Folates in plants: research advances and progress in crop biofortification

NASA Astrophysics Data System (ADS)

Gorelova, Vera; Ambach, Lars; Rébeillé, Fabrice; Stove, Christophe; Van Der Straeten, Dominique

2017-03-01

Folates, also known as B9 vitamins, serve as donors and acceptors in one-carbon (C1) transfer reactions. The latter are involved in synthesis of many important biomolecules, such as amino acids, nucleic acids and vitamin B5. Folates also play a central role in the methyl cycle that provides one-carbon groups for methylation reactions. The important functions fulfilled by folates make them essential in all living organisms. Plants, being able to synthesize folates de novo, serve as an excellent dietary source of folates for animals that lack the respective biosynthetic pathway. Unfortunately, the most important staple crops such as rice, potato and maize are rather poor sources of folates. Insufficient folate consumption is known to cause severe developmental disorders in humans. Two approaches are employed to fight folate deficiency: pharmacological supplementation in the form of folate pills and biofortification of staple crops. As the former approach is considered rather costly for the major part of the world population, biofortification of staple crops is viewed as a decent alternative in the struggle against folate deficiency. Therefore strategies, challenges and recent progress of folate enhancement in plants will be addressed in this review. Apart from the ever-growing need for the enhancement of nutritional quality of crops, the world population faces climate change catastrophes or environmental stresses, such as elevated temperatures, drought, salinity that severely affect growth and productivity of crops. Due to immense diversity of their biochemical functions, folates take part in virtually every aspect of plant physiology. Any disturbance to the plant folate metabolism leads to severe growth inhibition and, as a consequence, to a lower productivity. Whereas today’s knowledge of folate biochemistry can be considered very profound, evidence on the physiological roles of folates in plants only starts to emerge. In the current review we will discuss the implication of folates in various aspects of plant physiology and development.

Sclerosing bone dysplasias: genetic, clinical and radiology update of hereditary and non-hereditary disorders

PubMed Central

Boulet, Cedric; Madani, Hardi; Lenchik, Leon; Vanhoenacker, Filip; Amalnath, Deepak S; de Mey, Johan

2016-01-01

There is a wide variety of hereditary and non-hereditary bone dysplasias, many with unique radiographic findings. Hereditary bony dysplasias include osteopoikilosis, osteopathia striata, osteopetrosis, progressive diaphyseal dysplasia, hereditary multiple diaphyseal sclerosis and pyknodysostosis. Non-hereditary dysplasias include melorheostosis, intramedullary osteosclerosis and overlap syndromes. Although many of these dysplasias are uncommon, radiologists should be familiar with their genetic, clinical and imaging findings to allow for differentiation from acquired causes of bony sclerosis. We present an overview of hereditary and non-hereditary bony dysplasias with focus on the pathogenesis, clinical and radiographic findings of each disorder. PMID:26898950

Regulatory aspects of the glutamylation of methotrexate in cultured hepatoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nimec, Z.; Galivan, J.

1983-10-15

The glutamylation of methotrexate has been evaluated in H35 hepatoma cells in vitro as a function of the conditions of culture. Glutamylation yields methotrexate polyglutamate with two to five additional glutamate residues and is a saturable process. The rate of glutamylation increases little above 10 microM extracellular methotrexate which corresponds to an intracellular concentration of approximately 4 microM. The rate of glutamylation measured over a 6-h period was stimulated by a reduction in cellular folates and prior incubation of the cells with insulin. Glutamylation was also more rapid in dividing cultures than in confluent cells. The combination of insulin inclusionmore » and folate reduction, which was additive, caused approximately a fourfold increase in the rate of glutamylation over control cells under the conditions tested. The maximal rate of methotrexate glutamylation, which was 100 nmol/g/h, occurred in folate-depleted, insulin-supplemented cells. Supplementing folate-depleted cells with reduced folate coenzymes caused the glutamylation to be reduced by more than 90%. In addition to showing that folates can modify the rates of methotrexate polyglutamate formation, data are presented suggesting that methotrexate polyglutamates can regulate their own synthesis. The consequences of the formation of these retained forms of methotrexate in H35 hepatoma cells and the effects of potential regulators of this process are discussed in terms of the glutamylation of folates in the cells and the chemotherapeutic effects of antifolates.« less

Expression of Folate Pathway Genes in the Cartilage of Hoxd4 and Hoxc8 Transgenic Mice

PubMed Central

Kruger, Claudia; Talmadge, Catherine; Kappen, Claudia

2014-01-01

BACKGROUND Hox transcription factors are well known for their role in skeletal patterning in vertebrates. They regulate gene expression during the development of cartilage, the precursor to mature bone. We previously reported that overexpression of the homeobox genes Hoxc8 and Hoxd4 results in severe cartilage defects, reduced proteoglycan content, accumulation of immature chondrocytes, and decreased maturation to hypertrophy. We have also shown that Hoxd4 transgenic mice whose diets were supplemented with folate had their skeletal development restored. Since folate is required for growth and differentiation of chondrocytes, we hypothesized that the beneficial effect of folate in Hoxd4 transgenic mice might indicate a local deficiency in folate utilization, possibly caused by deregulation of genes encoding folate transport proteins or folate metabolic enzymes. METHODS We assayed the prevalence of transcripts for 22 folate transport proteins and metabolizing enzymes, here collectively referred to as folate pathway genes. Quantitative real-time PCR was performed on cDNA samples derived from RNA isolated from primary chondrocytes of individual rib cartilages from Hoxd4 and Hoxc8 transgenic mice, respectively. RESULTS This study shows that the Hox transgenes produce overexpression of Hoxd4 and Hoxc8 in primary chondrocytes from perinatal transgenic mice. However, no differences were found in expression levels of the folate pathway genes in transgenic cells compared to littermate controls. CONCLUSIONS Our results provide evidence that folate pathway genes are only indirect targets of Hox transgene overexpression in our transgenic animals. These expression studies provide a baseline for future studies into the role of folate metabolism in chondrocyte differentiation. PMID:16586448

[The progress and prospect of application of genetic testing technology-based gene detection technology in the diagnosis and treatment of hereditary cancer].

PubMed

He, J X; Jiang, Y F

2017-08-06

Hereditary cancer is caused by specific pathogenic gene mutations. Early detection and early intervention are the most effective ways to prevent and control hereditary cancer. High-throughput sequencing based genetic testing technology (NGS) breaks through the restrictions of pedigree analysis, provide a convenient and efficient method to detect and diagnose hereditary cancer. Here, we introduce the mechanism of hereditary cancer, summarize, discuss and prospect the application of NGS and other genetic tests in the diagnosis of hereditary retinoblastoma, hereditary breast and ovarian cancer syndrome, hereditary colorectal cancer and other complex and rare hereditary tumors.

Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing

PubMed Central

Porter, Kirsty; Hoey, Leane; Hughes, Catherine F.; Ward, Mary; McNulty, Helene

2016-01-01

The potential protective roles of folate and the metabolically related B-vitamins (vitamins B12, B6 and riboflavin) in diseases of ageing are of increasing research interest. The most common cause of folate and riboflavin deficiencies in older people is low dietary intake, whereas low B12 status is primarily associated with food-bound malabsorption, while sub-optimal vitamin B6 status is attributed to increased requirements in ageing. Observational evidence links low status of folate and the related B-vitamins (and/or elevated concentrations of homocysteine) with a higher risk of degenerative diseases including cardiovascular disease (CVD), cognitive dysfunction and osteoporosis. Deficient or low status of these B-vitamins alone or in combination with genetic polymorphisms, including the common MTHFR 677 C → T polymorphism, could contribute to greater disease risk in ageing by causing perturbations in one carbon metabolism. Moreover, interventions with the relevant B-vitamins to optimise status may have beneficial effects in preventing degenerative diseases. The precise mechanisms are unknown but many have been proposed involving the role of folate and the related B-vitamins as co-factors for one-carbon transfer reactions, which are fundamental for DNA and RNA biosynthesis and the maintenance of methylation reactions. This review will examine the evidence linking folate and related B-vitamins with health and disease in ageing, associated mechanisms and public health implications. PMID:27854316

Role of methotrexate exposure in apoptosis and proliferation during early neurulation.

PubMed

Wang, Xiuwei; Wang, Jianhua; Guan, Tao; Xiang, Qian; Wang, Mingsheng; Guan, Zhen; Li, Guannan; Zhu, Zhiqiang; Xie, Qiu; Zhang, Ting; Niu, Bo

2014-08-01

Apoptosis and proliferation play important roles in embryonic development and are required for neural tube closure. The antifolate drug methotrexate (MTX) induces folate dysmetabolism by inhibition of dihydrofolate reductase and causes abnormal apoptosis and proliferation. In this study, we established an animal model of neural tube defects (NTDs) using MTX to investigate the role of apoptosis and proliferation in NTDs caused by folate deficiency. Differential gene expressions were studied by microarray and reverse transcription-polymerase chain reaction in the NTD animal model. Results showed that 30.8% of NTDs were caused by using MTX in treatment regimens. Microarray indicated that 166 genes were significantly different between the control and NTD mice, including four apoptosis-related genes (Endog, Trp53, Casp3, Bax) and three proliferation-related genes (Ptch1, Pla2g4a, Foxg1). Levels of Endog, Trp53, Casp3, Bax (fold change>1.5) were upregulated but Ptch1, Pla2g4a, Foxg1 (fold change<0.67) were downregulated (P<0.05). These results were confirmed by reverse transcription-polymerase chain reaction. TUNEL, immunohistochemical assays and Western blot were further used to detect apoptosis and proliferation in the NTD animal model. It was found that apoptosis in neuroepithelial cells was increased as determined by TUNEL (P<0.05). Expressions of caspase-3 were significantly enhanced (P<0.05) but expressions of phosphohistone H3 were greatly decreased (P<0.05). These results concluded that MTX caused a folate and folate-associated dysmetabolism, and further induced abnormal apoptosis and proliferation, which may play a critical role in the occurrence of NTDs caused by folate deficiency. Copyright © 2013 John Wiley & Sons, Ltd.

Mechanistic Target of Rapamycin Is a Novel Molecular Mechanism Linking Folate Availability and Cell Function.

PubMed

Silva, Elena; Rosario, Fredrick J; Powell, Theresa L; Jansson, Thomas

2017-07-01

Folate deficiency has been linked to a wide range of disorders, including cancer, neural tube defects, and fetal growth restriction. Folate regulates cellular function mediated by its involvement in the synthesis of nucleotides, which are needed for DNA synthesis, and its function as a methyl donor, which is critical for DNA methylation. Here we review current data showing that folate sensing by mechanistic target of rapamycin (mTOR) constitutes a novel and distinct pathway by which folate modulates cell functions such as nutrient transport, protein synthesis, and mitochondrial respiration. The mTOR signaling pathway responds to growth factors and changes in nutrient availability to control cell growth, proliferation, and metabolism. mTOR exists in 2 complexes, mTOR complex (mTORC) 1 and mTORC2, which have distinct upstream regulators and downstream targets. Folate deficiency in pregnant mice caused a marked inhibition of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues, downregulation of placental amino acid transporters, and fetal growth restriction. In addition, folate deficiency in primary human trophoblast (PHT) cells resulted in inhibition of mTORC1 and mTORC2 signaling and decreased the activity of key amino acid transporters. Folate sensing by mTOR in PHT cells is independent of the accumulation of homocysteine and requires the proton-coupled folate transporter (PCFT; solute carrier 46A1). Furthermore, mTORC1 and mTORC2 regulate trophoblast folate uptake by modulating the cell surface expression of folate receptor α and the reduced folate carrier. These findings, which provide a novel link between folate availability and cell function, growth, and proliferation, may have broad biological significance given the critical role of folate in normal cell function and the multiple diseases that have been associated with decreased or excessive folate availability. Low maternal folate concentrations are linked to restricted fetal growth, and we propose that the underlying mechanisms involve trophoblast mTOR folate sensing resulting in inhibition of mTORC1 and mTORC2 and downregulation of placental amino acid transporters. © 2017 American Society for Nutrition.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Gui-Bin; Wang, Hua, E-mail: wanghuadev@126.

Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl{sub 2} (2.5 or 5.0 mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl{sub 2} on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure onmore » GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl{sub 2}. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl{sub 2} on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl{sub 2} on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. - Highlights: • Maternal Cd exposure during organogenesis causes NTDs and FGR. • Maternal Cd exposure during organogenesis impairs placental development. • Cd disturbs transport of folate by down-regulating placental folate transporters.« less

Is Increased Intracellular Calcium in Red Blood Cells a Common Component in the Molecular Mechanism Causing Anemia?

PubMed Central

Hertz, Laura; Huisjes, Rick; Llaudet-Planas, Esther; Petkova-Kirova, Polina; Makhro, Asya; Danielczok, Jens G.; Egee, Stephane; del Mar Mañú-Pereira, Maria; van Wijk, Richard; Vives Corrons, Joan-Lluis; Bogdanova, Anna; Kaestner, Lars

2017-01-01

For many hereditary disorders, although the underlying genetic mutation may be known, the molecular mechanism leading to hemolytic anemia is still unclear and needs further investigation. Previous studies revealed an increased intracellular Ca2+ in red blood cells (RBCs) from patients with sickle cell disease, thalassemia, or Gardos channelopathy. Therefore we analyzed RBCs' Ca2+ content from 35 patients with different types of anemia (16 patients with hereditary spherocytosis, 11 patients with hereditary xerocytosis, 5 patients with enzymopathies, and 3 patients with hemolytic anemia of unknown cause). Intracellular Ca2+ in RBCs was measured by fluorescence microscopy using the fluorescent Ca2+ indicator Fluo-4 and subsequent single cell analysis. We found that in RBCs from patients with hereditary spherocytosis and hereditary xerocytosis the intracellular Ca2+ levels were significantly increased compared to healthy control samples. For enzymopathies and hemolytic anemia of unknown cause the intracellular Ca2+ levels in RBCs were not significantly different. These results lead us to the hypothesis that increased Ca2+ levels in RBCs are a shared component in the mechanism causing an accelerated clearance of RBCs from the blood stream in channelopathies such as hereditary xerocytosis and in diseases involving defects of cytoskeletal components like hereditary spherocytosis. Future drug developments should benefit from targeting Ca2+ entry mediating molecular players leading to better therapies for patients. PMID:28932200

Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

PubMed

Giavina-Bianchi, Pedro; França, Alfeu T; Grumach, Anete S; Motta, Abílio A; Fernandes, Fátima R; Campos, Regis A; Valle, Solange O; Rosário, Nelson A; Sole, Dirceu

2011-01-01

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Nutriepigenetic regulation by folate-homocysteine-methionine axis: a review.

PubMed

Bhargava, Seema; Tyagi, S C

2014-02-01

Although normally folic acid is given during pregnancy, presumably to prevent neural tube defects, the mechanisms of this protection are unknown. More importantly it is unclear whether folic acid has other function during development. It is known that folic acid re-methylates homocysteine (Hcy) to methionine by methylene tetrahydrofolate reductase-dependent pathways. Folic acid also generates high-energy phosphates, behaves as an antioxidant and improves nitric oxide (NO) production by endothelial NO synthase. Interestingly, during epigenetic modification, methylation of DNA/RNA generate homocysteine unequivocally. The enhanced overexpression of methyl transferase lead to increased yield of Hcy. The accumulation of Hcy causes vascular dysfunction, reduces perfusion in the muscles thereby causing musculopathy. Another interesting fact is that children with severe hyperhomocysteinaemia (HHcy) have skeletal deformities, and do not live past teenage. HHcy is also associated with the progeria syndrome. Epilepsy is primarily caused by inhibition of gamma-amino-butyric-acid (GABA) receptor, an inhibitory neurotransmitter in the neuronal synapse. Folate deficiency leads to HHcy which then competes with GABA for binding on the GABA receptors. With so many genetic and clinical manifestations associated with folate deficiency, we propose that folate deficiency induces epigenetic alterations in the genes and thereby results in disease.

Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome.

PubMed

Ramaekers, V Th; Segers, K; Sequeira, J M; Koenig, M; Van Maldergem, L; Bours, V; Kornak, U; Quadros, E V

2018-05-01

Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5-6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions. Copyright © 2018 Elsevier Inc. All rights reserved.

Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status

PubMed Central

Mackie, Fiona L.; Lean, Samantha C.; Greenwood, Susan L.; Heazell, Alexander E. P.; Forbes, Karen; Jones, Rebecca L.

2017-01-01

Scope Low maternal folate status during pregnancy increases the risk of delivering small for gestational age (SGA) infants, but the mechanistic link between maternal folate status, SGA, and placental dysfunction is unknown. microRNAs (miRNAs) are altered in pregnancy pathologies and by folate in other systems. We hypothesized that low maternal folate status causes placental dysfunction, mediated by altered miRNA expression. Methods and results A prospective observational study recruited pregnant adolescents and assessed third trimester folate status and placental function. miRNA array, QPCR, and bioinformatics identified placental miRNAs and target genes. Low maternal folate status is associated with higher incidence of SGA infants (28% versus 13%, p < 0.05) and placental dysfunction, including elevated trophoblast proliferation and apoptosis (p < 0.001), reduced amino acid transport (p < 0.01), and altered placental hormones (pregnancy‐associated plasma protein A, progesterone, and human placental lactogen). miR‐222‐3p, miR‐141‐3p, and miR‐34b‐5p were upregulated by low folate status (p < 0.05). Bioinformatics predicted a gene network regulating cell turnover. Quantitative PCR demonstrated that key genes in this network (zinc finger E‐box binding homeobox 2, v‐myc myelocytomatosis viral oncogene homolog (avian), and cyclin‐dependent kinase 6) were reduced (p < 0.05) in placentas with low maternal folate status. Conclusion This study supports that placental dysfunction contributes to impaired fetal growth in women with low folate status and suggests altered placental expression of folate‐sensitive miRNAs and target genes as a mechanistic link. PMID:28105727

Influence of high-pressure processing on the profile of polyglutamyl 5-methyltetrahydrofolate in selected vegetables.

PubMed

Wang, Chao; Riedl, Ken M; Somerville, Jeremy; Balasubramaniam, V M; Schwartz, Steven J

2011-08-24

In plants, folate occurs predominantly as 5-methyltetrahydrofolate (5MTHF) polyglutamyl forms. Differences in stability and bioavailability of food folate compared to synthetic folic acid have been attributed to the presence of the polyglutamyl chain. High-pressure processing (HPP) was tested for whether it might shorten polyglutamyl chains of 5MTHF species in fresh vegetables by enabling action of native γ-glutamylhydrolase (GGH). A validated ultrahigh-performance reversed-phase liquid chromatography-tandem mass spectrometry method using stable isotope as internal standard was applied for characterizing 5MTHF polyglutamyl profiles. HPP conditions included 300, 450, and 600 MPa at 30 °C for 0 or 5 min, and vegetables were vacuum-packed before treatment. Investigated vegetables included cauliflower (Brassica oleracea), baby carrots (Daucus carota), and carrot greens (D. carota). HPP treatment caused conversion of polyglutamyl 5MTHF species to short-chain and monoglutamyl forms. Maximal conversion of polyglutamyl folate to monoglutamyl folate occurred at the highest pressure/time combination investigated, 600 MPa/30 °C/5 min. Under this condition, cauliflower monoglutamyl folate increased nearly 4-fold, diglutamyl folate 32-fold, and triglutamyl folate 8-fold; carrot monoglutamyl increased 23-fold and diglutamyl 32-fold; and carrot greens monoglutamyl increased 2.5-fold and the diglutamyl form 19-fold. Although some folate degradation was observed at certain intermediate HPP conditions, total 5MTHF folate was largely preserved at 600 MPa/5 min. Thus, HPP of raw vegetables is a feasible strategy for enhancing vegetable monoglutamate 5MTHF.

Influence of High-Pressure Processing on the Profile of Polyglutamyl 5-Methyltetrahydrofolate in Selected Vegetables

PubMed Central

Wang, Chao; Riedl, Ken M.; Somerville, Jeremy; Balasubramaniam, V. M.; Schwartz, Steven J.

2013-01-01

In plants, folate occurs predominantly as 5-methyltetrahydrofolate (5MTHF) polyglutamyl forms. Differences in stability and bioavailability of food folate compared to synthetic folic acid have been attributed to the presence of the polyglutamyl chain. High-pressure processing (HPP) was tested for whether it might shorten polyglutamyl chains of 5MTHF species in fresh vegetables by enabling action of native γ-glutamylhydrolase (GGH). A validated ultrahigh-performance reversed-phase liquid chromatography–tandem mass spectrometry method using stable isotope as internal standard was applied for characterizing 5MTHF polyglutamyl profiles. HPP conditions included 300, 450, and 600 MPa at 30 °C for 0 or 5 min, and vegetables were vacuum-packed before treatment. Investigated vegetables included cauliflower (Brassica oleracea), baby carrots (Daucus carota), and carrot greens (D. carota). HPP treatment caused conversion of polyglutamyl 5MTHF species to short-chain and monoglutamyl forms. Maximal conversion of polyglutamyl folate to monoglutamyl folate occurred at the highest pressure/time combination investigated, 600 MPa/30 °C/5 min. Under this condition, cauliflower monoglutamyl folate increased nearly 4-fold, diglutamyl folate 32-fold, and triglutamyl folate 8-fold; carrot monoglutamyl increased 23-fold and diglutamyl 32-fold; and carrot greens monoglutamyl increased 2.5-fold and the diglutamyl form 19-fold. Although some folate degradation was observed at certain intermediate HPP conditions, total 5MTHF folate was largely preserved at 600 MPa/5 min. Thus, HPP of raw vegetables is a feasible strategy for enhancing vegetable monoglutamate 5MTHF. PMID:21770413

The role of the folate pathway in pancreatic cancer risk

PubMed Central

Chittiboyina, Shirisha; Chen, Zhongxue; Chiorean, E. Gabriela; Kamendulis, Lisa M.

2018-01-01

Background Pancreatic cancer is the third leading cause of cancer related deaths in the United States. Several dietary factors have been identified that modify pancreatic cancer risk, including low folate levels. In addition to nutrition and lifestyle determinants, folate status may be influenced by genetic factors such as single nucleotide polymorphisms (SNPs). In the present study, we investigated the association between folate levels, genetic polymorphisms in genes of the folate pathway, and pancreatic cancer. Methods Serum and red blood cell (RBC) folate levels were measured in pancreatic cancer and control subjects. Genotypes were determined utilizing Taqman probes and SNP frequencies between cases and controls were assessed using Fisher’s exact test. Logistic regression was used to estimate the odds ratio (OR) and corresponding 95% confidence intervals (CIs) to measure the association between genotypes and pancreatic cancer risk. The association between folate levels and SNP expression was calculated using one-way ANOVA. Results Mean RBC folate levels were significantly lower in pancreatic cancer cases compared to unrelated controls (508.4 ± 215.9 ng/mL vs 588.3 ± 229.2 ng/mL, respectively) whereas serum folate levels were similar. Irrespective of cancer status, several SNPs were found to be associated with altered serum folate concentrations, including the D919G SNP in methionine synthase (MTR), the L474F SNP in serine hydroxymethyl transferase 1 (SHMT1) and the V175M SNP in phosphatidyl ethanolamine methyltransferase (PEMT). Further, the V allele of the A222V SNP and the E allele of the E429A SNP in methylene tetrahydrofolate reductase (MTHFR) were associated with low RBC folate levels. Pancreatic cancer risk was found to be significantly lower for the LL allele of the L78R SNP in choline dehydrogenase (CHDH; OR = 0.29; 95% CI 0.12–0.76); however, it was not associated with altered serum or RBC folate levels. PMID:29474406

Gastric tumours in hereditary cancer syndromes: clinical features, molecular biology and strategies for prevention.

PubMed

Sereno, María; Aguayo, Cristina; Guillén Ponce, Carmen; Gómez-Raposo, César; Zambrana, Francisco; Gómez-López, Miriam; Casado, Enrique

2011-09-01

Gastric cancer is the major cause of cancer-related deaths worldwide. The majority of them are classified as sporadic, whereas the remaining 10% exhibit familial clustering. Hereditary diffuse gastric cancer (HDGC) syndrome is the most important condition that leads to hereditary gastric cancer. However, other hereditary cancer syndromes, such as hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, Peutz-Jeghers syndrome, Li-Fraumeni syndrome and hereditary breast and ovarian cancer, entail a higher risk compared to the general population for developing this kind of neoplasia. In this review, we describe briefly the most important aspects related to clinical features, molecular biology and strategies for prevention in hereditary gastric associated to different cancer syndromes.

Hereditary Hearing Loss.

ERIC Educational Resources Information Center

Tran, LenhAnh P.; Grundfast, Kenneth M.

1997-01-01

This article discusses inheritance patterns in hearing loss, epidemiology, clues to genetic causes, locating genes that cause hereditary disorders, genes related to hearing loss disorders in individuals with Usher syndrome, Waardenburg syndrome, Treacher-Collins syndrome, Branchio-oto-renal and Pendred syndromes, and the significance of finding…

Folate depletion changes gene expression of fatty acid metabolism, DNA synthesis, and circadian cycle in male mice.

PubMed

Champier, Jacques; Claustrat, Francine; Nazaret, Nicolas; Fèvre Montange, Michelle; Claustrat, Bruno

2012-02-01

Folate is essential for purine and thymidylate biosynthesis and in methyl transfer for DNA methylation. Folate deficiency alters the secretion of melatonin, a hormone involved in circadian rhythm entrainment, and causes hyperhomocysteinemia because of disruption of homocysteine metabolism. Adverse effects of homocysteine include the generation of free radicals, activation of proliferation or apoptosis, and alteration of gene expression. The liver is an important organ for folate metabolism, and its genome analysis has revealed numerous clock-regulated genes. The variations at the level of their expression during folate deficiency are not known. The aim of our study was to investigate the effects of folate deficiency on gene expression in the mouse liver. A control group receiving a synthetic diet and a folate-depleted group were housed for 4 weeks on a 12-hour/12-hour light/dark cycle. Three mice from each group were euthanized under dim red light at the beginning of the light cycle, and 3, at the beginning of the dark period. Gene expression was studied in a microarray analysis. Of the 53 genes showing modified daily expression in the controls, 52 showed a less marked or no difference after folate depletion. Only 1, lpin1, showed a more marked difference. Ten genes coding for proteins involved in lipid metabolism did not show a morning/evening difference in controls but did after folate depletion. This study shows that, in the mouse liver, dietary folate depletion leads to major changes in expression of several genes involved in fatty acid metabolism, DNA synthesis, and expression of circadian genes. Copyright © 2012 Elsevier Inc. All rights reserved.

Previously undiagnosed hereditary spherocytosis in a patient with jaundice and pyelonephritis: a case report.

PubMed

Tateno, Yuki; Suzuki, Ryoji; Kitamura, Yukihiro

2016-12-01

Hereditary spherocytosis is autosomal dominant inherited extravascular hemolytic disorder and is the commonest cause of inherited hemolysis in northern Europe and the United States. The classical clinical features of hereditary spherocytosis are anemia, jaundice, and splenomegaly. However, all of these classical features are not always revealed in the case of mild hemolysis or when hemolysis is well compensated. Patients with hereditary spherocytosis may remain undiagnosed for years if their hemolysis is mild. A 42-year-old Asian woman presented to our clinic with a sudden onset of high fever with shaking chills and jaundice, suggesting septicemia; however, following detailed investigation, the patient was diagnosed with pyelonephritis and accelerated hemolysis of hereditary spherocytosis due to infection. It is important to note that transient anemia or jaundice can sometimes be the only initial presenting symptoms in cases of undiagnosed latent hereditary spherocytosis. This case also highlights the fact that physicians should consider concomitant hemolytic disease in patients in whom jaundice and infections that rarely cause jaundice coexist.

Causes of childhood blindness in a developing country and an underdeveloped country.

PubMed

Santos-Bueso, E; Dorronzoro-Ramírez, E; Gegúndez-Fernández, J A; Vinuesa-Silva, J M; Vinuesa-Silva, I; García-Sánchez, J

2015-05-01

The causes of childhood blindness depend on factors such as geographic location or the human development index of the populations under study. The main causes in developed countries are genetic and hereditary diseases, while infectious and contagious diseases, together with nutritional and vitamin deficiencies, are the main causes in underdeveloped countries (UDCs). Study of the causes of blindness among children admitted to a regional centre in Nador, Morocco, and among children in Mekele, Ethiopia. The study was carried out in collaboration with two non-governmental organizations based in Madrid, Spain. First, we worked with Fudación Adelias in June 2010, and with Proyecto Visión in October 2012. The study comprised a total of 27 children in Morocco and 85 in Ethiopia. The average age of the children was 10.92 and 6.94 years, respectively. The main causes of blindness in Morocco were hereditary pathologies (25.92%) and refractive errors (14.82%), although trauma (7.40%) and corneal disease (7.40%) are relevant. Among the children from Ethiopia, corneal disease (27.05%) and trauma (20%) were the main causes of blindness, while congenital and hereditary diseases had a lower prevalence (4.70%). The causes of blindness depend on the human development index of the populations under study. While corneal disease and trauma are the main causes observed in UDCs like Ethiopia, hereditary pathologies and refractive errors are the main causes within the Moroccan population studied. A mixed form can be observed in this country, as the cause of blindness found in developed countries, such as congenital and hereditary pathologies which are present alongside the causes normally found in LDCs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development.

PubMed

Molloy, Anne M; Kirke, Peadar N; Brody, Lawrence C; Scott, John M; Mills, James L

2008-06-01

The importance of folate in reproduction can be appreciated by considering that the existence of the vitamin was first suspected from efforts to explain a potentially fatal megaloblastic anemia in young pregnant women in India. Today, low maternal folate status during pregnancy and lactation remains a significant cause of maternal morbidity in some communities. The folate status of the neonate tends to be protected at the expense of maternal stores; nevertheless, there is mounting evidence that inadequate maternal folate status during pregnancy may lead to low infant birthweight, thereby conferring risk of developmental and long-term adverse health outcomes. Moreover, folate-related anemia during childhood and adolescence might predispose children to further infections and disease. The role of folic acid in prevention of neural tube defects (NTD) is now established, and several studies suggest that this protection may extend to some other birth defects. In terms of maternal health, clinical vitamin B12 deficiency may be a cause of infertility or recurrent spontaneous abortion. Starting pregnancy with an inadequate vitamin B12 status may increase risk of birth defects such as NTD, and may contribute to preterm delivery, although this needs further evaluation. Furthermore, inadequate vitamin B12 status in the mother may lead to frank deficiency in the infant if sufficient fetal stores of vitamin B12 are not laid down during pregnancy or are not available in breastmilk. However, the implications of starting pregnancy and lactation with low vitamin B12 status have not been sufficiently researched.

The role of folate metabolism in orofacial development and clefting

PubMed Central

Wahl, Stacey E.; Kennedy, Allyson E.; Wyatt, Brent H.; Moore, Alexander D.; Pridgen, Deborah E.; Cherry, Amanda M.; Mavila, Catherine B.; Dickinson, Amanda J.G.

2015-01-01

Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation. We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage. In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts. In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition. This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects. PMID:26144049

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

PubMed

Tsai, Pei-Chien; Soong, Bing-Wen; Mademan, Inès; Huang, Yen-Hua; Liu, Chia-Rung; Hsiao, Cheng-Tsung; Wu, Hung-Ta; Liu, Tze-Tze; Liu, Yo-Tsen; Tseng, Yen-Ting; Lin, Kon-Ping; Yang, Ueng-Cheng; Chung, Ki Wha; Choi, Byung-Ok; Nicholson, Garth A; Kennerson, Marina L; Chan, Chih-Chiang; De Jonghe, Peter; Cheng, Tzu-Hao; Liao, Yi-Chu; Züchner, Stephan; Baets, Jonathan; Lee, Yi-Chung

2017-05-01

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Consumer preferences for micronutrient strategies in China. A comparison between folic acid supplementation and folate biofortification.

PubMed

De Steur, Hans; Feng, Shuyi; Xiaoping, Shi; Gellynck, Xavier

2014-06-01

Despite public health efforts, folate deficiency is still largely prevalent in poor, rural populations and continues to cause a large burden of disease. The present paper determines and compares consumer preferences for two folate strategies: folic acid supplementation v. folate biofortification, i.e. the enhancement of the folate content in staple crops. Experimental auctions with non-repeated information rounds are applied to rice in order to obtain willingness-to-pay for folate products. Thereby, GM or non-GM folate-biofortified rice (FBR) is auctioned together with rice that is supplemented with free folic acid pills (FAR). Shanxi Province (China) as a high-risk region of folate deficiency. One hundred and twenty-six women of childbearing age, divided into a school (n 60) and market sample (n 66). Despite differences according to the targeted sample, a general preference for folate biofortification is observed, regardless of the applied breeding technology. Premiums vary between 33·9 % (GM FBR), 36·5 % (non-GM FBR) and 19·0 % (FAR). Zero bidding behaviour as well as the product choice question, respectively, support and validate these findings. The targeted sample, the timing of the auction, the intention to consume GM food and the responsibility for rice purchases are considered key determinants of product choice. A novel ex-post negative valuation procedure shows low consistency in zero bidding. While the low attractiveness of FAR provides an additional argument for the limited effectiveness of past folic acid supplementation programmes, the positive reactions towards GM FBR further support its potential as a possible complementary micronutrient intervention.

Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

PubMed

Caress, James B; Johnson, Janel O; Abramzon, Yevgeniya A; Hawkins, Gregory A; Gibbs, J Raphael; Sullivan, Elizabeth A; Chahal, Chamanpreet S; Traynor, Bryan J

2017-11-01

Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS. We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing. Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV. This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017. © 2016 Wiley Periodicals, Inc.

Efficacy and Stability studies of microbial folate fortified fruit juices prepared using probiotic microorganism.

PubMed

Deep, S; Ojha, S; Kundu, S

2017-07-31

Folate, natural form of water soluble vitamin folic acid, is significant for humans as involved in most important metabolic reactions i.e. nucleotide synthesis and amino acid inter conversions. Thus its deficiency causes neural tube defects in newborns and cardiovascular diseases, and cancers. Humans cannot synthesize folate de novo so consumption through diet is essential. Natural food sources, supplements and fortified food products are the choices available to complete the Daily recommended intake. However microbial fortification using probiotics recently gained wide attention due to dual advantage of natural food matrix with enhanced folate content along with the probiotics benefits. Current study was focused on the microbial fortification of fruit juices and their efficacy and stability studies. Freshly filtered orange and tomato juice was prepared and inoculated with Streptococcus thermophilus NCIM 2904. Incubation was done at 40°C and samples were collected at different time interval. Folate extraction was done using human plasma and content was measured by microbiological assay using Lactobacillus casei NCIM No. 2364. Efficacy and stability studies were carried out to ensure the quality of juices to be consumed in terms of folate content, viable cell count and pH after 4 weeks of storage at low temperature. Positive results were observed as folate content was quite stable whereas viable cell count was also found to be significant till some time without adding any preservatives. The results indicated that fortified fruit juices could be used as probiotic beverages with enhanced folate content.

Comparative analysis of human tissue interactomes reveals factors leading to tissue-specific manifestation of hereditary diseases.

PubMed

Barshir, Ruth; Shwartz, Omer; Smoly, Ilan Y; Yeger-Lotem, Esti

2014-06-01

An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the human body. Here we analyzed this phenomenon for over 300 hereditary diseases by using comparative network analysis. We created an extensive resource of protein expression and interactions in 16 main human tissues, by integrating recent data of gene and protein expression across tissues with data of protein-protein interactions (PPIs). The resulting tissue interaction networks (interactomes) shared a large fraction of their proteins and PPIs, and only a small fraction of them were tissue-specific. Applying this resource to hereditary diseases, we first show that most of the disease-causing genes are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. Upon testing for factors that could lead to tissue-specific vulnerability, we find that disease-causing genes tend to have elevated transcript levels and increased number of tissue-specific PPIs in their disease tissues compared to unaffected tissues. We demonstrate through several examples that these tissue-specific PPIs can highlight disease mechanisms, and thus, owing to their small number, provide a powerful filter for interrogating disease etiologies. As two thirds of the hereditary diseases are associated with these factors, comparative tissue analysis offers a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases.

Folate Insufficiency Due to Celiac Disease in a 49-Year-Old Woman of Southeast Asian-Indian Ethnicity

PubMed Central

Datta Mitra, Ananya; Gupta, Asha; Jialal, Ishwarlal

2016-01-01

The clinical presentation of celiac disease has evolved from chronic diarrhea and malnutrition to mild nutrient insufficiencies. Recently diagnosed adults with celiac disease should be assessed for micronutrient deficiencies because early institution of a gluten-free diet (GFD) prevents morbidity and reduces the incidence of gastrointestinal malignant neoplasms and osteoporosis. In this report, we present the case of a 49-year-old woman of Southeast Asian–Indian descent living in the United States who had folate insufficiency, as manifested by low serum and red blood cell (RBC) folate levels. Further investigation, including serologic testing and intestinal biopsy, confirmed a diagnosis of celiac disease and other nutrient deficiencies. Managing the condition of this patient with folate supplements and implementation of a recommended GFD reversed the folate insufficiency. In conclusion, when serum and/or RBC levels are low in a person of Southeast Asian-Indian descent living in a country with folate fortification of the grain supply, such as the United States, the medical team needs to look for an organic cause, as in our patient, to diagnose and manage celiac disease early and, hopefully, forestall complications. PMID:27406144

Deleterious Effects of Chronic Folate Deficiency in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Helm, Susan; Blayney, Morgan; Whited, Taylor; Noroozi, Mahjabin; Lin, Sen; Kern, Semira; Green, David; Salehi, Ahmad

2017-01-01

Folate is an important B vitamin naturally found in the human diet and plays a critical role in methylation of nucleic acids. Indeed, abnormalities in this major epigenetic mechanism play a pivotal role in the pathogenesis of cognitive deficit and intellectual disability in humans. The most common cause of cognitive dysfunction in children is Down syndrome (DS). Since folate deficiency is very common among the pediatric population, we questioned whether chronic folate deficiency (CFD) exacerbates cognitive dysfunction in a mouse model of DS. To test this, adult Ts65Dn mice and their disomic littermates were chronically fed a diet free of folic acid while preventing endogenous production of folate in the digestive tract for a period of 8 weeks. Our results show that the Ts65Dn mouse model of DS was significantly more vulnerable to CFD in terms of plasma homocysteine and N5-methyltetrahydrofolate (5-MTHF) levels. Importantly, these changes were linked to degenerative alterations in hippocampal dendritic morphology and impaired nest building behavior in Ts65Dn mice. Based on our results, a rigorous examination of folate intake and its metabolism in individuals with DS is warranted. PMID:28649192

Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing.

PubMed

Chyra Kufova, Zuzana; Sevcikova, Tereza; Januska, Jaroslav; Vojta, Petr; Boday, Arpad; Vanickova, Pavla; Filipova, Jana; Growkova, Katerina; Jelinek, Tomas; Hajduch, Marian; Hajek, Roman

2018-02-17

Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance. Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients. We present design of NGS panel for 11 genes ( TTR , FGA , APOA1 , APOA2 , LYZ , GSN , CST3 , PRNP , APP , B2M , ITM2B ) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population. We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh2

PubMed Central

Gamble, Mary V; Ahsan, Habibul; Liu, Xinhua; Factor-Litvak, Pam; Ilievski, Vesna; Slavkovich, Vesna; Parvez, Faruque; Graziano, Joseph H

2007-01-01

Background Indian Asian men residing in the United Kingdom have a higher prevalence of hyperhomocysteinemia than do their European counterparts. This has been largely attributed to dietary deficiencies in cobalamin associated with vegetarianism among these Indian Asians. Objective We aimed to ascertain the prevalence of folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh. Design Plasma concentrations of homocysteine, folate, and cobalamin and urinary concentrations of creatinine were assessed in 1650 adults in Bangladesh. Results The prevalence of hyperhomocysteinemia (men: >11.4 μmol/L; women: >10.4 μmol/L) was markedly (P < 0.0001) greater among men (63%; x̄ ± SD: 15.3 ± 9.5 μmol/L) than among women (26%; 9.5 ± 4.7 μmol/L). Folate was lower (9.8 ± 6.5 and 12.3 ± 7.6 nmol/L, respectively), whereas cobalamin was higher (281 ± 115 and 256 ± 118 pmol/L, respectively) (P < 0.0001 for both) among men than among women. Folate explained 15% and cobalamin explained 5% of the variation in homocysteine concentrations. For men, folate (P = 0.005) and cobalamin (P = 0.03) were positively correlated with urinary creatinine. Smoking (P < 0.0003) and betelnut use (P < 0.0002) were independent negative predictors of folate. Conclusions Bangladeshi men have a high prevalence of hyperhomocysteinemia, which is more closely associated with folate than with cobalamin, although other factors, eg, smoking and betelnut use, may also contribute to its cause. The positive correlations between urinary creatinine and plasma folate and cobalamin were unanticipated and could suggest that, in marginal nutrition, these vitamins may be limiting for creatine biosynthesis. PMID:15941889

Genetics Home Reference: hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis

MedlinePlus

... which scar tissue forms in the lungs . Pulmonary fibrosis eventually causes difficulty breathing and can be life-threatening within ... Keavney B, Bézieau S, Mayosi BM. Mutations in FAM111B cause hereditary fibrosing ... myopathy, and pulmonary fibrosis. Am J Hum Genet. 2013 Dec 5;93( ...

Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of (161)Tb-folate and (177)Lu-folate.

PubMed

Haller, Stephanie; Pellegrini, Giovanni; Vermeulen, Christiaan; van der Meulen, Nicholas P; Köster, Ulli; Bernhardt, Peter; Schibli, Roger; Müller, Cristina

2016-12-01

The radiolanthanide (161)Tb has, in recent years, attracted increasing interest due to its favorable characteristics for medical application. (161)Tb exhibits similar properties to the widely-used therapeutic radionuclide (177)Lu. In contrast to (177)Lu, (161)Tb yields a significant number of short-ranging Auger/conversion electrons (≤50 keV) during its decay process. (161)Tb has been shown to be more effective for tumor therapy than (177)Lu if applied using the same activity. The purpose of this study was to investigate long-term damage to the kidneys after application of (161)Tb-folate and compare it to the renal effects caused by (177)Lu-folate. Renal side effects were investigated in nude mice after the application of different activities of (161)Tb-folate (10, 20, and 30 MBq per mouse) over a period of 8 months. Renal function was monitored by the determination of (99m)Tc-DMSA uptake in the kidneys and by measuring blood urea nitrogen and creatinine levels in the plasma. Histopathological analysis was performed by scoring of the tissue damage observed in HE-stained kidney sections from euthanized mice. Due to the co-emitted Auger/conversion electrons, the mean absorbed renal dose of (161)Tb-folate (3.0 Gy/MBq) was about 24 % higher than that of (177)Lu-folate (2.3 Gy/MBq). After application of (161)Tb-folate, kidney function was reduced in a dose- and time-dependent manner, as indicated by the decreased renal uptake of (99m)Tc-DMSA and the increased levels of blood urea nitrogen and creatinine. Similar results were obtained when (177)Lu-folate was applied at the same activity. Histopathological investigations confirmed comparable renal cortical damage after application of the same activities of (161)Tb-folate and (177)Lu-folate. This was characterized by collapsed tubules and enlarged glomeruli with fibrin deposition in moderately injured kidneys and glomerulosclerosis in severely damaged kidneys. Tb-folate induced dose-dependent radionephropathy over time, but did not result in more severe damage than (177)Lu-folate when applied at the same activity. These data are an indication that Auger/conversion electrons do not exacerbate overall renal damage after application with (161)Tb-folate as compared to (177)Lu-folate, even though they result in an increased dose deposition in the renal tissue. Global toxicity affecting other tissues than kidneys remains to be investigated after (161)Tb-based therapy, however.

Identification of Patients at Risk for Hereditary Colorectal Cancer

PubMed Central

Mishra, Nitin; Hall, Jason

2012-01-01

Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing. PMID:23730221

Hereditary Gigantism-the biblical giant Goliath and his brothers

PubMed Central

Donnelly, Deirdre E; Morrison, Patrick J

2014-01-01

The biblical giant Goliath has an identifiable family tree suggestive of autosomal dominant inheritance. We suggest that he had a hereditary pituitary disorder possibly due to the AIP gene, causing early onset and familial acromegaly or gigantism. We comment on the evidence within the scriptures for his other relatives including a relative with six digits and speculate on possible causes of the six digits. Recognition of a hereditary pituitary disorder in the biblical Goliath and his family sheds additional information on his and other family members’ battles with David and his relatives. PMID:25075136

Hereditary Gigantism-the biblical giant Goliath and his brothers.

PubMed

Donnelly, Deirdre E; Morrison, Patrick J

2014-05-01

The biblical giant Goliath has an identifiable family tree suggestive of autosomal dominant inheritance. We suggest that he had a hereditary pituitary disorder possibly due to the AIP gene, causing early onset and familial acromegaly or gigantism. We comment on the evidence within the scriptures for his other relatives including a relative with six digits and speculate on possible causes of the six digits. Recognition of a hereditary pituitary disorder in the biblical Goliath and his family sheds additional information on his and other family members' battles with David and his relatives.

Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy.

PubMed

Funalot, Benoît; Reynier, Pascal; Vighetto, Alain; Ranoux, Danièle; Bonnefont, Jean-Paul; Godinot, Catherine; Malthièry, Yves; Mas, Jean-Louis

2002-09-01

Leber's hereditary optic neuropathy is a mitochondrial disease caused by point mutations in mitochondrial DNA. It usually presents as severe bilateral visual loss in young adults. We report on a neurological disorder resembling Leigh syndrome, which complicated Leber's hereditary optic neuropathy in three unrelated male patients harboring mitochondrial DNA mutations at nucleotide positions 3460, 14459, and 14484, respectively. This Leigh-like encephalopathy appears to be associated with a much more severe outcome than isolated Leber's hereditary optic neuropathy.

Impact of folate supplementation on the efficacy of sulfadoxine/pyrimethamine in preventing malaria in pregnancy: the potential of 5-methyl-tetrahydrofolate.

PubMed

Nzila, Alexis; Okombo, John; Molloy, Anne M

2014-02-01

Malaria remains the leading cause of mortality and morbidity in children under the age of 5 years and pregnant women. To counterbalance the malaria burden in pregnancy, an intermittent preventive treatment strategy has been developed. This is based on the use of the antifolate sulfadoxine/pyrimethamine, taken at specified intervals during pregnancy, and reports show that this approach reduces the malaria burden in pregnancy. Pregnancy is also associated with the risk of neural tube defects (NTDs), especially in women with low folate status, and folic acid supplementation is recommended in pregnancy to lower the risk of NTDs. Thus, in malaria-endemic areas, pregnant women have to take both antifolate medication to prevent malaria and folic acid to lower the risk of NTDs. However, the concomitant use of folate and antifolate is associated with a decrease in antifolate efficacy, exposing pregnant women to malaria. Thus, there is genuine concern that this strategy may not be appropriate. We have reviewed work carried out on malaria folate metabolism and antifolate efficacy in the context of folate supplementation. This review shows that: (i) the folate supplementation effect on antifolate efficacy is dose-dependent, and folic acid doses required to protect pregnant women from NTDs will not decrease antifolate activity; and (ii) 5-methyl-tetrahydrofolate, the predominant form of folate in the blood circulation, could be administered (even at high dose) concomitantly with antifolate without affecting antifolate efficacy. Thus, strategies exist to protect pregnant women from malaria while maintaining adequate folate levels in the body to reduce the occurrence of NTDs.

Effect of Enterococcus faecium SF68 on serum cobalamin and folate concentrations in healthy dogs.

PubMed

Lucena, R; Olmedilla, A B; Blanco, B; Novales, M; Ginel, P J

2018-04-17

To study the effect of a 14-day administration of the probiotic Enterococcus faecium SF68 on serum concentrations of cobalamin and folate in healthy dogs. Thirty-six healthy dogs were randomly allocated between probiotic and control groups. Enterococcus faecium SF68 was administered to the probiotic group for 14 days whereas the control group did not receive any product. A blood sample was taken from all dogs when starting the administration (day 1), when the administration ended (day 14) and 14 days later (day 28). Serum cobalamin and folate concentrations and the canine inflammatory bowel disease activity index scores were determined at each time point. There was a progressive reduction of mean serum cobalamin in the probiotic group during the 28-day study, with significantly lower concentration at day 28 compared to baseline and day 14 concentrations. Moderate hypocobalaminaemia was observed in eight dogs at day 28. Probiotic administration was associated with a non-significant increase in mean serum folate concentration at day 14, and a significant decrease at day 28 compared with day 1. The canine inflammatory bowel disease activity index score remained unaltered during the study. Short-term Enterococcus faecium SF68 administration caused a significant reduction of mean cobalamin concentration and moderate hypocobolaminaemia in eight of 18 dogs. Monitoring serum folate appears unnecessary because the probiotic caused a non-significant increase that returned to baseline values after administration was discontinued. © 2018 British Small Animal Veterinary Association.

Rickets in Denmark.

PubMed

Beck-Nielsen, Signe Sparre

2012-02-01

Rickets is a heterogeneous group of diseases of the growing child caused by defect mineralization of bone. Nutritional rickets is caused by deficiency of vitamin D, calcium or both. Several hereditary forms of rickets exist where the disease proceeds into adulthood. Nutritional rickets was common in the past, but by introduction of preventative administration of cod liver oil and vitamin D supplementation, nutritional rickets became a rarity. During the last decades, case reports of nutritional rickets reappear in the industrialized countries. It is the general conception that in the industrialized countries, hereditary rickets is the most prevalent cause of rickets today. However, the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets in Scandinavia are unknown. The most common form of hereditary rickets is hypophosphatemic rickets (HR). The geno- and phenotype among Scandinavian patients have not been characterized. Especially, the disease in adult patients is not well described. Moreover, there are conflicting reports of the benefits of medical treatment throughout childhood, and in addition on gender differences in disease severity.

Hereditary chronic pancreatitis: implications for surgical treatment and follow-up.

PubMed

Cowles, R A; Eckhauser, F E; Knol, J A

2001-02-01

Hereditary pancreatitis is an uncommon cause of chronic pancreatitis in Western society. It should be suspected when chronic pancreatitis presents in young adults. The diagnosis is made when chronic pancreatitis is present in several members of the same family who are determined not to have other risk factors for chronic pancreatitis. Molecular research focusing on mutations in the trypsinogen gene has uncovered the genetic defects associated with hereditary pancreatitis, and this knowledge has suggested the possible pathophysiologic mechanism of this disease. Because patients with hereditary pancreatitis develop their disease early in life they are very likely to require treatment for complications. As in patients with chronic pancreatitis of other etiologies those with hereditary pancreatitis should be treated medically for acute exacerbations. When complications occur or when the disease causes intractable pain surgery is recommended. Surgical therapy is tailored to the patient's pancreatic anatomy based on endoscopic retrograde cholangiopancreatography or CT scan. The two patients described in this report underwent successful longitudinal pancreaticojejunostomy (Puestow procedure) with good results. Finally it has been shown that patients with hereditary pancreatitis are at increased risk for developing pancreatic adenocarcinoma. Although not widely used pancreatic cancer screening programs have been suggested for surveillance of these patients.

Excess folate during adolescence suppresses thyroid function with permanent deficits in motivation and spatial memory

PubMed Central

Sittig, L. J.; Herzing, L. B. K.; Xie, H.; Batra, K. K.; Shukla, P. K.; Redei, E. E.

2012-01-01

Cognitive and memory deficits can be caused or exacerbated by dietary folate deficiency, which has been combatted by the addition of folate to grains and dietary supplements. The recommended dose of the B9 vitamin folate is 400 μg/day for adolescents and non-pregnant adults, and consumption above the recommended daily allowance is not considered to be detrimental. However, the effects of excess folate have not been tested in adolescence when neuro and endocrine development suggest possible vulnerability to long-term cognitive effects. We administered folate-supplemented (8.0 mg folic acid/kg diet) or control lab chow (2.7 mg folic acid/kg diet) to rats ad libitum from 30 to 60 days of age, and subsequently tested their motivation and learning and memory in the Morris water maze. We found that folate-supplemented animals had deficits in motivation and spatial memory, but they showed no changes of the learning- and memory-related molecules growth-associated protein-43 or Gs-α subunit protein in the hippocampus. They had decreased levels of thyroxine (T4) and triiodothyronine (T3) in the periphery and decreased protein levels of thyroid receptor-α1 and -α2 (TRα1 and TRα2) in the hippocampus. The latter may have been due to an observed increase of cytosine–phosphate–guanosine island methylation within the putative thyroid hormone receptor-α promoter, which we have mapped for the first time in the rat. Overall, folate supplementation in adolescence led to motivational and spatial memory deficits that may have been mediated by suppressed thyroid hormone function in the periphery and hippocampus. PMID:22050771

Excess folate during adolescence suppresses thyroid function with permanent deficits in motivation and spatial memory.

PubMed

Sittig, L J; Herzing, L B K; Xie, H; Batra, K K; Shukla, P K; Redei, E E

2012-03-01

Cognitive and memory deficits can be caused or exacerbated by dietary folate deficiency, which has been combatted by the addition of folate to grains and dietary supplements. The recommended dose of the B9 vitamin folate is 400 µg/day for adolescents and non-pregnant adults, and consumption above the recommended daily allowance is not considered to be detrimental. However, the effects of excess folate have not been tested in adolescence when neuro and endocrine development suggest possible vulnerability to long-term cognitive effects. We administered folate-supplemented (8.0 mg folic acid/kg diet) or control lab chow (2.7 mg folic acid/kg diet) to rats ad libitum from 30 to 60 days of age, and subsequently tested their motivation and learning and memory in the Morris water maze. We found that folate-supplemented animals had deficits in motivation and spatial memory, but they showed no changes of the learning- and memory-related molecules growth-associated protein-43 or Gs-α subunit protein in the hippocampus. They had decreased levels of thyroxine (T4) and triiodothyronine (T3) in the periphery and decreased protein levels of thyroid receptor-α1 and -α2 (TRα1 and TRα2) in the hippocampus. The latter may have been due to an observed increase of cytosine-phosphate-guanosine island methylation within the putative thyroid hormone receptor-α promoter, which we have mapped for the first time in the rat. Overall, folate supplementation in adolescence led to motivational and spatial memory deficits that may have been mediated by suppressed thyroid hormone function in the periphery and hippocampus. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Hyperhomocysteinemia and vitamin B-12 deficiency are more striking in Syrians than in Germans--causes and implications.

PubMed

Herrmann, Wolfgang; Obeid, Rima; Jouma, Muhidien

2003-01-01

Hyperhomocysteinemia is an accepted risk factor for coronary artery disease, but the determining factors are not fully understood. We investigated hyperhomocysteinemia and vitamin deficiency in Syrian coronary patients and apparently healthy Syrian and German controls. We enrolled 273 Syrian patients with angiographically confirmed stenosis, along with 159 Syrian and 75 German controls. Plasma total homocysteine (HCY), cystathionine, methylmalonic acid (MMA), vitamin B-6, B-12, folate, lipids, apolipoproteins and methylenetetrahydrofolate reductase (C677T-MTHFR) mutation were analysed. There was a very high prevalence of hyperhomocysteinemia (>12 micromol/l) in Syrians (patients 61%, controls 44%, Germans 16%) together with functional vitamin B-12 deficiency diagnosed by elevated MMA (patients 49%, controls 47%, Germans 3%), which was in contrast to the low frequency of decreased serum vitamin B-12 (12% in patients, 7% in Syrian controls). The HCY concentration in German controls was lower than in Syrians, median 8.8 vs. 11.3 micromol/l. The vitamin B-12 deficiency induces folate trapping; higher levels of folate are needed to prevent hyperhomocysteinemia. Germans achieved the HCY level of < or =12 micromol/l at significantly lower folate concentrations > or =4.4 ng/ml, than Syrians with normal MMA (> or =16.7 nmol/l folate) or Syrians with high MMA (> or =23.3 nmol/l folate). Smoking and homozygous state for C677T-MTHFR mutation contributed to hyperhomocysteinemia. We could confirm that the reasons for hyperhomocysteinemia in Syrians were in fact mostly related to a relative folate deficiency, which is due to a vitamin B-12 shortage. Vitamin B-12 deficiency induces folate trapping. Besides lifestyle, other presently unknown factors may contribute to hyperhomocysteinemia and vitamin B-12 deficiency in Syrians.

Seasonal folate serum concentrations at different nutrition.

PubMed

Krajcovicová-Kudlácková, Marica; Valachovicová, Martina; Blazícek, Pavel

2013-03-01

Folic acid (vitamin B9) rich sources are leafy green vegetables, legumes, whole grains, egg yolk, liver, and citrus fruit. In winter and early spring, there could be insufficient supply of vegetables and fruit and thus lower intake of folic acid and possible deficient folic acid blood concentrations. The aim of the study was to assess serum vitamin B9 concentrations depending on the season (the last third of winter - March, the last third of spring - May/June and the beginning of autumn - September) and different nutritional habits (apparently healthy adults non-smoking, non-obese 366 subjects; 204 persons of general population on traditional mixed diet; and 162 long-term lacto-ovo vegetarians). In general population group, the mean concentration of folate in March was low (narrowly above lower reference limit) with high incidence of deficient values - 31.5%. In May/ June vs. March was folate concentration significantly higher with deficient values in 13.2% of individuals. The highest serum values were observed in September with 11.1% of deficient values. In vegetarian vs. non-vegetarian group, significantly higher folate concentrations were found in each season with no deficient values. Folate and vitamin B12 are the regulators of homocysteinemia; plant food lacks of vitamin B12. The deficient folate serum values in March caused the mild hyperhomocysteinemia in 12.3% of individuals vs. only 5.9% and 4.8% of subjects in groups investigated in May/June and September. In spite of high folate concentrations in all investigations and no deficient value, 19.6-22.8% of vegetarians suffer from mild hyperhomocysteinemia as a consequence of deficient vitamin B12 concentrations in one quarter of subjects. As far as the general population is concerned, our findings suggest that winter and early spring are critical seasons in regards to optimal serum folate concentrations.

[Hereditary hypophosphatemia in adults].

PubMed

Vélayoudom-Céphise, F-L; Vantyghem, M-C; Wémeau, J-L

2005-12-17

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).

Hereditary pediatric cataract on the Arabian Peninsula

PubMed Central

Khan, Arif O.

2011-01-01

Hereditary pediatric cataract on the Arabian Peninsula does not follow the same epidemiological patterns as described for Western populations. This article describes selected genetic causes for inherited pediatric cataract in the region. PMID:23960971

Hereditary Gingival Fibromatosis

ERIC Educational Resources Information Center

Nevin, N. C.

1971-01-01

Case studies of two siblings suffering from a gum disorder in which enlargement of the gingival mucosa is caused by a fibrosis. The disorder in the two children was felt to be an hereditary recessive trait. (CD)

Nutritional causes of anemia in Mexican children under 5 years. Results from the 2006 National Health and Nutrition Survey.

PubMed

De la Cruz-Góngora, Vanessa; Villalpando, Salvador; Rebollar, Rosario; Shamah-Levy, Teresa; Méndez-Gómez Humarán, Ignacio

2012-01-01

To describe the frequency and severity of anemia and the nutritional variables associated to hemoglobin levels (Hb) in children <5 years of age. We studied 981 children measuring hemoglobin and serum concentrations of ferritin, soluble transferrin receptors (sTfR), C-reactive protein (CRP), zinc, iron, copper, magnesium, folate and vitamin B12. Ordinal logit or multiple regression models were constructed to assess the risk for anemia and the associations among nutritional variables. The overall prevalence of anemia was 20.6%, of which 14% were mild cases and 6.38% moderate. Anemia was associated with iron deficiency (ID) in 42.17% of the cases, whereas ID coexisted with either folate or vitamin B12 deficiency in 9%. Only 2% of cases of anemia were associated with either folate or vitamin B12 deficiencies. CRP (coef: 0.17 g/dl) and third tertile of s-copper (coef: -0.85 g/dl) were associated to unexplained anemia (p<0.05). ID is the main cause of anemia in children <5 y. Folate and vitamin B12 concentrations were associated with anemia. CRP was associated to unexplained anemia. However, vitamin A deficiency, which is associated with anemia, was not studied.

Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration.

PubMed

Field, Martha S; Shields, Kelsey S; Abarinov, Elena V; Malysheva, Olga V; Allen, Robert H; Stabler, Sally P; Ash, Jessica A; Strupp, Barbara J; Stover, Patrick J; Caudill, Marie A

2013-01-01

Impaired utilization of folate is caused by insufficient dietary intake and/or genetic variation and has been shown to prompt changes in related pathways, including choline and methionine metabolism. These pathways have been shown to be sensitive to variation within the Mthfd1 gene, which codes for a folate-metabolizing enzyme responsible for generating 1-carbon (1-C)-substituted folate derivatives. The Mthfd1(gt/+) mouse serves as a potential model of human Mthfd1 loss-of-function genetic variants that impair MTHFD1 function. This study investigated the effects of the Mthfd1(gt/+) genotype and folate intake on markers of choline, folate, methionine, and transsulfuration metabolism. Male Mthfd1(gt/+) and Mthfd1(+/+) mice were randomly assigned at weaning (3 wk of age) to either a control (2 mg/kg folic acid) or folate-deficient (0 mg/kg folic acid) diet for 5 wk. Mice were killed at 8 wk of age following 12 h of food deprivation; blood and liver samples were analyzed for choline, methionine, and transsulfuration biomarkers. Independent of folate intake, mice with the Mthfd1(gt/+) genotype had higher hepatic concentrations of choline (P = 0.005), betaine (P = 0.013), and dimethylglycine (P = 0.004) and lower hepatic concentrations of glycerophosphocholine (P = 0.002) relative to Mthfd1(+/+) mice. Mthfd1(gt/+) mice also had higher plasma concentrations of homocysteine (P = 0.0016) and cysteine (P < 0.001) as well as lower plasma concentrations of methionine (P = 0.0003) and cystathionine (P = 0.011). The metabolic alterations observed in Mthfd1(gt/+) mice indicate perturbed choline and folate-dependent 1-C metabolism and support the future use of Mthfd1(gt/+) mice as a tool to investigate the impact of impaired 1-C metabolism on disease outcomes.

Genotoxicity testing of peptides: folate deprivation as a marker of exaggerated pharmacology.

PubMed

Guérard, Melanie; Zeller, Andreas; Festag, Matthias; Schubert, Christine; Singer, Thomas; Müller, Lutz

2014-09-15

The incidence of micronucleated-cells is considered to be a marker of a genotoxic event and can be caused by direct- or indirect-DNA reactive mechanisms. In particular, small increases in the incidence of micronuclei, which are not associated with toxicity in the target tissue or any structurally altering properties of the compound, trigger the suspicion that an indirect mechanism could be at play. In a bone marrow micronucleus test of a synthetic peptide (a dual agonist of the GLP-1 and GIP receptors) that had been integrated into a regulatory 13-week repeat-dose toxicity study in the rat, small increases in the incidence of micronuclei had been observed, together with pronounced reductions in food intake and body weight gain. Because it is well established that folate plays a crucial role in maintaining genomic integrity and pronounced reductions in food intake and body weight gain were observed, folate levels were determined from plasma samples initially collected for toxicokinetic analytics. A dose-dependent decrease in plasma folate levels was evident after 4 weeks of treatment at the mid and high dose levels, persisted until the end of the treatment duration of 13-weeks and returned to baseline levels during the recovery period of 4 weeks. Based on these properties, and the fact that the compound tested (peptide) per se is not expected to reach the nucleus and cause DNA damage, the rationale is supported that the elevated incidence of micronucleated polychromatic erythrocytes is directly linked to the exaggerated pharmacology of the compound resulting in a decreased folate level. Copyright © 2014 Elsevier Inc. All rights reserved.

What is in a cause? Exploring the relationship between genetic cause and felt stigma

PubMed Central

Sankar, Pamela; Cho, Mildred K.; Wolpe, Paul Root; Schairer, Cynthia

2008-01-01

Purpose Concern over stigma as a consequence of genetic testing has grown in response to the recent increase in genetic research and testing resulting from the Human Genome Project. However, whether a genetic or hereditary basis necessarily confers a stigma to a condition remains unexamined. Methods We performed a qualitative interview study with 86 individuals with one of four conditions: deafness or hearing loss, breast cancer, sickle cell disease, and cystic fibrosis. The first two groups were divided approximately between people who ascribed their conditions to a genetic or hereditary cause and those who did not. Results Respondents interpreted genetic or hereditary causes and nongenetic causes in a variety of ways. Subjects with breast cancer reported the most consistently negative interpretation of genetic cause. This response concerned future ill health, not an enduring sense of stigma. Deaf and hard of hearing subjects provided the most consistently positive comments about a genetic or hereditary basis to their condition, casting familial hearing loss as a vital component of group and individual identity. Respondents with sickle cell disease and cystic fibrosis offered similar and positive interpretations of the genetic cause of their condition insofar as it meant their conditions were not contagious. Conclusions Although some subjects report feeling stigmatized as a result of their condition, this stigmatization is not uniformly associated with the condition’s cause, genetic or otherwise. Instead, stigma emerges from a variety of sources in the context of the lived experience of a particular condition. PMID:16418597

Genotoxicity testing of peptides: Folate deprivation as a marker of exaggerated pharmacology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guérard, Melanie, E-mail: melanie.guerard@roche.com; Zeller, Andreas; Festag, Matthias

2014-09-15

The incidence of micronucleated-cells is considered to be a marker of a genotoxic event and can be caused by direct- or indirect-DNA reactive mechanisms. In particular, small increases in the incidence of micronuclei, which are not associated with toxicity in the target tissue or any structurally altering properties of the compound, trigger the suspicion that an indirect mechanism could be at play. In a bone marrow micronucleus test of a synthetic peptide (a dual agonist of the GLP-1 and GIP receptors) that had been integrated into a regulatory 13-week repeat-dose toxicity study in the rat, small increases in the incidencemore » of micronuclei had been observed, together with pronounced reductions in food intake and body weight gain. Because it is well established that folate plays a crucial role in maintaining genomic integrity and pronounced reductions in food intake and body weight gain were observed, folate levels were determined from plasma samples initially collected for toxicokinetic analytics. A dose-dependent decrease in plasma folate levels was evident after 4 weeks of treatment at the mid and high dose levels, persisted until the end of the treatment duration of 13-weeks and returned to baseline levels during the recovery period of 4 weeks. Based on these properties, and the fact that the compound tested (peptide) per se is not expected to reach the nucleus and cause DNA damage, the rationale is supported that the elevated incidence of micronucleated polychromatic erythrocytes is directly linked to the exaggerated pharmacology of the compound resulting in a decreased folate level. - Highlights: • A synthetic peptide has been evaluated for potential genotoxicity • Small increases in an integrated (13-weeks) micronucleus test were observed • Further, animals had a pronounced reductions in food intake and body weight gain • A dose-dependent decrease in plasma folate levels was evident from week 4 onwards • Elevated micronuclei-incidence due to the exaggerated pharmacology.« less

Familial Gastric Cancers

PubMed Central

Setia, Namrata; Clark, Jeffrey W.; Duda, Dan G.; Hong, Theodore S.; Kwak, Eunice L.; Mullen, John T.

2015-01-01

Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%–3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. Implications for Practice: Although the majority of gastric adenocarcinomas are sporadic with many of those related to chronic Helicobacter pylori infection, approximately 10% of the cases show familial aggregation, and a specific hereditary cause is determined in 1%–3% cases. This review describes the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. Ultimately, a better understanding of the biology of these conditions should allow early identification and intervention as part of a multidisciplinary approach involving oncologists, surgeons, genetic counselors, and pathologists. PMID:26424758

Serum levels of folate and cobalamin in women with recurrent spontaneous abortion.

PubMed

Sütterlin, M; Bussen, S; Ruppert, D; Steck, T

1997-10-01

We evaluated the folate and cobalamin status in 29 non-pregnant women with a history of recurrent spontaneous abortion (three or more consecutive) of unknown aetiology in comparison to 29 healthy nulligravidae of similar reproductive age (controls). Serum concentrations of folate and cobalamin showed no significant differences between the two groups. No correlation between age and vitamin concentrations was found. In the study group there was a significant negative correlation of the number of previous abortions and the concentration of serum folate. Patients with at least four previous miscarriages had significantly lower serum values of folic acid than women with three abortions, but not than controls. The underlying cause of this finding remains unclear. In conclusion, the serum concentrations of folic acid and vitamin B12 are not significantly altered in women with unexplained recurrent spontaneous abortions, and an association between a deficiency of these vitamins and an increased risk of pregnancy loss appears to be questionable in the majority of gestations.

The epigenetic effects of a high prenatal folate intake in male mouse fetuses exposed in utero to arsenic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsang, Verne; Fry, Rebecca C.; Niculescu, Mihai D.

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never beenmore » thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. Highlights: ► We used transplacental CD1 mice model for inorganic arsenic (iAs) carcinogenesis. ► We examined the effects of gestational iAs and high folate exposure on DNA methylation. ► iAs–folate interaction resulted in low fetal weights and changes in DNA methylation. ► Epigenetically altered genes were associated with cancer and neurodevelopment. ► We showed that in utero iAs–folate interaction negatively affects fetal development.« less

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

PubMed Central

Estrada-Cuzcano, Alejandro; Martin, Shaun; Chamova, Teodora; Synofzik, Matthis; Timmann, Dagmar; Holemans, Tine; Andreeva, Albena; Reichbauer, Jennifer; De Rycke, Riet; Chang, Dae-In; van Veen, Sarah; Samuel, Jean; Schöls, Ludger; Pöppel, Thorsten; Mollerup Sørensen, Danny; Asselbergh, Bob; Klein, Christine; Zuchner, Stephan; Jordanova, Albena; Vangheluwe, Peter; Tournev, Ivailo; Schüle, Rebecca

2017-01-01

Abstract Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement. PMID:28137957

Inhibition of ligand exchange kinetics via active-site trapping with an antibody fragment.

PubMed

Oyen, David; Steyaert, Jan; Barlow, John N

2014-04-01

We describe the first example of an inhibitory antibody fragment (nanobody ca1697) that binds simultaneously to an enzyme (the enzyme dihydrofolate reductase from Escherichia coli) and its bound substrate (folate). Binding of the antibody to the substrate causes a 20-fold reduction in the rate of folate exchange kinetics. This work opens up the prospect of designing new types of antibody-based inhibitors of enzymes and receptors through suitable design of immunogens.

Effect of Freezing, Thermal Pasteurization, and Hydrostatic Pressure on Fractionation and Folate Recovery in Egg Yolk.

PubMed

Naderi, Nassim; Pouliot, Yves; House, James D; Doyen, Alain

2017-09-06

In this study, the impact of pasteurization and freezing of raw material, as performed at a commercial scale, on egg yolk fractionation and folate recovery was assessed. Freezing induced denaturation of the lipoproteins in egg yolk, which prevented further fractionation of the yolk. Thermal pasteurization of egg yolk at 61.1 °C for 3.5 min as well as high hydrostatic pressure (HHP) treatment (400 MPa for 5 min) did not change (p < 0.05) the composition of egg yolk or yolk fractions after their recovery by centrifugation. Expressed as dry matter, folate in pasteurized yolk was measured to be 599 μg/100 g, while its concentration reached 1969.7 μg/100 g for pasteurized granule and 1902.5 μg/100 g for HHP-treated granule. Folate was not detected in plasma, emphasizing the complete separation of yolk folate into granule. Further, we studied the effect of HHP on different dilutions of egg yolk, which were then fractionated. Egg yolk was diluted with water at different concentrations (0.1, 1.0, 10, 25, and 50%), HHP-treated at 400 MPa for 5 min, and centrifuged. Characterization of the compositions of the separated granule and plasma followed. Folate was stable under the HHP conditions used. However, HHP caused separation of folate from the yolk structure into water-soluble plasma. After HHP processing, the amount of folate detected in the plasma fraction was significantly (p < 0.05) higher (1434.9 μg/100 g) in the 25% diluted samples but was significantly (p < 0.05) lower in HHP-treated granule samples. Native sodium dodecyl sulfate-polyacrylamide gel electrophoresis results showed that phosvitin, α-livetin, and apovitellenin VIa were the proteins most resistant to HHP. This study confirms that dilution of egg yolk before HHP treatment can significantly (p < 0.05) change the composition of granule and plasma fractions after centrifugal fractionation of egg yolk.

