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Sample records for folate transport deficiency

  1. Increased synthesis of folate transporters regulates folate transport in conditions of ethanol exposure and folate deficiency.

    PubMed

    Thakur, Shilpa; More, Deepti; Rahat, Beenish; Khanduja, Krishan Lal; Kaur, Jyotdeep

    2016-01-01

    Excessive alcohol consumption and dietary folate inadequacy are the main contributors leading to folate deficiency (FD). The present study was planned to study regulation of folate transport in conditions of FD and ethanol exposure in human embryonic kidney cell line. Also, the reversible nature of effects mediated by ethanol exposure and FD was determined by folate repletion and ethanol removal. For ethanol treatment, HEK293 cells were grown in medium containing 100 mM ethanol, and after treatment, one group of cells was shifted on medium that was free from ethanol. For FD treatment, cells were grown in folate-deficient medium followed by shifting of one group of cells on folate containing medium. FD as well as ethanol exposure resulted in an increase in folate uptake which was due to an increase in expression of folate transporters, i.e., reduced folate carrier, proton-coupled folate transporter, and folate receptor, both at the mRNA and protein level. The effects mediated by ethanol exposure and FD were reversible on removal of treatment. Promoter region methylation of folate transporters remained unaffected after FD and ethanol exposure. As far as transcription rate of folate transporters is concerned, an increase in rate of synthesis was observed in both ethanol exposure and FD conditions. Additionally, mRNA life of folate transporters was observed to be reduced by FD. An increased expression of folate transporters under ethanol exposure and FD conditions can be attributed to enhanced rate of synthesis of folate transporters.

  2. Folate deficiency

    MedlinePlus

    ... micrograms of folate daily. Women who may become pregnant should take folic acid supplements to ensure that they get enough each day. Specific recommendations depend on a person's age, gender, and other factors (such as pregnancy ...

  3. Folate-deficiency anemia

    MedlinePlus

    ... medlineplus.gov/ency/article/000551.htm Folate-deficiency anemia To use the sharing features on this page, please enable JavaScript. Folate-deficiency anemia is a decrease in red blood cells (anemia) ...

  4. Autism and Folate Deficiency

    DTIC Science & Technology

    2010-05-01

    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...risk factor for autism : alterations in m ethionine metabolism in autistic patients may be due to a functional folate deficiency, and folate receptor

  5. Cerebral Folate Deficiency

    ERIC Educational Resources Information Center

    Gordon, Neil

    2009-01-01

    Cerebral folate deficiency (CFD) is associated with low levels of 5-methyltetrahydrofolate in the cerebrospinal fluid (CSF) with normal folate levels in the plasma and red blood cells. The onset of symptoms caused by the deficiency of folates in the brain is at around 4 to 6 months of age. This is followed by delayed development, with deceleration…

  6. 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…

  7. Diagnosis and management of cerebral folate deficiency

    PubMed Central

    Al-Baradie, Raidah S.; Chudary, Mohammed W.

    2014-01-01

    Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests. PMID:25274592

  8. Iron and Folate-Deficiency Anaemias.

    ERIC Educational Resources Information Center

    Hercberg, Serge

    1990-01-01

    Nutritional anemia is believed to be the most widespread nutritional disorder in the world. While it generally affects developing countries, developed countries are also affected to an extent sufficient to justify the implementation of preventive measures at a national level. This report focuses on iron and folate deficiencies, which are by far…

