Dissertations / Theses on the topic 'Folic acid deficiency'
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1
Goyette, Philippe. "Molecular characterization of methylenetetrahydrofolate reductase deficiency." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0005/NQ44442.pdf.
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Low-Nang, Lawrence. "Investigation of mutations in methylenetetrahydrofolate reductase deficiency." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60720.
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Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylene THF to 5-methyl THF, the carbon donor for the methylation of homocysteine to methionine. Patients with severe MTHFR deficiency (MRD) have neurologic abnormalities while a milder form (a thermolabile MTHFR variant) has been shown to be associated with coronary artery disease (CAD). Ten MRD patients, with reduced or non-detectable activity, were studied to characterize the nature of the mutation. Southern, Northern and Western analysis did not reveal any defects in the patients. These results suggest that the mutations may be minor insertions/deletions or single base substitutions that affect catalytic activity. Single strand conformation polymorphism (SSCP) analysis was used to detect base substitutions; 3 RFLPs were identified with this protocol. One was in the coding region (SphI) while the other two were in the 3$ sp prime$ untranslated region (MaeIII and MnlI). A difference in frequency of the SphI RFLP was found between control subjects and a small sample of CAD patients whose homocysteine levels were greater than the 99th percentile.
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Milan, Julie E. "The Women's Folate Study: A Stage-Tailored, Web-Based Intervention for College Women." Fogler Library, University of Maine, 2004. http://www.library.umaine.edu/theses/pdf/MilanJE2004.pdf.
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Mascisch, Allegra. "Characterization of a CHO cell line deficient in the folate-dependent trifunctional protein, MTHFD." Thesis, McGill University, 1990. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60015.
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MTHFD is a folate-dependent trifunctional protein comprised of three activities: N$ sp5$,N$ sp{10}$-methylenetetrahydrofolate dehydrogenase, N$ sp5$,N$ sp{10}$-methenyltetrahydrofolate cyclohydrolase and N$ sp{10}$-formyltetrahydrofolate synthetase. The enzymes catalyse the sequential interconversion of tetrahydrofolate derivatives required for purine, methionine and thymidylate synthesis. A Chinese hamster ovary cell line, reported to have reduced cyclohydrolase activity, was studied to characterize the nature of its mutation.Enzymatic assays showed reduced activities of all three enzymes. Immunoblotting and immunoprecipitation of radiolabelled cell extracts indicated that the gene product was greatly reduced or absent in the mutant. Southern analysis showed no differences between normal and mutant cells, indicating that the defect was not due to a major gene rearrangement. RNA analysis, by Northern blotting and by RNA amplification using the polymerase chain reaction, showed that a mRNA for MTHFD of normal size was present in mutant cells. These results suggest that the mutation is post-transcriptional and that it disrupts the synthesis of MTHFD.
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Sibani, Sahar. "Genetic and nutritional folate deficiency : implications for homocystinuria and intestinal neoplasia." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31539.
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Folate deficiency, a prevalent vitamin deficiency in America, can stem from environmental and/or genetic causes. The most common inborn error of folate metabolism is deficiency of methylenetetrahydrofolate reductase (MTHFR), which catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Severe MTHFR deficiency results in hyperhomocysteinemia and homocystinuria; patients present with developmental delay, and various neurological and vascular disorders. This thesis describes three mutations identified in the MTHFR locus in patients with severe deficiency: 1025T→C (M→T), 1027T→G (W→G), and 1768G→A (E→K). Genotype-phenotype correlations are described, along with biochemical characterization of three mutations (983A→G (N→S), 1025T→C, 1027T→G). All three mutations exert their effect by decreasing Vmax without changing the enzyme's affinity for its substrate, 5-methyltetrahydrofolate. The 983A→G variant also conferred decreased affinity for FAD, a cofactor.The more common and mild deficiency observed in the general healthy population is probably due in part to insufficient dietary intake of folate. Folate deficiency has been associated with increased risk for colon cancer. In a pilot study presented here, the impact of altered folate intake on tumor multiplicity in the Min mouse, a model for multiple intestinal neoplasia, was assessed. Folate deficient diets did not produce a consistent change in tumor numbers. However, a linear correlation between S-adenosylmethionine and S-adenosylhomocysteine content of preneoplastic tissue and tumor multiplicity was identified.
This thesis contributes to our understanding of the impact of genetic- and/or dietary-induced folate deficiency on cellular and organismal functions.
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Crott, Jimmy. "The effects of folic acid deficiency and defects in folate metabolism on chromosome damage in vitro." Title page, table of contents and abstract only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phc9515.pdf.
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Reprints of the author's previously published articles included as an appendix. Bibliography: leaves 165-188. "This thesis describes a series of experiments that aimed to investigate the effects of folic acid deficiency and defects in folate metabolism on chromosome damage rates in human lymphocytes. The accumulation of chromosome damage over time is an important issue because it is thought to contribute to the mechanism of ageing and the aetiology of diseases of age such as cancer and Alzheimer's disease."
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Hilton, John Frederick. "The molecular basis of glutamate formiminotransferase deficiency /." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33776.
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Glutamate formiminotransferase deficiency (OMIM 229100) is an autosomal recessive disorder marked by clinical heterogeneity. The severe phenotype, first identified in patients of Japanese descent, includes high levels of formiminoglutamate (FIGLU) in the urine in response to histidine loading, megaloblastic anemia, and mental retardation. The mild phenotype is marked by high levels of FIGLU in the urine in the absence of histidine loading, mild developmental delay and no hematological abnormalities. The gene for human glutamate formiminotransferase-cyclodeaminase consists of 15 exons and is located at 21q22.3. The protein consists of a tetramer of dimers, with dimerization essential for both formiminotransferase and cyclodeaminase activity.Genomic DNA extracted from cell lines from three patients with suspected glutamate formiminotransferase deficiency was analyzed by PCR and sequencing of individual exons. Cell lines WG 1758 and WG 1759 are from two siblings of Germanic descent. Both siblings are heterozygous for the mutations c457 C → T and c940 G → C. The c457 C → T changes a conserved arginine to a cysteine in a loop involved in the binding of formiminotetrahydrofolate to the enzyme. The c940 G → C mutation converts an arginine to a proline in an alpha-helix essential for the dimerization of the formiminotransferase domain. Cell line WG 1795 is from a patient of Danish descent. The patient appears to be hemizygous for a c1033 insG mutation. Quantitative PCR suggests the presence of a deletion on the other chromosome, which minimally encompasses exon 9. All of the FTCD gene changes were absent in 100 control individuals (200 alleles).
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Pai, Aditya P. "Isolation and partial characterization of the mouse gene for methylenetetrahydrofolate reductase (MTHFR)." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=22868.
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Methylenetetrahydrofolate reductase (MTHFR), an important enzyme in folate metabolism, mediates the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which serves as the carbon donor for the conversion of homocysteine to methionine. It is also inhibited by S-adenosylmethionine which has shown to be actively demethylated to form S-adenosylhomocysteine, which is hydrolysed to homocysteine. MTHFR deficiency exhibits well-documented clinical and biochemical symptoms. The human MTHFR cDNA was isolated by Goyette et al (1994), and fifteen mutations have been identified at this locus.An animal model would prove to be useful for designing therapeutic approaches for understanding the pathogenesis of this genetic disease at the molecular level. The mouse MTHFR gene and cDNA have been isolated and partially characterized. Four genomic clones were isolated by library screening. One of these clones (clone 3) contained the 5$ sp prime$ end of the gene and was completely characterized. The clone was shown to have no rearrangements and is to be used to design targeting vectors for 'knockout mice' and mice carrying a common mutation which has been postulated to be a genetic risk factor for cardiovascular disease. The other three clones contain the remaining 3$ sp prime$ portion of the gene. The coding portion has approximately 90% homology with the human cDNA and also shows a similar gene structure.
A 2.2 Kb mouse MTHFR cDNA was isolated by library screening and was found to contain a 320 base pair extension at the 5$ sp prime$ end which has not been found in the human cDNA. The cDNA contains exons -1 -3, but also contains two possibly unspliced introns. A portion of this cDNA can however still be used to rescreen libraries to isolate a full length cDNA. The above research is the first genetic data on the mouse MTHFR gene and provides the basis for future research involving mouse models of MTHFR deficiency.
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Shalchi-Toosi, Marjan. "Implications of methionine and S-adenosylmethionine for the brain function." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=26132.
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We have studied the effect of S-adenosylmethionine (SAM) on tail flick latency in the rat. We also studied the effect of methionine the immediate precursor of SAM. Administration of methionine to the rat increases brain SAM, but little is known about its behavioral effects. Long-Evans rats were given SAM and methionine orally at different doses and tail-flick latency was measured at various times. Both methionine and SAM increased tail-flick latency, but methionine did so at a lower dose. A biochemical study showed that methionine was more effective than SAM in raising brain SAM probably because it is transported better into brain. The biochemical measurements were not consistent with the idea that the effects of SAM and methionine were mediated by an increase in brain 5-HT.Folate deficiency can lower brain SAM levels and cause depression. Thus, methionine, which raises brain SAM, may overcome the effects of folate deficiency. Seven day food records were done by 26 psychiatric outpatients who were stable on lithium treatment. Eight patients had mean daily folate intakes below those recommended. Some of those with low folate intake had high methionine intake consistent with the idea that methionine could substitute metabolically for folate deficiency. Daily methionine intakes ranged from 13 to 304% of the recommended intake. As methionine had behavioral effects in the rat at doses much less than the daily dietary intake this raises the question of whether varying daily intakes of methionine in humans have behavioral implications. (Abstract shortened by UMI.)
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Frosst, Phyllis D. "Investigation of methylenetetrahydrofolate reductase in vascular disease and neural tube effects." Thesis, McGill University, 1995. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23399.