The Epigenetic Effects of a High Prenatal Folate Intake in Male Mouse Fetuses Exposed In Utero to Arsenic

PubMed Central

Tsang, Verne; Fry, Rebecca C.; Niculescu, Mihai D.; Rager, Julia E.; Saunders, Jesse; Paul, David S.; Zeisel, Steven H.; Waalkes, Michael P.; Stýblo, Miroslav; Drobná, Zuzana

2012-01-01

Inorganic arsenic (iAs) is a complete transplacental carcinogen in mice. Previous studies have demonstrated that in utero exposure to iAs promotes cancer in adult mouse offspring, possibly acting through epigenetic mechanisms. Humans and rodents enzymatically convert iAs to its methylated metabolites. This reaction requires S-adenosylmethionine (SAM) as methyl group donor. SAM is also required for DNA methylation. Supplementation with folate, a major dietary source of methyl groups for SAM synthesis, has been shown to modify iAs metabolism and the adverse effects of iAs exposure. However, effects of gestational folate supplementation on iAs metabolism and fetal DNA methylation have never been thoroughly examined. In the present study, pregnant CD1 mice were fed control (i.e. normal folate, or 2.2 mg/kg) or high folate diet (11 mg/kg) from gestational day (GD) 5 to 18 and drank water with 0 or 85 ppm of As (as arsenite) from GD8 to 18. The exposure to iAs significantly decreased body weight of GD18 fetuses and increased both SAM and S-adenosylhomocysteine (SAH) concentrations in fetal livers. High folate intake lowered the burden of total arsenic in maternal livers but did not prevent the effects of iAs exposure on fetal weight or hepatic SAM and SAH concentrations. In fact, combined folate-iAs exposure caused further significant body weight reduction. Notably, iAs exposure alone had little effect on DNA methylation in fetal livers. In contrast, the combined folate-iAs exposure changed the CpG island methylation in 2,931 genes, including genes known to be imprinted. Most of these genes were associated with neurodevelopment, cancer, cell cycle, and signaling networks. The canonical Wnt-signaling pathway, which regulates fetal development, was among the most affected biological pathways. Taken together, our results suggest that a combined in utero exposure to iAs and a high folate intake may adversely influence DNA methylation profiles and weight of fetuses, compromising fetal development and possibly increasing the risk for early-onset of disease in offspring. PMID:22959928

Hereditary Angioedema: Not An Allergy

PubMed Central

Bhivgade, Sanjay; Melkote, Shubha; Ghate, Smita; Jerajani, H R

2012-01-01

Hereditary angioedema is a genetic disorder due to a deficiency or malfunction of C1 esterase inhibitor. We herein describe a case of 25-year-old male who presented with swelling over face since one day. There was history of similar episodes since two years with gradual subsidence of swelling without any treatment. Investigations revealed grossly reduced complement C4 and C1 esterase inhibitor level. Patient was diagnosed to have hereditary angioedema type 1 and started on stanozolol 2 mg three times a day with no recurrence in one year of follow-up. Hereditary angioedema resembles angioedema of an allergic reaction. However, the cause is different. PMID:23248378

Heterogeneity of Hereditary Hearing Loss in Iran: a Comprehensive Review

PubMed Central

Beheshtian, Maryam; Babanejad, Mojgan; Azaiez, Hela; Bazazzadegan, Niloofar; Kolbe, Diana; Sloan-Heggen, Christina; Arzhangi, Sanaz; Booth, Kevin; Mohseni, Marzieh; Frees, Kathy; Hossein Azizi, Mohammad; Daneshi, Ahmad; Farhadi, Mohammad; Kahrizi, Kimia; Smith, Richard JH; Najmabadi, Hossein

2017-01-01

A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran. In this review, we present more than 39 deafness genes reported to cause non-syndromic HHL in Iran, of which the most prevalent causative genes include GJB2, SLC26A4, MYO15A, and MYO7A. In addition, we highlight some of the more common genetic causes of syndromic HHL in Iran. These results are of importance for further investigation and elucidation of the molecular basis of HHL in Iran and also for developing a national diagnostic tool tailored to the Iranian context enabling early and efficient diagnosis of hereditary hearing impairment. PMID:27743438

Targeting Trypsin-Inflammation Axis for Pancreatitis Therapy in a Humanized Pancreatitis Model

DTIC Science & Technology

2016-10-01

PRSS1 gene) causing hereditary pancreatitis is now well established. We developed a transgenic mouse using a Bacterial Artificial Chromosome harboring...trypsinogen gene (PRSS1 gene) causing hereditary pancreatitis is now well established. We developed a transgenic mouse using a Bacterial Artificial... Breeding and expansion of the R122H mouse colony: Period: February 2016-present. After rederivation, the colony of R122H has been expanded at the

De novo REEP2 missense mutation in pure hereditary spastic paraplegia.

PubMed

Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-05-01

Alterations in proteins that regulate endoplasmic reticulum morphology are common causes of hereditary spastic paraplegia (SPG1-78, plus others). Mutations in the REEP1 gene that encodes an endoplasmic reticulum-shaping protein are well-known causes of SPG31, a common autosomal dominant spastic paraplegia. A closely-related gene, REEP2, is mutated in SPG72, with both autosomal and recessive inheritances. Here, we report a patient with a pure hereditary spastic paraplegia due to a de novo missense mutation (c.119T > G, p.Met40Arg) in REEP2 at a highly-conserved residue very close to another known pathogenic missense change. This represents only the second autosomal dominant SPG72 missense mutation reported.

Combined pulmonary involvement in hereditary lysozyme amyloidosis with associated pulmonary sarcoidosis: a case report.

PubMed

McCarthy, Cormac; Deegan, Alexander P; Garvey, John F; McDonnell, Timothy J

2013-12-17

Sarcoidosis is a multisystem inflammatory disorder of unknown cause which can affect any organ system. Autosomal dominant lysozyme amyloidosis is a very rare form of hereditary amyloidosis. The Arg64 variant is extraordinarily rare with each family showing a particular pattern of organ involvement, however while Sicca syndrome, gastrointestinal involvement and renal failure are common, lymph node involvement is very rare. In this case report we describe the first reported case of sarcoidosis in association with hereditary lysozyme amyloidosis.

Clinical guideline seom: hereditary colorectal cancer.

PubMed

Guillén-Ponce, C; Serrano, R; Sánchez-Heras, A B; Teulé, A; Chirivella, I; Martín, T; Martínez, E; Morales, R; Robles, L

2015-12-01

Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer; these mutations are estimated to account for only 5-6 % of colorectal cancer (CRC) cases overall. Up to 25-30 % of patients have a family history of CRC that suggests a hereditary component, common exposures among family members, or a combination of both. Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases. A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer. We describe genetics, current diagnosis and management of CRC hereditary syndromes pointing to a multidisciplinary approach to achieve the best results in patients and family outcomes.

The effects of feeding rats diets deficient in folic acid and related methyl donors on the blood pressure and glucose tolerance of the offspring.

PubMed

Maloney, Christopher A; Hay, Susan M; Rees, William D

2009-05-01

In humans poor maternal folate status is associated with a decrease in infant birth weight. As low birth weight increases the risk of cardiovascular and metabolic disease in adults, an inadequate supply of folic acid in the mother's diet may increase the susceptibility of the offspring to disease. We have fed laboratory rats diets deficient in folic acid and the related methyl donors methionine and choline to examine the effects on growth, blood pressure and insulin action in the offspring. Poor folate status transiently increased fetal growth but did not produce a long-term change in body weight. There were, however, small changes in the hearts of the female offspring. When folate deficiency was combined with low intakes of methionine and choline, the kidneys of the male offspring were proportionately smaller, probably because of the limited availability of methionine. There was no effect on the blood pressure of either the male or female offspring. The pancreatic insulin content of fetuses from animals fed the folate-deficient diets were higher than those of the controls. Following an oral glucose challenge, there was a weak trend for glucose-stimulated insulin release to be increased in the offspring of dams fed the folate-deficient diet. The changes in insulin concentrations were, however, much smaller than the corresponding changes observed in the offspring of animals fed protein-deficient diets. These results suggest that folate deficiency during gestation causes modest changes to the insulin axis of the fetus.

Association between dietary folate intake and blood status of folate and homocysteine in Malaysian adults.

PubMed

Chew, Siew-Choo; Khor, Geok-Lin; Loh, Su-Peng

2011-01-01

Folate is of prime interest among investigators in nutrition due to its multiple roles in maintaining health, especially in preventing neural tube defects and reducing the risk of cardiovascular diseases. We investigated the effect of dietary folate intake on blood folate, vitamin B(12), vitamin B(6), and homocysteine status. One hundred subjects consisting of Chinese and Malay subjects volunteered to participate in this cross-sectional study. Dietary folate intake was assessed by 24-h dietary recall and a food-frequency questionnaire (FFQ). Serum and red blood cell folate were analyzed using a microbiological assay, while serum vitamin B(12) was determined by electrochemiluminescence immunoassay (ECLIA), and high-performance liquid chromatography (HPLC) was used for the determination of serum vitamin B(6) and homocysteine. The mean folate intake, serum folate, RBC folate, serum vitamin B(12), and B(6), were higher in female subjects, with the exception of serum homocysteine. The Chinese tended to have higher folate intake, serum folate, RBC folate, and vitamin B(12). A positive association was found between folate intake and serum folate while a negative association was found between folate intake and serum homocysteine. Stepwise linear regression of serum folate showed a significant positive coefficient for folate intake whilst a significant negative coefficient was found for serum homocysteine when controlling for age, gender, and ethnicity. In conclusion, high dietary folate intake helps to increase serum folate and to lower the homocysteine levels.

Calcium absorption, kinetics, bone density, and bone structure in patients with hereditary vitamin D-resistant rickets

USDA-ARS?s Scientific Manuscript database

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the vitamin D receptor gene. Children with HVDRR suffer from severe hypocalcemia and rickets that are treatable with extremely high-dose calcium supplements. Surprisingly, spontaneous recovery of calcium metabolis...

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.

PubMed

Castellanos, Elisabeth; Gel, Bernat; Rosas, Inma; Tornero, Eva; Santín, Sheila; Pluvinet, Raquel; Velasco, Juan; Sumoy, Lauro; Del Valle, Jesús; Perucho, Manuel; Blanco, Ignacio; Navarro, Matilde; Brunet, Joan; Pineda, Marta; Feliubadaló, Lidia; Capellá, Gabi; Lázaro, Conxi; Serra, Eduard

2017-01-04

We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk.

Assessing the association between natural food folate intake and blood folate concentrations: a systematic review and Bayesian meta-analysis of trials and observational studies.

PubMed

Marchetta, Claire M; Devine, Owen J; Crider, Krista S; Tsang, Becky L; Cordero, Amy M; Qi, Yan Ping; Guo, Jing; Berry, Robert J; Rosenthal, Jorge; Mulinare, Joseph; Mersereau, Patricia; Hamner, Heather C

2015-04-10

Folate is found naturally in foods or as synthetic folic acid in dietary supplements and fortified foods. Adequate periconceptional folic acid intake can prevent neural tube defects. Folate intake impacts blood folate concentration; however, the dose-response between natural food folate and blood folate concentrations has not been well described. We estimated this association among healthy females. A systematic literature review identified studies (1 1992-3 2014) with both natural food folate intake alone and blood folate concentration among females aged 12-49 years. Bayesian methods were used to estimate regression model parameters describing the association between natural food folate intake and subsequent blood folate concentration. Seven controlled trials and 29 observational studies met the inclusion criteria. For the six studies using microbiologic assay (MA) included in the meta-analysis, we estimate that a 6% (95% Credible Interval (CrI): 4%, 9%) increase in red blood cell (RBC) folate concentration and a 7% (95% CrI: 1%, 12%) increase in serum/plasma folate concentration can occur for every 10% increase in natural food folate intake. Using modeled results, we estimate that a natural food folate intake of ≥ 450 μg dietary folate equivalents (DFE)/day could achieve the lower bound of an RBC folate concentration (~ 1050 nmol/L) associated with the lowest risk of a neural tube defect. Natural food folate intake affects blood folate concentration and adequate intakes could help women achieve a RBC folate concentration associated with a risk of 6 neural tube defects/10,000 live births.

[Asymptomatic classical hereditary xanthinuria type 1].

PubMed

Yakubov, Renata; Nir, Vered; Kassem, Eiass; Klein-Kremer, Adi

2012-06-01

We report on a girl who was diagnosed with classical hereditary xanthinuria due to an incidental finding of extremely low Levels of uric acid in the blood. The girl is compLetely asymptomatic. Hereditary xanthinuria is a rare autosomal recessive disease that usually causes early urolithiasis but may cause rheumatoid arthritis-like disease and even be associated with defects in the formation of bone, hair and teeth. In Israel it has mostly been described in patients of Bedouin origin. Throughout the world, only about 150 cases have been described; about two thirds of these patients were asymptomatic. Since the clinical presentation and age of symptom appearance are diverse, the case raises questions as to the required follow-up of these patients and as to whether a low oxalate diet should be initiated.

Hereditary medullary thyroid carcinoma: the management dilemma.

PubMed

Zhou, Ping; Liu, Jian; Cheng, Shao-Wen; Wang, Bing; Yang, Rong; Peng, Ling

2012-06-01

Hereditary medullary thyroid carcinoma (hereditary MTC) is a rare malignancy, accounting for 25-30% of all MTC. It occurs as part of multiple endocrine neoplasia type 2 (MEN 2). Autosomal dominant gain-of-function mutations in the RET proto-oncogene is the cause of the disease, in which the common mutations are codons 609, 611, 618, 620, 630, 634 and 918. In recent years, the spectrum of RET gene mutations has changed. The classical mutations reduced, whereas the less aggressive mutations increased. Hereditary MTC is a time-dependent disease. Stages of the disorder at diagnosis can significantly influence survival rates. Based on the genotype-phenotype, RET mutations have been classified into four risk levels by American Thyroid Association (ATA) at 2009. The classification system guides the hereditary MTC management, including risk assessment, biochemical screenings and surgical intervention. Though the application of genetic testing and codon-specific phenotypes in hereditary MTC diagnosis is effective with high accuracy, there are some difficulties in implementing RET gene testing as a routine for MTC diagnosis. And most of carriers with RET mutations did not undergo thyroidectomy at the age recommended by the ATA guidelines. The aim of the study is to review the hereditary MTC and discuss the management dilemma.

Biofortification of riboflavin and folate in idli batter, based on fermented cereal and pulse, by Lactococcus lactis N8 and Saccharomyces boulardii SAA655.

PubMed

Chandrasekar Rajendran, S C; Chamlagain, B; Kariluoto, S; Piironen, V; Saris, P E J

2017-06-01

Lactococcus lactis N8 and Saccharomyces boulardii SAA655 were investigated for their ability to synthesize B-vitamins (riboflavin and folate) and their functional role as microbial starters in idli fermentation. In this study, ultra-high performance liquid chromatography and microbiological assay were used to determine the total riboflavin and folate content respectively. Increased levels of folate were evident in both L. lactis N8 and S. boulardii SAA655 cultivated medium. Enhanced riboflavin levels were found only in S. boulardii SAA655 grown medium, whereas decreased riboflavin level was found in L. lactis N8 cultivated medium. To evaluate the functional role of microbial starter strains, L. lactis N8 and S. boulardii SAA655 were incorporated individually and in combination into idli batter, composed of wet grounded rice and black gram. For the experiments, naturally fermented idli batter was considered as control. The results indicated that natural idli fermentation did not enhance the riboflavin level and depleted folate levels by half. In comparison with control, L. lactis N8 and S. boulardii SAA655 incorporated idli batter (individually and in combination) increased riboflavin and folate levels by 40-90%. Apart from compensating the folate loss caused by natural fermentation, S. boulardii SAA655 fermented idli batter individually and in combination with L. lactis N8 also showed the highest leavening character. Moreover, the microbial starter incorporation did not significantly influence the pH of idli batter. Incorporation of L. lactis N8 and S. boulardii SAA655 can evidently enhance the functional and technological characteristics of idli batter. UN General Assembly declared 2016 the International Year of pulses emphasizing the importance of legumes as staple food. Furthermore, this is the first experimental report of in situ biofortifcation of riboflavin and folate using microbes in pulse based fermented staple food. The current study suggests possible avenues for research towards an economical strategy to reduce B-vitamin deficiency among the consuming population. © 2017 The Society for Applied Microbiology.

Familial Gastric Cancers.

PubMed

Setia, Namrata; Clark, Jeffrey W; Duda, Dan G; Hong, Theodore S; Kwak, Eunice L; Mullen, John T; Lauwers, Gregory Y

2015-12-01

Although the majority of gastric carcinomas are sporadic, approximately 10% show familial aggregation, and a hereditary cause is determined in 1%-3% cases. Of these, hereditary diffuse gastric cancer is the most recognized predisposition syndrome. Although rare, the less commonly known syndromes also confer a markedly increased risk for development of gastric cancer. Identification and characterization of these syndromes require a multidisciplinary effort involving oncologists, surgeons, genetic counselors, biologists, and pathologists. This article reviews the molecular genetics, clinical and pathologic features, surveillance guidelines, and preventive measures of common and less common hereditary gastric cancer predisposition syndromes. ©AlphaMed Press.

Folate content and availability in Malaysian cooked foods.

PubMed

Chew, S C; Khor, G L; Loh, S P

2012-12-01

Data on folate availability of Malaysian cooked foods would be useful for estimation of dietary folate intake; however such information is scarce. A total of 53 samples of frequently consumed foods in Malaysia were selected from the Nutrient Composition of Malaysian Foods. Folate content was determined using HPLC method hyphenated with a stainless steel C18 column and ultraviolet detector (lambda = 280 nm). The index of folate availability was defined as the proportion of folate identified as monoglutamyl derivatives from the total folate content. Total folate content of different food samples varied from 30-95 microg/100g fresh weight. Among rice-based dishes, the highest and the lowest total folate was in coconut milk rice (nasi lemak) and ghee rice (nasi minyak), respectively. In noodle dishes, fried rice noodle (kuey teow goreng) and curry noodle (mee kari) had the highest folate contents. The highest index of folate availability was in a flat rice noodle dish (kuey teow bandung) (12.13%), while the lowest was in a festival cake (kuih bakul) (0.13%). Folate content was found to be negatively related to its availability. This study determined folate content and folate availability in commonly consumed cooked foods in Malaysia. The uptake of folate from foods with high folate content may not be necessarily high as folate absorption also depends on the capacity of intestinal deconjugation and the presence of high fibre in the foods.

Hereditary internal anal sphincter myopathy causing proctalgia fugax and constipation: further clinical and histological characterization in a patient.

PubMed

König, P; Ambrose, N S; Scott, N

2000-01-01

Hereditary internal anal sphincter myopathy is a very rare condition, only three families have so far been described in the literature. In this case report further clinical and histological findings of one affected member of one of the above families are presented.

Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

PubMed

Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

2014-10-01

Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.

PubMed

Comino-Méndez, Iñaki; Gracia-Aznárez, Francisco J; Schiavi, Francesca; Landa, Iñigo; Leandro-García, Luis J; Letón, Rocío; Honrado, Emiliano; Ramos-Medina, Rocío; Caronia, Daniela; Pita, Guillermo; Gómez-Graña, Alvaro; de Cubas, Aguirre A; Inglada-Pérez, Lucía; Maliszewska, Agnieszka; Taschin, Elisa; Bobisse, Sara; Pica, Giuseppe; Loli, Paola; Hernández-Lavado, Rafael; Díaz, José A; Gómez-Morales, Mercedes; González-Neira, Anna; Roncador, Giovanna; Rodríguez-Antona, Cristina; Benítez, Javier; Mannelli, Massimo; Opocher, Giuseppe; Robledo, Mercedes; Cascón, Alberto

2011-06-19

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.

Pes cavus and hereditary neuropathies: when a relationship should be suspected.

PubMed

Piazza, S; Ricci, G; Caldarazzo Ienco, E; Carlesi, C; Volpi, L; Siciliano, G; Mancuso, M

2010-12-01

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

Serum homocysteine, folate, vitamin B12 and total antioxidant status in vegetarian children.

PubMed

Ambroszkiewicz, J; Klemarczyk, W; Chełchowska, M; Gajewska, J; Laskowska-Klita, T

2006-01-01

The results of several studies point to the positive role of vegetarian diets in reducing the risk of diabetes, some cancers and cardiovascular diseases. However, exclusion of animal products in vegetarian diets may affect the cobalamin status and cause an elevation of the plasma homocysteine level. The aim of this study was to assess the effect of vegetarian diets on serum concentrations of homocysteine, folate, vitamin B12 and total antioxidant status (TAS) in children. The study included 32 vegetarians (including 5 vegans), age 2-10 years. Dietary constituents were analyzed using a local nutritional programme. Serum homocysteine, folate and vitamin B12 were determined with fluorescence and chemiluminescence immunoassays. The concentration of TAS was measured by a colorimetric method. Average daily energy intake and the percentage of energy from protein, fat and carbohydrates in the diets of the studied children were just above or similar to the recommended amounts. It could be shown that vegetarian diets contain high concentrations of folate. In vegan diets it even exceeds the recommended dietary allowance. Mean daily intake of vitamin B12 in the studied diets was adequate but in vegans was below the recommended range. The serum concentrations of homocysteine, folate, vitamin B12 and TAS in vegetarian children remained within the physiological range. The presented data indicate that vegetarian children, contrary to adults, have enough vitamin B12 in their diet (excluding vegans) and normal serum concentrations of homocysteine, folate and vitamin B12. Therefore, in order to prevent deficiencies in the future, close monitoring of vegetarian children (especially on a vegan diet) is important to make sure that they receive adequate quantities of nutrients needed for healthy growth.

Causes of permanent childhood hearing impairment.

PubMed

Korver, Anna M H; Admiraal, Ronald J C; Kant, Sarina G; Dekker, Friedo W; Wever, Capi C; Kunst, Henricus P M; Frijns, Johan H M; Oudesluys-Murphy, Anne Marie

2011-02-01

The causes of Permanent Childhood Hearing Impairment (PCHI) are often quoted as being hereditary in 50%, acquired in 25%, and unknown in 25% of cases. Interest in the causes of PCHI has grown recently due to increasing diagnostic possibilities. We investigated the evidence for the reported distribution of these causes. Population-based study and a systematic review. Inclusion criteria for population-based study: children born between 2003 and 2005, resident in The Netherlands at birth, known at an Audiology Center with PCHI at the age of 3-5 years. The causes of PCHI were determined prospectively by detection of congenital cytomegalovirus on dried blood spots and/or genetic diagnostic investigations in addition to reviewing data from medical records. A systematic review was carried out using three terms (hearing loss, infant, and etiology) and limited to articles published between January 1997 and July 2009. Main outcome measures were: the (weighted) proportions of the various causes of PCHI following diagnostic investigations. In the study-population (n = 185) a hereditary cause was found in 38.9%, acquired cause in 29.7%, miscellaneous cause in 7.1%, and the cause remained unknown in 24.3%. The systematic review of the literature (n = 9 articles) resulted in a weighted mean of 30.4% hereditary, 19.2% acquired, and 48.3% unknown causes of PCHI. The systematic review and the results of the population-based study provided little support for the generally accepted distribution of causes of PCHI. Copyright © 2010 The American Laryngological, Rhinological, and Otological Society, Inc.

Validation of Folate-Enriched Eggs as a Functional Food for Improving Folate Intake in Consumers

PubMed Central

Altic, Leslie; McNulty, Helene; Hoey, Leane; McAnena, Liadhan; Pentieva, Kristina

2016-01-01

Functional foods enriched with folate may be beneficial as a means of optimizing folate status in consumers. We recently developed novel eggs enriched with folate through folic acid supplementation of the hen’s feed, but their potential to influence consumer folate status is unknown because the natural folate forms incorporated into the eggs may not necessarily be retained during storage and cooking. This study aimed to determine the stability of natural folates in folate-enriched eggs under typical conditions of storage and cooking. Total folate was determined by microbiological assay following tri-enzyme treatment in folate-enriched eggs and un-enriched (barn and free-range) on the day they were laid, after storage (up to 27 days) and after using four typical cooking methods (boiling, poaching, frying, scrambling) for different durations. On the day of laying, the folate content of enriched eggs was found to be significantly higher than that of un-enriched barn or free-range eggs (mean ± SD; 123.2 ± 12.4 vs. 41.2 ± 2.8 vs. 65.6 ± 18.5 µg/100 g; p < 0.001). Storage at refrigerator and room temperature for periods up to the Best Before date resulted in no significant losses to the folate content of folate-enriched eggs. Furthermore, folate in enriched eggs remained stable when cooked by four typical methods for periods up to the maximum cooking time (e.g., 135 ± 22.5, 133.9 ± 23.0 and 132.5 ± 35.1; p = 0.73, for raw, scrambled for 50 s and scrambled for 2 min, respectively). Thus, natural folates in folate-enriched eggs remain highly stable with little or no losses following storage and cooking. These findings are important because they demonstrate the feasibility of introducing folate-enriched eggs into the diet of consumers as functional foods with enriched folate content. Further studies will confirm their effectiveness in optimizing the biomarker folate status of consumers. PMID:27916895

Validation of Folate-Enriched Eggs as a Functional Food for Improving Folate Intake in Consumers.

PubMed

Altic, Leslie; McNulty, Helene; Hoey, Leane; McAnena, Liadhan; Pentieva, Kristina

2016-11-30

Functional foods enriched with folate may be beneficial as a means of optimizing folate status in consumers. We recently developed novel eggs enriched with folate through folic acid supplementation of the hen's feed, but their potential to influence consumer folate status is unknown because the natural folate forms incorporated into the eggs may not necessarily be retained during storage and cooking. This study aimed to determine the stability of natural folates in folate-enriched eggs under typical conditions of storage and cooking. Total folate was determined by microbiological assay following tri-enzyme treatment in folate-enriched eggs and un-enriched (barn and free-range) on the day they were laid, after storage (up to 27 days) and after using four typical cooking methods (boiling, poaching, frying, scrambling) for different durations. On the day of laying, the folate content of enriched eggs was found to be significantly higher than that of un-enriched barn or free-range eggs (mean ± SD; 123.2 ± 12.4 vs. 41.2 ± 2.8 vs. 65.6 ± 18.5 µg/100 g; p < 0.001). Storage at refrigerator and room temperature for periods up to the Best Before date resulted in no significant losses to the folate content of folate-enriched eggs. Furthermore, folate in enriched eggs remained stable when cooked by four typical methods for periods up to the maximum cooking time (e.g., 135 ± 22.5, 133.9 ± 23.0 and 132.5 ± 35.1; p = 0.73, for raw, scrambled for 50 s and scrambled for 2 min, respectively). Thus, natural folates in folate-enriched eggs remain highly stable with little or no losses following storage and cooking. These findings are important because they demonstrate the feasibility of introducing folate-enriched eggs into the diet of consumers as functional foods with enriched folate content. Further studies will confirm their effectiveness in optimizing the biomarker folate status of consumers.

Folate deficiency

MedlinePlus

... as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole) Eating an unhealthy diet that does not include enough fruits and vegetables Kidney dialysis Symptoms Folic acid deficiency may cause: Fatigue, irritability, or diarrhea Poor growth Smooth and ...

Determining bioavailability of food folates in a controlled intervention study.

PubMed

Hannon-Fletcher, Mary P; Armstrong, Nicola C; Scott, John M; Pentieva, Kristina; Bradbury, Ian; Ward, Mary; Strain, J J; Dunn, Adele A; Molloy, Anne M; Kerr, Maeve A; McNulty, Helene

2004-10-01

The concept of dietary folate equivalents (DFEs) in the United States recognizes the differences in bioavailability between natural food folates and the synthetic vitamin, folic acid. However, many published reports on folate bioavailability are problematic because of several confounding factors. We compared the bioavailability of food folates with that of folic acid under controlled conditions. To broadly represent the extent to which natural folates are conjugated in foods, we used 2 natural sources of folate, spinach (50% polyglutamyl folate) and yeast (100% polyglutamyl folate). Ninety-six men were randomly assigned according to their screening plasma homocysteine (tHcy) concentration to 1 of 4 treatment groups for an intervention period of 30 d. Each subject received (daily under supervision) either a folate-depleted "carrier" meal or a drink plus 1) placebo tablet, 2) 200 microg folic acid in a tablet, 3) 200 microg natural folate provided as spinach, or 4) 200 microg natural folate provided as yeast. Among the subjects who completed the intervention, responses (increase in serum folate, lowering of tHcy) relative to those in the placebo group (n = 18) were significant in the folic acid group (n = 18) but not in the yeast folate (n = 19) or the spinach folate (n = 18) groups. Both natural sources of folate were significantly less bioavailable than was folic acid. Overall estimations of folate bioavailability relative to that of folic acid were found to be between 30% (spinach) and 59% (yeast). Relative bioavailability estimates were consistent with the estimates from the metabolic study that were used as a basis to derive the US DFE value.

Effect of germination and thermal treatments on folates in rye.

PubMed

Kariluoto, Susanna; Liukkonen, Kirsi-Helena; Myllymäki, Olavi; Vahteristo, Liisa; Kaukovirta-Norja, Anu; Piironen, Vieno

2006-12-13

Effects of germination conditions and thermal processes on folate contents of rye were investigated. Total folate contents were determined microbiologically with Lactobacillus rhamnosus (ATCC 7469) as the growth indicator organism, and individual folates were determined by high-performance liquid chromatography after affinity chromatographic purification. Germination increased the folate content by 1.7-3.8-fold, depending on germination temperature, with a maximum content of 250 micro g/100 g dry matter. Hypocotylar roots with their notably high folate concentrations (600-1180 micro g/100 g dry matter) contributed 30-50% of the folate contents of germinated grains. Germination altered the proportions of folates, increasing the proportion of 5-methyltetrahydrofolate and decreasing the proportion of formylated folate compounds. Thermal treatments (extrusion, autoclaving and puffing, and IR and toasting) resulted in significant folate losses. However, folate levels in grains that were germinated and then were heat processed were higher than for native (nongerminated) grains. Opportunities to optimize rye processing to enhance folate levels in rye-based foods are discussed.

[Paediatric retinal detachment and hereditary vitreoretinal disorders].

PubMed

Meier, P

2013-09-01

The number of retinal detachments in children is very low in comparison to the number in adults. One predisposing factor for development of paediatric retinal detachment is suffering from hereditary vitreoretinal degeneration (e.g., Stickler syndrome, Wagner syndrome, Kniest dysplasia, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, Knobloch syndrome, incontinentia pigmenti, Norrie disease). Hereditary vitreoretinopathies are characterised by an abnormal-appearing vitreous gel with associated retinal changes. In most of these eyes further ocular abnormalities can be diagnosed. A group of hereditary disorders is associated with characteristic systemic abnormalities. Allied conditions should be considered in the clinical diagnosis. Vitreoretinopathies are the most common cause of inherited retinal detachment. In most eyes primary vitrectomy is necessary, and disease-specific surgical treatment is discussed. Georg Thieme Verlag KG Stuttgart · New York.

Gene specific epigenetic regulation of hepatic folate transport system is responsible for perturbed cellular folate status during aging and exogenous modulation.

PubMed

Ahmad Najar, Rauf; Rahat, Beenish; Hussain, Aashiq; Thakur, Shilpa; Kaur, Jaspreet; Kaur, Jyotdeep; Hamid, Abid

2016-06-01

The present study was designed to identify the molecular mechanism of folate modulation and aging on aberrant liver folate transporter system. An in vivo rat model was used, in which weanling, young and adult rats were given folate deficient diet for 3 and 5 months and after 3 months of folate deficiency, one group received physiological folate repletion (2 mg/kg diet) and another group received over supplemented folate diet (8 mg/kg diet) for another 2 months. In adult group, 3 and 5 months of folate deficiency decreased serum and tissue folate levels with decreased uptake of folate, further associated with decreased expression levels of reduced folate carrier (RFC) and increased expression levels of folate exporter (ABCG2) at both mRNA and protein levels, which in turn regulated by promoter hypermethylation of RFC and promoter hypomethylation of ABCG2 gene. Promoter hypermethylation of RFC and promoter hypomethylation of ABCG2 may be attributed to the down regulation of RFC and up regulation of ABCG2 at mRNA and protein levels in conditions of 3 and 5 months of folate deficiency in the adult group. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Overexpression of folate biosynthesis genes in rice (Oryza sativa L.) and evaluation of their impact on seed folate content.

PubMed

Dong, Wei; Cheng, Zhi-jun; Lei, Cai-lin; Wang, Xiao-le; Wang, Jiu-lin; Wang, Jie; Wu, Fu-qing; Zhang, Xin; Guo, Xiu-ping; Zhai, Hu-qu; Wan, Jian-min

2014-12-01

Folate (vitamin B9) deficiency is a global health problem especially in developing countries where the major staple foods such as rice contain extremely low folates. Biofortification of rice could be an alternative complement way to fight folate deficiency. In this study, we evaluated the availability of the genes in each step of folate biosynthesis pathway for rice folate enhancement in the japonica variety kitaake genetic background. The first enzymes GTP cyclohydrolase I (GTPCHI) and aminodeoxychorismate synthase (ADCS) in the pterin and para-aminobenzoate branches resulted in significant increase in seed folate content, respectively (P < 0.01). Overexpression of two closely related enzymes dihydrofolate synthase (DHFS) and folypolyglutamate synthase (FPGS), which perform the first and further additions of glutamates, produced slightly increase in seed folate content separately. The GTPCHI transgene was combined with each of the other transgenes except ADCS to investigate the effects of gene stacking on seed folate accumulation. Seed folate contents in the gene-stacked plants were higher than the individual low-folate transgenic parents, but lower than the high-folate GTPCHI transgenic lines, pointing to an inadequate supply of para-aminobenzoic acid (PABA) precursor initiated by ADCS in constraining folate overproduction in gene-stacked plants.

Hereditary breast cancer: from molecular pathology to tailored therapies.

PubMed

Tan, D S P; Marchiò, C; Reis-Filho, J S

2008-10-01

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have demonstrated that mutations in two high-penetrance genes, namely BRCA1 and BRCA2, are responsible for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find another high-penetrance breast cancer susceptibility gene, several genes that confer a moderate to low risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused by mutations in BRCA1, BRCA2, Fanconi anaemia (FANC) genes, CHK2 and ATM tumour suppressor genes. We describe the hallmark histological features of these carcinomas compared with non-hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat patients with BRCA1 and BRCA2 germ line mutations, including cross-linking agents and PARP inhibitors, are discussed.

Phenotypic Description of the Spanish Multicentre Genetic Glaucoma Group Cohort

PubMed Central

Gamundi, Maria José; Duch, Susana; Rios, Jose; Carballo, Miguel; Study Group, EMEIGG

2017-01-01

Introduction The aim of the study was to make a phenotypic description of the Spanish multicentre glaucoma group cohort of patients. Design Retrospective, observational, multicentre, cohort study. Material and Methods The clinical charts of 152 patients with hereditary glaucoma from18 Spanish eye centres were reviewed in order to make an epidemiologic description of the type of glaucoma and associated factors. True hereditary cases were compared with familiar cases according to the Gong et al. criteria. Results 61% were true hereditary cases and 39% familiar cases. Ocular comorbidity, optic disc damage, and visual field mean defect were significantly more severe in hereditary patients, who required significantly more first-line hypotensive drugs and surgical interventions to control intraocular pressure than familiar patients. Conclusions The strength of the hereditary component of glaucoma seems to worsen the clinical course, causing more structural and functional damage and requiring more intense glaucoma treatment. The family history of glaucoma should be carefully investigated and taken into consideration when making treatment decisions or intensifying previous treatment. PMID:29082038

Folate content in tomato ( Lycopersicon esculentum ). influence of cultivar, ripeness, year of harvest, and pasteurization and storage temperatures.

PubMed

Iniesta, M Dolores; Pérez-Conesa, Darío; García-Alonso, Javier; Ros, Gaspar; Periago, M Jesús

2009-06-10

The effects of cultivar, on-vine ripening, and year of harvest on the folate content of raw tomatoes were studied. Folate content in hot-break tomato puree (HTP) subjected to pasteurization at different temperatures and its evolution during the shelf life of tomato juice were also investigated. 5-Methyltetrahydrofolate (5-CH(3)-H(4)-folate) was the only folate compound identified in raw tomatoes and HTP, but tetrahydrofolate (H(4)-folate) was 10% of the folate detected in tomato juice. The content of folates in raw tomatoes ranged from 4.1 to 35.3 microg/100 g of fresh weight and was highly influenced by all of the factors studied. No clear trend of folate content with ripening stage was observed. The extractability of 5-CH(3)-H(4)-folate from HTP increased significantly after pasteurization at 98 degrees C for 40 s, but higher temperatures decreased its content. Tomato juice showed folate losses during storage independent of the storage temperature. Folate losses were higher when tomato juice was packed in glass bottles than in Tetra Pak.

Folic acid in diet

MedlinePlus

... carries genetic information Folate deficiency may cause: Diarrhea Gray hair Mouth ulcers Peptic ulcer Poor growth Swollen ... used at recommended levels. Folic acid dissolves in water. This means that it is regularly removed from ...

Folates in lettuce: a pilot study

PubMed Central

Johansson, Madelene; Jägerstad, Margaretha; Frølich, Wenche

2007-01-01

Background Leafy vegetables are good sources of folates and food shops nowadays offer an increasing number of lettuce varieties. Objective To obtain data on the folate content and forms in common lettuce varieties and spinach sold in the Nordic countries, and to investigate effects of different storage conditions and preparations in the consumer's home or at lunchtime restaurants. Design Folate was analysed in eight different lettuce varieties and spinach using a validated high-performance liquid chromatographic method and the detected forms of folates were confirmed by a mass spectrometric detector [liquid chromatography–mass spectrometry (LC-MS)] following heat extraction, deconjugation with rat serum and purification by solid-phase extraction. Results Folate content, expressed in folic acid equivalents, in the lettuce samples varied six-fold, from 30 to 198 µg 100 g−1 on a fresh weight basis. The folate content was decreased by 14% after storage at 4°C for 8 days and by 2–40% after storage at 22°C for 2–4 h, depending on whether samples were stored as whole leaves, or small torn or cut pieces. LC-MS confirmed the identity of the folate forms: H4folate, 5-CH3-H4folate, 5-HCO-H4folate and 10-HCO-H4folate. Conclusion The considerable variation in folate content between varieties of lettuce in this pilot study, with one variety reaching the level found in spinach, indicates the potential to increase folate intake considerably by choosing folate-rich varieties of lettuce and storing at low temperatures.

Folate content in strawberries (Fragaria x ananassa): effects of cultivar, ripeness, year of harvest, storage, and commercial processing.

PubMed

Strålsjö, Lena M; Witthöft, Cornelia M; Sjöholm, Ingegerd M; Jägerstad, Margaretha I

2003-01-01

Folate concentrations in strawberries and folate retention during storage and commercial processing of strawberries were investigated. No previous study has focused on the effects of cultivar, ripeness, and year of harvest of strawberries with respect to the folate content. This study showed the folate concentration in strawberries to significantly depend on all of these different factors. Total folate was quantified using a modified and validated radioprotein-binding assay with external calibration (5-CH(3)-H(4)folate). Folate content in 13 different strawberry cultivars varied from 335 microg/100 g of dry matter (DM) for cv. Senga Sengana to 644 microg/100 g of DM for cv. Elsanta. Swedish harvests from 1999 and 2001 yielded higher folate concentrations than did the harvest from 2000, and the grade of ripeness affected the folate content in strawberries. This study indicated high folate retention in intact berries during storage until 3 or 9 days at 4 degrees C (71-99%) and also in most tested commercial products (79-103%). On the basis of these data fresh strawberries as well as processed strawberry products are recommended to be good folate sources. For instance, 250 g (fresh weight) of strawberries ( approximately 125 microg of folate) supplies approximately 50% of the recommended daily folate intake in various European countries (200-300 microg/day) or 30% of the U.S. recommendation (400 microg/day).

[Hereditary motor and sensory Lom-neuropathy--first Hungarian case report].

PubMed

Szabó, Antal; Siska, Eva; Molnár, Mária Judit

2007-01-20

Hereditary motor and sensory neuropathy-Lom is an autosomal recessive disorder of the peripheral nervous system, which occurs only in the european Roma population. The symptoms start in the first decade with slowly progressive gait disturbance, weakness and wasting of distal upper extremity muscles, joint deformities and hearing loss develop later in the second and third decades. This disorder is caused by a homozygous missense mutation of the NDRG1 gene, located in the 8q24 region. The Schwann cell dysfunction is most probably caused by altered lipid metabolism as a consequence of the NDRG1 mutation. Molecular genetic testing can be a first diagnostic step among roma individuals showing a Lom neuropathy phenotype, making evaluation of such patients and also genetic counselling faster and easier. Screening for hereditary neuromuscular disorders in this genetically isolated community may become an important public health issue in the near future.

Growing Mouse Oocytes Transiently Activate Folate Transport via Folate Receptors As They Approach Full Size.

PubMed

Meredith, Megan; MacNeil, Allison H; Trasler, Jacquetta M; Baltz, Jay M

2016-06-01

The folate cycle is central to cellular one-carbon metabolism, where folates are carriers of one-carbon units that are critical for synthesis of purines, thymidylate, and S-adenosylmethionine, the universal methyl donor that forms the cellular methyl pool. Although folates are well-known to be important for early embryo and fetal development, their role in oogenesis has not been clearly established. Here, folate transport proteins were detected in developing neonatal ovaries and growing oocytes by immunohistochemistry, Western blot, and immunofluorescence. The folate receptors FOLR1 and FOLR2 as well as reduced folate carrier 1 (RFC1, SLC19A1 protein) each appeared to be present in follicular cells including granulosa cells. In growing oocytes, however, only FOLR2 immunoreactivity appeared abundant. Localization of apparent FOLR2 immunofluorescence near the plasma membrane increased with oocyte growth and peaked in oocytes as they neared full size. We assessed folate transport using the model folate leucovorin (folinic acid). Unexpectedly, there was a transient burst of folate transport activity for a brief period during oocyte growth as they neared full size, while folate transport was otherwise undetectable for the rest of oogenesis and in fully grown germinal vesicle stage oocytes. This folate transport was inhibited by dynasore, an inhibitor of endocytosis, but insensitive to the anion transport inhibitor stilbene 4-acetamido-40-isothiocyanato-stilbene-2,20-disulfonic acid, consistent with folate receptor-mediated transport but not with RFC1-mediated transport. Thus, near the end of their growth, growing oocytes may take up folates that could support the final stage of oogenesis or be stored to provide the endogenous folates needed in early embryogenesis. © 2016 by the Society for the Study of Reproduction, Inc.

Critical evaluation of lowering the recommended dietary intake of folate.

PubMed

Obeid, Rima; Koletzko, Berthold; Pietrzik, Klaus

2014-04-01

We evaluated the recommendation of the Austrian, German, and Swiss Societies for Nutrition of lowering dietary folate intake from 400 to 300 μg dietary folate equivalents/d. A dose-response relation exists between folate intake or plasma level and disease risk within the normal range. Improving folate status can prevent between 30% and 75% of neural tube defects. A prepregnancy plasma folate of >18.0 nmol/L (mean 26.1 nmol/L) is associated with low total homocysteine (tHcy) (<10.0 μmol/L) and optimal prevention of birth defects. Because the closure of the neural tube occurs in the first 8 weeks after conception, women with low prepregnancy folate intake cannot achieve maximal risk reduction. The Austrian, German, and Swiss Societies for Nutrition recommend that young women should additionally supplement with 400 μg folic acid at least 4 weeks before conception. This short time window is not sufficient to achieve optimal plasma folate and tHcy levels in the majority of women. Factors affecting the relation between folate intake and blood biomarkers are total folate intake, baseline plasma folate, time available for supplement use, dose and form (folic acid or methyl folate), genetic polymorphisms, physiological and lifestyle factors. Lowering the recommended dietary folate intake may have important public health consequences. Elderly people and young women are at risk for diseases related to folate shortage. Reducing birth defects through supplementation of folic acid remains a poor option, as <20% of young women (i.e., in Germany) supplement with the vitamin. Recommending adequate food folate intake is crucial for reaching the target protective plasma folate levels in the population. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Mechanistic insights of intestinal absorption and renal conservation of folate in chronic alcoholism.

PubMed

Wani, Nissar Ahmad; Thakur, Shilpa; Najar, Rauf Ahmad; Nada, Ritambhara; Khanduja, Krishan Lal; Kaur, Jyotdeep

2013-03-01

Folate mediated one-carbon metabolism is of fundamental importance for various cellular processes, including DNA synthesis and methylation of biological molecules. Due to the exogenous requirement of folate in mammals, there exists a well developed epithelial folate transport system for regulation of normal folate homeostasis. The intestinal and renal folate uptake is tightly and diversely regulated and disturbances in folate homeostasis like in alcoholism have pathological consequences. The study was sought to delineate the regulatory mechanism of folate uptake in intestine and reabsorption in renal tubular cells that could evaluate insights of malabsorption during alcoholism. The folate transporters PCFT and RFC were found to be associated with lipid rafts of membrane surfaces in intestine and kidney. Importantly, the observed lower intestinal and renal folate uptake was associated with decreased levels of folate transporter viz. PCFT and RFC in lipid rafts of intestinal and renal membrane surfaces. The decreased association of folate transporters in lipid rafts was associated with decreased protein and mRNA levels. In addition, immunohistochemical studies showed that alcoholic conditions deranged that localization of PCFT and RFC. These findings could explain the possible mechanistic insights that may result in folate malabsorption during alcoholism. Copyright © 2013 Elsevier Inc. All rights reserved.

REEP1 Mutation Spectrum and Genotype/Phenotype Correlation in Hereditary Spastic Paraplegia Type 31

ERIC Educational Resources Information Center

Beetz, Christian; Schule, Rebecca; Deconinck, Tine; Tran-Viet, Khanh-Nhat; Zhu, Hui; Kremer, Berry P. H.; Frints, Suzanna G. M.; van Zelst-Stams, Wendy A. G.; Byrne, Paula; Otto, Susanne; Nygren, Anders O. H.; Baets, Jonathan; Smets, Katrien; Ceulemans, Berten; Dan, Bernard; Nagan, Narasimhan; Kassubek, Jan; Klimpe, Sven; Klopstock, Thomas; Stolze, Henning; Smeets, Hubert J. M.; Schrander-Stumpel, Constance T. R. M.; Hutchinson, Michael; van de Warrenburg, Bart P.; Braastad, Corey; Deufel, Thomas; Pericak-Vance, Margaret; Schols, Ludger; de Jonghe, Peter; Zuchner, Stephan

2008-01-01

Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for "REEP1" mutations and copy number variations. We identified 13 novel and 2 known "REEP1"…

How I treat anemia in pregnancy: iron, cobalamin, and folate.

PubMed

Achebe, Maureen M; Gafter-Gvili, Anat

2017-02-23

Anemia of pregnancy, an important risk factor for fetal and maternal morbidity, is considered a global health problem, affecting almost 50% of pregnant women. In this article, diagnosis and management of iron, cobalamin, and folate deficiencies, the most frequent causes of anemia in pregnancy, are discussed. Three clinical cases are considered. Iron deficiency is the most common cause. Laboratory tests defining iron deficiency, the recognition of developmental delays and cognitive abnormalities in iron-deficient neonates, and literature addressing the efficacy and safety of IV iron in pregnancy are reviewed. An algorithm is proposed to help clinicians diagnose and treat iron deficiency, recommending oral iron in the first trimester and IV iron later. Association of folate deficiency with neural tube defects and impact of fortification programs are discussed. With increased obesity and bariatric surgery rates, prevalence of cobalamin deficiency in pregnancy is rising. Low maternal cobalamin may be associated with fetal growth retardation, fetal insulin resistance, and excess adiposity. The importance of treating cobalamin deficiency in pregnancy is considered. A case of malarial anemia emphasizes the complex relationship between iron deficiency, iron treatment, and malaria infection in endemic areas; the heightened impact of combined etiologies on anemia severity is highlighted. © 2017 by The American Society of Hematology.

Pathogenic proline mutation in the linker between spectrin repeats: disease caused by spectrin unfolding

PubMed Central

Johnson, Colin P.; Gaetani, Massimiliano; Ortiz, Vanessa; Bhasin, Nishant; Harper, Sandy

2007-01-01

Pathogenic mutations in α and β spectrin result in a variety of syndromes, including hereditary elliptocytosis (HE), hereditary pyropoikilocytosis (HPP), and hereditary spherocytosis (HS). Although some mutations clearly lie at sites of interaction, such as the sites of spectrin α-βtetramer formation, a surprising number of HE-causing mutations have been identified within linker regions between distal spectrin repeats. Here we apply solution structural and single molecule methods to the folding and stability of recombinant proteins consisting of the first 5 spectrin repeats of α-spectrin, comparing normal spectrin with a pathogenic linker mutation, Q471P, between repeats R4 and R5. Results show that the linker mutation destabilizes a significant fraction of the 5-repeat construct at 37°C, whereas the WT remains fully folded well above body temperature. In WT protein, helical linkers propagate stability from one repeat to the next, but the mutation disrupts the stabilizing influence of adjacent repeats. The results suggest a molecular mechanism for the high frequency of disease caused by proline mutations in spectrin linkers. PMID:17192394

Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.

PubMed

Beetz, Christian; Johnson, Adam; Schuh, Amber L; Thakur, Seema; Varga, Rita-Eva; Fothergill, Thomas; Hertel, Nicole; Bomba-Warczak, Ewa; Thiele, Holger; Nürnberg, Gudrun; Altmüller, Janine; Saxena, Renu; Chapman, Edwin R; Dent, Erik W; Nürnberg, Peter; Audhya, Anjon

2013-03-26

Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.

Homogeneous bioluminescence competitive binding assay for folate based on a coupled glucose-6-phosphate dehydrogenase--bacterial luciferase enzyme system.

PubMed

Huang, W; Feltus, A; Witkowski, A; Daunert, S

1996-05-01

A homogeneous bioluminescence competitive binding assay for folate was developed by using a coupled enzyme system of glucose-6-phosphate dehydrogenase (G6PDH) and bacterial luciferase. A highly substituted G6PDH-folate conjugate was prepared by employing an N-hydroxysuccinimide/carbodiimide method. Folate binding protein inhibits the activity of the conjugate. In the presence of folate, there is a competition between folate and the G6PDH-folate conjugate for the binding site of the folate binding protein, and the activity of the conjugate is recovered. Thus, the concentration of folate can be related to the activity of the G6PDH-folate conjugate, which is directly related to the bioluminescence produced by the coupled enzyme reaction. Using this assay, dose-response curves with a detection limit of 2.5 x 10(-8) M folate were obtained, which is an improvement of an order of magnitude with respect to an assay that monitors G6PDH activity spectrophotometrically. The assay was validated using vitamin tablets and a cell culture medium.

Axon Transport and Neuropathy

PubMed Central

Tourtellotte, Warren G.

2017-01-01

Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. PMID:26724390

Sulfamethazine Suppresses Epigenetic Silencing in Arabidopsis by Impairing Folate Synthesis[W

PubMed Central

Zhang, Huiming; Deng, Xiangyang; Miki, Daisuke; Cutler, Sean; La, Honggui; Hou, Yueh-Ju; Oh, JeeEun; Zhu, Jian-Kang

2012-01-01

DNA methylation is a critical, dynamically regulated epigenetic mark. Small chemicals can be valuable tools in probing cellular processes, but the set of chemicals with broad effects on epigenetic regulation is very limited. Using the Arabidopsis thaliana repressor of silencing1 mutant, in which transgenes are transcriptionally silenced, we performed chemical genetic screens and found sulfamethazine (SMZ) as a chemical suppressor of epigenetic silencing. SMZ treatment released the silencing of transgenes as well as endogenous transposons and other repetitive elements. Plants treated with SMZ exhibit substantially reduced levels of DNA methylation and histone H3 Lys-9 dimethylation, but heterochromatic siRNA levels were not affected. SMZ is a structural analog and competitive antagonist to p-aminobenzoic acid (PABA), which is a precursor of folates. SMZ decreased the plant folate pool size and caused methyl deficiency, as demonstrated by reductions in S-adenosylmethionine levels and in global DNA methylation. Exogenous application of PABA or compounds downstream in the folate biosynthesis pathway restored transcriptional silencing in SMZ-treated plants. Together, our results revealed a novel type of chemical suppressor of epigenetic silencing, which may serve as a valuable tool for studying the roles and mechanisms of epigenetic regulation and underscores an important linkage between primary metabolism and epigenetic gene regulation. PMID:22447685

Hepatic and renal failure associated with amiodarone infusion in a patient with hereditary fructose intolerance.

PubMed

Curran, B J; Havill, J H

2002-06-01

Hereditary fructose intolerance is a rare inherited metabolic disorder. Although fructose intolerance usually presents in the paediatric age group, individuals can survive into adulthood by self.manipulation of diet. Hospitalisation can become a high.risk environment for these individuals because of loss of control of their strict dietary constraints and the added danger of administration of medications containing fructose, sucrose and sorbitol. We report a case of hereditary fructose intolerance in an adult presenting with hepatic and renal failure associated with an amiodarone infusion and explore the possibility of polysorbate 80 as a cause of this patient's hepatic and renal failure.

Controlled release of folic acid through liquid-crystalline folate nanoparticles.

PubMed

Misra, Rahul; Katyal, Henna; Mohanty, Sanat

2014-11-01

The present study explores folate nanoparticles as nano-carriers for controlled drug delivery. Cross-linked nanoparticles of liquid crystalline folates are composed of ordered stacks. This paper shows that the folate nanoparticles can be made with less than 5% loss in folate ions. In addition, this study shows that folate nanoparticles can disintegrate in a controlled fashion resulting in controlled release of the folate ions. Release can be controlled by the size of nanoparticles, the extent of cross-linking and the choice of cross-linking cation. The effect of different factors like agitation, pH, and temperature on folate release was also studied. Studies were also carried out to show the effect of release medium and role of ions in the release medium on disruption of folate assembly. Copyright © 2014. Published by Elsevier B.V.

Enhancement of the folate content in Egyptian pita bread.

PubMed

Hefni, Mohammed; Witthöft, Cornelia M

2012-01-01

Egypt has a high incidence of neural tube defects related to folate deficiency. One major food source for folate is pita (baladi) bread, which is consumed daily. Bioprocessing (e.g. germination) has been reported to increase the folate content in cereals. The aim was to produce pita bread with increased folate content using germinated wheat flour (GWF). Prior to milling the effects of germination and drying conditions on folate content in wheat grains were studied. Pita bread was baked from wheat flour substituted with different levels of GWF. The folate content in dough and bread and rheological properties of dough were determined. Germination of wheat grains resulted in, depending on temperature, 3- to 4-fold higher folate content with a maximum of 61 µg/100 g DM (dry matter). The folate content in both flour and bread increased 1.5 to 4-fold depending on the level of flour replacement with GWF. Pita bread baked with 50% sieved GWF was acceptable with respect to colour and layer separation, and had a folate content of 50 µg/100 g DM compared with 30 µg/100 g DM in conventional pita bread (0% GWF). Using 50% GWF, pita bread with increased folate content, acceptable for the Egyptian consumer, was produced. Consumption of this bread would increase the average daily folate intake by 75 µg.

Monoallelic mutation analysis (MAMA) for identifying germline mutations.

PubMed

Papadopoulos, N; Leach, F S; Kinzler, K W; Vogelstein, B

1995-09-01

Dissection of germline mutations in a sensitive and specific manner presents a continuing challenge. In dominantly inherited diseases, mutations occur in only one allele and are often masked by the normal allele. Here we report the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed MAMA (monoallelic mutation analysis). We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).

Aplastic crisis in occult hereditary spherocytosis caused by human parvovirus (HPV B19).

PubMed

Rappaport, E S; Quick, G; Ransom, D; Helbert, B; Frankel, L S

1989-02-01

We have reported a case of aplastic crisis occurring in an 11-year-old black boy with occult hereditary spherocytosis. An etiologic diagnosis of human parvovirus (HPV) B19 infection was confirmed serologically. The Coulter Model S + IV proved useful for both diagnosis and treatment monitoring through serial histograms. The relationship of HPV infection and aplastic crisis is discussed.

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011–2

PubMed Central

Pfeiffer, Christine M.; Sternberg, Maya R.; Fazili, Zia; Lacher, David A.; Zhang, Mindy; Johnson, Clifford L.; Hamner, Heather C.; Bailey, Regan L.; Rader, Jeanne I.; Yamini, Sedigheh; Berry, R. J.; Yetley, Elizabeth A.

2016-01-01

Serum and red blood cell (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured serum folate forms [5-methyltetrahydrofolate (5-methylTHF), unmetabolized folic acid (UMFA), non-methyl folate (sum of THF, 5-formylTHF, 5,10-methenylTHF), and MeFox (5-methylTHF oxidation product)] by HPLC-MS/MS and RBC total folate by microbiologic assay in US persons ≥1 year (n ~7500) participating in the National Health and Nutrition Examination Survey 2011–2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37.5 nmol/L; 100%), UMFA (1.21 nmol/L; 99.9%), MeFox (1.53 nmol/L; 98.8%), and THF (1.01 nmol/L; 85.2%) were mostly detectable. 5-FormylTHF (3.6%) and 5,10-methenylTHF (4.4%) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86.7%); UMFA (4.0%), non-methyl folate (4.7%), and MeFox (4.5%) contributed smaller amounts. Age was positively related to MeFox but showed a U-shaped pattern for other folates. We generally noted sex and race-ethnic biomarker differences and weak (Spearman r <0.4) but significant (P <0.05) correlations with physiologic and lifestyle variables. Fasting, kidney function, smoking, and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiologic, and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics. PMID:25917925

Deprivation amblyopia and congenital hereditary cataract.

PubMed

Mansouri, Behzad; Stacy, Rebecca C; Kruger, Joshua; Cestari, Dean M

2013-01-01

Amblyopia is a neurodevelopmental disorder of vision associated with decreased visual acuity, poor or absent stereopsis, and suppression of information from one eye.(1,2) Amblyopia may be caused by strabismus (strabismic amblyopia), refractive error (anisometropic amblyopia), or deprivation from obstructed vision (deprivation amblyopia). 1 In the developed world, amblyopia is the most common cause of childhood visual impairment, 3 which reduces quality of life 4 and also almost doubles the lifetime risk of legal blindness.(5, 6) Successful treatment of amblyopia greatly depends on early detection and treatment of predisposing disorders such as congenital cataract, which is the most common cause of deprivational amblyopia. Understanding the genetic causes of congenital cataract leads to more effective screening tests, early detection and treatment of infants and children who are at high risk for hereditary congenital cataract.

Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine and DNA uracil concentrations

USDA-ARS?s Scientific Manuscript database

Background: Folate is an essential nutrient which supports nucleotide synthesis and biological methylation reactions. Diminished folate status results in chromosome breakage and is associated with several diseases including colorectal cancer. Folate status is also inversely related to plasma homocys...

Developmental and feedforward control of the expression of folate biosynthesis genes in tomato fruit

USDA-ARS?s Scientific Manuscript database

Little is known about how plants regulate their folate content, including whether the expression of folate biosynthesis genes is orchestrated during development or modulated by folate levels. Nor is much known about how folate levels impact the expression of other genes. These points were addressed ...

Folate and Breast Cancer: Role of Intake, Blood Levels, and Metabolic Gene Polymorphisms

DTIC Science & Technology

2006-06-01

polymorphisms . The specific aims are 1) methodological training in the analysis of gene - gene and gene -environment interactions by studying folate...evaluation of folate intake, plasma folate, and metabolic gene polymorphisms in relation to breast cancer risk: Months 1-19. b. Prepare blood samples...isolated for the folate and gene polymorphism assays among the 184 cases and matched controls. The folate assays are on-going at this time and over

Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting.

PubMed

Kim, Woo Hyoung; Kim, Chang Guhn; Kim, Myoung Hyoun; Kim, Dae-Weung; Park, Cho Rong; Park, Ji Yong; Lee, Yun-Sang; Youn, Hyewon; Kang, Keon Wook; Jeong, Jae Min; Chung, June-Key

2016-06-01

The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model. Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE. The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95 % for up to 4 h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4 h after injection in KB tumor was 16.4, 23.2, and 17.6 % injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4 % when excess free folate was co-administered. Tumor:normal organ ratios at 4 h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16 h after injection was 17.4, 21.7, 24.1, and 15.6 %ID/g, respectively. Tumor:normal organ ratios at 8 h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re-188-folate-GGCE. The tumor uptake of these molecules was completely suppressed when excess free folate was co-administered. Isostructural Tc-99m- and Re-188-folate-GGCE showed high and FR-specific uptake by tumors and generally favorable tumor:normal organ ratios. The tumor targeting capabilities of Tc-99m- and Re-188-folate-GGCE were clearly evident on serial imaging studies. This isostructural pair may have potential diagnostic and theranostic applications for FR-positive tumors.

Prevalence and aetiology of anaemia in lymphoid malignancies.

PubMed

Ghosh, J; Singh, R K Bikramjit; Saxena, R; Gupta, R; Vivekanandan, S; Sreenivas, V; Raina, V; Sharma, A; Kumar, L

2013-01-01

We prospectively studied the prevalence, type and causes of anaemia in newly diagnosed patients with lymphoid malignancies. Between January 2007 and June 2008, a total of 316 newly diagnosed, consecutive patients (aged 15 years or above) of Hodgkin lymphoma, non-Hodgkin lymphoma and chronic lymphocytic leukaemia with anaemia (haemoglobin <11 g/dl), were analysed to determine the prevalence and a subgroup of 46 patients was analysed for the cause of anaemia. Hodgkin lymphoma, non-Hodgkin lymphoma and chronic lymphocytic leukaemia were the diagnoses in 81 (25.8%), 203 (64.7%) and 30 (9.6%) patients, respectively. Anaemia was present in 134 patients (42.4%). Anaemia of chronic disease was present in 33/46 (71.7%) and iron deficiency in 18/46 (39.1%) patients. Vitamin B12 and/or folate deficiency was detected in 10/46 (21.7%) patients (B12 deficiency alone in 7, folate deficiency alone in 1 and combined B12 and folate deficiency in 2). Autoimmune haemolytic anaemia was detected in 5/46 (10.9%) although direct Coombs test was positive in 17/46 (37%) patients. Among patients with Hodgkin lymphoma and non-Hodgkin lymphoma, anaemia due to bone marrow involvement was present in 16/40 (40%). In most patients with bone marrow involvement, anaemia was due to other causes. In only 3 patients, anaemia was attributable to bone marrow involvement alone. Anaemia was multifactorial in 18/46 (39.1%) patients. Nutritional deficiency alone or in combination was present in 22/46 (47.8%) patients. Anaemia is common in lymphoid malignancies at initial presentation. Besides managing anaemia of chronic disease and bone marrow involvement, nutritional and autoimmune causes should be ruled out. Copyright 2013, NMJI.

Extremely high concentration of folates in premature newborns.

PubMed

Zikavska, T; Brucknerova, I

2014-01-01

Extremely high concentration of folates in premature newborns: case reports. Folates are a group of water soluble compounds, which are important for metabolic processes in human body. These are important during periods of rapid cell growth. The most accurate indicator of long-term folate level status in the body is the determination of red blood cell (RBC) folate concentrations. The optimal level of RBC folate is not known in neonatal period. Authors discuss the reasons for extremely high level of RBC folate concentrations. In our work we present the cases of two premature newborns with extremely high level of RBC folate concentrations, which were analyzed immunochemically on the first day of life and after six weeks of life. In both cases we measured RBC folate concentrations on the 1st day of life. After 6 weeks we found extremely high RBC folate concentration level (5516.67 ng/ml) in the first case after RBC transfusions. In second case after two months of life the RBC folate concentration level was doubled (2335.1 ng/ml) until 24 hours after RBC transfusion compared to levels after birth. The normal range of RBC folate values vary in newborns. The upper limit of daily dose of folic acid in pregnancy and neonatal period is not known. On the other hand it is an easily excreted water-soluble vitamin but in premature newborn it can lead to the disruption of metabolic balance and slow its degradation. Some factors can have an impact on RBC folate concentration. Blood transfusion can be one of the main influences on RBC folate concentration. To clarify these mechanisms further studies are required (Ref. 29).

Enhancement of the folate content in Egyptian pita bread

PubMed Central

Hefni, Mohammed; Witthöft, Cornelia M.

2012-01-01

Introduction Egypt has a high incidence of neural tube defects related to folate deficiency. One major food source for folate is pita (baladi) bread, which is consumed daily. Bioprocessing (e.g. germination) has been reported to increase the folate content in cereals. The aim was to produce pita bread with increased folate content using germinated wheat flour (GWF). Methods Prior to milling the effects of germination and drying conditions on folate content in wheat grains were studied. Pita bread was baked from wheat flour substituted with different levels of GWF. The folate content in dough and bread and rheological properties of dough were determined. Results Germination of wheat grains resulted in, depending on temperature, 3- to 4-fold higher folate content with a maximum of 61 µg/100 g DM (dry matter). The folate content in both flour and bread increased 1.5 to 4-fold depending on the level of flour replacement with GWF. Pita bread baked with 50% sieved GWF was acceptable with respect to colour and layer separation, and had a folate content of 50 µg/100 g DM compared with 30 µg/100 g DM in conventional pita bread (0% GWF). Conclusion Using 50% GWF, pita bread with increased folate content, acceptable for the Egyptian consumer, was produced. Consumption of this bread would increase the average daily folate intake by 75 µg. PMID:22489220

EFFECT OF VARYING MATERNAL FOLATE STATUS AND DIETARY FOLATE INTAKE ON RESPONSE TO DIVERSE DEVELOPMENTAL TOXICANTS IN THE RAT

EPA Science Inventory

Periconceptional and early pregnancy folate supplements are associated with reduced recurrence and occurrence of birth defects in humans. This study was undertaken to assess the influence of maternal folate status and dietary folate intake on outcome of exposures to diverse terat...

Physiology of folic acid in health and disease.

PubMed

Stanger, O

2002-04-01

Folates are important cofactors in the transfer and utilization of one-carbon-groups and play a key role in the remethylation of methionine thus providing essential methyl groups for numerous biological reactions. Furthermore, folates donate one-carbon units in the process of DNA-biosynthesis with implications for the regulation of gene expression, transcription, chromatine structure, genomic repair and genomic stability. As the role of folate deficiency in atherosclerotic cardiovascular disease, neurological and neuropsychiatric disorders, in congenital defects and carcinogenesis has become better understood, folate has been recognized as having great potential to prevent these many disorders through folate supplementation for the general population. Folate acts directly to produce antioxidant effects, interactions with enzyme endothelial NO synthase (eNOS) and effects on cofactor bioavailability of NO. Folate acts indirectly to lower homocysteine levels and insure optimal functioning of the methylation cycle. Folate metabolism provides an interesting example of gene-environmental interaction. A great part of the population, especially subgroups with higher demand, appears to have suboptimal folate intake, as determined through more sensitive parameters now widely determined. The available data strongly suggest that criteria for "folate deficiency" may have to be redefined.

Fluorescence behaviour of 5,10-methenyltetrahydrofolate, 10-formyltetrahydrofolate, 10-formyldihydrofolate, and 10-formylfolate in aqueous solution at pH 8

NASA Astrophysics Data System (ADS)

Tyagi, A.; Penzkofer, A.; Batschauer, A.; Wolf, E.

2009-06-01

The fluorescence spectroscopic behaviour of (6R,S)-5,10-methenyltetrahydrofolate (MTHF), (6R,S)-10-formyltetrahydrofolate (10-HCO-H4folate), 10-formyldihydrofolate (10-HCO-H2folate), and 10-formylfolate (10-HCO-folate) in aqueous Tris-HCl buffer at pH 8 is studied. MTHF and 10-HCO-folate were commercially available. 10-HCO-H4folate was prepared from MTHF by hydrolysis at room temperature under anaerobic conditions. 10-HCO-H2folate was prepared by oxidation of 10-HCO-H4folate under aerobic conditions. Fluorescence quantum distributions at room temperature and fluorescence signal decays at room temperature and liquid nitrogen temperature were measured. The fluorescence lifetimes determined at room temperature (liquid nitrogen temperature) are 10 ps (2.9 ns) for MTHF, 38 ps (3.7 ns) for 10-HCO-H4folate, 80 ps (10.5 ns) for 10-HCO-H2folate, and 7.1 ns (20 ns) for 10-HCO-folate. The results are discussed in terms of dyadic (pterin-benzoyl-glutamate) photo-induced electron transfer and dyadic fluorescent dynamics.

Updated folate data in the Dutch Food Composition Database and implications for intake estimates

PubMed Central

Westenbrink, Susanne; Jansen-van der Vliet, Martine; van Rossum, Caroline

2012-01-01

Background and objective Nutrient values are influenced by the analytical method used. Food folate measured by high performance liquid chromatography (HPLC) or by microbiological assay (MA) yield different results, with in general higher results from MA than from HPLC. This leads to the question of how to deal with different analytical methods in compiling standardised and internationally comparable food composition databases? A recent inventory on folate in European food composition databases indicated that currently MA is more widely used than HPCL. Since older Dutch values are produced by HPLC and newer values by MA, analytical methods and procedures for compiling folate data in the Dutch Food Composition Database (NEVO) were reconsidered and folate values were updated. This article describes the impact of this revision of folate values in the NEVO database as well as the expected impact on the folate intake assessment in the Dutch National Food Consumption Survey (DNFCS). Design The folate values were revised by replacing HPLC with MA values from recent Dutch analyses. Previously MA folate values taken from foreign food composition tables had been recalculated to the HPLC level, assuming a 27% lower value from HPLC analyses. These recalculated values were replaced by the original MA values. Dutch HPLC and MA values were compared to each other. Folate intake was assessed for a subgroup within the DNFCS to estimate the impact of the update. Results In the updated NEVO database nearly all folate values were produced by MA or derived from MA values which resulted in an average increase of 24%. The median habitual folate intake in young children was increased by 11–15% using the updated folate values. Conclusion The current approach for folate in NEVO resulted in more transparency in data production and documentation and higher comparability among European databases. Results of food consumption surveys are expected to show higher folate intakes when using the updated values. PMID:22481900

Systematic Review of Observational Studies with Dose-Response Meta-Analysis between Folate Intake and Status Biomarkers in Adults and the Elderly.

PubMed

Novaković, Romana; Geelen, Anouk; Ristić-Medić, Danijela; Nikolić, Marina; Souverein, Olga W; McNulty, Helene; Duffy, Maresa; Hoey, Leane; Dullemeijer, Carla; Renkema, Jacoba M S; Gurinović, Mirjana; Glibetić, Marija; de Groot, Lisette C P G M; Van't Veer, Pieter

2018-06-07

Dietary reference values for folate intake vary widely across Europe. MEDLINE and Embase through November 2016 were searched for data on the association between folate intake and biomarkers (serum/plasma folate, red blood cell [RBC] folate, plasma homocysteine) from observational studies in healthy adults and elderly. The regression coefficient of biomarkers on intake (β) was extracted from each study, and the overall and stratified pooled β and SE (β) were obtained by random effects meta-analysis on a double log scale. These dose-response estimates may be used to derive folate intake reference values. For every doubling in folate intake, the changes in serum/plasma folate, RBC folate and plasma homocysteine were +22, +21, and -16% respectively. The overall pooled regression coefficients were β = 0.29 (95% CI 0.21-0.37) for serum/plasma folate (26 estimates from 17 studies), β = 0.28 (95% CI 0.21-0.36) for RBC (13 estimates from 11 studies), and β = -0.21 (95% CI -0.31 to -0.11) for plasma homocysteine (10 estimates from 6 studies). These estimates along with those from randomized controlled trials can be used for underpinning dietary recommendations for folate in adults and elderly. © 2018 S. Karger AG, Basel.

Folate, colorectal cancer and the involvement of DNA methylation.

PubMed

Williams, Elizabeth A

2012-11-01

Diet is a major factor in the aetiology of colorectal cancer (CRC). Epidemiological evidence suggests that folate confers a modest protection against CRC risk. However, the relationship is complex, and evidence from human intervention trials and animal studies suggests that a high-dose of folic acid supplementation may enhance the risk of colorectal carcinogenesis in certain circumstances. The molecular mechanisms underlying the apparent dual modulatory effect of folate on colorectal carcinogenesis are not fully understood. Folate is central to C1 metabolism and is needed for both DNA synthesis and DNA methylation, providing plausible biological mechanisms through which folate could modulate cancer risk. Aberrant DNA methylation is an early event in colorectal carcinogenesis and is typically associated with the transcriptional silencing of tumour suppressor genes. Folate is required for the production of S-adenosyl methionine, which serves as a methyl donor for DNA methylation events; thereby folate availability is proposed to modulate DNA methylation status. The evidence for an effect of folate on DNA methylation in the human colon is limited, but a modulation of DNA methylation in response to folate has been demonstrated. More research is required to clarify the optimum intake of folate for CRC prevention and to elucidate the effect of folate availability on DNA methylation and the associated impact on CRC biology.

