidelines – policies designed to improve folate status and reduce the incidence of poor birth outcomes. Though optimal folate concentrations have been linked to health benefits, concerns have been raised regarding potential associations with adverse health outcomes. Direct biochemical assessment of the folate status of Canadians based on a nationally representative sample has not been done in more than 40 years. The overall purpose of this research was to investigate the folate status of the Canadian population.
All analyses used the nationally representative 2007–2009 Canadian Health Measures Survey (CHMS). Red blood cell (RBC) folate was measured by Immulite 2000 immunoassay. Key findings indicate that folate deficiency (<305 nmol/L) was virtually non-existent in the Canadian population (6–79 years old). Still, one-fifth of women of childbearing age (WCBA; 15–45 years old) had sub-optimal concentrations for the prevention of neural tube defects (<906 nmol/L). Folic acid supplement intake was a primary determinant of WCBA achieving a RBC folate concentration ≥906 nmol/L. A distinct shift towards elevated RBC folate concentrations emerged. Three hypothetical cut-offs (1450 nmol/L, 1800 nmol/L and 2150 nmol/L) were examined to create dialogue since a universal definition of high RBC folate concentration does not exist. Females, participants aged 60¬–79 years, and those who were overweight or obese had the greatest prevalence of having high RBC folate at each cut-off. We conducted the first national-level comparison of RBC folate concentrations between the United States and Canada. Two different folate assay methods – microbiologic assay (NHANES) and Immulite 2000 immunoassay (CHMS) – necessitated the application of a conversion equation. Median Canadian RBC folate concentrations (adjusted to microbiologic assay) were lower than those of Americans but unadjusted Canadian median RBC folate values were higher. Canadian WCBA were less likely than American WCBA to have RBC folate ≥906 nmol/L, though Canadian WCBA with unadjusted RBC folate values were more likely to achieve this cut-off.
These results indicate a need for strategies targeting WCBA to improve compliance with folic acid supplement recommendations. The strength and necessity of supplements for the general population should be re-assessed. Further, harmonization of folate measurement procedures in future surveillance efforts would support comparisons and inform policy directions.
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Reid, Deborah Jane. "Folate and zinc status of chronic hemodialysis patients." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/29786.
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Folate supplementation at a level of 15 to 35 mg per week is routinely prescribed for many chronic hemodialysis patients in B.C. In recent studies involving these levels of folate supplementation, RBC folate concentrations ranged from near the upper limit of normal to 1.5 times this upper limit. Initially there was research suggesting that high dose folate supplementation impaired zinc absorption but more recent studies refute this hypothesis. A beneficial effect of high dose folate supplementation is lowering of plasma homocysteine levels. This may be desirable since the homocysteinemia observed in chronic renal failure patients may be a factor in their commonly occurring premature vascular disease.
The present study addressed folate needs on a nutritional basis but did not investigate folate's effect on homocysteine levels. The study involved chronic hemodialysis patients and was designed to:
1. assess whether patients consuming the Recommended Nutrient Intake for folate, require a folate supplement to maintain normal folate stores;
2. assess whether patients receiving a supplement of 5 mg of folate per day will have RBC folate levels exceeding the upper limit of the normal range;
3. compare serum zinc concentrations (and in some cases hair zinc levels as well) of patients receiving no zinc supplement or a 22.5 mg per day zinc supplement, to each other and to normal values; 4. assess whether a supplement of 5 mg of folate per day is associated with impaired zinc status;
5. in the event that a 5 mg per day folate supplement is associated with impaired zinc status, assess whether a supplement of 22.5 mg of zinc per day is associated with an improvement in zinc status; and
6. determine average daily energy, protein, folate and zinc intakes of patients.
A 2x2 factorial quasiexperimental design was employed. The study included 21 clinically stable chronic hemodialysis patients between the ages of 25 and 69, who were receiving folate and/or zinc supplements at certain specific levels. Subjects were entered into treatment groups based on the following folate/zinc supplementation levels: no folate, no zinc; no folate, 22.5 mg zinc/day; 5 mg folate/day, no zinc; 5 mg folate/day, 22.5 mg zinc/day. Folate status was assessed using RBC folate concentration. Serum zinc concentration was measured in all subjects. Hair zinc level was determined in 6 of the zinc-supplemented subjects. A food frequency questionnaire was developed to determine dietary folate and zinc intakes. Subjects kept 3 day food records so average daily energy and protein intakes could be determined.