  9. Clinical recognition and aspects of the cerebral folate deficiency syndromes.

    PubMed

    Ramaekers, Vincent; Sequeira, Jeffrey M; Quadros, Edward V

    2013-03-01

    We characterized cerebral folate deficiency (CFD) as any neuro-psychiatric condition associated with low spinal fluid (CSF) N5-methyltetrahydrofolate (MTHF) but normal folate status outside the central nervous system (CNS). The commonest cause underlying CFD syndromes is the presence of serum autoantibodies of the blocking type directed against folate receptor-α (FRα) attached to the plasma-side of choroid plexus epithelial cells. Blocking FR antibodies inhibit MTHF transport across the choroid plexus. Serum titers of FR antibodies may fluctuate significantly over time. Less frequent causes of CFD are FOLR-1 mutations, mitochondrial disorders and inborn errors affecting folate metabolism. Maternal FR antibodies have been associated with neural tube defects while the presence of FR antibodies in either one or both parents increases the risk of an offspring with infantile autism. Recognizable CFD syndromes attributed to FR-antibodies in childhood are infantile-onset CFD presenting 4-6 months after birth, infantile autism with neurological deficits, and a spastic ataxic syndrome from the age of 1 year, while progressive dystonic or schizophrenic syndromes develop during adolescence. FR autoantibodies are frequently found in autism spectrum disorders, in an Aicardi-Goutières variant and in Rett syndrome. The heterogeneous phenotype of CFD syndromes might be determined by different ages of onset and periods when FR autoantibodies are generated with consequent CNS folate deficiency. Folate deficiency during various critical stages of fetal and infantile development affects structural and functional refinement of the brain. Awareness of CFD syndromes should lead to early detection, diagnosis and improved prognosis of these potentially treatable group of autoimmune and genetically determined conditions.

  10. Increased folate uptake prevents dietary development of folate deficiency in the rat brain

    SciTech Connect

    McMartin, K.E.; Collins, T.D.; Eisenga, B.H.; Bhandari, S.D. )

    1990-02-26

    Folic acid and folate deficiency have been implicated in disorders of the central nervous system. In a study of the mechanism for the effects of chronic ethanol on folate homeostasis, the uptake of {sup 3}H-folic acid by the rat brain has been studied. Male Sprague-Dawley rats were fed sulfonamide-supplemented folate-sufficient and folate-deficient liquid diets containing either ethanol or isoenergic carbohydrate as a control. After 16 weeks, severe folate depletion occurred in tissues (liver, kidney, spleen, lung intestine, testes), but not in the brain. Tissue retention of {sup 3}H-folic acid was increased four-fold in the brain of folate-deficient rats. A smaller increase in uptake was observed in the other tissues, except for the liver, in which the retention of {sup 3}H-folic acid was slightly decreased. Chronic ethanol feeding decreased hepatic folate uptake, but not that by the increase the uptake of folate from the plasma of folate-deficient rats, thereby inhibiting the development of brain folate deficiency.

  11. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice.

    PubMed

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-08-04

    The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor α (ERα) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone.

  12. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    PubMed Central

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-01-01

    The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34) immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA), placental growth factor (PLGF), and VEGF receptor 2 (VEGFR2) were also tested. Serum levels of homocysteine (Hcy), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone (P4), and estradiol (E2) were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR) and estrogen receptor α (ERα) were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone. PMID:26247969

  13. 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...

  14. The metabolic basis for developmental disorders due to defective folate transport.

    PubMed

    Desai, Ankuri; Sequeira, Jeffrey M; Quadros, Edward V

    2016-07-01

    Folates are essential in the intermediary metabolism of amino acids, synthesis of nucleotides and for maintaining methylation reactions. They are also linked to the production of neurotransmitters through GTP needed for the synthesis of tetrahydrobiopterin. During pregnancy, folate is needed for fetal development. Folate deficiency during this period has been linked to increased risk of neural tube defects. Disturbances of folate metabolism due to genetic abnormalities or the presence of autoantibodies to folate receptor alpha (FRα) can impair physiologic processes dependent on folate, resulting in a variety of developmental disorders including cerebral folate deficiency syndrome and autism spectrum disorders. Overall, adequate folate status has proven to be important during pregnancy as well as neurological development and functioning in neonates and children. Treatment with pharmacologic doses of folinic acid has led to reversal of some symptoms in many children diagnosed with cerebral folate deficiency syndrome and autism, especially in those positive for autoantibodies to FRα. Thus, as the brain continues to develop throughout fetal and infant life, it can be affected and become dysfunctional due to a defective folate transport contributing to folate deficiency. Treatment and prevention of these disorders can be achieved by identification of those at risk and supplementation with folinic acid.

  15. Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice.