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Methylenetetrahydrofolate reductase catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency have $<$20% residual enzyme activity, moderate hyperhomocysteinemia, vascular lesions and neurological dysfunction. Mildly-deficient individuals with a thermolabile enzyme are at increased risk for developing cardiovascular disease.Two MTHFR sequence changes were identified. The first was a C to T transition at bp 764 altering a proline to a leucine codon; this change was found in one severely-deficient patient. The second was a C to T transition at bp 677, substituting a valine for a highly-conserved alanine codon. The $ rm A to V$ substitution was identified on 35-40% of chromosomes. Expression of the $ rm A to V$ mutation in prokaryotic cells revealed increased thermolability over the wild-type enzyme. Genotyping for the $ rm A to V$ mutation in three vascular disease studies showed that it was associated with mild hyperhomocysteinemia, a risk factor for vascular disease.
The preventative effects of folate supplementation on the occurrence and recurrence of neural tube defects (NTDs) have been repeatedly demonstrated. The curly-tail (ct) mouse model for NTDs was used to investigate the involvement of MTHFR in these defects. Ct mice had significantly increased homocysteine levels although differences in MTHFR activity were not demonstrated. The mouse MTHFR gene was mapped to distal chromosome 4, close to the major gene for NTDs in ct. MTHFR is suggested as a candidate locus for the ct defect.
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Knock, Erin Heather 1981. "Long-term dietary folate deficiency and intestinal tumor development in mice." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115689.
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Epidemiological evidence linking dietary folate deficiency and risk for colorectal cancer is conflicting. Studies using animal models indicate that timing, dose and presence of pre-malignant lesions will influence whether folate deficiency prevents or promotes tumor formation. In this thesis a new model of spontaneous tumor formation due to long-term dietary folate deficiency alone, in non-transgenic mice and without carcinogen induction, is developed. The mechanisms by which folate deficiency might influence cancer risk are also examined.BALB/c mice, with or without a null allele in a key folate-metabolizing enzyme, Methylenetetrahydrofolate reductase (Mthfr ), develop intestinal tumors due to dietary folate deficiency alone. On folate-deficient (FD) diets, 12.5% of Mthfr+/+ mice and 28.1% of Mthfr+/- mice developed tumors; mice on control diet (CD) did not. C57B1/6 mice (a strain resistant to other methods of tumor induction) placed on the same diets for the same amount of time did not develop any tumors. To investigate possible mechanisms the levels of DNA damage (dUTP/dTTP ratio and p-H2AX staining) and DNA methylation (thin layer chromatography) were examined. FD BALB/c, but not C57B1/6 mice, had a trend towards increased dUTP/dTTP and DNA double-strand breaks and decreased global DNA methylation compared to CD mice. To determine why the FD diet affects the BALB/c and not the C57Bl/6 strain, the expression of genes involved in folate metabolism was examined. Several changes in gene expression were observed. In particular, BALB/c mice had increased Mthfr expression and MTHFR activity compared to C57Bl/6 mice. Increased MTHFR activity may deplete 5,10-methylenetetrahydrofolate supplies for the dTMP synthesis, increasing the dUMP levels and, possibly, DNA damage. The levels of several DNA repair genes were also examined. Two genes involved in base excision repair, Thymine DNA glycosylase (Tdg) and Apurinic/apyrimidinic endonuclease 1 (Apex1), were increased in FD C57B1/6 compared to FD BALB/c mice suggesting increased DNA repair capacity.
These results support the evidence that dietary folate deficiency promotes intestinal tumor formation possibly through increased DNA damage, with subsequent defects in DNA repair.
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George, Lena. "Spontaneous abortion : risk factors and measurement of exposures /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-921-1/.
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Bilousova, Ganna. "The role of impaired cellular fitness in leukemia promotion /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2007.
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Thesis (Ph.D. in Biochemistry) -- University of Colorado Denver, 2007.Typescript. Includes bibliographical references (leaves 137-161). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;
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Chen, Zhoutao 1972. "A mouse model for methylenetetrahydrofolate reductase deficiency and biochemical studies of the recombinant human enzyme /." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37878.
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Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. Nutritional and/or genetic disruptions in homocysteine metabolism can cause hyperhomocysteinemia. Mild methylenetetrahydrofolate reductase (MTHFR) deficiency due to the 677C → T mutation in the MTHFR gene is the most common genetic cause of hyperhomocysteinemia. The 677C → T variant is associated with an increased risk for neural tube defects, pregnancy complications, schizophrenia and Down syndrome, and with a decreased risk for colon cancer and leukemia. This variant is also a potential risk factor for vascular disease. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. We have generated mice with a knockout of the Mthfr gene. The Mthfr-deficient mice exhibit hyperhomocysteinemia and decreased methylation capacity. The Mthfr+/- mice appear normal, whereas the Mthfr-/- mice are smaller and have reduced survival. Abnormal external granule neuron development associated with increased cell death in the cerebellum was observed in the Mthfr-/- mice.Evidence for cardiovascular pathology was obtained in several ways. Impaired aortic relaxation response to acetylcholine was seen in the Mthfr +/- mice fed a high methionine diet. Both Mthfr+/- and Mthfr-/- mice fed a low folate high methionine diet developed myocardial fibrosis in the left ventricle. Abnormal lipid deposition in the proximal portion of the aorta was observed in older Mthfr+/- and Mthfr-/- mice. After crossing Mthfr -deficient mice with apoE-null mice, we demonstrated that MTHFR deficiency promoted atherogenesis and its progression in the apoE-null mice.
Gene expression in brain of Mthfr-deficient mice was investigated via microarray analysis. Five genes with altered expression in the brain of Mthfr-/- mouse were validated by RT-PCR. In biochemical studies of human MTHFR, both FAD and folate were shown to stabilize the purified recombinant wild type and mutant MTHFRs from the baculovirus expression system against heat inactivation. The effect of folate appeared to be secondary to that of FAD, and S-adenosylmethionine (SAM) inhibited purified wild type and mutant MTHFRs with similar efficiency.
This dissertation will significantly contribute to our understanding of the role of MTHFR in human disease.
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Vesna, Vasić. "Folna kiselina u terapiji depresivnog poremećaja." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2014. http://www.cris.uns.ac.rs/record.jsf?recordId=87827&source=NDLTD&language=en.
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Cilj ovog istraživanja je bio da se utvrdi nivo folne kiseline u serumu (fiziološka vrednost je od 16,31 do 34,88 nmol/l) i proceni težina kliničke slike instrumentima kliničke procene (HAMD 17 i 21, MADRS i CGI skala) u populaciji bolnički lečenih pacijenata, koji boluju od teške depresivne epizode, ili rekurententog depresivnog poremećaja, i njihov odgovor na inicijalnu antidepresivnu terapiju sprovođenu prema smernicama nacionalnog vodiča. Odgovor na antidepresivnu terapiju je određivan nakon četiri i osam nedelja lečenja u odnosu na nivo folne kiseline i prema nadoknadi folne kiseline u dozi od 15 mg dnevno (kod pacijenata koji nisu adekvatno odreagovali na terapiju). Smatrano je da je antidepresivni odgovor adekvatan ukoliko je utvrđena redukcija skora na HAMD (17, 21) i MADRS za 50%. Istraživanje je obuhvatilo 102 pacijenata (69 osoba ženskog pola i 33 osobe muškog pola) starosti između 18 i 70 godina života. Utvrđeno je da je snižen nivo folne kiseline u krvi imalo 41,2% pacijenata. X2 testom je ustanovljeno da postoje značajne razlike nivoa folne kiseline u krvi u odnosu na pol. Snižen nivo folne kiseline je zastupljeniji kod osoba muškog pola. Pacijenati sa sniženim nivoom folne kiseline su imali inicijalno značajno više skorove na skalama kliničke procene i izostanak adekvatnog terapijskog odgovora u četvrtoj nedelji lečenja. U osmoj nedelji lečenja se ta razlika u terapijskom odgovoru izgubila. Utvrđena je statistički značajna razlika u skorovima na HAMD (17) i MADRS u tri merenja u zavisnosti od nivoa folne kiseline i nadoknade uz upotrebu višesmerne mešovite analize varijanse (ANOVA). Utvrđeno je da postoji značajan glavni efekat merenja (skorovi se značajno razlikuju od merenja do merenja), i značajan efekat interakcije merenja i nadoknade.The aim of this paper is to establish the levels of folic acid in serum (physiological values is from 16.31 to 34.88 nmol/l) and the assessment of seriousness of clinical picture by clinical assessment instruments (HAMD 17 and 21, MADRS and CGI scales) in the population of hospitalized patients suffering from severe depressive episodes, or recurrent depressive disorder, and their response to the initial anti-depressant therapy administered according to national guidelines. The response to anti-depressant therapy was determined after four or eight weeks of treatment in relation to the levels of folic acid and according to recuperation of folic acid in the dose of 15 mg daily (in patients who did not react adequately to the therapy). It was believed that the anti-depressive response was satisfying in case of the established score reduction on HAMD (17, 21) and MADRS for 50%. The research encircled 102 patients (69 of whom female patients and 33 males) aged between 18 and 70. A reduced level of folic acid in blood was found in 41.2% of the patients. By X2 test determined that there were significant differences in the levels of folic acid in relation to the patient gender. A reduced level was more found in male patients. The patients with reduced levels of folic acid had initially significantly higher scores on clinical assessment scales and the lack of an adequate therapeutic response in the fourth week of the treatment. In the eighth week of the treatment that difference vanished in therapeutic response. A statistically significant difference was determined on HAMD (17) and MADRS during three measurements depending on the levels of folic acid and its recuperation by using a multiway diverse analysis of variance (ANOVA). It was determined that there is a significant central effect of measurements (scores significantly differ from measurement to measurement), as well as an effect of interaction of measurements and the recuperation.
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Chan, Jessica See Wen 1984. "The role of 5,10-methylenetetrahydrofolate reductase and nutritional deficiencies in cardiac development /." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111553.