Study results indicated no significant difference in protein intake (g/kg b.w.) or energy intake (expressed as a percent of requirement) among the four treatment groups. Differences in dietary folate intakes among the four treatment groups as well as between zinc-supplemented and non zinc-supplemented subjects, were not significant (p≤0.05). Mean dietary folate intake for all study subjects was 4.2 ug/kg b.w. RBC folate concentration was normal in both treatment groups receiving no supplemental folate. In contrast, the RBC folate concentration for both folate-supplemented groups was approximately 6.5 to 7 times the upper limit of the normal range. The difference between RBC folate concentration for folate supplemented and unsupplemented groups was highly significant (p<0.00001) and remained so when analysis of covariance was done with number of months of folate supplementation as the covariate. RBC folate levels did not differ significantly between zinc-supplemented and unsupplemented groups (p≤0.05). Differences in dietary zinc intakes among the four treatment groups as well as between zinc-supplemented and non zinc-supplemented subjects were not significant (p≤0.05). Mean dietary zinc intake for all study subjects was 9.39 mg/day. Serum zinc levels were below normal in both treatment groups receiving no supplemental zinc. The 22.5 mg zinc, no folate group had a serum zinc concentration near the lower limit of the lower range while that in the 22.5 mg zinc, 5 mg folate group was slightly below normal. When all zinc supplemented subjects were combined, serum zinc concentration was just within the normal range. Hair zinc analysis was conducted in a subgroup of 6 zinc-supplemented subjects and a group of non zinc-supplemented healthy controls. Hair zinc level was significantly higher in the zinc-supplemented subjects than in the controls (p≤O.01).
In conclusion, folate supplementation does not appear to be required on a nutritional basis in clinically stable chronic hemodialysis patients not receiving medications known to affect folate status, who are consuming a diet providing a minimum of 1 g of protein per kg b.w. and 4.6 ug of folate per kg b.w. The low serum zinc concentrations observed in both zinc-supplemented and non zinc-supplemented patients may have been due to a shift of zinc from serum to other "zinc pools" in the body as reported in the literature.Land and Food Systems, Faculty of
Graduate
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Miller, Pamela N. "The effect of folate deficiency on mammalian pregnancy." Thesis, University of Leicester, 1988. http://hdl.handle.net/2381/34165.
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The consequence of a folate deficiency during organogenesis has been investigated in the rat embryo. In vitro culture of 9.5 day embryos in serum from dietary induced folate deficient rats frequently resulted in abnormal embryos. Many were growth retarded and exhibited a defect in the turning mechanism which inverts the embryo from ventrally to dorsally convex. Affected embryos displayed abnormal twisting or kinking of the neural tube. Gross anaemia was also frequently observed and the protein content of the embryos was markedly less than that of embryos grown in normal rat serum. Supplementation of the deficient serum with folic acid improved growth and greatly reduced the occurrence of deformities. It virtually eliminated the incidence of gross anaemia but only partially restored the protein content to the level observed in embryos cultured in normal rat serum. The effects of the folate deficiency could not be reversed by supplementation with multivitamins or by increasing the volume of culture serum. They were, however, eliminated by supplementing the deficient culture serum with normal rat serum. The effects could also be overcome by in vivo folate supplementation; rats which had previously been so folate deficient that culture in their serum would have resulted in malformed embryos, after restoration to a folate supplemented diet produced serum which supported completely normal embryonic growth. The results indicate that embryos undergoing organogenesis require adequate folate in order for normal growth and differentiation to take place. They also suggest that some of the embryopathic effects of maternal folate deficiency are mediated by secondary effects. These may involve complex growth or metabolic factors which can be corrected in vivo but are not readily reversed in vitro.
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Johansson, Madelene. "Analytical and nutritional aspects of folate in cereals /." Uppsala : Dept. of Food Science, Swedish University of Agricultural Sciences, 2005. http://epsilon.slu.se/200507.pdf.
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Patel, Harshila. "The compartmentalization of folate metabolism in mammalian cells /." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85091.