    PubMed

    Lawrance, Andrea K; Deng, Liyuan; Brody, Lawrence C; Finnell, Richard H; Shane, Barry; Rozen, Rima

    2007-05-01

    Epidemiological studies indicate that adequate dietary folate is protective against colon cancer, although mechanisms remain largely elusive. We investigated the effects of genetic disruptions of folate transport and metabolism and of dietary folate deficiency in a mouse model of colon cancer, the Apc(min/+) mouse. Apc(min/+) mice with heterozygous knockout of the gene for reduced folate carrier 1 (Rfc1(+/-)) developed significantly fewer adenomas compared to Rfc1(+/+)Apc(min/+) mice [30.3+/-4.6 vs. 60.4+/-9.4 on a control diet (CD) and 42.6+/-4.4 vs. 55.8+/-7.6 on a folate-deficient diet, respectively]. Rfc1(+/-)Apc(min/+) mice also carried a lower tumor load, an indicator of tumor size as well as of tumor number. In contrast, there were no differences in adenoma formation between Apc(min/+) mice carrying a knockout allele for methionine synthase (Mtr(+/-)), an enzyme that catalyzes folate-dependent homocysteine remethylation, and Mtr(+/+)Apc(min/+) mice. However, in both Mtr groups of mice, dietary folate deficiency significantly increased adenoma number (from 32.3+/-3.8 on a CD to 48.1+/-4.2 on a folate-deficient diet), increased plasma homocysteine, decreased global DNA methylation in preneoplastic intestines and increased apoptosis in tissues. There were no genotype-associated differences in these parameters in the Rfc1 group, suggesting that the protection conferred by Rfc1 deficiency is carried out through a different mechanism. In conclusion, genetic and nutritional disturbances in folate metabolism can have distinct influences on tumorigenesis in Apc(min/+) mice; altered levels of homocysteine, global DNA methylation and apoptosis may contribute mechanistically to dietary influence.

  16. Folate and Thiamine Transporters mediated by Facilitative Carriers (SLC19A1-3 and SLC46A1) and Folate Receptors

    PubMed Central

    Zhao, Rongbao; Goldman, I. David

    2013-01-01

    The reduced folate carrier (RFC,SLC19A1), thiamine transporter-1 (ThTr1,SLC19A2) and thiamine transporter-2 (ThTr2,SLC19A3) evolved from the same family of solute carriers. SLC19A1 transports folates but not thiamine. SLC19A2 and SLC19A3 transport thiamine but not folates. SLC19A1 and SLC19A2 deliver their substrates to systemic tissues; SLC19A3 mediates intestinal thiamine absorption. The proton-coupled folate transporter (PCFT,SLC46A1) is the mechanism by which folates are absorbed across the apical-brush-border membrane of the proximal small intestine. Two folate receptors (FOLR1 and FOLR2) mediate folate transport across epithelia by an endocytic process. Folate transporters are routes of delivery of drugs for the treatment of cancer and inflammatory diseases. There are autosomal recessive disorders associated with mutations in genes encoded for SLC46A1 (hereditary folate malabsorption), FOLR1 (cerebral folate deficiency), SLC19A2 (thiamine-responsive megaloblastic anemia), and SLC19A3 (biotin-responsive basal ganglia disease). PMID:23506878

  17. Thiamine absorption is not compromised in folate-deficient rats

    SciTech Connect

    Walzem, R.L.; Clifford, A.J.

    1988-11-01

    Thiamine absorption and excretion were assessed in rats with severe folate deficiency (FD) by determining the fate of oral TH-labeled and intravenous UC-labeled thiamine over a 6-h test period. Thiamine status was evaluated in these same rats by measuring transketolase activity levels of blood before (TKA) and after (TPPE) addition of thiamine pyrophosphate to the incubation mixture of the assay procedure. Two additional experiments assessed active transport of thiamine and the effect of dietary succinylsulfathiazole (SST) on TKA and TPPE in rats with moderate FD. Intestinal absorption in general and thiamine absorption in particular and thiamine status were unaltered in rats with severe FD. Inanition associated with severe FD may impair thiamine status. Thiamine absorption by active transport was not compromised in FD, and dietary succinylsulfathiazole did not affect thiamine status.