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Disruptions in folate metabolism are known to increase the risk for neural tube defects (NTD) and this is preventable by folic acid supplementation. However, the relationship between folate metabolism and cardiac development remains unclear. The interaction between other folate pathway nutrients, choline and riboflavin, and folate metabolism was studied in a murine model of methylenetetrahydrofolate reductase (MTHFR) deficiency. Maternal choline deficiency, riboflavin deficiency and MTHFR deficiency adversely affected embryonic or heart development. The promoters of MTHFR were also examined for interactions with GATA-4, TBX5, MEF2A and NKX-2.5, known transcription factors of cardiac development. Upstream promoter activity was increased in the presence of GATA-4 and this interaction was further enhanced upon the addition of MEF2A. TBX5 appeared to decrease upstream promoter activity. GATA-4 modestly increased downstream promoter activity. These results highlight the importance of adequate nutrient intake during pregnancy and provide a link between folate metabolism and cardiac development.
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Tshitaudzi, Gilbert Tshimangadzo. "Nutritional status of pregnant women (under 20 years of age) with special emphasis on iron and folic acid status." Thesis, Stellenbosch : Stellenbosch University, 2003. http://hdl.handle.net/10019.1/53529.
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Thesis (Mnutr)--University of Stellenbosch, 2003.ENGLISH ABSTRACT: Pregnancy and growth have been found to have a detrimental effect on the micronutrient status of adolescent girls. Dietary studies in adolescents have shown serious shortfalls in their dietary iron and folate intake. The competition for nutrients between the fetus and a pregnant adolescent may carry the risk of complications such as intrauterine growth retardation, pre-eclampsia, both maternal and fetal intrapartum mortality, the increased risk of birth injuries and low birth weight. The aim of the study was to assess the nutritional status of rural black, pregnant teenagers attending the antenatal clinic at Siloam Hospital in the Limpopo Province, with special emphasis on iron and folic acid intake, and evaluation of the newborn babies in terms of weight status and neural tube defects. The nutritional status was determined in 40 pregnant and 40 non-pregnant adolescent girls. The pregnant girls were selected during their first visit to the antenatal clinic, and the non-pregnant girls were selected from nearby schools. The demographic and dietary history questionnaires were used to collect information from the subjects. The dietary intake of the subjects was collected by the completion of a pre-tested quantified food frequency questionnaire. The anthropometric questionnaire was used to get information from the pregnant adolescents and the control group. The infant anthropometric measurements questionnaire provided information on the infant and the outcome of birth. Blood was collected from the pregnant adolescent girls and the control subjects. Anaemia was observed in 57.5% of the pregnant and 27.5% of the non-pregnant adolescents (haemoglobin
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Eneroth, Hanna. "Infant Anemia and Micronutrient Status : Studies of Early Determinants in Rural Bangladesh." Doctoral thesis, Uppsala universitet, Internationell mödra- och barnhälsovård (IMCH), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-143058.
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Anemia and micronutrient deficiencies in infancy are common in low-income settings. These are partly due to maternal malnutrition and may impair child health and development. We studied the impact of maternal food and micronutrient supplementation, duration of exclusive breastfeeding (EBF), growth and infection on infant anemia and micronutrient status. In the MINIMat trial in Matlab, Bangladesh, pregnant women were randomized to Early or Usual promotion of enrolment in a food supplementation program and to one of three daily micronutrient supplements. Capsules containing 400µg folic acid and (a) 30 mg iron (Fe30Fol), (b) 60 mg iron (Fe60Fol), (c) 30 mg iron and other micronutrients (MMS) were provided from week 14 of gestation. Capsule intake was assessed with the eDEM device recording supplement container openings. Blood samples (n=2377) from women at week 14 and 30 were analyzed for hemoglobin (Hb). Duration of EBF and infant morbidity was based on monthly maternal recalls. Infants were weighed and measured monthly. Blood samples (n=1066) from 6-months-old infants were analyzed for Hb and plasma ferritin, zinc, retinol, vitamin B12 and folate. In women, Hb increase per capsule reached a plateau at 60 Fe60Fol capsules, indicating that nine weeks of daily supplementation produced maximum Hb response. Anemia was common (36%) at capsule intakes >60 indicating other causes of anemia than iron deficiency. In infants, vitamin B12 deficiency prevalence was lower in the MMS (26.1%) than in the Fe30Fol group (36.5%), (p=0.003) and zinc deficiency prevalence was lower in the Usual than in the Early group. There were no other differential effects of food or micronutrient supplementation on infant anemia or micronutrient status. Infants exclusively breast-fed for 4-6 months had a higher mean plasma zinc concentration (9.9±2.3 µmol/L) than infants exclusively breast-fed for <4 months (9.5±2.0 µmol/L), (p< 0.01). No other differences in anemia, iron or zinc status were observed between EBF categories. Infection, low birth weight and iron deficiency were independent risk factors for infant anemia. Regardless of studied interventions, prevalence of anemia (43%), deficiency of zinc (56%), vitamin B12, vitamin A (19%) and iron (22%) in infancy was high and further preventive strategies are needed.MINIMat
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Tran, Pamela. "Regulation of mouse methylenetetrahydrofolate reductase (Mthfr) and its role in early development." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38426.
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Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, a methyl donor for conversion of homocysteine to methionine. A common thermolabile variant causes mild MTHFR deficiency, induces mild hyperhomocysteinemia when plasma folate levels are low and increases risk for neural tube defects (NTD) and pregnancy loss. To increase our understanding of Mthfr regulation, the 5' and 3' regions of the mouse cDNA and gene were characterized. These studies revealed two major promoters, an internal coding exon in the 5'UTR, alternative transcriptional and translational start sites and alternative splicing and polyadenylation. These data suggest that Mthfr regulation is likely to be complex. To investigate the role of Mthfr in NTD, several approaches were taken. First, folate and MTHFR co-factor, flavin adenine dinucleotide, were shown to stabilize normal and thermolabile MTHFR during heat inactivation, suggesting that folate might prevent hyperhomocysteinemia in individuals with thermolabile enzyme through protein stabilization. Next, in situ hybridization of neurulating mouse embryos showed that Mthfr is expressed in the forebrain, hindbrain, branchial arches, blood vessels, gut, and importantly, in the ventral part of the neural tube. Mthfr+/- mice were then used as a model of mild deficiency to address the effects of maternal and embryonic Mthfr deficiency on development. When combined with inadequate dietary folate, Mthfr +/- pregnant females showed a two-fold higher rate of pregnancy loss than Mthfr+/+ pregnant females. As well, a percentage of day 10.5 embryos from only the Mthfr+/- pregnant females were underdeveloped by 2 days. These effects were not apparent when dietary folate was sufficient, consistent with a genetic-nutritional interactive effect. Finally, folate metabolism was investigated in an NTD model, the curly-tail (ct) mouse, since the ct defect and Mthfr were mapped in close proximity. However, Mthfr sequence in ct mice was simila
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Nägga, Katarina. "Aspects on clinical diagnosis of dementia, with focus on biological markers / Katarina Nägga." Linköping, 2004. http://www.bibl.liu.se/liupubl/disp/disp2004/med839s.pdf.
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Gutierrez, Cristiane Minot. "Etanol, deficiência de ácido fólico e associação desses dois fatores durante a gestação de camundongos swiss." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/17/17143/tde-30032007-154911/.