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Folate metabolism is compartmentalized between the cytoplasm and the mitochondria of mammalian cells. Certain folate-dependent enzymes are present in both of these compartments, such as methylenetetrahydrofolate dehydrogenases, which are required to interconvert one-carbon substituted tetra hydrofolates. In the cytoplasm, there is a trifunctional NADP-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase-synthetase (DCS). Its mitochondrial counterpart is a bifunctional NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase (NMDMC), expressed during embryogenesis and in immortalized cells. A comparison of the 3' untranslated region of the NMDMC cDNA with the synthetase domain of the DCS cDNA and gene among different species have revealed significant regions of homology. This suggests that the mammalian mitochondrial NAD-dependent DC evolved from an NADP-dependent DCS precursor through a change in cofactor specificity of the dehydrogenase from NADP to NAD.Although the folate pathways are compartmentalized, the mitochondrial folate pathway makes an important contribution to total cellular folate metabolism. Mouse fibroblasts that have a completely inactivated NMDMC gene are glycine auxotrophs. Furthermore, growth of these Nmdmc-/- cell lines is stimulated by supplementation with formate or hypoxanthine. These cell lines also show enhanced incorporation of radioactivity into DNA from formate as compared to serine, demonstrating that formate is a preferred one-carbon donor for the Nmdmc-/- cell lines. This indicates that NMDMC is required for optimal purine biosynthesis during periods of rapid cellular proliferation such as embryogenesis and tumorigenesis. The rescue of these Nmdmc-/- cell lines with NMDMC expression reversed the glycine auxotrophy and the formate to serine incorporation ratio reverted toward the wild type ratio. The rescue of these Nmdmc-/- cell lines with the NAD-dependent monofunctional dehydrogenase activity also reversed the glycine auxotrophy but these cell lines did not grow as well as the NMDMC-rescued cell lines. This indicates that although the cyclohydrolase activity is not required in the mitochondria, the rate of 10-formyl-THF production is not optimal in its absence. Furthermore, when these Nmdmc-/- cell lines were rescued with the expression of the NADP-dependent DCS in the mitochondria there was reversal of the glycine auxotrophy as well, indicating that the NAD cofactor specificity of the mitochondrial methylenetetrahydrofolate dehydrogenase is not absolutely essential to maintain the flux of one-carbon metabolites.
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Rios-Orlandi, Ethel Marie. "Kinetic properties of two folate-dependent dehydrogenase-hydrolases." Thesis, McGill University, 1988. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75844.
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The kinetic relationship between the activities of multifunctional enzymes from folate-mediated one-carbon metabolism were examined. Formyltetrahydrofolate dehydrogenase catalyzes the main disposal reaction for excess one-carbon units produced in the liver. The enzyme, which catalyzes also a hydrolytic reaction, was purified from porcine liver and a radioactive assay was developed to measure both activities simultaneously. These and other kinetic measurements established that the dehydrogenase and hydrolase are kinetically independent activities of a single type of polypeptide. NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is found in all transformed mammalian cells and catalyzes sequential reactions with channeling of the metabolic intermediate. However, these activities are kinetically independent in contrast to similar activities of the NADP-dependent trifunctional enzyme found in all eukaryotic cells. These properties explain the observation that only the NAD-dependent enzyme conjugate can catalyze the conversion of formyl- to methylenetetrahydrofolate in vitro.
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Bhattacharya, Shiladitya. "Novel folate amphiphile conjugates for targeted drug delivery." Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/2360.
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Cancer is not only difficult to treat but the patients also suffer from the pain associated with anticancer treatments. Targeted chemotherapeutics can reduce the adverse effects by reducing the dose required for tumor cell kill. Cancers of various origins often have characteristic marker molecules that distinguish them from the normal tissues. Folate receptors are such marker molecules present in ovarian and cervical cancers. The hypothesis for the current study is that amphiphiles constructed out of folic acid, the natural ligand for the folate receptor, can deliver paclitaxel, a chemotherapeutic compound, to folate receptor expressing cancer cells. To test this hypothesis, amphiphilic molecules were synthesized out of folic acid and fatty acids or long chain aliphatic amines. The gamma carboxylic group of folic acid was converted to an N-alkyl substituted amide. The alkyl group had various chain lengths varying from eleven methylene groups to seventeen methylene groups giving rise to a number of amphiphiles. The amphiphiles formed micelles in aqueous solutions. The critical micellization concentrations of the amphiphiles were measured by pyrene fluorescence and were found to be in the range of 10–70μM. HeLa and Caco-2 cells were taken as in vitro tumor models. Folate receptor expression was verified in HeLa and Caco-2 cells by western blot analysis. HeLa showed more than forty fold expression of the receptor when compared to Caco-2 and was chosen as receptor positive cell line while Caco-2 served as a negative control. Uptake of the folate labeled delivery system in the cell lines was tested by a fluorescent probe (aminocoumarin) labeled amphiphile. To test the specificity of the delivery system towards the receptor positive HeLa cells, the receptors were knocked down (70%) by folate receptor specific siRNA. Fluorescent amphiphile uptake in the knockdown cells was comparable to that of the negative control, Caco-2. Finally cytotoxicity studies were performed for paclitaxel formulated with the folate labeled amphiphiles and compared to free drug treatment in HeLa and Caco-2. IC50 values in HeLa for formulations with the folate labeled amphiphiles were ten folds less than those observed for free drug treatment whereas in Caco-2 no significant difference was noted.