  18. Periconceptional Folate Deficiency and Implications in Neural Tube Defects

    PubMed Central

    Safi, J.; Joyeux, L.; Chalouhi, G. E.

    2012-01-01

    Nutritional deficiencies are preventable etiological and epigenetic factors causing congenital abnormalities, first cause of infant mortality. Folate deficiency has a well-established teratogenic effect, leading to an increasing risk of neural tube defects. This paper highlights the most recent medical literature about folate deficiency, be it maternal or paternal. It then focuses on associated deficiencies as nutritional deficiencies are multiple and interrelated. Observational and interventional studies have all been consistent with a 50–70% protective effect of adequate women consumption of folates on neural tube defects. Since strategies to modify women's dietary habits and vitamin use have achieved little progress, scientific as well as political effort is mandatory in order to implement global preventive public health strategies aimed at improving the alimentation of women in reproductive age, especially folic acid supplementation. Even with the recent breakthrough of fetal surgery for myelomeningocele, the emphasis should still be on prevention as the best practice rather than treatment of neural tube defects. PMID:22900183

  19. Thiamine metabolism in folate deficient rats

    SciTech Connect

    Walzem, R.L.

    1987-01-01

    Folate status (FS) and resultant alterations in thiamine status (TS) were evaluated in weanling rats fed either 17% amino acids (RHAA); 14% amino acids (LOGLU); 20% Vitamin Free casein (VFC) + 8% gelatin (HICG); 10% VFC + 4% gelatin + 0.3% methionine (CGM); or 10% VFC + 4 % gelatin (LOCG). Diets were fed with and without 8 mg FA/kg diet. HICG diet contained 54 ug/kg endogenous folate, the CGM and LOCG, 27 ug/kg, RHAA and LOGLU were folate free. FS was assessed by growth rate, hematology, formiminoglutamic acid excretion following a histidine load and tissue folate levels. TS was assessed by determining the fate of oral /sup 3/H-labeled and intravenous /sup 14/C-labeled thiamine over a six hour test period and by measurement of blood transketolase activity (TKA) and TPP effect (TPPE). TKA and TPPE were measured by an enzymatic single-point assay developed during these investigations.

  20. Folate Transporters in Placentas from Preterm Newborns and Their Relation to Cord Blood Folate and Vitamin B12 Levels

    PubMed Central

    Castaño, Erika; Caviedes, Lorena; Hirsch, Sandra; Llanos, Miguel; Iñiguez, Germán; Ronco, Ana María

    2017-01-01

    Folate deficiency during pregnancy has been related to low birth weight, preterm (PT) birth and other health risks in the offspring; however, it is unknown whether prematurity is related to low folate transport through the placenta due to altered expression of specific folate transporters. We determined placental expression (mRNA and protein concentrations by RT-qPCR and WB respectively) of specific folate transporters: RFC, PCFT/HCP1 and FOLR1 in chorionic (fetal) and basal (maternal) plates of placentas of PT pregnancies (PT, 32–36 weeks, n = 51). Term placentas were used as controls (T, 37–41 weeks, n = 47). Folates and vitamin B12 levels were measured by electrochemiluminescence in umbilical cord blood of newborns. FOLR1 mRNA expression was lower and protein concentration higher in PT placentas (both plates) relative to the control group (p <0.05). In addition, gestational age was positively correlated with mRNA expression (Rho = 0.7), and negatively with protein concentration (Rho = -0.7 for chorionic and -0.43 for basal plate). PCFT/HCP1 mRNA was lower in PT placentas, without changes in protein levels. RFC did not differ in PT placentas compared to controls. PT newborns presented higher cord blood folate level (p = 0.049) along with lower vitamin B12 concentration compared to controls (p = 0.037).In conclusion, placental FOLR1 mRNA was positively associated with gestational age. Conversely, FOLR1 protein concentrations along with folate/vitamin B12 ratio in cord blood were negatively associated with gestational age. Placental FOLR1 is likely the main placental folate transporter to the fetus in newborns. PMID:28103309

  1. Causes of Vitamin B12 and Folate Deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor B12 status are a low dietary intake of the vitamin (i.e., a low intake of animal-source foods) and malabsorption. Although it has long been known that strict vegetar...