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Embora os efeitos teratogênicos do etanol sejam bem conhecidos, ele ainda é um agente exógeno muito usado por mulheres em idade reprodutiva e sabe-se que ele interfere com o transporte, absorção e metabolismo do ácido fólico. O objetivo deste trabalho foi determinar os efeitos da administração de etanol, da deficiência do ácido fólico na dieta e da associação desses dois fatores durante a gestação de camundongos Swiss. O estudo foi feito com dois experimentos, no primeiro examinou-se a influência do etanol diluído em salina a 25% (v/v) em doses baixa (0,4g/Kg de peso corporal) e alta (4,0g/Kg de peso corporal) em animais alimentados com ração comercial e no segundo a influência do etanol nas mesmas doses em animais alimentados com dieta deficiente em folato. Em ambos os experimentos os animais foram divididos em 6 grupos com 6 animais cada: C= controle; Eb= etanol baixa dose; Ea= etanol alta dose (Experimento 1) e DF= controle da deficiência de folato; DFEb= deficiência de folato + etanol baixa dose; DFEa= deficiência de folato + etanol alta dose (Experimento 2). Os animais dos Grupos C e DF receberam apenas salina. Etanol e salina foram administrados por via intraperitoneal, em três dias consecutivos da gestação: 7°, 8° e 9°. A eutanásia foi realizada em câmara de CO2 no 18º dia gestacional e os cornos uterinos foram retirados por cesárea para observação e contagem dos fetos vivos, mortes fetais tardias e reabsorções. Anomalias congênitas foram encontradas apenas no Grupo Ea, representadas por defeito de fechamento do tubo neural isolado (6,45%), agenesia de membros e cauda (6,45%), defeito de fechamento do tubo neural associado a defeito da face média (2,15%) e gastrosquise (1,08%). Foi observada entre os grupos variação no número de fetos vivos (C= 98,97%; Eb= 97,98%; Ea= 87,74%; DF= 90,91%; DFEb = 72,22%; DFEa= 61,39%), de reabsorções (C= 1,03%; Eb= 2,02%; Ea= 1,89%; DF= 8,08%; DFEb= 14,44%; DFEa= 18,81%) e de mortes fetais tardais (C= 0; Eb= 0; Ea= 10,38%; DF= 1,01%; DFEb= 13,33%; DFEa= 19,80%). Houve variação no comprimento vértice-sacral fetal (machos/fêmeas: C= 2,6/2,5cm; Eb= 2,5/2,5cm; Ea= 2,4/2,3cm; DF=2,4/2,3cm; DFEb= 2,0/2,0cm; DFEa= 1,9/1,8cm), no peso corpóreo fetal (machos/fêmeas: C= 1,50/1,40g; Eb= 1,49/1,40g; Ea= 1,31/1,19g; DF= 1,28/1,17g; DFEb= 0,81/0,82g; DFEa= 0,83/0,73g), no diâmetro placentário (machos/fêmeas: C=0,8/0,8cm; Eb= 0,8/0,7cm; Ea= 0,8/0,7cm; DF= 0,8/0,8cm; DFEb= 0,8/0,8cm; DFEa= 0,7/0,7cm) e no peso placentário (machos/fêmeas: C= 0,14/0,12g; Eb= 0,14/0,11g; Ea= 0,12/0,10g; DF= 0,13/0,11g; DFEb= 0,09/0,09g; DFEa= 0,09/0,09g). Os resultados indicam que alta dose de etanol durante o consumo de ração comercial é mais deletério que baixa dose, pois além de provocar anomalias congênitas, causou restrição do crescimento intra-uterino e placentário e produziu mortes fetais tardias. A deficiência de ácido fólico, por si só, também é deletéria, interferiu com o desenvolvimento fetal e placentário e produziu reabsorções. A associação da deficiência de folato e etanol agravou ainda mais esse desenvolvimento e produziu um maior número de reabsorções e mortes fetais tardias. Além disso, na deficiência de folato, baixa dose de etanol foi tão deletéria quanto alta dose, indicando que a nutrição materna tem um papel fundamental no desenvolvimento fetal. Dessa forma, a ação sinérgica de dois fatores isolados, etanol e deficiência de ácido fólico, permite reforçar a noção do risco humano em condições semelhantes, já que mulheres jovens tendem a apresentar mais deficiência de ácido fólico e estão mais expostas a comportamentos que levam ao consumo de etanol.In spite of the well known teratogenic effect of ethanol, it is still the most consumed exogenous abuse substance by women of reproductive age. Ethanol also impairs the absorption, transport and metabolism of folic acid. The aim of this study was to investigate the effects of ethanol, dietary deficiency of folic acid and the association of both on the outcome of Swiss mouse pregnancy. We aimed to analyze the result of low (0.4g/Kg) and high (4g/Kg) of ethanol dose diluted in saline 25% (v/v) given to animals fed a commercial diet (Experiment I) or its effect on mice fed a folate-free diet (Experiment II). The pregnant mice were divided in 6 groups of 6 animals each: (Experiment I) C=Control; low dose ethanol (Eb); high dose ethanol (Ea); (Experiment II) DF= Control of Folate deficiency; DFEb= Folate deficiency plus low dose ethanol, and DFa= Folate deficiency plus high dose ethanol. On the 7th, 8th and 9th gestational day (GD) either saline (Groups C and DF) or ethanol (other groups) were administered by intraperitoneal injection and the sacrifice was on the 18th GD on a CO2 chamber after which the uterine horns were harvested by cesarean section for examination and counting of live fetuses, late fetal death and resorptions. Congenital anomalies were found only in Group Ea, represented by isolated Neural Tube Defect (NTD) (6.45%), limb and tail agenesis (6,45%), NTD plus middle face anomaly (2,15%) and gastroschisis (1,08%). The number of live fetuses (C= 98,97%; Eb= 97,98%; Ea= 87,74%; DF= 90,91%; DFEb = 72,22%; DFEa= 61,39%), resorptions (C= 1,03%; Eb= 2,02%; Ea= 1,89%; DF= 8,08%; DFEb= 14,44%; DFEa= 18,81%) and late fetal death (C= 0; Eb= 0; Ea= 10,38%; DF= 1,01%; DFEb= 13,33%; DFEa= 19,80%) differed among groups. It was also noted a gender related variation in crown-rump length (male/female: C= 2,6/2,5cm; Eb= 2,5/2,5cm; Ea= 2,4/2,3cm; DF=2,4/2,3cm; DFEb= 2,0/2,0cm; DFEa= 1,9/1,8cm), body weight (male/female:C= 1,50/1,40g; Eb= 1,49/1,40g; Ea= 1,31/1,19g; DF= 1,28/1,17g; DFEb= 0,81/0,82g; DFEa= 0,83/0,73g), placental diameter (male/female: C=0,8/0,8cm; Eb= 0,8/0,7cm; Ea= 0,8/0,7cm; DF= 0,8/0,8cm; DFEb= 0,8/0,8cm; DFEa= 0,7/0,7cm) and placental weight (male/female: C= 0,14/0,12g; Eb= 0,14/0,11g; Ea= 0,12/0,10g; DF= 0,13/0,11g; DFEb= 0,09/0,09g; DFEa= 0,09/0,09g). Our results indicate that high ethanol dose given to pregnant mice fed on a commercial diet is more deleterious than low dose because it induced congenital anomalies and intrauterine growth restriction, decreased placental weight and diameter and increased fetal death. Isolated folic acid deficiency is harmful to gestation, decreasing fetal and placental development and inducing resorptions. The association of ethanol and folic acid deficiency increased the developmental impairment and induced more resorption and late fetal death. In folate deficient mice, low dose of ethanol was as detrimental as high dose indicating that maternal nutritional status plays a major role in fetal development. In conclusion, the synergistic action of two factors, ethanol and folate deficiency, may help to understand the human risk in similar situation, as young women are prone to this vitamin deficiency and are more exposed to a behavior that stimulate alcohol intake.
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Guimarães, José Luiz Miranda 1959. "Influência de polimorfismos gênicos do metabolismo do ácido fólico na susceptibilidade ao adenocarcinoma colorretal esporádico = Influence of genetic polymorphisms in metabolism of folic acid in susceptibility to sporadic colorectal adenocarcinoma." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308622.
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Orientadores: Carmen Silvia Passos Lima, Maria de Lourdes Setsuko AyrizonoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O desenvolvimento de câncer colorretal (CCR) é resultado de uma complexa interação de variáveis, incluindo elementos externos, como a exposição a agentes ambientais e dietéticos, e fatores internos, de natureza somática ou hereditária. Não está estabelecido se genótipos de polimorfismos de baixa penetrância em genes relacionados com o metabolismo do ácido fólico, como o metilenotetrahidrofolato redutase (MTHFR C677T e MTHFR A1298C), o metionina sintase (MTR A2756G), o metionina sintase redutase (MTRR A66G) e o timidilato sintase (TS 2R3R), estão associados com o risco de ocorrência da doença ou com suas manifestações clínicas. Portanto, o objetivo deste estudo foi verificar se esses polimorfismos gênicos influenciam o risco de ocorrência do adenocarcinoma colorretal esporádico (ACRE) e suas manifestações clínicas e biológicas em pacientes da região sudeste do Brasil. Foram avaliados 113 pacientes com ACRE e 188 controles, considerando os aspectos clínicos como a idade, o sexo, a raça, a localização, o grau de diferenciação do tumor, o estágio e os genótipos de cada gene. Os genótipos dos polimorfismos dos genes MTHFR, MTR, MTRR e TS foram avaliados por meio da reação em cadeia da polimerase (PCR) seguida ou não por digestão enzimática. O significado estatístico das diferenças entre grupos foi calculado por meio do teste da probabilidade exata de Fisher ou qui-quadrado. As determinações dos riscos de ocorrência do ACRE, a que pacientes e controles foram submetidos, foram obtidas por meio das razões das chances (ORs) e calculadas considerando um intervalo de confiança de 95%. Portadores dos genótipos MTRR 66AG+GG, do MTHFR 1298AC+CC+677CT+TT, do MTHFR 677CT+TT+MTR 2756AG+GG, do MTHFR 1298AC+CC + 677CT+TT + MTR 2756AG+GG e MTHFR 1298AC+CC + 677CT+TT + MTRR 66AG+GG apresentaram riscos 1,99, 3,26, 2,22, 10,92 e 14,88 vezes maiores, respectivamente, de desenvolver ACRE do que os outros. Além disso, os indivíduos com o genótipo MTHFR 677CT+TT e os genótipos MTR 2756AG+GG tiveram um risco de 2,12 e 1,42 vezes maior de desenvolver ACRE com idade menor do que 50 anos. Afro-Brasileiros com o genótipo GG do polimorfismo MTRR A66G tiveram risco 1,98 vezes maior de desenvolver ACRE, e indivíduos com o genótipo MTR 2756AG+GG e os genótipos MTHFR 677CT+TT estiveram sob risco 2,11 e risco 1,62 vezes maiores de ocorrência de tumores indiferenciados e avançados, respectivamente, do que os demais. Portadores dos genótipos MTHFR 1298AC+CC e MTHFR 1298AC+CC + MTRR 66AG+GG estiveram sob riscos 1,42 e 3,07 vezes maiores de tumor no reto, respectivamente, enquanto que portadores dos genótipos MTHFR 677CT+TT e MTHFR 677CT+TT + TS 2R3R+3R3R estiveram sob riscos 1,55 e 5,39 vezes maiores de tumor de cólon, respectivamente, do que portadores dos genótipos selvagens. Estes dados sugerem que polimorfismos dos genes MTHFR, MTR, MTRR e TS, que codificam enzimas que participam do metabolismo do ácido fólico, especialmente em combinação, têm papéis consistentes para o risco de desenvolver ACRE em indivíduos da região sudeste do Brasil