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Alvarez, Mary Allison. "Pyridinium Bis-retinoids: Extraction, Synthesis, and Folate Coupling." BYU ScholarsArchive, 2007. https://scholarsarchive.byu.edu/etd/8870.
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This thesis is divided into two parts.Part I describes the organic extraction, separation, and liquid chromatographic-mass spectrometric analysis of chromophores from human and bovine retinal pigment epithelium. Flurorophores in the retinal pigment epithelium have been implicated in age related macular degeneration. In addition, the synthesis and characterization of a number of bis-retinoid type compounds that may potentially be found in such extracts, or that may be used for insight into pyridinium bis-retinoid reactivity, was accomplished.Part II describes a study of pyridinium bis-retinoid-folic acid coupling with respect to linker type, linker length, and nature of the linkage. Folic acid has been used as a targeting compound for a variety of cancer types. Development of HPLC and UV-Vis conditions suitable for the analysis of this new type of macromolecule was performed.
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Baker, Bernadette. "The effect of folate deficiency on placental function." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/the-effect-of-folate-deficiency-on-placental-function(2e4035d8-ab44-4f5c-a92b-f851f65a3609).html.
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Insufficient maternal folate during pregnancy increases the risk of the baby being small for gestational age (SGA). Studies in teenagers, a population vulnerable to folate deficiency and SGA birth, have shown that low maternal folate status is associated with impaired placental cell turnover and reduced transport suggesting placental dysfunction underlies SGA in maternal folate deficiency. Mechanisms through which folate-depletion compromises placental function are currently unknown. In non-placental cells, folate modulates microRNAs (miRs), post-transcriptional regulators of cellular functions. Expression of miRs is altered in placentas of SGA compared to normally grown babies but there are no data on differential miR expression or regulation in placentas from folate deficient women. This PhD investigated the hypothesis that placental dysfunction observed in folate deficient women is mediated by altered miR expression. Three placental preparations were compared (villous tissue in explant culture, BeWo choriocarcinoma cells and isolated cytotrophoblast cells) to determine the optimum in vitro system to study the direct effects of folate deficiency. In cytotrophoblast cells, folate deficiency significantly elevated apoptosis and reduced the activity of the system A amino acid transporter, consistent with observations in the placentas of folate-deficient teenagers. The reduction in system A activity by low folate was not associated with altered mRNA expression for the isoforms of system A, implicating an effect of low folate on post-translational regulation of the nutrient transporter. Targeted examination of villous tissue from teenagers with low folate status identified up-regulation of miR-222-3p a folate-sensitive miR. An unbiased miR array identified up-regulation of a further 16 miRs suggesting that maternal folate deficiency in vivo results in aberrant placental miR expression. Bioinformatic analysis of the folate sensitive miRs predicted gene targets known to be altered in placentas from SGA pregnancy that were likely to alter placental function. Two miRs altered in placentas from women with low folate status, miR-30e-3p and miR-34b-5p, were also significantly altered in folate deficient cytotrophoblasts confirming a direct effect of folate on trophoblast miR expression. Inhibition of these miRs in vitro had no effects on placental functions that are altered in vivo in folate-deficient women. Gene array and in silico analysis identified functional endpoints affected by these folate sensitive miRs, including cell signalling for proliferation and survival and oxidative stress, which might contribute to placental dysfunction in folate deplete women. Overall, this study has demonstrated for the first time that folate deficient conditions can directly alter trophoblast system A transport and cell survival and thus could contribute to the increased susceptibility to SGA births in folate deficient women. It has also contributed to the knowledge that miR expression is differentially altered in placentas exposed to folate-deficient versus sufficient conditions in vivo and that miRs are directly altered by folate depletion in vitro. These studies provide the foundation for future research to define the functional consequences of altered expression of folate-sensitive miRs and their target genes to explain how altered miRs could be affecting placental function resulting in development of SGA.