  2. EFFECT OF DIETARY FOLATE DEFICIENCY ON ARSENIC GENOTOXICITY IN MICE

    EPA Science Inventory

    Arsenic, a human carcinogen found in drinking water supplies throughout the world, is clastogenic in human and rodent cells. An estimated ten percent of Americans are deficient in folate, a methyl donor necessary for normal nucleotide metabolism, DNA synthesis, and DNA methylatio...

  3. The human proton-coupled folate transporter

    PubMed Central

    Desmoulin, Sita Kugel; Hou, Zhanjun; Gangjee, Aleem; Matherly, Larry H.

    2012-01-01

    This review summarizes the biology of the proton-coupled folate transporter (PCFT). PCFT was identified in 2006 as the primary transporter for intestinal absorption of dietary folates, as mutations in PCFT are causal in hereditary folate malabsorption (HFM) syndrome. Since 2006, there have been major advances in understanding the mechanistic roles of critical amino acids and/or domains in the PCFT protein, many of which were identified as mutated in HFM patients, and in characterizing transcriptional control of the human PCFT gene. With the recognition that PCFT is abundantly expressed in human tumors and is active at pHs characterizing the tumor microenvironment, attention turned to exploiting PCFT for delivering novel cytotoxic antifolates for solid tumors. The finding that pemetrexed is an excellent PCFT substrate explains its demonstrated clinical efficacy for mesothelioma and non-small cell lung cancer, and prompted development of more PCFT-selective tumor-targeted 6-substituted pyrrolo[2,3-d]pyrimidine antifolates that derive their cytotoxic effects by targeting de novo purine nucleotide biosynthesis. PMID:22954694

  4. Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction.

    PubMed

    Qiu, Andong; Min, Sang Hee; Jansen, Michaela; Malhotra, Usha; Tsai, Eugenia; Cabelof, Diane C; Matherly, Larry H; Zhao, Rongbao; Akabas, Myles H; Goldman, I David

    2007-11-01

    This laboratory recently identified a human gene that encodes a novel folate transporter [Homo sapiens proton-coupled folate transporter (HsPCFT); SLC46A1] required for intestinal folate absorption. This study focused on mouse (Mus musculus) PCFT (MmPCFT) and rat (Rattus norvegicus) PCFT (RnPCFT) and addresses their secondary structure, specificity, tissue expression, and regulation by dietary folates. Both rodent PCFT proteins traffic to the cell membrane with the NH(2)- and COOH-termini accessible to antibodies targeted to these domains only in permeabilized HeLa cells. This, together with computer-based topological analyses, is consistent with a model in which rodent PCFT proteins likely contain 12 transmembrane domains. Transport of [(3)H]folates was optimal at pH 5.5 and decreased with increasing pH due to an increase in K(m) and a decrease in V(max). At pH 7.0, folic acid and methotrexate influx was negligible, but there was residual (6S)5-methyltetrahydrofolate transport. Uptake of folates in PCFT-injected Xenopus oocytes was electrogenic and pH dependent. Folic acid influx K(m) values of MmPCFT and RnPCFT, assessed electrophysiologically, were 0.7 and 0.3 microM at pH 5.5 and 1.1 and 0.8 microM at pH 6.5, respectively. Rodent PCFTs were highly specific for monoglutamyl but not polyglutamyl methotrexate. MmPCFT mRNA was highly expressed in the duodenum, proximal jejunum, liver, and kidney with lesser expression in the brain and other tissues. MmPCFT protein was localized to the apical brush-border membrane of the duodenum and proximal jejunum. MmPCFT mRNA levels increased approximately 13-fold in the proximal small intestine in mice fed a folate-deficient vesus folate-replete diet, consistent with the critical role that PCFT plays in intestinal folate absorption.