Temperature effects on separation of Gd3+ from Gd-DTPA-folate using nanofiltration method

NASA Astrophysics Data System (ADS)

Rahayu, I.; Indraneli, R. P.; Yuliyati, Y. B.; Anggraeni, A.; Soedjanaatmadja, U. M. S.; Bahti, H. H.

2018-05-01

MRI is one of the best techniques in medical diagnostics. Contrast agents are used to improve the visual of organs that are difficult to distinguish through MRI. Gd-DTPA-folate is one of the specific contrast agents against cancer diagnosis, because it has a high affinity to folate receptors. In the complexing Gd-DTPA-folate, does not rule out the complexity step runs imperfectly, so there is still Gd3+ in the Gd-DTPA-folate complex. The separation of Gd3+ from the Gd-DTPA-folate complex is important to eliminate toxic effects on the contrast agent. This study aims to determine the effect of temperature on the separation of Gd-DTPA-folate from Gd3+ with nanofiltration. The method are preparation Gd-DTPA-folate from GdCl3.6H2O and DTPA-folate by reflux method, then separated Gd-DTPA-folate complex from Gd3+ with nanofiltration at variation temperature (40, 41, 42, 43, 44oC ). Then, the values of flux and rejection coefficients were analyzed. The results showed that the optimum temperature for the separation of Gd3+ from Gd-DTPA-folate was achieved at 42.6°C with the rejection coefficient of 24% and the permeate flux of 403 L.m-2.h-1.

Folate status and concentrations of serum folate forms in the US population: National Health and Nutrition Examination Survey 2011-2.

PubMed

Pfeiffer, Christine M; Sternberg, Maya R; Fazili, Zia; Lacher, David A; Zhang, Mindy; Johnson, Clifford L; Hamner, Heather C; Bailey, Regan L; Rader, Jeanne I; Yamini, Sedigheh; Berry, R J; Yetley, Elizabeth A

2015-06-28

Serum and erythrocyte (RBC) total folate are indicators of folate status. No nationally representative population data exist for folate forms. We measured the serum folate forms (5-methyltetrahydrofolate (5-methylTHF), unmetabolised folic acid (UMFA), non-methyl folate (sum of tetrahydrofolate (THF), 5-formyltetrahydrofolate (5-formylTHF), 5,10-methenyltetrahydrofolate (5,10-methenylTHF)) and MeFox (5-methylTHF oxidation product)) by HPLC-MS/MS and RBC total folate by microbiologic assay in US population ≥ 1 year (n approximately 7500) participating in the National Health and Nutrition Examination Survey 2011-2. Data analysis for serum total folate was conducted including and excluding MeFox. Concentrations (geometric mean; detection rate) of 5-methylTHF (37·5 nmol/l; 100 %), UMFA (1·21 nmol/l; 99·9 %), MeFox (1·53 nmol/l; 98·8 %), and THF (1·01 nmol/l; 85·2 %) were mostly detectable. 5-FormylTHF (3·6 %) and 5,10-methenylTHF (4·4 %) were rarely detected. The biggest contributor to serum total folate was 5-methylTHF (86·7 %); UMFA (4·0 %), non-methyl folate (4·7 %) and MeFox (4·5 %) contributed smaller amounts. Age was positively related to MeFox, but showed a U-shaped pattern for other folates. We generally noted sex and race/ethnic biomarker differences and weak (Spearman's r< 0·4) but significant (P< 0·05) correlations with physiological and lifestyle variables. Fasting, kidney function, smoking and alcohol intake showed negative associations. BMI and body surface area showed positive associations with MeFox but negative associations with other folates. All biomarkers showed significantly higher concentrations with recent folic acid-containing dietary supplement use. These first-time population data for serum folate forms generally show similar associations with demographic, physiological and lifestyle variables as serum total folate. Patterns observed for MeFox may suggest altered folate metabolism dependent on biological characteristics.

A Milk-Free Diet Downregulates Folate Receptor Autoimmunity in Cerebral Folate Deficiency Syndrome

ERIC Educational Resources Information Center

Ramaekers, Vincent T.; Sequeira, Jeffrey M.; Blau, Nenad; Quadros, Edward V.

2008-01-01

In cerebral folate deficiency syndrome, the presence of autoantibodies against the folate receptor (FR) explains decreased folate transport to the central nervous system and the clinical response to folinic acid. Autoantibody crossreactivity with milk FR from different species prompted us to test the effect of a milk-free diet. Intervention with a…

Enhancing the natural folate level in wine using bioengineering and stabilization strategies.

PubMed

Liu, Yazheng; Walkey, Christopher J; Green, Timothy J; van Vuuren, Hennie J J; Kitts, David D

2016-03-01

Folate deficiency is linked to many diseases, some of which may have higher probability in individuals with alcohol-induced alterations in one-carbon metabolism. Our study shows that folate content in commercial wine is not related to white or red varieties, but associated with the yeast that is used to produce the wine. The stability of folate in these wines, once opened for consumption, did not correlate with total phenolic or sulfite content. In addition, we employed yeast bioengineering to fortify wine with folate. We confirmed by overexpression that FOL2 was the key gene encoding the rate-limiting step of folate biosynthesis in wine yeast. In this study, we also show that overexpression of other folate biosynthesis genes, including ABZ1, ABZ2, DFR1, FOL1 and FOL3, had no effect on folate levels in wine. Ensuring stability of the increased natural folate in all wines was achieved by the addition of ascorbate. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chronic ethanol exposure and folic acid supplementation: fetal growth and folate status in the maternal and fetal guinea pig.

PubMed

Hewitt, Amy J; Knuff, Amber L; Jefkins, Matthew J; Collier, Christine P; Reynolds, James N; Brien, James F

2011-05-01

Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. Copyright © 2011 Elsevier Inc. All rights reserved.

Folate content and retention in commonly consumed vegetables in the South Pacific.

PubMed

Maharaj, Prayna P P; Prasad, Surendra; Devi, Riteshma; Gopalan, Romila

2015-09-01

This paper reports the effect of boiling and frying on the retention of folate in commonly consumed Fijian vegetables (drumstick leaves, taro leaves, bele leaves, amaranth leaves, fern/ota, okra and French bean). The folate content was determined by microbiological assay (Lactobacillus casei rhamnosus) and tri-enzyme (protease, α-amylase and chicken pancreas conjugase) extraction treatment. The folate loss varied among the vegetables from 10-64% on boiling while 1-36% on frying. The higher folate loss was observed during boiling. The folate content in the water derived after boiling different vegetables ranged from 11.9 ± 0.5 to 61.6 ± 2.5 μg/100mL. The folate loss on boiling was accounted for in the cooking water. The predominant way of folate loss on boiling was leaching rather than thermal degradation which makes boiling the better choice of cooking the studied vegetables for folate intake, provided the cooking water is consumed together with the vegetables. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dietary and other lifestyle correlates of serum folate concentrations in a healthy adult population in Crete, Greece: a cross-sectional study

PubMed Central

Hatzis, Christos M; Bertsias, George K; Linardakis, Manolis; Scott, John M; Kafatos, Anthony G

2006-01-01

Background Folate has emerged as a key nutrient for optimising health. Impaired folate status has been identified as a risk factor for cardiovascular disease, various types of cancers, and neurocognitive disorders. The study aimed at examining the distribution and determinants of serum folate concentrations in a healthy adult population in Crete, Greece. Methods A cross-sectional sample of 486 healthy adults (250 men, 236 women) aged 39 ± 14 years, personnel of the Medical School and the University Hospital of Crete in Greece, was examined. Serum folate and vitamin B12 concentrations were measured by microbiological assay, and total homocysteine was determined fluorometrically and by high-pressure liquid chromatography. Lifestyle questionnaires were completed, and nutrient intakes and food consumption were assessed by 24-h dietary recalls. Multivariate analyses were performed using SPSS v10.1. Results The geometric mean (95% confidence interval) concentrations of serum folate were 15.6 μmol/l (14.6–16.8) in men and 19.2 μmol/l (17.9–20.7) in women (p < 0.001). Inadequate folate levels (≤7 nmol/l) were present in 6.8% of men and 2.1% of women (p < 0.001). Approximately 76% of men and 87% of women did not meet the reference dietary intake for folate (400 μg/day). Serum folate was inversely related to total homocysteine levels (p < 0.001). Increased tobacco and coffee consumption were associated with lower folate concentrations (p < 0.05 for both) but these associations disappeared after controlling for nutrient intakes. In multivariate analysis, intakes of MUFA, fibre, calcium, magnesium, folate, and vitamins A, E, C, B1, and B6 were positively associated with serum folate. Consumption of potatoes, legumes, fruits, and vegetables were favourably related to the serum folate status. Conclusion Serum folate concentrations were associated with various demographic, lifestyle and dietary factors in healthy Cretan adults. Large-scale epidemiological studies should be conducted within the general Greek adult population to assess the prevalence of impaired folate status and further examine associations with dietary patterns and chronic disease risk. Considering the importance of folate in health maintenance, it is important to increase the public's awareness of modifiable lifestyle patterns and diet and tobacco use in particular, which may be associated with improved folate status. PMID:16472386

Cholesterol in brain disease: sometimes determinant and frequently implicated

PubMed Central

Martín, Mauricio G; Pfrieger, Frank; Dotti, Carlos G

2014-01-01

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell–cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function. PMID:25223281

Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment.

PubMed Central

Lever, E G; Elwes, R D; Williams, A; Reynolds, E H

1986-01-01

Subacute combined degeneration of the cord is a rare complication of folate deficiency. Disturbance of methylation reactions in nervous tissue probably underlie subacute combined degeneration of the cord arising from folate as well as vitamin B12 deficiency. Methyl tetrahydrofolate is the form in which folic acid is transported into the CNS. Therefore methyl tetrahydrofolate treatment of the neurological and psychiatric manifestations of folate deficiency would seem to be theoretically advantageous. A case of subacute combined degeneration of the cord due to dietary folate deficiency and associated with an organic brain syndrome is reported. There was striking haematological, neurological and psychiatric response to methyl folate treatment. PMID:3783183

Cryptophane-Folate Biosensor for 129Xe NMR

DTIC Science & Technology

2014-12-01

folate receptor type alpha in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix . Cancer Epidemiol. Biomarkers Prev. 8...conjugated cryptophane was developed for targeting cryptophane to membrane-bound folate receptors that are overexpressed in many human cancers . The...through a folate receptor-mediated pathway. Flow cytometry revealed 10-fold higher cellular internalization in KB cancer cells overexpressing folate

Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.

PubMed

Zhao, Yan; Guo, Chenyang; Hu, Hongtao; Zheng, Lin; Ma, Junli; Jiang, Li; Zhao, Erjiang; Li, Hailiang

2017-02-07

Previously reported findings on the association between folate intake or serum folate levels and esophageal cancer risk have been inconsistent. This study aims to summarize the evidence regarding these relationships using a dose-response meta-analysis approach. We performed electronic searches of the Pubmed, Medline and Cochrane Library electronic databases to identify studies examining the effect of folate on the risk of esophageal cancer. Ultimately, 19 studies were included in the meta-analysis. Summary odds ratios (ORs) were estimated using a random effects model. A linear regression analysis of the natural logarithm of the OR was carried out to assess the possible dose-response relationship between folate intake and esophageal cancer risk. The pooled ORs for esophageal cancer in the highest vs. lowest levels of dietary folate intake and serum folate were 0.63 (95% CI: 0.56-0.71) and 0.71 (95% CI: 0.55-0.92), respectively. The dose-response meta-analysis indicated that a 100 μg/day increment in dietary folate intake reduced the estimate risk of esophageal cancer by 12%. These findings suggest that dietary and serum folate exert a protective effect against esophageal carcinogenesis.

Effect of folate deficiency on promoter methylation and gene expression of Esr1, Cav1, and Elavl1, and its influence on spermatogenesis.

PubMed

Yuan, Hong-Fang; Zhao, Kai; Zang, Yu; Liu, Chun-Yan; Hu, Zhi-Yong; Wei, Jia-Jing; Zhou, Ting; Li, Ying; Zhang, Hui-Ping

2017-04-11

This study aims to investigate the effect of folate deficiency on the male reproductive function and the underlying mechanism. A total of 269 screened participants from 421 recruitments were enrolled in this study. An animal model of folate deficiency was constructed. Folate concentration was measured in the ejaculate, and its association with semen parameters was then determined. The expression and promoter methylation status of ESR1, CAV1, and ELAVL1 were also evaluated. Results showed that seminal plasma folate level was significantly lower among subjects with azoospermia than those with normozoospermia. Low folate level was significantly correlated with low sperm concentration in men with normozoospermia. Folate deficiency significantly reduced the expression of ESR1, CAV1, and ELAVL1, which are critical to spermatogenesis. However, low folate levels did not increase the methylation levels of the promoter regions of ESR1, CAV1, and ELAVL1 in human sperm DNA. Thus, folate deficiency impairs spermatogenesis may partly due to inhibiting the expression of these genes. Thus future research should determine the significance of sufficient folate status in male fertilization and subsequent pregnancy outcomes.

Folate intake and the MTHFR C677T genotype influence choline status in young Mexican American women☆

PubMed Central

Abratte, Christian M.; Wang, Wei; Li, Rui; Moriarty, David J.; Caudill, Marie A.

2009-01-01

Numerous studies have reported a relationship between folate status, the methylenetetrahydrofolate reductase (MTHFR) 677C→T variant and disease risk. Although folate and choline metabolism are inter-related, only limited data are available on the relationship between choline and folate status in humans. This study sought to examine the influences of folate intake and the MTHFR 677C→T variant on choline status. Mexican-American women (n =43; 14 CC, 12 CT and 17 TT) consumed 135 μg/day as dietary folate equivalents (DFE) for 7 weeks followed by randomization to 400 or 800 μg DFE/day for 7 weeks. Throughout the study, total choline intake remained unchanged at ∼350 mg/day. Plasma concentrations of betaine, choline, glycerophosphocholine, phosphatidylcholine and sphingomyelin were measured via LC-MS/MS for Weeks 0, 7 and 14. Phosphatidylcholine and sphingomyelin declined ( P=.001, P=.009, respectively) in response to folate restriction and increased ( P=.08, P=.029, respectively) in response to folate treatment. The increase in phosphatidylcholine occurred in response to 800 ( P=.03) not 400 ( P=.85) μg DFE/day (week×folate interaction, P=.017). The response of phosphatidylcholine to folate intake appeared to be influenced by MTHFR C677T genotype. The decline in phosphatidylcholine during folate restriction occurred primarily in women with the CC or CT genotype and not in the TT genotype (week×genotype interaction, P=.089). Moreover, when examined independent of folate status, phosphatidylcholine was higher ( P <.05) in the TT genotype relative to the CT genotype. These data suggest that folate intake and the MTHFR C677T genotype influence choline status in humans. PMID:17588738

Effects of yeasts and bacteria on the levels of folates in rye sourdoughs.

PubMed

Kariluoto, Susanna; Aittamaa, Marja; Korhola, Matti; Salovaara, Hannu; Vahteristo, Liisa; Piironen, Vieno

2006-02-01

Fermentation of rye dough is often accompanied with an increase in folate content. In this study, three sourdough yeasts, Candida milleri CBS 8195, Saccharomyces cerevisiae TS 146, and Torulaspora delbrueckii TS 207; a control, baker's yeast S. cerevisiae ALKO 743; and four Lactobacillus spp., L. acidophilus TSB 262, L. brevis TSB 307, L. plantarum TSB 304, and L. sanfranciscensis TSB 299 originally isolated from rye sourdough were examined for their abilities to produce or consume folates. The microorganisms were grown in yeast extract-peptone-d-glucose medium as well as in small-scale fermentations that modelled the sourdough fermentation step used in rye baking. Total folate contents were determined using Lactobacillus rhamnosus (ATCC 7469) as the growth indicator organism. The microorganisms studied did not excrete folates into the media in significant amounts. Yeasts increased the folate contents of sterilised rye flour-water mixtures from 6.5 microg/100 g to between 15 and 23 microg/100 g after 19-h fermentation, whereas lactic acid bacteria decreased it to between 2.9 and 4.2 microg/100 g. Strains of Lactobacillus bulgaricus, L. casei, L. curvatus, L. fermentum, L. helveticus, Pediococcus spp., and Streptococcus thermophilus that were also tested gave folate contents after fermentation that varied between 2 and 10.4 microg/100 g. Although the four Lactobacillus spp. from sourdough consumed folates their effect on folate contents in co-cultivations was minimal. It was concluded that the increase of folate content during fermentation was mainly due to folate synthesis by yeasts. Fermentation of non-sterilised flour-water mixtures as such resulted in three-fold increases in the folate contents. Two folate producing bacteria were isolated from the non-sterilised flour and identified as Enterobacter cowanii and Pantoea agglomerans.

An overview of folate status in a population-based study from São Paulo, Brazil and the potential impact of 10 years of national folic acid fortification policy.

PubMed

Steluti, J; Selhub, J; Paul, L; Reginaldo, C; Fisberg, R M; Marchioni, D M L

2017-10-01

Food fortification is an important strategy in public health policy for controlling micronutrient malnutrition and a major contributing factor in the eradication of micronutrients' deficiencies. Approximately 50 countries worldwide have adopted food fortification with folic acid (FA). FA fortification of wheat and maize flours has been mandatory in Brazil since 2004. To assess the effect of 10 years of FA food fortification policy on folate status of residents of São Palo, Brazil using a population-based survey. Data were from 750 individuals aged ⩾12 years who participated in a cross-sectional population-based survey in São Paulo city, Brazil. Fasting blood samples were collected, and folate was assayed by affinity-high performance liquid chromatografy method with electrochemical detection. The participants provided information about food intake based on two 24 h dietary recall. Only 1.76% of population had folate deficiency (<6.8 nmol/l). The mean folate concentration was 29.5 (95% confidence interval: 27.3-31.7) nmol/l for all sex-age groups. The mean folate intake for the population was 375.8 (s.e.m.=6.4) μg/day of dietary folate equivalents (DFEs). When comparing folate intake in DFE from food folate and FA from fortified foods, FA contributed 50% or more of the DFE in almost all sex-age groups. The major contributors of folate intake are processed foods made from wheat flour fortified with FA, especially among subjects younger than 20 years old. The deficiency of folate is very low, and food fortification contributed to folate intake and had a notable influence on rankings of food contributors of folate.

The Folate Pathway and Nonsyndromic Cleft Lip and Palate

PubMed Central

Blanton, Susan H.; Henry, Robin R.; Yuan, Quiping; Mulliken, John B.; Stal, Samuel; Finnell, Richard H.; Hecht, Jacqueline T.

2013-01-01

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth malformation caused by genetic, environmental and gene-environment interactions. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects (NTDs) and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) SNP polymorphisms, C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. In this study, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP and, if so, were there detectable interactions between these genes and environmental exposures. In addition, we evaluated the data for a sex effect. Fourteen folate metabolism related genes were interrogated using eighty-nine SNPs in multiplex and simplex non-Hispanic White (NHW) (317) and Hispanic (128) NSCLP families. Evidence for a risk association between NSCLP and SNPs in nitrous oxide 3 (NOS3) and thymidylate synthetase (TYMS) was detected in the NHW group, whereas associations with methionine synthase (MTR), betaine-homocysteine methyltransferase (BHMT2), MTHFS and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with sex of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated. PMID:21254359

Dietary folate does not significantly affect the intestinal microbiome, inflammation or tumorigenesis in azoxymethane-dextran sodium sulphate-treated mice.

PubMed

MacFarlane, Amanda J; Behan, Nathalie A; Matias, Fernando M G; Green, Judy; Caldwell, Don; Brooks, Stephen P J

2013-02-28

Inflammatory bowel disease (IBD) is a risk factor for the development of colon cancer. Environmental factors including diet and the microflora influence disease outcome. Folate and homocysteine have been associated with IBD-mediated colon cancer but their roles remain unclear. We used a model of chemically induced ulcerative colitis (dextran sodium sulphate (DSS)) with or without the colon carcinogen azoxymethane (AOM) to determine the impact of dietary folic acid (FA) on colonic microflora and the development of colon tumours. Male mice (n 15 per group) were fed a FA-deficient (0 mg/kg), control (2 mg/kg) or FA-supplemented (8 mg/kg) diet for 12 weeks. Folate status was dependent on the diet (P< 0·001) and colitis-induced treatment (P= 0·04) such that mice with colitis had lower circulating folate. FA had a minimal effect on tumour initiation, growth and progression, although FA-containing diets tended to be associated with a higher tumour prevalence in DSS-treated mice (7-20 v. 0%, P= 0·08) and the development of more tumours in the distal colon of AOM-treated mice (13-83% increase, P= 0·09). Folate deficiency was associated with hyperhomocysteinaemia (P< 0·001) but homocysteine negatively correlated with tumour number (r - 0·58, P= 0·02) and load (r - 0·57, P= 0·02). FA had no effect on the intestinal microflora. The present data indicate that FA intake has no or little effect on IBD or IBD-mediated colon cancer in this model and that hyperhomocysteinaemia is a biomarker of dietary status and malabsorption rather than a cause of IBD-mediated colon cancer.

One year B-vitamins increases serum and whole blood folate forms and lowers plasma homocysteine in older Germans.

PubMed

Kirsch, Susanne H; Herrmann, Wolfgang; Kruse, Vera; Eckert, Rudolf; Gräber, Stefan; Geisel, Jürgen; Obeid, Rima

2015-02-01

We aimed to study the effect of long-term supplementation of B-vitamins on folate forms in serum and whole blood (WB) in elderly German subjects. 59 participants (mean age 67 years) were randomized to daily receive either vitamin D3 (1200 IU), folic acid (500 μg), vitamin B12 (500 μg), vitamin B6 (50 mg), and calcium carbonate (456 mg) or vitamin D3 plus calcium carbonate. Serum and WB folate forms were measured before and after 6 and 12 months. B-vitamins supplementation for 6 months led to higher concentrations of 5-methyltetrahydrofolate (5-methylTHF) in serum (mean 49.1 vs. 19.6 nmol/L) and WB (1332 vs. 616 nmol/L). Also non-methyl-folate concentrations in serum and WB were higher after 6 months with B-vitamins supplementation. Unmetabolized folic acid (UFA) increased after supplementation. tHcy concentration was lowered after 1 year of B-vitamin supplementation (mean 13.1 vs. 9.6 μmol/L). A stronger reduction of tHcy after 1 year was found in participants who had baseline level >12.5 μmol/L (mean 17.0 vs. 11.9 μmol/L) compared to those with baseline tHcy lower than this limit (mean 9.1 vs. 7.4 μmol/L). In contrast, the increases in serum and WB 5-methylTHF were comparable between the two groups. One year B-vitamins supplementation increased the levels of 5-methylTHF and non-methyl-folate in serum and WB, normalized tHcy, but caused an increase in the number of cases with detectable UFA in serum. Lowering of tHcy was predicted by baseline tHcy, but not by baseline serum or WB 5-methylTHF.

Correspondence of folate dietary intake and biomarker data123

PubMed Central

Fulgoni, Victor L; Taylor, Christine L; Pfeiffer, Christine M; Thuppal, Sowmyanarayanan V; McCabe, George P; Yetley, Elizabeth A

2017-01-01

Background: Public health concerns with regard to both low and high folate status exist in the United States. Recent publications have questioned the utility of self-reported dietary intake data in research and monitoring. Objectives: The purpose of this analysis was to examine the relation between self-reported folate intakes and folate status biomarkers and to evaluate their usefulness for several types of applications. Design: We examined usual dietary intakes of folate by using the National Cancer Institute method to adjust two 24-h dietary recalls (including dietary supplements) for within-person variation and then compared these intakes with serum and red blood cell (RBC) folate among 4878 men and nonpregnant, nonlactating women aged ≥19 y in NHANES 2011–2012, a nationally representative, cross-sectional survey, with respect to consistency across prevalence estimates and rank order comparisons. Results: There was a very low prevalence (<1%) of folate deficiency when serum (<7 nmol/L) and RBC (<305 nmol/L) folate were considered, whereas a higher proportion of the population reported inadequate total dietary folate intakes (6%). Similar patterns of change occurred between intakes and biomarkers of folate status when distributions were examined (i.e., dose response), particularly when diet was expressed in μg. Intakes greater than the Tolerable Upper Intake Level greatly increased the odds of having high serum folate (OR: 17.6; 95% CI: 5.5, 56.0). Conclusions: When assessing folate status in the United States, where fortification and supplement use are common, similar patterns in the distributions of diet and biomarkers suggest that these 2 types of status indicators reflect the same underlying folate status; however, the higher prevalence estimates for inadequate intakes compared with biomarkers suggest, among other factors, a systematic underestimation bias in intake data. Caution is needed in the use of dietary folate data to estimate the prevalence of inadequacy among population groups. The use of dietary data for rank order comparisons or to estimate the potential for dietary excess is likely more reliable. PMID:28446502

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

PubMed Central

Kettenbach, Kathrin; Reffert, Laura M.; Schieferstein, Hanno; Pektor, Stefanie; Eckert, Raphael; Miederer, Matthias; Rösch, Frank

2018-01-01

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging. PMID:29562610

Association of homocysteine with global DNA methylation in vegetarian Indian pregnant women and neonatal birth anthropometrics.

PubMed

Gadgil, Maithili S; Joshi, Kalpana S; Naik, Sadanand S; Pandit, Anand N; Otiv, Suhas R; Patwardhan, Bhushan K

2014-11-01

The present study was designed to evaluate if plasma maternal folate, vitamin B-12 and homocysteine levels had an effect on maternal global DNA methylation and neonatal anthropometrics in Indian pregnant women. A total of 49 participants having completed ≥36 weeks of pregnancy were enrolled in the study. Estimation of folate was by Ion capture assay, vitamin B-12 by microparticle enzyme immunoassay, total homocysteine by fluorescence polarization immunoassay and global DNA methylation using Cayman's DNA methylation enzyme immunoassay (EIA) kit. Folate and vitamin B-12 were inversely correlated to homocysteine in pregnant women consuming vegetarian and non-vegetarian diet. No difference in global DNA methylation was found between the vegetarian and non-vegetarian pregnant women. Folate and vitamin B-12 did not show association with global DNA methylation, however plasma total homocysteine of the vegetarian group showed significant correlation to global DNA methylation (r(2 )= 0.49, p = 0.011). Plasma total homocysteine was inversely related to tricep skinfold (r(2 )= -0.484, p = 0.01) and chest circumference (r(2 )= -0.104, p = 0.04) of neonates in vegetarian group. Moderate vitamin B-12 deficiency in vegetarian pregnant women might be the cause of hyperhomocystinemia, hypermethylation when compared to vitamin B-12 sufficient non-vegetarian group.

Methylation reactions, the redox balance and atherothrombosis: the search for a link with hydrogen sulfide.

PubMed

Lupoli, Roberta; Di Minno, Alessandro; Spadarella, Gaia; Franchini, Massimo; Sorrentino, Raffaella; Cirino, Giuseppe; Di Minno, Giovanni

2015-06-01

It is now clear that homocysteine (Hcy) is irreversibly degraded to hydrogen sulfide (H(2)S), an endogenous gasotransmitter that causes in vivo platelet activation via upregulation of phospholipase A2 and downstream boost of the arachidonate cascade. This mechanism involves a transsulfuration pathway. Based on these new data, clinical and experimental models on the relationships between Hcy and folate pathways in vascular disease and information on the Hcy controversy have been reanalyzed in the present review. Most interventional trials focused on Hcy lowering by folate administration did not exclude patients routinely taking the arachidonate inhibitor aspirin. This may have influenced the results of some of these trials. It is also clear that nutritional intake of folate affects several enzymatic reactions of the methionine-Hcy cycle and associated one-carbon metabolism and, thereby, both methylation reactions and redox balance. Hence, it is conceivable that the abnormally high Hcy levels seen in pathologic states reflect a poorly elucidated perturbation of such reactions and of such balance. While it is unknown whether there is an interplay between H2S, methylation reactions, and redox balance, measuring the sole reduction of blood Hcy that follows folate administration may well be an oversimplified approach to a complex biologic perturbation. The need to investigate this complex framework is thoroughly discussed in this article. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Nonflowering Plants Possess a Unique Folate-Dependent Phenylalanine Hydroxylase That Is Localized in Chloroplasts[W

PubMed Central

Pribat, Anne; Noiriel, Alexandre; Morse, Alison M.; Davis, John M.; Fouquet, Romain; Loizeau, Karen; Ravanel, Stéphane; Frank, Wolfgang; Haas, Richard; Reski, Ralf; Bedair, Mohamed; Sumner, Lloyd W.; Hanson, Andrew D.

2010-01-01

Tetrahydropterin-dependent aromatic amino acid hydroxylases (AAHs) are known from animals and microbes but not plants. A survey of genomes and ESTs revealed AAH-like sequences in gymnosperms, mosses, and algae. Analysis of full-length AAH cDNAs from Pinus taeda, Physcomitrella patens, and Chlamydomonas reinhardtii indicated that the encoded proteins form a distinct clade within the AAH family. These proteins were shown to have Phe hydroxylase activity by functional complementation of an Escherichia coli Tyr auxotroph and by enzyme assays. The P. taeda and P. patens AAHs were specific for Phe, required iron, showed Michaelian kinetics, and were active as monomers. Uniquely, they preferred 10-formyltetrahydrofolate to any physiological tetrahydropterin as cofactor and, consistent with preferring a folate cofactor, retained activity in complementation tests with tetrahydropterin-depleted E. coli host strains. Targeting assays in Arabidopsis thaliana mesophyll protoplasts using green fluorescent protein fusions, and import assays with purified Pisum sativum chloroplasts, indicated chloroplastic localization. Targeting assays further indicated that pterin-4a-carbinolamine dehydratase, which regenerates the AAH cofactor, is also chloroplastic. Ablating the single AAH gene in P. patens caused accumulation of Phe and caffeic acid esters. These data show that nonflowering plants have functional plastidial AAHs, establish an unprecedented electron donor role for a folate, and uncover a novel link between folate and aromatic metabolism. PMID:20959559

First-trimester serum folate levels and subsequent risk of abortion and preterm birth among Japanese women with singleton pregnancies.

PubMed

Yamada, Takashi; Morikawa, Mamoru; Yamada, Takahiro; Kishi, Reiko; Sengoku, Kazuo; Endo, Toshiaki; Saito, Tsuyoshi; Cho, Kazutoshi; Minakami, Hisanori

2013-01-01

To determine whether a low serum folate level during the first trimester predicts subsequent late abortion, preterm birth, or fetal growth restriction (FGR). A prospective cohort study involving 5,075 women whose serum folate levels were measured during the first trimester. The participants were informed of their serum folate levels. The pregnancy duration, birthweight, rate of late abortion/preterm birth, and the rate of FGR did not differ significantly among the four groups classified according to folate status. The mean serum folate levels did not differ among quartiles classified according to the gestational week at the time of delivery. Nineteen of the 20 women with folate deficiency gave birth at term to infants with a birthweight of 3.132 ± 321 g; only one infant had FGR. Low serum folate levels during the first trimester were not associated with the risk of late abortion, preterm birth, or FGR.

Large –scale wheat flour folic acid fortification program increases plasma folate levels among women of reproductive age in urban Tanzania

PubMed Central

Abioye, Ajibola I.; Ulenga, Nzovu; Msham, Salum; Kaishozi, George; Gunaratna, Nilupa S; Mwiru, Ramadhani; Smith, Erin; Dhillon, Christina Nyhus; Spiegelman, Donna; Fawzi, Wafaie

2017-01-01

There is widespread vitamin and mineral deficiency problem in Tanzania with known deficiencies of at least vitamin A, iron, folate and zinc, resulting in lasting negative consequences especially on maternal health, cognitive development and thus the nation’s economic potential. Folate deficiency is associated with significant adverse health effects among women of reproductive age, including a higher risk of neural tube defects. Several countries, including Tanzania, have implemented mandatory fortification of wheat and maize flour but evidence on the effectiveness of these programs in developing countries remains limited. We evaluated the effectiveness of Tanzania’s food fortification program by examining folate levels for women of reproductive age, 18–49 years. A prospective cohort study with 600 non-pregnant women enrolled concurrent with the initiation of food fortification and followed up for 1 year thereafter. Blood samples, dietary intake and fortified foods consumption data were collected at baseline, and at 6 and 12 months. Plasma folate levels were determined using a competitive assay with folate binding protein. Using univariate and multivariate linear regression, we compared the change in plasma folate levels at six and twelve months of the program from baseline. We also assessed the relative risk of folate deficiency during follow-up using log-binomial regression. The mean (±SE) pre–fortification plasma folate level for the women was 5.44-ng/ml (±2.30) at baseline. These levels improved significantly at six months [difference: 4.57ng/ml (±2.89)] and 12 months [difference: 4.27ng/ml (±4.18)]. Based on plasma folate cut-off level of 4 ng/ml, the prevalence of folate deficiency was 26.9% at baseline, and 5% at twelve months. One ng/ml increase in plasma folate from baseline was associated with a 25% decreased risk of folate deficiency at 12 months [(RR = 0.75; 95% CI = 0.67–0.85, P<0.001]. In a setting where folate deficiency is high, food fortification program with folic acid resulted in significant improvements in folate status among women of reproductive age. PMID:28797054

High plasma folate is negatively associated with leukocyte telomere length in Framingham Offspring cohort.

PubMed

Paul, Ligi; Jacques, Paul F; Aviv, Abraham; Vasan, Ramachandran S; D'Agostino, Ralph B; Levy, Daniel; Selhub, Jacob

2015-03-01

Shortening of telomeres, the protective structures at the ends of eukaryotic chromosomes, is associated with age-related pathologies. Telomere length is influenced by DNA integrity and DNA and histone methylation. Folate plays a role in providing precursors for nucleotides and methyl groups for methylation reactions and has the potential to influence telomere length. We determined the association between leukocyte telomere length and long-term plasma folate status (mean of 4 years) in Framingham Offspring Study (n = 1,044, females = 52.1 %, mean age 59 years) using data from samples collected before and after folic acid fortification. Leukocyte telomere length was determined by Southern analysis and fasting plasma folate concentration using microbiological assay. There was no significant positive association between long-term plasma folate and leukocyte telomere length among the Framingham Offspring Study participants perhaps due to their adequate folate status. While the leukocyte telomere length in the second quintile of plasma folate was longer than that in the first quintile, the difference was not statistically significant. The leukocyte telomere length of the individuals in the fifth quintile of plasma folate was shorter than that of those in the second quintile by 180 bp (P < 0.01). There was a linear decrease in leukocyte telomere length with higher plasma folate concentrations in the upper four quintiles of plasma folate (P for trend = 0.001). Multivitamin use was associated with shorter telomeres in this cohort (P = 0.015). High plasma folate status possibly resulting from high folic acid intake may interfere with the role of folate in maintaining telomere integrity.

[Relationship and interaction between folate and expression of methyl-CpG-binding protein 2 in cervical cancerization].

PubMed

Li, Q L; Ding, L; Nan, J; Liu, C L; Yang, Z K; Chen, F; Liang, Y L; Wang, J T

2016-07-01

To explore the interaction between folate and the expression of methyl-CpG-binding protein 2(MeCP2)in cervical cancerization. Forty one patients diagnosed with cervical squamous cell carcinoma(SCC), 71 patients diagnosed with cervical intraepithelial neoplasm(CIN1, n=34; CIN2 +, n=37)and 61 women with normal cervix(NC)were recruited in this study. Microbiological assay was conducted to detect the levels of serum folate and RBC folate, Western blot assay and real-time PCR were performed to detect the expression levels of MeCP2 protein and mRNA, respectively. The data were analyzed by Kruskal-Wallis H test, χ(2) test, trend χ(2) test and Spearman correlation with SPSS statistical software(version 20.0), and the interaction were evaluated by using generalized multifactor dimensionality reduction(GMDR)model. The levels of serum folate(H=44.71, P<0.001; trend χ(2)=24.48, P<0.001)and RBC folate(H=5.28, P<0.001; trend χ(2)=3.83, P<0.05)decreased gradually along with the severity of cervical lesions. There was a positive correlation between serum folate level and RBC folate level(r=0.270, P< 0.001). The expression levels of MeCP2 protein(H=33.72, P<0.001; trend χ(2)=14.74, P<0.001)and mRNA(H=19.50, P<0.001; trend χ(2)=10.74, P<0.001)increased gradually along with the severity of cervical lesions. There were negative correlation between folate level and the expression level of MeCP2 protein(serum folate: r=-0.226, P=0.003; RBC folate: r=-0.164, P=0.004). Moreover, the results by GMDR model revealed there were interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and MeCP2 mRNA high expression in SCC and CIN2 + patients. Folate deficiency and high expression of MeCP2 gene might increase the risk of cervical cancer and its precancerous lesions through interaction among serum folate deficiency, RBC folate deficiency, MeCP2 protein high expression and mRNA high expression in the progression of cervical cancerization.

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11

PubMed Central

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J. Christopher; Franzka, Patricia; Huebner, Antje K.; Kessels, Michael M.; Biskup, Christoph; Jentsch, Thomas J.; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A.

2015-01-01

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice. PMID:26284655

In Vivo Evidence for Lysosome Depletion and Impaired Autophagic Clearance in Hereditary Spastic Paraplegia Type SPG11.

PubMed

Varga, Rita-Eva; Khundadze, Mukhran; Damme, Markus; Nietzsche, Sandor; Hoffmann, Birgit; Stauber, Tobias; Koch, Nicole; Hennings, J Christopher; Franzka, Patricia; Huebner, Antje K; Kessels, Michael M; Biskup, Christoph; Jentsch, Thomas J; Qualmann, Britta; Braulke, Thomas; Kurth, Ingo; Beetz, Christian; Hübner, Christian A

2015-08-01

Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice.

Folates in Asian noodles: II. A comparison of commercial samples and the impact of cooking.

PubMed

Bui, Lan T T; Small, Darryl M

2007-06-01

The folate contents of 26 commercial noodle samples were investigated. The impact of ingredients, pH, and cooking on folate content was studied for the 3 predominant styles of noodles: white salted, yellow alkaline, and instant. Some variability was found in the proportion of folate present in the free form and the noodles generally had low total folate contents. The pH values of the samples covered a wide range, varying from 3.7 to 10.3; however, the results did not provide strong evidence for a relationship between pH and folate content for any of the noodle styles studied. Higher folate levels were typically found in yellow alkaline samples compared to white salted and instant noodles. The storage of noodles in dry or moist forms did not appear to influence total folate contents, and subsequent losses during cooking depended upon the time of exposure to elevated temperatures. The enzymatic treatment of samples was particularly important for cooked noodles, indicating that folates were bound or entrapped during this process.

Role of folate status and methylenetetrahydrofolate reductase genotype on the toxicity and outcome of induction chemotherapy in children with acute lymphoblastic leukemia.

PubMed

Roy Moulik, Nirmalya; Kumar, Archana; Agrawal, Suraksha; Awasthi, Shally; Mahdi, Abbas Ali; Kumar, Ashutosh

2015-05-01

The effect of serum folate levels and methylenetetrahydrofolate reductase (MTHFR) genotype on complications and outcome of induction chemotherapy in 150 children with acute lymphoblastic leukemia (ALL) was studied. Folate deficiency in 26% at baseline was more common in children with MTHFR 677 mutations. Folate deficient children had a higher incidence of neutropenia (p = 0.03), thrombocytopenia (p = 0.02) and febrile neutropenia (p = 0.01) and higher transfusion requirement during induction compared to folate sufficient children. Sepsis related induction deaths were more frequent in folate deficient children (p = 0.02) during induction. Children with 677 and 1298 mutations had a higher incidence of cytopenias (p = 0.01) and mucositis (p = 0.007), the risks of which increased with concomitant folate deficiency. A significant fall in folate levels was observed post-induction (p = 0.02), most markedly in mutant 677 genotypes. Multivariate analysis revealed associations of baseline folate deficiency with low counts at day 14 (p = 0.001) and MTHFR 1298 mutations with mucositis (p = 0.02).

Development of a lateral flow dipstick immunoassay for evaluation of folate levels in maize.

PubMed

Liang, Qiuju; Yi, Chen; Jiang, Ling; Tan, Guiyu; Zhang, Chunyi; Wang, Baomin

2017-09-01

Folates (vitamin B9) are essential for all organisms as cofactors for one-carbon metabolism. However, measurement of folates is technically complicated and time-consuming. In this study, we developed a dipstick immunoassay using a folate-specific monoclonal antibody (mAb), allowing rapid and low-cost detection of folates. The indicator range of the dipstick for 5-formylterahydrofolate (5-CHO-THF), 5-methyltetrahydrofolate (5-CH 3 -THF) and their polyglutamyl forms was 100-200 ng mL -1 ; moreover, no cross-reactivity was observed with tetrahydrofolate (THF) or 5,10-methenyltetrahydrofolate (5,10-CH=THF) at 500 ng mL -1 , or with the folate precursors pterin-6-COOH, p-aminobenzoate (pABA), and L-glutamate, or with the folate analogues methotrexate and 10-formyltetrahydrofolate (10-CHO-THF) at up to 1000 ng mL -1 . The dipstick immunoassay was tested in maize seeds; the results classified the seeds into those with low, moderate, and high levels of folates, and were in agreement with those of liquid chromatography-mass spectrometry. Thus, we conclude that the dipstick assay will provide a versatile tool to facilitate large-scale screening of maize rich in folates. Graphical Abstract The dipstick based immunoassay for analyzing folate level in maize.

Associations between Folate and Vitamin B12 Levels and Inflammatory Bowel Disease: A Meta-Analysis.

PubMed

Pan, Yun; Liu, Ya; Guo, Haizhuo; Jabir, Majid Sakhi; Liu, Xuanchen; Cui, Weiwei; Li, Dong

2017-04-13

Inflammatory bowel disease (IBD) patients may be at risk of vitamin B12 and folate insufficiencies, as these micronutrients are absorbed in the small intestine, which is affected by IBD. However, a consensus has not been reached on the association between IBD and serum folate and vitamin B12 concentrations. In this study, a comprehensive search of multiple databases was performed to identify studies focused on the association between IBD and serum folate and vitamin B12 concentrations. Studies that compared serum folate and vitamin B12 concentrations between IBD and control patients were selected for inclusion in the meta-analysis. The main outcome was the mean difference in serum folate and vitamin B12 concentrations between IBD and control patients. Our findings indicated that the average serum folate concentration in IBD patients was significantly lower than that in control patients, whereas the mean serum vitamin B12 concentration did not differ between IBD patients and controls. In addition, the average serum folate concentration in patients with ulcerative colitis (UC) but not Crohn's disease (CD) was significantly lower than that in controls. This meta-analysis identified a significant relationship between low serum folate concentration and IBD. Our findings suggest IBD may be linked with folate deficiency, although the results do not indicate causation. Thus, providing supplements of folate and vitamin B12 to IBD patients may improve their nutritional status and prevent other diseases.

Novel insights on interactions between folate and lipid metabolism

PubMed Central

da Silva, Robin P; Kelly, Karen B; Al Rajabi, Ala; Jacobs, René L

2014-01-01

Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. © 2013 BioFactors, 40(3):277–283, 2014 PMID:24353111

Targeting the folate receptor: improving efficacy in inorganic medicinal chemistry.

PubMed

Carron, Pauraic Mc; Crowley, Aisling; O'Shea, Denis; McCann, Malachy; Howe, Orla; Hunt, Mary; Devereux, Michael

2018-02-09

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor's overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Determination of folate content in ready-to-eat food products].

PubMed

Fajardo Martín, Violeta; Alonso-Aperte, Elena; Varela-Moreiras, Gregorio

2013-01-01

In the last years, the consumption of ready-to-eat foods has become an increasing part of the current Spanish diet. Accordingly, the nutritional composition of these food categories should be investigated in order to estimate its contribution to vitamin and nutrient intakes, in particular its folate content. The broad lack of folate data in food composition tables and databases justifies this approach. The aim of this work was to screen the current availability and to supply new folate data in ready-to-eat commercial products in the Spanish market. Seventeen ready-to-eat foods, including mainly vegetable ingredients, were analysed for total folate content using a validated method that relies on Lactobacillus casei ssp. rhamnosus chloramphenicol-resistant folate dependent growth. The accuracy of the analytical procedure was checked using a certified reference material and by a recovery test. Mean TF content ranged from 13.6 to 103.8 μg/100 g in different food matrices on a fresh weight basis. Higher TF quantity was found for vegetable hamburguers, recipes including chickpeas, peas or artichockes. Selected precooked products were also analysed after a soft heat treatment as recommended by the manufacter before its consumption. No significant differences were found in the folate content after processing. The coefficient of variation for the duplicates of the same product was less than 15%. Folate content in ready-to-eat products indicates the potential to considerably increase folate intake by choosing folate-rich foods. There have been no previous reports on folate data in chilled ready-to-eat meals. The present data will assist dietary studies to estimate and evaluate the adequacy of population folate intakes. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

A NOS3 polymorphism determines endothelial response to folate in children with type 1 diabetes or obesity.

PubMed

Wiltshire, Esko J; Peña, Alexia S; MacKenzie, Karen; Bose-Sundernathan, Tulika; Gent, Roger; Couper, Jennifer J

2015-02-01

To determine the effect of polymorphisms in NOS3 and folate pathway enzymes on vascular function and folate status and endothelial response to folate in children with diabetes or obesity. A total of 244 subjects (age 13.8 ± 2.8 years, 125 males) were studied for NOS3 and/or folate pathway polymorphisms using polymerase chain reaction/restriction fragment length polymorphism, including at baseline: 139 with type 1 diabetes; 58 with obesity; and 47 controls. The effect of NOS3 genotype on endothelial response to folate (5 mg) was assessed in 85 subjects with diabetes and 28 obese subjects who received active treatment during intervention trials. Vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation), clinical, and biochemical measurements were assessed at baseline and 8 weeks in folate intervention studies. Folate pathway enzyme and NOS3 polymorphisms did not significantly affect baseline vascular function. The polymorphism in intron 4 of endothelial nitric oxide synthase altered endothelial response to folate significantly: in subjects with diabetes FMD improved by 6.4 ± 5% (insertion carriers) vs 2.3 ± 6.6% (deletion carriers), P = .01; in obese subjects FMD improved by 1.8 ± 5.4% (insertion carriers) and deteriorated by -3.2 ± 7.2% (deletion carriers), P = .05. More subjects carrying the insertion normalized FMD after folate supplementation (insertion 64% vs deletion 28%, χ(2) = 10.14, P = .001). A NOS3 polymorphism predicts endothelial response to folate in children with diabetes or obesity, with implications for vascular risk and folate intervention studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Folate intake and the risk of oral cavity and pharyngeal cancer: a pooled analysis within the INHANCE Consortium

PubMed Central

Galeone, Carlotta; Edefonti, Valeria; Parpinel, Maria; Leoncini, Emanuele; Matsuo, Keitaro; Talamini, Renato; Olshan, Andrew F.; Zevallos, Jose P.; Winn, Deborah M.; Jayaprakash, Vijayvel; Moysich, Kirsten; Zhang, Zuo-Feng; Morgenstern, Hal; Levi, Fabio; Bosetti, Cristina; Kelsey, Karl; McClean, Michael; Schantz, Stimson; Yu, Guo-Pei; Boffetta, Paolo; Lee, Yuan-Chin Amy; Hashibe, Mia; La Vecchia, Carlo; Boccia, Stefania

2014-01-01

There are suggestions of an inverse association between folate intake and serum folate levels and the risk of oral cavity and pharyngeal cancers (OPC), but most studies are limited in sample size, with only few reporting information on the source of dietary folate. This study aims to investigate the association between folate intake and the risk of OPC within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. We analyzed pooled individual-level data from 10 case-control studies participating in the INHANCE consortium, including 5,127 cases and 13,249 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated for the associations between total folate intake (natural, fortification and supplementation) and natural folate only, and OPC risk. We found an inverse association between total folate intake and overall OPC risk (the adjusted OR for the highest versus the lowest quintile was 0.65, 95% CI: 0.43–0.99), with a stronger association for oral cavity (OR=0.57, 95% CI: 0.43–0.75). A similar inverse association, though somewhat weaker, was observed for folate intake from natural sources only (OR=0.64, 95% CI: 0.45–0.91). The highest OPC risk was observed in heavy alcohol drinkers with low folate intake as compared to never/light drinkers with high folate (OR=4.05, 95% CI: 3.43–4.79); the attributable proportion due to interaction was 11.1%(95% CI: 1.4–20.8%). The present project of a large pool of case-control studies supports a protective effect total folate intake on OPC risk. PMID:24974959

Total folate and folic acid intakes from foods and dietary supplements of US children aged 1–13 y1234

PubMed Central

Bailey, Regan L; McDowell, Margaret A; Dodd, Kevin W; Gahche, Jaime J; Dwyer, Johanna T; Picciano, Mary Frances

2010-01-01

Background: Total folate intake includes naturally occurring food folate and folic acid from fortified foods and dietary supplements. Recent reports have focused on total folate intakes of persons aged ≥14 y. Information on total folate intakes of young children, however, is limited. Objective: The objective was to compute total folate and total folic acid intakes of US children aged 1–13 y by using a statistical method that adjusts for within-person variability and to compare these intakes with the Dietary Reference Intake guidelines for adequacy and excess. Design: Data from the 2003–2006 National Health and Nutrition Examination Survey, a nationally representative cross-sectional survey, were analyzed. Total folate intakes were derived by combining intakes of food folate (naturally occurring and folic acid from fortified foods) on the basis of 24-h dietary recall results and folic acid intakes from dietary supplements on the basis of a 30-d questionnaire. Results: More than 95% of US children consumed at least the Estimated Average Requirement (EAR) for folate from foods alone. More than one-third (35%) of US children aged 1–13 y used dietary supplements, and 28% used dietary supplements containing folic acid. Supplement users had significantly higher total folate and folic acid intakes than did nonusers. More than half (53%) of dietary supplement users exceeded the Tolerable Upper Intake Level (UL) for total folic acid (fortified food + supplements) as compared with 5% of nonusers. Conclusions: Total folate intakes of most US children aged 1–13 y meet the EAR. Children who used dietary supplements had significantly higher total folate intakes and exceeded the UL by >50%. PMID:20534747

The association between MTHFR 677C>T genotype and folate status and genomic and gene-specific DNA methylation in the colon of individuals without colorectal neoplasia.

PubMed

Hanks, Joanna; Ayed, Iyeman; Kukreja, Neil; Rogers, Chris; Harris, Jessica; Gheorghiu, Alina; Liu, Chee Ling; Emery, Peter; Pufulete, Maria

2013-12-01

Decreased genomic and increased gene-specific DNA methylation predispose to colorectal cancer. Dietary folate intake and the methylenetetrahydrofolate reductase polymorphism (MTHFR 677C>T) may influence risk by modifying DNA methylation. We investigated the associations between MTHFR 677C>T genotype, folate status, and DNA methylation in the colon. We conducted a cross-sectional study of 336 men and women (age 19-92 y) in the United Kingdom without colorectal neoplasia. We obtained blood samples for measurement of serum and red blood cell folate, plasma homocysteine, and MTHFR 677C>T genotype and colonic tissue biopsies for measurement of colonic tissue folate and DNA methylation (genomic- and gene-specific, estrogen receptor 1, ESR1; myoblast determination protein 1, MYOD1; insulin-like growth factor II, IGF2; tumor suppressor candidate 33, N33; adenomatous polyposis coli, APC; mut-L homolog 1, MLH1; and O(6)-methylguanine-DNA methyltransferase, MGMT) by liquid chromatography/electrospray ionization mass spectrometry and pyrosequencing, respectively. Of the 336 subjects recruited, 185 (55%) carried the CC, 119 (35%) the CT, and 32 (10%) the TT alleles. No significant differences in systemic markers of folate status and colonic tissue folate between genotypes were found. The MTHFR TT genotype was not associated with genomic or gene-specific DNA methylation. Biomarkers of folate status were not associated with genomic DNA methylation. Relations between biomarkers of folate status and gene-specific methylation were inconsistent. However, low serum folate was associated with high MGMT methylation (P = 0.001). MTHFR 677C>T genotype and folate status were generally not associated with DNA methylation in the colon of a folate-replete population without neoplasia.

Plasma folate levels and associated factors in women planning to become pregnant in a population with high prevalence of neural tube defects.

PubMed

Ma, Rui; Wang, Linlin; Jin, Lei; Li, Zhiwen; Ren, Aiguo

2017-07-17

Optimal blood folate levels of women before pregnancy are critical to the prevention of neural tube defects (NTDs). However, few studies have focused on blood folate levels of women planning to become pregnant. The aims of this study were to assess plasma folate levels in women who planned to become pregnant in a population with high prevalence of NTDs, to identify factors associated with plasma folate levels, and to evaluate the risk of NTDs at the population level. A total of 2065 women were enrolled at the time of premarital health check-up in two rural counties in northern China from November 2009 to December 2012. Fasting venous blood samples were collected and plasma folate concentrations were measured by microbiological method. The overall median of plasma folate was 10.5 nmol/L. 50% of the women had a plasma folate level below 10.5 nmol/L, a cutoff for megaloblastic anemia, and 88% below 18 nmol/L, a proposed optimal plasma folate level for the prevention of NTDs. Folic acid supplementation was the only factor to be associated with plasma folate concentrations, but only 1.9% of the women reported having taken folic acid supplements. A population risk of 29.3 NTD cases per 10,000 births was predicted. Women who planned to become pregnant had very low plasma folate in the population. Folic acid supplementation was the only factor to be associated with a high plasma folate concentration. High NTD risk would remain if women would get pregnant without having taken folic acid supplements. Birth Defects Research 109:1039-1047, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The Effect of Folate and Folate Plus Zinc Supplementation on Endocrine Parameters and Sperm Characteristics in Sub-Fertile Men: A Systematic Review and Meta-Analysis.

PubMed

Irani, Morvarid; Amirian, Malihe; Sadeghi, Ramin; Lez, Justine Le; Latifnejad Roudsari, Robab

2017-08-29

To evaluate the effect of folate and folate plus zinc supplementation on endocrine parameters and sperm characteristics in sub fertile men. We conducted a systematic review and meta-analysis. Electronic databases of Medline, Scopus , Google scholar and Persian databases (SID, Iran medex, Magiran, Medlib, Iran doc) were searched from 1966 to December 2016 using a set of relevant keywords including "folate or folic acid AND (infertility, infertile, sterility)".All available randomized controlled trials (RCTs), conducted on a sample of sub fertile men with semen analyses, who took oral folic acid or folate plus zinc, were included. Data collected included endocrine parameters and sperm characteristics. Statistical analyses were done by Comprehensive Meta-analysis Version 2. In total, seven studies were included. Six studies had sufficient data for meta-analysis. "Sperm concentration was statistically higher in men supplemented with folate than with placebo (P < .001)". However, folate supplementation alone did not seem to be more effective than the placebo on the morphology (P = .056) and motility of the sperms (P = .652). Folate plus zinc supplementation did not show any statistically different effect on serum testosterone (P = .86), inhibin B (P = .84), FSH (P = .054), and sperm motility (P = .169) as compared to the placebo. Yet, folate plus zinc showed statistically higher effect on the sperm concentration (P < .001), morphology (P < .001), and serum folate level (P < .001) as compared to placebo. Folate plus zinc supplementation has a positive effect on sperm characteristics in sub fertile men. However, these results should be interpreted with caution due to the important heterogeneity of the studies included in this meta-analysis. Further trials are still needed to confirm the current findings.

Rare hereditary cause of chronic pancreatitis in a young male: SPINK1 mutation

PubMed Central

Patel, Janaki; Madan, Arina; Gammon, Amanda; Sossenheimer, Michael; Samadder, Niloy Jewel

2017-01-01

Hereditary chronic pancreatitis associated with a mutation in the serine protease inhibitor, Kazal Type-1 (SPINK-1 gene) is extremely rare. The SPINK1 mutation results in trypsinogen activation which predisposes to chronic pancreatitis predominately when combined with CFTR gene mutations. It presents as either chronic or recurrent acute pancreatitis. Symptom control and management of complications is important. Active surveillance with cross-sectional imaging for pancreatic malignancy in individuals with hereditary pancreatitis is advocated due to individuals being high risk. We present an unusual case of a young male who initially presented with renal colic and was incidentally diagnosed with severe chronic pancreatitis on abdominal imaging, with genetic testing confirming a homozygous SPINK1 mutation. PMID:29515728

Rare hereditary cause of chronic pancreatitis in a young male: SPINK1 mutation.

PubMed

Patel, Janaki; Madan, Arina; Gammon, Amanda; Sossenheimer, Michael; Samadder, Niloy Jewel

2017-01-01

Hereditary chronic pancreatitis associated with a mutation in the serine protease inhibitor, Kazal Type-1 (SPINK-1 gene) is extremely rare. The SPINK1 mutation results in trypsinogen activation which predisposes to chronic pancreatitis predominately when combined with CFTR gene mutations. It presents as either chronic or recurrent acute pancreatitis. Symptom control and management of complications is important. Active surveillance with cross-sectional imaging for pancreatic malignancy in individuals with hereditary pancreatitis is advocated due to individuals being high risk. We present an unusual case of a young male who initially presented with renal colic and was incidentally diagnosed with severe chronic pancreatitis on abdominal imaging, with genetic testing confirming a homozygous SPINK1 mutation.

Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain.

PubMed

Creus, Montserrat; Deulofeu, Ramon; Peñarrubia, Joana; Carmona, Francisco; Balasch, Juan

2013-03-01

Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. Sixty consecutive patients with ≥ 3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation.

The dynamics of folic acid metabolism in an adult given a small tracer dose of 14C-folic acid.

PubMed

Clifford, A J; Arjomand, A; Dueker, S R; Schneider, P D; Buchholz, B A; Vogel, J S

1998-01-01

Folate is an essential nutrient that is involved in many metabolic pathways, including amino acid interconversions and nucleotide (DNA) synthesis. In genetically susceptible individuals and populations, dysfunction of folate metabolism is associated with severe illness. Despite the importance of folate, major gaps exist in our quantitative understanding of folate metabolism in humans. The gaps exist because folate metabolism is complex, a suitable animal model that mimics human folate metabolism has not been identified, and suitable experimental protocols for in vivo studies in humans are not developed. In general, previous studies of folate metabolism have used large doses of high specific activity tritium and 14C-labeled folates in clinical patients. While stable isotopes such as deuterium and 13C-labeled folate are viewed as ethical alternatives to radiolabeled folates for studying metabolism, the lack of sensitive mass spectrometry methods to quantify them has impeded advancement of the field using this approach. In this chapter, we describe a new approach that uses a major analytical breakthrough, Accelerator Mass Spectrometry (AMS). Because AMS can detect attomole concentrations of 14C, small radioactive dosages (nCi) can be safely administered to humans and traced over long periods of time. The needed dosages are sufficiently small that the total radiation exposure is only a fraction of the natural annual background radiation of Americans, and the generated laboratory waste may legally be classified non-radioactive in many cases. The availability of AMS has permitted the longest (202 d) and most detailed study to date of folate metabolism in a healthy adult human volunteer. Here we demonstrate the feasibility of our approach and illustrate its potential by determining empirical kinetic values of folate metabolism. Our data indicate that the mean sojourn time for folate is in the range of 93 to 120 d. It took > or = 350 d for the absorbed portion of small bolus dose of 14C-folic acid to be eliminated completely from the body.

Low folate status enhances pregnancy changes in plasma betaine and dimethylglycine concentrations and the association between betaine and homocysteine.

PubMed

Fernàndez-Roig, Sílvia; Cavallé-Busquets, Pere; Fernandez-Ballart, Joan D; Ballesteros, Monica; Berrocal-Zaragoza, Maria Isabel; Salat-Batlle, Judith; Ueland, Per M; Murphy, Michelle M

2013-06-01

Folate, choline, and betaine participate in homocysteine metabolism. It is not known whether they interact during pregnancy. The objective was to investigate how folate status affects choline, betaine, and dimethylglycine during pregnancy. Fasting plasma folate, cobalamin, free choline, betaine, dimethylglycine, and total homocysteine (tHcy) were measured longitudinally at <12, 15, 24-27, and 34 gestational weeks (GW); at labor (nonfasting); and in the cord in participants (n = 522) from the Reus-Tarragona Birth Cohort (NUTrició i Creixement Intrauterí Retardat phase). Timing, dose, and duration of folic acid supplement use were recorded. Folate status was classified as below (low) or above (high) median plasma folate at baseline (27.6 nmol/L) and at 24-27 GW (11.4 nmol/L). Associations between folate or betaine with tHcy were investigated by using multiple linear regression analysis. Plasma betaine decreased by 34.8% (1.0%) throughout pregnancy, and dimethylglycine increased by 39.7% (2.7%) between 24-27 GW and labor (all P < 0.001). Compared with high folate status, low status was associated with a higher dimethylglycine/betaine ratio from 15 GW and with lower plasma betaine and higher dimethylglycine from 24 to 27 GW, for the rest of pregnancy. Regression analysis showed that by 24-27 GW, both plasma folate and betaine were inversely associated with tHcy when folate status was low and that the association between betaine and tHcy depended on folate status at 24-27 and 34 GW (interaction terms: P < 0.001 and P < 0.01). Betaine was inversely associated with tHcy at labor regardless of folate status. Low folate status enhances the reduction in betaine and the increase in dimethylglycine during pregnancy and strengthens the association between betaine and tHcy. This trial was registered at clinicaltrials.gov as NCT01778205.

Higher dietary folate intake reduces the breast cancer risk: a systematic review and meta-analysis

PubMed Central

Chen, P; Li, C; Li, X; Li, J; Chu, R; Wang, H

2014-01-01

Background: Many epidemiological studies have investigated the association between folate intake, circulating folate level and risk of breast cancer; however, the findings were inconsistent between the studies. Methods: We searched the PubMed and MEDLINE databases updated to January, 2014 and performed the systematic review and meta-analysis of the published epidemiological studies to assess the associations between folate intake level, circulating folate level and the overall risk of breast cancer. Results: In all, 16 eligible prospective studies with a total of 744 068 participants and 26 205 breast cancer patients and 26 case–control studies with a total of 16 826 cases and 21 820 controls that have evaluated the association between folate intake and breast cancer risk were identified. Pooled analysis of the prospective studies and case–control studies suggested a potential nonlinearity relationship for dietary folate intake and breast cancer risk. Prospective studies indicated a U-shaped relationship for the dietary folate intake and breast cancer risk. Women with daily dietary folate intake between 153 and 400 μg showed a significant reduced breast cancer risk compared with those <153 μg, but not for those >400 μg. The case–control studies also suggested a significantly negative correlation between the dietary folate intake level and the breast cancer risk. Increased dietary folate intake reduced breast cancer risk for women with higher alcohol intake level, but not for those with lower alcohol intake. No significant association between circulating folate level and breast cancer risk was found when the results of 8 identified studies with 5924 participants were pooled. Conclusions: Our studies suggested that folate may have preventive effects against breast cancer risk, especially for those with higher alcohol consumption level; however, the dose and timing are critical and more studies are warranted to further elucidate the questions. PMID:24667649

Folate intake in a Swedish adult population: Food sources and predictive factors.

PubMed

Monteagudo, Celia; Scander, Henrik; Nilsen, Bente; Yngve, Agneta

2017-01-01

Introduction : Folate plays an important role in cell metabolism, but international studies show that intake is currently below recommendations, especially among women. The study objective was to identify folate food sources by food group, gender, and age group, and to identify factors influencing folate intake, based on food consumption data for Swedish adults in the 2010-11 Riksmaten study. M ethods : The sample included a representative Swedish population aged 18-80 years ( n  = 1657; 56.3% female). Food and nutrient intakes were estimated from self-reported food records during 4 consecutive days. Food consumption was categorized into 26 food groups. Stepwise regression was used to analyze food groups as folate sources for participants. Factors predicting the highest folate intake (third tertile) were determined by logistic regression analysis. Results : Vegetables and pulses represented the most important folate source for all age groups and both genders, especially in women aged 45-64 years (49.7% of total folate intake). The next folate source in importance was dairy products for the youngest group (18-30 years), bread for men, and fruit and berries for women. The likelihood of being in the highest tertile of folate intake (odds ratio = 1.69, 95% confidence interval 1.354-2.104) was higher for men. Influencing factors for folate intake in the highest tertile were low body mass index and high educational level in the men, and high educational level, vegetarian diet, organic product consumption, non-smoking, and alcohol consumption within recommendations in the women. Conclusion : This study describes the folate intake per food group of Swedish adults according to the 2010-11 Riksmaten survey, identifying vegetables and pulses as the most important source. Data obtained on factors related to folate consumption may be useful for the development of specific nutrition education programs to increase the intake of this vitamin in high-risk groups.

Folate intake in a Swedish adult population: Food sources and predictive factors

PubMed Central

Monteagudo, Celia; Scander, Henrik; Nilsen, Bente; Yngve, Agneta

2017-01-01

ABSTRACT Introduction: Folate plays an important role in cell metabolism, but international studies show that intake is currently below recommendations, especially among women. The study objective was to identify folate food sources by food group, gender, and age group, and to identify factors influencing folate intake, based on food consumption data for Swedish adults in the 2010–11 Riksmaten study. Methods: The sample included a representative Swedish population aged 18–80 years (n = 1657; 56.3% female). Food and nutrient intakes were estimated from self-reported food records during 4 consecutive days. Food consumption was categorized into 26 food groups. Stepwise regression was used to analyze food groups as folate sources for participants. Factors predicting the highest folate intake (third tertile) were determined by logistic regression analysis. Results: Vegetables and pulses represented the most important folate source for all age groups and both genders, especially in women aged 45–64 years (49.7% of total folate intake). The next folate source in importance was dairy products for the youngest group (18–30 years), bread for men, and fruit and berries for women. The likelihood of being in the highest tertile of folate intake (odds ratio = 1.69, 95% confidence interval 1.354–2.104) was higher for men. Influencing factors for folate intake in the highest tertile were low body mass index and high educational level in the men, and high educational level, vegetarian diet, organic product consumption, non-smoking, and alcohol consumption within recommendations in the women. Conclusion: This study describes the folate intake per food group of Swedish adults according to the 2010–11 Riksmaten survey, identifying vegetables and pulses as the most important source. Data obtained on factors related to folate consumption may be useful for the development of specific nutrition education programs to increase the intake of this vitamin in high-risk groups. PMID:28659736

Hereditary myopathies with early respiratory insufficiency in adults.

PubMed

Naddaf, Elie; Milone, Margherita

2017-11-01

Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease-causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult-onset Pompe disease, myofibrillar myopathy, multi-minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017. © 2017 Wiley Periodicals, Inc.

CDC Grand Rounds: Family History and Genomics as Tools for Cancer Prevention and Control.

PubMed

Rodriguez, Juan L; Thomas, Cheryll C; Massetti, Greta M; Duquette, Debra; Avner, Lindsay; Iskander, John; Khoury, Muin J; Richardson, Lisa C

2016-11-25

Although many efforts in cancer prevention and control have routinely focused on behavioral risk factors, such as tobacco use, or on the early detection of cancer, such as colorectal cancer screening, advances in genetic testing have created new opportunities for cancer prevention through evaluation of family history and identification of cancer-causing inherited mutations. Through the collection and evaluation of a family cancer history by a trained health care provider, patients and families at increased risk for a hereditary cancer syndrome can be identified, referred for genetic counseling and testing, and make informed decisions about options for cancer risk reduction (1). Although hereditary cancers make up a small proportion of all cancers, the number of affected persons can be large, and the level of risk among affected persons is high. Two hereditary cancer syndromes for which public health professionals have worked to reduce the burden of morbidity and mortality are hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome.

Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.

PubMed

Newton, Timothy; Allison, Rachel; Edgar, James R; Lumb, Jennifer H; Rodger, Catherine E; Manna, Paul T; Rizo, Tania; Kohl, Zacharias; Nygren, Anders O H; Arning, Larissa; Schüle, Rebecca; Depienne, Christel; Goldberg, Lisa; Frahm, Christiane; Stevanin, Giovanni; Durr, Alexandra; Schöls, Ludger; Winner, Beate; Beetz, Christian; Reid, Evan

2018-05-01

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

Prevalence of Vitamin B12 and Folate Deficiency in School Children Residing at High Altitude Regions in India.

PubMed

Gupta, Aakriti; Kapil, Umesh; Ramakrishnan, Lakshmy; Pandey, Ravindra Mohan; Yadav, Chander Prakash

2017-04-01

To assess the prevalence of vitamin B 12 and folate deficiencies among children residing at high altitude regions of Himachal Pradesh, India. A total of 215 school children in the age group of 6-18 y were included. Biochemical estimation of serum vitamin B 12 and folate levels was undertaken using chemiluminescence immunoassay method. The consumption pattern of foods high in dietary vitamin B 12 and folate was recorded using Food Frequency Questionnaire. The median levels (interquartile range) of serum vitamin B 12 and folate were 326 (259-395) pg/ml and 7.7 (6-10) ng/ml respectively. The prevalence of vitamin B 12 and folate deficiency amongst school age children was found as 7.4% and 1.5% respectively. A low prevalence of vitamin B 12 and folate deficiencies was found amongst children aged 6-18 y living at high altitude regions in India. This is possibly due to high frequency of consumption of foods rich in vitamin B 12 and folate.

Effects of industrial processing on folate content in green vegetables.

PubMed

Delchier, Nicolas; Ringling, Christiane; Le Grandois, Julie; Aoudé-Werner, Dalal; Galland, Rachel; Georgé, Stéphane; Rychlik, Michael; Renard, Catherine M G C

2013-08-15

Folates are described to be sensitive to different physical parameters such as heat, light, pH and leaching. Most studies on folates degradation during processing or cooking treatments were carried out on model solutions or vegetables only with thermal treatments. Our aim was to identify which steps were involved in folates loss in industrial processing chains, and which mechanisms were underlying these losses. For this, the folates contents were monitored along an industrial canning chain of green beans and along an industrial freezing chain of spinach. Folates contents decreased significantly by 25% during the washing step for spinach in the freezing process, and by 30% in the green beans canning process after sterilisation, with 20% of the initial amount being transferred into the covering liquid. The main mechanism involved in folate loss during both canning green beans and freezing spinach was leaching. Limiting the contact between vegetables and water or using steaming seems to be an adequate measure to limit folates losses during processing. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hereditary vacuolar internal anal sphincter myopathy causing proctalgia fugax and constipation: a new case contribution.

PubMed

de la Portilla, Fernando; Borrero, Juan José; Rafel, Enrique

2005-03-01

Hereditary anal sphincter myopathy is rare. We present a family with one affected member with proctalgia fugax, constipation and internal anal sphincter hypertrophy. Ultrastructural findings show vacuolization of smooth muscle cells without the characteristic polyglucosan inclusion. Further relief of symptoms was obtained using an oral calcium antagonist. Based on clinical presentation, endosonography and morphological findings, we consider our case is a histological variant of the vacuolar myopathy originally described.

Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

PubMed

Tey, S; Ahmad-Annuar, A; Drew, A P; Shahrizaila, N; Nicholson, G A; Kennerson, M L

2016-08-01

The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Folate receptor 1 is necessary for neural plate cell apical constriction during Xenopus neural tube formation

PubMed Central

Balashova, Olga A.; Visina, Olesya

2017-01-01

Folate supplementation prevents up to 70% of neural tube defects (NTDs), which result from a failure of neural tube closure during embryogenesis. The elucidation of the mechanisms underlying folate action has been challenging. This study introduces Xenopus laevis as a model to determine the cellular and molecular mechanisms involved in folate action during neural tube formation. We show that knockdown of folate receptor 1 (Folr1; also known as FRα) impairs neural tube formation and leads to NTDs. Folr1 knockdown in neural plate cells only is necessary and sufficient to induce NTDs. Folr1-deficient neural plate cells fail to constrict, resulting in widening of the neural plate midline and defective neural tube closure. Pharmacological inhibition of folate action by methotrexate during neurulation induces NTDs by inhibiting folate interaction with its uptake systems. Our findings support a model in which the folate receptor interacts with cell adhesion molecules, thus regulating the apical cell membrane remodeling and cytoskeletal dynamics necessary for neural plate folding. Further studies in this organism could unveil novel cellular and molecular events mediated by folate and lead to new ways of preventing NTDs. PMID:28255006

Erythrocyte volume, folate levels, and the presence of methylenetetrahydrofolate reductase polymorphism.