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Alvarez, Mary Allison Lawyer. "Pyridinium bis-retinoids : extraction, synthesis, and folate coupling /." Diss., CLICK HERE for online access, 2007. http://contentdm.lib.byu.edu/ETD/image/etd1745.pdf.
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Leininger, Dawn. "Consumption and knowledge of folate among college students /." View online, 1998. http://repository.eiu.edu/theses/docs/32211130891409.pdf.
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Öhrvik, Veronica. "Folate bioavailability in vitro experiments and human trials /." Uppsala : Dept. of Food Science, Swedish University of Agricultural Sciences, 2009. http://epsilon.slu.se/200963.pdf.
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Pereira, Perla Menezes. "Consumo de cobalamina e folato por gestantes: relação com o metabolismo da homocisteína e com os polimorfismos nos genes da metionina sintase, metilenotetraidrofolato redutase e metionina sintase redutase." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-04042007-164324/.
Full textAbstract:
Os consumos inadequados de cobalamina (Cbl) e de folato associados aos polimorfismos em genes de enzimas chaves do metabolismo da homocisteína podem agravar as comorbidades relacionadas a deficiências destas vitaminas. Os objetivos deste estudo foram avaliar o consumo de cobalamina, de folato e de vitamina 86 por gestantes através de três inquéritos recordatórios de 24 horas (IR24h); determinar as correlações entre as concentrações séricas de folato, de cobalamina, de metionina, de .S-adenosilmetionina (SAM), de Sadenosilhomocisteína (SAH), de homocisteína total (tHcy) e de ácido metilmalônico (MMA) com as vitaminas e as proteínas ingeridas na dieta pelas mulheres; analisar as associações entre os polimorfismos MTHFR C677T, MTHFR A1298C, MTR A2756G e MTRR A66G e alterações nas concentrações das vitaminas e dos metabólitos, além de avaliar os determinantes nutricionais e genéticos das concentrações dos metabólitos tHcy\" SAM, MMA e SAM/SAH durante a gestação. Participaram do estudo 73 mulheres com idades gestacionais de 16, 28 e 36 semanas, no qual foram aplicados três IR24h para cada gestante, um em cada idade gestacional. Foram realizadas as dosagens séricas de cobalamina sérica, folato sérico e eritrocitário, homocisteína total, metionina, MMA, SAM e SAH. As genotipagens dos polimorfismos MTHFR C677T, MTHFR A1298C, MTR A2756G e MTRR A66G foram feitas por PCR-RFLP. Observou-se que a ingestão de folato foi baixa em relação ao valor de 600 µg/dia recomendado para gestantes, a ingestão de cobalamina foi menor que a encontrada na literatura, a ingestão de vitamina 86 e a de proteínas totais foram semelhantes às da literatura. As concentrações de Cbl séricas foram diretamente relacionadas com a ingestão de proteínas. As concentrações de MMA estavam relacionadas inversamente com a ingestão de cobalamina, com a ingestão das proteínas totais e com a renda per capita. Houve redução das concentrações de cobalamina sérica e aumento de MMA no decorrer das idades gestacionais, sendo observada maior concentração sérica de MMA entre as mulheres que ingeriram menos cobalamina. Não houve associação entre os polimorfismos MTHFR A1298C e MTRR A66G e as variações nas concentrações de vitaminas e de metabólitos. Com relação ao polimorfismo MTHFR C677T, as mulheres portadoras do alelo 677T possuíam menores concentrações médias de foiato eritrocitário, e para o polimorfismo MTR A2756G, as mulheres com genótipos AG e GG apresentaram menores concentrações de metionina. As concentrações aumentadas de tHcy foram explicadas pelas menores concentrações de folato eritrocitário, pela menor ingestão de proteínas totais, pelas maiores concentrações de creatinina sérica e pela ingestão de vitamina 86. A creatinina sérica foi a responsável pela variabilidade das concentrações da SAM. Maiores concentrações de folato sérico e menores concentrações de creatinina sérica foram os responsáveis pelo aumento dos valores da SAM/SAH. As maiores concentrações de MMA foram atribuídas à menor ingestão de cobalamina, à menor renda per capita e à menor concentração sérica de cobalamina. Conclusões: a ingestão de folato foi menor que a metade do recomendado. A ingestão de cobalamina atingiu o recomendado, no entanto não foi suficiente para manter o metabolismo materno. Os polimorfismos não foram associados a baixa ingestão de vitaminas para explicar as alterações nas concentrações de tHcy, da SAM, da SAM/SAH e do MMA.The inadequate intake of cobalamin and folate associated to polymorphisms in key-enzyme genes of homocysteine can worsen comorbidities related to the deficiency of these vitamins. The aims of this study were to evaluate the intake of cobalamin, foiate and vitamin 86 by pregnant women through three 24-hour dietary recaIl (IR24h); to assess the correlation between serum concentrations of folate, cobalamin, methionine, S-adenosilmethionine (SAM), S-adenosilhomocysteine (SAH), total homocysteine (tHcy) and methylmalohic acid (MMA)towards vitamins and proteins intaked by women, to analyze association between MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G polymorphisms and changes on vitamin and metabolites concentration, and to determine the nutritional and genetic determinants during a gestational period. 