Abstract: The development of colorectal cancer (CRC) is the result of a complex interaction of variables, including external factors such as exposure to environmental agents and dietary factors and internal factors, whether somatic or hereditary. Is not been established genotypes with low penetrance polymorphisms in genes related to metabolism of folic acid such as methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS 2R3R), are associated with the risk of the disease or its clinical manifestations. Therefore, the aim of this study was to determine whether these genetic polymorphisms influence the risk of sporadic colorectal adenocarcinoma (SCA) and their clinical and biological manifestations in patients from southeast Brazil. For this, we analyzed 113 patients with SCA and 188 controls, considering the clinical aspects such as age, sex, race, location, stage, degree of tumor differentiation and the genotypes of each gene described above. The genotypes of the polymorphisms of the MTHFR, MTR, MTRR and TS were assessed by polymerase chain reaction (PCR) and enzyme digestion. The statistical significance of differences between groups was calculated using the probability test of Fisher's exact or chi-square. Determination of the risks of SCA, the patients and controls were submitted, was obtained through the odds ratios (ORs) and calculated assuming a range of 95%. Carriers of the MTRR 66AG + GG, the MTHFR 1298AC+CC + 677CT+TT, the MTHFR 677CT+TT + MTR 2756AG+GG, the MTHFR 1298AC+CC + 677CT+TT + MTR 2756AG+GG, and the MTHFR 1298AC+CC + 677CT+TT + MTRR 66AG+GG genotypes had a 1.99, a 3.26, a 2.22, a 10.92 and a 14.88-fold increased risks for SCA than others, respectively. In addition, individuals with the MTHFR 677CT+TT and the MTR 2756AG+GG genotypes had a 2.12 and a 1.42-fold increased risks for SCA diagnosed under 50 years. African-Brazilians with the MTRR 66GG genotype had a 1.98-fold increased risk for SCA, and individuals with the MTR 2756AG+GG and the MTHFR 677CT+TT genotypes were under a 2.11 and a 1.62-fold increased risks for undifferentiated and advanced tumors, respectively, than others. Carriers of the MTHFR 1298AC+CC and the MTHFR 1298AC+CC + MTRR 66AG+GG genotypes had a 1.42 and a 3.07-fold increased risks for rectal tumor, respectively, while carriers of the MTHFR 677CT+TT and the MTHFR 677CT+TT + TS 2R3R+3R3R genotypes had a 1.55 and a 5.39-fold increased risks for colon tumor, respectively, than carriers of the wild genotypes. This data suggest that polymorphisms of genes MTHFR, MTR, MTRR and TS, which encode folate-dependent enzymes, particularly in combination, have consistent roles for SCA risk in southeastern Brazil
Doutorado
Fisiopatologia Cirúrgica
Doutor em Ciências
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Carvalho, Beatriz Assis. "Estado nutricional de ferro de lactentes atendidos em unidades básicas de saúde." Universidade Federal de Goiás, 2015. http://repositorio.bc.ufg.br/tede/handle/tede/4498.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
To evaluate the nutritional status of iron and its related factors in children 12 to 15 months assisted in Health Units in Goiânia, Goiás. METHODS: This is a cross-sectional study nested in research "Effectiveness of home fortification with vitamins and minerals in the prevention of iron deficiency and anemia in children under one year of age: a multicenter study in Brazilian cities ". The study was conducted with 230 children, aged between 12 and 15 months, assisted in Health Units in Goiânia, from June 2012 to February 2013. The prevalence of iron deficiency, iron deficiency anemia and anemia were assessed by the plasma means concentration of ferritin and transferrin receptor, hemoglobin and C-reactive protein. Multiple linear regression was used to estimate the effect of independent variables on the log plasma concentrations of ferritin. These variables were socioeconomic, demographic, maternal, pregnancy, anthropometric, breastfeeding, use of supplement, and biochemical parameters. RESULTS: Regarding the iron status, iron deficiency and iron deficiency anemia prevalence was 14.1% and 1.5%, respectively. Also, anemia prevalence was 5.6% of the infants studied. The predictors of ferritin were folate, vitamin B12 and the use of iron supplement at the time of collection, which each unit raised the log plasma concentration of ferritin in 0.009 mg/L, 0.001 mg/L and 0.315 mg/L, respectively. CONCLUSION: The results of this study showed low prevalence of iron deficiency and anemia in children studied. The use of iron supplements and serum concentrations of vitamin B12 and folate correlated ferritin concentrations and consequently the iron status in this population. Keywords: Iron Deficiency; Ferritins; Receptors, transferrin; Folic Acid; Vitamin B 12; Infant.
Avaliar o estado nutricional de ferro e os seus fatores relacionados em crianças de 12 a 15 meses atendidas em Unidades Básicas de Saúde de Goiânia, Goiás. MÉTODOS: Trata-se de um estudo transversal aninhado a pesquisa “Efetividade da fortificação caseira com vitaminas e minerais na prevenção da deficiência de ferro e anemia em crianças menores de um ano: estudo multicêntrico em cidades brasileiras”. O trabalho foi realizado com 230 crianças, de 12 e 15 meses, atendidas em Unidades Básicas de Saúde de Goiânia, no período de junho de 2012 a fevereiro de 2013. As prevalências de deficiência de ferro, anemia por deficiência de ferro e anemia foram avaliadas por meio da concentração plasmática de ferritina e receptor de transferrina, hemoglobina e proteína C-reativa. Foi utilizada regressão linear múltipla para estimar o efeito de variáveis independentes sobre o log das concentrações plasmáticas de ferritina. Estas variáveis foram condições socioeconômicas, demográficas, maternas, gestacionais, antropomêtricas, amamentação, uso de suplemento, e parâmetros bioquímicos. RESULTADOS: Com relação ao estado nutricional de ferro, as prevalências de deficiência de ferro e anemia por deficiência de ferro foram de 14,1% e 1,5% respectivamente. Além disso, foi encontrada prevalência de 5,6% de anemia nos lactentes estudados. Os fatores associados a ferritina foram o folato, a vitamina B12 e o uso de suplemento de ferro no momento da coleta, os quais cada unidade elevaram o log da concentração plasmática de ferritina em 0,009 μg/L, 0,001 μg/L e 0,315 μg/L, respectivamente. CONCLUSÃO: Os dados do presente estudo evidenciaram baixas prevalências de deficiência de ferro e anemia nas crianças estudadas. O uso de suplemento de ferro e as concentrações séricas das vitaminas B12 e folato correlacionaram-se as concentrações de ferritina e consequentemente, o estado nutricional de ferro nesta população.
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Stanislava, Nikolić. "Uticaj metformina na nastanak deficita vitamina B12 kod pacijenata sa tipom 2 dijabetes melitusa." Phd thesis, Univerzitet u Novom Sadu, Medicinski fakultet u Novom Sadu, 2019. https://www.cris.uns.ac.rs/record.jsf?recordId=110042&source=NDLTD&language=en.
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Prema podacima iz 2011 godine, u Srbiji je približno 630 000 ljudi (8,6%) obolelo od dijabetes melitus-a, a procenjuje se da će taj broj porasti na 730 000 (10,2%) do 2030 godine. Preko 90% obolelih ima tip 2 dijabetes melitus (T2DM). Prva linija medikamentne terapije predstavljaju bigvanidi čiji je najznačajniji predstavnik metformin. Prema literaturnim podacima, u oko 10-30% sluĉajeva, kontinuirana upotreba metformina ima za posledicu smanjenu intestinalnu apsorpciju vitamina B12. Tačan patofiziološki mehanizam koji dovodi do metforminom indukovane malapsorpcije vitamina B12 nije u potpunosti ispitan i poznat i postoji nekoliko aktuelnih teorija s ciljem objašnjenja ovog kompleksnog problema. Cilj rada je bio utvrđivanje nivoa, dinamike, trenda i učestalosti promena vitamina B12, holotranskobalamina (B12 aktiv), homocisteina i folne kiseline tokom kontinuirane primene metformina tokom godinu dana. Studija praćenja je sprovedena u Centru za laboratorijsku medicinu a u saradnji sa Klinikom za endokrinologiju, dijabetes i bolesti metabolizma, Kliničkog centra Vojvodine. Ovom studijom je obuhvaćeno 50 ispitanika obolelih od T2DM a u momentu uvođenja metformina. Svim ispitanicima je određivana koncentracija vitamina B12, B12 aktiva, homocisteina i folne kiseline, u momentu uvođenja terapije kao i nakon 4, 8 i 12 meseci primene metformina. Za dvanaest meseci kontinuirane primene metformina, utvrđen je kontinuirani pad i redukcija vrednosti ukupnog vitamina B12 za 25.29 %, odnosno vrednosti B12 aktiva za 23.26 %. U toku ispitivanja, utvrđen je kontinuirani trend porasta vrednosti homocisteina u krvi, s statistički značajnim porastom vrednosti homocisteina nakon osam meseci primene metformina. Pošavši od predpostavki da metformin istovremeno blokira apsorpciju vitamina B12 u gastrointestinalnom traktu kao i raspoloživost iz postojećih, tkivnih rezervi, zatečene količine ovog vitamina u ciljnim ćelijama se postepeno redukuju i troše, rezultujući krajnjem snižavanju nivoa metabolički aktivnih oblika kobalamina, te posledičnoj akumulaciji homocisteina kako u ćelijskom, tako i u vanćelijskom prostoru. Na osnovu dobijenih rezultata ispitivanja može se predložiti opservacija nivoa ukupnog vitamina B12 i homocisteina u krvi pre uvođenja metformina u terapiju tipa 2 dijabetes melitusa kao i dvanaest meseci nakon toga. Na osnovu nivoa jednogodišnjeg pada koncentracija ukupnog vitamina B12, porasta koncentracija homocisteina, kao i drugih kliničkih i laboratorijskih parametara, može se razmatrati opcija uvođenja supstitucione terapije vitaminom B12 ili dalja opservacija nivoa vitamin B12 u krvi i ćelijskom prostoru.According to data from 2011, in Serbia, approximately 630.000 people (8.6%) were diagnosed with diabetes mellitus, and it is estimated that this number will increase to 730.000 (10.2%) by 2030. Over 90% are type 2 diabetes mellitus (T2DM) patients. The first line of medication therapy is metformin. According to the literature data, in about 10-30% of cases, continuous use of metformin causes impared intestinal absorption of vitamin B12. The exact pathophysiological mechanism leading to metformin induced malabsorption of vitamin B12 has not been fully known, and there are several current theories to explain this complex problem. The aim of this study was to determine the level, dynamics, trend and frequency of changes in blood levels of total vitamin B12, holotranscobalamin (B12 active), homocysteine and folic acid during continuous application of metformin, over a year. The study was carried out at the Center of Laboratory Medicine in cooperation with the Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Vojvodina. This study included 50 T2DM patients at the time of the introduction of metformin therapy. Levels of vitamin B12, holotranscobalamin, homocysteine and folic acid are determined before and after 4, 8 and 12 months of metformin administration, to all subjects. After a year of metformin use, the level of total vitamin B12 has been reduced by 25.29%, as well as holotranskobalamin by 23.26%. During the study, a continuous elevation of homocysteine levels was determined, with statistically significant increase in homocysteine values after eight months of metformin administration. Starting from the assumption that metformin blocks the absorption of vitamin B12 in the gastrointestinal tract as well as the availability of existing tissue reserves, the amount of this vitamin in the target cells is gradually reduced, resulting in an extremely low level of metabolically active forms of this vitamin and the consequent accumulation of homocysteine in intracellular and extracellular space. On the basis of the obtained test results, it may suggest observation of the level of total vitamin B12 and homocysteine prior to the introduction of metformin in T2DM therapy and after one year thereafter. Based on the level of one-year decline of total vitamin B12 and the increase of homocysteine concentrations, as well as other clinical and laboratory parameters, substitution therapy with vitamin B12 or further monitoring of laboratory parameters of vitamin B12 metabolism may be proposed.