PubMed

García-García, Inés; García-Fragoso, Lourdes; Renta, Jessicca; Arce, Sylvia; Cadilla, Carmen L

2002-03-01

Homozygosity for a common polymorphism in the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been associated to an increased risk of neural tube defects as well as derangements in folate, homocysteine, and hematological parameters. This study analyzed the relationship between folate levels, the erythrocyte volume, and the presence of homozygosity for the C677T polymorphism in a group of 126 Puerto Rican healthy women of childbearing age. Blood samples were analyzed for erythrocyte mean corpuscular volume (MCV), mean erythrocyte hemoglobin content (MCH), folate, and RBC folate. Homozygosity for the C677T mutation was determined by PCR. Thirty-two percent (32%) of women used a folic acid supplement during the three months prior to sampling. Mean folate and RBC folate levels were within the normal range. Individuals homozygous for the MTHFR C677T polymorphism had no elevation of MCV (p = 0.70) or MCH (p = 0.68). Women in the lower quartile of folate levels did not show differences in their MCV or MCH. In this sample of Puerto Rican women, homozygosity for the C677T MTHFR polymorphism was not associated to elevations of MCV or MCH even in the presence of lower folate levels.

Folate content in faba beans (Vicia faba L.)-effects of cultivar, maturity stage, industrial processing, and bioprocessing.

PubMed

Hefni, Mohammed E; Shalaby, Mohamed T; Witthöft, Cornelia M

2015-01-01

Faba beans are an important source of folate and commonly consumed in Egypt. This study examined the effects of Egyptian industrial food processing (e.g., canning and freezing), germination, cultivar, and maturity stages on folate content, with the aim to develop a candidate functional canned faba bean food with increased folate content. The folate content in four cultivars of green faba beans ranged from 110 to 130 μg 100 g(-1) fresh weight (535-620 μg 100 g(-1) dry matter [DM]), which was four- to sixfold higher than in dried seeds. Industrial canning of dried seeds resulted in significant folate losses of ∼20% (P = 0.004), while industrial freezing had no effect. Germination of faba beans increased the folate content by >40% (P < 0.0001). A novel industrial canning process involving pregermination of dried faba beans resulted in a net folate content of 194 μg 100 g(-1) DM, which is 52% more than in conventional canned beans. The consumption of green faba beans should be recommended, providing ∼120 μg dietary folate equivalents per 100 g/portion.

Cognitive Impairment in Folate-Deficient Rats Corresponds to Depleted Brain Phosphatidylcholine and Is Prevented by Dietary Methionine without Lowering Plasma Homocysteine12

PubMed Central

Troen, Aron M.; Chao, Wei-Hsun; Crivello, Natalia A.; D'Anci, Kristen E.; Shukitt-Hale, Barbara; Smith, Don E.; Selhub, Jacob; Rosenberg, Irwin H.

2008-01-01

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction. PMID:19022979

Self-illuminating nanoprobe for in vivo imaging of cancers over-expressing the folate receptor

NASA Astrophysics Data System (ADS)

Miller, Steven C.; Beviglia, Lucia; Yeung, Pete; Bhattacharyya, Sukanta; Sobek, Daniel

2012-03-01

New in vivo imaging reagents with increased sensitivity and penetration depth are needed to advance our understanding of metastases and accelerate the development of therapeutics. The folate receptor (FR) is a promising imaging target that is up-regulated in many human carcinomas, including cancers of the ovary, breast, pancreas, endometrium, lungs, kidneys, colon, brain, and myeloid cells. Zymera has developed a self-illuminating Bioluminescence Resonance Energy Transfer Quantum Dot (BRET-Qdot) nanoprobe conjugated with folate (BQ-Folate) for in vivo imaging of cancers overexpressing FR. BQ-Folate is a novel nanoprobe formed by co-conjugating Renilla reniformis luciferase enzyme and folate to near-infrared (NIR) emitting quantum dots. The luciferase substrate, coelenterazine, activates the BQ-Folate nanoprobe generating luminescence emission in the near-infrared (NIR) region (655 nm) for increased sensitivity and penetration depth. Because BQ-Folate requires no external light source for light emission, it has significant advantages for challenging in vivo preclinical optical imaging applications, such as the detection of early stage metastases. Zymera and OncoMed Pharmaceuticals have demonstrated that in vivo imaging with the BQ-Folate nanoprobe detected the primary tumor and early stage metastases in an orthotopic NOD/SCID mouse model of human pancreatic cancer.

Serum Folate Shows an Inverse Association with Blood Pressure in a Cohort of Chinese Women of Childbearing Age: A Cross-Sectional Study

PubMed Central

Shen, Minxue; Tan, Hongzhuan; Zhou, Shujin; Retnakaran, Ravi; Smith, Graeme N.; Davidge, Sandra T.; Trasler, Jacquetta; Walker, Mark C.; Wen, Shi Wu

2016-01-01

Background It has been reported that higher folate intake from food and supplementation is associated with decreased blood pressure (BP). The association between serum folate concentration and BP has been examined in few studies. We aim to examine the association between serum folate and BP levels in a cohort of young Chinese women. Methods We used the baseline data from a pre-conception cohort of women of childbearing age in Liuyang, China, for this study. Demographic data were collected by structured interview. Serum folate concentration was measured by immunoassay, and homocysteine, blood glucose, triglyceride and total cholesterol were measured through standardized clinical procedures. Multiple linear regression and principal component regression model were applied in the analysis. Results A total of 1,532 healthy normotensive non-pregnant women were included in the final analysis. The mean concentration of serum folate was 7.5 ± 5.4 nmol/L and 55% of the women presented with folate deficiency (< 6.8 nmol/L). Multiple linear regression and principal component regression showed that serum folate levels were inversely associated with systolic and diastolic BP, after adjusting for demographic, anthropometric, and biochemical factors. Conclusions Serum folate is inversely associated with BP in non-pregnant women of childbearing age with high prevalence of folate deficiency. PMID:27182603

Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts.

PubMed

Chiang, E-P; Wang, Y-C; Tang, F-Y

2007-04-01

The homozygous mutation (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene reduces enzyme activity and alters cellular folate composition. Previous epidemiological studies reported a potential protective effect of MTHFR677C --> T against acute lymphocytic leukemia and malignant lymphoma, but the mechanism remains to be determined. We investigated the biochemical impacts of MTHFR677C --> T on cellular S-adenosyl methionine (adoMet) synthesis, global DNA methylation, and de novo purine synthesis, all of which are potential regulatory pathways involved in tumorigenesis. Metabolic fluxes of homocysteine remethylation and de novo purine synthesis were compared between Epstein-Barr virus-transformed lymphoblasts expressing MTHFR 677C and MTHFR 677T using stable isotopic tracers and GCMS. MTHFR TT genotype significantly reduced folate-dependent remethylation under folate restriction, reflecting limited methylated folates under folate restriction. Data also suggested increased formylated folate pool and increased purine synthesis when folate is adequate. The impacts of MTHFR 677T polymorphism appeared closely related to folate status, and such alterations may modulate metabolic pathways involved in cancer onset/progression. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in hematological malignancies. These transformed cells are potential models for studying the consequences of human genetic variation and cancer pathogenesis.

Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.

PubMed

Chandrasekar, Durairaj; Sistla, Ramakrishna; Ahmad, Farhan J; Khar, Roop K; Diwan, Prakash V

2007-07-01

Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (r(e)) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T(e)) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency. Copyright 2007 Wiley Periodicals, Inc.

High Serum Folate Is Associated with Brain Atrophy in Older Diabetic People with Vitamin B12 Deficiency.

PubMed

Deng, Y; Wang, D; Wang, K; Kwok, T

2017-01-01

Previous studies have reported the adverse cognitive effects of high folate status in older individuals with vitamin B12 (VB12) deficiency. Thus, the aim of this study was to investigate how high serum folate and VB12 deficiency could collaboratively aggravate neuronal degeneration. In total, 146 older non-demented diabetic individuals with an average age of 75 ± 3.9 were recruited. VB12 deficiency and high folate status were based on high serum methylmalonic acid (MMA) concentrations (> 0.3 μmol/L) and the serum folate concentration being in the top tertile (> 31.4 nmol/L) respectively. Among these subjects, there were 20 with elevated MMA and high folate. The structural magnetic resonance imaging data of these subjects were analyzed by performing flexible factorial analysis with the "folate level" and "MMA level" added as main effects, and the interaction effect of folate and VB12 on brain volume was evaluated. The results showed significant gray matter atrophy of the right middle occipital gyrus and the opercular part of the inferior frontal gyrus in subjects with a simultaneous high folate status and VB12 deficiency. Together with previous observational studies on cognitive function, this study lends support to the notion that high serum folate concentrations in older people with VB12 deficiency may be associated with increased neurodegeneration.

Folate distribution in barley (Hordeum vulgare L.), common wheat (Triticum aestivum L.) and durum wheat (Triticum turgidum durum Desf.) pearled fractions.

PubMed

Giordano, Debora; Reyneri, Amedeo; Blandino, Massimo

2016-03-30

Wholegrain cereals are an important source of folates. In this study, total folate was analysed in pearled fractions of barley and wheat cultivars employing AOAC Official Method 2004.05. In particular, the distribution of folate in the kernels was evaluated in three barley cultivars (two hulled types and a hulless one as well as two- and six-row types) and in a common and a durum wheat cultivar. A noticeable variation in the folate content was observed between the barley [653-1033 ng g(-1) dry matter (DM)] and wheat cultivars (1024-1119 ng g(-1) DM). The highest folate content was detected in the hulless barley cultivar (1033 ng g(-1) DM). A significant reduction in total folate, from 63% to 86%, was observed in all cultivars from the outermost to the innermost pearled fractions. Results proved that folates are mainly present in the germ and in the outer layers of the kernel. This is the first study reporting the folate distribution in kernels of both common and durum wheat and in a hulless barley cultivar. Results suggest that the pearling process could be useful for the selection of intermediate fractions that could be used in order to develop folate-enhanced ingredients and products. © 2015 Society of Chemical Industry.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baggott, Joseph E.; Gorman, Gregory S.; Morgan, Sarah L.

To evaluate folate-dependent carbon incorporation into the purine ring, we measured {sup 13}C-enrichment independently at C{sub 2} and C{sub 8} of urinary uric acid (the final catabolite of purines) in a healthy male after an independent oral dose of [6RS]-5-[{sup 13}C]-formyltetrahydrofolate ([6RS]-5-H{sup 13}CO-H{sub 4}folate) or 10-H{sup 13}CO-7,8-dihydrofolate (10-H{sup 13}CO-H{sub 2}folate). The C{sub 2} position was {sup 13}C-enriched more than C{sub 8} after [6RS]-5-H{sup 13}CO-H{sub 4}folate, and C{sub 2} was exclusively enriched after 10-H{sup 13}CO-H{sub 2}folate. The enrichment of C{sub 2} was greater from [6RS]-5-H{sup 13}CO-H{sub 4}folate than 10-H{sup 13}CO-H{sub 2}folate using equimolar bioactive doses. Our data suggest that formyl Cmore » of [6RS]-10-H{sup 13}CO-H{sub 4}folate was not equally utilized by glycinamide ribotide transformylase (enriches C{sub 8}) and aminoimidazolecarboxamide ribotide (AICAR) transformylase (enriches C{sub 2}), and the formyl C of 10-H{sup 13}CO-H{sub 2}folate was exclusively used by AICAR transformylase. 10-HCO-H{sub 2}folate may function in vivo as the predominant substrate for AICAR transformylase in humans.« less

Characterization and Interrelations of One-Carbon Metabolites in Tissues, Erythrocytes, and Plasma in Mice with Dietary Induced Folate Deficiency

PubMed Central

Kopp, Markus; Morisset, Rosalie; Rychlik, Michael

2017-01-01

Studies on one-carbon metabolism for the assessment of folate deficiency have focused on either metabolites of folate metabolism or methionine cycle. To bridge the gap between deficiency markers in these pathways we designed a dietary induced folate deficiency study using male C57BL/6N mice. After weaning (3 weeks) mice were fed a defined control diet (1 week) before being fed a folate deficient diet (n = 6 mice) and the control diet (n = 6 mice) for 12 additional weeks. Thereafter, we determined total homocysteine in plasma and folate in erythrocytes as well as S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers in tissues including 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, 5,10-methenyltetrahydrofolate, tetrahydrofolate, 10-formylfolic acid, and folic acid by means of stable isotope dilution assays coupled with liquid chromatography tandem mass spectrometry. In all organs, except heart (mainly 5-mehtyltetrahydrofolate), tetrahydrofolate constitutes the main vitamer. Moreover, in liver tetrahydrofolate was most abundant followed by 5-methyltetrahydrofolate (heart: tetrahydrofolate), 5-formyltetrahydrofolate, and 5,10-methenyltetrahydrofolate. Because of the significant decrease (p < 0.05) of folate status and S-adenosylmethionine/S-adenosylhomocysteine ratio accompanied with increasing S-adenosylhomocysteine (p < 0.05), hepatocytes are most susceptible to folate deficiency. To the best of our knowledge, we herein present the first method for simultaneous quantitation of eight metabolites for both folate and methionine cycle in one tissue sample, tHcy in plasma, and erythrocyte folate to shed light on physiological interrelations of one-carbon metabolism. PMID:28475162

A novel A781V mutation in the CSF1R gene causes hereditary diffuse leucoencephalopathy with axonal spheroids☆

PubMed Central

Ahmed, Rebekah; Guerreiro, Rita; Rohrer, Jonathan D.; Guven, Gamze; Rossor, Martin N.; Hardy, John; Fox, Nick C.

2013-01-01

We report a family with a novel CSF1R mutation causing hereditary diffuse leucoencephalopathy with axonal spheroids. Family members presented with neuropsychiatric and behavioural symptoms, with subsequent development of motor symptoms and gait disturbance. MRI brain showed extensive white matter change with a frontal predominance and associated atrophy in two members of the family. Genetic testing revealed a novel mutation c.2342C > T (p.A781V) in the CSF1R gene in two brothers of the family. This report highlights the difficulties in diagnosing HDLS and discusses the indications for testing for mutations in the CSF1R gene. PMID:23816250

Pathophysiological consequences and benefits of HFE mutations: 20 years of research

PubMed Central

Hollerer, Ina; Bachmann, André; Muckenthaler, Martina U.

2017-01-01

Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers. PMID:28280078

The folate hydrolase 1561 C>T polymorphism is associated with depressive symptoms in Puerto Rican adults

USDA-ARS?s Scientific Manuscript database

Low plasma folate has been associated with depression. Variants of genes involved in the uptake, retention and metabolism of folate have been linked with plasma folate and homocysteine concentrations. It remains unclear whether such variants are also associated with depressive symptoms, directly or ...

Folate Metabolism and the Risk of Down Syndrome

ERIC Educational Resources Information Center

Patterson, David

2008-01-01

Folate is an important vitamin that contributes to cell division and growth and is therefore of particular importance during infancy and pregnancy. Folate deficiency has been associated with slowed growth, anaemia, weight loss, digestive disorders and some behavioural issues. Adequate folate intake around the time of conception and early pregnancy…

Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial.

PubMed

Obeid, Rima; Kirsch, Susanne H; Dilmann, Sarah; Klein, Cosima; Eckert, Rudolf; Geisel, Jürgen; Herrmann, Wolfgang

2016-04-01

Unmetabolized folic acid (UMFA) is common in serum of elderly individuals receiving folic acid (FA)-fortified foods or supplements. We studied the effect of supplementing FA or B-complex on serum concentrations of (6S)-5-methyltetrahydropteroylglutamate [(6S)-5-CH3-H4Pte] and UMFA in elderly people and explored factors associated with detectable UMFA post-supplementation. This is a randomized single-blind non-controlled trial on 58 elderly people using daily 400 µg FA (n = 31) or 400 µg FA, 10 µg cyanocob(III)alamin and 8 mg pyridoxine (n = 27) for a median of 23 days. Main outcome includes changes in concentrations of serum (6S)-5-CH3-H4Pte and UMFA. Total homocysteine declined by a median of 1.6 (p = 0.074) in the FA and 1.3 µmol/L (p = 0.009) in the B-complex arms (p = 0.66 between the arms). Serum (6S)-5-CH3-H4Pte significantly (p < 0.001 vs. baseline) increased by a median of 9.2 and 6.5 nmol/L in the FA and B-complex groups, respectively (p = 0.152 between the groups). Compared to FA, B-complex reduced cystathionine and caused lower post-intervention serum UMFA, percentage of UMFA to (6S)-5-CH3-H4Pte and prevalence of UMFA ≥ 0.21 nmol/L. Higher serum cystathionine and whole-blood folate predicted higher post-intervention serum UMFA. FA caused higher UMFA as compared to B-complex. Pyridoxine appears to improve folate recycling. Data on serum UMFA should be interpreted in relation to other vitamins involved in folate metabolism. Serum UMFA is suggested to play a sensory role through which the cell recognizes FA available for metabolism via dihydrofolate reductase.

Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate's Role2

PubMed Central

Yang, Thomas P.; Berry, Robert J; Bailey, Lynn B.

2012-01-01

ABSTRACT DNA methylation is an epigenetic modification critical to normal genome regulation and development. The vitamin folate is a key source of the one carbon group used to methylate DNA. Because normal mammalian development is dependent on DNA methylation, there is enormous interest in assessing the potential for changes in folate intake to modulate DNA methylation both as a biomarker for folate status and as a mechanistic link to developmental disorders and chronic diseases including cancer. This review highlights the role of DNA methylation in normal genome function, how it can be altered, and the evidence of the role of folate/folic acid in these processes. PMID:22332098

Whole-exome sequencing for diagnosis of hereditary ichthyosis.

PubMed

Sitek, J C; Kulseth, M A; Rypdal, K B; Skodje, T; Sheng, Y; Retterstøl, L

2018-02-14

Hereditary ichthyosis constitutes a diverse group of cornification disorders. Identification of the molecular cause facilitates optimal patient care. We wanted to estimate the diagnostic yield of applying whole-exome sequencing (WES) in the routine genetic workup of inherited ichthyosis. During a 3-year-period, all ichthyosis patients, except X-linked and mild vulgar ichthyosis, consecutively admitted to a university hospital clinic were offered WES with subsequent analysis of ichthyosis-related genes as a first-line genetic investigation. Clinical and molecular data have been collected retrospectively. Genetic variants causative for the ichthyosis were identified in 27 of 34 investigated patients (79.4%). In all, 31 causative mutations across 13 genes were disclosed, including 12 novel variants. TGM1 was the most frequently mutated gene, accounting for 43.7% of patients suffering from autosomal recessive congenital ichthyosis (ARCI). Whole-exome sequencing appears an effective tool in disclosing the molecular cause of patients with hereditary ichthyosis seen in clinical practice and should be considered a first-tier genetic test in these patients. © 2018 European Academy of Dermatology and Venereology.

Total folate content and retention in rosehips (Rosa ssp.) after drying.

PubMed

Strålsjö, Lena; Alklint, Charlotte; Olsson, Marie E; Sjöholm, Ingegerd

2003-07-16

Folate concentrations in rosehips and commercial rosehip products and factors affecting folate retention during drying were investigated. On the basis of the raw material studied during 3 years, rosehips were shown to be a rich folate source, 400-600 microg/100 g based on dry matter and 160-185 microg/100 g based on the fresh weight (edible part). Rosehips are not often consumed fresh; therefore, drying to produce stable semimanufactures is a crucial step. The degradation of folate was shown to be dependent on the drying time until the water activity was below 0.75. The required drying time was reduced by cutting the rosehips in slices and to some extent also by increasing the temperature. Retention of folate and ascorbic acid was affected by the same factors, and high content of ascorbic acid could provide a possible protection for folate degradation.

Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II.

PubMed

Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Rouleau, Guy A

2008-07-01

Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system-specific exon of the with-no-lysine(K)-1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII.

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

PubMed Central

Shekarabi, Masoud; Girard, Nathalie; Rivière, Jean-Baptiste; Dion, Patrick; Houle, Martin; Toulouse, André; Lafrenière, Ronald G.; Vercauteren, Freya; Hince, Pascale; Laganiere, Janet; Rochefort, Daniel; Faivre, Laurence; Samuels, Mark; Rouleau, Guy A.

2008-01-01

Hereditary sensory and autonomic neuropathy type II (HSANII) is an early-onset autosomal recessive disorder characterized by loss of perception to pain, touch, and heat due to a loss of peripheral sensory nerves. Mutations in hereditary sensory neuropathy type II (HSN2), a single-exon ORF originally identified in affected families in Quebec and Newfoundland, Canada, were found to cause HSANII. We report here that HSN2 is a nervous system–specific exon of the with-no-lysine(K)–1 (WNK1) gene. WNK1 mutations have previously been reported to cause pseudohypoaldosteronism type II but have not been studied in the nervous system. Given the high degree of conservation of WNK1 between mice and humans, we characterized the structure and expression patterns of this isoform in mice. Immunodetections indicated that this Wnk1/Hsn2 isoform was expressed in sensory components of the peripheral nervous system and CNS associated with relaying sensory and nociceptive signals, including satellite cells, Schwann cells, and sensory neurons. We also demonstrate that the novel protein product of Wnk1/Hsn2 was more abundant in sensory neurons than motor neurons. The characteristics of WNK1/HSN2 point to a possible role for this gene in the peripheral sensory perception deficits characterizing HSANII. PMID:18521183

Cognitive impairment in folate-deficient rats corresponds to depleted brain phosphatidylcholine and is prevented by methionine without lowering homocysteine

USDA-ARS?s Scientific Manuscript database

Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely believed to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate ...

The influence of folate serum levels on depressive mood and mental processing in patients with epilepsy treated with enzyme-inducing anti-epileptic drugs.

PubMed

Rösche, J; Uhlmann, C; Weber, R; Fröscher, W

2003-04-01

Folate deficiency is common in patients with epilepsy and also occurs in patients with depression or cognitive deficits. This study investigates whether low serum folate levels may contribute to depressive mood and difficulties in mental processing in patients with epilepsy treated with anti-epileptic drugs inducing the cytochrome P450. We analysed the serum folate levels, the score in the Self Rating Depression Scale (SDS) and the results of a bedside test in mental processing in 54 patients with epilepsy. There was a significant negative correlation between the serum folate levels and the score in SDS and significant positive correlations between the score in SDS and the time needed to process an interference task or a letter-reading task. Low serum folate levels may contribute to depressive mood and therefore to difficulties in mental processing. Further studies utilizing total plasma homocysteine as a sensitive measure of functional folate deficiency and more elaborate tests of mental processing are required to elucidate the impact of folate metabolism on depressive mood and cognitive function in patients with epilepsy.

Folate and asthma.

PubMed

Blatter, Joshua; Han, Yueh-Ying; Forno, Erick; Brehm, John; Bodnar, Lisa; Celedón, Juan C

2013-07-01

Findings from experimental studies and animal models led to the hypothesis that folic acid supplementation during pregnancy confers an increased risk of asthma. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between folate status and asthma. In industrialized nations, the prevalence of asthma was rising before widespread fortification of foodstuffs with folic acid or folate supplementation before or during pregnancy, thus suggesting that changes in folate status are an unlikely explanation for "the asthma epidemic." Consistent with this ecologic observation, evidence from human studies does not support moderate or strong effects of folate status on asthma. Given known protective effects against neural tube and cardiac defects, there is no reason to alter current recommendations for folic acid supplementation during conception or pregnancy based on findings for folate and asthma. Although we believe that there are inadequate data to exclude a weak effect of maternal folate status on asthma or asthma symptoms, such effects could be examined within the context of very large (and ongoing) birth cohort studies. At this time, there is no justification for funding new studies of folate and asthma.

Folate dietary insufficiency and folic acid supplementation similarly impair metabolism and compromise hematopoiesis

PubMed Central

Henry, Curtis J.; Nemkov, Travis; Casás-Selves, Matias; Bilousova, Ganna; Zaberezhnyy, Vadym; Higa, Kelly C.; Serkova, Natalie J.; Hansen, Kirk C.; D’Alessandro, Angelo; DeGregori, James

2017-01-01

While dietary folate deficiency is associated with increased risk for birth defects and other diseases, evidence suggests that supplementation with folic acid can contribute to predisposition to some diseases, including immune dysfunction and cancer. Herein, we show that diets supplemented with folic acid both below and above the recommended levels led to significantly altered metabolism in multiple tissues in mice. Surprisingly, both low and excessive dietary folate induced similar metabolic changes, which were particularly evident for nucleotide biosynthetic pathways in B-progenitor cells. Diet-induced metabolic changes in these cells partially phenocopied those observed in mice treated with anti-folate drugs, suggesting that both deficiency and excessive levels of dietary folic acid compromise folate-dependent biosynthetic pathways. Both folate deficiency and excessive dietary folate levels compromise hematopoiesis, resulting in defective cell cycle progression, persistent DNA damage, and impaired production of lymphocytes. These defects reduce the reconstitution potential in transplantation settings and increase radiation-induced mortality. We conclude that excessive folic acid supplementation can metabolically mimic dietary folate insufficiency, leading to similar functional impairment of hematopoiesis. PMID:28883079

Folate and nutrients involved in the 1-carbon cycle in the pretreatment of patients for colorectal cancer.

PubMed

Ferrari, Ariana; de Carvalho, Aline Martins; Steluti, Josiane; Teixeira, Juliana; Marchioni, Dirce Maria Lobo; Aguiar, Samuel

2015-06-02

To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions.

Folic acid: influence on the outcome of pregnancy.

PubMed

Scholl, T O; Johnson, W G

2000-05-01

The periconceptional use of folic acid-containing supplements reduces the first occurrence, as well as the recurrence, of neural tube defects. Women of populations in which adverse pregnancy outcomes are prevalent often consume diets that contain a low density of vitamins and minerals, including folate. Folate intake may need to be sustained after complete closure of the neural tube to decrease the risk of other poor pregnancy outcomes. A central feature of embryonic and fetal development is widespread cell division; folate is central because of its role in nucleic acid synthesis. During gestation, marginal folate nutriture can impair cellular growth and replication in the fetus or placenta. Folate deficiency can occur because dietary folate intake is low or because the metabolic requirement for folate is increased by a particular genetic defect or defects. During pregnancy, low concentrations of dietary and circulating folate are associated with increased risks of preterm delivery, infant low birth weight, and fetal growth retardation. A metabolic effect of folate deficiency is an elevation of blood homocysteine. Likewise, the presence of maternal homocysteine concentrations have been associated both with increased habitual spontaneous abortion and pregnancy complications (eg, placental abruption and preeclampsia), which increase the risk of poor pregnancy outcome and of decreased birth weight and gestation duration.

The Vitamin D–Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas

PubMed Central

Lucock, Mark; Veysey, Martin; Beckett, Emma

2018-01-01

Vitamin D is unique in being generated in our skin following ultraviolet radiation (UVR) exposure. Ongoing research into vitamin D must therefore always consider the influence of UVR on vitamin D processes. The close relationship between vitamin D and UVR forms the basis of the “vitamin D–folate hypothesis”, a popular theory for why human skin colour has evolved as an apparent adaption to UVR environments. Vitamin D and folate have disparate sensitivities to UVR; whilst vitamin D may be synthesised following UVR exposure, folate may be degraded. The vitamin D–folate hypothesis proposes that skin pigmentation has evolved as a balancing mechanism, maintaining levels of these vitamins. There are several alternative theories that counter the vitamin D–folate hypothesis. However, there is significant overlap between these theories and the now known actions of vitamin D and folate in the skin. The focus of this review is to present an update on the vitamin D–folate hypothesis by integrating these current theories and discussing new evidence that supports associations between vitamin D and folate genetics, UVR, and skin pigmentation. In light of recent human migrations and seasonality in disease, the need for ongoing research into potential UVR-responsive processes within the body is also discussed. PMID:29710859

Folate content in faba beans (Vicia faba L.)—effects of cultivar, maturity stage, industrial processing, and bioprocessing

PubMed Central

Hefni, Mohammed E; Shalaby, Mohamed T; Witthöft, Cornelia M

2015-01-01

Faba beans are an important source of folate and commonly consumed in Egypt. This study examined the effects of Egyptian industrial food processing (e.g., canning and freezing), germination, cultivar, and maturity stages on folate content, with the aim to develop a candidate functional canned faba bean food with increased folate content. The folate content in four cultivars of green faba beans ranged from 110 to 130 μg 100 g−1 fresh weight (535–620 μg 100 g−1 dry matter [DM]), which was four- to sixfold higher than in dried seeds. Industrial canning of dried seeds resulted in significant folate losses of ∼20% (P = 0.004), while industrial freezing had no effect. Germination of faba beans increased the folate content by >40% (P < 0.0001). A novel industrial canning process involving pregermination of dried faba beans resulted in a net folate content of 194 μg 100 g−1 DM, which is 52% more than in conventional canned beans. The consumption of green faba beans should be recommended, providing ∼120 μg dietary folate equivalents per 100 g/portion. PMID:25650294

Association of Folate Level in Blood with the Risk of Schizophrenia.

PubMed

Ding, Yujie; Ju, Mingliang; He, Lin; Chen, Wenzhong

2017-01-01

The aim of this study was to evaluate the association between folate level and the risk of schizophrenia and to identify possible biomarker for schizophrenia. Data about folate were extracted from 16 high quality studies. The association of folate level in blood and schizophrenia was evaluated using standardized mean difference (SMD) and 95% confidence interval (CI). Totally 1183 (52.1%) cases and 1089 (47.9%) controls were included in the current metaanalysis. Folate level in schizophrenia patients was significantly lower than that in healthy controls (SMD= -0.65; 95% CI: [-0.86, -0.45]; P <0.00001). Subgroup analysis demonstrated that the decreased folate level was found in both Asian and European patients (SMD=-0.86, P<0.00001; SMD=-0.44, P<0.00001, respectively), while there were no significant differences in patients from other areas (P>0.05). Sensitivity analysis confirmed that these results were stable and reliable, no publication bias existed in our meta-analysis based on Egger's and Begg's tests (P=0.48 and 0.30, respectively). These results suggest that decreased folate may be a risk factor for schizophrenia. More epidemiological and biochemistry studies are required to describe how folate or folate supplementation play roles in the progress of schizophrenia. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Hyperhomocysteinemia and neurologic disorders: a review.

PubMed

Ansari, Ramin; Mahta, Ali; Mallack, Eric; Luo, Jin Jun

2014-10-01

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders.

Hyperhomocysteinemia and Neurologic Disorders: a Review

PubMed Central

Ansari, Ramin; Mallack, Eric; Luo, Jin Jun

2014-01-01

Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. It has a physiologic role in DNA metabolism via methylation, a process governed by the presentation of folate, and vitamins B6 and B12. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy (eHcy) can be caused by deficiency of either vitamin B12 or folate, or a combination thereof. Certain genetic factors also cause eHcy, such as C667T substitution of the gene encoding methylenetetrahydrofolate reductase. eHcy has been observed in several medical conditions, such as cardiovascular disorders, atherosclerosis, myocardial infarction, stroke, minimal cognitive impairment, dementia, Parkinson's disease, multiple sclerosis, epilepsy, and eclampsia. There is evidence from laboratory and clinical studies that Hcy, and especially eHcy, exerts direct toxic effects on both the vascular and nervous systems. This article provides a review of the current literature on the possible roles of eHcy relevant to various neurologic disorders. PMID:25324876

Genetic testing in hyperlipidemia.

PubMed

Bilen, Ozlem; Pokharel, Yashashwi; Ballantyne, Christie M

2015-05-01

Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic Testing in Hyperlipidemia.

PubMed

Bilen, Ozlem; Pokharel, Yashashwi; Ballantyne, Christie M

2016-03-01

Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Epigenetic synergies between biotin and folate in the regulation of pro-inflammatory cytokines and repeats

PubMed Central

Xue, Jing; Zempleni, Janos

2013-01-01

The protein biotin ligase, holocarboxylase synthetase (HLCS), is a chromatin protein that interacts physically with the DNA methyltransferase DNMT1, the methylated cytosine binding protein MeCP2, and the histone H3 K9-methyltransferase EHMT1, all of which participate in folate-dependent gene repression. Here we tested the hypothesis that biotin and folate synergize in the repression of pro-inflammatory cytokines and long-terminal repeats (LTRs), mediated by interactions between HLCS and other chromatin proteins. Biotin and folate supplementation could compensate for each other’s deficiency in the repression of LTRs in Jurkat and U937 cells. For example, when biotin-deficient Jurkat cells were supplemented with folate, the expression of LTRs decreased by >70%. Epigenetic synergies were more complex in the regulation of cytokines compared with LTRs. For example, the abundance of TNF-α was 100% greater in folate- and biotin-supplemented U937 cells compared with biotin-deficient and folate-supplemented cells. The NF-κB inhibitor curcumin abrogated the effects of folate and biotin in cytokine regulation, suggesting that transcription factor signaling adds an extra layer of complexity to the regulation of cytokine genes by epigenetic phenomena. We conclude that biotin and folate synergize in the repression of LTRs and that these interactions are probably mediated by HLCS-dependent epigenetic mechanisms. In contrast, synergies between biotin and folate in the regulation of cytokines need to be interpreted in the context of transcription factor signaling. PMID:24007195

Reduction in unnecessary red blood cell folate testing by restricting computerized physician order entry in the electronic health record.

PubMed

MacMillan, Thomas E; Gudgeon, Patrick; Yip, Paul M; Cavalcanti, Rodrigo B

2018-05-02

Red blood cell folate is a laboratory test with limited clinical utility. Previous attempts to reduce physician ordering of unnecessary laboratory tests, including folate, have resulted in only modest success. The objective of this study was to assess the effectiveness and impacts of restricting red blood cell folate ordering in the electronic health record. This was a retrospective observational study from January 2010 to December 2016 at a large academic healthcare network in Toronto, Canada. All inpatients and outpatients who underwent at least 1 red blood cell folate or vitamin B12 test during the study period were included. Red blood cell folate ordering was restricted to clincians in gastroenterology and hematology and was removed from other physicians' computerized order entry screen in the electronic health record in June 2013. Red blood cell folate testing decreased by 94.4% during the study, from a mean of 493.0 (SD 48.0) tests/month before intervention to 27.6 (SD 10.3) tests/month after intervention (P<.001). Restricting red blood cell folate ordering in the electronic health record resulted in a large and sustained reduction in red blood cell folate testing. Significant cost savings estimated at over a quarter-million dollars (CAD) over three years were achieved. There was no significant clinical impact of the intervention on the diagnosis of folate deficiency. Copyright © 2018. Published by Elsevier Inc.

Experimental and Metabolic Modeling Evidence for a Folate-Cleaving Side-Activity of Ketopantoate Hydroxymethyltransferase (PanB)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thiaville, Jennifer J.; Frelin, Océane; García-Salinas, Carolina

Tetrahydrofolate (THF) and its one-carbon derivatives, collectively termed folates, are essential cofactors, but are inherently unstable. While it is clear that chemical oxidation can cleave folates or damage their pterin precursors, very little is known about enzymatic damage to these molecules or about whether the folate biosynthesis pathway responds adaptively to damage to its end-products. The presence of a duplication of the gene encoding the folate biosynthesis enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) in many sequenced bacterial genomes combined with a strong chromosomal clustering of the folK gene with panB, encoding the 5,10-methylene-THF-dependent enzyme ketopantoate hydroxymethyltransferase, led us to infer that PanBmore » has a side activity that cleaves 5,10-methylene-THF, yielding a pterin product that is recycled by FolK. Genetic and metabolic analyses of Escherichia coli strains showed that overexpression of PanB leads to accumulation of the likely folate cleavage product 6-hydroxymethylpterin and other pterins in cells and medium, and—unexpectedly—to a 46% increase in total folate content. In silico modeling of the folate biosynthesis pathway showed that these observations are consistent with the in vivo cleavage of 5,10-methylene-THF by a side-activity of PanB, with FolK-mediated recycling of the pterin cleavage product, and with regulation of folate biosynthesis by folates or their damage products.« less

Comparison of standardised dietary folate intake across ten countries participating in the European Prospective Investigation into Cancer and Nutrition.

PubMed

Park, Jin Young; Nicolas, Genevieve; Freisling, Heinz; Biessy, Carine; Scalbert, Augustin; Romieu, Isabelle; Chajès, Véronique; Chuang, Shu-Chun; Ericson, Ulrika; Wallström, Peter; Ros, Martine M; Peeters, Petra H M; Mattiello, Amalia; Palli, Domenico; María Huerta, José; Amiano, Pilar; Halkjær, Jytte; Dahm, Christina C; Trichopoulou, Antonia; Orfanos, Philippos; Teucher, Birgit; Feller, Silke; Skeie, Guri; Engeset, Dagrun; Boutron-Ruault, Marie-Christine; Clavel-Chapelon, Françoise; Crowe, Francesca; Khaw, Kay-Tee; Vineis, Paolo; Slimani, Nadia

2012-08-01

Folate plays an important role in the synthesis and methylation of DNA as a cofactor in one-carbon metabolism. Inadequate folate intake has been linked to adverse health events. However, comparable information on dietary folate intake across European countries has never been reported. The objective of the present study was to describe the dietary folate intake and its food sources in ten countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A cross-sectional analysis was conducted in 36 034 participants (aged 35-74 years) who completed a single 24 h dietary recall using a computerised interview software program, EPIC-Soft® (International Agency for Research on Cancer, Lyon). Dietary folate intake was estimated using the standardised EPIC Nutrient DataBase, adjusted for age, energy intake, weight and height and weighted by season and day of recall. Adjusted mean dietary folate intake in most centres ranged from 250 to 350 μg/d in men and 200 to 300 μg/d in women. Folate intake tended to be lower among current smokers and heavier alcohol drinkers and to increase with educational level, especially in women. Supplement users (any types) were likely to report higher dietary folate intake in most centres. Vegetables, cereals and fruits, nuts and seeds were the main contributors to folate intake. Nonetheless, the type and pattern of consumption of these main food items varied across the centres. These first comparisons of standardised dietary folate intakes across different European populations show moderate regional differences (except the UK health conscious group), and variation by sex, educational level, smoking and alcohol-drinking status, and supplement use.

A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting.

PubMed

Zhang, Lin; Zhu, Weiwei; Yang, Chunfen; Guo, Hongxia; Yu, Aihua; Ji, Jianbo; Gao, Yan; Sun, Min; Zhai, Guangxi

2012-01-01

The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research. The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor(®) EL, 32.5% Transcutol(®) HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.

Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women's Health Initiative observational study.

PubMed

Neuhouser, Marian L; Cheng, Ting-Yuan David; Beresford, Shirley A A; Brown, Elissa; Song, Xiaoling; Miller, Joshua W; Zheng, Yingye; Thomson, Cynthia A; Shikany, James M; Vitolins, Mara Z; Rohan, Thomas; Green, Ralph; Ulrich, Cornelia M

2015-08-15

The relationship between folate and colorectal cancer (CRC) risk is unclear. We investigated the association of two biomarkers of folate status, plasma folate and red blood cell (RBC) folate, with CRC risk using a nested case-control design in the Women's Health Initiative Observational Study. Postmenopausal women (n = 93,676) aged 50-79 years were enrolled in the Women's Health Initiative Observational Study (1993-1998). A fasting blood draw and extensive health, dietary and lifestyle data were collected upon enrollment. Through 2008, 988 incident CRC cases were reported and confirmed with medical records adjudication. Cases and controls were matched on age (± 3 years), enrollment date (± 1 year), race/ethnicity, blood draw date (± 6 months) and hysterectomy status. Plasma and RBC folate were determined by radio assay. Folate biomarker values were divided into quartiles, and conditional logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CI) for the associations of folate with total CRC, by tumor site and by stage at diagnosis. Additional analyses examined whether risks varied across time periods corresponding to the United States folic acid fortification policy: prefortification (1994-1995), perifortification (1996-1997) and postfortification (1998). ORs for overall CRC risk comparing Q4 vs. Q1 were 0.91 (95% CI 0.67-1.24) and 0.91 (95% CI 0.67-1.23) for RBC and plasma folate, respectively. There were no changes in risk attributable to food supply fortification. These results do not support an overall association of folate with CRC risk and suggest that folic acid fortification of the US food supply did not alter the associations in these postmenopausal women. © 2015 UICC.

Stable Isotope Dilution Assays for Clinical Analyses of Folates and Other One-Carbon Metabolites: Application to Folate-Deficiency Studies

PubMed Central

Kopp, Markus; Morisset, Rosalie; Koehler, Peter

2016-01-01

Folate deficiency is generally accepted as a potential direct or indirect risk factor for diseases including spina bifida, coronary heart diseases, malfunctions of the central nervous system, and cancer. The direct inclusion of folates in the methylation cycle, including the remethylation of homocysteine and regeneration of S-adenosylmethionine, underlines the importance of these vitamins and other components of one-carbon metabolism. Therefore, the aim of the present study was to develop a multiple stable isotope dilution assay (SIDA) for the respective analytes in plasma and tissue samples to allow for a closer look at the interaction between a severe folate deficiency and local folate status, as well as further interactions with circulating S-adenosylmethionine, S-adenosylhomocysteine, and homocysteine. The analytical methods were based on SIDAs coupled with liquid chromatography—tandem mass spectrometry (LC-MS/MS) analysis using the deuterated folates [2H4]-5-methyltetrahydrofolic acid, [2H4]-5-formyltetrahydrofolic acid, [2H4]-tetrahydrofolic acid, [2H4]-10-formylfolic acid, and [2H4]-folic acid and the deuterated one-carbon metabolites [2H4]-homocysteine, [2H4]-S-adenosylhomocysteine, and [2H3]-S-adenosylmethionine as internal standards. Three analytical methods have been developed for the analysis of homocysteine, S-adenosylmethionine, S-adenosylhomocysteine, and six folate vitamers. Validation data for the analysis of C1-metabolites in plasma and tissue samples or folate analysis in tissue samples revealed excellent sensitivity, precision, and recovery for all analytes studied. The miniaturized methods using sample volumes as low as 50 μL and weighed portions of 5–25 mg will allow the assessment of the status of folates and additional biomarkers of impaired one-carbon metabolism during folate deficiency. PMID:27276031

The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer's Disease.

PubMed

Min, Jin-Young; Min, Kyoung-Bok

2016-03-21

Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality.

Plasma folate levels and risk of spontaneous abortion.

PubMed

George, Lena; Mills, James L; Johansson, Anna L V; Nordmark, Anna; Olander, Bodil; Granath, Fredrik; Cnattingius, Sven

2002-10-16

Both folate deficiency and folic acid supplements have been reported to increase the risk of spontaneous abortion. The results are inconclusive, however, and measurements of folate have not been available in all studies. To study the association between plasma folate levels and the risk of spontaneous abortion. Population-based, matched, case-control study of case women with spontaneous abortion and control women from January 1996 through December 1998 in Uppsala County, Sweden. Plasma folate measurements were available for 468 cases and 921 controls at 6 to 12 gestational weeks. Risk of spontaneous abortion vs maternal plasma folate level. Compared with women with plasma folate levels between 2.20 and 3.95 ng/mL (5.0 and 8.9 nmol/L), women with low (< or =2.19 ng/mL [< or =4.9 nmol/L]) folate levels were at increased risk of spontaneous abortion (adjusted odds ratio [OR], 1.47; 95% confidence interval [CI], 1.01-2.14), whereas women with higher folate levels (3.96-6.16 ng/mL [9.0-13.9 nmol/L] and > or =6.17 ng/mL [> or =14.0 nmol/L]) showed no increased risk of spontaneous abortion (OR, 0.84; 95% CI, 0.59-1.20; and OR, 0.74; 95% CI, 0.47-1.16, respectively). Low folate levels were associated with a significantly increased risk when the fetal karyotype was abnormal (OR, 1.95; 95% CI, 1.09-3.48) but not when the fetal karyotype was normal (OR, 1.11; 95% CI, 0.55-2.24) or unknown (OR, 1.45; 95% CI, 0.90-2.33). Low plasma folate levels were associated with an increased risk of early spontaneous abortion.

Pretreatment red blood cell total folate is associated with response to pemetrexed in stage IV non-squamous non-small-cell lung cancer

PubMed Central

Bagley, Stephen J.; Vitale, Steven; Zhang, Suhong; Aggarwal, Charu; Evans, Tracey L.; Alley, Evan W.; Cohen, Roger B.; Langer, Corey J.; Blair, Ian A.; Vachani, Anil; Whitehead, Alexander S.

2016-01-01

Objectives Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Prior studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic marker of cellular folate status, was associated with response to pemetrexed-based chemotherapy in advanced non-squamous non-small-cell lung cancer (NSCLC). Materials and methods We conducted a prospective cohort study of patients with stage IV non-squamous NSCLC receiving first-line chemotherapy containing pemetrexed. Pretreatment RBC total folate was quantified using liquid chromatography/mass spectrometry. We then compared objective response rate (ORR) between patients with RBC total folate concentrations above and below an optimal cut-off value determined from the receiver operating characteristic (ROC) curve. A logistic regression model was used to adjust for age, sex, and use of bevacizumab. Results The ORR was 62% (32 of 52 patients). ROC analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and non-responders. Patients with RBC total folate below 364.5 nM had an ORR of 27%, compared to 71% in patients with RBC total folate above this value (p=0.01). This difference persisted after adjusting for age, sex, and use of bevacizumab (OR 0.07, 95% CI 0.01 - 0.57, p=0.01). Conclusions Low pretreatment RBC total folate is associated with inferior response to pemetrexed-based chemotherapy in stage IV non-squamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response. PMID:27863923

Pretreatment Red Blood Cell Total Folate Concentration Is Associated With Response to Pemetrexed in Stage IV Nonsquamous Non-Small-cell Lung Cancer.

PubMed

Bagley, Stephen J; Vitale, Steven; Zhang, Suhong; Aggarwal, Charu; Evans, Tracey L; Alley, Evan W; Cohen, Roger B; Langer, Corey J; Blair, Ian A; Vachani, Anil; Whitehead, Alexander S

2017-03-01

Pemetrexed inhibits folate-dependent enzymes involved in pyrimidine and purine synthesis. Previous studies of genetic variation in these enzymes as predictors of pemetrexed efficacy have yielded inconsistent results. We investigated whether red blood cell (RBC) total folate, a phenotypic rather than genotypic, marker of cellular folate status was associated with the response to pemetrexed-based chemotherapy in advanced nonsquamous non-small-cell lung cancer (NSCLC). We conducted a prospective cohort study of patients with stage IV nonsquamous NSCLC receiving first-line chemotherapy containing pemetrexed. The pretreatment RBC total folate level was quantified using liquid chromatography mass spectrometry. We then compared the objective response rate (ORR) between patients with RBC total folate concentrations greater than and less than an optimal cutoff value determined from the receiver operating characteristic curve. A logistic regression model was used to adjust for age, sex, and the use of bevacizumab. The ORR was 62% (32 of 52 patients). Receiver operating characteristic analysis was used to establish that a RBC total folate cutoff value of 364.6 nM optimally discriminated between pemetrexed responders and nonresponders. Patients with RBC total folate < 364.5 nM had an ORR of 27% compared with 71% for patients with RBC total folate > 364.5 nM (P = .01). This difference persisted after adjusting for age, sex, and the use of bevacizumab (odds ratio, 0.07; 95% confidence interval, 0.01-0.57; P = .01). A low pretreatment RBC total folate was associated with an inferior response to pemetrexed-based chemotherapy in stage IV nonsquamous NSCLC. Larger, multicenter studies are needed to validate RBC total folate as a predictive marker of pemetrexed response. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification of three novel loci of ALDH2 Gene for Serum Folate levels in a Male Chinese Population by Genome-Wide Association Study.

PubMed

Deng, Caiwang; Tang, Shaomei; Huang, Xiaoliang; Gao, Jiamin; Tian, Jiarong; Zhou, Xianguo; Xie, Yuanliang; Liao, Ming; Mo, Zengnan; Wang, Qiuyan

2018-06-25

Serum folate is important in clinical researches and DNA synthesis and methylation. Some loci and genes that are associated with folate levels had been detected by genome-wide association studies (GWAS), such as rs1801133 in MTHFR and rs1979277 in SHMT1. Nevertheless, only a small part of variants has been clearly identified for serum folate. Hence, we conducted a GWAS to discover new inherited susceptibility and gene-environment interactions on serum folate concentration. In a healthy Chinese population of 1999 men, genotyping was performed using Illumina HumanOmni1-Quad BeadChip. Serum folate levels were measured by enzyme-linked immunosorbent assay (ELISA), pathway enrichment analysis and statistical analysis were performed by Database for Annotation, Visualization and Integrated Discovery (DAVID) and Statistic Package for Social Science (SPSS). We validated that rs1801133 in MTHFR was significantly involved in serum folate (P = 4.21 × 10 -19 ). Surprisingly, we discovered three novel loci rs3782886, rs671, and rs4646776 of ALDH2 gene were suggestively significantly associated with folate serum folate levels in the male population studied (P = 2.17 × 10 -7 , P = 3.60 × 10 -7 , P = 3.99 × 10 -7 , respectively) after adjusting for population stratification, BMI and age. Men with the AA genotype had significantly higher serum folate levels compared with men with the GG/AG genotype. But we found ALDH2 gene mutation no relation to part of environmental factors on serum folate levels. In a male Chinese population, genome-wide association study discovered that three novel SNPs rs3782886, rs671 and rs4646776 of ALDH2 gene were suggestively significantly associated with serum folate levels. Copyright © 2018. Published by Elsevier B.V.

Neither Folic Acid Supplementation nor Pregnancy Affects the Distribution of Folate Forms in the Red Blood Cells of Women1–3

PubMed Central

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

2016-01-01

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

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

PubMed

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

2014-09-01

It is not known whether folate metabolism is altered during pregnancy to support increased DNA and RNA biosynthesis. By using a state-of-the-art LC tandem mass spectrometry technique, the aim of this study was to investigate differences in RBC folate forms between pregnant and nonpregnant women and between nonpregnant women consuming different concentrations of supplemental folic acid. Forms of folate in RBCs were used to explore potential shifts in folate metabolism during early erythropoiesis. Total RBC folate and folate forms [tetrahydrofolate; 5-methyltetrahydrofolate (5-methyl-THF); 4α-hydroxy-5-methyl-tetrahydrofolate (an oxidation product of 5-methyl-THF); 5-formyl-tetrahydrofolate; and 5,10-methenyl-tetrahydrofolate] were measured in 4 groups of women (n = 26): pregnant women (PW) (30-36 wk of gestation) consuming 1 mg/d of folic acid, and nonpregnant women consuming 0 mg/d (NPW-0), 1 mg/d (NPW-1), and 5 mg/d (NPW-5) folic acid. The mean ± SD RBC folate concentration of the NPW-0 group (890 ± 530 nmol/L) was lower than the NPW-1 (1660 ± 350 nmol/L) and NPW-5 (1980 ± 570 nmol/L) groups as assessed by microbiologic assay (n = 26, P < 0.0022). No difference was found between the NPW-1 and NPW-5 groups. We detected 5-methyl-THF [limit of detection (LOD) = 0.06 nmol/L] in all groups and tetrahydrofolate (LOD = 0.2 nmol/L) in most women regardless of methylenetetrahydrofolate reductase genotype. Most women consuming folic acid supplements had detectable concentrations of 5,10-methenyl-tetrahydrofolate (LOD = 0.31 nmol/L). However, there was no difference in the relative distribution of 5-methyl-THF (83-84%), sum of non-methyl folates (0.6-3%), or individual non-methyl folate forms in RBCs across groups. We conclude that although folic acid supplementation in nonpregnant women increases RBC total folate and the concentration of individual folate forms, it does not alter the relative distribution of folate forms. Similarly, distribution of RBC folate forms did not differ between pregnant and nonpregnant women. This trial was registered at clinicaltrials.gov as NCT01741077. © 2014 American Society for Nutrition.

Association of Maternal Prepregnancy BMI and Plasma Folate concentrations with Child Metabolic Health

PubMed Central

Wang, Guoying; Hu, Frank B.; Mistry, Kamila B.; Zhang, Cuilin; Ren, Fazheng; Huo, Yong; Paige, David; Bartell, Tami; Hong, Xiumei; Caruso, Deanna; Ji, Zhicheng; Chen, Zhu; Ji, Yuelong; Pearson, Colleen; Ji, Hongkai; Zuckerman, Barry; Cheng, Tina L.; Wang, Xiaobin

2016-01-01

Importance Previous reports have linked maternal prepregnancy obesity with low folate concentrations and child overweight or obesity (OWO) in separate studies. The role of maternal folate concentrations, alone or in combination with maternal OWO, in child metabolic health has not been examined in a prospective birth cohort. Objective We tested the hypotheses that maternal folate concentrations can significantly affect child metabolic health and that maternal sufficient folate concentrations can mitigate prepregnancy obesity-induced child metabolic risk. Design Prospective birth cohort study Setting The Boston Medical Center, MA, USA Participants This study included 1517 mother-child dyads recruited at birth from 1998–2012 and followed prospectively up to 9 years (median age: 6.2 years, range: 2–9 years). Main Outcomes and Measures Child BMI z-score calculated according to U.S. reference data, OWO defined as BMI≥85th percentile for age and gender, and metabolic biomarkers (leptin, insulin, and adiponectin). Results An “L-shaped” relationship between maternal folate concentrations and child OWO was observed: the risk of OWO was higher in the lowest quartile (Q1) as compared to Q2–Q4 with an odds ratio (OR) of 1.45 (95% confidence interval [CI], 1.13 to 1.87). The highest risk of child OWO was found among children of obese mothers with low folate concentrations (OR, 3.05, 95%CI, 1.91 to 4.86) compared to children of normal weight mothers with folate concentrations in Q2–Q4 after accounting for multiple covariables. Among children of obese mothers, their risk of OWO was associated with 43% reduction (OR, 0.57, 95%CI, 0.34–0.95) if their mothers had folate concentrations in Q2–Q4 compared to Q1. Similar patterns were observed for child metabolic biomarkers. Conclusions and Relevance In this urban low-income prospective birth cohort, we demonstrated an L-shaped relationship between maternal plasma folate concentrations and child OWO and the benefit of sufficient folate concentrations, especially among obese mothers. The “threshold” concentration identified in this study far exceeded the clinical definition of folate deficiency (<10.0 nmol/L), which was primarily based on the hematological effect of folate. Our findings underscore the need to establish “optimal” rather than minimal folate concentrations for preventing adverse metabolic outcomes in the offspring. PMID:27295011

Evidence Favoring a Positive Feedback Loop for Physiologic Auto Upregulation of hnRNP-E1 during Prolonged Folate Deficiency in Human Placental Cells1234

PubMed Central

Tang, Ying-Sheng; Khan, Rehana A; Xiao, Suhong; Hansen, Deborah K; Stabler, Sally P; Kusumanchi, Praveen; Jayaram, Hiremagalur N; Antony, Aśok C

2017-01-01

Background: Previously, we determined that heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) functions as an intracellular physiologic sensor of folate deficiency. In this model, l-homocysteine, which accumulates intracellularly in proportion to the extent of folate deficiency, covalently binds to and thereby activates homocysteinylated hnRNP-E1 to interact with folate receptor-α mRNA; this high-affinity interaction triggers the translational upregulation of cell surface folate receptors, which enables cells to optimize folate uptake from the external milieu. However, integral to this model is the need for ongoing generation of hnRNP-E1 to replenish homocysteinylated hnRNP-E1 that is degraded. Objective: We searched for an interrelated physiologic mechanism that could also maintain the steady-state concentration of hnRNP-E1 during prolonged folate deficiency. Methods: A novel RNA-protein interaction was functionally characterized by using molecular and biochemical approaches in vitro and in vivo. Results: l-homocysteine triggered a dose-dependent high-affinity interaction between hnRNP-E1 and a 25-nucleotide cis element within the 5′-untranslated region of hnRNP-E1 mRNA; this led to a proportionate increase in these RNA-protein complexes, and translation of hnRNP-E1 both in vitro and within placental cells. Targeted perturbation of this RNA-protein interaction either by specific 25-nucleotide antisense oligonucleotides or mutation within this cis element or by small interfering RNA to hnRNP-E1 mRNA significantly reduced cellular biosynthesis of hnRNP-E1. Conversely, transfection of hnRNP-E1 mutant proteins that mimicked homocysteinylated hnRNP-E1 stimulated both cellular hnRNP-E1 and folate receptor biosynthesis. In addition, ferrous sulfate heptahydrate [iron(II)], which also binds hnRNP-E1, significantly perturbed this l-homocysteine–triggered RNA-protein interaction in a dose-dependent manner. Finally, folate deficiency induced dual upregulation of hnRNP-E1 and folate receptors in cultured human cells and tumor xenografts, and more selectively in various fetal tissues of folate-deficient dams. Conclusions: This novel positive feedback loop amplifies hnRNP-E1 during prolonged folate deficiency and thereby maximizes upregulation of folate receptors in order to restore folate homeostasis toward normalcy in placental cells. It will also functionally impact several other mRNAs of the nutrition-sensitive, folate-responsive posttranscriptional RNA operon that is orchestrated by homocysteinylated hnRNP-E1. PMID:28250194

Orthodontic treatment for a patient with hereditary angiodema: a case report.

PubMed

Waldon, Kate; Barber, Sophy Kathleen; Spencer, Richard James

2015-05-01

Hereditary angiodema (HAE), also known as C1 esterase inhibitor deficiency, causes sufferers to experience episodic subcutaneous and submucosal oedema. These episodes can be triggered by dental treatment and manifest as life-threatening oedematous swelling in the head and neck region. This case report reviews an adolescent with hereditary angiodema whose malocclusion required orthodontic intervention. Due to her complex and unpredictable reaction to dental treatment, various options were explored before determining the appropriate care pathway for this patient. Trial placement of a sectional fixed appliance tested the tissue reaction prior to comprehensive treatment including extractions and fixed orthodontic appliances. This report demonstrates successful interdisciplinary management facilitating orthodontic care in a patient with HAE. © 2014 BSPD, IAPD and John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Exploring folate diversity in wild and primitive potatoes for modern crop improvement

USDA-ARS?s Scientific Manuscript database

Malnutrition is one of the world’s largest health concerns. Folate (a.k.a. vitamin B9) is essential in the human diet and without adequate folate intake several serious health concerns such as congenital birth defects and an increased risk of stroke and heart disease can occur. Most people’s folate ...

Increased chromosome fragility as a consequence of blood folate levels, smoking status, and coffee consumption

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, A.T.L.; Reidy, J.A.; Annest, J.L.

1989-01-01

Chromosome fragility in 96 h, low-folate cultures was found to be associated with smoking status, coffee consumption, and blood folate level. The higher proportion of cells with chromosome aberrations in cigarette smokers was attributable to lower red cell folate levels in smokers compared with nonsmokers. There was a positive linear relationship between the average cups of coffee consumed per day and the proportion of cells with aberrations. This association was independent of the effects of smoking and red cell folate level. These data suggest that smoking history, coffee consumption, and red cell folate level are important considerations for the designmore » and interpretation of fragile site studies in cancer cytogenetics.« less

Dietary folate intake levels in rural women immediately before pregnancy in Northern China.

PubMed

Meng, Qinqin; Zhang, Le; Liu, Jufen; Li, Zhiwen; Jin, Lei; Zhang, Yali; Wang, Linlin; Ren, Aiguo

2015-01-01

The study aims to assess dietary folate levels and food sources in women immediately before pregnancy in a rural area of northern China associated with a high prevalence of neural tube defects. Information was collected by face-to-face interviews with women who sought premarital healthcare and planned to become pregnant within the next 12 months from November 2009 through December 2012. Information regarding food consumption was obtained by means of 24-hr dietary recall. Folate values were assigned to foods according to the China Food Composition 2004. Factors associated with dietary folate intake were analyzed by multiple linear regression. Mean (± standard deviation) and median (interquartile range) daily folate intake levels were 114.3 ± 59.7 and 102.8 (69.3-146.8) μg/day, respectively. Over 99% of the subjects had an intake level below 320 μg/day, the estimated average requirement for nonpregnant women. Only 1% and 7% of the women consumed 75% and 50%, respectively, of the recommended daily folate intake of 400 μg for nonpregnant women. Over 80% of total folate consumption came from cereals, vegetables, and tubers, whereas fruit consumption was severely lacking. Underweight women, farmers, women enrolled during the winter, and women with access to fewer food types or daily meals were more likely to exhibit low folate intake levels. Dietary folate intake among study participants was far below the recommended intake level. Folic acid fortification of cereals is advised to raise folate intake in rural Chinese women planning to become pregnant. © 2014 Wiley Periodicals, Inc.

The effect of MTHFR(C677T) genotype on plasma homocysteine concentrations in healthy children is influenced by gender.

PubMed

Papoutsakis, C; Yiannakouris, N; Manios, Y; Papaconstantinou, E; Magkos, F; Schulpis, K H; Zampelas, A; Matalas, A L

2006-02-01

To explore the influence of gender, together with folate status, on the relation between the common methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and plasma total homocysteine (tHcy) concentrations in healthy children. Cross-sectional study by face-to-face interview. A total of 186 sixth-grade students participated from twelve randomly selected primary schools in Volos, Greece. Fasting tHcy, folate, and vitamin B(12) were measured in plasma. The MTHFR genotypes were determined. Anthropometric and dietary intake data by 24-h recall were collected. Geometric means for plasma tHcy, plasma folate and energy-adjusted dietary folate did not differ between females and males. The homozygous mutant TT genotype was associated with higher tHcy only in children with lower plasma folate concentrations (<19.9 nmol/l, P = 0.012). As a significant gender interaction was observed (P = 0.050), we stratified the lower plasma folate group by gender and found that the association between the genotype and tHcy was restricted to males (P = 0.026). Similar results were obtained when folate status was based on estimated dietary folate. Specifically, only TT males that reported lower dietary folate consumption (<37 microg/MJ/day) had tHcy that was significantly higher than tHcy levels of C-allele carriers (P = 0.001). Under conditions of lower folate status (as estimated by either plasma concentration or reported dietary consumption), gender modifies the association of the MTHFR(C677T) polymorphism with tHcy concentrations in healthy children. Kellog Europe.

Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy.

PubMed

Samadian, Hadi; Hosseini-Nami, Samira; Kamrava, Seyed Kamran; Ghaznavi, Habib; Shakeri-Zadeh, Ali

2016-11-01

Conventional cancer treatment methods suffer from many limitations such as non-specificity and low efficacy in discrimination between healthy and cancer cells. Recent developments in nanotechnology have introduced novel and smart therapeutic nanomaterials that basically take advantage of various targeting approaches. Targeted nanomaterials selectively bind to the cancer cells and affect them with minor effects on healthy cells. Folic acid (folate) is an essential molecule in DNA synthesis pathway which is highly needed for cancer cell duplication. Some certain cancer cells overexpress folate receptors higher than normal cells, and this fact is the basis of folate targeting strategy. There are many publications reporting various folate conjugated nanomaterials among which folate-conjugated gold nanoparticles hold great promises in targeted cancer therapy. Gold nanoparticles have been identified as promising candidates for new cancer therapy modalities because of biocompatibility, easy synthesis and functionalization, chemo-physical stability, and optical tunable characteristics. In the last decade, there has been a significant explosion in gold nanoparticles research, with a rapid increase in publications related to the area of biomedicine. Although there are many reports published on "gold nanoparticles" and "folate targeting," there are a few reports on "folate-conjugated gold nanoparticles" in biomedical literature. This paper intends to review and illustrate the recent advances in biomedicine which have been designed on the basis of folate-conjugated gold nanoparticles.

Use of Folic Acid Supplements in Early Pregnancy in Relation to Maternal Plasma Levels in Week 18 of Pregnancy

PubMed Central

Roth, Christine; Monsen, Anne Lise B.; Reichborn-Kjennerud, Ted; Nilsen, Roy M.; Smith, George Davey; Stoltenberg, Camilla; Surén, Pål; Susser, Ezra; Ueland, Per Magne; Vollset, Stein Emil; Magnus, Per

2013-01-01

We compared plasma-folate at week 18 of gestation with self-reported use of supplements containing folic acid from before pregnancy to 17 weeks gestation. Birth cohorts typically measure plasma-folate in mid-gestation, but effects of folic acid supplementation are sometimes specific to the periconceptional period. The relationship between mid-gestation plasma-folate and periconceptional supplementation is not known. The sample comprised 2911 women from The Norwegian Mother and Child Cohort Study. For women reporting continuous supplementation from gestational week -4-17 (N=238), median plasma-folate was 15.72 at week 18 (in nmol/L). This was about threefold higher than the median plasma-folate of 5.67 for women reporting no supplementation from week -4-17 (N=844), but only slightly higher than the median plasma-folate of 13.34 for all women reporting supplementation in week 13-17 (N=1158). Reported supplementation before week 8 was not associated with plasma-folate at week 18, in an analysis that adjusted for continued supplementation after week 8. Overall we found a strong and coherent relationship between self-reported folic acid use and plasma-folate at week 18. We also found that plasma-folate at week 18 did not reflect self-reported supplementation before 8 weeks. For periconceptional supplementation per se, self-report data may offer a better measure. PMID:23065724

Autism and Folate Deficiency

DTIC Science & Technology

2010-05-01

social interaction that remains to be characterized more fully. Conclusion Ablation of genes in the folate pathway may result in abnormal adult...W81XWH-09-1-0246 TITLE: Autism and Folate Deficiency PRINCIPAL INVESTIGATOR: Richard H. Finnell, Ph.D...5a. CONTRACT NUMBER W81XWH-09-1-0246 Autism and Folate Deficiency 5b. GRANT NUMBER AR080064-Concept Award 5c. PROGRAM ELEMENT NUMBER

Role of folate in nonalcoholic fatty liver disease.

PubMed

Sid, Victoria; Siow, Yaw L; O, Karmin

2017-10-01

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis, and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.

Recent Developments in Folate Nutrition.

PubMed

Naderi, Nassim; House, James D

The term folate (vitamin B9) refers to a group of water-soluble compounds that are nutritionally essential for the support of optimal human health and development. Folates participate in numerous one-carbon transfer reactions, including the methylation of important biomolecules (lipids, amino acids, DNA). A deficiency of folate leads to pathological outcomes including anemia and impairments in reproductive health and fetal development. Due to the linkage of impaired folate status with an increased prevalence of neural tube defects (NTDs) in babies, several jurisdictions required the fortification of the food supply with folic acid, a synthetic and stable form of folate. Data from the postfortification era have provided strong evidence for the reduction of NTDs due to folic acid fortification. However, concern is now growing with respect to the amount of synthetic folic acid within the human food supply. Excess folic acid intake has been linked to a masking of vitamin B12 deficiency, and concerns regarding the promotion of folate-sensitive cancers, including colorectal cancer. New strategies to ensure the supply of optimal folate to at-risk populations may be needed, including the use of biofortification approaches, in order to address recent concerns. © 2018 Elsevier Inc. All rights reserved.

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation.

PubMed

Iskandar, Bermans J; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H; Jarrard, David F; Banerjee, Ruma V; Skene, J H Pate; Nelson, Aaron; Patel, Nirav; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D; Hogan, Kirk J

2010-05-01

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries.

Folate regulation of axonal regeneration in the rodent central nervous system through DNA methylation

PubMed Central

Iskandar, Bermans J.; Rizk, Elias; Meier, Brenton; Hariharan, Nithya; Bottiglieri, Teodoro; Finnell, Richard H.; Jarrard, David F.; Banerjee, Ruma V.; Skene, J.H. Pate; Nelson, Aaron; Patel, Nirav; Gherasim, Carmen; Simon, Kathleen; Cook, Thomas D.; Hogan, Kirk J.

2010-01-01

The folate pathway plays a crucial role in the regeneration and repair of the adult CNS after injury. Here, we have shown in rodents that such repair occurs at least in part through DNA methylation. In animals with combined spinal cord and sciatic nerve injury, folate-mediated CNS axon regeneration was found to depend on injury-related induction of the high-affinity folate receptor 1 (Folr1). The activity of folate was dependent on its activation by the enzyme dihydrofolate reductase (Dhfr) and a functional methylation cycle. The effect of folate on the regeneration of afferent spinal neurons was biphasic and dose dependent and correlated closely over its dose range with global and gene-specific DNA methylation and with expression of both the folate receptor Folr1 and the de novo DNA methyltransferases. These data implicate an epigenetic mechanism in CNS repair. Folic acid and possibly other nontoxic dietary methyl donors may therefore be useful in clinical interventions to promote brain and spinal cord healing. If indeed the benefit of folate is mediated by epigenetic mechanisms that promote endogenous axonal regeneration, this provides possible avenues for new pharmacologic approaches to treating CNS injuries. PMID:20424322

The Role of Folate Transport in Antifolate Drug Action in Trypanosoma brucei*

PubMed Central

Dewar, Simon; Sienkiewicz, Natasha; Ong, Han B.; Wall, Richard J.; Horn, David

2016-01-01

The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells. RNA interference target sequencing experiments identified a tandem array of genes encoding a folate transporter family, TbFT1–3, as major contributors to antifolate drug uptake. RNAi knockdown of TbFT1–3 substantially reduced folate transport into trypanosomes and reduced the parasite's susceptibly to the classical antifolates methotrexate and raltitrexed. In contrast, knockdown of TbFT1–3 increased susceptibly to the non-classical antifolates pyrimethamine and nolatrexed. Both folate and methotrexate transport were inhibited by classical antifolates but not by non-classical antifolates or biopterin. Thus, TbFT1–3 mediates the uptake of folate and classical antifolates in trypanosomes, and TbFT1–3 loss-of-function is a mechanism of antifolate drug resistance. PMID:27703008

[Folates and fetal programming: role of epigenetics and epigenomics].

PubMed

Guéant, Jean-Louis; Daval, Jean-Luc; Vert, Paul; Nicolas, Jean-Pierre

2012-12-01

Folates are needed for synthesis of methionine, the precursor of S-adenosyl methionine (SAM). They play therefore a key role in nutrition and epigenomics by fluxing monocarbons towards synthesis or methylation of DNA and RNA, and methylation of gene transregulators, respectively. The deficiency produces intrauterine growth retardation and birth dejects. Folate deficiency deregulates epigenomic mechanisms related to fetal programming through decreased cellular availability of SAM. Epigenetic mechanisms of folate deficiency are illustrated by inheritance of coat colour of agouti mice model and altered expression of Igf2/H19 imprinting genes. Dietary exposure to fumonisin FB1 acts synergistically with folate deficiency on alterations of heterochromatin assembly. Deficiency in folate and vitamin B12 produces impaired fatty acid oxidation in liver and heart through imbalanced methylation and acetylation of PGC1-alpha and decreased expression of SIRT1, and long-lasting cognitive disabilities through impaired hippocampal cell proliferation, differentiation and plasticity and atrophy of hippocampal CA1. Deciphering these mechanisms will help understand the discordances between experimental models and population studies on folate supplementation.

Nutrition and the brain.

PubMed

Morley, John E

2010-02-01

Severe nutritional deficiencies, such as protein energy malnutrition and deficiency of nicotinamide, vitamin B(12), folate, and thiamine, have long been recognized to cause severe confusion. Lesser vitamin deficiencies have been linked to the pathogenesis of delirium. Hypo- and hyperglycemia and hypertriglyceridemia can cause cognitive deficits. Epidemiologic and animal studies have linked several other nutrients (omega-3 fatty acids, lutein, alpha-lipoic acid, and the Mediterranean diet) to cognitive performance and the prevention of dementia.

Vitamin A, folate, and choline as a possible preventive intervention to fetal alcohol syndrome.

PubMed

Ballard, Mark S; Sun, Muxin; Ko, Jenny

2012-04-01

It is recognized that alcohol consumption during pregnancy is associated with fetal alcohol syndrome (FAS). Alcohol can trigger a pattern of neurodegeneration in rat brains similar to other known gamma-aminobutyric acid (GABA) specific agonists. However this does not seem to explain FAS entirely, as impoverished care-giving environments have been shown to increase the risk of FAS. Individuals living under the poverty level are at risk for micronutrient deficiencies due to insufficient intake. In particular, three nutrients commonly found to be deficient are folate, choline and vitamin A. There is evidence to suggest that ethanol alone may not explain the entire spectrum of anomalies seen in individuals with FAS. It is hypothesized that FAS may be caused more by the nutritional deficiencies that are exacerbated by alcohol than by direct alcoholic neurotoxicity. It is known that ethanol inhibits folate, choline, and vitamin A/retinoic acid metabolism at multiple steps. Additionally, mice exposed to ethanol demonstrated epigenetic changes, or variations in the methylation of DNA to control gene expression. Folate is important in the production of methyl groups, which are subsequently used to create and methylate DNA. Choline (which is metabolized to acetylcholine) is important in neurotransmission and neurodevelopment. It is also involved in an alternative pathway in the production of methyl groups. In fact a study by Thomas et al. in 2009 found that nutritional supplementation with choline in rats exposed to ethanol in utero almost completely mitigated the degenerative effects of ethanol on development and behaviour. Lastly, vitamin A and retinoic acid metabolism is associated with the regulation of one sixth of the entire proteome. Thus supplementation of folate, choline and vitamin A to mothers may mitigate the effects of the alcohol and reduce the severity or prevalence of FAS. Copyright © 2012 Elsevier Ltd. All rights reserved.