73 pregnant women participated in this study, with gestational ages of 16,28 and 36 weeks, onto whom were applied three IR24h to each woman, being one in each gestational age. Serum concentrations of cobalamin, foiate and red blood cell foiate, total homocysteine, methionine, MMA, SAM and SAH were evaluated. The polymorphisms of MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRRA66G were performed by PCR-RFLP. It was observed that folate intake was low in relationship to recommended value for pregnant women of 600 µg/day. Cobalamin intake was less than the one found in literature. Vitamin 86 and total protein intake was similar to the one found in literature. Serum Cbl concentrations were directly related to protein intake. MMA concentrations were in,verselycorrelated to cobalamin intake, to total proteins intakes and mounth per capita income. There were reduction of serum cobalamin concentration and enhance of MMAthroughout pregnancy weeks, being observed higher serum concentration of MMAamongst women that intaked less cobalamin. There was no association between MTHFRA1298Cand RRA66Gpolymorphism and the change in vitamins and metabolites concentrations. The women carrying allele 2756G for MTR polymorphism presented lesser serum methionine concentrations and alieie 677T for MTHFR C677T had less concentration of red blood cell folate. The red blood cell folate concentrations, intake of total proteins, serum creatinine concentrations and intake of vitamin 86 were eterminant of tHcy concentration. Serum creatinine was responsible for SAMconcentrations variability. Higher concentrations of serum foiate and lesse r concentrations of serum creatinine were responsible for the enhance of SAM/SAHvalues. The higher concentrations of MMAwere attributed to lesse r cobalamin intake, to lower per capita income and to lesser seruro concentration Df coba}amin. ConcJusions: lo/ate intake was less than ha(f of recommended amount, and cobalamina intake reached the recommended amount, however this amount was not enough to keeping the maternal metabolism. The poly~orphisms were not associated to low vitamin intake for explaining the changes Inserum concentrationsof tHcy,SAM,SAM/SAHand MMA.
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Brockton, Nigel Trevellyan. "Genetic polymorphisms in folate and xenobiotic metabolism and susceptibility to colorectal cancer." Thesis, University of Aberdeen, 2003. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU496469.
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Colorectal cancer (CRC) is the second most common cancer, in both sexes, in developed countries and the incidence rates are rising in many populations. Less than 10% of cases are thought to be due to recognised familial syndromes: Familial Adenomatous Polyposis (FAP) and Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Epidemiological studies suggest that dietary factors play an important role in the aetiology of CRC; disease incidence is inversely associated with diets high in folate and has been positively associated with red meat consumption. Folate is important in DNA methylation and synthesis. The increased risk associated with red meat is proposed to be due to the formation of heterocyclic amines during cooking rather than meat consumption per se. The current study, a population-based case-control study (269 case and 408 control subjects) was carried out in the Grampian region and investigated polymorphisms in genes involved in folate and xenobiotic metabolism. Inter-individual differences in the activation and detoxification of xenobiotics and the metabolism of folate might alter risk of CRC. Mouthwash samples were collected from all participants and genomic DNA was extracted for genotypic analysis of MTHFR, CYP1A1, NAT2, GSTM1 and GSTT1. Homozygous possession of the MTHFR A1298C substitution was associated with a reduced risk of colon cancer. The reduced risk of rectal cancer associated with possession of the MTHFR C677T substitution approached statistical significance. A proposed mechanism is presented to explain the inverse association between CRC and MTHFR allelic variants. The CYP1A1 C2453A substitution was inversely associated with CRC risk. No significant alteration of risk was associated with deletions of GSTM1 or GSTT1 genes or acetylation status imputed from NAT2 genotype. Genomic DNA extracted from mouthwash samples, collected by post from an elderly population, was effective as template for PCR/RFLP methods of genotyping.