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Paula, Bruna Morais Faleiros de. "Padrões de metilação e expressão do gene Pomc na prole de ratas submetidas às dietas deficiente e suplementada com ácido fólico." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17138/tde-30032017-093539/.
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A epigenética é uma subárea da Genética, na qual são estudados mecanismos que são essenciais para o adequado desenvolvimento dos mamíferos, sendo que, alterações neste estágio podem levar a vários distúrbios metabólicos, como a obesidade. Atualmente a obesidade é um grave problema de saúde pública mundial, tem origem multifatorial envolvendo tanto fatores ambientais quanto genéticos. Existem alguns genes que estão envolvidos com a obesidade, como por exemplo, o gene da pró-opiomelanocortina (POMC). O objetivo do presente projeto de pesquisa é investigar os padrões de expressão e metilação do gene Pomc na prole de ratas submetidas às dietas deficiente e suplementada com ácido fólico. Os animais utilizados foram ratos Wistar. O estudo envolveu filhotes (n=24) machos e fêmeas que foram desmamados com a mesma dieta de suas respectivas mães, sendo três grupos de tratamento, o grupo controle (2,0 mg de ácido fólico/kg de ração), o grupo deficiente (0,5 mg de ácido fólico/kg de ração) e o grupo suplementado (8 mg de ácido fólico/kg de ração). Foram coletadas amostras do núcleo arqueado do hipotálamo, a partir das quais foram extraídos DNA, RNA e proteínas utilizando kits comerciais seguindo o protocolo do fabricante. Com o DNA foi realizada a análise do padrão de metilação. O mRNA foi utilizado para a análise da expressão gênica, por PCR em tempo real, pelo sistema TaqMan® (Life Technologies(TM)). O estudo de proteômica foi realizado por Western blotting. De modo geral, observou-se que o peso corpóreo dos filhotes machos não apresentou diferença estatística entre os grupos. O consumo de ração do grupo deficiente em ácido fólico foi estatisticamente (p = 0,03) maior do que o grupo controle. Em relação aos filhotes fêmeas observou-se que o peso corpóreo do grupo suplementado foi estatisticamente (p = 0,01) maior do que o grupo controle, e referente ao consumo de ração, não houve diferença estatística significativa entre os grupos de tratamento. As análises de peso cerebral, expressão gênica, metilação e expressão proteica de Pomc não apresentaram diferenças estatísticas significativas entre os grupos de tratamento de ambos os sexos. Conclui-se que a intervenção com dietas com diferentes concentrações de ácido fólico não ocasionou alterações significativas na prole, em relação ao estudo de proteômica e aos padrões de metilação e expressão do gene Pomc. Quanto ao peso corpóreo e consumo de ração dos animais mostrou-se que a suplementação com ácido fólico durante a gestação e no pós desmame foi capaz de alterar estes dois parâmetros, com resposta divergente entre os machos e fêmeas na prole adulta.Epigenetic mechanisms are essential for proper development in mammals, and that changes at this stage may lead to various metabolic disorders such as obesity. Currently obesity is a serious problem of public health worldwide, has a multifactorial origin involving both environmental and genetic factors. There are some genes that are involved with obesity, such as the proopiomelanocortin gene (POMC). The aim of this research project is to investigate the expression and methylation patterns of the Pomc gene in the offspring of rats subjected to deficient and supplemented diets with folic acid. Animals used were Wistar rats. The study involved males and females pups (n = 24) that were weaned at the same diet their mothers, three treatment groups, control group (2,0 mg/kg of folic acid), deficient group (0,5 mg/kg of folic acid) and the supplemented group (8,0 mg/kg of folic acid). The arcuate nucleus of the hypothalamus tissue were collected, from which was extracted DNA, RNA and proteins using commercially available kits following the manufacturer\'s protocol. The DNA methylation pattern analysis was performed. The mRNA was used for the analysis of gene expression by real time PCR, the TaqMan (Life Technologies (TM)) system. The proteomic study was carried out by Western blotting. In general, we found that the body weight of the male offspring showed no statistical difference between the groups. The feed intake of folic acid deficient group was statistically (p = 0.03) higher than the control group. In relation to female offspring was observed that the body weight of the supplemented group was statistically (p = 0.01) higher than the control group, and related to feed intake, there was no statistically significant difference between the treatment groups. The analysis of brain weight, gene expression, methylation and protein expression of Pomc no significant statistical differences among treatment groups of both sexes. Concluded that the intervention diets with different folic acid concentrations did not cause significant changes in the offspring compared to the study of proteomics and methylation and expression patterns of the Pomc gene. As for the body weight and feed consumption of animals it showed that supplementation with folic acid during pregnancy and post weaning was able to alter these two parameters with differing response between males and females in the adult offspring.
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Aléssio, Ana Claudia Morandi. "Avaliação da hiperhomocisteinemia leve na evolução da aterosclerose em camundongos normais, com hemofilia B, deficiencia dos receptores para LDL ou da apolipoproteina E." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310158.
Full textAbstract:
Orientador: Joyce Maria Annichino-BizzacchiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Nosso estudo teve o objetivo de analisar o efeito da hiperhomocisteinemia (HHcy) leve e controlada no desenvolvimento da aterosclerose em modelos murinos normais, deficientes de apolipoproteína E (apoE-/-), deficientes dos receptores de LDL (LDLR-/-) ou hemofílicos B. Foi realizada a quantificação das lesões ateroscleróticas no seio aórtico e análise do estresse do retículo endoplasmático (RE) pela técnica de western-blot. As concentrações de ácido fólico e vitamina B12 foram determinadas por radioimunoensaio e, a concentração da homocisteína (Hcy) plasmática por HPLC-MS/MS. Os camundongos receberam dietas enriquecidas em metionina por gavage com baixos ou altos níveis de ácido fólico, vitamina B12 e B6 (dietas B e C, respectivamente), e dieta com baixos níveis de ácido fólico, vitamina B12 e B6 (dieta D), para induzir uma HHcy leve. Os animais alimentados com dietas B, C e D apresentaram níveis de Hcy 3 a 5 vezes maiores que os encontrados nos animais normais alimentados com dieta padrão (dieta A), o que é proporcional à definição de HHcy leve em humanos. Os camundongos normais e hemofílicos B não desenvolveram lesão aterosclerótica, mesmo na presença da HHcy. Entretanto, os camundongos normais com dieta B por 24 semanas apresentaram aumento na expressão das proteínas Grp78 e Grp94, representando um estresse do RE. Os camundongos apoE-/- e LDLR-/- com dietas B, C e D por 8 e 20 semanas apresentaram aumento progressivo da lesão aterosclerótica, comparados aos camundongos alimentados com dieta A. Os camundongos apoE-/- com dieta B por 20 semanas apresentaram maior lesão quando comparados aos camundongos com dietas C e D. Esses resultados sugerem que a interação de fatores de risco podem ter um efeito aditivo e/ou sinérgico sobre o desenvolvimento da aterosclerose. Os camundongos apoE-/- tratados com dieta enriquecida em ácido fólico, vitamina B12 e B6 (dieta C) por 20 semanas mostraram menor desenvolvimento de lesões ateroscleróticas que os camundongos apoE-/- tratados com dieta deficiente destas vitaminas (dieta B), ambos submetidos a uma sobrecarga de metionina. Estes resultados corroboram o efeito protetor das vitaminas, particularmente a longo prazo. Como já sugerido em outros estudos, a metionina parece ter um efeito tóxico sobre a vasculatura arterial, evidenciado neste estudo pelo maior grau de lesão nos grupos de animais que tiveram como diferença na dieta a presença deste aminoácido (grupo B vs grupo D). Como os animais hemofílicos morreram muito precocemente, em decorrência de hemorragias, a análise dos resultados ficou comprometida, apenas permitindo demonstrar que não houve formação de lesão aterosclerótica com 8 semanas de exposição às dietas, apesar do aumento da Hcy
Abstract: This study evaluated the effect of controlled mild hyperhomocysteinemia (HHcy) in the development of atherosclerosis using normal, apolipoprotein E-deficient (apoE-/-), LDL receptor-deficient (LDLR-/-), or hemophilia B mice. We quantified atherosclerotic lesions at the aortic sinus and analyzed endoplasmic reticulum (RE) stress by western-blot technique. Concentrations of folic acid and vitamin B12 were determined using radioimmunoassay and homocysteine (Hcy) plasma levels were determined using HPLC-MS/MS. Mice received diets enriched in methionine with low or high levels of folic acid, vitamin B12, and B6 (diets B and C, respectively), and diet only with low levels of folic acid, vitamin B12, and B6 (diet D), to induce mild HHcy. Mice that received diets B, C, and D presented Hcy levels of about 3 to 5 fold the concentration found in wild-type mice fed on standard rodent chow (diet A), representing the same proportional increase of mild HHcy defined in humans. Normal mice and hemophilia B mice did not develop atherosclerotic lesions, even in the presence of mild HHcy. However, normal mice fed on diet B for 24 weeks presented increases in protein Grp78 and Grp94 expressions, representing RE stress. The apoE-/- and LDLR-/- mice fed on diets B, C, and D for 8 and 20 weeks presented a progressive increase in arteriosclerotic lesions, compared to mice fed on diet A. The apoE-/- mice fed on diet B for 20 weeks presented a greater area of the lesion than mice fed on diets C and D. These results suggest that an interaction of risk factors may have a synergic or additive effect in the development of atherosclerosis. The apoE-/- mice fed on the diet enriched in folic acid, vitamin B12, and B6 (diet C) for 20 weeks showed a lower development of atherosclerotic lesions than apoE-/- mice fed on a diet with low levels these vitamins (diet B), both subjected to an overload of methionine. These results corroborated the protective effect of vitamins, particularly in the long term. As suggested in other studies, methionine may have a toxic effect on arterial vasculature, demonstrated in this study by greater lesions in the animal groups that presented this amino acid in the diet (group B vs group D). Since hemophilia B mice died very early, due to hemorrhage, the analysis of the results was compromised. We could only demonstrate that they did not develop atherosclerotic lesions with 8 weeks of exposure to diets, in spite of increase of Hcy levels
Doutorado
Medicina Experimental
Doutor em Fisiopatologia Medica
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Felix, Temis Maria. "Metabolismo da homocisteína e defeitos do tubo neural : um estudo bioquímico e molecular no sul do Brasil." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2002. http://hdl.handle.net/10183/3700.