Neurotoxicity induced by dexamethasone in the human neuroblastoma SH-SY5Y cell line can be prevented by folic acid.

PubMed

Budni, J; Romero, A; Molz, S; Martín-de-Saavedra, M D; Egea, J; Del Barrio, L; Tasca, C I; Rodrigues, A L S; López, M G

2011-09-08

Folic acid (folate) is a vitamin of the B-complex group that is essential for cell replication. Folate is a major determinant of one-carbon metabolism, in which S-adenosylmethionine donates methyl groups that are crucial for neurological function. Many roles for folic acid have been reported, including neuroprotective and antidepressant properties. On the other hand, increased concentrations of corticoids have proven neurotoxic effects and hypersecretion of glucocorticoids has been linked to different mood disorders. The purpose of this study was to investigate the potential protective effect of folic acid on dexamethasone-induced cellular death in SH-SY5Y neuroblastoma cell line and the possible intracellular signaling pathway involved in such effect. Exposure to 1 mM dexamethasone for 48 h caused a significant reduction of cell viability measured as 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) reduction. Exposure of SH-SY5Y cells for 72 h to increasing concentrations of folate (1-300 μM) was not cytotoxic. However, pretreatment with folate (10-300 μM) reduced dexamethasone-induced toxicity in a significant manner. To explore the putative intracellular signaling pathways implicated in the protective effect of folate we used different protein kinase inhibitors. The protective effect of folic acid on dexamethasone-induced neurotoxicity was reversed by the phosphatidylinositol-3 kinase/Akt (PI3K/Akt, LY294002), Ca²⁺/Calmodulin-dependent protein kinase II (CaMKII, KN-93), and protein kinase A (PKA, H-89) inhibitors, but not the mitogen-activated protein/extracellular signal-regulated kinase (MEK1/2, PD98059) and protein kinase C (PKC, chelerythrine) inhibitors. In conclusion, the results of this study show that folic acid can protect against dexamethasone-induced neurotoxicity and its protective mechanism is related to a signaling pathway that involves PI3K/Akt, CaMKII, and PKA. Copyright © 2011. Published by Elsevier Ltd.

Justifying the "Folate trap" in folic acid fortification programs.

PubMed

Mahajan, Niraj N; Mahajan, Kshitija N; Soni, Rajani N; Gaikwad, Nilima L

2007-01-01

Many countries have now adopted fortification, where folic acid is added to flour and intended to benefit all with rise in blood folate level. During many transformations of folate from one form to another, a proportion is accidentally converted to N(5)-methyl-THF, an inactive metabolite, the so-called "folate trap". Consideration should be given to including B(12) as well as folic acid in any program of supplementation or food fortification to prevent NTDs. This is especially applicable to developing countries like India where the majority of women are vegetarians and have borderline levels of vitamin B(12). Administration of [6S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. Therefore, we urge to reconsider the "folate trap" in folic acid fortification programs.

Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy

PubMed Central

Lee, Jessica J. Y.; Drögemoller, Britt; Shyr, Casper; Tarailo-Graovac, Maja; Eydoux, Patrice; Ross, Colin J.; Wasserman, Wyeth W.; Björnson, Bruce; Wu, John K.

2016-01-01

Distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss. Their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing. The authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151+1G>T variant in SIGMAR1. This variant was recently proposed as causal for the same condition in a consanguineous Chinese family. Compared to this family, the Afghan ethnic origin of our patient is distinct, yet the features are identical, validating the SIGMAR1 deficiency phenotype: progressive muscle wasting/weakness in lower and upper limbs without sensory loss. Rapid disease progression during adolescent growth is similar and may be due to SIGMAR1’s role in regulating axon elongation and tau phosphorylation. Finally, the authors conclude that SIGMAR1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies. PMID:28503617

Association Between Maternal Prepregnancy Body Mass Index and Plasma Folate Concentrations With Child Metabolic Health.

PubMed

Wang, Guoying; Hu, Frank B; Mistry, Kamila B; Zhang, Cuilin; Ren, Fazheng; Huo, Yong; Paige, David; Bartell, Tami; Hong, Xiumei; Caruso, Deanna; Ji, Zhicheng; Chen, Zhu; Ji, Yuelong; Pearson, Colleen; Ji, Hongkai; Zuckerman, Barry; Cheng, Tina L; Wang, Xiaobin

2016-08-01

Previous reports have linked maternal prepregnancy obesity with low folate concentrations and child overweight or obesity (OWO) in separate studies. To our knowledge, the role of maternal folate concentrations, alone or in combination with maternal OWO, in child metabolic health has not been examined in a prospective birth cohort. To test the hypotheses that maternal folate concentrations can significantly affect child metabolic health and that sufficient maternal folate concentrations can mitigate prepregnancy obesity-induced child metabolic risk. This prospective birth cohort study was conducted at the Boston Medical Center, Boston, Massachusetts. It included 1517 mother-child dyads recruited at birth from 1998 to 2012 and followed up prospectively up to 9 years from 2003 to 2014. Child body mass index z score calculated according to US reference data, OWO defined as a body mass index in the 85th percentile or greater for age and sex, and metabolic biomarkers (leptin, insulin, and adiponectin). The mean (SD) age was 28.6 (6.5) years for mothers and 6.2 (2.4) years for the children. An L-shaped association between maternal folate concentrations and child OWO was observed: the risk for OWO was higher among those in the lowest quartile (Q1) as compared with those in Q2 through Q4, with an odds ratio of 1.45 (95% CI, 1.13-1.87). The highest risk for child OWO was found among children of obese mothers with low folate concentrations (odds ratio, 3.05; 95% CI, 1.91-4.86) compared with children of normal-weight mothers with folate concentrations in Q2 through Q4 after accounting for multiple covariables. Among children of obese mothers, their risk for OWO was associated with a 43% reduction (odds ratio, 0.57; 95% CI, 0.34-0.95) if their mothers had folate concentrations in Q2 through Q4 compared with Q1. Similar patterns were observed for child metabolic biomarkers. In this urban low-income prospective birth cohort, we demonstrated an L-shaped association between maternal plasma folate concentrations and child OWO and the benefit of sufficient folate concentrations, especially among obese mothers. The threshold concentration identified in this study exceeded the clinical definition of folate deficiency, which was primarily based on the hematological effect of folate. Our findings underscore the need to establish optimal rather than minimal folate concentrations for preventing adverse metabolic outcomes in the offspring.

Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications

PubMed Central

Zetterberg, Henrik

2004-01-01

The pathogenesis of human spontaneous abortion involves a complex interaction of several genetic and environmental factors. The firm association between increased homocysteine concentration and neural tube defects (NTD) has led to the hypothesis that high concentrations of homocysteine might be embryotoxic and lead to decreased fetal viability. There are several genetic polymorphisms that are associated with defects in folate- and vitamin B12-dependent homocysteine metabolism. The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms cause elevated homocysteine concentration and are associated with an increased risk of NTD. Additionally, low concentration of vitamin B12 (cobalamin) or transcobalamin that delivers vitamin B12 to the cells of the body leads to hyperhomocysteinemia and is associated with NTD. This effect involves the transcobalamin (TC) 776C>G polymorphism. Importantly, the biochemical consequences of these polymorphisms can be modified by folate and vitamin B12 supplementation. In this review, I focus on recent studies on the role of hyperhomocysteinemia-associated polymorphisms in the pathogenesis of human spontaneous abortion and discuss the possibility that periconceptional supplementation with folate and vitamin B12 might lower the incidence of miscarriage in women planning a pregnancy. PMID:14969589

Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications.

PubMed

Zetterberg, Henrik

2004-02-17

The pathogenesis of human spontaneous abortion involves a complex interaction of several genetic and environmental factors. The firm association between increased homocysteine concentration and neural tube defects (NTD) has led to the hypothesis that high concentrations of homocysteine might be embryotoxic and lead to decreased fetal viability. There are several genetic polymorphisms that are associated with defects in folate- and vitamin B12-dependent homocysteine metabolism. The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms cause elevated homocysteine concentration and are associated with an increased risk of NTD. Additionally, low concentration of vitamin B12 (cobalamin) or transcobalamin that delivers vitamin B12 to the cells of the body leads to hyperhomocysteinemia and is associated with NTD. This effect involves the transcobalamin (TC) 776C>G polymorphism. Importantly, the biochemical consequences of these polymorphisms can be modified by folate and vitamin B12 supplementation. In this review, I focus on recent studies on the role of hyperhomocysteinemia-associated polymorphisms in the pathogenesis of human spontaneous abortion and discuss the possibility that periconceptional supplementation with folate and vitamin B12 might lower the incidence of miscarriage in women planning a pregnancy.

Peripheral neuropathy in diabetes: it's not always what it looks like.

PubMed

Maltese, G; Tan, S V; Bruno, E; Brackenridge, A; Thomas, S

2018-06-04

Hereditary Neuropathy with liability to Pressure Palsies (HNPP) is an autosomal dominant neuropathy, associated with deletion of the Peripheral Myelin Protein-22 (PMP-22) gene, causing recurrent painless palsies with age of onset between 10 and 30 years old. Only a few cases of Type 2 Diabetes and HNPP have been described and the coexistence of HNPP and Type 1 diabetes has never been reported. A 54-year old man with a history of Type 1 diabetes, managed with continuous subcutaneous insulin infusion (CSII), presented with deterioration of long-standing motor and sensory symptoms, previously attributed to golfer's elbow, diabetic neuropathy and spinal degenerative disease. He had multilevel severe spine degenerative changes and L4/L5 and L5/S1 root impingements with a L4/L5 discectomy performed when he was 25 years old. On physical examination he had normal power and distal hypoaesthesia of the digits and plantar aspect of the feet. Investigations revealed normal full blood count, liver and renal function, electrolytes, vitamin B12 and serum folate. He suffered from primary hypothyroidism and thyroid function tests indicated adequate levothyroxine replacement. Nerve conduction studies revealed a generalized demyelinating sensorimotor neuropathy, with more severe involvement of nerves over entrapment sites. Further history that his father suffered from episodes of weakness and numbness was elicited. Genetic analysis revealed one copy of the PMP22 gene at 17p11.2 confirming the diagnosis of HNPP. In people with diabetes the evaluation of peripheral neuropathy should include a careful history, a comprehensive physical examination, blood tests and in some cases nerve conduction studies and genetic testing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Folate

MedlinePlus

... Guidelines for Americans and the U.S. Department of Agriculture's MyPlate . Where can I find out more about ... on food sources of folate: U.S. Department of Agriculture's (USDA) National Nutrient Database Nutrient List for folate ( ...

TAS2R38 bitter taste genetics, dietary vitamin C, and both natural and synthetic dietary folic acid predict folate status, a key micronutrient in the pathoaetiology of adenomatous polyps.

PubMed

Lucock, Mark; Ng, Xiaowei; Boyd, Lyndell; Skinner, Virginia; Wai, Ron; Tang, Sa; Naylor, Charlotte; Yates, Zoë; Choi, Jeong-Hwa; Roach, Paul; Veysey, Martin

2011-08-01

Taste perception may influence dietary preferences and nutrient intakes contributing to diet-related disease susceptibility. This study examined bitter taste genetics and whether variation in the TAS2R38 gene at three polymorphic loci (A49P, V262A and I296V) could alter dietary and systemic folate levels and dietary vitamin C intake, and whether a nutrigenetic circuit existed that might link bitter taste, folate/antioxidant status and risk for a colonic adenomatous polyp. TAS2R38 diplotype predicted bitter taste (PROP) phenotype (p value <0.00001) and red cell folate status (p=0.0179) consistent with the diplotype that has the broadest range of bitter perception (AVI/PAV) also possessing the highest average red cell folate value. However, TAS2R38 diplotype did not predict dietary intake of methylfolic acid, pteroylmonoglutamic acid or total folic acid. Neither did it predict dietary intake of vitamin C. Despite this, intake of dietary folate predicts red cell folate with analysis pointing to a key nutrient-nutrient interaction between vitamin C intake and systemic folate status. Analysis of 38 patients with an adenomatous polyp and 164 controls showed that individually, dietary nutrient intake, nutrient status and taste diplotype did not influence polyp risk. However, red cell folate status (in individuals below the population median value) did interact with bitter taste diplotype (AVI/PAV) to predict polyp risk (p=0.0145). Furthermore, synthetic folic acid (below median intake) was statistically associated with adenoma occurrence (p=0.0215); individuals with adenomatous polyps had a 1.77× higher intake than controls. Additionally, stepwise regression taking account of all dietary nutrients showed a tight relationship between methylfolic acid (but not pteroylmonoglutamic acid) intake and red cell folate level in those with a low folate status and occurrence of an adenomatous polyp (p=0.0039). These findings point to a role for folate in the pathoaetiology of adenomatous polyps, with the natural and synthetic vitamers not necessarily having the same biological effect. This journal is © The Royal Society of Chemistry 2011

Pilot Study on Folate Bioavailability from a Camembert Cheese Reveals Contradictory Findings to Recent Results from a Human Short-term Study.

PubMed

Mönch, Sabine; Netzel, Michael; Netzel, Gabriele; Ott, Undine; Frank, Thomas; Rychlik, Michael

2016-01-01

Different dietary sources of folate have differing bioavailabilities, which may affect their nutritional "value." In order to examine if these differences also occur within the same food products, a short-term human pilot study was undertaken as a follow-up study to a previously published human trial to evaluate the relative native folate bioavailabilities from low-fat Camembert cheese compared to pteroylmonoglutamic acid as the reference dose. Two healthy human subjects received the test foods in a randomized cross-over design separated by a 14-day equilibrium phase. Folate body pools were saturated with a pteroylmonoglutamic acid supplement before the first testing and between the testings. Folates in test foods and blood plasma were analyzed by stable isotope dilution assays. The biokinetic parameters C max, t max, and area under the curve (AUC) were determined in plasma within the interval of 0-12 h. When comparing the ratio estimates of AUC and C max for the different Camembert cheeses, a higher bioavailability was found for the low-fat Camembert assessed in the present study (≥64%) compared to a different brand in our previous investigation (8.8%). It is suggested that these differences may arise from the different folate distribution in the soft dough and firm rind as well as differing individual folate vitamer proportions. The results clearly underline the importance of the food matrix, even within the same type of food product, in terms of folate bioavailability. Moreover, our findings add to the increasing number of studies questioning the general assumption of 50% bioavailability as the rationale behind the definition of folate equivalents. However, more research is needed to better understand the interactions between individual folate vitamers and other food components and the potential impact on folate bioavailability and metabolism.

Pilot Study on Folate Bioavailability from a Camembert Cheese Reveals Contradictory Findings to Recent Results from a Human Short-term Study

PubMed Central

Mönch, Sabine; Netzel, Michael; Netzel, Gabriele; Ott, Undine; Frank, Thomas; Rychlik, Michael

2016-01-01

Different dietary sources of folate have differing bioavailabilities, which may affect their nutritional “value.” In order to examine if these differences also occur within the same food products, a short-term human pilot study was undertaken as a follow-up study to a previously published human trial to evaluate the relative native folate bioavailabilities from low-fat Camembert cheese compared to pteroylmonoglutamic acid as the reference dose. Two healthy human subjects received the test foods in a randomized cross-over design separated by a 14-day equilibrium phase. Folate body pools were saturated with a pteroylmonoglutamic acid supplement before the first testing and between the testings. Folates in test foods and blood plasma were analyzed by stable isotope dilution assays. The biokinetic parameters Cmax, tmax, and area under the curve (AUC) were determined in plasma within the interval of 0–12 h. When comparing the ratio estimates of AUC and Cmax for the different Camembert cheeses, a higher bioavailability was found for the low-fat Camembert assessed in the present study (≥64%) compared to a different brand in our previous investigation (8.8%). It is suggested that these differences may arise from the different folate distribution in the soft dough and firm rind as well as differing individual folate vitamer proportions. The results clearly underline the importance of the food matrix, even within the same type of food product, in terms of folate bioavailability. Moreover, our findings add to the increasing number of studies questioning the general assumption of 50% bioavailability as the rationale behind the definition of folate equivalents. However, more research is needed to better understand the interactions between individual folate vitamers and other food components and the potential impact on folate bioavailability and metabolism. PMID:27092303

Baseline investigations of folate status in Aboriginal and non-Aboriginal West Australians prior to the introduction of mandatory fortification.

PubMed

Maxwell, Susannah J; Brameld, Kate J; Bower, Caroline; D'Antoine, Heather; Hickling, Siobhan; Marley, Julia; O'Leary, Peter

2013-02-01

In September 2009, Australia implemented mandatory folic acid fortification of wheat flour for bread-making to reduce the incidence of neural tube defects. Our study aimed to establish baseline folate status data in Aboriginal and non-Aboriginal Western Australians. Patients who presented at a health service or collection centre for blood tests were invited to participate. One hundred and ninety-one Aboriginals and 159 non-Aboriginals were recruited between April 2008 and September 2009. Participants completed a five-minute questionnaire and had blood taken for red blood cell (RBC) folate and serum vitamin B12. Data were analysed using SPSS (version 17.0.2, SPSS Inc., Chicago, IL, USA). Ten per cent (95% confidence intervals (CI): 5, 19) of the Aboriginal women participants and 26% (95% CI: 16, 40) of men had RBC folate concentrations below 250 ng/mL, the cut-off associated with folate deficiency. None of the non-Aboriginal women (95% CI: 0, 4) and 4% of the non-Aboriginal men (95% CI: 2, 12) had RBC folate concentrations below 250 ng/mL. All participants were vitamin B12 replete. None of the 96 Aboriginal and 8% of non-Aboriginal women aged 16-44 reported consumption of supplements with a daily intake of >400 μg folic acid during the previous week. This study established a baseline of RBC folate, folate consumption and supplement use in Aboriginal and non-Aboriginal groups. We identified 10% of Aboriginal women and none of non-Aboriginal women participants with low folate concentrations. The higher prevalence of folate deficiency in Aboriginal participants suggests they are more likely to benefit from a universal program of folate fortification. © 2012 The Authors ANZJOG © 2012 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Folate deficiency in north Indian children undergoing maintenance chemotherapy for acute lymphoblastic leukemia-Implications and outcome.

PubMed

Roy Moulik, Nirmalya; Kumar, Archana; Agrawal, Suraksha; Mahdi, Abbas Ali

2018-01-01

Treatment-related toxicity and mortality are not uncommon during maintenance chemotherapy for childhood acute lymphoblastic leukemia (ALL), especially in the low- and middle-income countries (LMIC). Undernutrition and micronutrient deficiencies are commonly seen in children from LMICs undergoing treatment for ALL. The present study examines the prevalence and clinical implications of folate deficiency in north Indian children with ALL during the maintenance phase of treatment in view of prolonged antifolate treatment and high population prevalence of folate deficiency. Pre-cycle folate levels/deficiency as well as weight for age z-score and serum albumin level were determined and correlated with complications of treatment and mortality encountered during the maintenance phase of treatment. Twenty-nine of 52 children enrolled in the study had folate deficiency at some point during maintenance chemotherapy. Neutropenia (18 of 29 vs. 4 of 23; P = 0.002), thrombocytopenia (17 of 29 vs. 4 of 23; P = 0.005), febrile neutropenia (17 of 29 vs. 4 of 23; P = 0.005), and need for chemotherapy dose reduction (20 of 29 vs. 7 of 21; P = 0.01) were more common in folate-deficient children. Maintenance deaths were higher (8 of 29 vs. 1 of 23; P = 0.03) and survival lower (P = 0.02) in deficient children. In multivariate analysis, hypoalbuminemia (P = 0.02) and folate deficiency (P = 0.01) were associated with febrile neutropenia, and folate deficiency with maintenance deaths (P = 0.03). Folate deficiency was associated with treatment-related complications and adverse outcome in our patients. The risks and benefits of folate supplementation in deficient children during maintenance chemotherapy need to be explored with properly designed randomized studies in similar settings. © 2017 Wiley Periodicals, Inc.

Folate Deficiency, Atopy, and Severe Asthma Exacerbations in Puerto Rican Children.

PubMed

Blatter, Joshua; Brehm, John M; Sordillo, Joanne; Forno, Erick; Boutaoui, Nadia; Acosta-Pérez, Edna; Alvarez, María; Colón-Semidey, Angel; Weiss, Scott T; Litonjua, Augusto A; Canino, Glorisa; Celedón, Juan C

2016-02-01

Little is known about folate and atopy or severe asthma exacerbations. We examined whether folate deficiency is associated with number of positive skin tests to allergens or severe asthma exacerbations in a high-risk population and further assessed whether such association is explained or modified by vitamin D status. Cross-sectional study of 582 children aged 6 to 14 years with (n = 304) and without (n = 278) asthma in San Juan, Puerto Rico. Folate deficiency was defined as plasma folate less than or equal to 20 ng/ml. Our outcomes were the number of positive skin tests to allergens (range, 0-15) in all children and (in children with asthma) one or more severe exacerbations in the previous year. Logistic and negative binomial regression models were used for the multivariate analysis. All multivariate models were adjusted for age, sex, household income, residential proximity to a major road, and (for atopy) case/control status; those for severe exacerbations were also adjusted for use of inhaled corticosteroids and vitamin D insufficiency (a plasma 25[OH]D < 30 ng/ml). In a multivariate analysis, folate deficiency was significantly associated with an increased degree of atopy and 2.2 times increased odds of at least one severe asthma exacerbation (95% confidence interval for odds ratio, 1.1-4.6). Compared with children who had normal levels of both folate and vitamin D, those with both folate deficiency and vitamin D insufficiency had nearly eightfold increased odds of one or more severe asthma exacerbation (95% confidence interval for adjusted odds ratio, 2.7-21.6). Folate deficiency is associated with increased degree of atopy and severe asthma exacerbations in school-aged Puerto Ricans. Vitamin D insufficiency may further increase detrimental effects of folate deficiency on severe asthma exacerbations.

Interaction between cytotoxic effects of gamma-radiation and folate deficiency in relation to choline reserves.

PubMed

Batra, Vipen; Devasagayam, Thomas Paul Asir

2009-01-08

The search for non-toxic radio-protective drugs has yielded many potential agents but most of these compounds have certain amount of toxicity. Recent studies have indicated that bio-molecules such as folate and choline might be of radio-protective value as they are, within broad dose ranges, non-toxic to humans and experimental animals. The objective of the present study was to investigate choline dependent adaptive response to potential synergistic cytotoxic effect of folate deficiency and gamma-radiation. Male Swiss mice maintained on folate sufficient diet (FSD) and folate free diet (FFD) based on AIN-93M formula, were subjected to 1-4Gy total body gamma-irradiation. To investigate liver DNA damage, apurinic/apyrimidinic sites (AP sites) were quantified. A significant increase in liver DNA AP sites with concomitant depletion of liver choline reserves was observed when gamma-radiation was combined with folate deficiency. Further work in this direction suggested that cytotoxic interaction between folate deficiency and gamma radiation might induce utilization of choline and choline containing moieties by modifying levels of key regulatory enzymes dihydrofolate reductase (DHFR) and choline oxidase (ChoOx). Another major finding of these studies is that significant liver damage at higher doses of radiation (3-4Gy), might release considerable amounts of choline reserves to serum. In conclusion, a plausible interpretation of the present studies is that folate deprivation and gamma-radiation interact to mobilize additional choline reserves of hepatic tissue, for redistribution to other organs, which could not be utilized by folate deficiency alone. Present results clearly indicated a distinct choline pool in liver and kidney tissues that could be utilized by folate deficient animals only under radiation stress conditions.

Folate supplementation in schizophrenia: a possible role for MTHFR genotype.

PubMed

Hill, Michele; Shannahan, Kelsey; Jasinski, Sarah; Macklin, Eric A; Raeke, Lisa; Roffman, Joshua L; Goff, Donald C

2011-04-01

Folate deficiency and the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism have been linked to negative symptoms in schizophrenia both independently and synergistically. This study examined the effect of folate supplementation on negative symptoms overall and in relation to MTHFR 677C>T genotype. Forty-six stable adult schizophrenia outpatients were enrolled and 32 were randomised, double-blind, in a parallel-group, twelve week add-on trial of folate 2mg/d or matching placebo. The primary outcome measure was change from baseline to week 12 on the modified SANS total score using a mixed-model analysis. In addition, we measured the effect of MTHFR genotype on treatment effects and on changes in serum folate by grouping participants with T/T genotype together with C/T genotype and comparing their interactions to patients with C/C genotype. Twenty-eight participants completed the trial. Folate supplementation did not significantly affect negative symptoms compared to placebo across the entire cohort. However, there was a significant genotype×treatment effect on negative symptoms (F=7.13, df=1,39, p=0.01). In addition, MTHFR status significantly moderated the relationship between change in serum folate and change in negative symptoms: among participants with at least one copy of the T allele negative symptoms were more likely to improve with increased serum folate (p=0.03). We did not detect a therapeutic benefit of folate supplementation in a sample of patients with residual negative symptoms. However, a possible association between genotypes associated with reduced MTHFR activity and benefit from folate supplementation should be investigated further. Copyright © 2010 Elsevier B.V. All rights reserved.

Plasma folate levels in early to mid pregnancy after a nation-wide folic acid supplementation program in areas with high and low prevalence of neural tube defects in China.

PubMed

Liu, Jufen; Gao, Lili; Zhang, Yali; Jin, Lei; Li, Zhiwen; Zhang, Le; Meng, Qinqin; Ye, Rongwei; Wang, Linlin; Ren, Aiguo

2015-06-01

Folic acid supplementation is recommended for all women of child-bearing age to prevent neural tube defects (NTDs). A nation-wide folic acid supplementation program was implemented in rural areas of China since 2009; however, changes in plasma folate levels in pregnant women were unknown. A cross-sectional survey was conducted in 2011 to 2012, with 1736 pregnant women enrolled, and results were compared with a previous survey in 2002 to 2004. A microbiological method was used to determine plasma folate levels. Preprogram and postprogram median plasma folate concentrations were compared while stratified by prevalence of NTDs and residence. In the high NTD prevalence population, plasma folate concentration increased to 33.4 (18.7, 58.4) nmol/L in the postprogram sample, which is 2.9 times of the preprogram. In the low NTD prevalence population, plasma folate increased to 67.9 (44.5, 101.9) nmol/L, which is 1.9 times of the preprogram. Gaps remained in plasma folate levels with respect to prevalence of NTDs and residence. Folic acid supplementation has a strong impact on plasma folate concentrations. Earlier supplementation (before the last menstrual period), increased supplementation frequency and more total days of supplementation were associated with a higher plasma folate concentration as demonstrated in both the high- and low-prevalence populations. Plasma folate levels among pregnant Chinese women increased dramatically after the nation-wide folic acid supplementation program in both rural and urban areas, and in populations of high and low NTD prevalence. The nation-wide program should have a component to ensure that supplementation begins before pregnancy. © 2015 Wiley Periodicals, Inc.

Validation of a semiquantitative food frequency questionnaire to assess folate status. Results discriminate a high-risk group of women residing on the Mexico-US border.

PubMed

Bacardí-Gascón, Montserrat; Ley y de Góngora, Silvia; Castro-Vázquez, Brenda Yuniba; Jiménez-Cruz, Arturo

2003-01-01

The purpose of the study was to estimate dietary intake of folate in two groups of women from different economic backgrounds and to evaluate validity of the 5-day-weighed food registry (5-d-WFR) and Food Frequency Questionnaire (FFQ) using biological markers. A cross-sectional study was conducted in two samples of urban Mexican women: one represented the middle socioeconomic status (middle SES) and the other, low socioeconomic status (low SES). Middle SES included 34 women recruited from 1998 to 1999. Participants were between the ages of 18 and 32 years and were employed in the banking industry (middle SES) in the US-Mexican border city of Tijuana, Baja California. Low SES included 70 women between the ages of 18 and 35 years recruited during the year 2000. These women were receiving care at a primary health care center in Ensenada, Baja California Norte State, Mexico (low SES). Pearson correlations were calculated between folate intake among 5-day diet registry, FFQ, and biochemical indices. FFQ reproducibility was performed by Spearman correlation of each food item daily and of weekly intake. Average folate intake in middle SES from 5-d-WFR was 210 microg +/- 171. Fifty four percent of participants had intakes <200 microg/daily. Average folate intake from FFQ was 223 +/- 78 microg/day. Pearson correlation between log transformed and within individually adjusted 5-d-WFR folate intakes and serum folate was 0.40 (p=0.02). Mexican women of reproductive age living in the US-Mexican border State of Baja California are at very high risk of NTDs as a result of low folate intake and low serum folate and RBC folate concentrations.

Vitamin B12 and folate during pregnancy and offspring motor, mental and social development at 2 years of age.

PubMed

Bhate, V K; Joshi, S M; Ladkat, R S; Deshmukh, U S; Lubree, H G; Katre, P A; Bhat, D S; Rush, E C; Yajnik, C S

2012-04-01

Insufficiency of vitamin B12 (B12) and folate during pregnancy can result in low concentrations in the fetus and have adverse effects on brain development. We investigated the relationship between maternal B12 and folate nutrition during pregnancy and offspring motor, mental and social development at two years of age (2 y). Mothers (n = 123) and their offspring (62 girls, 61 boys) from rural and middle-class urban communities in and around Pune city were followed through pregnancy up to 2 y. Maternal B12 and folate concentrations were measured at 28 and 34 weeks of gestation. At 2 y, the Developmental Assessment Scale for Indian Infants was used to determine motor and mental developmental quotients and the Vineland Social Maturity Scale for the social developmental quotient. Overall, 62% of the mothers had low B12 levels (<150 pmol/l) and one mother was folate deficient during pregnancy. Maternal B12 at 28 and 34 weeks of gestation was associated with offspring B12 at 2 y (r = 0.29, r = 0.32, P < 0.001), but folate was not associated with offspring folate. At 2 y, motor development was associated with maternal folate at 28 and 34 weeks of gestation. Mental and social development quotients were associated positively with head circumference and negatively with birth weight. In addition, pregnancy B12 and folate were positively associated with mental and social development quotients. Maternal B12 and folate during intrauterine life may favorably influence brain development and function. Pregnancy provides a window of opportunity to enhance fetal psychomotor (motor and mental) development.

Polymorphisms of 5,10-methylenetetrahydrofolate reductase and thymidylate synthase, dietary folate intake, and the risk of leukemia in adults.

PubMed

Liu, Ping; Zhang, Min; Xie, Xing; Jin, Jie; Holman, C D'Arcy J

2016-03-01

The 5,10-methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) are critical enzymes in folate metabolism. Previous studies have reported conflicting results on the associations between MTHFR/TS polymorphisms and adult leukemia risk, which may due to the lack of information on folate intake. We investigated the risks of adult leukemia with genetic polymorphisms of folate metabolic enzymes (MTHFR C677T, A1298C, and TS) and evaluated if the associations varied by dietary folate intake from a multicenter case-control study conducted in Chinese. This study comprised 442 incident adult leukemia cases and 442 outpatient controls, individually matched to cases by gender, birth quinquennium, and study site. Genotypes were determined by a polymerase chain reaction (PCR) or PCR-based restriction fragment length polymorphism assay. Dietary folate intake was assessed by face-to-face interviews using a validated food-frequency questionnaire. The MTHFR 677TT genotype conferred a significant higher risk of leukemia in males than in females and exhibited an increased risk of acute myeloid leukemia (AML) but a decreased risk of acute lymphoblastic leukemia (ALL). The MTHFR 1298AC genotype appeared to decrease the risks of leukemia in both genders, in AML and ALL. Stratified analysis by dietary folate intake showed the increased risks of leukemia with the MTHFR 677TT and TS 2R3R/2R2R genotypes were only significant in individuals with low folate intake. A significant interaction between TS polymorphism and dietary folate intake was observed (P = 0.03). This study suggests that dietary folate intake and gender may modify the associations between MTHFR/TS polymorphisms and adult leukemia risk.

Serum and erythrocyte folate status of New Zealand women of childbearing age following a countrywide voluntary programme by the baking industry to fortify bread with folic acid.

PubMed

Bradbury, Kathryn E; Williams, Sheila M; Mann, Jim I; Oey, Indrawati; Aitchison, Cindy; Parnell, Winsome; Fleming, Liz; Brown, Rachel C; Skeaff, C Murray

2016-11-01

To estimate the folate status of New Zealand women of childbearing age following the introduction, in 2010, of a new voluntary folic acid fortification of bread programme. The 2011 Folate and Women's Health Survey was a cross-sectional survey of women aged 18-44 years carried out in 2011. The survey used a stratified random sampling technique with the Electoral Roll as the sampling frame. Women were asked about consumption of folic-acid-fortified breads and breakfast cereals in a telephone interview. During a clinic visit, blood was collected for serum and erythrocyte folate measurement by microbiological assay. A North Island (Wellington) and South Island (Dunedin) city centre in New Zealand. Two hundred and eighty-eight women, of whom 278 completed a clinic visit. Geometric mean serum and erythrocyte folate concentrations were 30 nmol/l and 996 nmol/l, respectively. Folate status was 30-40 % higher compared with women of childbearing age sampled as part of a national survey in 2008/09, prior to the introduction of the voluntary folic acid bread fortification programme. In the 2011 Folate and Women's Health Survey, reported consumption of fortified bread and fortified breakfast cereal in the past week was associated with 25 % (P=0·01) and 15 % (P=0·04) higher serum folate concentrations, respectively. Serum and erythrocyte folate concentrations have increased in New Zealand women of childbearing age since the number of folic-acid-fortified breads was increased voluntarily in 2010. Consumption of fortified breads and breakfast cereals was associated with a higher folate status.

Plasma folate, related genetic variants, and colorectal cancer risk in EPIC.

PubMed

Eussen, Simone J P M; Vollset, Stein Emil; Igland, Jannicke; Meyer, Klaus; Fredriksen, Ase; Ueland, Per Magne; Jenab, Mazda; Slimani, Nadia; Boffetta, Paolo; Overvad, Kim; Tjønneland, Anne; Olsen, Anja; Clavel-Chapelon, Françoise; Boutron-Ruault, Marie-Christine; Morois, Sophie; Weikert, Cornelia; Pischon, Tobias; Linseisen, Jakob; Kaaks, Rudolf; Trichopoulou, Antonia; Zilis, Demosthenes; Katsoulis, Michael; Palli, Domenico; Berrino, Franco; Vineis, Paolo; Tumino, Rosario; Panico, Salvatore; Peeters, Petra H M; Bueno-de-Mesquita, H Bas; van Duijnhoven, Fränzel J B; Gram, Inger Torhild; Skeie, Guri; Lund, Eiliv; González, Carlos A; Martínez, Carmen; Dorronsoro, Miren; Ardanaz, Eva; Navarro, Carmen; Rodríguez, Laudina; Van Guelpen, Bethany; Palmqvist, Richard; Manjer, Jonas; Ericson, Ulrika; Bingham, Sheila; Khaw, Kay-Tee; Norat, Teresa; Riboli, Elio

2010-05-01

A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort. In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber. Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% confidence interval; Ptrend) for the fifth versus the first quintile of folate status was 0.94 (0.74-1.20; 0.44). The polymorphisms MTHFR677C-->T, MTHFR1298A-->C, MTR2756A-->G, MTRR66A-->G, and MTHFD11958G-->A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically nonsignificant increased CRC risk [RR (95% CI; Ptrend) TT versus CC=1.39 (0.87-2.21); 0.12], whereas those with the highest folate concentrations showed a nonsignificant decreased CRC risk [RR TT versus CC=0.74 (0.39-1.37); 0.34]. The SLC19A180G-->A showed a positive association with CRC risk [RR AA versus GG 1.30 (1.06-1.59); <0.01]. This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms. Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions. Copyright (c) 2010 AACR

Identification of Transport-critical Residues in a Folate Transporter from the Folate-Biopterin Transporter (FBT) Family*

PubMed Central

Eudes, Aymerick; Kunji, Edmund R. S.; Noiriel, Alexandre; Klaus, Sebastian M. J.; Vickers, Tim J.; Beverley, Stephen M.; Gregory, Jesse F.; Hanson, Andrew D.

2010-01-01

The Synechocystis Slr0642 protein and its plastidial Arabidopsis (Arabidopsis thaliana) ortholog At2g32040 belong to the folate-biopterin transporter (FBT) family within the major facilitator superfamily. Both proteins transport folates when expressed in Escherichia coli. Because the structural requirements for transport activity are not known for any FBT protein, we applied mutational analysis to identify residues that are critical to transport and interpreted the results using a comparative structural model based on E. coli lactose permease. Folate transport was assessed via the growth of an E. coli pabA abgT strain, which cannot synthesize or take up folates or p-aminobenzoylglutamate. In total, 47 residues were replaced with Cys or Ala. Mutations at 22 positions abolished folate uptake without affecting Slr0642 expression in membranes, whereas other mutations had no effect. Residues important for function mostly line the predicted central cavity and are concentrated in the core α-helices H1, H4, H7, and H10. The essential residue locations are consistent with a folate-binding site lying roughly equidistant from both faces of the transporter. Arabidopsis has eight FBT proteins besides At2g32040, often lacking conserved critical residues. When six of these proteins were expressed in E. coli or in Leishmania folate or pterin transporter mutants, none showed evidence of folate or pterin transport activity, and only At2g32040 was isolated by functional screening of Arabidopsis cDNA libraries in E. coli. Such negative data could reflect roles in transport of other substrates. These studies provide the first insights into the native structure and catalytic mechanism of FBT family carriers. PMID:19923217

Folate, Alcohol, and Liver Disease

PubMed Central

Medici, Valentina; Halsted, Charles H.

2013-01-01

Alcoholic liver disease (ALD) is typically associated with folate deficiency, which is the result of reduced dietary folate intake, intestinal malabsorption, reduced liver uptake and storage, and increased urinary folate excretion. Folate deficiency favors the progression of liver disease through mechanisms that include its effects on methionine metabolism with consequences for DNA synthesis and stability and the epigenetic regulation of gene expression involved in pathways of liver injury. This paper reviews the pathogenesis of alcoholic liver disease with particular focus on ethanol-induced alterations in methionine metabolism which may act in synergy with folate deficiency to decrease antioxidant defense as well as DNA stability while regulating epigenetic mechanisms of relevant gene expressions. We also review the current evidence available on potential treatments of alcoholic liver disease based on correcting abnormalities in methionine metabolism and the methylation regulation of relevant gene expressions. PMID:23136133

[Serum folate levels in adolescent population in Madrid, Spain].

PubMed

Gil, Ruth; Esteban, Jesús; Hernández, Valentín; Cano, Beatriz; de Oya, Manuel; Gil, Angel

2008-10-25

Serum folate concentrations in children are essential to establish values which allow to compare different regions or countries, and raise the possibility of fortifying diet with group B vitamins and folic acid as a secondary prevention against cardiovascular diseases. A cross-sectional epidemiological study was performed to assess serum folate levels in school children, aged 13-15 years, in Madrid. Folate and vitamin B12 determinations were determined in blood samples of fasting children. Genotype C677T of methylentetrahydrofolate reductase (MTHFR) enzyme was determined by polymerase chain reaction. Average folate levels obtained in our study were 7.83 nmol/l (95% confidence interval, 7.42 to 8.23 nmol/l). Median was 6.89 nmol/l (interquartilic range: 5.30 to -9.30 nmol/l). No statistically significant differences were found by gender, age or presence of menstruation. Serum folate concentration decreased significantly with the mutation of the C677T genotype for MTHFR. Prevalence of deficits of folate (< 5.3 nmol/l) was 23.8% and raised significantly with the mutation of the C677T genotype for MTHFR: 18.8% for CC, 20.4% for CT, and 46.7% for TT. This effect was mainly observed in girls after menstruation. Homozygosis mutation in C677T genotype of the enzyme MTHFR induces lower folate levels, mainly in girls after menstruation. 5.3 nmol/l is proposed as a threshold to define deficient serum folate levels in the Spanish adolescent population.

Arthritis imaging using a near-infrared fluorescence folate-targeted probe

PubMed Central

Chen, Wei-Tsung; Mahmood, Umar; Weissleder, Ralph; Tung, Ching-Hsuan

2005-01-01

A recently developed near-infrared fluorescence-labeled folate probe (NIR2-folate) was tested for in vivo imaging of arthritis using a lipopolysaccharide intra-articular injection model and a KRN transgenic mice serum induction mouse model. In the lipopolysaccharide injection model, the fluorescence signal intensity of NIR2-folate (n = 12) and of free NIR2 (n = 5) was compared between lipopolysaccharide-treated and control joints. The fluorescence signal intensity of the NIR2-folate probe at the inflammatory joints was found to be significantly higher than the control normal joints (up to 2.3-fold, P < 0.001). The NIR2-free dye injection group showed a persistent lower enhancement ratio than the NIR2-folate probe injection group. Excessive folic acid was also given to demonstrate a competitive effect with the NIR2-folate. In the KRN serum transfer model (n = 4), NIR2-folate was applied at different time points after serum transfer, and the inflamed joints could be detected as early as 30 hours after arthritogenic antibody transfer (1.8-fold increase in signal intensity). Fluorescence microscopy, histology, and immunohistochemistry validated the optical imaging results. We conclude that in vivo arthritis detection was feasible using a folate-targeted near-infrared fluorescence probe. This receptor-targeted imaging method may facilitate improved arthritis diagnosis and early assessment of the disease progress by providing an in vivo characterization of active macrophage status in inflammatory joint diseases. PMID:15743478

Epigenetic Mechanisms of Folate Nutrition in Breast Cancer

DTIC Science & Technology

2011-04-01

relationships between folate , one carbon metabolism, DNA methylation and gene expression within the context of breast cancer. Our hypothesis is that the...lentivirus plasmids containing miRNA against DHFR and AHCY. 2. Test effects of folate deficiency on global and gene specific DNA methylation and gene...including mammary tumors. The B vitamin folate is required for the synthesis of purines, thymidine, and S-adenosylmethionine (SAM), the methyl donor for DNA

Small Arteriovenous Malformation of the Common Bile Duct Causing Hemobilia in a Patient with Hereditary Hemorrhagic Telangiectasia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayashi, Sadao, E-mail: hayashi@m.kufm.kagoshima-u.ac.jp; Baba, Yasutaka; Ueno, Kazuto

We report a 54-year-old male patient with arteriovenous malformation located at the common bile duct and hereditary hemorrhagic telangiectasia. The patient was treated as gallstone pancreatitis at first. Three days after endoscopic nasobiliary drainage (ENBD) for biliary drainage to subside gallstone pancreatitis, hemobilia was drained from the ENBD tube and the serum hemoglobin level gradually decreased. Cholangioscopy and angiography revealed that hemobilia was due to a small arteriovenous malformation located at the common bile duct. Subsequently, the patient was successfully treated by endovascular intervention.

Effect of Pre-treatment Nutritional Status, Folate and Vitamin B12 Levels on Induction Chemotherapy in Children with Acute Lymphoblastic Leukemia.

PubMed

Tandon, Sneha; Moulik, Nirmalya Roy; Kumar, Archana; Mahdi, Abbas Ali; Kumar, Ashutosh

2015-05-01

To evaluate pre-treatment undernutrition, and folate and B12 deficiency in children with acute lymphoblastic leukemia, and their correlation with complications and outcome of induction chemotherapy. Observational study. Tertiary care teaching hospital in Northern India. 50 children with acute lymphoblastic leukemia. Children were assessed for nutritional status (Weight for age Z-score, serum albumin, folate and B12) at presentation, and were followed-up during induction for bone marrow response, counts and outcome. Folate and B12 were repeated twice at monthly intervals after induction. Univariate and multivariate analyses were done to determine the association of nutritional parameters with the outcome variables. Baseline undernutrition was observed in 66%, hypo-albuminemia in 32.6%, folate deficiency in 41.3% and B12 deficiency in 36.9% of included children. Significant decline in folate levels was noted on serial assays during chemotherapy (P=0.001). Folate deficient children had higher risk for delayed marrow recovery and counts on day 14 (P=0.007 and P=0.001). Hypoalbuminemia (P=0.04), B12 deficiency (P=0.001) and folate (P=0.03) deficiency were associated with toxic deaths during induction. Baseline nutritional deficiencies negatively influence the outcome and occurrence of complications during induction chemotherapy in children with acute lymphoblastic leukemia.

Longitudinal change in plasma total homocysteine during pregnancy and postpartum in Brazilian women and its relation with folate status and other factors.

PubMed

Glorimar, R; Pereira, S E A; Trugo, N M F

2004-03-01

Fasting plasma total homocysteine (tHcy) concentration was determined in a cohort of pregnant Brazilian women (n = 46) supplemented with folic acid from the second trimester of pregnancy. Blood samples were obtained in the first and third trimesters from all women, and 30-40 days postpartum from seventeen women. Plasma tHcy decreased during pregnancy from 10.3 to 8.7 micromol/L, and was 11.6 micromol/L in the postpartum. Plasma and erythrocyte folate increased, consistent with use of the folate supplement, but decreased slightly in the postpartum, whereas the opposite occurred for plasma vitamin B12. tHcy was inversely correlated with plasma and erythrocyte folate in the third trimester (r = -0.585 and -0.460, respectively). This relationship occurred despite the fact that all women had attained what could be considered adequate levels of folate indices. Furthermore, the change (third trimester minus first trimester levels) of tHcy was inversely correlated (p < 0.01) with the changes in plasma (r = -0.573) and erythrocyte folate (r = -0.525). tHcy had no correlation in any of the periods tested with plasma vitamin B12, plasma albumin, hematocrit, hemoglobin, iron indices, dietary intakes of folate, vitamins B12 and B6, and levels of folate supplement.

Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition.

PubMed

Wibowo, Ardian S; Singh, Mirage; Reeder, Kristen M; Carter, Joshua J; Kovach, Alexander R; Meng, Wuyi; Ratnam, Manohar; Zhang, Faming; Dann, Charles E

2013-09-17

Antifolates, folate analogs that inhibit vitamin B9 (folic acid)-using cellular enzymes, have been used over several decades for the treatment of cancer and inflammatory diseases. Cellular uptake of the antifolates in clinical use occurs primarily via widely expressed facilitative membrane transporters. More recently, human folate receptors (FRs), high affinity receptors that transport folate via endocytosis, have been proposed as targets for the specific delivery of new classes of antifolates or folate conjugates to tumors or sites of inflammation. The development of specific, FR-targeted antifolates would be accelerated if additional biophysical data, particularly structural models of the receptors, were available. Here we describe six distinct crystallographic models that provide insight into biological trafficking of FRs and distinct binding modes of folate and antifolates to these receptors. From comparison of the structures, we delineate discrete structural conformations representative of key stages in the endocytic trafficking of FRs and propose models for pH-dependent conformational changes. Additionally, we describe the molecular details of human FR in complex with three clinically prevalent antifolates, pemetrexed (also Alimta), aminopterin, and methotrexate. On the whole, our data form the basis for rapid design and implementation of unique, FR-targeted, folate-based drugs for the treatment of cancer and inflammatory diseases.

A food industry perspective on folic acid fortification.

PubMed

Schaller, D R; Olson, B H

1996-03-01

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

Vitamin B12 and folate levels in long-term vegans.

PubMed

Bar-Sella, P; Rakover, Y; Ratner, D

1990-06-01

Serum vitamin B12, serum folate and red blood cell (RBC) folate levels were examined among 36 strict vegans of 5-35 years' duration. Vitamin B12 levels among the vegans were generally lower than in a control population. Most of the vegans had vitamin B12 values less than 200 pg/ml. RBC folate levels were normal but serum folate levels among the vegans were higher than among the controls. None of the vegans had any hematologic evidence of vitamin B12 deficiency, however four of them had neurologic complaints. Long-standing vegans should be monitored for vitamin B12 levels.

Folate content in fresh-cut vegetable packed products by 96-well microtiter plate microbiological assay.

PubMed

Fajardo, Violeta; Alonso-Aperte, Elena; Varela-Moreiras, Gregorio

2015-02-15

Ready-to-eat foods have nowadays become a significant portion of the diet. Accordingly, nutritional composition of these food categories should be well-known, in particular its folate content. However, there is a broad lack of folate data in food composition tables and databases. A total of 21 fresh-cut vegetable and fruit packed products were analysed for total folate (TF) content using a validated method that relies on the folate-dependent growth of chloramphenicol-resistant Lactobacillus casei subspecies rhamnosus (NCIMB 10463). Mean TF content ranged from 10.0 to 140.9μg/100g for the different matrices on a fresh weight basis. Higher TF quantity, 140.9-70.1μg/100g, was found in spinach, rocket, watercress, chard and broccoli. Significant differences were observed between available data for fresh vegetables and fruits from food composition tables or databases and the analysed results for fresh-cut packed products. Supplied data support the potential of folate-rich fresh-cut ready-to-eat vegetables to increase folate intake significantly. Copyright © 2014 Elsevier Ltd. All rights reserved.

Maternal folic acid-deficient diet causes congenital malformations in the mouse eye.

PubMed

Maestro-de-las-Casas, Carmen; Pérez-Miguelsanz, Juliana; López-Gordillo, Yamila; Maldonado, Estela; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Martínez-Álvarez, Concepción

2013-09-01

The eye is a very complex structure derived from the neural tube, surface ectoderm, and migratory mesenchyme from a neural crest origin. Because structures that evolve from the neural tube may be affected by a folate/folic acid (FA) deficiency, the aim of this work was to investigate whether a maternal folic acid-deficient diet may cause developmental alterations in the mouse eye. Female C57BL/6J mice (8 weeks old) were assigned into two different folic acid groups for periods ranging between 2 and 16 weeks. Animals were killed at gestation day 17. Hepatic folate was analyzed, and the eyes from 287 fetuses were macroscopically studied, sectioned and immunolabeled with anti-transforming growth factor (TGF)-β2 and anti-TGF-βRII. Mice exposed to a FA-deficient diet exhibited numerous eye macroscopic anomalies, such as anophthalmia and microphthalmia. Microscopically, the eye was the most affected organ (43.7% of the fetuses). The highest incidence of malformations occurred from the 8th week onward. A statistically significant linear association between the number of maternal weeks on the FA-deficient diet and embryonic microscopic eye malformations was observed. The optic cup derivatives and structures forming the eye anterior segment showed severe abnormalities. In addition, TGF-β2 and TGF-βRII expression in the eye was also altered. This study suggests that an adequate folic acid/folate status plays a key role in the formation of ocular tissues and structures, whereas a vitamin deficiency is negatively associated with a normal eye development even after a short-term exposure. Copyright © 2013 Wiley Periodicals, Inc.

Diabetes insipidus

MedlinePlus

... may be caused by: Certain drugs, such as lithium Genetic problems High level of calcium in the ... years of use of some medicines, such as lithium, nephrogenic DI can be permanent. Hereditary nephrogenic DI ...

Maternal Folate Intake during Pregnancy and Childhood Asthma in a Population-based Cohort.

PubMed

Parr, Christine L; Magnus, Maria C; Karlstad, Øystein; Haugen, Margaretha; Refsum, Helga; Ueland, Per M; McCann, Adrian; Nafstad, Per; Håberg, Siri E; Nystad, Wenche; London, Stephanie J

2017-01-15

A potential adverse effect of high folate intake during pregnancy on children's asthma development remains controversial. To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age 7 years when the diagnosis is more reliable than at preschool age. This study included eligible children born 2002-2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age 7 was defined by asthma medications dispensed at least twice in the year (1,901 cases; n = 39,846) or by maternal questionnaire report (1,624 cases; n = 28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. Risk of asthma was increased in the highest versus lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval, 1.06-1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median, 308; interquartile range, 241-366 μg/d) and nearly all took at least 400 μg/d of supplemental folic acid (median, 500; interquartile range, 400-600 μg/d). In this large prospective population-based cohort with essentially complete follow-up, pregnant women taking supplemental folic acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level associated with a slightly increased risk of asthma in children.

Dietary choline and folate relationships with serum hepatic inflammatory injury markers in Taiwanese adults.

PubMed

Cheng, Chin-Pao; Chen, Chien-Hung; Kuo, Chang-Sheng; Kuo, Hsing-Tao; Huang, Kuang-Ta; Shen, Yu-Li; Chang, Chin-Hao; Huang, Rwei Fen S

The relationships of dietary choline and folate intake with hepatic function have yet to be established in the Taiwanese population. We investigated the associations of choline and folate intake with hepatic inflammatory injury in Taiwanese adults. Blood samples and data on dietary choline components and folate intake from 548 Taiwanese adults without pathological liver disease were collected. Dietary intake was derived using a semiquantitative food-frequency questionnaire. Serum liver injury markers of alanine transaminase, aspartate transaminase, and hepatitis viral infection were measured. Elevated serum hepatic injury markers (>40 U/L) were associated with low folate and free choline intake (p<0.05). Folate intake was the most significant dietary determinant of serum aspartate transaminase concentration (beta=-0.05, p=0.04), followed by free choline intake (beta=-0.249, p=0.055). Folate intake exceeding the median level (268 μg/d) was correlated with a reduced rate of hepatitis viral infection (p=0.032) and with normalized serum aspartate transaminase (odds ratio [OR]=0.998, 95% confidence interval [CI]=0.996-1, p=0.042) and alanine transaminase (OR=0.998, 95% CI=0.007-1, p=0.019). Total choline intake exceeding the median level (233 mg/d) was associated with normalized serum aspartate transaminase (OR=0.518, 95% CI=0.360-0.745, p=0.018). The newly established relationships of dietary intake of total choline and folate with normalized hepatic inflammatory markers can guide the development of dietary choline and folate intake recommendations for Taiwanese adults.

Reduced levels of folate transporters (PCFT and RFC) in membrane lipid rafts result in colonic folate malabsorption in chronic alcoholism.

PubMed

Wani, Nissar Ahmad; Kaur, Jyotdeep

2011-03-01

We studied the effect of chronic ethanol ingestion on folate transport across the colonic apical membranes (CAM) in rats. Male Wistar rats were fed 1 g/kg body weight/day ethanol (20%) solution orally for 3 months and folate transport was studied in the isolated colon apical membrane vesicles. The folate transport was found to be carrier mediated, saturable, with pH optima at 5.0. Chronic ethanol ingestion reduced the folate transport across the CAM by decreasing the affinity of transporters (high Km) for the substrate and by decreasing the number of transporter molecules (low Vmax) on the colon luminal surface. The decreased transport activity at the CAM was associated with down-regulation of the proton-coupled folate transporter (PCFT) and the reduced folate carrier (RFC) which resulted in decreased PCFT and RFC protein levels in the colon of rats fed alcohol chronically. Moreover, the PCFT and the RFC were found to be distributed in detergent insoluble fraction of the CAM in rats. Floatation experiments on Optiprep density gradients demonstrated the association of the PCFT and the RFC protein with lipid rafts (LR). Chronic alcoholism decreased the PCFT and the RFC protein levels in the CAM LR in accordance with the decreased synthesis. Hence, we propose that downregulation in the expression of the PCFT and the RFC in colon results in reduced levels of these transporters in colon apical membrane LR as a mechanism of folate malabsorption during chronic alcoholism. Copyright © 2010 Wiley-Liss, Inc.

Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study123

PubMed Central

Wallace, Julie MW; Bonham, Maxine P; Strain, JJ; Duffy, Emeir M; Robson, Paula J; Ward, Mary; McNulty, Helene; Davidson, Philip W; Myers, Gary J; Shamlaye, Conrad F; Clarkson, Tom W; Molloy, Anne M; Scott, John M; Ueland, Per M

2008-01-01

Background Both folate and betaine are important predictors of total homocysteine (tHcy) during pregnancy. However, studies to date have only been undertaken in populations with Western dietary patterns. Objective We investigated the predictors of tHcy in pregnant women recruited in the Seychelles, a population where access to fortified foods is limited and where women habitually consume diets rich in fish, eggs, rice, and fruit. Design Pregnant women (n = 226) provided blood samples at enrollment, at week 28 of gestation, and at delivery. Cord blood was obtained from a subset of participants (n = 135). Results As in other studies, maternal tHcy was lower during pregnancy than at delivery, whereas folate and vitamin B-12 status declined significantly to delivery. Despite low maternal folate status at delivery (median: 9.0 nmol/L), with 35% of women in the deficient range (serum folate: <6.8 nmol/L), cord blood folate status (median: 40.2 nmol/L) was similar to concentrations reported in Western populations. Folate was a significant predictor of tHcy at all time points (P < 0.001). In contrast with previous studies, betaine was only a significant predictor of maternal tHcy (P < 0.001) when the essential amino acid methionine was low. Conclusions The current study reports 2 important findings. First, fetal requirements for folate are paramount, such that cord blood folate status is maintained, even when maternal status is low. Second, betaine is a significant predictor of tHcy in pregnant women with low serum folate and low serum methionine concentrations. PMID:18258630

Homocysteine concentration, related B vitamins, and betaine in pregnant women recruited to the Seychelles Child Development Study.

PubMed

Wallace, Julie Mw; Bonham, Maxine P; Strain, Jj; Duffy, Emeir M; Robson, Paula J; Ward, Mary; McNulty, Helene; Davidson, Philip W; Myers, Gary J; Shamlaye, Conrad F; Clarkson, Tom W; Molloy, Anne M; Scott, John M; Ueland, Per M

2008-02-01

Both folate and betaine are important predictors of total homocysteine (tHcy) during pregnancy. However, studies to date have only been undertaken in populations with Western dietary patterns. We investigated the predictors of tHcy in pregnant women recruited in the Seychelles, a population where access to fortified foods is limited and where women habitually consume diets rich in fish, eggs, rice, and fruit. Pregnant women (n = 226) provided blood samples at enrollment, at week 28 of gestation, and at delivery. Cord blood was obtained from a subset of participants (n = 135). As in other studies, maternal tHcy was lower during pregnancy than at delivery, whereas folate and vitamin B-12 status declined significantly to delivery. Despite low maternal folate status at delivery (median: 9.0 nmol/L), with 35% of women in the deficient range (serum folate: <6.8 nmol/L), cord blood folate status (median: 40.2 nmol/L) was similar to concentrations reported in Western populations. Folate was a significant predictor of tHcy at all time points (P < 0.001). In contrast with previous studies, betaine was only a significant predictor of maternal tHcy (P < 0.001) when the essential amino acid methionine was low. The current study reports 2 important findings. First, fetal requirements for folate are paramount, such that cord blood folate status is maintained, even when maternal status is low. Second, betaine is a significant predictor of tHcy in pregnant women with low serum folate and low serum methionine concentrations.

Lower Circulating Folate Induced by a Fidgetin Intronic Variant Is Associated With Reduced Congenital Heart Disease Susceptibility.

PubMed

Wang, Dan; Wang, Feng; Shi, Kai-Hu; Tao, Hui; Li, Yang; Zhao, Rui; Lu, Han; Duan, Wenyuan; Qiao, Bin; Zhao, Shi-Min; Wang, Hongyan; Zhao, Jian-Yuan

2017-05-02

Folate deficiency is an independent risk factor for congenital heart disease (CHD); however, the maternal plasma folate level is paradoxically not a good diagnostic marker. Genome-wide surveys have identified variants of nonfolate metabolic genes associated with the plasma folate level, suggesting that these genetic polymorphisms are potential risk factors for CHD. To examine the effects of folate concentration-related variations on CHD risk in the Han Chinese population, we performed 3 independent case-control studies including a total of 1489 patients with CHD and 1745 control subjects. The expression of the Fidgetin (FIGN) was detected in human cardiovascular and decidua tissue specimens with quantitative real-time polymerase chain reaction and Western blotting. The molecular mechanisms were investigated by luciferase reporter assays, surface plasmon resonance, and chromatin immunoprecipitation. FIGN-interacting proteins were confirmed by tandem affinity purification and coimmunoprecipitation. Proteasome activity and metabolite concentrations in the folate pathway were quantified with a commercial proteasome activity assay and immunoassays, respectively. The +94762G>C (rs2119289) variant in intron 4 of the FIGN gene was associated with significant reduction in CHD susceptibility ( P =5.1×10 -14 for the allele, P =8.5×10 --13 for the genotype). Analysis of combined samples indicated that CHD risks in individuals carrying heterozygous (GC) or homozygous (CC) genotypes were reduced by 44% (odds ratio [OR]=0.56; 95% confidence interval [CI]=0.47-0.67) and 66% (OR=0.34; 95% CI=0.23-0.50), respectively, compared with those with the major GG genotype. Minor C allele carriers who had decreased plasma folate levels exhibited significantly increased FIGN expression because the transcription suppressor CREB1 did not bind the alternative promoter of FIGN isoform X3. Mechanistically, increased FIGN expression led to the accumulation of both reduced folate carrier 1 and dihydrofolate reductase via inhibition of their proteasomal degradation, which promoted folate absorption and metabolism. We report a previously undocumented finding that decreased circulating folate levels induced by increased folate transmembrane transport and utilization, as determined by the FIGN intronic variant, serves as a protective mechanism against CHD. Our results may explain why circulating folate levels do not have a good diagnostic value. © 2017 American Heart Association, Inc.

Effects of antineoplastic drugs on Lactobacillus casei and radioisotopic assays for serum folate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carmel, R.

1978-02-01

Microbiologic assay, usually employing Lactobacillus casei, remains the standard assay for serum folate to date. Among its disadvantages have been falsely low results in patients receiving bacteriostatic agents such as antibiotics. This study examined whether commonly used antineoplastic drugs had similar effect. Methotrexate and 5-fluorouracil depressed microbiologic serum folate levels. No effect was found for adriamycin, bleomycin, BCNU, cyclophosphamide, cytosine arabinoside, vincristine, vinblastine, mechlorethamine, mithramycin, hydroxyurea, and hydrocortisone. None of the drugs affected radioassay except methotrexate, which produced falsely high folate results. Thus, it appears that L. casei assay for folate becomes unreliable in patients receiving 5-fluorouracil and radioisotopic assaymore » becomes unreliable in those receiving methotrexate.« less

The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress.

PubMed

Chao de la Barca, Juan Manuel; Simard, Gilles; Amati-Bonneau, Patrizia; Safiedeen, Zainab; Prunier-Mirebeau, Delphine; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Gueguen, Naïg; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Ferré, Marc; Bris, Céline; Kouassi Nzoughet, Judith; Bocca, Cinzia; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Lenaers, Guy; Martinez, M Carmen; Procaccio, Vincent; Reynier, Pascal

2016-11-01

Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q 2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as the greater expression of C/EBP homologous protein and the increased XBP1 splicing, in fibroblasts from affected patients, all these changes being reversed by the endoplasmic reticulum stress inhibitor, TUDCA (tauroursodeoxycholic acid). Thus, our metabolomic analysis reveals a pharmacologically-reversible endoplasmic reticulum stress in complex I-related Leber's hereditary optic neuropathy fibroblasts, a finding that may open up new therapeutic perspectives for the treatment of Leber's hereditary optic neuropathy with endoplasmic reticulum-targeting drugs. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Confocal Raman microspectroscopic study of folate receptor-targeted delivery of 6-mercaptopurine-embedded gold nanoparticles in a single cell.

PubMed

Park, Jin; Jeon, Won Il; Lee, So Yeong; Ock, Kwang-Su; Seo, Ji Hye; Park, Jinho; Ganbold, Erdene-Ochir; Cho, Keunchang; Song, Nam Woong; Joo, Sang-Woo

2012-05-01

We investigate the cellular uptake behaviors and efficacy of folate-coated gold nanoparticles (AuNPs) for the targeted drug delivery system in human cancer cells. Folate-conjugated AuNPs embedded with a purine analogue cancer drug of 6-mercaptopurine (6MP) were assembled via a 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) coupling reaction between the amino group of 4-aminobenzenethiol (ABT) and the carboxyl group of folic acid. The assembly of folate and 6MP on AuNPs has been examined by absorption spectroscopy, transmission electron microscopy (TEM), and confocal Raman spectroscopy. The internalization of the conjugated AuNPs inside the folate receptor-positive HeLa and KB cells was checked by TEM and dark-field microscopy (DFM) combined with label-free confocal spectroscopy over the depth variable z at a micrometer resolution. DFM live cell imaging of folate-conjugated AuNPs in HeLa cells indicated that the targeted AuNPs appeared to attach on the cell surfaces and enter into the cell with an hour. The cell viability was also compared to estimate the efficacy of folate-conjugated AuNP delivery systems. Folate receptor-targeted AuNP systems appeared to decrease cancer cell viability both in vitro and in vivo more than did the use of the 6MP-coated AuNPs drug without any targeting systems. Copyright © 2012 Wiley Periodicals, Inc.

The development of folate-PAMAM dendrimer conjugates for targeted delivery of anti-arthritic drugs and their pharmacokinetics and biodistribution in arthritic rats.

PubMed

Chandrasekar, Durairaj; Sistla, Ramakrishna; Ahmad, Farhan J; Khar, Roop K; Diwan, Prakash V

2007-01-01

The aim of this study was to synthesize folate-dendrimer conjugates as suitable vehicle for site specific delivery of anti-arthritic drug (indomethacin) to inflammatory regions and to determine its targeting efficiency, biodistribution in adjuvant induced arthritic rats. Folic acid was coupled to the surface amino groups of G4-PAMAM dendrimer (G4D) via a carbodiimide reaction and loaded with indomethacin. The conjugates were characterized by (1)H-NMR and IR spectroscopy. The drug content and percent encapsulation efficiency increased with increasing folate content for the dendrimer conjugates. The in vitro release rate was decreased for the folate conjugates when compared with unconjugated dendrimer (DNI). The plasma concentration profile showed a biphasic curve indicating rapid distribution followed by slow elimination. The AUC(0-infinity), half-life and residence time of indomethacin in inflamed paw was higher for folate-dendrimer conjugates. The time-averaged relative drug exposure (r(e)) of the drug in paw and overall drug targeting efficiency (T(e)) were higher for folate conjugate with 21 folate moieties (4.1 and 2.78, respectively) when compared with DNI (1.91 and 1.88, respectively). This study demonstrated the superiority of active targeting over dendrimer mediated passive targeting and also for the first time, folate-mediated targeting of an anti-arthritic drug to the inflammatory tissues.

Blood levels of folate at birth and risk of childhood leukemia

PubMed Central

Chokkalingam, Anand P.; Chun, Danielle S.; Noonan, Emily J.; Pfeiffer, Christine M.; Zhang, Mindy; Month, Stacy R.; Taggart, Denah R.; Wiemels, Joseph L.; Metayer, Catherine; Buffler, Patricia A.

2013-01-01

Background A role for folate in cancer etiology has long been suspected due to folate’s function as a cofactor in DNA methylation and maintenance of DNA synthesis. Previous case-control studies examining the association between risk of childhood acute lymphoblastic leukemia (ALL) and mothers’ self-reported folate intake and supplementation have been inconclusive. Materials and Methods We utilized a quantitative microbiologic assay to measure newborn folate concentrations in archived dried bloodspots collected at birth from 313 incident ALL cases, 44 incident acute myeloid leukemia (AML) cases, and 405 matched population-based controls. Results Overall, we found no difference in hemoglobin-normalized newborn folate concentrations (HbFol, nmol/g) between ALL cases and controls (2.76 vs. 2.77, p=0.97) or between AML cases and controls (2.93 vs. 2.76, p=0.32). Null results persisted after stratification by both birth period (1982-94, 1995-98, and 1999-2002) to account for the start of folate fortification of grain products in the US, and by self-reported maternal pre-pregnancy supplement use. Similarly, no association was observed for major ALL subgroups. Conclusions Our results do not support an association between birth folate concentrations and risk of childhood AML or major ALL subgroups. Impact However, they do not rule out a role for folate through exposures after birth or in early stages of fetal development. PMID:23576692

Neonatal hydrocephalus is a result of a block in folate handling and metabolism involving 10-formyltetrahydrofolate dehydrogenase.

PubMed

Naz, Naila; Jimenez, Alicia Requena; Sanjuan-Vilaplana, Anna; Gurney, Megan; Miyan, Jaleel

2016-08-01

Folate is vital in a range of biological processes and folate deficiency is associated with neurodevelopmental disorders such as neural tube defects and hydrocephalus (HC). 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is a key regulator for folate availability and metabolic interconversion for the supply of 1-carbon groups. In previous studies, we found a deficiency of FDH in CSF associated with the developmental deficit in congenital and neonatal HC. In this study, we therefore aimed to investigate the role of FDH in folate transport and metabolism during the brain development of the congenital hydrocephalic Texas (H-Tx) rat and normal (Sprague-Dawley) rats. We show that at embryonic (E) stage E18 and E20, FDH-positive cells and/or vesicles derived from the cortex can bind methyl-folate similarly to folate receptor alpha, the main folate transporter. Hydrocephalic rats expressed diminished nuclear FDH in both liver and brain at all postnatal (P) ages tested (P5, P15, and P20) together with a parallel increase in hepatic nuclear methyl-folate at P5 and cerebral methylfolate at P15 and P20. A similar relationship was found between FDH and 5-methyl cytosine, the main marker for DNA methylation. The data indicated that FDH binds and transports methylfolate in the brain and that decreased liver and brain nuclear expression of FDH is linked with decreased DNA methylation which could be a key factor in the developmental deficits associated with congenital and neonatal HC. Folate deficiency is associated with neurodevelopmental disorders such as neural tube defects and hydrocephalus. 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is a key regulator for folate availability and metabolic interconversion. We show that FDH binds and transports methylfolate in the brain. Moreover, we found that a deficiency of FDH in the nucleus of brain and liver is linked with decreased DNA methylation which could be a key factor in the developmental deficits associated with congenital and neonatal hydrocephalus cells. © 2016 International Society for Neurochemistry.

[Mutation analysis of FGFR3 gene in a family featuring hereditary dwarfism].

PubMed

Zhang, Qiong; Jiang, Hai-ou; Quan, Qing-li; Li, Jun; He, Ting; Huang, Xue-shuang

2011-12-01

To investigate the clinical symptoms and potential mutation in FGFR3 gene for a family featuring hereditary dwarfism in order to attain diagnosis and provide prenatal diagnosis. Five patients and two unaffected relatives from the family, in addition with 100 healthy controls, were recruited. Genome DNA was extracted. Exons 10 and 13 of the FGFR3 gene were amplified using polymerase chain reaction (PCR). PCR products were sequenced in both directions. All patients had similar features including short stature, short limbs, lumbar hyperlordosis but normal craniofacial features. A heterozygous mutation G1620T (N540K) was identified in the cDNA from all patients but not in the unaffected relatives and 100 control subjects. A heterozygous G380R mutation was excluded. The hereditary dwarfism featured by this family has been caused by hypochondroplasia (HCH) due to a N540K mutation in the FGFR3 gene.

FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED GENOTOXICITY IN MICE

EPA Science Inventory

Folate deficiency increases background levels of DNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary folate deficiency on arsenic induction of micronuclei (MN) in peripheral blood cells. Male C5...

DIETARY FOLATE DEFICIENCY ENHANCES ARSENIC-INDUCED MICRONUCLEUS FORMATION IN MICE

EPA Science Inventory

Dietary folate deficiency enhances arsenic-induced micronucleus formation in mice.

Folate deficiency increases background levels ofDNA damage and can enhance the mutagenicity of chemical agents. Duplicate experiments were performed to investigate the effect of dietary...

Post-weaning selenium and folate supplementation affects gene and protein expression and global DNA methylation in mice fed high-fat diets.

PubMed

Bermingham, Emma N; Bassett, Shalome A; Young, Wayne; Roy, Nicole C; McNabb, Warren C; Cooney, Janine M; Brewster, Di T; Laing, William A; Barnett, Matthew P G

2013-03-05

Consumption of high-fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in offspring of female mice fed a high-fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets inadequate in selenium and folate during gestation and lactation can alter global DNA methylation in liver. This may be one factor through which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health.

Aspects of Weak Interactions between Folate and Glycine Betaine.