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Gonzalez-Jorge, Sabrina. "Dissecting the genetic control of folate homeostasis in plants." Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491008.
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Because of its central role in purine and thymidylate biosynthesis, folate-mediated one-carbon metabolism has been the target of many anticancer drug therapies. The objective of this study is to utilise the structural similarity of the anticancer drug, nnethotrexate (MTX) to folate, and optimise chemical-based genetic screens for the isolation of folate transporters and/or elements important for folate homeostasis in Arabidopsis thaliana.
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Castelazo, Anahi Santoyo. "Comprehensive folate profiling in plants using LC-MS/MS." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508152.
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Mehrshahi, Payam. "Characterising the functional importance of folate polyglytamylation in plants." Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.478929.
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Doshi, Sagar Navinchandra. "Homocysteine, folate and endothelial function in coronary heart disease." Thesis, Cardiff University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444121.
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Dewar, Simon. "Folate transport and drug resistance in the African trypanosome." Thesis, University of Dundee, 2017. https://discovery.dundee.ac.uk/en/studentTheses/816f1fc5-dd5a-41d9-83a5-45e825f0af06.
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The aim of this thesis was to expand upon the knowledge of the mechanism of action and resistance of antifolate drugs in African trypanosomes with a specific focus on transport mechanisms. A media deficient in folate and thymidine was established which enabled the assessment of their modulation on antifolate in vitro potencies and also screen a small set of antifolate compounds. The phenomenon of ‘thyminelessdeath’ was found to account for methotrexate toxicity, as well as the primary mechanism of raltitrexed toxicity. This was confirmed by cell cycle studies demonstrating cell cycle arrest in S phase which could be rescued with thymidine. Transport kinetics of folate and methotrexate were characterised and found to be competitive substrates for uptake in T. brucei. Transport of these substrates was inhibited by classical antifolates, but not by non-classical antifolates. Genome-wide RNAi library screens with methotrexate and raltitrexed identified the putative folate transporter genes to be involved in drug resistance. RNAi knockdown of the folate transport genes resulted in a substantial reduction in folate transport was seen. RNAi knockdown also led to cross-resistance to classical antifolates, whereas these parasites became hypersensitive to non-classical antifolates. Methotrexate-resistant trypanosomes were generated in which transport of methotrexate and folate was substantially reduced. Amino acid changes were evident in the putative folate transporter genes but no change in transcription or copy number was evident. Cross resistance to classical antifolates was demonstrated in these resistant parasites and cells become hypersensitivity to non-classical antifolates (a similar phenotype to folate transporter RNAi knockdown). Proteomic studies were performed in drugresistant trypanosomes; however, no conclusive findings were evident due to limitations of these experiments. In conclusion, these studies demonstrate good evidence of both transport-mediated drug action and drug resistance.
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Padmanabhan, Nisha. "The biological and molecular effects of abnormal folate metabolism." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708242.
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Zilliox, Trish, and Silva Vanessa da. "Folate & Folic Acid- Healthy Moms Mean Healthy Babies." College of Agriculture, University of Arizona (Tucson, AZ), 2017. http://hdl.handle.net/10150/625289.
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4 pp.Before they may even know they are pregnant; women’s bodies and their level of folate play a critical role in preventing certain birth defects, specifically neural tube defects (NTDs). NTDs are birth defects in the brain, spinal cord, or spine. Considered ‘one of the most important public health discoveries of this century’ is that daily supplemental folic acid taken before becoming pregnant significantly reduces the risk of NTDs (1). In 1998, the United States made sweeping efforts that fortified cereal grains with folic acid to ensure all Americans consume adequate amounts of this vitamin. So what exactly is folate? What are the functions of this vitamin? What foods have high levels of folate and what is the recommended daily intake? This article will answer these questions and will go on to explain folic acid fortification and the impact fortification has had on the incidence of NTDs in Arizona.