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Os defeitos de fechamento de tubo neural constituem uma das malformações mais freqüentes na espécie humana, apresentando alta morbi-mortalidade. Sua etiologia é considerada multifatorial, estando envolvidos fatores genéticos e ambientais. Estes fatores estão relacionados principalmente com o metabolismo da homocisteína. Realizamos um estudo de caso-controle com o objetivo de estudar os fatores bioquímicos e genéticos relacionados ao DTN na nossa população. Em pares de afetados com DTN e suas mães e pares de pacientes normais e suas mães foram avaliados dosagem de folato, vitamina B12, homocisteína e polimorfismos da enzima metileno tetraidrofolato redutase (MTHFR), C677T e A1298C. A dosagem de folato nos casos foi 11,37 ng/mL(±6,72) e nos controles 5,64 ng/mL(±4,16) (p<0,001). O folato sérico das mães foi 7,27 ng/mL (±4,48) e 3,90 ng/mL (±1,77) nas mães controles (p<0,001). A média de dosagem de vitamina B12 foi de 641,88 pg/mL ((±262,21) nos casos e 743,27 pg/mL (±433,52) nos controles (p= 0,205). A média de dosagem de vitamina B12 nas mães dos casos foi 354,75 pg/mL (±142,06) e 465,25 pg/mL (±194,91) nas mães controles (p=0,004). O nível de homocisteína plasmático médio foi 6,89 μmol/L(±4,48) para os casos e 5,41 μmol/L (±2,55) para os controles (p=0,099). Nas mães dos casos a dosagem média de homocisteína foi 7,23 μmol/L (±2,64) e 7,00 μmol/L (±2,24) nas mães controles (p=0,666). Não houve diferença entre a freqüência dos genótipos C677T e A1298C da MTHFR nos casos e controles e suas mães. Para o polimorfismo C677T as freqüências dos alelo C e T foram respectivamente 0,6585 e 0,3414 nos pacientes com DTN; 0,6590 e 0,3410 nos controles; 0,6460 e 0,3540 nas mães dos casos e 0,6136 e 0,3860 nas mães controles. Para o polimorfismo A1298C as freqüências dos alelos A e C foram respectivamente 0,7436 e 0,2564 nos pacientes com DTN; 0,7610 e 0,2390 nos controles; 0,8055 e 0,1945 nas mães dos casos e 0,8065 e 0,1935 nas mães controles. Identificamos que indivíduos homozigotos 677TT apresentam um maior nível de homocisteína e este é inversamente relacionado com os níveis de vitamina B12. Estes achados sugerem que uma alteração metabólica relacionada ao metabolismo da homocisteína e principalmente devido à diminuição da vitamina B12 seja um fator de risco para DTN na nossa população.Neural tube defects (NTD) are among the most common birth defect leading to great disabilities. The etiology is multifactorial, involving the combined action of both genetic and environmental factors. Those factors have been related to homocysteine metabolism. We performed a case control study in order to evaluate the biochemical and genetic factors related to NTD in the South of Brazil. A mother- NTD children pair and mother normal children were evaluated for folate, vitamin B12, homocysteine and two polymorphism of the methylene tetrahydrofolate reductase (MTHFR), C677T and A1298C. The folate level was 11,37 ng/mL (±6,72) in the NTD patients and 5,64 ng/mL(±4,16) in the controls (p<0,001). The folate was 7,27 ng/mL (±4,48) in the NTD mothers and 3,90 ng/mL (±1,77) in the control mothers (p<0,001). The level of vitamin B12 was 641,88 pg/mL ((±262,21) in the NTD case and 743,27 pg/mL (±433,52) in the controls (p= 0,205). The levels of vitamin B12 in the NTD mothers was 354,75 pg/mL (±142,06) and 465,25 pg/mL (±194,91) in the control mothers (p=0,004). The pasmatic homocysteine level was 6,89 μmol/L(±4,48) for the NTD cases and 5,41 μmol/L (±2,55) for the controls (p=0,099). The NTD mothers showed homocysteine level of 7,23 μmol/L (±2,64) and the controls mothers demonstrated 7,00 μmol/L (±2,24) (p=0,666). We could not observed a difference between the frequency of the genotypes C677T and A1298C in case and controls. The frequency of the alele C and T for the polymorphism C677T were respectively 0,6585 and 0,3414 for the NTD patients; 0,6590 and 0,3410 for the controls; 0,6460 and 0,3540 for NTD mothers; 0,6136 and 0,3860 for the control mothers. The frequencies of the allele A and C for the polymorphism A1298C were respectively 0,7436 and 0,2564 for NTD patients, 0,7610 and 0,2390 for controls; 0,8055 and 0,1945 for NTD mothers; 0,8065 and 0,1935 for controls mothers. We could demonstrated that the homozygous 677TT had a higher level of homocysteine and this was related to low level of vitamin B12. Those findings suggest that biochemical and genetic factors related to homocysteine metabolism and vitamin B12 deficiency are a risk factor to NTD in our population.
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Colman, Neville. "The use of food fortification to prevent folate deficiency in poorly-nourished communities." Thesis, 2015. http://hdl.handle.net/10539/16990.
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Hsu, Hung Chih, and 許宏志. "Investigation of Folic Acid Deficiency on Apoptosis of Synoviocytes and Pancreatic Beta Cells." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/348w33.
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博士長庚大學
臨床醫學研究所
105
Oxidative stress is known as the major risk factor for the onset and progression of a variety of chronic diseases including osteoarthritis and diabetes. Since accumulating evidence has shown that folate deficiency (FD) often causes overproduction of reactive oxygen species (ROS) and stimulates apoptosis in various types of cells, we here investigate whether FD affects cell growth and redox homeostasis of synoviocytes and islet β cells, two critical cell types involved in the pathogenesis of osteoarthritis and diabetes, respectively. In the first part of the study, we cultivated synoviocytes (HIG-82) under FD condition and found that FD significantly induces cell apoptosis in a time-dependent manner. Furthermore, our results reveal that the increased apoptosis in synoviocytes caused by FD are attributed to the overproduction of ROS and the elevated release of cytosolic calcium (Ca2+). Importantly, we uncover that FD-induced ROS overproduction is originated from mitochondrial complex II and NADPH oxidase. These results therefore suggest that folate supplement may be beneficial to patients with osteoarthritis. In the second part of the study, we cultivated pancreatic RIN-m5F islet β cells under FD condition, and showed that FD induces oxidative stress, nitrosative stress, cytosolic calcium overload, and cell apoptosis in RIN-m5F islet β cells. Mechanistically, we demonstrate that nitrosative stress triggered by FD is mediated through a NF-κB-dependent iNOS-mediated overproduction of nitric oxide (NO). The latter could trigger depletion of endoplasmic reticulum (ER) calcium (Ca2+), causing cytosolic Ca2+ overload and ER stress. Additionally, the FD-induced apoptosis of RIN-m5F cells is shown to correlate with a time-dependent depletion of intracellular glutathione and a down-regulation of Bcl-2 expression. During the experiments, we also found that FD could markedly impair RIN-m5F cells to synthesize insulin and affect the response of RIN-m5F cells to glucose stimulation. Interestingly, we also found that folate replenishment would not restore the ability of RIN-m5F cells to synthesize insulin, suggesting that folate deficiency is an important risk factor in the pathogenesis of diabetes. Taken together, our current studies propose that FD may act as not only an important predisposing factor for the progression of osteoarthritis and diabetes, but also a causative factor for these two chronic diseases.
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Beetstra, Alexandra Johanna. "Folate deficiency and methionine-dependence phenotype : impact on genome stability and breast cancer risk in BRCA1 and BRCA2 germline mutation carriers." 2006. http://arrow.unisa.edu.au:8081/1959.8/45967.