PubMed

Bhojane, Purva P; Duff, Michael R; Bafna, Khushboo; Rimmer, Gabriella P; Agarwal, Pratul K; Howell, Elizabeth E

2016-11-15

Folate, or vitamin B 9 , is an important compound in one-carbon metabolism. Previous studies have found weaker binding of dihydrofolate to dihydrofolate reductase in the presence of osmolytes. In other words, osmolytes are more difficult to remove from the dihydrofolate solvation shell than water; this shifts the equilibrium toward the free ligand and protein species. This study uses vapor-pressure osmometry to explore the interaction of folate with the model osmolyte, glycine betaine. This method yields a preferential interaction potential (μ 23 /RT value). This value is concentration-dependent as folate dimerizes. The μ 23 /RT value also tracks the deprotonation of folate's N3-O4 keto-enol group, yielding a pK a of 8.1. To determine which folate atoms interact most strongly with betaine, the interaction of heterocyclic aromatic compounds (as well as other small molecules) with betaine was monitored. Using an accessible surface area approach coupled with osmometry measurements, deconvolution of the μ 23 /RT values into α values for atom types was achieved. This allows prediction of μ 23 /RT values for larger molecules such as folate. Molecular dynamics simulations of folate show a variety of structures from extended to L-shaped. These conformers possess μ 23 /RT values from -0.18 to 0.09 m -1 , where a negative value indicates a preference for solvation by betaine and a positive value indicates a preference for water. This range of values is consistent with values observed in osmometry and solubility experiments. As the average predicted folate μ 23 /RT value is near zero, this indicates folate interacts almost equally well with betaine and water. Specifically, the glutamate tail prefers to interact with water, while the aromatic rings prefer betaine. In general, the more protonated species in our small molecule survey interact better with betaine as they provide a source of hydrogens (betaine is not a hydrogen bond donor). Upon deprotonation of the small molecule, the preference swings toward water interaction because of its hydrogen bond donating capacities.

Folate Deficiency, Atopy, and Severe Asthma Exacerbations in Puerto Rican Children

PubMed Central

Blatter, Joshua; Brehm, John M.; Sordillo, Joanne; Forno, Erick; Boutaoui, Nadia; Acosta-Pérez, Edna; Alvarez, María; Colón-Semidey, Angel; Weiss, Scott T.; Litonjua, Augusto A.; Canino, Glorisa

2016-01-01

Background: Little is known about folate and atopy or severe asthma exacerbations. We examined whether folate deficiency is associated with number of positive skin tests to allergens or severe asthma exacerbations in a high-risk population and further assessed whether such association is explained or modified by vitamin D status. Methods: Cross-sectional study of 582 children aged 6 to 14 years with (n = 304) and without (n = 278) asthma in San Juan, Puerto Rico. Folate deficiency was defined as plasma folate less than or equal to 20 ng/ml. Our outcomes were the number of positive skin tests to allergens (range, 0–15) in all children and (in children with asthma) one or more severe exacerbations in the previous year. Logistic and negative binomial regression models were used for the multivariate analysis. All multivariate models were adjusted for age, sex, household income, residential proximity to a major road, and (for atopy) case/control status; those for severe exacerbations were also adjusted for use of inhaled corticosteroids and vitamin D insufficiency (a plasma 25[OH]D < 30 ng/ml). Measurements and Main Results: In a multivariate analysis, folate deficiency was significantly associated with an increased degree of atopy and 2.2 times increased odds of at least one severe asthma exacerbation (95% confidence interval for odds ratio, 1.1–4.6). Compared with children who had normal levels of both folate and vitamin D, those with both folate deficiency and vitamin D insufficiency had nearly eightfold increased odds of one or more severe asthma exacerbation (95% confidence interval for adjusted odds ratio, 2.7–21.6). Conclusions: Folate deficiency is associated with increased degree of atopy and severe asthma exacerbations in school-aged Puerto Ricans. Vitamin D insufficiency may further increase detrimental effects of folate deficiency on severe asthma exacerbations. PMID:26561879

Folate intake and depressive symptoms in Japanese workers considering SES and job stress factors: J-HOPE study.

PubMed

Miyaki, Koichi; Song, Yixuan; Htun, Nay Chi; Tsutsumi, Akizumi; Hashimoto, Hideki; Kawakami, Norito; Takahashi, Masaya; Shimazu, Akihito; Inoue, Akiomi; Kurioka, Sumiko; Shimbo, Takuro

2012-04-20

Recently socioeconomic status (SES) and job stress index received more attention to affect mental health. Folate intake has been implicated to have negative association with depression. However, few studies were published for the evidence association together with the consideration of SES and job stress factors. The current study is a part of the Japanese study of Health, Occupation and Psychosocial factors related Equity (J-HOPE study) that focused on the association of social stratification and health and our objective was to clarify the association between folate intake and depressive symptoms in Japanese general workers. Subjects were 2266 workers in a Japanese nationwide company. SES and job stress factors were assessed by self-administered questionnaire. Folate intake was estimated by a validated, brief, self-administered diet history questionnaire. Depressive symptoms were measured by Kessler's K6 questionnaire. "Individuals with depressive symptoms" was defined as K6≥9 (in K6 score of 0-24 scoring system). Multiple logistic regression and linear regression model were used to evaluate the association between folate and depressive symptoms. Several SES factors (proportion of management positions, years of continuous employment, and annual household income) and folate intake were found to be significantly lower in the subjects with depressive symptom (SES factors: p < 0.001; folate intake: P = 0.001). There was an inverse, independent linear association between K6 score and folate intake after adjusting for age, sex, job stress scores (job strains, worksite supports), and SES factors (p = 0.010). The impact of folate intake on the prevalence of depressive symptom by a multiple logistic model was (ORs[95% CI]: 0.813 [0.664-0.994]; P =0.044). Our cross-sectional study suggested an inverse, independent relation of energy-adjusted folate intake with depression score and prevalence of depressive symptoms in Japanese workers, together with the consideration of SES and job stress factors.

Post-weaning selenium and folate supplementation affects gene and protein expression and global DNA methylation in mice fed high-fat diets

PubMed Central

2013-01-01

Background Consumption of high-fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in offspring of female mice fed a high-fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Methods Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets inadequate in selenium and folate during gestation and lactation can alter global DNA methylation in liver. This may be one factor through which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. PMID:23497688

Low molecular weight chitosan conjugated with folate for siRNA delivery in vitro: optimization studies

PubMed Central

Fernandes, Julio C; Qiu, Xingping; Winnik, Francoise M; Benderdour, Mohamed; Zhang, Xiaoling; Dai, Kerong; Shi, Qin

2012-01-01

The low transfection efficiency of chitosan is one of its drawbacks as a gene delivery carrier. Low molecular weight chitosan may help to form small-sized polymer-DNA or small interfering RNA (siRNA) complexes. Folate conjugation may improve gene transfection efficiency because of the promoted uptake of folate receptor-bearing cells. In the present study, chitosan was conjugated with folate and investigated for its efficacy as a delivery vector for siRNA in vitro. We demonstrate that the molecular weight of chitosan has a major influence on its biological and physicochemical properties, and very low molecular weight chitosan (below 10 kDa) has difficulty in forming stable complexes with siRNA. In this study, chitosan 25 kDa and 50 kDa completely absorbed siRNA and formed nanoparticles (≤220 nm) at a chitosan to siRNA weight ratio of 50:1. The introduction of a folate ligand onto chitosan decreased nanoparticle toxicity. Compared with chitosan-siRNA, folate-chitosan-siRNA nanoparticles improved gene silencing transfection efficiency. Therefore, folate-chitosan shows potential as a viable candidate vector for safe and efficient siRNA delivery. PMID:23209368

Periconceptional Folic Acid Supplementation Benefit to Development of Early Sensory-Motor Function through Increase DNA Methylation in Rat Offspring

PubMed Central

Li, Wen; Li, Zhenshu; Li, Shou; Wang, Xinyan; Wilson, John X.; Huang, Guowei

2018-01-01

Periconceptional maternal folate levels may alter DNA methylation patterns and health outcomes in offspring. We hypothesized that maternal folic acid supplementation alters fetal neural development through DNA methylation in the fetal brain. Twenty-eight rats were randomly assigned to four groups: three groups of the female rats were fed folate-normal, folate-deficient or folate-supplemented diets from seven days before mating to delivery. In another group, folic acid supplementation diet short-period group was fed a folate-normal diet, except for 10 days (begin mating) when this group was fed a folate-supplemented diet. After delivery, the diets were changed to folate-normal diet for all four groups. The cliff avoidance and forelimb grip tests were used to assess sensory motor function of rat offspring. The results indicate that maternal folic acid supplementation improved the early development of sensory-motor function in offspring. Maternal folic acid supplementation increased the methylation potential, global DNA methylation (5-mC) and DNA methyltransferase expression and activity in the brains of the offspring. In conclusion, maternal folic acid supplementation increases DNA methylation pattern in offspring brain and improves the early development of sensory-motor function. PMID:29494536

Chitosan-folate decorated carbon nanotubes for site specific lung cancer delivery.

PubMed

Singh, Rahul Pratap; Sharma, Gunjan; Sonali; Singh, Sanjay; Bharti, Shreekant; Pandey, Bajarangprasad L; Koch, Biplob; Muthu, Madaswamy S

2017-08-01

The aim of this work was to formulate chitosan-folate conjugated multi-walled carbon nanotubes for the lung cancer targeted delivery of docetaxel. The chitosan-folate conjugate was synthesized and the conjugation was confirmed by Fourier transform infrared spectroscopy. The multi-walled carbon nanotubes were characterized for their particle size, polydispersity, zeta potential, surface morphology, drug encapsulation efficiency and in vitro release study. The in vitro cellular uptake, cytotoxicity, and cell cycle analysis of the docetaxel/coumarin-6 loaded multi-walled carbon nanotubes were carried out to compare the effectiveness of the formulations. The biocompatibility and safety of chitosan-folate conjugated multi-walled carbon nanotubes was analyzed by lung histopathology in comparison with marketed docetaxel formulation (Docel™) and acylated multi-walled carbon nanotubes. The cellular internalization study shown that the chitosan-folate conjugated multi-walled carbon nanotubes could be easily internalized into the lung cancer cells through a folate receptor-mediated endocytic pathway. The IC 50 values exhibited that chitosan-folate conjugated multi-walled carbon nanotubes could be 89-fold more effective than Docel™ in human lung cancer cells (A549 cells). Copyright © 2017 Elsevier B.V. All rights reserved.

A multifunctional lipid nanoparticle for co-delivery of paclitaxel and curcumin for targeted delivery and enhanced cytotoxicity in multidrug resistant breast cancer cells

PubMed Central

Baek, Jong-Suep; Cho, Cheong-Weon

2017-01-01

The objective of the work was to develop a multifunctional nanomedicine based on a folate-conjugated lipid nanoparticles loaded with paclitaxel and curcumin. The novel system combines therapeutic advantageous of efficient targeted delivery via folate and timed-release of curcumin and paclitaxel via 2-hydroxypropyl-ß-cyclodextrin, thereby overcoming multidrug resistance in breast cancer cells (MCF-7/ADR). The faster release of curcumin from the folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles enables sufficient p-glycoprotein inhibition, which allows increased cellular uptake and cytotoxicity of paclitaxel. In western blot assay, curcumin can efficiently inhibit the expression of p-glycoprotein, conformed the enhancement of cytotoxicity by paclitaxel. Furthermore, folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles exhibited increased uptake of paclitaxel and curcumin into MCF-7/ADR cells through the folate receptor-mediated internalization. Taken together, these results indicate that folate-conjugated curcumin and paclitaxel-loaded lipid nanoparticles enables the enhanced, folate-targeted delivery of multiple anticancer drugs by inhibiting the multi-drug resistance efficiently, which may also serve as a useful nano-system for co-delivery of other anticancer drugs. PMID:28423731

Natural variation of folate tuber content in potato

USDA-ARS?s Scientific Manuscript database

Folates are essential vitamins in the human diet. Folate deficiency is still a common worldwide problem that is linked to various serious disorders, such as birth defects, certain types of cardiovascular diseases and cancers, megaloblastic anemia, impaired cognitive performance and depression. There...

The Genetics of Deafness in Domestic Animals

PubMed Central

Strain, George M.

2015-01-01

Although deafness can be acquired throughout an animal’s life from a variety of causes, hereditary deafness, especially congenital hereditary deafness, is a significant problem in several species. Extensive reviews exist of the genetics of deafness in humans and mice, but not for deafness in domestic animals. Hereditary deafness in many species and breeds is associated with loci for white pigmentation, where the cochlear pathology is cochleo-saccular. In other cases, there is no pigmentation association and the cochlear pathology is neuroepithelial. Late onset hereditary deafness has recently been identified in dogs and may be present but not yet recognized in other species. Few genes responsible for deafness have been identified in animals, but progress has been made for identifying genes responsible for the associated pigmentation phenotypes. Across species, the genes identified with deafness or white pigmentation patterns include MITF, PMEL, KIT, EDNRB, CDH23, TYR, and TRPM1 in dog, cat, horse, cow, pig, sheep, ferret, mink, camelid, and rabbit. Multiple causative genes are present in some species. Significant work remains in many cases to identify specific chromosomal deafness genes so that DNA testing can be used to identify carriers of the mutated genes and thereby reduce deafness prevalence. PMID:26664958

Management of women at high risk of hereditary breast cancer in the Veneto Regional Program for Prevention.

PubMed

Del Sole, Annamaria; Cinquetti, Sandro; Fedato, Chiara; Montagna, Marco; Russo, Francesca; Sbrogiò, Luca Gino; Zorzi, Manuel

2015-01-01

Today it is well-known that high risk of genetic breast cancer concerns a very limited part of the population: no more than 2-3 women are affected every thousand and this condition as a whole accounts for no more than 3%-5% of all breast cancers. Following the directions contained in the 2014-2018 National Prevention Plan, Veneto's 2014-2018 Regional Program of Prevention (PRP), approved by Regional Council Resolution (DGR) No. 749 of 14.5.2015, consolidation of a pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma is thus proposed. The principal activities of this policy will be the following: creation of a regional working group, survey of currently existing pathways for the identification of women at risk of hereditary breast cancer and adoption of the same, approval and consolidation of a structured regional pathway for women at high risk of hereditary breast and/or ovarian cancer, from paths of oncogenetic consultation and genetic testing to management of disease risk. Subsequent to the recognition of the pathway of diagnosis, observation, and prophylaxis for women at high risk of hereditary breast carcinoma, the Veneto region undertakes to develop a co-ordinated program of information and training on this pathway directed at the population and healthcare workers. It is firmly hoped that with the inclusion of a program for the management of women at high risk of hereditary breast cancer within the Veneto PRP this topic may become more defined and structured in terms of sustainability, integration with the existing regional networks (mammography network, Breast Unit), contrasting inequality, monitoring and evaluation, in this way pursuing the objectives of a reduction of cause-specific mortality and improvement of quality of life.

Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia.

PubMed

Roffman, Joshua L; Brohawn, David G; Nitenson, Adam Z; Macklin, Eric A; Smoller, Jordan W; Goff, Donald C

2013-03-01

Low serum folate levels previously have been associated with negative symptom risk in schizophrenia, as has the hypofunctional 677C>T variant of the MTHFR gene. This study examined whether other missense polymorphisms in folate-regulating enzymes, in concert with MTHFR, influence negative symptoms in schizophrenia, and whether total risk allele load interacts with serum folate status to further stratify negative symptom risk. Medicated outpatients with schizophrenia (n = 219), all of European origin and some included in a previous report, were rated with the Positive and Negative Syndrome Scale. A subset of 82 patients also underwent nonfasting serum folate testing. Patients were genotyped for the MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), MTR 2756A>G (rs1805087), MTRR 203A>G (rs1801394), FOLH1 484T>C (rs202676), RFC 80A>G (rs1051266), and COMT 675G>A (rs4680) polymorphisms. All genotypes were entered into a linear regression model to determine significant predictors of negative symptoms, and risk scores were calculated based on total risk allele dose. Four variants, MTHFR 677T, MTR 2756A, FOLH1 484C, and COMT 675A, emerged as significant independent predictors of negative symptom severity, accounting for significantly greater variance in negative symptoms than MTHFR 677C>T alone. Total allele dose across the 4 variants predicted negative symptom severity only among patients with low folate levels. These findings indicate that multiple genetic variants within the folate metabolic pathway contribute to negative symptoms of schizophrenia. A relationship between folate level and negative symptom severity among patients with greater genetic vulnerability is biologically plausible and suggests the utility of folate supplementation in these patients.

Paclitaxel-loaded folate-coated long circulating and pH-sensitive liposomes as a potential drug delivery system: A biodistribution study.

PubMed

Monteiro, Liziane O F; Fernandes, Renata S; Oda, Caroline M R; Lopes, Sávia C; Townsend, Danyelle M; Cardoso, Valbert N; Oliveira, Mônica C; Leite, Elaine A; Rubello, Domenico; de Barros, André L B

2018-01-01

A range of antitumor agents for cancer treatment is available; however, they show low specificity, which often limit their use. Recently, we have reported the preparation of folate-coated long-circulating and pH-sensitive liposomes (SpHL-folate-PTX) loaded with paclitaxel (PTX), an effective drug for the treatment of solid tumors, including breast cancer. The purpose of this study was to prepare and characterize SpHL-PTX and SpHL-folate-PTX radiolabeled with technetium-99m ( 99m Tc). Biodistribution studies and scintigraphic images were performed after intravenous administration of 99m Tc-PTX, 99m Tc-SpHL-PTX and 99m Tc-SpHL-folate-PTX into healthy and tumor-bearing mice. High radiochemical purity (>98%) and in vitro stability (>90%) were achieved for both liposome formulations. The pharmacokinetic properties of 99m Tc-SpHL-DTPA-PTX and 99m Tc-SpHL-folate-DTPA-PTX decreased in a monophasic manner showing half-life of 400.1 and 541.8min, respectively. Scintigraphic images and biodistribution studies showed a significant uptake in liver, spleen and kidneys, demonstrating these routes as way for excretion. At 8h post-injection, the liposomal tumor uptake was higher than 99m Tc-PTX. Interesting, 4h after administration, the liposome folate coated showed higher tumor-to-muscle ratio than 99m Tc-SpHL-DTPA-PTX and 99m Tc-PTX. In conclusion, the liposomal systems, showed high tumor uptake by scintigraphic images, especially the 99m Tc-SpHL-folate-DTPA-PTX that showed a sustained and higher tumor-to-muscle ratio than non-functionalized liposome, which indicate its feasibility as a PTX delivery system to folate positive tumors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Solar cycle predicts folate-sensitive neonatal genotypes at discrete phases of the first trimester of pregnancy: a novel folate-related human embryo loss hypothesis.

PubMed

Lucock, Mark; Glanville, Tracey; Yates, Zoë; Walker, James; Furst, John; Simpson, Nigel

2012-08-01

Folate, a key periconceptional nutrient, is ultraviolet light (UV-R) sensitive. We therefore hypothesise that a relationship exists between sunspot activity, a proxy for total solar irradiance (particularly UV-R) reaching Earth, and the occurrence of folate-sensitive, epigenomic-related neonatal genotypes during the first trimester of pregnancy. Limited data is provided to support the hypothesis that the solar cycle predicts folate-related human embryo loss: 379 neonates born at latitude 54°N between 1998 and 2000 were examined for three folate-sensitive, epigenome-related polymorphisms, with solar activity for trimester one accessed via the Royal Greenwich Observatory-US Air force/National Oceanic and Atmospheric Administration Sunspot Database (34,110 total observation days). Logistic regression showed solar activity predicts C677T-methylenetetrahydrofolate reductase (C677T-MTHFR) and A66G-methionine synthase reductase (A66G-MSR) genotype at discrete phases of trimester one. Total and maximal sunspot activity predicts C677T-MTHFR genotype for days 31-60 of trimester one (p=0.0181 and 0.0366, respectively) and A66G-MSR genotype for days 61-90 of trimester one (p=0.0072 and 0.0105, respectively). Loss of UV-R sensitive folate associated with the sunspot cycle might therefore interact with variant folate genes to perturb DNA methylation and/or elaboration of the primary base sequence (thymidylate synthesis), as well as increase embryo-toxic homocysteine. We hypothesise that this may influence embryo viability leading to 677CC-MTHFR and 66GG-MSR embryo loss at times of increased solar activity. This provides an interesting and plausible link between well recognised 'folate gene originated developmental disorders' and 'solar activity/seasonality modulated developmental disorders'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Relationships of maternal folate and vitamin B12 status during pregnancy with perinatal depression: The GUSTO study.

PubMed

Chong, Mary F F; Wong, Jocelyn X Y; Colega, Marjorelee; Chen, Ling-Wei; van Dam, Rob M; Tan, Chuen Seng; Lim, Ai Lin; Cai, Shirong; Broekman, Birit F P; Lee, Yung Seng; Saw, Seang Mei; Kwek, Kenneth; Godfrey, Keith M; Chong, Yap Seng; Gluckman, Peter; Meaney, Michael J; Chen, Helen

2014-08-01

Studies in the general population have proposed links between nutrition and depression, but less is known about the perinatal period. Depletion of nutrient reserves throughout pregnancy and delayed postpartum repletion could increase the risk of perinatal depression. We examined the relationships of plasma folate and vitamin B12 concentrations during pregnancy with perinatal depression. At 26th-28th weeks of gestation, plasma folate and vitamin B12 were measured in women from the GUSTO mother-offspring cohort study in Singapore. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3-month postpartum. EPDS scores of ≥15 during pregnancy or ≥13 at postpartum were indicative of probable depression. Of 709 women, 7.2% (n = 51) were identified with probable antenatal depression and 10.4% (n = 74) with probable postnatal depression. Plasma folate concentrations were significantly lower in those with probable antenatal depression than those without (mean ± SD; 27.3 ± 13.8 vs 40.4 ± 36.5 nmol/L; p = 0.011). No difference in folate concentrations was observed in those with and without probable postnatal depression. In adjusted regression models, the likelihood of probable antenatal depression decreases by 0.69 for every unit variation (increase) in folate (OR = 0.69 per SD increase in folate; 95% CI: 0.52, 0.94). Plasma vitamin B12 concentrations were not associated with perinatal depression. Lower plasma folate status during pregnancy was associated with antenatal depression, but not with postnatal depression. Replication in other studies is needed to determine the direction of causality between low folate and antenatal depression. NCT01174875. Copyright © 2014 Elsevier Ltd. All rights reserved.

Maternal Folate Intake during Pregnancy and Childhood Asthma in a Population-based Cohort

PubMed Central

Magnus, Maria C.; Karlstad, Øystein; Haugen, Margaretha; Refsum, Helga; Ueland, Per M.; McCann, Adrian; Nafstad, Per; Håberg, Siri E.; Nystad, Wenche; London, Stephanie J.

2017-01-01

Rationale: A potential adverse effect of high folate intake during pregnancy on children’s asthma development remains controversial. Objectives: To prospectively investigate folate intake from both food and supplements during pregnancy and asthma at age 7 years when the diagnosis is more reliable than at preschool age. Methods: This study included eligible children born 2002–2006 from the Norwegian Mother and Child Cohort Study, a population-based pregnancy cohort, linked to the Norwegian Prescription Database. Current asthma at age 7 was defined by asthma medications dispensed at least twice in the year (1,901 cases; n = 39,846) or by maternal questionnaire report (1,624 cases; n = 28,872). Maternal folate intake was assessed with a food frequency questionnaire validated against plasma folate. We used log-binomial and multinomial regression to calculate adjusted relative risks with 95% confidence intervals. Measurements and Main Results: Risk of asthma was increased in the highest versus lowest quintile of total folate intake with an adjusted relative risk of 1.23 (95% confidence interval, 1.06–1.44) that was similar for maternally reported asthma. Mothers in the highest quintile had a relatively high intake of food folate (median, 308; interquartile range, 241–366 μg/d) and nearly all took at least 400 μg/d of supplemental folic acid (median, 500; interquartile range, 400–600 μg/d). Conclusions: In this large prospective population-based cohort with essentially complete follow-up, pregnant women taking supplemental folic acid at or above the recommended dose, combined with a diet rich in folate, reach a total folate intake level associated with a slightly increased risk of asthma in children. PMID:27518161

Maternal Prepregnancy Folate Intake and Risk of Spontaneous Abortion and Stillbirth

PubMed Central

Gaskins, Audrey J.; Rich-Edwards, Janet W.; Hauser, Russ; Williams, Paige L.; Gillman, Matthew W.; Ginsburg, Elizabeth S.; Missmer, Stacey A.; Chavarro, Jorge E.

2014-01-01

Objective To evaluate prospectively the relationship between prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Methods Women in the Nurses’ Health Study-II who self-reported a pregnancy between 1992 and 2009 were included in this analysis. Dietary folate and supplement use was assessed every 4 years, starting in 1991, by a food-frequency questionnaire. Pregnancies were self-reported, with case pregnancies lost spontaneously (spontaneous abortion <20 weeks of gestation and stillbirth 20+ weeks of gestation) and comparison pregnancies ending in ectopic pregnancy, induced abortion, or live birth. Results Among the 11,072 women, 15,950 pregnancies were reported of which 2,756(17.3%) ended in spontaneous abortion and 120(0.8%) ended in stillbirth. Compared to women in the lowest quintile of prepregnancy folate intake (<285μg/day), those in the highest quintile (>851μg/day) had a relative risk (RR) of spontaneous abortion of 0.91 (95% CI 0.82,1.02) after multivariable adjustment (P-trend=0.04). This association was primarily attributable to intake of folate from supplements. Compared to women without supplemental folate intake (0μg/day), those in the highest category (>730μg/day) had a RR of spontaneous abortion of 0.80 (95% CI 0.71,0.90) after multivariable adjustment (P-trend=<0.001). The association of prepregnancy supplemental folate with risk of spontaneous abortion was consistent across gestational period of loss. A similar inverse trend was observed with the risk of stillbirth, which fell short of conventional significance (P-trend=0.06). Conclusions Higher intake of folate from supplements was associated with reduced risk of spontaneous abortion. Women at risk of pregnancy should use supplemental folate for neural tube defect prevention and because it may decrease the risk of spontaneous abortion,. PMID:24901281

Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth.

PubMed

Gaskins, Audrey J; Rich-Edwards, Janet W; Hauser, Russ; Williams, Paige L; Gillman, Matthew W; Ginsburg, Elizabeth S; Missmer, Stacey A; Chavarro, Jorge E

2014-07-01

To evaluate prospectively the relationship between prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Women in the Nurses' Health Study II who self-reported a pregnancy between 1992 and 2009 were included in this analysis. Dietary folate and supplement use was assessed every 4 years, starting in 1991, by a food frequency questionnaire. Pregnancies were self-reported with case pregnancies lost spontaneously (spontaneous abortion less than 20 weeks of gestation and stillbirth 20+ weeks of gestation) and comparison pregnancies ending in ectopic pregnancy, induced abortion, or live birth. Among the 11,072 women, 15,950 pregnancies were reported of which 2,756 (17.3%) ended in spontaneous abortion and 120 (0.8%) ended in stillbirth. Compared with women in the lowest quintile of prepregnancy folate intake (less than 285 micrograms/d), those in the highest quintile (greater than 851 micrograms/d) had a relative risk of spontaneous abortion of 0.91 (95% confidence interval [CI] 0.82-1.02) after multivariable adjustment (P trend=.04). This association was primarily attributable to intake of folate from supplements. Compared with women without supplemental folate intake (0 micrograms/d), those in the highest category (greater than 730 micrograms/d) had a relative risk of spontaneous abortion of 0.80 (95% CI 0.71-0.90) after multivariable adjustment (P trend <.001). The association of prepregnancy supplemental folate with risk of spontaneous abortion was consistent across gestational period of loss. A similar inverse trend was observed with the risk of stillbirth, which fell short of conventional significance (P trend=.06). Higher intake of folate from supplements was associated with reduced risk of spontaneous abortion. Women at risk of pregnancy should use supplemental folate for neural tube defect prevention and because it may decrease the risk of spontaneous abortion. : II.

Factors associated with compliance of prenatal iron folate supplementation among women in Mecha district, Western Amhara: a cross-sectional study

PubMed Central

Taye, Bekele; Abeje, Gedefaw; Mekonen, Alemetsehaye

2015-01-01

Introduction Iron and folate supplementation can effectively control and prevent anaemia in pregnancy. In Ethiopia, all pregnant women are prescribed iron folate during their ANC visit. However, limited adherence is thought to be a major reason for the low effectiveness of iron supplementation programs. Therefore this study was done to investigate factors associated with compliance of prenatal iron folate supplementation among women who gave birth in the last 12 months before the survey in Mecha district. Methods Community based cross sectional study design was employed in Mecha district from June 25 - July 15/2013. A sample of 634 women who gave birth 12 months before the survey was included in the study. Study participants were selected by systematic random sampling technique after allocating the total sample to each kebele proportionally. Data were collected using a pre-tested structured Amharic questionnaire. Collected data were edited, coded and entered to Epi info version 3.1 and exported to‘ SPSS version 16. Bivariate and multivariable analysis was computed. Results A total of 628 women who gave birth twelve months before the survey were enrolled. In this study only 20.4% of participants were compliant with iron foliate supplementation. In multivariable analysis, age of the mother, educational status of the mother, knowledge of anaemia and iron folate tablets, and history of anaemia during pregnancy were significantly associated with compliance to iron folate supplementation (P < .05). Belief that too many tablets would harm the baby and fear of side effects were the major reasons given for noncompliance. Conclusion Compliance to iron folate supplementation is very low in the study area. Increasing female education and increasing knowledge of women about anaemia and iron folate tablets are recommended to increase compliance to iron folate supplementation. PMID:26090001

Factors associated with compliance of prenatal iron folate supplementation among women in Mecha district, Western Amhara: a cross-sectional study.

PubMed

Taye, Bekele; Abeje, Gedefaw; Mekonen, Alemetsehaye

2015-01-01

Iron and folate supplementation can effectively control and prevent anaemia in pregnancy. In Ethiopia, all pregnant women are prescribed iron folate during their ANC visit. However, limited adherence is thought to be a major reason for the low effectiveness of iron supplementation programs. Therefore this study was done to investigate factors associated with compliance of prenatal iron folate supplementation among women who gave birth in the last 12 months before the survey in Mecha district. Community based cross sectional study design was employed in Mecha district from June 25 - July 15/2013. A sample of 634 women who gave birth 12 months before the survey was included in the study. Study participants were selected by systematic random sampling technique after allocating the total sample to each kebele proportionally. Data were collected using a pre-tested structured Amharic questionnaire. Collected data were edited, coded and entered to Epi info version 3.1 and exported to' SPSS version 16. Bivariate and multivariable analysis was computed. A total of 628 women who gave birth twelve months before the survey were enrolled. In this study only 20.4% of participants were compliant with iron foliate supplementation. In multivariable analysis, age of the mother, educational status of the mother, knowledge of anaemia and iron folate tablets, and history of anaemia during pregnancy were significantly associated with compliance to iron folate supplementation (P<.05). Belief that too many tablets would harm the baby and fear of side effects were the major reasons given for noncompliance. Compliance to iron folate supplementation is very low in the study area. Increasing female education and increasing knowledge of women about anaemia and iron folate tablets are recommended to increase compliance to iron folate supplementation.

Gender and body size affect the response of erythrocyte folate to folic acid treatment.

PubMed

Winkels, Renate M; Brouwer, Ingeborg A; Verhoef, Petra; van Oort, Floor V A; Durga, Jane; Katan, Martijn B

2008-08-01

The recommended dietary allowance (RDA) differs between men and women for some vitamins, but not for folate. The RDA for folate is derived mainly from metabolic studies in women. We assessed if men differ from women in their response of erythrocyte folate to folic acid supplementation. We used data from 2 randomized placebo-controlled trials with folic acid: a 3-y trial in which subjects ingested 800 mug/d of folic acid (294 men and 112 women) and a 12-wk trial in which 187 men and 129 women ingested 0, 50, 100, 200, 400, 600, or 800 microg/d of folic acid in a parallel design (n = 38-42 per treatment group). In the 3-y trial, the erythrocyte folate concentration increased 10% (143 nmol/L, [95%CI 46, 241]) less in men than in women. In the 12-wk trial, regression analysis showed that the response of erythrocyte folate upon folic acid intake for men was 47 nmol/L lower than for women (P for beta(gender) = 0.022); for an intake of 800 microg/d folic acid, this resulted in a 5% lower response in men than in women. Differences in lean body size explained 56% of the difference in response of erythrocyte folate between men and women in the 3-y trial and 70% in the 12-wk trial. Men need more folic acid than women to achieve the same erythrocyte folate concentration, mainly because men have a larger lean body mass. This could be an indication that the RDA for folate should be higher for men than for women, or that the RDA should be expressed per kilogram of lean body mass.

Folate-deficiency induced cell-specific changes in the distribution of lymphocytes and granulocytes in rats.

PubMed

Abe, Ikumi; Shirato, Ken; Hashizume, Yoko; Mitsuhashi, Ryosuke; Kobayashi, Ayumu; Shiono, Chikako; Sato, Shogo; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

2013-01-01

Folate (vitamin B(9)) plays key roles in cell growth and proliferation through regulating the synthesis and stabilization of DNA and RNA, and its deficiency leads to lymphocytopenia and granulocytopenia. However, precisely how folate deficiency affects the distribution of a variety of white blood cell subsets, including the minor population of basophils, and the cell specificity of the effects remain unclear. Therefore, we examined the effects of a folate-deficient diet on the circulating number of lymphocyte subsets [T-lymphocytes, B-lymphocytes, and natural killer (NK) cells] and granulocyte subsets (neutrophils, eosinophils, and basophils) in rats. Rats were divided into two groups, with one receiving the folate-deficient diet (FAD group) and the other a control diet (CON group). All rats were pair-fed for 8 weeks. Plasma folate level was dramatically lower in the FAD group than in the CON group, and the level of homocysteine in the plasma, a predictor of folate deficiency was significantly higher in the FAD group than in the CON group. The number of T-lymphocytes, B-lymphocytes, and NK cells was significantly lower in the FAD group than in the CON group by 0.73-, 0.49-, and 0.70-fold, respectively, indicating that B-lymphocytes are more sensitive to folate deficiency than the other lymphocyte subsets. As expected, the number of neutrophils and eosinophils was significantly lower in the FAD group than in the CON group. However, the number of basophils, the least common type of granulocyte, showed transiently an increasing tendency in the FAD group as compared with the CON group. These results suggest that folate deficiency induces lymphocytopenia and granulocytopenia in a cell-specific manner.

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age.

PubMed

Crivello, Natalia A; Blusztajn, Jan K; Joseph, James A; Shukitt-Hale, Barbara; Smith, Donald E

2010-10-01

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). Folate-deficient diet consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions. Copyright © 2010 Elsevier Inc. All rights reserved.

Folate, vitamin B12, and vitamin B6 status of a group of high socioeconomic status women in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort.

PubMed

Fayyaz, Faiqa; Wang, Flora; Jacobs, René L; O'Connor, Deborah L; Bell, Rhonda C; Field, Catherine J

2014-12-01

Folic acid supplementation and food fortification policies have improved folate status in North American women of child bearing age. Recent studies have reported the possible inadequacy of vitamin B12 and B6 in the etiology of neural tube defects in folate-fortified populations. The aims of this study were to describe folate status and its relationship to supplementation and to assess vitamin B12 and B6 status in a cohort of pregnant women. Supplement intake data were collected in each trimester from the first cohort (n = 599) of the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Red blood cell folate (RBCF) and plasma folate, holotranscobalamin, and pyridoxal 5-phosphate were measured. Overt folate deficiency was rare (3%) but 24% of women in their first trimester had suboptimal RBCF concentration (<906 nmol·L(-1)). The proportion of the cohort in this category declined substantially in second (9%) and third (7%) trimesters. High RBCF (>1360 nmol·L(-1)) was observed in approximately half of the women during each pregnancy trimester. Vitamin B12 and B6 deficiencies were rare (<1% of the cohort). Women consuming folic acid supplements above the upper level had significantly higher RBCF and plasma folate concentrations. In conclusion, the prevalence of vitamin B12 and B6 deficiency was very low. A quarter of the women had suboptimal folate status in the first trimester of pregnancy and over half the women had abnormally high RBCF, suggesting that supplementation during pregnancy is not appropriate in a cohort of women considered to be healthy and a low risk for nutritional deficiencies.

Folate Intake, Mthfr Genotype, and Sex Modulate Choline Metabolism in Mice123

PubMed Central

Chew, Tina W.; Jiang, Xinyin; Yan, Jian; Wang, Wei; Lusa, Amanda L.; Carrier, Bradley J.; West, Allyson A.; Malysheva, Olga V.; Brenna, J. Thomas; Gregory, Jesse F.; Caudill, Marie A.

2011-01-01

Choline and folate are interrelated in 1-carbon metabolism, mostly because of their shared function as methyl donors for homocysteine remethylation. Folate deficiency and mutations of methylenetetrahydrofolate reductase (MTHFR) reduce the availability of a major methyl donor, 5-methyltetrahydrofolate, which in turn may lead to compensatory changes in choline metabolism. This study investigated the hypothesis that reductions in methyl group supply, either due to dietary folate deficiency or Mthfr gene deletion, would modify tissue choline metabolism in a sex-specific manner. Mthfr wild type (+/+) or heterozygous (+/−) knockout mice were randomized to a folate-deficient or control diet for 8 wk during which time deuterium-labeled choline (d9-choline) was consumed in the drinking water (~10 μmol/d). Mthfr heterozygosity did not alter brain choline metabolite concentrations, but it did enhance their labeling in males (P < 0.05) and tended to do so in females (P < 0.10), a finding consistent with greater turnover of dietary choline in brains of +/− mice. Dietary folate deficiency in females yielded 52% higher (P = 0.027) hepatic glycerophosphocholine, which suggests that phosphatidylcholine (PtdCho) degradation was enhanced. Labeling of the hepatic PtdCho in d3 form was also reduced (P < 0.001) in females, which implies that fewer of the dietary choline-derived methyl groups were used for de novo PtdCho biosynthesis under conditions of folate insufficiency. Males responded to folate restriction with a doubling (P < 0.001) of hepatic choline dehydrogenase transcripts, a finding consistent with enhanced conversion of choline to the methyl donor, betaine. Collectively, these data show that several adaptations in choline metabolism transpire as a result of mild perturbations in folate metabolism, presumably to preserve methyl group homeostasis. PMID:21697299

Pseudohypoparathyroidism

MedlinePlus

... one parent needs to pass you the faulty gene for you to have the condition. It is also called Albright hereditary osteodystrophy. The condition causes short stature, round face, obesity, developmental delay, and short hand bones. Symptoms depend ...

Industrialization and the increasing risk of genome instability in developing countries: nutrigenomics as a promising antidote.

PubMed

Anetor, J I

2010-12-01

Increased reliance on chemicals in the industrializing developing countries places new demands on them, as they have limited resources to adequately regulate exposure to these chemicals. Majority of the chemicals cause mutation in DNA among others. The consequences of increased exposure to chemicals on the genome and their mitigation by Nutrigenomics, a science concerned with the prevention of genome damage by nutritional factors is poorly recognized in these countries. Growing evidence indicates that genome instability in the absence of overt exposure to genotoxicants is a sensitive marker of nutritional deficiency. Therefore, the increasing prevalence of chemicals in these countries which contribute to genome disturbances and the widespread nutritional deficiency, at least double the risk of genome instability.Environmental pollutants such polychlorobiphenyls, metal fumes, and fly ash, common in these countries are known to increase urinary level of 8-hydroxy deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, precursor of genome instability.Increasing evidence emphasizes the importance of zinc in both genetic stability and function. Zinc deficiency has been linked with oxidative stress, DNA damage and impairment of repair mechanisms as well as risk of cancer. Zinc plays an important role in vitamin A metabolism from which the retinoids are derived. Zinc is also an important component of the p53 protein, a DNA damage sensor which prevents genetic lesions contributing to genome instability.Zinc deficiency ranks among the top 10 leading causes of death in developing countries. A large proportion of the population in these countries ingests less than 50% of the RDA for Zn.This makes this genome protective nutrient among others grossly inadequate. Folate now also recognized for its role in genome stability, is among the nutrients frequently cited as critical to genome stability. Folate deficiency of sub- clinical degree is common. Reduced folate intake causes as much genome damage as that induced by exposure to a high dose of ionizing radiation. Even moderate folate deficiency causes very severe damage to the genome in the general population. All these accentuate the susceptibility of populations in these nations to environmental toxic assault requiring preventive measures employing the science of Nutrigenomics, probably augmented with adaptive response pathways such as the Nrf2 signaling pathway. Human populations in developing countries are increasingly exposed to a diverse array of industrial chemicals, which adversely modify the genome, the precursor of many diseases especially cancer. Nutrigenomics encompasses nutritional factors that protect the genome from damage and is a promising new field that can be exploited, perhaps augmented with the Nrf2 signaling pathway with international collaboration in these nations as an antidote to chemical-induced genome instability.

DIETARY FOLATE DEFICIENCY ENHANCES INDUCTION OF MICRONUCLEI BY ARSENIC IN MICE

EPA Science Inventory

Folate deficiency increases background levels of DNA damage and can enhance the genotoxicity of chemical agents. Arsenic, a known human carcinogen present in drinking water supplies around the world, induces chromosomal and DNA damage. The effect of dietary folate deficiency on...

Folates in Asian noodles: III. Fortification, impact of processing, and enhancement of folate intakes.

PubMed

Bui, Lan T T; Small, Darryl M

2007-06-01

Asian noodles, a widely consumed staple food, were evaluated as potential vehicles for fortification with folic acid. Samples of white salted, yellow alkaline, and instant noodles, prepared under controlled laboratory conditions, were fortified and folates were measured at each stage of processing using a microbiological assay. Although the 3 styles showed differing patterns of retention, overall losses were slightly more than 40% and were similar for all styles. White salted and yellow alkaline noodles showed no significant decrease in total folate content during production. In contrast, significant losses occurred for instant noodles during steaming and deep-frying of the noodle strands. In all cases, substantial losses occurred during subsequent cooking of the dried noodles. Fortification at a rate of 50% of the reference value per serving resulted in retention of folate at levels corresponding to 30% following cooking, whereas unfortified noodles contributed less than 4% per serving. It is concluded that fortifying Asian noodles provides an effective means for enhancing folate intake.

Changing micronutrient intake through (voluntary) behaviour change. The case of folate.

PubMed

Jensen, Birger B; Lähteenmäki, Liisa; Grunert, Klaus G; Brown, Kerry A; Timotijevic, Lada; Barnett, Julie; Shepherd, Richard; Raats, Monique M

2012-06-01

The objective of this study was to relate behaviour change mechanisms to nutritionally relevant behaviour and demonstrate how the different mechanisms can affect attempts to change these behaviours. Folate was used as an example to illuminate the possibilities and challenges in inducing behaviour change. The behaviours affecting folate intake were recognised and categorised. Behaviour change mechanisms from "rational model of man", behavioural economics, health psychology and social psychology were identified and aligned against folate-related behaviours. The folate example demonstrated the complexity of mechanisms influencing possible behavioural changes, even though this only targets the intake of a single micronutrient. When considering possible options to promote folate intake, the feasibility of producing the desired outcome should be related to the mechanisms of required changes in behaviour and the possible alternatives that require no or only minor changes in behaviour. Dissecting the theories provides new approaches to food-related behaviour that will aid the development of batteries of policy options when targeting nutritional problems. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Clinical and genetic special features of Niemann-Pick disease, type C].

PubMed

Zakharova, E Iu; Mikhaĭlova, S V; Proshliakova, T Iu; Rudenskaia, G E

2012-01-01

Niemann-Pick disease, type C is a rare hereditary disorder of the group of lisosomal storage diseases, caused by mutations in the genes NPC1 or NPC2. Depending on the onset age, several clinical forms of this disease, which differs by manifestation age, main clinical signs and clinical course, are distinguished. Niemann-Pick disease type C can imitate other hereditary and acquired diseases, which complicates its early diagnostics. Clinical and genetic diversity of this disorder, considered on the clinical cases diagnosed at the FSI "RCMG" of RAMS, are discussed in this review.

Folate targeted polymeric 'green' nanotherapy for cancer

NASA Astrophysics Data System (ADS)

Narayanan, Sreeja; Binulal, N. S.; Mony, Ullas; Manzoor, Koyakutty; Nair, Shantikumar; Menon, Deepthy

2010-07-01

The concept of 'green' chemotherapy by employing targeted nanoparticle mediated delivery to enhance the efficacy of phytomedicines is reported. Poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulating a well known nutraceutical namely, grape seed extract (GSE)—'NanoGSE'—was prepared by a nanoprecipitation technique. The drug-loaded nanoparticles of size ~ 100 nm exhibited high colloidal stability at physiological pH. Molecular receptor targeting of this nanophytomedicine against folate receptor over-expressing cancers was demonstrated in vitro by conjugation with a potential cancer targeting ligand, folic acid (FA). Fluorescence microscopy and flow cytometry data showed highly specific cellular uptake of FA conjugated NanoGSE on folate receptor positive cancer cells. Studies were also conducted to investigate the efficiency of targeted (FA conjugated) versus non-targeted (non-FA conjugated) nanoformulations in causing cancer cell death. The IC50 values were lowered by a factor of ~ 3 for FA-NanoGSE compared to the free drug, indicating substantially enhanced bioavailability to the tumor cells, sparing the normal ones. Receptor targeting of FA-NanoGSE resulted in a significant increase in apoptotic index, which was also quantified by flow cytometry and fluorescence microscopy. This in vitro study provides a basis for the use of nanoparticle mediated delivery of anticancer nutraceuticals to enhance bioavailability and effectively target cancer by a 'green' approach.

Vitamin-responsive disorders: cobalamin, folate, biotin, vitamins B1 and E.

PubMed

Baumgartner, Matthias R

2013-01-01

The catalytic properties of many enzymes depend on the participation of vitamins as obligatory cofactors. Vitamin B12 (cobalamin) and folic acid (folate) deficiencies in infants and children classically present with megaloblastic anemia and are often accompanied by neurological signs. A number of rare inborn errors of cobalamin and folate absorption, transport, cellular uptake, and intracellular metabolism have been delineated and identification of disease-causing mutations has improved our ability to diagnose and treat many of these conditions. Two inherited defects in biotin metabolism are known, holocarboxylase synthetase and biotinidase deficiency. Both lead to multiple carboxylase deficiency manifesting with metabolic acidosis, neurological abnormalities, and skin rash. Thiamine-responsive megaloblastic anemia is characterized by megaloblastic anemia, non-type I diabetes, and sensorineural deafness that responds to pharmacological doses of thiamine (vitamin B1). Individuals affected with inherited vitamin E deficiencies including ataxia with isolated vitamin E deficiency and abetalipoproteinemia present with a spinocerebellar syndrome similar to patients with Friedreich's ataxia. If started early, treatment of these defects by oral or parenteral administration of the relevant vitamin often results in correction of the metabolic defect and reversal of the signs of disease, stressing the importance of early and correct diagnosis in these treatable conditions. Copyright © 2013 Elsevier B.V. All rights reserved.

Is it intestinal tuberculosis again? Case report.

PubMed

Brat, Kristián; Merta, Zdeněk; Čundrle, Ivan

This case report focuses on an immigrant admitted to the Department of Respiratory Diseases, University Hospital Brno due to suspicion of relapsing intestinal tuberculosis. The patient presented with fever, night sweat, weight loss, diarrhea, and a history of several tuberculosis attacks in the last few years. None of the examinations confirmed the presence of active tuberculosis but raised suspicion of hematological malignancy. Pancytopenia was present in the peripheral blood. However, bone marrow examination and flowcytometry excluded the presence of a hematological malignancy. The results pointed to the possibility of vitamin B12 or folate deficiency that were both confirmed consequently by serum biochemical tests. Cobalamin and folate deficiency were caused by short bowel syndrome that developed after a major intestinal resection that the patient underwent in his past. Combined treatment including vitamins, pancreatic enzymes substitution, antidiarrhoics and spasmolytics was administered. The general health status of the patient improved rapidly with restitution of hematopoiesis, weight gain, and a decrease by 80% in daily number of stools. Clinical appearance of intestinal tuberculosis, short bowel syndrome and of cobalamin and folate deficiency as well as pathophysiology, diagnosis and treatment of these uncommon or even rare diseases are discussed in this case report.Key words: intestinal tuberculosis - pancytopenia - short bowel syndrome - vitamin B12 deficiency.

Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy

PubMed Central

Kumar, Ajay; Chelvam, Venkatesh; Sakkarapalayam, Mahalingam; Li, Guo; Sanchez-Cruz, Pedro; Piñero, Natasha S.; Low, Philip S.; Alegria, Antonio E.

2016-01-01

Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a constitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered. PMID:27066312

A comparison of caveolae and caveolin-1 to folate receptor α in retina and retinal pigment epithelium

PubMed Central

Bridges, Christy C.; El-Sherbeny, Amira; Roon, Penny; Ola, M. Shamsul; Kekuda, Ramesh; Ganapathy, Vadivel; Cameron, Richard S.; Cameron, Patricia L.

2015-01-01

Summary Caveolae are flask-shaped membrane invaginations present in most mammalian cells. They are distinguished by the presence of a striated coat composed of the protein, caveolin. Caveolae have been implicated in numerous cellular processes, including potocytosis in which caveolae are hypothesized to co-localize with folate receptor α and participate in folate uptake. Our laboratory has recently localized folate receptor α to the basolateral surface of the retinal pigment epithelium (RPE). It is present also in many other cells of the retina. In the present study, we asked whether caveolae were present in the RPE, and if so, whether their pattern of distribution was similar to folate receptor α. We also examined the distribution pattern of caveolin-1, which can be a marker of caveolae. Extensive electron microscopical analysis revealed caveolae associated with endothelial cells. However, none were detected in intact or cultured RPE. Laser scanning confocal microscopical analysis of intact RPE localized caveolin-1 to the apical and basal surfaces, a distribution unlike folate receptor α. Western analysis confirmed the presence of caveolin-1 in cultured RPE cells and laser scanning confocal microscopy localized the protein to the basal plasma membrane of the RPE, a distribution like that of folate receptor α. This distribution was confirmed by electron microscopic immunolocalization. The lack of caveolae in the RPE suggests that these structures may not be essential for folate internalization in the RPE. PMID:11508338

The targeted behavior of folate-decorated N-succinyl-N'-octyl chitosan evaluated by NIR system in mouse model

NASA Astrophysics Data System (ADS)

Zhu, Hongyan; Deng, Dawei; Chen, Haiyan; Qian, Zhiyu; Gu, Yueqing

2010-11-01

The development of more selective delivery systems for cancer diagnosis and chemotherapy is one of the most important goals of current anticancer research. The purpose of this study is to construct and evaluate the folate-decorated, self-assembled nanoparticles as candidates to deliver near infrared fluorescent dyes into tumors and to investigate the mechanisms underlying the tumor targeting with folate-decorated, self-assembled nanoparticles. Folate-decorated N-succinyl-N'-octyl chitosan (folate-SOC) were synthesized. The chemical modification chitosan could self-assemble into stable micelles in aqueous medium. Micelle size determined by size analysis was around 140 nm in a phosphate-buffered saline (PBS, PH 7.4). Folate-SOC could maintain their structure for up to 15 days in PBS. Near infrared dye ICG-Der-01 as a mode drug was loaded in the micelles, and the entrapment efficiency (EE) and drug loading (DL) were investigated. The targeted behavior of folate-SOC was evaluated by near-infrared fluorescence imaging in vivo on different groups of denuded mice, with A549 or Bel-7402 tumors. The optical imaging results indicated that folated-decorated SOC showed an excellent tumor specificity in Bel-7402 tumor-bearing mice, and weak tumor specificity in A549 tumor bearing mice. We believe that this work can provide insight for the engineering of nanoparticles and be extended to cancer therapy and diagnosis so as to deliver multiple therapeutic agents and imaging probes at high local concentrations.

Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model.

PubMed

Chuang, Shu-Chun; Rota, Matteo; Gunter, Marc J; Zeleniuch-Jacquotte, Anne; Eussen, Simone J P M; Vollset, Stein Emil; Ueland, Per Magne; Norat, Teresa; Ziegler, Regina G; Vineis, Paolo

2013-10-01

Most epidemiologic studies on folate intake suggest that folate may be protective against colorectal cancer, but the results on circulating (plasma or serum) folate are mostly inconclusive. We conducted a meta-analysis of case-control studies nested within prospective studies on circulating folate and colorectal cancer risk by using flexible meta-regression models to test the linear and nonlinear dose-response relationships. A total of 8 publications (10 cohorts, representing 3,477 cases and 7,039 controls) were included in the meta-analysis. The linear and nonlinear models corresponded to relative risks of 0.96 (95% confidence interval (CI): 0.91, 1.02) and 0.99 (95% CI: 0.96, 1.02), respectively, per 10 nmol/L of circulating folate in contrast to the reference value. The pooled relative risks when comparing the highest with the lowest category were 0.80 (95% CI: 0.61, 0.99) for radioimmunoassay and 1.03 (95% CI: 0.83, 1.22) for microbiological assay. Overall, our analyses suggest a null association between circulating folate and colorectal cancer risk. The stronger association for the radioimmunoassay-based studies could reflect differences in cohorts and study designs rather than assay performance. Further investigations need to integrate more accurate measurements and flexible modeling to explore the effects of folate in the presence of genetic, lifestyle, dietary, and hormone-related factors.

A validated ultra-high-performance liquid chromatography-tandem mass spectrometry method for the selective analysis of free and total folate in plasma and red blood cells.

PubMed

Kiekens, Filip; Van Daele, Jeroen; Blancquaert, Dieter; Van Der Straeten, Dominique; Lambert, Willy E; Stove, Christophe P

2015-06-12

A stable isotope dilution LC-MS/MS method is the method of choice for the selective quantitative determination of several folate species in clinical samples. By implementing an integrated approach to determine both the plasma and red blood cell (RBC) folate status, the use of consumables and time remains limited. Starting from a single 300μl whole blood sample, the folate status in plasma and RBCs can be determined after separating plasma and RBCs and sequential washing of the latter with isotonic buffer, followed by reproducible lysis using an ammonium-based buffer. Acidification combines both liberation of protein bound folates and protein precipitation. Sample cleanup is performed using a 96-well reversed-phase solid-phase extraction procedure, similar for both plasma and RBC samples. Analyses are performed by UHPLC-MS/MS. Method validation was successfully performed based on EMA-guidelines and encompassed selectivity, carry-over, linearity, accuracy, precision, recovery, matrix effect and stability. Plasma and RBC folates could be quantified in the range of 1-150nmol/l and 5-1500nmol/l, respectively. This method allows for the determination of 6 folate monoglutamates in both plasma and RBCs. It can be used to determine short and long term folate status in both normal and severely deficient subjects in a single analytical sequence. Copyright © 2015 Elsevier B.V. All rights reserved.

Polymorphism of SLC25A32, the folate transporter gene, is associated with plasma folate levels and bone fractures in Japanese postmenopausal women.

PubMed

Urano, Tomohiko; Shiraki, Masataka; Saito, Mitsuru; Sasaki, Noriko; Ouchi, Yasuyoshi; Inoue, Satoshi

2014-10-01

Elevation of homocysteine is associated with an increased risk for bone fractures. We previously reported that the methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is associated with homocysteine levels and fracture. The association between the fracture and folate levels or their related gene polymorphisms is not completely clear. We speculated that the SLC25A32 gene, the mitochondrial inner membrane folate transporter, also could be implicated in the regulation of folate metabolism and fracture. A total of 851 Japanese postmenopausal women participated in the association study between the single nucleotide polymorphism genotype and plasma homocysteine or folate. We also tested the association between the candidate single nucleotide polymorphism and 663 postmenopausal women. The AA genotype of rs2241777 single nucleotide polymorphism at the 3'UTR region in the SLC25A32 gene was associated with lower plasma folate concentration compared with the other genotypes in 851 postmenopausal women. A total of 674 postmenopausal ambulatory Japanese women were followed up for 5.5 ± 0.1 years (mean ± SE). The AA genotype groups also showed an apparently higher rate and earlier onset of incident fractures than the other genotypes. A total of 407 participants had >70% young-adult mean bone mineral density at the start of the observation. These results show that the SLC25A32 gene polymorphism could be a risk factor for lower folate concentration and future fracture. © 2013 Japan Geriatrics Society.

Molecular photoacoustic imaging of breast cancer using an actively targeted conjugated polymer

PubMed Central

Balasundaram, Ghayathri; Ho, Chris Jun Hui; Li, Kai; Driessen, Wouter; Dinish, US; Wong, Chi Lok; Ntziachristos, Vasilis; Liu, Bin; Olivo, Malini

2015-01-01

Conjugated polymers (CPs) are upcoming optical contrast agents in view of their unique optical properties and versatile synthetic chemistry. Biofunctionalization of these polymer-based nanoparticles enables molecular imaging of biological processes. In this work, we propose the concept of using a biofunctionalized CP for noninvasive photoacoustic (PA) molecular imaging of breast cancer. In particular, after verifying the PA activity of a CP nanoparticle (CP dots) in phantoms and the targeting efficacy of a folate-functionalized version of the same (folate-CP dots) in vitro, we systemically administered the probe into a folate receptor-positive (FR+ve) MCF-7 breast cancer xenograft model to demonstrate the possible application of folate-CP dots for imaging FR+ve breast cancers in comparison to CP dots with no folate moieties. We observed a strong PA signal at the tumor site of folate-CP dots-administered mice as early as 1 hour after administration as a result of the active targeting of the folate-CP dots to the FR+ve tumor cells but a weak PA signal at the tumor site of CP-dots-administered mice as a result of the passive accumulation of the probe by enhanced permeability and retention effect. We also observed that folate-CP dots produced ~4-fold enhancement in the PA signal in the tumor, when compared to CP dots. These observations demonstrate the great potential of this active-targeting CP to be used as a contrast agent for molecular PA diagnostic imaging in various biomedical applications. PMID:25609951

Nutrients in folate-mediated, one-carbon metabolism and risk of rectal tumors in men and women

PubMed Central

Curtin, Karen; Samowitz, Wade S.; Ulrich, Cornelia M.; Wolff, Roger K.; Herrick, Jennifer S; Caan, Bette J.; Slattery, Martha L.

2011-01-01

In an investigation of rectal tumors characterized by CpG Island Methylator Phenotype (CIMP), KRAS2 mutation, and TP53 mutation, we examined associations with dietary and supplemental folate, riboflavin, vitamins B6 andB12, and methionine, nutrients involved in folate-mediated one-carbon metabolism. We also examined folate intake and common MTHFR polymorphisms in relation to CIMP. Data from a population-based study of 951 cases (750 with tumor markers) and 1,205 controls were evaluated using multiple logistic regression models and generalized estimating equations. Reduced risk of methylated tumors was suggested in women with upper tertiles of folate intake (≥0.42 mg/day) vs. lower tertile: OR=0.6, 95%CI 0.3–1.2. In men, a significant 3-fold increased risk of CIMP+ tumor was observed for the upper tertile of folate (≥0.75 mg/day) vs. the lower tertile (<0.44 mg/day): OR=3.2, 95%CI 1.5–6.7. These men consumed a greater proportion of folic-acid fortified foods relative to natural, primarily plant-based sources (52% vs. 48%) than women with CIMP+ tumor (22% vs. 78%). MTHFR 1298A>C influenced folate in male CIMP+ risk (P-interaction<0.01). Our findings suggest folate supplementation effects may differ between genders, perhaps due to variation in MTHFR and/or endogenous/exogenous hormones, and may be important in the initiation and progression of methylated rectal tumors in men. PMID:21462086

Influence of thermal processing on hydrolysis and stability of folate poly-gamma-glutamates in broccoli (Brassica oleracea var. italica), carrot (Daucus carota) and tomato (Lycopersicon esculentum).

PubMed

Munyaka, Ann Wambui; Verlinde, Philippe; Mukisa, Ivan Muzira; Oey, Indrawati; Van Loey, Ann; Hendrickx, Marc

2010-04-14

The folate poly-gamma-glutamate profile, their concentrations, and hydrolysis by endogenous gamma-glutamyl hydrolase (GGH) were evaluated in broccoli, carrot and tomato. Further studies on the effect of time and temperature on folate poly-gamma-glutamate hydrolysis and stability were carried out in broccoli since this vegetable showed the highest long-chain and total folate poly-gamma-glutamate concentration. The evolution of l-ascorbic acid, total phenols and Trolox equivalent antioxidant capacity (TEAC) values was evaluated in parallel. Upon thermal inactivation of GGH prior to crushing, it was observed that broccoli, carrot and tomato contained poly-gamma-glutamates with one to seven glutamate residues but differed in the predominant poly-gamma-glutamates. Crushing of raw broccoli, carrot and tomato resulted in significant poly-gamma-glutamate profile changes in broccoli and carrot (indicating GGH-catalyzed hydrolysis) but not in tomato. In this study, the actual crushing of raw broccoli matrix had a greater effect on folate poly-gamma-glutamate hydrolysis than incubation conditions (0-30 min at 25-55 degrees C). During treatments at 25-140 degrees C, folate retention was higher at 80 and 100 degrees C than at the other temperatures. A similar trend in thermal stability was observed for folates, vitamin C, total phenols and TEAC value, an indication that conditions that result in endogenous antioxidants degradation might also result in folate degradation.

Low concentrations of folate, not hyperhomocysteinemia, are associated with carotid intima-media thickness.

PubMed

Durga, Jane; Bots, Michiel L; Schouten, Evert G; Kok, Frans J; Verhoef, Petra

2005-04-01

We examined whether total homocysteine, B vitamins and the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism are related to common carotid intima-media thickness, a marker of atherosclerosis, and carotid distension, a marker of arterial stiffness. We used cross-sectional data from 819 individuals aged 50-70 years. B-mode ultrasound of the distal common carotid arteries was performed to determine maximum carotid intima-media thickness, mean carotid intima-media thickness and distension. Carotid intima-media thickness and distension did not differ across homocysteine, serum folate, vitamin B(6) and vitamin B(12) quartiles or between MTHFR C677T genotype. Erythrocyte folate was independently associated with maximum carotid intima-media thickness (mean difference first versus third quartile, 0.03 mm, 95% CI 0.004-0.06 mm; first versus fourth quartile, 0.03 mm, 95% CI -0.002 to 0.06 mm). Further adjustment for homocysteine did not affect this association. Folate deficient subjects had greater maximum carotid intima-media thickness than those with high-normal folate concentrations (serum folate: mean difference 0.05 mm, 95% CI 0.01-0.08 mm; erythrocyte folate: mean difference 0.04 mm, 95% CI -0.03 to 0.11 mm). Low folate concentrations, independent of hyperhomocysteinemia, may promote atherogenesis. Our findings confirm the null association of homocysteine with carotid intima-media thickness observed in other population-based studies, suggesting that hyperhomocysteinemia does not perpetuate atherosclerosis or arterial stiffness.

Quantifying folic acid-functionalized multi-walled carbon nanotubes bound to colorectal cancer cells for improved photothermal ablation

NASA Astrophysics Data System (ADS)

Graham, Elizabeth G.; MacNeill, Christopher M.; Levi-Polyachenko, Nicole H.

2013-05-01

Peritoneal metastases of colorectal cancer are a significant challenge in the field of medicine today due to poor results of systemic chemotherapy caused by the poor diffusion of drugs across the blood-peritoneal barrier. Multi-walled carbon nanotubes (MWNTs) are a biocompatible nanomaterial that strongly absorb near-infrared light to locally heat the surrounding area. Colorectal cancer is known to overexpress folate receptor; therefore, folic acid (FA) was covalently attached to MWNTs to target colorectal cancer cells. Results from real-time polymerase chain reaction found differing expression of folate receptor-α in two colorectal cancer cell lines, RKO and HCT116, as well as a healthy epithelial cell line, HEPM. A spectrophotometric method was developed to quantify the mass of MWNTs bound to cells, and it was determined that FA-targeted MWNTs resulted in a 400-500 % greater affinity for colorectal cancer cells than untargeted MWNTs. The non-cancerous cell line, HEPM, had higher non-specific MWNT interaction and similar MWNT-FA affinity. Stimulated by 1,064 nm light, FA-functionalized MWNTs caused a 50-60 % decrease in colorectal cancer cell viability compared to a 4-10 % decrease caused by untargeted MWNTs. Our results indicate that FA-targeted MWNTs may increase the therapeutic index of MWNT-induced photothermal therapy.

Folate composition of ten types of mushrooms determined by liquid chromatography-mass spectrometry

USDA-ARS?s Scientific Manuscript database

White button, crimini, shiitake, maitake, enoki, oyster, chanterelle, morel, portabella, and uv-treated portabella mushrooms were sampled from U.S. retail outlets and major producers. Folate (5-methyltetrahydrofolate [5MTHF], 10-formyl folate [10FF], 5-formyltetrahydrofolate [5FTHF]) was analyzed u...

Concentration of folate in colorectal tissue biopsies predicts prevalence of adenomatous polyps

USDA-ARS?s Scientific Manuscript database

Background and aims: Folate has been implicated as a potential aetiological factor for colorectal cancer. Previous research has not adequately exploited concentrations of folate in normal colonic mucosal biopsies to examine the issue. Methods: Logistic regression models were used to estimate ORs ...

Hereditary Mixed Polyposis Syndrome

MedlinePlus

... family. For most families with HMPS, a specific gene mutation causing the syndrome cannot be identified, although some ... Most, but not all, people with inherited GREM1 gene mutations are of Ashkenazi Jewish ancestry. How is HMPS ...

Folate supplementation in people with sickle cell disease.

PubMed

Dixit, Ruchita; Nettem, Sowmya; Madan, Simerjit S; Soe, Htoo Htoo Kyaw; Abas, Adinegara Bl; Vance, Leah D; Stover, Patrick J

2018-03-16

Sickle cell disease (SCD) is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with SCD, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with SCD, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating SCD. To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with SCD. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 17 November 2017. Randomised, placebo-controlled trials of folate supplementation for SCD. Four review authors assessed We used the standard Cochrane-defined methodological procedures.Four review authors independently assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. The quality of the evidence was assessed using GRADE. One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with SCD. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children).Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/L and values below 5 µg/L (low-quality evidence). In the folic acid group, values above 18 µg/L were observed in 33 of 41 (81%) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/L, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year (low-quality evidence). It is important to note that none of the raw data for the outcomes listed above were available for analysis.The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio (RR) 0.99 (95% confidence interval (CI) 0.85 to 1.15) (low-quality evidence); major infections, RR 0.89 (95% CI 0.47 to 1.66) (low-quality evidence); dactylitis, RR 0.67 (95% CI 0.35 to 1.27) (low-quality evidence); acute splenic sequestration, RR 1.07 (95% CI 0.44 to 2.57) (low-quality evidence); or episodes of pain, RR 1.16 (95% CI 0.70 to 1.92) (low-quality evidence). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05).Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups.The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low.There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet). One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with SCD was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear.If further trials were conducted, these may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to SCD-related morbidity. Such trials should include people with SCD of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow-up, than the trial currently included in this review. However, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

Folate supplementation in people with sickle cell disease

PubMed Central

Dixit, Ruchita; Nettem, Sowmya; Madan, Simerjit S; Soe, Htoo Htoo Kyaw; Abas, Adinegara BL; Vance, Leah D; Stover, Patrick J

2017-01-01

Background Sickle cell disease is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with sickle cell disease, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with sickle cell disease, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating sickle cell disease. Objectives To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with sickle cell disease. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group’s Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries. Date of last search: 07 December 2015. Selection criteria Randomised, placebo-controlled trials of folate supplementation for sickle cell disease. Data collection and analysis Four review authors assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. We used the standard Cochrane-defined methodological procedures. Main results One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with sickle cell disease. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children). Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 μg/l and values below 5 μg/l. In the folic acid group, values above 18 μg/l were observed in 33 of 41 (81 %) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 μg/l, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year. It is important to note that none of the raw data for the outcomes listed above were available for analysis. The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio 0.99 (95% confidence interval 0.85 to 1.15); major infections, risk ratio 0.89 (95% confidence interval 0.47 to 1.66); dactylitis, risk ratio 0.67 (95% confidence interval 0.35 to 1.27); acute splenic sequestration, risk ratio 1.07 (95% confidence interval 0.44 to 2.57); or episodes of pain, risk ratio 1.16 (95% confidence interval 0.70 to 1.92). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05). Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups. The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low. There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet). Authors’ conclusions One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with sickle cell disease was included in the review. Overall, the trial presented mixed evidence on the review’s outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear. Further trials may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to sickle cell disease-related morbidity. Trials should include people with sickle cell disease of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow up, than the trial currently included in this review. PMID:26880182

["Hereditary and racial welfare" in public health services: support and selection].

PubMed

Donhauser, J

2013-11-01

The long-term aim for the German public health service during National Socialism was a hereditary and racial welfare. Several following legal regulations contributed to the implementation of a specific national socialist population policy on the basis of racial hygiene and gave immense power to health officers. Especially with the Law for the Prevention of Hereditarily Sick Offspring, compulsory sterilisation was legalised and caused about 400,000 victims up to 1945. The central force in this new system was the public health office. The work of two health officers in neighbouring offices in upper Bavaria is compared. Results show that health officers had a large flexibility in their individual estimation. The restrictive interpretation of their duties did not necessarily cause any sanctions by the superior authority. © Georg Thieme Verlag KG Stuttgart · New York.

Genetic Causes of Rickets

PubMed Central

Acar, Sezer; Demir, Korcan; Shi, Yufei

2017-01-01

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches. PMID:29280738

GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.

PubMed

Hengel, H; Keimer, R; Deigendesch, W; Rieß, A; Marzouqa, H; Zaidan, J; Bauer, P; Schöls, L

2018-06-07

Various genetic defects can cause intellectual and developmental disabilities (IDD). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive GPT2 mutations have recently been associated with IDD in four families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in five patients from two consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Due to the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Identification of a Novel GJA8 (Cx50) Point Mutation Causes Human Dominant Congenital Cataracts

NASA Astrophysics Data System (ADS)

Ge, Xiang-Lian; Zhang, Yilan; Wu, Yaming; Lv, Jineng; Zhang, Wei; Jin, Zi-Bing; Qu, Jia; Gu, Feng

2014-02-01

Hereditary cataracts are clinically and genetically heterogeneous lens diseases that cause a significant proportion of visual impairment and blindness in children. Human cataracts have been linked with mutations in two genes, GJA3 and GJA8, respectively. To identify the causative mutation in a family with hereditary cataracts, family members were screened for mutations by PCR for both genes. Sequencing the coding regions of GJA8, coding for connexin 50, revealed a C > A transversion at nucleotide 264, which caused p.P88T mutation. To dissect the molecular consequences of this mutation, plasmids carrying wild-type and mutant mouse ORFs of Gja8 were generated and ectopically expressed in HEK293 cells and human lens epithelial cells, respectively. The recombinant proteins were assessed by confocal microscopy and Western blotting. The results demonstrate that the molecular consequences of the p.P88T mutation in GJA8 include changes in connexin 50 protein localization patterns, accumulation of mutant protein, and increased cell growth.

A Novel Approach to Evaluating the Iron and Folate Status of Women of Reproductive Age in Uzbekistan after 3 Years of Flour Fortification with Micronutrients

PubMed Central

Hund, Lauren; Northrop-Clewes, Christine A.; Nazario, Ronald; Suleymanova, Dilora; Mirzoyan, Lusine; Irisova, Munira; Pagano, Marcello; Valadez, Joseph J.

2013-01-01

Background The Uzbekistan 1996 Demographic Health Survey reported 60.4% of women of reproductive age (WRA) had low hemoglobin concentrations (<120 g/L), and anemia was an important public health problem. Fortification of wheat flour was identified as an appropriate intervention to address anemia due to the ubiquitous consumption of wheat flour. A National Flour Fortification Program (NFFP) was implemented in 2005. Methodology/Principal Findings After 3-years of the NFFP, a national survey using large country-lot quality assurance sampling was carried out to assess iron, folate, hemoglobin and inflammation status of WRA; the coverage and knowledge of the fortified first grade UzDonMakhsulot (UDM) flour/grey loaf program; and consumption habits of women to investigate the dietary factors associated with anemia. Estimated anemia prevalence was 34.4% (95% CI: 32.0, 36.7), iron depletion 47.5% (95% CI: 45.1, 49.9) and folate deficiency 28.8% (95% CI: 26.8, 30.8); the effect of inflammation was minimal (4% with CRP >5 mg/L). Severe anemia was more prevalent among folate deficient than iron depleted WRA. Presence of UDM first grade flour or the grey loaf was reported in 71.3% of households. Among WRA, 32.1% were aware of UDM fortification; only 3.7% mentioned the benefits of fortification and 12.5% understood causes of anemia. Consumption of heme iron-containing food (91%) and iron absorption enhancers (97%) was high, as was the consumption of iron absorption inhibitors (95%). Conclusions/Significance The NFFP coincided with a substantial decline in the prevalence of anemia. Folate deficiency was a stronger predictor of severe anemia than iron depletion. However, the prevalence of iron depletion was high, suggesting that women are not eating enough iron or iron absorption is inhibited. Fortified products were prevalent throughout Uzbekistan, though UDM flour must be adequately fortified and monitored in the future. Knowledge of fortification and anemia was low, suggesting consumer education should be prioritized. PMID:24260293

78 FR 117 - Certain Reduced Folate Nutraceutical Products and L- Methylfolate Raw Ingredients Used Therein...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-02

... INTERNATIONAL TRADE COMMISSION [Inv. No. 337-TA-857] Certain Reduced Folate Nutraceutical Products and L- Methylfolate Raw Ingredients Used Therein: Notice of Commission Determination Not To Review an... States of certain folate nutraceutical products and l-methylfolate raw ingredients used therein that...

77 FR 57115 - Certain Reduced Folate; Nutraceutical Products and L-Methylfolate Raw Ingredients Used Therein...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-17

... and L-Methylfolate Raw Ingredients Used Therein; Notice of Receipt of Complaint; Solicitation of... entitled Certain Reduced Folate Nutraceutical Products and L-methylfolate Raw Ingredients Used Therein, DN... importation of certain reduced folate nutraceutical products and L- methylfolate raw ingredients used therein...

Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer risk in three large nested case-control studies

USDA-ARS?s Scientific Manuscript database

Few prospective studies have examined the associations between blood levels of folate, in conjunction with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, and colorectal cancer. We evaluated the associations between plasma folate, MTHFR C677T, and A1298C, and colorectal cancer in three la...

Biomarkers of Nutrition for Development-Folate Review.

PubMed

Bailey, Lynn B; Stover, Patrick J; McNulty, Helene; Fenech, Michael F; Gregory, Jesse F; Mills, James L; Pfeiffer, Christine M; Fazili, Zia; Zhang, Mindy; Ueland, Per M; Molloy, Anne M; Caudill, Marie A; Shane, Barry; Berry, Robert J; Bailey, Regan L; Hausman, Dorothy B; Raghavan, Ramkripa; Raiten, Daniel J

2015-07-01

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. © 2015 American Society for Nutrition.

Macrophage uptake and accumulation of folates are polarization-dependent in vitro and in vivo and are regulated by activin A.

PubMed

Samaniego, Rafael; Palacios, Blanca Soler; Domiguez-Soto, Ángeles; Vidal, Carlos; Salas, Azucena; Matsuyama, Takami; Sánchez-Torres, Carmen; de la Torre, Inmaculada; Miranda-Carús, Maria Eugenia; Sánchez-Mateos, Paloma; Puig-Kröger, Amaya

2014-05-01

Vitamin B9, commonly known as folate, is an essential cofactor for one-carbon metabolism that enters cells through three major specialized transporter molecules (RFC, FR, and PCFT), which differ in expression pattern, affinity for substrate, and ligand-binding pH dependency. We now report that the expression of the folate transporters differs between macrophage subtypes and explains the higher accumulation of 5-MTHF-the major folate form found in serum-in M2 macrophages in vitro and in vivo. M1 macrophages display a higher expression of RFC, whereas FRβ and PCFT are preferentially expressed by anti-inflammatory and homeostatic M2 macrophages. These differences are also seen in macrophages from normal tissues involved in folate transit (placenta, liver, colon) and inflamed tissues (ulcerative colitis, RA), as M2-like macrophages from normal tissues express FRβ and PCFT, whereas TNF-α-expressing M1 macrophages from inflamed tissues are RFC+. Besides, we provide evidences that activin A is a critical factor controlling the set of folate transporters in macrophages, as it down-regulates FRβ, up-regulates RFC expression, and modulates 5-MTHF uptake. All of these experiments support the notion that folate handling is dependent on the stage of macrophage polarization. © 2014 Society for Leukocyte Biology.

Effect of genetic polymorphisms involved in folate metabolism on the concentration of serum folate and plasma total homocysteine (p-tHcy) in healthy subjects after short-term folic acid supplementation: a randomized, double blind, crossover study.

PubMed

Cabo, Rona; Hernes, Sigrunn; Slettan, Audun; Haugen, Margaretha; Ye, Shu; Blomhoff, Rune; Mansoor, M Azam

2015-05-01

Data on the effect of combined genetic polymorphisms, involved in folate metabolism, on the concentration of serum folate after folic acid supplementation are scarce. Therefore, we investigated the impact of seven gene polymorphisms on the concentration of serum folate and p-tHcy in healthy subjects after short-term folic acid supplementation. In a randomized, double blind, crossover study, apparently healthy subjects were given either 0.8 mg folic acid per day (n = 46) or placebo (n = 45) for 14 days. The washout period was 14 days. Fasting blood samples were collected on day 1, 15, 30 and 45. Data on subjects on folic acid supplementation (n = 91) and on placebo (n = 45) were used for the statistical analysis. The concentration of serum folate increased higher in subjects with higher age (53.5 ± 7.0 years) than in subjects with lower age (24.3 ± 3.2 years) after folic acid supplementation (p = 0.006). The baseline concentration of serum folate in subjects with polymorphism combination, reduced folate carrier protein, RFC1-80 GA and methylenetetrahydrofolate reductase, MTHFR677 CT+TT, was lower than RFC1-80 AA and MTHFR677 CT+TT (p = 0.002). After folic acid supplementation, a higher increase in the concentration of serum folate was detected in subjects with polymorphism combination RFC1-80 GA and MTHFR677 CC than RFC1-80 GG and MTHFR CT+TT combination (p < 0.0001). The baseline concentration of plasma total homocysteine (p-tHcy) was altered by combined polymorphisms in genes associated with folate metabolism. After folic acid supplementation, in subjects with combined polymorphisms in methylenetetrahydrofolate dehydrogenase, MTHFD1-1958 and MTHFR-677 genes, the concentration of p-tHcy was changed (p = 0.002). The combination of RFC1-80 and MTHFR-677 polymorphisms had a profound affect on the concentration of serum folate in healthy subjects before and after folic acid supplementation.

Study of wheat breakfast rolls fortified with folic acid. The effect on folate status in women during a 3-month intervention.

PubMed

Johansson, Madelene; Witthöft, Cornelia M; Bruce, Ake; Jägerstad, Margaretha

2002-12-01

Folate has come into focus due to its protective role against child birth defects such as neural tube defects (NTD). Swedish authorities recommend all fertile women to increase their folate intake to 400 microg/day by eating folate-rich foods. Because not all women follow these recommendations, there is a discussion today about whether Sweden should introduce folic acid fortification in wheat flour and sifted rye flour. This decision needs knowledge about the bioavailability of folic acid from fortified foods. To investigate effects of two folic acid fortification levels on folate status in healthy female volunteers and to study the folic acid stability during the baking procedure and storage of the fortified breakfast rolls. Twenty-nine healthy women were recruited. Folic acid-fortified wheat breakfast rolls were baked with the purpose to contain 200 microg folic acid/roll (roll L) and 400 microg folic acid/roll (roll H). Fourteen women were given one roll/day of roll L (group L) and 15 one roll/day of roll H (group H) during 12 weeks of intervention. Fasting venous blood samples were collected on days 0, 30, 60 and 90. Serum homocysteine concentrations were determined using an immunoassay. Serum and erythrocyte folate concentrations were analysed using a protein-binding assay with fluorescent quantification. The folic acid concentration in the breakfast rolls was analysed by HPLC on days 0, 30, 60 and 90. Total folate concentration was measured with microbiological assay on day 45. Group L Group L had initially an average erythrocyte folate concentration of 577 +/- 93 nmol/L. After 90 days of intervention, an increase of 20 % (p < 0.05) was observed. At day 0, mean serum folate concentrations were 16.9 +/- 4.3 nmol/L. The mean serum folate concentrations increased by 30 % (p < 0.001) after 90 days. At day 0, mean serum homocysteine concentrations were 9.1 +/- 2.0 micromol/L, which decreased by 20 % (p < 0.01) after 30 days. Group H Group H had an initial erythrocyte folate concentration of 784 +/- 238 nmol/L. After 90 days, an increase of 26 % (p < 0.05) was observed. Serum folate increased at least 22 % after 30 days, from a level of 18.7 +/- 4.8 nmol/L at day 0. Thereafter, all women of group H had serum concentrations at or above the upper limit of quantification (23 nmol/L). At day 0, mean serum homocysteine concentrations were 8.4 +/- 1.7 micromol/L, which decreased by 16 % (p < 0.05) after 30 days. The baking procedure resulted in 20-25 % loss of fortified folic acid in the rolls used in the present study. The size of the rolls affected the retention of folic acid during baking. No significant loss was seen in folic acid concentration in the rolls during the intervention period. The present study showed that in healthy women, subjected to a 12-week intervention with breakfast rolls fortified with either 166 microg or 355 microg folic acid, serum homocysteine concentration decreased (p < 0.05) and erythrocyte folate increased (p < 0.05). The lower level of fortification seems to be sufficient to improve the folate status. Together with the average daily intake of natural folates, these women reach the recommended intake of 400 microg/day. Folic acid is stable in fortified bread for 90 days storage at -20 degrees C.

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

PubMed Central

Davidson, G. L.; Murphy, S. M.; Polke, J. M.; Laura, M.; Salih, M. A. M.; Muntoni, F.; Blake, J.; Brandner, S.; Davies, N.; Horvath, R.; Price, S.; Donaghy, M.; Roberts, M.; Foulds, N.; Ramdharry, G.; Soler, D.; Lunn, M. P.; Manji, H.; Davis, M. B.; Houlden, H.; Reilly, M. M.

2013-01-01

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. PMID:22302274

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

PubMed

Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

2012-08-01

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

The Identification of Alpha-Synuclein as the First Parkinson Disease Gene

PubMed Central

Nussbaum, Robert L.

2017-01-01

In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey’s observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein’s role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide. PMID:28282812

The Identification of Alpha-Synuclein as the First Parkinson Disease Gene.

PubMed

Nussbaum, Robert L

2017-01-01

In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey's observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein's role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide.

Parent Beliefs about the Causes of Learning and Developmental Problems among Children with Autism Spectrum Disorder: Results from a National Survey

ERIC Educational Resources Information Center

Zuckerman, Katharine E.; Lindly, Olivia J.; Sinche, Brianna

2016-01-01

This study aimed to assess variation in parent beliefs about causes of learning and developmental problems in U.S. children with autism spectrum disorder, using data from a nationally representative survey. Results showed that beliefs about a genetic/hereditary cause of learning/developmental problems were most common, but nearly as many parents…

Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.

PubMed

Rogers, Eugene J

2008-09-01

The inverse association between maternal folate status and incidence of infants born with neural tube defects (NTD's) was recognized over twenty years ago and led the US health agencies in the early 1990s to recommend that women of childbearing age consume 400 microg of folic acid each day. The FDA followed by mandating that certain foods be fortified with folic acid and this has resulted in a significant enhancement of maternal folate status to levels that are often difficult to otherwise achieve naturally. At least one study indicates that this has decreased the incidence of NTD's. However, this same time period directly coincides with what many feel is the apparent beginning and continuous increase in the prevalence of Autism and related Autism Spectrum Disorders (ASD's) in the US. Are these similar time frames of changes in maternal folate status and possible Autism prevalence a random event or has improved maternal (and fetal) folate status during pregnancy played a role? It is not only plausible but highly likely. A particular polymorphic form to a key enzyme required to activate folate for methylation in neurodevelopment, 5-methylenetetrahydrofolate reductase (MTHFR), demonstrates reduced activity under low or normal folate levels but normal activity under conditions of higher folate nutritional status. A consequence of the presence of the polymorphic form of this enzyme during normal or reduced folate status are higher plasma homocysteine levels than noncarriers and the combination of these factors have been shown in several studies to result in an increase rate of miscarriage via thrombotic events. However, the incidence of hyperhomocysteinemia in the presence of the polymorphism is reduced under the common condition of enhanced folate status and thereby masks the latent adverse effects of the presence of this enzyme form during pregnancy. Of great importance is that this polymorphism, although common in the normal population, is found in significantly higher frequency in Autisic individuals. It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates. This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period. If these numbers have increased then so have the absolute number of infants that after birth fail to maintain the higher folate status experienced in utero thus leading to an increased number of cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well as other methionine cycle enzymes related to folate metabolism and methylation at birth as part of newborn screening programs could determine which newborns need be monitored and maintained on diets or supplements that ensure adequate folate status during this critical postnatal neurodevelopment period.

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

PubMed Central

Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N.; D’Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F.; Zeviani, Massimo; Salomao, Solange R.; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A.; Tancredi, Andrea; Mancini, Massimiliano; d’Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro

2014-01-01

Leber’s hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber’s hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber’s hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies. PMID:24369379

Influence of 5,10-methylenetetrahydrofolate reductase polymorphism on whole-blood folate concentrations measured by LC-MS/MS, microbiologic assay, and bio-rad radioassay.

PubMed

Fazili, Zia; Pfeiffer, Christine M; Zhang, Mindy; Jain, Ram B; Koontz, Deborah

2008-01-01

The 5,10-methylenetetrahydrofolate reductase (NADPH) (MTHFR) C677T polymorphism may affect whole-blood folate pattern measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and total folate measured by LC-MS/MS, microbiologic assay, and Bio-Rad radioassay (BR). We analyzed 171 whole blood hemolysates from 2 blood banks for folate pattern and total folate concentrations using these 3 methods and determined MTHFR genotype. The median (range) total folate concentration by LC-MS/MS was higher in the US set [378 (228-820) nmol/L; n = 96] than in the European set [250 (122-582) nmol/L; n = 75]. The whole-blood folate pattern [median (range)] was similar for individuals with C/C (n = 73) and C/T (n = 66) genotype: 88% (71%-91%) and 86% (50%-91%), respectively, for 5-methyltetrahydrofolic acid (5CH(3)THF) vs 12% (9%-29%) and 14% (9%-51%) for forms other than 5-methyltetrahydrofolic acid (non-5CH(3)THF). Individuals with T/T (n = 32) genotype had 58% (22%-87%) 5CH(3)THF vs 42% (13%-78%) non-5CH(3)THF. Compared with microbiologic assay results, LC-MS/MS (r = 0.94) and BR (r = 0.87) results were significantly lower (-10% and -45%, respectively); however, these differences were concentration dependent and also genotype dependent for the BR assay (-48% for C/C+C/T and -31% for T/T). The microbiologic assay completely recovered [mean (SD)] folates added to a whole blood hemolysate, except for tetrahydrofolic acid (THF) [46.4% (8.1%)]. The BR assay under-recovered 5CH(3)THF [51% (4.1%)] and 5-formyltetrahydrofolic acid [18% (0.1%)], and over-recovered THF [152% (19%)]. MTHFR C677T polymorphism influences the folate pattern in whole blood. The agreement between total folate by LC-MS/MS and microbiologic assay, independent of the MTHFR genotype, allows the use of one regression equation. Because BR results are genotype dependent, different regression equations should be used.

Treatment of depression: time to consider folic acid and vitamin B12.

PubMed

Coppen, Alec; Bolander-Gouaille, Christina

2005-01-01

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similarly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.

Super-Resolution Localization Microscopy of γ-H2AX and Heterochromatin after Folate Deficiency.

PubMed

Bach, Margund; Savini, Claudia; Krufczik, Matthias; Cremer, Christoph; Rösl, Frank; Hausmann, Michael

2017-08-08

Folate is an essential water-soluble vitamin in food and nutrition supplements. As a one-carbon source, it is involved in many central regulatory processes, such as DNA, RNA, and protein methylation as well as DNA synthesis and repair. Deficiency in folate is considered to be associated with an increased incidence of several malignancies, including cervical cancer that is etiologically linked to an infection with "high-risk" human papilloma viruses (HPV). However, it is still not known how a recommended increase in dietary folate after its deprivation affects the physiological status of cells. To study the impact of folate depletion and its subsequent reconstitution in single cells, we used quantitative chromatin conformation measurements obtained by super-resolution fluorescence microscopy, i.e., single molecule localization microscopy (SMLM). As a read-out, we examined the levels and the (re)positioning of γ-H2AX tags and histone H3K9me3 heterochromatin tags after immunostaining in three-dimensional (3D)-conserved cell nuclei. As model, we used HPV16 positive immortalized human keratinocytes that were cultivated under normal, folate deficient, and reconstituted conditions for different periods of time. The results were compared to cells continuously cultivated in standard folate medium. After 13 weeks in low folate, an increase in the phosphorylation of the histone H2AX was noted, indicative of an accumulation of DNA double strand breaks. DNA repair activity represented by the formation of those γ-H2AX clusters was maintained during the following 15 weeks of examination. However, the clustered arrangements of tags appeared to relax in a time-dependent manner. Parallel to the repair activity, the chromatin methylation activity increased as detected by H3K9me3 tags. The progress of DNA double strand repair was accompanied by a reduction of the detected nucleosome density around the γ-H2AX clusters, suggesting a shift from hetero- to euchromatin to allow access to the repair machinery. In conclusion, these data demonstrated a folate-dependent repair activity and chromatin re-organization on the SMLM nanoscale level. This offers new opportunities to further investigate folate-induced chromatin re-organization and the associated mechanisms.

Plasma choline and betaine correlate with serum folate, plasma S-adenosyl-methionine and S-adenosyl-homocysteine in healthy volunteers.

PubMed

Imbard, Apolline; Smulders, Yvo M; Barto, Rob; Smith, Desiree E C; Kok, Robert M; Jakobs, Cornelis; Blom, Henk J

2013-03-01

Choline is essential for mammalian cell function. It plays a critical role in cell membrane integrity, neurotransmission, cell signaling and lipid metabolism. Moreover, choline is involved in methylation in two ways: a) its synthesis requires methyl groups donated by S-adenosyl-methionine (AdoMet); and b) choline oxidation product betaine methylates homocysteine (Hcy) to methionine (Met) and produces dimethylglycine. This later donates one carbon units to tetrahydrofolate (THF). To evaluate the correlations of choline and betaine with folate, AdoMet, S-anenosyl-homocysteine (AdoHcy), total homocysteine (tHcy), and DNA methylation, choline, betaine and dimethylglycine were measured by LC-MS/MS in plasma of 109 healthy volunteers, in whom folate, AdoMet, AdoHcy, tHcy, and DNA methylation have previously been reported. Using a bivariate model, choline and betaine showed strong positive correlations with folate (r = 0.346 and r = 0.226), AdoHcy (r = 0.468 and r = 0.296), and correlated negatively with AdoMet/AdoHcy ratio (r = – 0.246 and r = – 0.379). Only choline was positively correlated with AdoMet (r = 0.453). Using a multivariate linear regression model, choline correlated strongly with folate ( β = 17.416), AdoMet ( β = 61.272), and AdoHcy ( β = 9.215). Betaine correlated positively with folate ( β = 0.133) and negatively with tHcy ( β = – 0.194) ratio. Choline is an integral part of folate and methylation pathways. Our data highlight the importance of integrating choline in studies concerning addressing pathological conditions related to folate, homocysteine and methylation metabolism.

The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins.

PubMed

Birn, Henrik

2006-07-01

Over the past 10 years, animal studies have uncovered the molecular mechanisms for the renal tubular recovery of filtered vitamin and vitamin carrier proteins. Relatively few endocytic receptors are responsible for the proximal tubule uptake of a number of different vitamins, preventing urinary losses. In addition to vitamin conservation, tubular uptake by endocytosis is important to vitamin metabolism and homeostasis. The present review focuses on the receptors involved in renal tubular recovery of folate, vitamin B12, and their carrier proteins. The multiligand receptor megalin is important for the uptake and tubular accumulation of vitamin B12. During vitamin load, the kidney accumulates large amounts of free vitamin B12, suggesting a possible storage function. In addition, vitamin B12 is metabolized in the kidney, suggesting a role in vitamin homeostasis. The folate receptor is important for the conservation of folate, mediating endocytosis of the vitamin. Interaction between the structurally closely related, soluble folate-binding protein and megalin suggests that megalin plays an additional role in the uptake of folate bound to filtered folate-binding protein. A third endocytic receptor, the intrinsic factor-B12 receptor cubilin-amnionless complex, is essential to the renal tubular uptake of albumin, a carrier of folate. In conclusion, uptake is mediated by interaction with specific endocytic receptors also involved in the renal uptake of other vitamins and vitamin carriers. Little is known about the mechanisms regulating intracellular transport and release of vitamins, and whereas tubular uptake is a constitutive process, this may be regulated, e.g., by vitamin status.

Dietary Supplement Use and Folate Status during Pregnancy in the United States1

PubMed Central

Branum, Amy M.; Bailey, Regan; Singer, Barbara J.

2016-01-01

Adequate folate and iron intake during pregnancy is critical for maternal and fetal health. No previous studies to our knowledge have reported dietary supplement use and folate status among pregnant women sampled in NHANES, a nationally representative, cross-sectional survey. We analyzed data on 1296 pregnant women who participated in NHANES from 1999 to 2006 to characterize overall supplement use, iron and folic acid use, and RBC folate status. The majority of pregnant women (77%) reported use of a supplement in the previous 30 d, most frequently a multivitamin/-mineral containing folic acid (mean 817 μg/d) and iron (48 mg/d). Approximately 55–60% of women in their first trimester reported taking a folic acid- or iron-containing supplement compared with 76–78% in their second trimester and 89% in their third trimester. RBC folate was lowest in the first trimester and differed by supplement use across all trimesters. Median RBC folate was 1628 nmol/L among users and 1041 nmol/L among nonusers. Among all pregnant women, median RBC folate increased with trimester (1256 nmol/L in the first, 1527 nmol/L in the second, and 1773 nmol/L in the third). Given the role of folic acid in the prevention of neural tube defects, it is notable that supplement use and median RBC folate was lowest in the first trimester of pregnancy, with 55% of women taking a supplement containing folic acid. Future research is needed to determine the reasons for low compliance with supplement recommendations, particularly folic acid, in early pregnancy. PMID:23365107

Betaine is as effective as folate at re-synthesizing methionine for protein synthesis during moderate methionine deficiency in piglets.

PubMed

McBreairty, Laura E; Robinson, Jason L; Harding, Scott V; Randell, Edward W; Brunton, Janet A; Bertolo, Robert F

2016-12-01

Both folate and betaine (synthesized from choline) are nutrients used to methylate homocysteine to reform the amino acid methionine following donation of its methyl group; however, it is unclear whether both remethylation pathways are of equal importance during the neonatal period when remethylation rates are high. Methionine is an indispensable amino acid that is in high demand in neonates not only for protein synthesis, but is also particularly important for transmethylation reactions, such as creatine and phosphatidylcholine synthesis. The objective of this study was to determine whether supplementation with folate, betaine, or a combination of both can equally re-synthesize methionine for protein synthesis when dietary methionine is limiting. Piglets were fed a low methionine diet devoid of folate, choline, and betaine, and on day 6, piglets were supplemented with either folate, betaine, or folate + betaine (n = 6 per treatment) until day 10. [1- 13 C]-phenylalanine oxidation was measured as an indicator of methionine availability for protein synthesis both before and after 2 days of supplementation. Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46 % lower with any methyl donor supplementation (P = 0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P < 0.05). These data demonstrate an equal capacity for betaine and folate to remethylate methionine for protein synthesis, as indicated by lower phenylalanine oxidation.

Learner-centered nutrition education improves folate intake and food-related behaviors in nonpregnant, low-income women of childbearing age.

PubMed

Cena, Emily R; Joy, Amy Block; Heneman, Karrie; Espinosa-Hall, Gloria; Garcia, Linda; Schneider, Connie; Wooten Swanson, Patti C; Hudes, Mark; Zidenberg-Cherr, Sheri

2008-10-01

Recent studies suggest low-income women of childbearing age may be at risk of suboptimal folate intake. To evaluate the effect of learner-centered nutrition education on folate intake and food-related behaviors among nonpregnant, low-income women of childbearing age, compared to education unrelated to nutrition. Participants were randomly assigned by recruitment site to receive either the nutrition lesson or a control lesson about resource management. Nonpregnant, low-income (< or =185% federal poverty level) women of childbearing age (18 to 45 years, n=155) from five California counties. Changes in folate intake and other food-related behaviors. Analysis of covariance, adjusting for baseline responses and potential confounders. Adjusting for baseline, participants who received the nutrition education had greater increases in folate intake and use of the Nutrition Facts label than the control group. Change in intake of specific folate-rich foods differed by ethnicity. Participants in the Special Supplemental Nutrition Program for Women, Infants, and Children who received the nutrition education increased folate intake but had no significant changes in other food-related behaviors. Food stamp recipients who received the nutrition education had no significant changes in folate intake but did increase the frequency of eating more than one kind of vegetable each day, compared to controls. This study supports the use of learner-centered approaches to nutrition education for low-income audiences, compared to education unrelated to nutrition. Future work is needed to compare learner-centered techniques to traditional pedagogical nutrition education, and to determine whether observed changes from this study persist over the long term.

The association of DNA damage response and nucleotide level modulation with the antibacterial mechanism of the anti-folate drug trimethoprim.

PubMed

Sangurdekar, Dipen P; Zhang, Zhigang; Khodursky, Arkady B

2011-11-28

Trimethoprim is a widely prescribed antibiotic for a variety of bacterial infections. It belongs to a class of anti-metabolites - antifolates - which includes drugs used against malarial parasites and in cancer therapy. However, spread of bacterial resistance to the drug has severely hampered its clinical use and has necessitated further investigations into its mechanism of action and treatment regimen. Trimethoprim selectively starves bacterial cells for tetrahydrofolate, a vital cofactor necessary for the synthesis of several metabolites. The outcome (bacteriostatic or bactericidal) of such starvation, however, depends on the availability of folate-dependent metabolites in the growth medium. To characterize this dependency, we investigated in detail the regulatory and structural components of Escherichia coli cellular response to trimethoprim in controlled growth and supplementation conditions. We surveyed transcriptional responses to trimethoprim treatment during bacteriostatic and bactericidal conditions and analyzed associated gene sets/pathways. Concurrent starvation of all folate dependent metabolites caused growth arrest, and this was accompanied by induction of general stress and stringent responses. Three gene sets were significantly associated with the bactericidal effect of TMP in different media including LB: genes of the SOS regulon, genes of the pyrimidine nucleotide biosynthetic pathway and members of the multiple antibiotic resistance (mar) regulon controlled by the MarR repressor. However, the SOS response was identified as the only universal transcriptional signature associated with the loss of viability by direct thymine starvation or by folate stress. We also used genome-wide gene knock-out screen to uncover means of sensitization of bacteria to the drug. We observed that among a number of candidate genes and pathways, the effect of knock-outs in the deoxyribose nucleotide salvage pathway, encoded by the deoCABD operon and under the control of the DeoR repressor, was most informative. Transcriptional induction of DNA damage response is an essential feature of the bactericidal effect of trimethoprim. Either the observation of the transcriptional response or DNA damage itself, or both, is made possible by thymine starvation when other folate-dependent metabolites are not limited. The effect of DNA damage by the drug takes place prior to its bactericidal effect, at the beginning of the lag stage of the treatment. Mutations in the deoxyribose nucleotide salvage pathway can affect duration of the lag as well as the rate of killing. This information can be used to postulate certain mechanistic differences between direct thymine starvation in thymidylate synthase deficient mutants and thymine starvation by anti-folate inhibitors. © 2011 Sangurdekar et al; licensee BioMed Central Ltd.

Dietary folate and choline status differentially affect lipid metabolism and behavior-mediated neurotransmitters in young rats

USDA-ARS?s Scientific Manuscript database

The relationship between choline and folate metabolisms is an important issue due to the essential role of these nutrients in brain plasticity and cognitive functions. Present study was designed to investigate whether modification of the dietary folate-choline status in young rats would affect brain...

DNA methyltransferase mediates dose-dependent stimulation of neural stem cell proliferation by folate.

PubMed

Li, Wen; Yu, Min; Luo, Suhui; Liu, Huan; Gao, Yuxia; Wilson, John X; Huang, Guowei

2013-07-01

The proliferative response of neural stem cells (NSCs) to folate may play a critical role in the development, function and repair of the central nervous system. It is important to determine the dose-dependent effects of folate in NSC cultures that are potential sources of transplantable cells for therapies for neurodegenerative diseases. To determine the optimal concentration and mechanism of action of folate for stimulation of NSC proliferation in vitro, NSCs were exposed to folic acid or 5-methyltetrahydrofolate (5-MTHF) (0-200 μmol/L) for 24, 48 or 72 h. Immunocytochemistry and methyl thiazolyl tetrazolium assay showed that the optimal concentration of folic acid for NSC proliferation was 20-40 μmol/L. Stimulation of NSC proliferation by folic acid was associated with DNA methyltransferase (DNMT) activation and was attenuated by the DNMT inhibitor zebularine, which implies that folate dose-dependently stimulates NSC proliferation through a DNMT-dependent mechanism. Based on these new findings and previously published evidence, we have identified a mechanism by which folate stimulates NSC growth. Copyright © 2013 Elsevier Inc. All rights reserved.

Anaemia, folate and vitamin B12 deficiency among pregnant women in an area of unstable malaria transmission in eastern Sudan.

PubMed

Abdelrahim, Ishraga I; Adam, Gamal K; Mohmmed, Ahmed A; Salih, Magdi M; Ali, Naji I; Elbashier, Mustafa I; Adam, Ishag

2009-05-01

A cross-sectional study was carried out between October 2007 and January 2008 to investigate the prevalence and types of anaemia among pregnant women of eastern Sudan. Socio-demographic and obstetrical data were collected using a questionnaire. Haemoglobin (Hb), serum ferritin, serum folate and vitamin B(12) were assessed using standard laboratory methods. Two hundred and seventy-nine pregnant Sudanese women were recruited. Anaemia (Hb <11 gdl) and iron deficiency (ferritin <15 microg/l) were prevalent in 80.3 and 14.3% of the study sample, respectively. Of the total sample, 11.1% had iron-deficiency anaemia. Serum folate (<6.6 ng/ml) and vitamin B(12) (<150 pg/ml) deficiency was reported in 57.7 and 1%, respectively, and none of the women had both folate and vitamin B(12) deficiencies. Univariate and multivariate analyses showed that ferritin, serum folate and vitamin B(12) levels were not significantly associated with anaemia. Thus, there was a high prevalence of anaemia and folate deficiency. Measures to control these should be considered.

Suppression of homocysteine levels by vitamin B12 and folates: age and gender dependency in the Jackson Heart Study.

PubMed

Henry, Olivia R; Benghuzzi, Hamed; Taylor, Herman A; Tucci, Michelle; Butler, Kenneth; Jones, Lynne

2012-08-01

To examine factors potentially contributing to premature cardiovascular disease mortality in African Americans (40% versus 20% all other populations), plasma homocysteine, serum vitamin B12 and folate levels were examined for African American participants in the Jackson Heart Study. Of 5192 African American Jackson Heart Study participants (21-94 years), 5064 (mean age, 55 ± 13 years; 63% female) had homocysteine levels measured via fasting blood samples, with further assessments of participants' vitamin B12 (n = 1790) and folate (n = 1788) levels. Regression analyses were used to examine age, gender, vitamin B12 and folate with homocysteine levels. Homocysteine levels, a purported surrogate risk factor for cardiovascular disease, increased with age, were inversely proportional to folate and vitamin B12 levels (P < 0.001) and were higher for men of all ages. The results show that, as with other populations, age, gender, vitamin B12 and folate may predict homocysteine levels for African Americans. Diet may be an important predictive factor as well, given the relationships that were observed between plasma homocysteine and serum B vitamin levels.

[Metabolic flux analysis of L-serine synthesis by Corynebacterium glutamicum SYPS-062].

PubMed

Zhang, Xiaomei; Dou, Wenfang; Xu, Hongyu; Xu, Zhenghong

2010-10-01

Corynebacterium glutamicum SYPS-062 was an L-serine producing strain stored at our lab and could produce L-serine directly from sugar. We studied the effects of cofactors in one carbon unit metabolism-folate and VB12 on the cell growth, sucrose consumption and L-serine production by SYPS-062. In the same time, the metabolic flux distribution was determined in different conditions. The supplementation of folate or VB12 enhanced the cell growth, energy synthesis, and finally increased the flux of pentose phosphate pathway (HMP), whereas the carbon flux to L-serine was decreased. The addition of VB12 not only increased the ratio of L-serine synthesis pathway on G3P joint, but also caused the insufficiency of tricarboxylic acid cycle (TCA) flux, which needed more anaplerotic reaction flux to replenish TCA cycle, that was an important limiting factor for the further increasing of the L-serine productivity.

Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006123

PubMed Central

Dodd, Kevin W; Gahche, Jaime J; Dwyer, Johanna T; McDowell, Margaret A; Yetley, Elizabeth A; Sempos, Christopher A; Burt, Vicki L; Radimer, Kathy L; Picciano, Mary Frances

2010-01-01

Background: The term total folate intake is used to represent folate that occurs naturally in food as well as folic acid from fortified foods and dietary supplements. Folic acid has been referred to as a double-edged sword because of its beneficial role in the prevention of neural tube defects and yet possible deleterious effects on certain cancers and cognitive function. Previous monitoring efforts did not include folic acid from dietary supplements and are therefore not complete. Objective: Our objective was to combine data on dietary folate (as measured by two 24-h recalls) and folic acid from dietary supplements (collected with a 30-d frequency questionnaire) with the use of the bias-corrected best power method to adjust for within-person variability. Design: The National Health and Nutrition Examination Survey (NHANES) is a nationally representative, cross-sectional survey. Linear contrasts were constructed to determine differences in dietary and total folate intake for age and racial-ethnic groups by sex; prevalence of inadequate and excessive intakes is presented. Results: In 2003–2006, 53% of the US population used dietary supplements; 34.5% used dietary supplements that contained folic acid. Total folate intake (in dietary folate equivalents) was higher for men (813 ± 14) than for women (724 ± 16) and higher for non-Hispanic whites (827 ± 19) than for Mexican Americans (615 ± 11) and non-Hispanic blacks (597 ± 12); 29% of non-Hispanic black women had inadequate intakes. Total folate and folic acid intakes are highest for those aged ≥50 y, and 5% exceed the Tolerable Upper Intake Level. Conclusions: Improved total folate intake is warranted in targeted subgroups, which include women of childbearing age and non-Hispanic black women, whereas other population groups are at risk of excessive intake. PMID:19923379

Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate123

PubMed Central

Miller, Joshua W; Garrod, Marjorie G; Allen, Lindsay H; Haan, Mary N

2009-01-01

Background: An analysis of data from the National Health and Nutrition Examination Survey indicated that in older adults exposed to folic acid fortification, the combination of low serum vitamin B-12 and elevated folate is associated with higher concentrations of homocysteine and methylmalonic acid and higher odds ratios for cognitive impairment and anemia than the combination of low vitamin B-12 and nonelevated folate. These findings await confirmation in other populations. Objective: The purpose was to compare metabolic indicators of vitamin B-12 status, cognitive function, and depressive symptoms among elderly Latinos with elevated and nonelevated plasma folate. Design: Cross-sectional data were analyzed for 1535 subjects (age: ≥60 y) from the Sacramento Area Latino Study on Aging. Subjects were divided into 4 groups on the basis of plasma vitamin B-12 (< or ≥148 pmol/L) and folate (≤ or >45.3 nmol/L). Homocysteine, methylmalonic acid, holotranscobalamin, ratio of holotranscobalamin to vitamin B-12, Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were compared between the groups. Results: Individuals with low vitamin B-12 and elevated folate (n = 22) had the highest concentrations of homocysteine and methylmalonic acid and the lowest concentration of holotranscobalamin and ratio of holotranscobalamin to vitamin B-12 when compared with all other groups (P ≤ 0.003). No differences in Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were observed between the low vitamin B-12 and elevated-folate group compared with other groups. Conclusions: Low vitamin B-12 is associated with more pronounced metabolic evidence of vitamin B-12 deficiency when folate is elevated than when folate is not elevated. These data should be considered when assessing the potential costs, risks, and benefits of folic acid and vitamin B-12 fortification programs. PMID:19726595

Folate-Dependent Purine Nucleotide Biosynthesis in Humans.

PubMed

Baggott, Joseph E; Tamura, Tsunenobu

2015-09-01

Purine nucleotide biosynthesis de novo (PNB) requires 2 folate-dependent transformylases-5'-phosphoribosyl-glycinamide (GAR) and 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) transformylases-to introduce carbon 8 (C8) and carbon 2 (C2) into the purine ring. Both transformylases utilize 10-formyltetrahydrofolate (10-formyl-H4folate), where the formyl-carbon sources include ring-2-C of histidine, 3-C of serine, 2-C of glycine, and formate. Our findings in human studies indicate that glycine provides the carbon for GAR transformylase (exclusively C8), whereas histidine and formate are the predominant carbon sources for AICAR transformylase (C2). Contrary to the previous notion, these carbon sources may not supply a general 10-formyl-H4folate pool, which was believed to equally provide carbons to C8 and C2. To explain these phenomena, we postulate that GAR transformylase is in a complex with the trifunctional folate-metabolizing enzyme (TFM) and serine hydroxymethyltransferase to channel carbons of glycine and serine to C8. There is no evidence for channeling carbons of histidine and formate to AICAR transformylase (C2). GAR transformylase may require the TFM to furnish 10-formyl-H4folate immediately after its production from serine to protect its oxidation to 10-formyldihydrofolate (10-formyl-H2folate), whereas AICAR transformylase can utilize both 10-formyl-H2folate and 10-formyl-H4folate. Human liver may supply AICAR to AICAR transformylase in erythrocytes/erythroblasts. Incorporation of ring-2-C of histidine and formate into C2 of urinary uric acid presented a circadian rhythm with a peak in the morning, which corresponds to the maximum DNA synthesis in the bone marrow, and it may be useful in the timing of the administration of drugs that block PNB for the treatment of cancer and autoimmune disease. © 2015 American Society for Nutrition.

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

PubMed Central

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

2013-01-01

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

Folate, vitamin B6, vitamin B12 and methionine intakes and risk for nasopharyngeal carcinoma in Chinese adults: a matched case-control study.

PubMed

Zeng, Fang-fang; Liu, Yuan-ting; Lin, Xiao-ling; Fan, Yu-Ying; Zhang, Xing-lan; Xu, Chun-hua; Chen, Yu-ming

2016-01-14

Many studies have suggested that folate-related one-carbon metabolism-related nutrients may play a role in certain cancer risks, but few studies have assessed their associations with the risk for nasopharyngeal carcinoma (NPC). In this study, we investigated the association between four folate-related one-carbon metabolism-related nutrients (folate, vitamin B6, vitamin B12 and methionine) and NPC risk in Chinese adults. A total of 600 patients newly diagnosed (within 3 months) with NPC were individually matched with 600 hospital-based controls by age, sex and household type (urban v. rural). Folate, vitamin B6, vitamin B12 and methionine intakes were measured using a validated seventy-eight-item FFQ. A higher dietary folate or vitamin B6 intake was associated with a lower NPC risk after adjusting for potential confounders. The adjusted OR of NPC for quartiles 2-4 (v. 1) were 0·66 (95% CI 0·48, 0·91), 0·52 (95% CI 0·37, 0·74) and 0·34 (95% CI 0·23, 0·50) (P(trend)<0·001) for folate and 0·72 (95% CI 0·52, 1·00), 0·55 (95% CI 0·39, 0·78) and 0·44 (95% CI 0·30, 0·63) (P(trend)<0·001) for vitamin B6. No significant association with NPC risk was observed for dietary vitamin B12 or methionine intake. The risk for NPC with dietary folate intake was more evident in the participants who were not exposed to toxic substances than in those who were exposed (P(interaction)=0·014). This study suggests that dietary folate and vitamin B6 may be protective for NPC in a high-risk population.

Socioeconomic factors are associated with folate and vitamin B12 intakes and related biomarkers concentrations in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence study.

PubMed

Iglesia, Iris; Mouratidou, Theodora; González-Gross, Marcela; Novakovic, Romana; Breidenassel, Christina; Jiménez-Pavón, David; Huybrechts, Inge; De Henauw, Stefaan; Geelen, Anouk; Gottrand, Frédéric; Kafatos, Anthony; Mistura, Lorenza; de Heredia, Fátima Pérez; Widhalm, Kurt; Manios, Yanis; Molnar, Denes; Stehle, Peter; Gurinovic, Mirjana; Cavelaars, Adrienne E J M; Van't Veer, Pieter; Moreno, Luis A

2014-03-01

Because socioeconomic factors (SEFs) may influence dietary quality and vitamin intakes, this study aimed to examine associations between socioeconomic factors and folate and vitamin B12 intakes as well as their related biomarkers in the Healthy Lifestyle in Europe by Nutrition in Adolescence study. Vitamin intakes were obtained from two 24-hour recalls in 2253 participants (47% males). Vitamin B biomarkers were assessed in a subsample of 977 participants (46% males). Socioeconomic factors were assessed by questionnaire, and 1-way analysis of covariance and linear regression analysis were applied. For males and females, mean intakes of folate were 211.19 and 177.18 μg/d, and for vitamin B12, 5.98 and 4.54 μg/d, respectively. Levels of plasma folate, red blood cell folate, serum B12, and holotranscobalamin were 18.74, 807.19, 330.64, and 63.04 nmol/L in males, respectively, and 19.13, 770.16, 377.9, and 65.63 nmol/L in females, respectively. Lower folate intakes were associated with several SEFs, including maternal and paternal education in both sexes. Regarding folate biomarkers, lower plasma folate intakes were associated with single/shared care in males and with lower paternal occupation in females. Lower vitamin B12 intakes were associated with almost all the studied SEFs, except paternal occupation in both sexes. In females, when considering vitamin B12 biomarkers, lower plasma vitamin B12 was associated with lower maternal education and occupation, and lower holotranscobalamin was associated with lower maternal education and lower paternal occupation. In conclusion, from the set of socioeconomic determinants studied in a sample of European adolescents, maternal education and paternal occupation were more consistently associated with folate and vitamin B12 intakes and biomarkers concentrations. Copyright © 2014 Elsevier Inc. All rights reserved.

The Fragile X Continuum: New Advances and Perspectives

ERIC Educational Resources Information Center

Cornish, K.; Turk, J.; Hagerman, R.

2008-01-01

Fragile X syndrome is the world's most common hereditary cause of intellectual disability in men and to a lesser extent in women. The disorder is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation Gene-1. A substantial body of research across the disciplines of molecular genetics, child psychiatry and…

Exposure to solar ultraviolet radiation is associated with a decreased folate status in women of childbearing age.

PubMed

Borradale, D; Isenring, E; Hacker, E; Kimlin, M G

2014-02-05

In vitro studies indicate that folate in collected human blood is vulnerable to degradation after exposure to ultraviolet (UV) radiation. This has raised concerns about folate depletion in individuals with high sun exposure. Here, we investigate the association between personal solar UV radiation exposure and serum folate concentration, using a three-week prospective study that was undertaken in females aged 18-47years in Brisbane, Australia (153 E, 27 S). Following two weeks of supplementation with 500μg of folic acid daily, the change in serum folate status was assessed over a 7-day period of measured personal sun exposure. Compared to participants with personal UV exposures of <200 Joules per day, participants with personal UV exposures of 200-599 and >600 Joules per day had significantly higher depletion of serum folate (p=0.015). Multivariable analysis revealed personal UV exposure as the strongest predictor accounting for 20% of the overall change in serum folate (Standardised B=-0.49; t=-3.75; p=<0.01). These data show that increasing solar UV radiation exposures reduces the effectiveness of folic acid supplementation. The consequences of this association may be most pronounced for vulnerable individuals, such as women who are pregnant or of childbearing age with high sun exposures. Copyright © 2014 Elsevier B.V. All rights reserved.

Folate status in women of reproductive age as basis of neural tube defect risk assessment.

PubMed

Bailey, Lynn B; Hausman, Dorothy B

2018-02-01

Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific "optimal" red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

Folate and vitamin B12 status of adolescent girls in northern Nigeria.

PubMed Central

VanderJagt, D. J.; Spelman, K.; Ambe, J.; Datta, P.; Blackwell, W.; Crossey, M.; Glew, R. H.

2000-01-01

The diets of populations in many developing countries are low in folate and vitamin B12 and a deficiency of either of these vitamins results in increased risk for cardiovascular disease and neural tube defects. The rates of neural tube defects in Nigeria are among the highest reported worldwide. Since many girls marry at an early age in northern Nigeria, we therefore determined the folate and vitamin B12 status of adolescent girls between 12 and 16 years of age in Maiduguri, Nigeria. The mean serum folate concentration for subjects was 15.3 +/- 5.2 nmol/L. Whereas only four subjects (2.4%) had serum folate concentrations lower than 6.8 nmol/L, a level indicative of negative folate balance, 9% of the subjects had serum vitamin B12 concentrations at or below 134 pmol/L, the lower limit of the reference range for their age group. Serum homocysteine was measured in 56 of the 162 subjects and the mean level was 15.9 +/- 5.0 mumol/L. The majority of subjects had serum homocysteine concentrations above the upper limit of the reference range for their age group. We conclude that the adolescent girls we studied were at greater risk for vitamin B12 deficiency than folate deficiency. This conclusion is consistent with the fact that their diet included few foods that contained vitamin B12. PMID:10946529

Blood folate concentrations among women of childbearing age by race/ethnicity and acculturation, NHANES 2001-2010.

PubMed

Marchetta, Claire M; Hamner, Heather C

2016-01-01

Hispanic women have higher rates of neural tube defects and report lower total folic acid intakes than non-Hispanic white (NHW) women. Total folic acid intake, which is associated with neural tube defect risk reduction, has been found to vary by acculturation factors (i.e. language preference, country of origin, or time spent in the United States) among Hispanic women. It is unknown whether this same association is present for blood folate status. The objective of this research was to assess the differences in serum and red blood cell (RBC) folate concentrations between NHW women and Mexican American (MA) women and among MA women by acculturation factors. Cross-sectional data from the 2001-2010 National Health and Nutrition Examination Survey (NHANES) were used to investigate how blood folate concentrations differ among NHW or MA women of childbearing age. The impact of folic acid supplement use on blood folate concentrations was also examined. MA women with lower acculturation factors had lower serum and RBC folate concentrations compared with NHW women and to their more acculturated MA counterparts. Consuming a folic acid supplement can minimize these disparities, but MA women, especially lower acculturated MA women, were less likely to report using supplements. Public health efforts to increase blood folate concentrations among MA women should consider acculturation factors when identifying appropriate interventions. © 2014 John Wiley & Sons Ltd.

Compliance to the recommended use of folic acid supplements for women in Sweden is higher among those under treatment for infertility than among fertile controls and is also related to socioeconomic status and lifestyle.

PubMed

Murto, Tiina; Yngve, Agneta; Skoog Svanberg, Agneta; Altmäe, Signe; Salumets, Andres; Wånggren, Kjell; Stavreus-Evers, Anneli

2017-01-01

Background : Folate has been discussed in relation to fertility among women, but studies on women under treatment for infertility are lacking. Objective : The objective of this study was to investigate folic acid supplement use and folate status among women under treatment for infertility (hereafter infertile) and fertile women also in regard to socioeconomic and lifestyle factors. Design : Lifestyle and dietary habits, and use of dietary supplements were assessed using a questionnaire. Blood samples were obtained for analysis of folate status. 24-hour recall interviews were also performed. Results : Highly educated, employed and infertile women were most prone to using folic acid supplements. The infertile women had a significantly better folate status than the fertile women. Folate status did not correlate with socioeconomic or lifestyle factors. The infertile women were physically more active, smoked less and were employed. Our questionnaire data had only fair agreement with the data from 24-hour recalls, but the folate status data was clearly correlated to our questionnaire results. Conclusions : Infertile women were most prone to using folic acid supplements and had better folate status than the controls. High educational and employment status were found to be key factors for high compliance to the recommended use folic acid supplements.

Hereditary neuropathy with liability to pressure palsy: two cases of difficult diagnosis.

PubMed

Beydoun, Said R; Cho, Justin

2013-09-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited autosomal dominant disorder that causes a polyneuropathy with predisposition for involvement at sites of compression and is often underdiagnosed or misdiagnosed due to its heterogeneity in clinical and electrophysiological presentation. We report 2 cases of HNPP, which were initially diagnosed and treated as either an acquired demyelinating disorder or alternative inherited demyelinating disorder. Thorough evaluation of repeat electrodiagnostic studies and genetic testing confirmed the diagnosis of HNPP in both cases. One case showed the classic peripheral myelin protein 22 (PMP22) deletion and the other case showed a previously reported single base pair deletion at Leu145 causing a frameshift mutation at the PMP22 gene. These cases underscore the difficulty of diagnosing HNPP, because of the variations in clinical and electrophysiological findings and reinforce the importance of a combination high index of clinical suspicion, electrodiagnostic testing, and genetic testing to make the diagnosis.

[Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a mutation in TFG].

PubMed

Ishiura, Hiroyuki; Tsuji, Shoji

2013-01-01

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal dominant neurodegenerative disease characterized by proximal predominant weakness and muscle atrophy accompanied by distal sensory disturbance. Linkage analysis using 4 families identified a region on chromosome 3 showing a LOD score exceeding 4. Further refinement of candidate region was performed by haplotype analysis using high-density SNP data, resulting in a minimum candidate region spanning 3.3 Mb. Exome analysis of an HMSN-P patient revealed a mutation (c.854C>T, p.Pro285Leu) in TRK-fused gene (TFG). The identical mutation was found in the four families, which cosegregated with the disease. The mutation was neither found in Japanese control subjects nor public databases. Detailed haplotype analysis suggested two independent origins of the mutation. These findings indicate that the mutation in TFG causes HMSN-P.

[Treatment of hereditary angioedema].

PubMed

Qian, X

1990-06-01

Hereditary angioedema is a rare familial disease caused by the defect of complement C1esterase inhibitor (C1-INH). It is characterized by recurrent acute edema of the extremities, the face, the respiratory tract and the gastrointestinal tract. Acute laryngeal edema usually produces laryngeal obstruction. Two cases have been treated since 1986, one of them had been admitted for forty-five times because of recurrent acute laryngeal edema. Investigations showed two families with a high incidence of this disease. Laboratory examination showed a remarkable decrease of C1-INH and C4. Tracheotomy is indicated in patients with laryngeal edema. Great success was achieved in two patients treated with danazol.

Hereditary spastic paraplegias: membrane traffic and the motor pathway

PubMed Central

Blackstone, Craig; O’Kane, Cahir J.; Reid, Evan

2017-01-01

Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution — in axonal maintenance and degeneration. PMID:21139634

Hereditary spastic paraplegias: membrane traffic and the motor pathway.

PubMed

Blackstone, Craig; O'Kane, Cahir J; Reid, Evan

2011-01-01

Voluntary movement is a fundamental way in which animals respond to, and interact with, their environment. In mammals, the main CNS pathway controlling voluntary movement is the corticospinal tract, which encompasses connections between the cerebral motor cortex and the spinal cord. Hereditary spastic paraplegias (HSPs) are a group of genetic disorders that lead to a length-dependent, distal axonopathy of fibres of the corticospinal tract, causing lower limb spasticity and weakness. Recent work aimed at elucidating the molecular cell biology underlying the HSPs has revealed the importance of basic cellular processes — especially membrane trafficking and organelle morphogenesis and distribution— in axonal maintenance and degeneration.

DNA testing in neurologic diseases.

PubMed

O'Brien, D P; Leeb, T

2014-01-01

DNA testing is available for a growing number of hereditary diseases in neurology and other specialties. In addition to guiding breeding decisions, DNA tests are important tools in the diagnosis of diseases, particularly in conditions for which clinical signs are relatively nonspecific. DNA testing also can provide valuable insight into the risk of hereditary disease when decisions about treating comorbidities are being made. Advances in technology and bioinformatics will make broad screening for potential disease-causing mutations available soon. As DNA tests come into more common use, it is critical that clinicians understand the proper application and interpretation of these test results. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Dental experience and self-perceived dental care needs of patients with angioedema.

PubMed

Lodi, G; Sardella, A; Bez, C; Demarosi, F; Cicardi, M; Carrassi, A

2001-01-01

The purpose of this study was to investigate the self-perceived dental care needs and dental experiences of patients with angioedema. At the 1998 annual meeting of the Voluntary Association for the Fight, Study and Treatment of Hereditary Angioedema ("Associazione volontaria per la lotta, lo studio e la terapia dell'angioedema ereditario"), a self-administered questionnaire was distributed to participants affected by hereditary or acquired angioedema. Fifty-seven persons completed the questionnaire (37 females, 20 males; mean age, 39 +/- 17 yrs; range, 5-76). The vast majority (91%) had the hereditary form of the disease. One-third of the respondents had some problems in obtaining oral treatment, with one person having been refused care. About half of the group had experienced an acute attack following dental treatment. Preventive measures needed improvement in about two-thirds of respondents. More than half (58%) of the group perceived a need for dental care. We conclude that persons with angioedema may experience difficulty in obtaining dental treatment, a common cause of acute attacks.

Extrachromosomal Inheritance of Carbon Dioxide Sensitivity in the Mosquito CULEX QUINQUEFASCIATUS

PubMed Central

Shroyer, Donald A.; Rosen, Leon

1983-01-01

Mosquitoes from a laboratory colony of Culex quinquefasciatus from Matsu Island, China, develop irreversible paralytic symptoms after exposure to carbon dioxide at 1°. This CO2 sensitivity is caused by an inherited infectious agent, probably a virus. Crossing studies between CO2-sensitive and -resistant mosquitoes showed that the sensitivity trait is inherited extrachromosomally in a fashion strictly analogous to the hereditary transmission of sigma virus in Drosophila melanogaster. Sensitivity could be maintained through maternal transmission alone, despite nine generations of backcrossing of "stabilized" CO2-sensitive females to males from a resistant strain. CO2-sensitive males crossed to resistant females transmitted sensitivity to a portion of their F 1 progeny, and only the female F1 sensitives were capable of further hereditary transmission.—Matsu, or a very similar hereditary infectious agent, is common in natural populations of Cx. quinquefasciatus on Oahu, Hawaii. Fifty-nine percent of the families reared from field-collected egg rafts contained CO2-sensitive mosquitoes, and some families contained only sensitive mosquitoes. PMID:6413297

[Hereditary sensory and autonomic neuropathy type II A: early neurological and skeletal findings].

PubMed

Esmer, C; Díaz Zambrano, S; Santos Díaz, M A; González Huerta, L M; Cuevas Covarrubias, S A; Bravo Oro, A

2014-04-01

The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Genetic disorder in carbohydrates metabolism: hereditary fructose intolerance associated with celiac disease.

PubMed

Păcurar, Daniela; Leşanu, Gabriela; Dijmărescu, Irina; Ţincu, Iulia Florentina; Gherghiceanu, Mihaela; Orăşeanu, Dumitru

2017-01-01

Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye's-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age.

Vitamin B12 and folate levels in healthy Swiss senior citizens: a prospective study evaluating reference intervals and decision limits.

PubMed

Risch, Martin; Meier, Dominik W; Sakem, Benjamin; Medina Escobar, Pedro; Risch, Corina; Nydegger, Urs; Risch, Lorenz

2015-07-11

The vitamin B12 and folate status in nonanaemic healthy older persons needs attention the more so as decrease in levels may be anticipated from reduced haematinic provision and/or impaired intestinal uptake. A total of 1143 subjectively healthy Swiss midlands participants (637 females and 506 males), ≥60 years of age were included in this study. Levels of vitamin B12, holotranscobalamin (holoTC), methylmalonic acid (MMA), homocysteine (Hcy), serum folate, red blood cell (RBC) folate were measured. Further, Fedosov's wellness score was determined. Associations of age, gender, and cystatin C/creatinine-based estimated kidney function, with the investigated parameters were assessed. Reference intervals were calculated. Further, ROC analysis was done to assess accuracy of the individual parameters in recognizing a deficient vitamin B12 status. Finally, decision limits for sensitive, specific and optimal recognition of vitamin B12 status with individual parameters were derived. Three age groups: 60-69, 70-79 and ≥ 80 had median B12 (pmol/L) levels of 237, 228 and 231 respectively (p = 0.22), holoTC (pmol/L) of 52, 546 and 52 (p = 0.60) but Hcy (μmol/L) 12, 15 and 16 (p < 0.001), MMA (nmol/L) 207, 221 and 244 (p < 0.001). Hcy and MMA (both p < 0.001), but not holoTC (p = 0.12) and vitamin B12 (p = 0.44) were found to be affected by kidney function. In a linear regression model Fedosov's wellness score was independently associated with kidney function (p < 0.001) but not with age. Total serum folate and red blood cell (RBC) folate drift apart with increasing age: whereas the former decreases (p = 0.01) RBC folate remains in the same bandwidth across all age groups (p = 0.12) A common reference interval combining age and gender strata can be obtained for vitamin B12 and holoTC, whereas a more differentiated approach seems warranted for serum folate and RBC folate. Whereas the vitamin B12 and holoTC levels remain steady after 60 years of age, we observed a significant increment in MMA levels accompanied by increments in Hcy; this is better explained by age-related reduced kidney function than by vitamin B12 insufficiency. Total serum folate levels but not RBC folate levels decreased with progressing age.

Heterozygous carriers of classical homocystinuria tend to have higher fasting serum homocysteine concentrations than non-carriers in the presence of folate deficiency.

PubMed

Lu, Yung-Hsiu; Cheng, Li-Mei; Huang, Yu-Hsiu; Lo, Ming-Yu; Wu, Tina Jui-Ting; Lin, Hsiang-Yu; Hsu, Ting-Rong; Niu, Dau-Ming

2015-12-01

Many studies have reported that serum total homocysteine (tHcy) levels in cystathionine-beta-synthase (CBS) carriers are usually normal and only elevated after a methionine load. However, the amount of methionine required for a loading test is non-physiological and is never reached with regular feeding. Therefore, CBS carriers do not seem to be at an increased risk of cardiovascular diseases. However, the risk of cardiovascular diseases of CBS carriers with folate deficiency has not been studied. We recently found an extraordinarily high carrier rate (1/7.78) of a novel CBS mutation (p.D47E, c.T141A) in an Austronesian Taiwanese Tao tribe who live in a geographic area with folate deficiency. We evaluated if the CBS carriers tend to have higher fasting serum tHcy concentrations than non-carriers in presence of folate deficiency. The serum tHcy and folate levels before and after folate replacement were measured in 48 adult Tao carriers, 40 age-matched Tao non-carriers and 40 age-matched Han Taiwanese controls. The serum tHcy level of the Tao CBS carriers (17.9 ± 3.8 μmol/l) was significantly higher than in Tao non-carriers (15.7 ± 3.5 μmol/l; p < 0.008) and Taiwanese controls (11.8 ± 2.9 μmol/l; p < 0.001). Furthermore, a high prevalence of folate deficiency in the Tao compared with the Taiwanese controls (4.9 ± 1.8 ng/ml vs. 10.6 ± 5.5 ng/ml; p < 0.001) was also noted. Of note, the difference in tHcy levels between the carriers and non-carriers was eliminated by folate supplementation. (carriers:13.65 ± 2.13 μmol/l; non-carriers:12.39 ± 3.25 μmol/l, p = 0.321). CBS carriers tend to have a higher tHcy level in the presence of folate deficiency than non-carriers. Although many reports have indicated that CBS carriers are not associated with cardiovascular disease, the risk for CBS carriers with folate deficiency has not been well studied. Owing to a significantly elevated level of fasting tHcy without methionine loading, it is important to evaluate the risk of cardiovascular disease in CBS carriers with folate deficiency. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Dietary and blood folate status of Malaysian women of childbearing age.

PubMed

Khor, Geok Lin; Duraisamy, G; Loh, Su Peng; Green, Timothy

2006-01-01

The protective role of folic acid taken during the periconceptual period in reducing the occurrence of neural tube defects (NTD) has been well documented by epidemiological evidence, randomized controlled trials and intervention studies. Much of the evidence is derived from western populations while similar data on Asian subjects is relatively nascent. Baseline data on folate status of Malaysian women is lacking, while NTD prevalence is estimated as 10 per 10,000 births. This study was conducted with the objective of determining the dietary and blood folate status of Malaysian women of childbearing age. A total of 399 women comprising 140 Malay, 131 Chinese and 128 Indian subjects were recruited from universities and worksites in the suburbs of Kuala Lumpur. Inclusion criteria were that the subjects were not pregnant or breastfeeding, not taking folic acid supplements, not habitual drinkers or smokers. Based on a 24-hour recall, the median intake level for folate was 66 microg (15.7-207.8 microg), which amounts to 16.5% of the Malaysian Recommended Nutrient Intakes level. The median (5-95th percentiles) values for plasma and red cell folate (RBC) concentrations were 11 (4-33) nmol/L and 633 (303-1209) nmol/L respectively. Overall, nearly 15.1% showed plasma folate deficiency (< 6.8 nmol/L), with Indian subjects having the highest prevalence (21.5%). Overall prevalence of RBC folate deficiency (<363 nmol/L) was 9.3%, and an almost similar level prevailed for each ethnic group. Only 15.2% had RBC concentration exceeding 906 nmol/L, which is associated with a very low risk of NTD. The result of this study point to the need for intervention strategies to improve the blood folate status of women of childbearing age, so that they have adequate protection against the occurrence of NTD at birth.

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age

PubMed Central

Crivello, Natalia A.; Blusztajn, Jan K.; Joseph, James A.; Shukitt-Hale, Barbara; Smith, Donald E.

2010-01-01

The hypothesis of this study is that a folate-deficient diet (FD) has a greater effect on cholinergic system in the peripheral nervous system than in the brain, and that this effect escalates with age. It was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats fed either control or folate-deficient diets for 10 weeks, starting at age 4 weeks (the young group) or 9 months (the adult group). FD consumption resulted in depletion of plasma folate in both age groups. In young folate-deficient rats, liver and lung choline levels were significantly lower than those in the respective controls. No other significant effects of FD on choline and acetylcholine metabolism were found in young rats. In adult rats, FD consumption markedly decreased choline levels in the liver, kidneys, and heart; furthermore, choline levels in the cortex and striatum were moderately elevated, although hippocampal choline levels were not affected. Acetylcholine levels were higher in the heart, cortex, and striatum but lower in the hippocampus in adult folate-deficient rats, as compared to controls. Higher acetylcholine levels in the striatum in adult folate-deficient rats were also associated with higher dopamine release in the striatal slices. Thus, both age groups showed higher cholinergic metabolic sensitivity to FD in the peripheral nervous system than in the brain. However, compensatory abilities appeared to be better in the young group, implicating the adult group as a preferred model for further investigation of folate-choline-acetylcholine interactions and their role in brain plasticity and cognitive functions. PMID:21056288

Tales of Dihydrofolate Binding to R67 Dihydrofolate Reductase

PubMed Central

2015-01-01

Homotetrameric R67 dihydrofolate reductase possesses 222 symmetry and a single active site pore. This situation results in a promiscuous binding site that accommodates either the substrate, dihydrofolate (DHF), or the cofactor, NADPH. NADPH interacts more directly with the protein as it is larger than the substrate. In contrast, the p-aminobenzoyl-glutamate tail of DHF, as monitored by nuclear magnetic resonance and crystallography, is disordered when bound. To explore whether smaller active site volumes (which should decrease the level of tail disorder by confinement effects) alter steady state rates, asymmetric mutations that decreased the half-pore volume by ∼35% were constructed. Only minor effects on kcat were observed. To continue exploring the role of tail disorder in catalysis, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide-mediated cross-linking between R67 DHFR and folate was performed. A two-folate, one-tetramer complex results in the loss of enzyme activity where two symmetry-related K32 residues in the protein are cross-linked to the carboxylates of two bound folates. The tethered folate could be reduced, although with a ≤30-fold decreased rate, suggesting decreased dynamics and/or suboptimal positioning of the cross-linked folate for catalysis. Computer simulations that restrain the dihydrofolate tail near K32 indicate that cross-linking still allows movement of the p-aminobenzoyl ring, which allows the reaction to occur. Finally, a bis-ethylene-diamine-α,γ-amide folate adduct was synthesized; both negatively charged carboxylates in the glutamate tail were replaced with positively charged amines. The Ki for this adduct was ∼9-fold higher than for folate. These various results indicate a balance between folate tail disorder, which helps the enzyme bind substrate while dynamics facilitates catalysis. PMID:26637016

Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects.

PubMed

Zhu, Huiping; Yang, Wei; Lu, Wei; Etheredge, Analee J; Lammer, Edward J; Finnell, Richard H; Carmichael, Suzan L; Shaw, Gary M

2012-05-01

We evaluated 35 variants among four folate-mediated one-carbon metabolism pathway genes, MTHFD1, SHMT1, MTHFR, and DHFR as risk factors for conotruncal heart defects. Cases with a diagnosis of single gene disorders or chromosomal aneusomies were excluded. Controls were randomly selected from area hospitals in proportion to their contribution to the total population of live-born infants. Odds ratios (OR) and the 95% confidence intervals (CI) were computed for each genotype (homozygous variant or heterozygote, vs. homozygous wildtype) and for increase of each less common allele (log-additive model). Interactions between each variant and three folate intake variables (maternal multivitamin use, maternal dietary folate intake, and combined maternal folate intake) were also evaluated under the log-additive model. In general, we did not identify notable associations. The A allele of MTHFD1 rs11627387 was associated with a 1.7-fold increase in conotruncal defects risk in both Hispanic mothers (OR = 1.7, 95% CI = 1.1-2.5) and Hispanic infants (OR = 1.7, 95% CI = 1.2-2.3). The T allele of MTHFR rs1801133 was associated with a 2.8-fold increase of risk among Hispanic women whose dietary folate intake was ≤ 25th centile. The C allele of MTHFR rs1801131 was associated with a two-fold increase of risk (OR = 2.0, 95% CI = 1.0-3.9) only among those whose dietary folate intake was >25th centile. Our study suggested that MTHFD1 rs11627387 may be associated with risk of conotruncal defects through both maternal and offspring genotype effect among the Hispanics. Maternal functional variants in MTHFR gene may interact with dietary folate intake and modify the conotruncal defects risk in the offspring. Copyright © 2012 Wiley Periodicals, Inc.

The effect of folate status on the uptake of physiologically relevant compounds by Caco-2 cells.

PubMed

Tavares, Sandra; Sousa, Joana; Gonçalves, Pedro; Araújo, João R; Martel, Fátima

2010-08-25

The aim of this work was to investigate the effect of folate status on the uptake of several physiologically relevant substances by Caco-2 cells. For this, Caco-2 cells cultured in high-folate conditions (HF) and low-folate conditions (LF) were compared. Growth rates of HF and LF Caco-2 cells were similar. However, proliferation rate of LF cells was greater than that of HF cells during the first 2days of culture and slightly smaller thereafter, viability of LF cells was greater than that of HF cells, and apoptosis index was similar in both cell cultures. We verified that in LF cells, comparatively to HF cells: (1) uptake of [3H]folic acid is upregulated, via an increase in the Vmax of uptake; (2) uptake of [3H]deoxy-glucose, [3H]O-methyl-glucose and [3H]1-methyl-4-phenylpyridinium (MPP+) is downregulated, via a decrease in the Vmax of uptake; additionally, a reduction in Km was observed for [3H]O-methyl-glucose; (3) uptake of [3H]5-hydroxytryptamine and [14C]butyrate is not changed; and (4) the steady-state mRNA levels of the folic acid transporters RFC (reduced folate carrier), PCFT (proton-coupled folate transporter) and FRalpha (folate receptor alpha), of the organic cation transporter OCT1 (organic cation transporter type 1), of the glucose transporter GLUT2 (facilitative glucose transporter type 2) and of the butyrate transporter MCT1 (monocarboxylate transporter type 1) were decreased. In conclusion, folate deficiency produces substrate-specific changes in the uptake of bioactive compounds by Caco-2 cells. Moreover, these changes are associated with alterations in the mRNA levels of specific transporters for these compounds. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Blood as a surrogate marker for tissue-specific DNA methylation and changes due to folate depletion in post-partum female mice.

PubMed

McKay, Jill A; Xie, Long; Harris, Sarah; Wong, Yi K; Ford, Dianne; Mathers, John C

2011-07-01

DNA methylation patterns are tissue specific and may influence tissue-specific gene regulation. Human studies investigating DNA methylation in relation to environmental factors primarily use blood-derived DNA as a surrogate for DNA from target tissues. It is therefore important to know if DNA methylation changes in blood in response to environmental changes reflect those in target tissues. Folate intake can influence DNA methylation, via altered methyl donor supply. Previously, manipulations of maternal folate intake during pregnancy altered the patterns of DNA methylation in offspring but, to our knowledge, the consequences for maternal DNA methylation are unknown. Given the increased requirement for folate during pregnancy, mothers may be susceptible to aberrant DNA methylation due to folate depletion. Female mice were fed folate-adequate (2 mg folic acid/kg diet) or folate-deplete (0.4 mg folic acid/kg diet) diets prior to mating and during pregnancy and lactation. Following weaning, dams were killed and DNA methylation was assessed by pyrosequencing® in blood, liver, and kidney at the Esr1, Igf2 differentially methylated region (DMR)1, Igf2 DMR2, Slc39a4CGI1, and Slc39a4CGI2 loci. We observed tissue-specific differences in methylation at all loci. Folate depletion reduced Igf2 DMR1 and Slc39a4CGI1 methylation across all tissues and altered Igf2 DMR2 methylation in a tissue-specific manner (p<0.05). Blood-derived DNA methylation measurements may not always reflect methylation within other tissues. Further measurements of blood-derived and tissue-specific methylation patterns are warranted to understand the complexity of tissue-specific responses to altered nutritional exposure. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Red Blood Cell Folate Insufficiency among Nonpregnant Women of Childbearing Age in Guatemala 2009 to 2010: Prevalence and Predicted Neural Tube Defects Risk

PubMed Central

Rosenthal, Jorge; Reeve, Mary-Elizabeth; Ramirez, Nicte; Crider, Krista S.; Sniezek, Joe; Vellozzi, Claudia; Devine, Owen; Lopez-Pazos, Eunice

2016-01-01

Background The World Health Organization recently released recommendations stating that red blood cell (RBC) folate concentrations should be above 400 ng/L (906 nmol/L) for optimal prevention of folate-sensitive neural tube defects (NTDs). The objective of this study was to determine the distribution of folate insufficiency (FI) (<906 nmol/L) and potential risk of NTDs based on RBC folate concentrations among nonpregnant women of child-bearing age in Guatemala. Methods A national and regional multistage cluster probability survey was completed during 2009 to 2010 among Guatemalan women of child-bearing age 15 to 49 years of age. Demographic and health information and blood samples for RBC folate analyses were collected from 1473 women. Prevalence rate ratios of FI and predicted NTD prevalence were estimated based on RBC folate concentrations comparing subpopulations of interest. Results National FI prevalence was 47.2% [95% confidence interval, 43.3–51.1] and showed wide variation by region (18–81%). In all regions, FI prevalence was higher among indigenous (27–89%) than among nonindigenous populations (16–44%). National NTD risk based on RBC folate concentrations was estimated to be 14 per 10,000 live births (95% uncertainty interval, 11.1–18.6) and showed wide regional variation (from 11 NTDS in the Metropolitan region to 26 NTDs per 10,000 live births in the Norte region). Conclusion FI remains a common problem in populations with limited access to fortified products, specifically rural, low income, and indigenous populations. However, among subpopulations that are most likely to have fortified food, the prevalence of FI is similar to countries with well-established fortification programs. PMID:27010602

A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status

PubMed Central

Friso, Simonetta; Choi, Sang-Woon; Girelli, Domenico; Mason, Joel B.; Dolnikowski, Gregory G.; Bagley, Pamela J.; Olivieri, Oliviero; Jacques, Paul F.; Rosenberg, Irwin H.; Corrocher, Roberto; Selhub, Jacob

2002-01-01

DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-l-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methylTHF), the methyl donor for synthesis of methionine from homocysteine and precursor of S-adenosyl-l-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (T/T) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/T genotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/μg DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T/T subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status. PMID:11929966

Red Blood Cell Folate Insufficiency among nonpregnant Women of Childbearing age in Guatemala 2009 to 2010: Prevalence and predicted Neural Tube Defects risk.