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This thesis describes a study on the impact of selected nutrients, growth hormones and in vivo genome stability on breast cancer risk in BRCA1 or BRCA2 germline mutation carriers. Peripheral blood lymphocyes of BRCA germline mutation carriers and healthy non-carrier controls were studied for the impact of folic acid deficiency on genome damage and the methionine-dependence phenotype (MDP; in combination with common polymorphisms in one-carbon metabolism) on breast cancer risk, respectively. Plasma IGF-1 and IGFBP-3 were determined and chromosome 17 aneuploidy and Her2 amplification were assessed in mononucleated lymphocytes to establish the association of these markers on breast cancer risk in BRCA germline mutation carriers, independently or in combination with plasma folate, vitamin B12, homocysteine, selenium and common gene variants in the one-carbon metabolism, DNA repair genes or glutathionine S-transferase.
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"Homocysteine, folate and risk of atherosclerosis: from bench to bedside." 2003. http://library.cuhk.edu.hk/record=b6073576.
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Qiao, Mu."June 2003."
Thesis (Ph.D.)--Chinese University of Hong Kong, 2003.
Includes bibliographical references (p. 190-209).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Mode of access: World Wide Web.
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Steele, Benjamin D. "The Masking Effect: A comparison of pre and post folic acid fortification periods for vitamin B-12 deficiency without macrocytosis in the United States." 2014. http://scholarworks.gsu.edu/nutrition_theses/56.
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Background: There has been a concern regarding the masking of vitamin B-12 deficiency in the post-fortification period (after January 1, 1998).
Objective: The objective of this study was to investigate the potential masking of vitamin B-12 deficiency by comparing the proportion of individuals with low serum B-12 without macrocytosis between pre- and post-fortification periods using data from the National Health and Nutrition Examination Survey (NHANES).
Methods: The study included 7242 individuals from NHANES III (pre-fortification group) and combined NHANES 1999-2000, 2001-2002, 2003-2004, 2005-2006 (post-fortification group). Vitamin B-12 deficiency and macrocytosis were defined as having <148 pmol/L of serum vitamin B-12 and mean corpuscular volume (MCV) of>98 fL, respectively. A multivariate logistic regression was performed to estimate the likelihood of being low serum B-12 without macrocytosis in the post-fortification period in relation to the pre-fortification period.
Results: Between pre- and post-fortification periods, there was no significant difference in the proportion of individuals with low serum vitamin B-12 without macrocytosis. However, odds of having low serum vitamin B-12 without macrocytosis in the post fortification era increased in men (OR=2.65, 1.24-5.65), non-Hispanic blacks (OR=3.12, 1.04-9.35), Non-smokers (OR=4.63, 1.90-11.27), and those aged 55 and older (OR=2.183, 1.01-4.74) compared their respective counterparts in the pre-fortification period.
Conclusions: No significant difference in the proportion of individuals with vitamin B-12 deficiency without macrocytosiss was seen between the pre and post-fortification periods suggesting no making of vitamin B-12 deficiency. In the post-fortification period, serum folate was found to be a predictor of the masking effect. The impact of increased folic acid intake in the post-fortification period needs to be evaluated on a periodic basis especially, in non-target population.
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"The effects of folic acid deficiency and defects in folate metabolism on chromosome damage in vitro / Jimmy Walter Crott." Thesis, 2001. http://hdl.handle.net/2440/21696.
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Reprints of the author's previously published articles included as an appendix.Bibliography: leaves 165-188.
xiv, 189 leaves : ill. (some col.) ; 30 cm.
"This thesis describes a series of experiments that aimed to investigate the effects of folic acid deficiency and defects in folate metabolism on chromosome damage rates in human lymphocytes. The accumulation of chromosome damage over time is an important issue because it is thought to contribute to the mechanism of ageing and the aetiology of diseases of age such as cancer and Alzheimer's disease."
Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 2002?
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Khoshnevisan, Mohammad H. "Selected genetic and environmental factors in the etiology of human oral clefting." 2001. http://catalog.hathitrust.org/api/volumes/oclc/62718696.html.
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Teh, Arnida Hani. "The effect of folic acid and methionine deficiency and excess on DNA damage and cancer growth in HT29 colon cancer cells and the Apc Min mouse model." Thesis, 2017. http://hdl.handle.net/2440/109790.
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Folate and methionine are critical for one-carbon metabolism, impacting DNA synthesis, repair, and methylation processes, as well as polyamine synthesis. These micronutrients have been implicated in colorectal cancer risk. The aim of this thesis was to examine in greater detail the role of folate and methionine in colon cancer initiation and progression by assessing DNA stability and tumour incidence. Studies were performed in vitro (using human colorectal adenocarcinoma HT29 cell line) and in vivo (using ApcMin/+ [Min/+ superscript] mouse model). The in vitro studies examining the effects of various folic acid and methionine concentrations within the physiological range on cell proliferation and genomic instability of HT29 cells, showed that restriction of folic acid or methionine inhibited cellular proliferation, while supra-physiological folate induced apoptosis. HT29 cells may be resistant to genome instability induced by folic acid or methionine deficiency under the experimental conditions reported for this study because no significant increases in micronuclei, nuclear buds or nucleoplasmic bridges were observed in the Cytokinesisblock micronucleus cytome (CBMN-Cyt) assay. The investigation on the effect of folic acid and methionine depletion on telomere length and DNA methylation in HT29 cells demonstrated that folate and methionine depletion may increase both telomere length and DNA methylation in HT29 cells. The length of telomere was positively correlated with DNA methylation. In the in vivo studies using the ApcMin/+ [Min/+ superscript] mouse model, the effect of supplementing a western-style diet with dietary folic acid and/or methionine on intestinal tumour development was assessed. A total of 113 mice were randomised to receive one of the four diet treatments; New Western Diet (NWD) as control diet, NWD with additional folic acid, NWD with additional methionine, and NWD with additional folic acid and methionine, administered at age of 3 until 13 weeks, with wild type (WT) mice used as controls. Supplementation of folic acid and methionine separately, resulted in marginally lower tumour numbers, when compared to the control diet. However, supplementation with both folic acid and methionine together appeared to annul the marginal protective effect of supplementing individually. The investigation on the effect of supplementing a western-style diet with dietary folic acid and/or methionine on genomic stability (measured via micronucleated erythrocyte assay on blood sample; telomere length and DNA methylation on the colon tissue) showed insufficient evidence that additional folic acid and/or methionine promotes DNA stability or instability in ApcMin/+ [Min/+ superscript] or WT mice. Dietary supplementation with folic acid and/or methionine at the levels and duration used in this study did not substantially promote or protect against DNA damage in WT or intestinal cancer-prone ApcMin/+ [Min/+ superscript] mouse model fed a western-style diet although a marginal effect on tumour number was evident. In conclusion, the results of this thesis support a role of methionine and folate in affecting intestinal cell proliferation and possibly tumour number. However, the impact of supplementation with folate and methionine on genome stability was marginal.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, Adelaide Medical School, 2017.
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AN, WU LI, and 吳禮安. "Role of Reactive Oxygen Species (ROS) and Mitochondria Calcium Overloading on the Folic Acid Deprivation-Triggered Apoptosis of Glucose-6-Phosphate Dehydrogenase (G6PD)-Deficient Human Foreskin Fibroblasts." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/51443919650091922411.
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碩士長庚大學
醫學生物技術研究所
94
Glucose-6-phosphate dehydrogenase (G6PD) is involved in the generation of NADPH for the proper maintenance of the cellular redox balance, G6PD deficiency predispose human fibroblasts (HFF) to retarded growth and accelerated cellular senescence. Thus far, the pivotal role of a micronutrient, such as folic acid, on the cellular functions of the normal and G6PD-deficient HFF have never been investigated. The objectives of the present research are two-fold: (1) To explore the possibility that folic acid deficiency can trigger the occurrence of apoptotic cell death in G6PD-deficient as well as G6PD-normal HFFs. Emphasis will be to elucidate if folate deficiency-induced apoptosis involves reactive oxygen species (ROS)-mediated mitochondrial calcium overload pathway; (2) Real time analysis of living intact cell in single cell level to address the questions if glutathione (GSH) depletion and lipid peroxidation are involved in the very early responses of both HFF-1 and HFF-3 fibroblasts to folate deficiency-induced apoptosis using probe-based confocal fluorescence imaging technique. Furthermore, the possibility as to whether or not the mitochondria calcium overload plays a pivotal role in arbitrating apoptotic process will be addressed in this project. Using DCF-DA as the fluorescence probe, we first monitored the production of mitochondrial ROS (mROS) in both types of fibroblasts cultivated under folate-deficiency condition. Our data indicated that HFF-1 cells (G6PD-deficient cells) produced substantially higher amounts of mROS than their folate-sufficient counterparts (HFF-3 cells) cultivated under folate-deficiency condition seven days. Next, using CMF-DA and BODIPY as the probes, we can able to attest that the folate-deficiency condition (7th day) could elicit GSH depletion and lipid peroxidation in the very early response of both types of fibroblasts to folate-induced oxidative stress situation. Using Fluo-4 (for cytosolic Ca++ probe ) and Rhod-2 (for mitochondrial Ca++ probe) as the probes, we also measured the temporal and spatial distribution of Ca++. In this study, we found that only HFF-1 cells had had increased quantity of Ca++ accumulation as reflected by the increased exhibition of the Rhod-2-mediated orange colored fluorescence. These data attested that mitochondrial calcium overload (mCa++) was the major contributing factor for increased susceptibility of HFF-1 cells to folate deficiency-induced apoptosis as compared to their folate-sufficient counterparts. In parallel, we also found out that increased mCa++ levels correlated with the loss of mitochondrial membrane potential (Δψm). Taken together, our data indicated folate-deficient fibroblasts was mediated via early ROS-evoked GSH depletion and lipid peroxidation and lipid peroxidation resulting in membrane damages. This was followed by a sudden inflex of Ca++ into mitochondria and thus Δψm changed leading to the eventual occurrence of apoptosis. G6PD-deficeincy rendered fibroblasts more prone to folate deficiency-induced apoptosis because of the double stresses situation imposed on these cells.