PubMed

Rosenthal, Jorge; Reeve, Mary-Elizabeth; Ramirez, Nicte; Crider, Krista S; Sniezek, Joe; Vellozzi, Claudia; Devine, Owen; Lopez-Pazos, Eunice

2016-07-01

The World Health Organization recently released recommendations stating that red blood cell (RBC) folate concentrations should be above 400 ng/L (906 nmol/L) for optimal prevention of folate-sensitive neural tube defects (NTDs). The objective of this study was to determine the distribution of folate insufficiency (FI) (<906 nmol/L) and potential risk of NTDs based on RBC folate concentrations among nonpregnant women of child-bearing age in Guatemala. A national and regional multistage cluster probability survey was completed during 2009 to 2010 among Guatemalan women of child-bearing age 15 to 49 years of age. Demographic and health information and blood samples for RBC folate analyses were collected from 1473 women. Prevalence rate ratios of FI and predicted NTD prevalence were estimated based on RBC folate concentrations comparing subpopulations of interest. National FI prevalence was 47.2% [95% confidence interval, 43.3-51.1] and showed wide variation by region (18-81%). In all regions, FI prevalence was higher among indigenous (27-89%) than among nonindigenous populations (16-44%). National NTD risk based on RBC folate concentrations was estimated to be 14 per 10,000 live births (95% uncertainty interval, 11.1-18.6) and showed wide regional variation (from 11 NTDS in the Metropolitan region to 26 NTDs per 10,000 live births in the Norte region). FI remains a common problem in populations with limited access to fortified products, specifically rural, low income, and indigenous populations. However, among subpopulations that are most likely to have fortified food, the prevalence of FI is similar to countries with well-established fortification programs. Birth Defects Research (Part A) 106:587-595, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Supplementation with fruit and okara soybean by-products and amaranth flour increases the folate production by starter and probiotic cultures.

PubMed

Albuquerque, Marcela Albuquerque Cavalcanti de; Bedani, Raquel; Vieira, Antônio Diogo Silva; LeBlanc, Jean Guy; Saad, Susana Marta Isay

2016-11-07

The ability of two starter cultures (Streptococcus (S.) thermophilus ST-M6 and St. thermophilus TA-40) and eleven probiotic cultures (St. thermophilus TH-4, Lactobacillus (Lb.) acidophilus LA-5, Lb. fermentum PCC, Lb. reuteri RC-14, Lb. paracasei subsp. paracasei, Lb. casei 431, Lb. paracasei subsp. paracasei F19, Lb. rhamnosus GR-1, and Lb. rhamnosus LGG, Bifidobacterium (B.) animalis subsp. lactis BB-12, B. longum subsp. longum BB-46, and B. longum subsp. infantis BB-02) to produce folate in a modified MRS broth (mMRS) supplemented with different fruit (passion fruit, acerola, orange, and mango) and okara soybean by-products and amaranth flour was investigated. Initially, the folate content of each vegetable substrate was determined: passion fruit by-product showed the lowest folate content (8±2ng/mL) and okara the highest (457±22ng/mL). When the orange by-product and amaranth flour were added to mMRS, all strains were able to increase folate production after 24h of fermentation. B. longum subsp infantis BB-02 produced the highest concentrations (1223±116ng/mL) in amaranth flour. Okara was the substrate that had the lowest impact on the folate production by all strains evaluated. Lb. acidophilus LA-5 (297±36ng/mL) and B. animalis subsp. lactis BB-12 (237±23ng/mL) were also able to produce folate after growth in mMRS containing acerola and orange by-products, respectively. The results of this study demonstrate that folate production is not only strain-dependent but also influenced by the addition of different substrates in the growth media. Copyright © 2016 Elsevier B.V. All rights reserved.

Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men.

PubMed

Zhou, Ziyi; Li, Jianping; Yu, Yaren; Li, Youbao; Zhang, Yan; Liu, Lishun; Song, Yun; Zhao, Min; Wang, Yu; Tang, Genfu; He, Mingli; Xu, Xiping; Cai, Yefeng; Dong, Qiang; Yin, Delu; Huang, Xiao; Cheng, Xiaoshu; Wang, Binyan; Hou, Fan Fan; Wang, Xiaobin; Qin, Xianhui; Huo, Yong

2018-01-01

We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke. The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers ( P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant ( P =0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16-0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48-0.99). Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885. © 2017 American Heart Association, Inc.

Interaction of plasma glutathione redox and folate deficiency on arsenic methylation capacity in Bangladeshi adults

PubMed Central

Niedzwiecki, Megan M.; Hall, Megan N.; Liu, Xinhua; Slavkovich, Vesna; Ilievski, Vesna; Levy, Diane; Alam, Shafiul; Siddique, Abu B.; Parvez, Faruque; Graziano, Joseph H.; Gamble, Mary V.

2014-01-01

Inorganic arsenic (InAs) is metabolized through a series of methylation reactions catalyzed by arsenic(III)-methyltransferase (AS3MT), resulting in the generation of monomethylarsonic (MMAs) and dimethylarsinic acids (DMAs). AS3MT activity requires the presence of the methyl donor S-adenosylmethionine (SAM), a product of folate-dependent one-carbon metabolism, and a reductant. Although glutathione (GSH), the primary endogenous antioxidant, is not required for As methylation, GSH stimulates As methylation rates in vitro. However, the relationship between GSH redox and As methylation capacity in humans is unknown. We wished to test the hypothesis that a more oxidized plasma GSH redox status is associated with decreased As methylation capacity, and examine whether these associations are modified by folate nutritional status. Concentrations of plasma GSH and GSSG, plasma folate, total blood As (bAs), total urinary As (uAs), and uAs metabolites were assessed in a cross-sectional study of n = 376 Bangladeshi adults who were chronically exposed to As in drinking water. We observed that a decreased plasma GSH/GSSG ratio (reflecting a more oxidized redox state) was significantly associated with increased urinary %MMA, decreased urinary %DMA, and increased total bAs in folate-deficient individuals (plasma folate ≤ 9.0 nmol/L). Concentrations of plasma GSH and GSSG were independently associated with increased and decreased As methylation capacity, respectively. No significant associations were observed in folate-sufficient individuals, and interactions by folate status were statistically significant. Our findings suggest that GSH/GSSG redox regulation might contribute to the large interindividual variation in As methylation capacity observed in human populations. PMID:24726863

Uracil misincorporation into DNA and folic acid supplementation123

PubMed Central

Selhub, Jacob; Chao, Wei-Hsun; Ueland, Per Magne; Hunter, David J; Baron, John A

2010-01-01

Background: Folate deficiency decreases thymidylate synthesis from deoxyuridylate, which results in an imbalance of deoxyribonucleotide that may lead to excessive uracil misincorporation (UrMis) into DNA during replication and repair. Objective: We evaluated the relation between UrMis in different tissues and the effect of folate supplementation on UrMis. Design: We analyzed UrMis concentrations in rectal mucosa (n = 92) and white blood cells (WBCs; n = 60) among individuals randomly assigned to receive supplementation with 1 mg folate/d or placebo, who were then evaluated for colorectal adenoma recurrence. Results: As expected, total homocysteine was significantly lower among the study participants who received active folate treatment (Wilcoxon's P = 0.003) than among those in the placebo group. The median UrMis concentration in rectal mucosa and WBCs among individuals treated with folate was not significantly lower than that in those who received placebo (Wilcoxon's P = 0.17). UrMis concentrations in both rectal mucosa and WBCs did not correlate significantly with folate measured in plasma and red blood cells. UrMis in rectal mucosa was marginally associated with an increased risk of adenoma recurrence (odds ratio per SD: 1.43; 95% CI: 0.91, 2.25). Conclusions: UrMis measurements in WBCs are not a robust surrogate for UrMis measurements in the rectal mucosa (Spearman correlation coefficient = 0.23, P = 0.08). Furthermore, folate supplementation in an already replete population (half treated with folic acid supplements and all exposed to folic acid fortification of the food supply) was not significantly associated with reduced UrMis in rectal mucosa cells or WBCs. Large-scale studies are needed to evaluate whether excessive UrMis concentrations are an important risk factor for colorectal neoplasia. This trial was registered at clinicaltrials.gov as NCT00272324. PMID:19923375

Do high blood folate concentrations exacerbate metabolic abnormalities in people with low vitamin B-12 status?123

PubMed Central

Mills, James L; Carter, Tonia C; Scott, John M; Troendle, James F; Gibney, Eileen R; Shane, Barry; Kirke, Peadar N; Ueland, Per M; Brody, Lawrence C; Molloy, Anne M

2011-01-01

Background: In elderly individuals with low serum vitamin B-12, those who have high serum folate have been reported to have greater abnormalities in the following biomarkers for vitamin B-12 deficiency: low hemoglobin and elevated total homocysteine (tHcy) and methylmalonic acid (MMA). This suggests that folate exacerbates vitamin B-12–related metabolic abnormalities. Objective: We determined whether high serum folate in individuals with low serum vitamin B-12 increases the deleterious effects of low vitamin B-12 on biomarkers of vitamin B-12 cellular function. Design: In this cross-sectional study, 2507 university students provided data on medical history and exposure to folic acid and vitamin B-12 supplements. Blood was collected to measure serum and red blood cell folate (RCF), hemoglobin, plasma tHcy, and MMA, holotranscobalamin, and ferritin in serum. Results: In subjects with low vitamin B-12 concentrations (<148 pmol/L), those who had high folate concentrations (>30 nmol/L; group 1) did not show greater abnormalities in vitamin B-12 cellular function in any area than did those with lower folate concentrations (≤30 nmol/L; group 2). Group 1 had significantly higher holotranscobalamin and RCF, significantly lower tHcy, and nonsignificantly lower (P = 0.057) MMA concentrations than did group 2. The groups did not differ significantly in hemoglobin or ferritin. Compared with group 2, group 1 had significantly higher mean intakes of folic acid and vitamin B-12 from supplements and fortified food. Conclusions: In this young adult population, high folate concentrations did not exacerbate the biochemical abnormalities related to vitamin B-12 deficiency. These results provide reassurance that folic acid in fortified foods and supplements does not interfere with vitamin B-12 metabolism at the cellular level in a healthy population. PMID:21653798

Glutamate carboxypeptidase II and folate deficiencies result in reciprocal protection against cognitive and social deficits in mice: implications for neurodevelopmental disorders.

PubMed

Schaevitz, Laura R; Picker, Jonathan D; Rana, Jasmine; Kolodny, Nancy H; Shane, Barry; Berger-Sweeney, Joanne E; Coyle, Joseph T

2012-06-01

Interactions between genetic and environmental risk factors underlie a number of neuropsychiatric disorders, including schizophrenia (SZ) and autism (AD). Due to the complexity and multitude of the genetic and environmental factors attributed to these disorders, recent research strategies focus on elucidating the common molecular pathways through which these multiple risk factors may function. In this study, we examine the combined effects of a haplo-insufficiency of glutamate carboxypeptidase II (GCPII) and dietary folic acid deficiency. In addition to serving as a neuropeptidase, GCPII catalyzes the absorption of folate. GCPII and folate depletion interact within the one-carbon metabolic pathway and/or of modulate the glutamatergic system. Four groups of mice were tested: wild-type, GCPII hypomorphs, and wild-types and GCPII hypomorphs both fed a folate deficient diet. Due to sex differences in the prevalence of SZ and AD, both male and female mice were assessed on a number of behavioral tasks including locomotor activity, rotorod, social interaction, prepulse inhibition, and spatial memory. Wild-type mice of both sexes fed a folic acid deficient diet showed motor coordination impairments and cognitive deficits, while social interactions were decreased only in males. GCPII mutant mice of both sexes also exhibited reduced social propensities. In contrast, all folate-depleted GCPII hypomorphs performed similarly to untreated wild-type mice, suggesting that reduced GCPII expression and folate deficiency are mutually protective. Analyses of folate and neurometabolite levels associated with glutamatergic function suggest several potential mechanisms through which GCPII and folate may be interacting to create this protective effect. Copyright © 2011 Wiley Periodicals, Inc.

Folate and human reproduction.

PubMed

Tamura, Tsunenobu; Picciano, Mary Frances

2006-05-01

The influence of folate nutritional status on various pregnancy outcomes has long been recognized. Studies conducted in the 1950s and 1960s led to the recognition of prenatal folic acid supplementation as a means to prevent pregnancy-induced megaloblastic anemia. In the 1990s, the utility of periconceptional folic acid supplementation and folic acid food fortification emerged when they were proven to prevent the occurrence of neural tube defects. These distinctively different uses of folic acid may well be ranked among the most significant public health measures for the prevention of pregnancy-related disorders. Folate is now viewed not only as a nutrient needed to prevent megaloblastic anemia in pregnancy but also as a vitamin essential for reproductive health. This review focuses on the relation between various outcomes of human reproduction (ie, pregnancy, lactation, and male reproduction) and folate nutrition and metabolism, homocysteine metabolism, and polymorphisms of genes that encode folate-related enzymes or proteins, and we identify issues for future research.

Preparation, co-assembling and interfacial crosslinking of photocurable and folate-conjugated amphiphilic block copolymers for controlled and targeted drug delivery: smart armored nanocarriers.

PubMed

Khoee, Sepideh; Kavand, Alireza

2014-02-12

Novel pH-sensitive, biodegradable and biocompatible copolymers based on polycaprolactone-poly(ethylene glycol) (PCL/PEG) were synthesized and further modified with folic acid and/or acryloyl chloride. The mixed polymeric micelles were formed by self-assembling of folated-copolymer and non-folated-copolymer with different compositions via nanoprecipitation method. The solubilization of quercetin as anti-cancer drug by the mixed micelle with the optimized composition (folated/non-folated 20/80) was more efficient than those made of each one alone. Nanogels with different crosslinking density were produced in the presence of ethylene glycol dimethacrylate (EGDMA) as the crosslinker via a photochemical method. Interfacial crosslinking of acrylated groups were utilized to produce a core-shell spherical nanoparticle to evaluate their in-vitro drug release and degradation rate. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The relationship between functional ovarian cysts and vitamin A, vitamin E, and folate intake.

PubMed

Tafazoli, Mahin; Fazeli, Elham; Nematy, Mohsen; Bahri, Narjes; Dadgar, Salmeh

2017-02-01

This study aimed to clarify the relationship between functional ovarian cysts and vitamin A, vitamin E, and folate intake. This case-control study evaluated 265 women of reproductive age who presented at gynaecology clinics of three hospitals in Mashhad, Iran. While women in the ovarian cyst group [n = 132] had functional ovarian cysts, control group [n = 133] consisted of women without functional ovarian cysts. The participants' vitamin A, vitamin E, and folate intake was assessed using the Food Frequency Questionnaire. Results showed that folate intake was significantly higher in the ovarian cyst group [p = .040]. No significant differences in vitamin A and vitamin E intake were observed between the two groups [p = .950 and .230, respectively]. It is concluded that women with functional ovarian cysts had significantly higher folate intake. Vitamin A and vitamin E intake had no significant effects on the incidence of these cysts.

Dietary folate deficiency in pseudopregnant mice has no effect on homeobox A10 promoter methylation or expression.

PubMed

Long, Chunlan; He, Junlin; Liu, Xueqing; Chen, Xuemei; Gao, Rufei; Wang, Yingxiong; Ding, Yubin

2012-12-01

During the reproductive cycle, a number of genes controlling endometrial changes are regulated by DNA methylation, a common epigenetic modification. Because dietary folate affects DNA methylation, we determined whether a folate-deficient diet (FDD) alters DNA methylation in endometria of pseudopregnant mice, focusing on the homeobox A10 (Hoxa10) promoter. Mice were given an FDD or control diet for 40 to 45 days and examined on day 5 of pseudopregnancy. Compared to control mice, FDD mice had lower folate levels in liver and serum (P = .004). However, the FDD did not significantly affect DNA methylation within the cytosine-guanine dinucleotide (CpG)-rich Hoxa10 promoter, even when specific CpG sites were examined (P > .05). In endometrial tissue sections, the localization of anti-Hoxa10 staining was unchanged in FDD mice. Therefore, folate deficiency did not significantly affect promoter methylation or expression of Hoxa10.

Hereditary hemochromatosis.

PubMed

Walker, E M; Wolfe, M D; Norton, M L; Walker, S M; Jones, M M

1998-01-01

Genetic (hereditary) hemochromatosis is probably the most common autosomal recessive disorder found in white Americans, of whom about 5/1,000 (0.5 percent) are homozygous for the associated gene. The hemochromatosis gene is probably located close to the HLA-A locus on the short arm of chromosome 6. Homozygous individuals may develop severe and potentially lethal hemochromatosis, especially after age 39. Hereditary hemochromatosis involves an increased rate of iron absorption from the gut with subsequent progressive storage of iron in soft organs of the body. Excess iron storage eventually produces pituitary, pancreatic, cardiac, and liver dysfunction and death may result from cardiac arrhythmias, congestive heart failure, and/or hepatic failure or cancer. Early diagnosis can prevent these excess iron-induced problems. Iron overload owing to HLA-linked hereditary hemochromatosis can be distinguished from other causes of hemochromatosis by liver biopsies and interpretations. Patients at risk for genetic hemochromatosis should be screened, identified, and treated as early as age 20 to prevent or minimize the deadly complications of hemochromatosis. Population screening should include measurements of serum iron concentration, total iron binding capacity (TIBC), percent saturation of transferrin, and serum ferritin concentrations. Family members of hereditary hemochromatosis patients are at increased risk and should be tested. Screening, identification and early treatment (phlebotomies, sometimes in combination with the use of Desferal or other iron-chelating agents) may help prevent or reduce iron-related organ damage and premature deaths. Early diagnosis and treatment will reduce the population of aging individuals with severe, complicated hemochromatosis and dramatically reduce medical costs (billions of U.S. dollars per annum) associated with the management of this disease.

The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features.

PubMed

Leonardis, L; Auer-Grumbach, M; Papić, L; Zidar, J

2012-07-01

  Mutations in atlastin-1 (ATL-1), a gene known to cause pure, early-onset autosomal dominant hereditary spastic paraplegia SPG3A, have been recently reported to cause hereditary sensory neuropathy I (HSN I). We describe the detailed clinical and electrophysiologic findings in the first family with ulcero-mutilating sensory neuropathy carrying the c. C1065A, p.N355K mutation in ATL-1.   Detailed clinical and electrophysiologic studies were performed in affected and at-risk family members. Motor and sensory nerve conductions studies (NCS) were carried out in upper and lower limbs. ATL-1 was screened for mutations by direct sequencing.   Ten patients were found to carry the N355K mutation. With the exception of the two youngest patients, all had trophic skin changes in the feet consisting mainly of painless ulcers. Frequently, amputation of toes, feet, or even more proximal parts of the lower legs became necessary. A variable degree of increased muscle tone was observed in younger patients, whilst some older affected individuals only presented with hyperreflexia of patellar tendon reflexes. NCS revealed signs of an axonal motor and sensory neuropathies.   Our family carrying the N355K ATL1 mutation, which was initially diagnosed as HSN I, enlarges the SPG3A phenotype. We therefore suggest that patients with HSN I excluded for more common causes of HSN I, and in particular, affected individuals who exhibit additional pyramidal tract features should also be screened for mutations in ATL1. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.

Four novel germline mutations in the MLH1 and PMS2 mismatch repair genes in patients with hereditary nonpolyposis colorectal cancer.

PubMed

Montazer Haghighi, Mahdi; Radpour, Ramin; Aghajani, Katayoun; Zali, Narges; Molaei, Mahsa; Zali, Mohammad Reza

2009-08-01

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common cause of early onset hereditary colorectal cancer. In the majority of HNPCC families, microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found. The entire coding sequence of MMR genes (MLH1, MLH2, MLH6, and PMS2) was analyzed using direct sequencing. Also, tumor tests were done as MSI and immunohistochemistry testing. We were able to find three novel MLH1 and one novel PMS2 germline mutations in three Iranian HNPCC patients. The first was a transversion mutation c.346A>C (T116P) and happened in the highly conserved HATPase-c region of MLH1 protein. The second was a transversion mutation c.736A>T (I246L), which caused an amino acid change of isoleucine to leucine. The third mutation (c.2145,6 delTG) was frameshift and resulted in an immature stop codon in five codons downstream. All of these three mutations were detected in the MLH1 gene. The other mutation was a transition mutation, c.676G>A (G207E), which has been found in exon six of the PMS2 gene and caused an amino acid change of glycine to glutamic acid. MSI assay revealed high instability in microsatellite for two patients and microsatellite stable for one patient. In all patients, an abnormal expression of the MMR proteins in HNPCC was related to the above novel mutations.

Hereditary Diffuse Gastric Cancer

MedlinePlus

... Hereditary Diffuse Gastric Cancer Request Permissions Hereditary Diffuse Gastric Cancer Approved by the Cancer.Net Editorial Board , 10/2017 What is hereditary diffuse gastric cancer? Hereditary diffuse gastric cancer (HDGC) is a rare ...

Genetics, biomarkers, hereditary cancer syndrome diagnosis, heterogeneity and treatment: a review.

PubMed

Lynch, Henry T; Drescher, Kristen; Knezetic, Joseph; Lanspa, Stephen

2014-09-01

Molecular genetic pathways that drive the phenotypic and genotypic heterogeneity of hereditary colorectal cancer also can affect response to chemotherapy and chemoprevention. These mutations also can alter patients' response to therapy. Environmental differences can affect this highly complex conundrum. We will use Lynch syndrome as a model to explore this issue. However, to begin with, after more than a century of documentation, we must ask what is meant by the eponym "Lynch syndrome". Germline mutations may act as drivers of chemoprevention and chemotherapy and therein may act positively or conversely they may have a negative effect in terms of inhibiting the inactivation of cancer-causing germline mutations. A relatively new field of hereditary cancer therapeutics has significantly impacted cancer care, from the standpoint of the sensitivity or resistance to a particular form of chemotherapy and/or chemoprevention. The question for the diagnostician and therapist must always concern what is the best possible management approach for the patient, particularly when he or she harbors a cancer-causing germline mutation, which, in this case, causes Lynch syndrome. Continued molecular genetic research might yield a more tailored effective treatment for Lynch syndrome. The ultimate goal of such hereditary oncologic research is to better understand the mutation's therapeutic task, namely, its potential to benefit the patient in terms of its treatment goal, thereby fulfilling the essence of personalized medicine. However, this goal may be exceedingly complicated. For example, in the natural clinical and molecular genetic history of hereditary forms of cancer, there will be a predominance of early-onset cancers of multiple anatomic sites. In our Lynch syndrome model, these will be most commonly colorectal, endometrial, and ovarian cancer. Attention must initially be focused upon cancer's early age of onset coupled with the tendency to multiple primary cancers so that, in the case of CRC, colonoscopic screening must be initiated by age 20-25 years and repeated every other year until age 40 years and then annually thereafter. However, screening will be of limited efficacy in the gynecologic cancers (endometrial and ovarian) so that once the family is completed, particularly by age 35-40 years, careful attention must be given to the option of prophylactic hysterectomy and bilateral salpingo-oophorectomy. Given issues of tumor heterogeneity, selected Lynch syndrome families may show an excess of urologic cancers or cancers of the small bowel, and highly targeted screening should be given serious consideration for these as well as cancers of other anatomic sites in such high-risk, cancer-prone patients.

Effect of folic acid on appetite in children: ordinal logistic and fuzzy logistic regressions.

PubMed

Namdari, Mahshid; Abadi, Alireza; Taheri, S Mahmoud; Rezaei, Mansour; Kalantari, Naser; Omidvar, Nasrin

2014-03-01

Reduced appetite and low food intake are often a concern in preschool children, since it can lead to malnutrition, a leading cause of impaired growth and mortality in childhood. It is occasionally considered that folic acid has a positive effect on appetite enhancement and consequently growth in children. The aim of this study was to assess the effect of folic acid on the appetite of preschool children 3 to 6 y old. The study sample included 127 children ages 3 to 6 who were randomly selected from 20 preschools in the city of Tehran in 2011. Since appetite was measured by linguistic terms, a fuzzy logistic regression was applied for modeling. The obtained results were compared with a statistical ordinal logistic model. After controlling for the potential confounders, in a statistical ordinal logistic model, serum folate showed a significantly positive effect on appetite. A small but positive effect of folate was detected by fuzzy logistic regression. Based on fuzzy regression, the risk for poor appetite in preschool children was related to the employment status of their mothers. In this study, a positive association was detected between the levels of serum folate and improved appetite. For further investigation, a randomized controlled, double-blind clinical trial could be helpful to address causality. Copyright © 2014 Elsevier Inc. All rights reserved.

The Application of a Chemical Determination of N-Homocysteinylation Levels in Developing Mouse Embryos: Implication for Folate Responsive Birth Defects

PubMed Central

Fathe, Kristin; Person, Maria D.; Finnell, Richard H.

2014-01-01

Elevated homocysteine levels have long been associated with various disease states, including cardiovascular disease and birth defects, including neural tube defects (NTDs). One hypothesis regarding the strong correlation between these various disorders and high levels of homocysteine is that a reactive form of this small molecule can attach to mammalian proteins in a phenomenon known as homocysteinylation. These posttranslational modifications may become antigenic, or may even directly disrupt certain protein function. It remains to be determined whether dietary influences that can cause globally increased levels of circulating homocysteine confer negative effects maternally, or may otherwise negatively and materially impact the metabolic balance in developing embryos. Herein we present the application of a chemical method of determination of N-homocysteinylation to a set of neural tube closure stage mouse embryos and their mothers. We explore the uses of this newly-described technique to investigate levels of maternal and embryonic N-homocysteinylation using dietary manipulations of onecarbon metabolism with two known folate responsive neural tube defect mouse models. The data presented reveals that although diet appeared to have significant effects on the maternal metabolic status, those effects did not directly correlate to the embryonic folate or N-homocysteinylation status. Our studies indicate that maternal diet and embryonic genotype most significantly affected the embryonic developmental outcome. PMID:25620692

Folate supplementation differently affects uracil content in DNA in the mouse colon and liver

USDA-ARS?s Scientific Manuscript database

High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C5...

TRIBROMOMETHANE EXPOSURE AND DIETARY FOLATE DEFICIENCY IN THE FORMATION OF ABERRANT CRYPT FOCI IN THE COLONS OF F344/N RATS

EPA Science Inventory

Folate and folic acid are forms of the B vitamin that are involved in the synthesis, repair and functioning of DNA and are required for the production and maintenance of cells. Low levels of folate have been associated with several forms of cancer, including colon cancer. Aberran...

Folate and vitamin B12 status in the Americas.

PubMed

Allen, Lindsay H

2004-06-01

There is growing interest in the potential for folic acid fortification in the Americas and recognition of the high prevalence of low plasma vitamin B12 concentrations reported in various studies. This review summarized available data on plasma vitamin B12 and folate concentrations in the Americas. At least 40% of individuals had deficient or marginal plasma vitamin B12 concentrations in almost all locations and across age groups. Low plasma folate concentrations were less common. It is hypothesized that vitamin B12 deficiency may result from a low intake of animal source foods, while a higher intake of refined flour may result in low plasma folate.

Passion fruit by-product and fructooligosaccharides stimulate the growth and folate production by starter and probiotic cultures in fermented soymilk.

PubMed

Albuquerque, Marcela Albuquerque Cavalcanti; Bedani, Raquel; LeBlanc, Jean Guy; Saad, Susana Marta Isay

2017-11-16

Two starter cultures (Streptococcus (St.) thermophilus ST-M6 and TA-40) and five probiotic strains (St. thermophilus TH-4, Lactobacillus (Lb.) acidophilus LA-5, Lb. rhamnosus LGG, Lb. fermentum PCC, and Lb. reuteri RC-14) were used to ferment different soymilk formulations supplemented with passion fruit by-product and/or fructo-oligosaccharides (FOS) with the aim of increasing folate concentrations. Growth and folate production of individual strains were evaluated and the results used to select co-cultures. Both St. thermophilus ST-M6 and TH-4 were the best folate producers and were able to increase the folate content of all soymilk formulations when used alone or in co-culture with lactobacilli strains, especially in the presence of both passion fruit by-product and FOS. Thus, passion fruit by-product and FOS could be used as dietary ingredients to stimulate the folate production by selected bacterial strains during the fermentation of soymilk. It was also shown that vitamin production by microorganisms is strain-dependent and may also be influenced by nutritional and environmental conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimization of the trienzyme extraction for the microbiological assay of folate in vegetables.

PubMed

Chen, Liwen; Eitenmiller, Ronald R

2007-05-16

Response surface methodology was applied to optimize the trienzyme digestion for the extraction of folate from vegetables. Trienzyme extraction is a combined enzymatic digestion by protease, alpha-amylase, and conjugase (gamma-glutamyl hydrolase) to liberate the carbohydrate and protein-bound folates from food matrices for total folate analysis. It is the extraction method used in AOAC Official Method 2004.05 for assay of total folate in cereal grain products. Certified reference material (CRM) 485 mixed vegetables was used to represent the matrix of vegetables. Regression and ridge analysis were performed by statistical analysis software. The predicted second-order polynomial model was adequate (R2 = 0.947), without significant lack of fit (p > 0.1). Both protease and alpha-amylase have significant effects on the extraction. Ridge analysis gave an optimum trienzyme digestion time: Pronase, 1.5 h; alpha-amylase, 1.5 h; and conjugase, 3 h. The experimental value for CRM 485 under this optimum digestion was close to the predicted value from the model, confirming the validity and adequacy of the model. The optimized trienzyme digestion condition was applied to five vegetables and yielded higher folate levels than the trienzyme digestion parameters employed in AOAC Official Method 2004.05.

Simulation of Food Folate Digestion and Bioavailability of an Oxidation Product of 5-Methyltetrahydrofolate

PubMed Central

Ringling, Christiane

2017-01-01

Generating bioavailability data from in vivo studies is time-consuming and expensive. In vitro simulation can help to investigate factors influencing bioavailability or facilitate quantifying the impact of such factors. For folates, an efficient deconjugation of polyglutamates to the corresponding monoglutamates is crucial for bioavailability and highly dependent on the food matrix. Therefore, the bioaccessibility of folates of different foodstuffs was examined using a simulated digestion model with respect to folate stability and the efficiency of deconjugation. For realistic simulated deconjugation, porcine brush border membrane was used during the phase of the simulated digestion in the small intestine. For a better understanding of folate behaviour during digestion, single folate monoglutamates were also investigated with this in vitro digestion model. The results for bioaccessibility were compared with data from a human bioavailability study. They support the idea that both stability and deconjugation have an influence on bioaccessibility and thus on bioavailability. Tetrahydrofolate is probably lost completely or at least to a high extent and the stability of 5-methyltetrahydrofolate depends on the food matrix. Additionally, 5-methyltetrahydrofolate can be oxidised to a pyrazino-s-triazine (MeFox), whose absorption in the human intestinal tract was shown tentatively. PMID:28862677

N-acetyltransferase 2 activity and folate levels

PubMed Central

Cao, Wen; Strnatka, Diana; McQueen, Charlene A.; Hunter, Robert J.; Erickson, Robert P.

2010-01-01

Aims To determine whether increased N-acetyltransferase (NAT) activity might have a toxic effect during development and an influence on folate levels since previous work has shown that only low levels of exogenous NAT can be achieved in constitutionally transgenic mice (Cao, et al, 2005) Main Methods A human NAT1 tet-inducible construct was used that would not be expressed until the inducer was delivered. Human NAT1 cDNA was cloned into pTRE2 and injected into mouse oocytes. Two transgenic lines were crossed to mouse line TgN(rtTahCMV)4Uh containing the CMV promoted “teton.”Measurements of red blood cell folate levels in inbred strains of mice were performed. Key findings Only low levels of human NAT1 could be achieved in kidney (highly responsive in other studies) whether the inducer, doxycycline, was given by gavage or in drinking water.An inverse correlation of folate levels with Nat2 enzyme activity was found. Significance Since increasing NAT1 activity decrease folate in at least one tissue, the detrimental effect of expression of human NAT1 in combination with endogenous mouse Nat2 may be a consequence of increased catabolism of folate. PMID:19932120

Suppression of Homocysteine Levels by Vitamin B12 and Folates: Age and Gender Dependency in the Jackson Heart Study

PubMed Central

Henry, Olivia R.; Benghuzzi, Hamed; Taylor, Herman A.; Tucci, Michelle; Butler, Kenneth; Jones, Lynne

2011-01-01

Objectives To examine factors potentially contributing to premature cardiovascular disease mortality in African Americans (40% versus 20% all other populations), plasma homocysteine, serum vitamin B12 and folate levels were examined for African American participants in the Jackson Heart Study. Methods Of 5,192 African American Jackson Heart Study participants (21–94 years), 5,064 (mean age, 55±13 years; 63% female) had homocysteine levels measured via fasting blood samples, with further assessments of participants’ vitamin B12 (n=1,790) and folate (n=1,788) levels. We used regression analyses to examine age, gender, vitamin B12, and folate with homocysteine levels. Results Homocysteine levels, a purported surrogate risk factor for cardiovascular disease, increased with age, were inversely proportional to folate and vitamin B12 levels (p<0.001), and higher for men of all ages. Conclusions Our results show that, as with other populations, age, gender, vitamin B12, and folate may predict homocysteine levels for African Americans. Diet may be an important predictive factor as well, given the relationships we observed between plasma homocysteine and serum B vitamin levels. PMID:22173042

Simulation of Food Folate Digestion and Bioavailability of an Oxidation Product of 5-Methyltetrahydrofolate.

PubMed

Ringling, Christiane; Rychlik, Michael

2017-09-01

Generating bioavailability data from in vivo studies is time-consuming and expensive. In vitro simulation can help to investigate factors influencing bioavailability or facilitate quantifying the impact of such factors. For folates, an efficient deconjugation of polyglutamates to the corresponding monoglutamates is crucial for bioavailability and highly dependent on the food matrix. Therefore, the bioaccessibility of folates of different foodstuffs was examined using a simulated digestion model with respect to folate stability and the efficiency of deconjugation. For realistic simulated deconjugation, porcine brush border membrane was used during the phase of the simulated digestion in the small intestine. For a better understanding of folate behaviour during digestion, single folate monoglutamates were also investigated with this in vitro digestion model. The results for bioaccessibility were compared with data from a human bioavailability study. They support the idea that both stability and deconjugation have an influence on bioaccessibility and thus on bioavailability. Tetrahydrofolate is probably lost completely or at least to a high extent and the stability of 5-methyltetrahydrofolate depends on the food matrix. Additionally, 5-methyltetrahydrofolate can be oxidised to a pyrazino-s-triazine (MeFox), whose absorption in the human intestinal tract was shown tentatively.

Genetics Home Reference: hereditary sensory and autonomic neuropathy type IE

MedlinePlus

... loss of sensation in the feet and legs (peripheral neuropathy). People with HSAN IE develop hearing loss that ... control, become apparent before problems with thinking skills. Peripheral neuropathy is caused by impaired function of nerve cells ...

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

PubMed Central

2005-01-01

Background & Aims: At least 500 μg of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 μg of folate or with one 500 μg capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p<0.001) and plasma tHcy decreased (p<0.001) with both therapies. Folate-rich foods decreased tHcy by 8.6% (95% CI: –15.9 to –1.2) and synthetic folic acid capsules by 8% (95% CI: –13.3 to –2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease. PMID:15968341

In Vivo Kinetics of Formate Metabolism in Folate-deficient and Folate-replete Rats*

PubMed Central

Morrow, Gregory P.; MacMillan, Luke; Lamarre, Simon G.; Young, Sara K.; MacFarlane, Amanda J.; Brosnan, Margaret E.; Brosnan, John T.

2015-01-01

It is now established that the mitochondrial production of formate is a major process in the endogenous generation of folate-linked one-carbon groups. We have developed an in vivo approach involving the constant infusion of [13C]formate until isotopic steady state is attained to measure the rate of endogenous formate production in rats fed on either a folate-replete or folate-deficient diet. Formate was produced at a rate of 76 μmol·h−1·100 g of body weight−1 in the folate-replete rats, and this was decreased by 44% in folate-deficient rats. This decreased formate production was confirmed in isolated rat liver mitochondria where formate production from serine, the principal precursor of one-carbon groups, was decreased by 85%, although formate production from sarcosine and dimethylglycine (choline metabolites) was significantly increased. We attribute this unexpected result to the demonstrated production of formaldehyde by sarcosine dehydrogenase and dimethylglycine dehydrogenase from their respective substrates in the absence of tetrahydrofolate and subsequent formation of formate by formaldehyde dehydrogenase. Comparison of formate production with the ingestion of dietary formate precursors (serine, glycine, tryptophan, histidine, methionine, and choline) showed that ∼75% of these precursors were converted to formate, indicating that formate is a significant, although underappreciated end product of choline and amino acid oxidation. Ingestion of a high protein diet did not result in increased production of formate, suggesting a regulation of the conversion of these precursors at the mitochondrial level to formate. PMID:25480787

Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

PubMed Central

Kelemen, Linda E.; Terry, Kathryn L.; Goodman, Marc T.; Webb, Penelope M.; Bandera, Elisa V.; McGuire, Valerie; Rossing, Mary Anne; Wang, Qinggang; Dicks, Ed; Tyrer, Jonathan P.; Song, Honglin; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Timorek, Agnieszka; Menon, Usha; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Ramus, Susan J.; Narod, Steven A.; Risch, Harvey A.; McLaughlin, John R.; Siddiqui, Nadeem; Glasspool, Rosalind; Paul, James; Carty, Karen; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; van Altena, Anne M.; Aben, Katja K. H.; Olson, Sara H.; Orlow, Irene; Cramer, Daniel W.; Levine, Douglas A.; Bisogna, Maria; Giles, Graham G.; Southey, Melissa C.; Bruinsma, Fiona; Kjær, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Høgdall, Claus K.; Lundvall, Lene; Engelholm, Svend-Aage; Heitz, Florian; du Bois, Andreas; Harter, Philipp; Schwaab, Ira; Butzow, Ralf; Nevanlinna, Heli; Pelttari, Liisa M.; Leminen, Arto; Thompson, Pamela J.; Lurie, Galina; Wilkens, Lynne R.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Lambrechts, Sandrina; Vergote, Ignace; Beesley, Jonathan; Fasching, Peter A.; Beckmann, Matthias W.; Hein, Alexander; Ekici, Arif B.; Doherty, Jennifer A.; Wu, Anna H.; Pearce, Celeste L.; Pike, Malcolm C.; Stram, Daniel; Chang-Claude, Jenny; Rudolph, Anja; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo B.; Bogdanova, Natalia; Antonenkova, Natalia; Odunsi, Kunle; Edwards, Robert P.; Kelley, Joseph L.; Modugno, Francesmary; Ness, Roberta B.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Fridley, Brooke L.; Vierkant, Robert A.; Cunningham, Julie M.; Wu, Xifeng; Lu, Karen; Liang, Dong; Hildebrandt, Michelle A.T.; Weber, Rachel Palmieri; Iversen, Edwin S.; Tworoger, Shelley S.; Poole, Elizabeth M.; Salvesen, Helga B.; Krakstad, Camilla; Bjorge, Line; Tangen, Ingvild L.; Pejovic, Tanja; Bean, Yukie; Kellar, Melissa; Wentzensen, Nicolas; Brinton, Louise A.; Lissowska, Jolanta; Garcia-Closas, Montserrat; Campbell, Ian G.; Eccles, Diana; Whittemore, Alice S.; Sieh, Weiva; Rothstein, Joseph H.; Anton-Culver, Hoda; Ziogas, Argyrios; Phelan, Catherine M.; Moysich, Kirsten B.; Goode, Ellen L.; Schildkraut, Joellen M.; Berchuck, Andrew; Pharoah, Paul D.P.; Sellers, Thomas A.; Brooks-Wilson, Angela; Cook, Linda S.; Le, Nhu D.

2014-01-01

Scope We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. Methods and Results Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006). Conclusions Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC. PMID:25066213

Folic acid and the methylation of homocysteine by Bacillus subtilis

PubMed Central

Salem, A. R.; Pattison, J. R.; Foster, M. A.

1972-01-01

1. Cell-free extracts of Bacillus subtilis synthesize methionine from serine and homocysteine without added folate. The endogenous folate may be replaced by tetrahydropteroyltriglutamate or an extract of heated Escherichia coli for the overall C1 transfer, but tetrahydropteroylmonoglutamate is relatively inactive. 2. Extracts of B. subtilis contain serine transhydroxymethylase and 5,10-methylenetetrahydrofolate reductase, which are non-specific with respect to the glutamate content of the folate substrates. Methyl transfer to homocysteine requires a polyglutamate folate as methyl donor. These properties are not affected by growth of the organism with added vitamin B12. 3. The synthesis of methionine from 5-methyltetrahydropteroyltriglutamate and homocysteine has the characteristics of the cobalamin-independent reaction of E. coli. No evidence for a cobalamin-dependent transmethylation was obtained. 4. S-Adenosylmethionine was not a significant precursor of the methyl group of methionine with cell-free extracts, neither was S-adenosylmethionine generated by methylation of S-adenosylhomocysteine by 5-methyltetrahydrofolate. 5. A procedure for the isolation and analysis of folic acid derivatives from natural sources is described. 6. The folates isolated from lysozyme extracts of B. subtilis are sensitive to folic acid conjugase. One has been identified as 5-formyltetrahydropteroyltriglutamate; the other is possibly a diglutamate folate. 7. A sequence is proposed for methionine biosynthesis in B. subtilis in which methyl groups are generated from serine and transferred to homocysteine by means of a cobalamin-independent pathway mediated by conjugated folate coenzymes. PMID:4627401

Lifespan Changes in Working Memory in Fragile X Premutation Males

ERIC Educational Resources Information Center

Cornish, Kim M.; Kogan, Cary S.; Li, Lexin; Turk, Jeremy; Jacquemont, Sebastien; Hagerman, Randi J.

2009-01-01

Fragile X syndrome is the world's most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the "FMR1" gene. The premutation (carrier) status, however, is less well documented but has an…

Next-generation sequencing identifies a novel compound heterozygous mutation in MYO7A in a Chinese patient with Usher Syndrome 1B.

PubMed

Wei, Xiaoming; Sun, Yan; Xie, Jiansheng; Shi, Quan; Qu, Ning; Yang, Guanghui; Cai, Jun; Yang, Yi; Liang, Yu; Wang, Wei; Yi, Xin

2012-11-20

Targeted enrichment and next-generation sequencing (NGS) have been employed for detection of genetic diseases. The purpose of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection of hereditary hearing loss, and identify inherited mutations involved in human deafness accurately and economically. To make genetic diagnosis of hereditary hearing loss simple and timesaving, we designed a 0.60 MB array-based chip containing 69 nuclear genes and mitochondrial genome responsible for human deafness and conducted NGS toward ten patients with five known mutations and a Chinese family with hearing loss (never genetically investigated). Ten patients with five known mutations were sequenced using next-generation sequencing to validate the sensitivity of the method. We identified four known mutations in two nuclear deafness causing genes (GJB2 and SLC26A4), one in mitochondrial DNA. We then performed this method to analyze the variants in a Chinese family with hearing loss and identified compound heterozygosity for two novel mutations in gene MYO7A. The compound heterozygosity identified in gene MYO7A causes Usher Syndrome 1B with severe phenotypes. The results support that the combination of enrichment of targeted genes and next-generation sequencing is a valuable molecular diagnostic tool for hereditary deafness and suitable for clinical application. Copyright © 2012 Elsevier B.V. All rights reserved.

Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1.

PubMed

Jaeger, Emma; Leedham, Simon; Lewis, Annabelle; Segditsas, Stefania; Becker, Martin; Cuadrado, Pedro Rodenas; Davis, Hayley; Kaur, Kulvinder; Heinimann, Karl; Howarth, Kimberley; East, James; Taylor, Jenny; Thomas, Huw; Tomlinson, Ian

2012-05-06

Hereditary mixed polyposis syndrome (HMPS) is characterized by apparent autosomal dominant inheritance of multiple types of colorectal polyp, with colorectal carcinoma occurring in a high proportion of affected individuals. Here, we use genetic mapping, copy-number analysis, exclusion of mutations by high-throughput sequencing, gene expression analysis and functional assays to show that HMPS is caused by a duplication spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. This unusual mutation is associated with increased allele-specific GREM1 expression. Whereas GREM1 is expressed in intestinal subepithelial myofibroblasts in controls, GREM1 is predominantly expressed in the epithelium of the large bowel in individuals with HMPS. The HMPS duplication contains predicted enhancer elements; some of these interact with the GREM1 promoter and can drive gene expression in vitro. Increased GREM1 expression is predicted to cause reduced bone morphogenetic protein (BMP) pathway activity, a mechanism that also underlies tumorigenesis in juvenile polyposis of the large bowel.

Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas.

PubMed

Li, Hong; Byers, Heather M; Diaz-Kuan, Alicia; Vos, Miriam B; Hall, Patricia L; Tortorelli, Silvia; Singh, Rani; Wallenstein, Matthew B; Allain, Meredith; Dimmock, David P; Farrell, Ryan M; McCandless, Shawn; Gambello, Michael J

2018-04-01

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of polymorphisms in endothelial nitric oxide synthase and folate metabolizing genes on the concentration of serum nitrate, folate, and plasma total homocysteine after folic acid supplementation: a double-blind crossover study.

PubMed

Cabo, Rona; Hernes, Sigrunn; Slettan, Audun; Haugen, Margaretha; Ye, Shu; Blomhoff, Rune; Mansoor, M Azam

2015-02-01

A number of studies have explored the effects of dietary nitrate on human health. Nitrate in the blood can be recycled to nitric oxide, which is an essential mediator involved in many important biochemical mechanisms. Nitric oxide is also formed in the body from l-arginine by nitric oxide synthase. The aim of this study was to investigate whether genetic polymorphisms in endothelial nitric oxide synthase (eNOS) and genes involved in folate metabolism affect the concentration of serum nitrate, serum folate, and plasma total homocysteine in healthy individuals after folic acid supplementation. In a randomized double-blind, crossover study, participants were given either folic acid 800 μg/d (n = 52) or placebo (n = 51) for 2 wk. Wash-out period was 2 wk. Fasting blood samples were collected, DNA was extracted by salting-out method and the polymorphisms in eNOS synthase and folate genes were genotyped by polymerase chain reaction methods. Measurement of serum nitrate and plasma total homocysteine (p-tHcy) concentration was done by high-performance liquid chromatography. The concentration of serum nitrate did not change in individuals after folic acid supplements (trial 1); however, the concentration of serum nitrate increased in the same individuals after placebo (P = 0.01) (trial 2). The individuals with three polymorphisms in eNOS gene had increased concentration of serum folate and decreased concentration of p-tHcy after folic acid supplementation. Among the seven polymorphisms tested in folate metabolizing genes, serum nitrate concentration was significantly decreased only in DHFR del 19 gene variant. A significant difference in the concentration of serum nitrate was detected among individuals with MTHFR C > T677 polymorphisms. Polymorphisms in eNOS and folate genes affect the concentration of serum folate and p-tHcy but do not have any effect on the concentration of NO3 in healthy individuals after folic acid supplementation. Copyright © 2015 Elsevier Inc. All rights reserved.

MTHFR Gene and Serum Folate Interaction on Serum Homocysteine Lowering: Prospect for Precision Folic Acid Treatment.

PubMed

Huang, Xiao; Qin, Xianhui; Yang, Wenbin; Liu, Lishun; Jiang, Chongfei; Zhang, Xianglin; Jiang, Shanqun; Bao, Huihui; Su, Hai; Li, Ping; He, Mingli; Song, Yun; Zhao, Min; Yin, Delu; Wang, Yu; Zhang, Yan; Li, Jianping; Yang, Renqang; Wu, Yanqing; Hong, Kui; Wu, Qinhua; Chen, Yundai; Sun, Ningling; Li, Xiaoying; Tang, Genfu; Wang, Binyan; Cai, Yefeng; Hou, Fan Fan; Huo, Yong; Wang, Hong; Wang, Xiaobin; Cheng, Xiaoshu

2018-03-01

This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase ( MTHFR ) C677T genotypes and serum folate levels. This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 μmol/L; P =0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 μmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 μmol/L, group difference: 1.61 μmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885. © 2018 American Heart Association, Inc.

From Arylamine N-Acetyltransferase to Folate-Dependent Acetyl CoA Hydrolase: Impact of Folic Acid on the Activity of (HUMAN)NAT1 and Its Homologue (MOUSE)NAT2

PubMed Central

Laurieri, Nicola; Dairou, Julien; Egleton, James E.; Stanley, Lesley A.; Russell, Angela J.; Dupret, Jean-Marie; Sim, Edith; Rodrigues-Lima, Fernando

2014-01-01

Acetyl Coenzyme A-dependent N-, O- and N,O-acetylation of aromatic amines and hydrazines by arylamine N-acetyltransferases is well characterised. Here, we describe experiments demonstrating that human arylamine N-acetyltransferase Type 1 and its murine homologue (Type 2) can also catalyse the direct hydrolysis of acetyl Coenzyme A in the presence of folate. This folate-dependent activity is exclusive to these two isoforms; no acetyl Coenzyme A hydrolysis was found when murine arylamine N-acetyltransferase Type 1 or recombinant bacterial arylamine N-acetyltransferases were incubated with folate. Proton nuclear magnetic resonance spectroscopy allowed chemical modifications occurring during the catalytic reaction to be analysed in real time, revealing that the disappearance of acetyl CH 3 from acetyl Coenzyme A occurred concomitantly with the appearance of a CH 3 peak corresponding to that of free acetate and suggesting that folate is not acetylated during the reaction. We propose that folate is a cofactor for this reaction and suggest it as an endogenous function of this widespread enzyme. Furthermore, in silico docking of folate within the active site of human arylamine N-acetyltransferase Type 1 suggests that folate may bind at the enzyme’s active site, and facilitate acetyl Coenzyme A hydrolysis. The evidence presented in this paper adds to our growing understanding of the endogenous roles of human arylamine N-acetyltransferase Type 1 and its mouse homologue and expands the catalytic repertoire of these enzymes, demonstrating that they are by no means just xenobiotic metabolising enzymes but probably also play an important role in cellular metabolism. These data, together with the characterisation of a naphthoquinone inhibitor of folate-dependent acetyl Coenzyme A hydrolysis by human arylamine N-acetyltransferase Type 1/murine arylamine N-acetyltransferase Type 2, open up a range of future avenues of exploration, both for elucidating the developmental role of these enzymes and for improving chemotherapeutic approaches to pathological conditions including estrogen receptor-positive breast cancer. PMID:24823794

Aspects of Weak Interactions between Folate and Glycine Betaine

PubMed Central

2016-01-01

Folate, or vitamin B9, is an important compound in one-carbon metabolism. Previous studies have found weaker binding of dihydrofolate to dihydrofolate reductase in the presence of osmolytes. In other words, osmolytes are more difficult to remove from the dihydrofolate solvation shell than water; this shifts the equilibrium toward the free ligand and protein species. This study uses vapor-pressure osmometry to explore the interaction of folate with the model osmolyte, glycine betaine. This method yields a preferential interaction potential (μ23/RT value). This value is concentration-dependent as folate dimerizes. The μ23/RT value also tracks the deprotonation of folate’s N3–O4 keto–enol group, yielding a pKa of 8.1. To determine which folate atoms interact most strongly with betaine, the interaction of heterocyclic aromatic compounds (as well as other small molecules) with betaine was monitored. Using an accessible surface area approach coupled with osmometry measurements, deconvolution of the μ23/RT values into α values for atom types was achieved. This allows prediction of μ23/RT values for larger molecules such as folate. Molecular dynamics simulations of folate show a variety of structures from extended to L-shaped. These conformers possess μ23/RT values from −0.18 to 0.09 m–1, where a negative value indicates a preference for solvation by betaine and a positive value indicates a preference for water. This range of values is consistent with values observed in osmometry and solubility experiments. As the average predicted folate μ23/RT value is near zero, this indicates folate interacts almost equally well with betaine and water. Specifically, the glutamate tail prefers to interact with water, while the aromatic rings prefer betaine. In general, the more protonated species in our small molecule survey interact better with betaine as they provide a source of hydrogens (betaine is not a hydrogen bond donor). Upon deprotonation of the small molecule, the preference swings toward water interaction because of its hydrogen bond donating capacities. PMID:27768285

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

PubMed Central

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

2014-01-01

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

Maternal folate status, but not that of vitamins B-12 or B-6, is associated with gestational age and preterm birth risk in a multiethnic Asian population.

PubMed

Chen, Ling-Wei; Lim, Ai Lin; Colega, Marjorelee; Tint, Mya-Thway; Aris, Izzuddin M; Tan, Chuen Seng; Chong, Yap-Seng; Gluckman, Peter D; Godfrey, Keith M; Kwek, Kenneth; Saw, Seang-Mei; Yap, Fabian; Lee, Yung Seng; Chong, Mary Foong-Fong; van Dam, Rob M

2015-01-01

Maternal folate, vitamin B-12, and vitamin B-6 concentrations during pregnancy have been shown to influence birth outcomes, but the evidence is inconclusive. We aimed to examine the associations of maternal B-vitamin status with gestational age, birth weight, and length in a birth cohort study in Singapore. Maternal blood samples (n = 999) collected during weeks 26-28 of gestation were assayed for plasma folate, vitamin B-12, and vitamin B-6 concentrations. Birth weight and gestational age data were obtained from hospital records, and other anthropometric variables were measured within 72 h after birth. Relations between B-vitamin status and birth outcomes were assessed by linear or logistic regression with adjustment for potential confounders. Median (IQR) plasma concentrations were 34.4 (24.5-44.6) nmol/L for folate, 209 (167-258) pmol/L for vitamin B-12, and 61.8 (25.9-113) nmol/L for vitamin B-6. We found that higher plasma folate concentrations were associated with a longer gestational age (0.12 wk per SD increase in folate; 95% CI: 0.02, 0.21) and tended to be associated with lower risk of all preterm birth (delivery at <37 wk of gestation; OR: 0.79; 95% CI: 0.63, 1.00) and spontaneous preterm birth (OR: 0.76; 95% CI: 0.56, 1.04). Overall, concentrations of maternal folate, vitamin B-12, and vitamin B-6 were not independently associated with birth weight or being born small for gestational age (SGA; birth weight <10th percentile for gestational age). Higher maternal folate concentrations during late pregnancy were associated with longer gestational age and tended to be associated with a lower risk of preterm birth in this multiethnic Asian population. In contrast, the results of our study suggested little or no benefit of higher folate concentrations for reducing the risk of SGA or of higher vitamin B-6 and vitamin B-12 concentrations for reducing the risk of preterm birth or SGA. © 2015 American Society for Nutrition.

A study of folate absorption and metabolism in man utilizing carbon-14—labeled polyglutamates synthesized by the solid phase method

PubMed Central

Butterworth, C. E.; Baugh, C. M.; Krumdieck, Carlos

1969-01-01

The absorption and metabolism of synthetic polyglutamates of folic acid have been compared with free pteroylglutamic acid in four subjects having chronic lymphatic leukemia and one with Hodgkin's granuloma. Pteroylpolyglutamates containing either three or seven glutamate residues were prepared by the solid-phase method permitting placement of carbon-14 labels in either the pteridine ring or in a selected glutamate unit of the gamma peptide chain. Complete dissociation was observed between biological folate activity and radioactivity of plasma after ingestion of pteroyltriglutamate labeled in the middle glutamate. This indicates cleavage to the monoglutamate form at the time of absorption from the intestine or very soon thereafter. A large portion of radioactivity liberated from the middle glutamate is recoverable as carbon dioxide in the exhaled air. Fecal losses of folate tended to be greater with increasing length of the poly-γ-glutamyl chain. Higher blood levels and greater urinary losses of folate tended to occur after ingestion of mono- and triglutamates than with the heptaglutamate. Calculations based on radioactivity determinations in feces plus urinary folate losses, judged by either radioactivity or microbiological assays, indicated net retention of 37-67% of the dose irrespective of chain length ingested and major avenue of loss. During the peak of absorption the folate circulating in plasma was active for both Streptococcus fecalis and Lactobacillus casei and carried specific radioactivity which was virtually identical with that of the administered dose. This suggests that neither methylation, conjugation, nor displacement of nonradioactive folate occurred to any significant extent during the 1st 2 hr. The specific radioactivity of 24-hr urine specimens as measured with L. casei corresponded closely with that of the administered dose. Evidence exists that methylation of the radioactive folate may occur, but significant displacement of nonradioactive methylfolate was not observed under the conditions of this study. Since 50-75% of administered heptaglutamate appears to be absorbable in man, estimates of dietary intake should include this fraction as well as the “free” folate. PMID:4977032

HFE Gene Mutations and Iron Status in 100 Healthy Polish Children.

PubMed

Kaczorowska-Hac, Barbara; Luszczyk, Marcin; Antosiewicz, Jedrzej; Ziolkowski, Wieslaw; Adamkiewicz-Drozynska, Elzbieta; Mysliwiec, Malgorzata; Milosz, Ewa; Kaczor, Jan J

2017-07-01

Iron participates in oxygen transport, energetic, metabolic, and immunologic processes. There are 2 main causes of iron overload: hereditary hemochromatosis which is a primary cause, is a metabolic disorder caused by mutations of genes that control iron metabolism and secondary hemochromatosis caused by multitransfusions, chronic hemolysis, and intake of iron rich food. The most common type of hereditary hemochromatosis is caused by HFE gene mutation. In this study, we analyzed iron metabolism in 100 healthy Polish children in relation to their HFE gene status. The wild-type HFE gene was predominant being observed in 60 children (60%). Twenty-five children (25%), presented with heterozygotic H63D mutation, and 15 children (15%), presented with other mutations (heterozygotic C282Y and S65C mutation, compound heterozygotes C282Y/S65C, C282Y/H63D, H63D homozygote). The mean concentration of iron, the level of ferritin, and transferrin saturation were statistically higher in the group of HFE variants compared with the wild-type group. H63D carriers presented with higher mean concentration of iron, ferritin levels, and transferrin saturation compared with the wild-type group. Male HFE carriers presented with higher iron concentration, transferrin saturation, and ferritin levels than females. This preliminary investigation demonstrates allelic impact on potential disease progression from childhood.

Congenital Defects.

ERIC Educational Resources Information Center

Goldman, Allen S.; And Others

There are two general categories (not necessarily mutually exclusive) of congenital defects: (1) abnormalities that have an hereditary basis, such as single and multiple genes, or chromosomal abberration; and (2) abnormalities that are caused by nonhereditary factors, such as malnutrition, maternal disease, radiation, infections, drugs, or…

Thermal degradation of (6R,S)-5,10-methenyltetrahydrofolate in aqueous solution at pH 8

NASA Astrophysics Data System (ADS)

Tyagi, A.; Penzkofer, A.; Batschauer, A.; Wolf, E.

2009-03-01

The degradation of the folate (6R,S)-5,10-methenyltetrahydrofolate chloride (MTHF-Cl) in aqueous solution at pH 8 at room temperature is studied by absorption spectra measurements. Samples with and without the reducing agent β-mercaptoethanol (β-ME) both under aerobic and anaerobic conditions are investigated. MTHF-Cl hydrolyses to (6R,S)-10-formyltetrahydrofolate (10-HCO-H4folate) in all four cases. 10-HCO-H4folate oxidizes to 10-formyldihydrofolate (10-HCO-H2folate) under aerobic conditions in the absence of β-ME. The degradation dynamics is analysed theoretically and conversion rate constants of hydrolysis and oxidation are determined.

Prevalence of iron, folate, and vitamin B12 deficiencies in 20 to 49 years old women: Ensanut 2012.

PubMed

Shamah-Levy, Teresa; Villalpando, Salvador; Mejía-Rodríguez, Fabiola; Cuevas-Nasu, Lucía; Gaona-Pineda, Elsa Berenice; Rangel-Baltazar, Eduardo; Zambrano-Mujica, Norma

2015-01-01

To describe the prevalence of iron, folate, and B12 deficiencies in Mexican women of reproductive age from the National Health and Nutrition Survey (Ensanut) 2012. Data came from a national probabilistic survey, representative from rural and urban areas, and different age groups. Blood samples were obtained from 4 263, 20 to 49 years old women for serum ferritin, vitamin B12 and serum folate concentrations. The prevalence of deficiencies, was assessed using adjusted logistic regression models. The deficiency of folate was 1.9% (95%CI 1.3-2.8), B12 deficiency was 8.5% (95%CI 6.7-10.1) and iron deficiency was 29.4% (95%CI 26.5-32.2). No differences were found when compared with 2006, 24.8% (95%CI 22.3-27.2). The vitamin B12 deficiency is still a problem for women of reproductive age and their offspring in Mexico, while folate deficiency disappeared as a problem. Iron deficiency needs prevention and fortification strategies.

Biofortification of folates in white wheat bread by selection of yeast strain and process.

PubMed

Hjortmo, Sofia; Patring, Johan; Jastrebova, Jelena; Andlid, Thomas

2008-09-30

We here demonstrate that folate content in yeast fermented food can be dramatically increased by using a proper (i) yeast strain and (ii) cultivation procedure for the selected strain prior to food fermentation. Folate levels were 3 to 5-fold higher in white wheat bread leavened with a Saccharomyces cerevisiae strain CBS7764, cultured in defined medium and harvested in the respiro-fermentative phase of growth prior to dough preparation (135-139 microg/100 dry matter), compared to white wheat bread leavened with commercial Baker's yeast (27-43 microg/100 g). The commercial Baker's yeast strain had been industrially produced, using a fed-batch process, thereafter compressed and stored in the refrigerator until bakings were initiated. This strategy is an attractive alternative to fortification of bread with synthetically produced folic acid. By using a high folate producing strain cultured a suitable way folate levels obtained were in accordance with folic acid content in fortified cereal products.

Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes.

PubMed

Lambrot, R; Xu, C; Saint-Phar, S; Chountalos, G; Cohen, T; Paquet, M; Suderman, M; Hallett, M; Kimmins, S

2013-01-01

Epidemiological studies suggest that a father's diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health.

Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes

PubMed Central

Lambrot, R.; Xu, C.; Saint-Phar, S.; Chountalos, G.; Cohen, T.; Paquet, M.; Suderman, M.; Hallett, M.; Kimmins, S.

2013-01-01

Epidemiological studies suggest that a father’s diet can influence offspring health. A proposed mechanism for paternal transmission of environmental information is via the sperm epigenome. The epigenome includes heritable information such as DNA methylation. We hypothesize that the dietary supply of methyl donors will alter epigenetic reprogramming in sperm. Here we feed male mice either a folate-deficient or folate-sufficient diet throughout life. Paternal folate deficiency is associated with increased birth defects in the offspring, which include craniofacial and musculoskeletal malformations. Genome-wide DNA methylation analysis and the subsequent functional analysis identify differential methylation in sperm of genes implicated in development, chronic diseases such as cancer, diabetes, autism and schizophrenia. While >300 genes are differentially expressed in offspring placenta, only two correspond to genes with differential methylation in sperm. This model suggests epigenetic transmission may involve sperm histone H3 methylation or DNA methylation and that adequate paternal dietary folate is essential for offspring health. PMID:24326934

Next generation sequencing for molecular confirmation of hereditary sudden cardiac death syndromes.

PubMed

Márquez, Manlio F; Cruz-Robles, David; Ines-Real, Selene; Vargas-Alarcón, Gilberto; Cárdenas, Manuel

2015-01-01

Hereditary sudden cardiac death syndromes comprise a wide range of diseases resulting from alteration in cardiac ion channels. Genes involved in these syndromes represent diverse mutations that cause the altered encoding of the diverse proteins constituting these channels, thus affecting directly the currents of the corresponding ions. In the present article we will briefly review how to arrive to a clinical diagnosis and we will present the results of molecular genetic studies made in Mexican subjects attending the SCD Syndromes Clinic of the National Institute of Cardiology of Mexico City. Copyright © 2014 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.

Multigeneration family with dominant SPG30 hereditary spastic paraplegia.

PubMed

Roda, Ricardo H; Schindler, Alice B; Blackstone, Craig

2017-11-01

Autosomal recessive KIF1A missense mutations cause hereditary spastic paraplegia (HSP) type SPG30, while recessive truncations lead to sensory and autonomic neuropathy (HSN2C) and many de novo missense mutations are associated with cognitive impairment. Here, we describe family members across three generations with pure HSP. A heterozygous p.Ser69Leu KIF1A mutation segregates with those afflicted. The same variant was previously reported in a Finnish father and son with pure HSP as well as four members of a Sicilian kindred with more intrafamilial phenotypic variability. This further validates the pathogenicity of the p.Ser69Leu mutation and suggests that it may represent a mutation hot spot.

NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia (SPG6)

PubMed Central

Rainier, Shirley; Chai, Jing-Hua; Tokarz, Debra; Nicholls, Robert D.; Fink, John K.

2003-01-01

The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders characterized by progressive lower-extremity weakness and spasticity. The molecular pathogenesis is poorly understood. We report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis. NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor. Identification of the NIPA1 function and ligand will aid an understanding of axonal neurodegeneration in HSP and may have important therapeutic implications. PMID:14508710

Iron Storage Disease: Facts, Fiction and Progress

PubMed Central

Beutler, Ernest

2007-01-01

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. PMID:17540589

Identification of small molecules that improve ATP synthesis defects conferred by Leber’s hereditary optic neuropathy mutations

PubMed Central

Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino

2016-01-01

Inherited mitochondrial complex I mutations cause blinding Leber's hereditary Optic Neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration-dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models. PMID:27497748

Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes.

PubMed

Lassi, Zohra S; Salam, Rehana A; Haider, Batool A; Bhutta, Zulfiqar A

2013-03-28

During pregnancy, fetal growth causes an increase in the total number of rapidly dividing cells, which leads to increased requirements for folate. Inadequate folate intake leads to a decrease in serum folate concentration, resulting in a decrease in erythrocyte folate concentration, a rise in homocysteine concentration, and megaloblastic changes in the bone marrow and other tissues with rapidly dividing cells To assess the effectiveness of oral folic acid supplementation alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2012) and we contacted major organisations working in micronutrient supplementation, including UNICEF Nutrition Section, World Health Organization (WHO) Maternal and Reproductive Health, WHO Nutrition Division, and National Center on Birth defects and Developmnetal Disabilities, US Centers for Disease Control and Prevention (CDC). All randomised, cluster-randomised and cross-over controlled trials evaluating supplementation of folic acid alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) in pregnancy. Two review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy. Thirty-one trials involving 17,771 women are included in this review. This review found that folic acid supplementation has no impact on pregnancy outcomes such as preterm birth (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.38; three studies, 2959 participants), and stillbirths/neonatal deaths (RR 1.33, 95% CI 0.96 to 1.85; three studies, 3110 participants). However, improvements were seen in the mean birthweight (mean difference (MD) 135.75, 95% CI 47.85 to 223.68). On the other hand, the review found no impact on improving pre-delivery anaemia (average RR 0.62, 95% CI 0.35 to 1.10; eight studies, 4149 participants; random-effects), mean pre-delivery haemoglobin level (MD -0.03, 95% CI -0.25 to 0.19; 12 studies, 1806 participants), mean pre-delivery serum folate levels (standardised mean difference (SMD) 2.03, 95% CI 0.80 to 3.27; eight studies, 1250 participants; random-effects), and mean pre-delivery red cell folate levels (SMD 1.59, 95% CI -0.07 to 3.26; four studies, 427 participants; random-effects). However, a significant reduction was seen in the incidence of megaloblastic anaemia (RR 0.21, 95% CI 0.11 to 0.38, four studies, 3839 participants). We found no conclusive evidence of benefit of folic acid supplementation during pregnancy on pregnancy outcomes.

Differences in folate-protein interactions result in differing inhibition of native rat liver and recombinant glycine N-methyltransferase by 5-methyltetrahydrofolate

DOE Office of Scientific and Technical Information (OSTI.GOV)

Luka, Zigmund; Pakhomova, Svetlana; Loukachevitch, Lioudmila V

2012-06-27

Glycine N-methyltransferase (GNMT) is a key regulatory enzyme in methyl group metabolism. In mammalian liver it reduces S-adenosylmethionine levels by using it to methylate glycine, producing N-methylglycine (sarcosine) and S-adenosylhomocysteine. GNMT is inhibited by binding two molecules of 5-methyltetrahydrofolate (mono- or polyglutamate forms) per tetramer of the active enzyme. Inhibition is sensitive to the status of the N-terminal valine of GNMT and to polyglutamation of the folate inhibitor. It is inhibited by pentaglutamate form more efficiently compared to monoglutamate form. The native rat liver GNMT contains an acetylated N-terminal valine and is inhibited much more efficiently compared to the recombinantmore » protein expressed in E. coli where the N-terminus is not acetylated. In this work we used a protein crystallography approach to evaluate the structural basis for these differences. We show that in the folate-GNMT complexes with the native enzyme, two folate molecules establish three and four hydrogen bonds with the protein. In the folate-recombinant GNMT complex only one hydrogen bond is established. This difference results in more effective inhibition by folate of the native liver GNMT activity compared to the recombinant enzyme.« less

Plastidial Folate Prevents Starch Biosynthesis Triggered by Sugar Influx into Non-Photosynthetic Plastids of Arabidopsis

PubMed Central

Hayashi, Makoto; Tanaka, Mina; Yamamoto, Saki; Nakagawa, Taro; Kanai, Masatake; Anegawa, Aya; Ohnishi, Miwa; Mimura, Tetsuro; Nishimura, Mikio

2017-01-01

Abstract Regulation of sucrose–starch interconversion in plants is important to maintain energy supplies necessary for viability and growth. Arabidopsis mutants were screened for aberrant responses to sucrose to identify candidates with a defect in the regulation of starch biosynthesis. One such mutant, fpgs1-4, accumulated substantial amounts of starch in non-photosynthetic cells. Dark-grown mutant seedlings exhibited shortened hypocotyls and accumulated starch in etioplasts when supplied with exogenous sucrose/glucose. Similar starch accumulation from exogenous sucrose was observed in mutant chloroplasts, when photosynthesis was prevented by organ culture in darkness. Molecular genetic analyses revealed that the mutant was defective in plastidial folylpolyglutamate synthetase, one of the enzymes engaged in folate biosynthesis. Active folate derivatives are important biomolecules that function as cofactors for a variety of enzymes. Exogenously supplied 5-formyl-tetrahydrofolate abrogated the mutant phenotypes, indicating that the fpgs1-4 mutant produced insufficient folate derivative levels. In addition, the antifolate agents methotrexate and 5-fluorouracil induced starch accumulation from exogenously supplied sucrose in dark-grown seedlings of wild-type Arabidopsis. These results indicate that plastidial folate suppresses starch biosynthesis triggered by sugar influx into non-photosynthetic cells, demonstrating a hitherto unsuspected link between plastidial folate and starch metabolism. PMID:28586467

Biomarkers of Nutrition for Development—Folate Review12345

PubMed Central

Bailey, Lynn B; Stover, Patrick J; McNulty, Helene; Fenech, Michael F; Gregory, Jesse F; Mills, James L; Pfeiffer, Christine M; Fazili, Zia; Zhang, Mindy; Ueland, Per M; Molloy, Anne M; Caudill, Marie A; Shane, Barry; Berry, Robert J; Bailey, Regan L; Hausman, Dorothy B; Raghavan, Ramkripa; Raiten, Daniel J

2015-01-01

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate’s history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. PMID:26451605

Structures of Mycobacterium Tuberculosis Folylpolyglutamate Synthase Complexed With ADP And AMPPCD

DOE Office of Scientific and Technical Information (OSTI.GOV)

Young, P.G.; Smith, C.A.; Metcalf, P.

2009-05-28

Folate derivatives are essential vitamins for cell growth and replication, primarily because of their central role in reactions of one-carbon metabolism. Folates require polyglutamation to be efficiently retained within the cell and folate-dependent enzymes have a higher affinity for the polyglutamylated forms of this cofactor. Polyglutamylation is dependent on the enzyme folylpolyglutamate synthetase (FPGS), which catalyzes the sequential addition of several glutamates to folate. FPGS is essential for the growth and survival of important bacterial species, including Mycobacterium tuberculosis, and is a potential drug target. Here, the crystal structures of M. tuberculosis FPGS in complex with ADP and AMPPCP aremore » reported at 2.0 and 2.3 angstroms resolution, respectively. The structures reveal a deeply buried nucleotide-binding site, as in the Escherichia coli and Lactobacillus casei FPGS structures, and a long extended groove for the binding of folate substrates. Differences from the E. coli and L. casei FPGS structures are seen in the binding of a key divalent cation, the carbamylation state of an essential lysine side chain and the adoption of an 'open' position by the active-site beta5-alpha6 loop. These changes point to coordinated events that are associated with dihydropteroate/folate binding and the catalysis of the new amide bond with an incoming glutamate residue.« less