  5. Long interspersed nucleotide element-1 hypomethylation in folate-deficient mouse embryonic stem cells.

    PubMed

    Chang, Shaoyan; Wang, Li; Guan, Yunqian; Shangguan, Shaofang; Du, Qingan; Wang, Yang; Zhang, Ting; Zhang, Yu

    2013-07-01

    Folate is thought to contribute to health and development by methylation regulation. Long interspersed nucleotide element-1 (LINE-1), which is regulated by methylation modification, plays an important role in sculpting the structure and function of genomes. Some studies have shown that folate concentration is related to LINE-1 methylation. However, the direct association between LINE-1 methylation and folate deficiency remains unclear. To explore whether folate deficiency directly induced LINE-1 hypomethylation and to analyze the relationship between folate concentration and the LINE-1 methylation level, mouse ESCs were treated with various concentrations of folate which was measured by chemiluminescent immunoassay, and the homocysteine content was detected by ELISA. LINE-1 methylation was examined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry at various time points. Concurrently, cell proliferation and differentiation were observed. The result showed that the intracellular folate decreases under folate-deficient condition, conversely, homocysteine content increased gradually and there was a negatively correlated between them. Folate insufficiency induced LINE-1 hypomethylation at the lowest levels in folate-free group and moderate in folate-deficient group, compared with that in the folate-normal group at day 18. Moreover, LINE-1 methylation level was positively correlated with folate content, and negatively correlated with homocysteine content. At corresponding time points, proliferation and differentiation of mouse ESCs showed no alteration in all groups. Our data indicated that folate deficiency affected the homeostasis of folate-mediated one-carbon metabolism, leading to reduced LINE-1 methylation in mouse ESCs. This study provides preliminary evidence of folate deficiency affecting early embryonic development.

  6. Biology of the major facilitative folate transporters SLC19A1 and SLC46A1.

    PubMed

    Hou, Zhanjun; Matherly, Larry H

    2014-01-01

    This chapter focuses on the biology of the major facilitative membrane folate transporters, the reduced folate carrier (RFC), and the proton-coupled folate transporter (PCFT). Folates are essential vitamins, and folate deficiency contributes to a variety of heath disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates intestinal absorption of dietary folates. Clinically relevant antifolates such as methotrexate (MTX) are transported by RFC, and the loss of RFC transport is an important mechanism of MTX resistance. PCFT is abundantly expressed in human tumors and is active under pH conditions associated with the tumor microenvironment. Pemetrexed (PMX) is an excellent substrate for PCFT as well as for RFC. Novel tumor-targeted antifolates related to PMX with selective membrane transport by PCFT over RFC are being developed. The molecular picture of RFC and PCFT continues to evolve relating to membrane topology, N-glycosylation, energetics, and identification of structurally and functionally important domains and amino acids. The molecular bases for MTX resistance associated with loss of RFC function, and for the rare autosomal recessive condition, hereditary folate malabsorption (HFM), attributable to mutant PCFT, have been established. From structural homologies to the bacterial transporters GlpT and LacY, homology models were developed for RFC and PCFT, enabling new mechanistic insights and experimentally testable hypotheses. RFC and PCFT exist as homo-oligomers, and evidence suggests that homo-oligomerization of RFC and PCFT monomeric proteins may be important for intracellular trafficking and/or transport function. Better understanding of the structure and function of RFC and PCFT should facilitate the rational development of new therapeutic strategies for cancer as well as for HFM.

  7. High Prevalence of Vitamin B12 Deficiency and No Folate Deficiency in Young Children in Nepal

    PubMed Central

    Ng’eno, Bernadette N.; Perrine, Cria G.; Whitehead, Ralph D.; Subedi, Giri Raj; Mebrahtu, Saba; Dahal, Pradiumna; Jefferds, Maria Elena D.

    2017-01-01

    Many children in low- and middle-income countries may have inadequate intake of vitamin B12 and folate; data confirming these inadequacies are limited. We used biochemical, demographic, behavioral and anthropometric data to describe the folate and vitamin B12 concentrations among six- to 23-month-old Nepalese children. Vitamin B12 (serum B12 < 150 pmol/L) and folate deficiencies (red blood cell (RBC) folate < 226.5 nmol/L) were assessed. We used logistic regression to identify predictors of vitamin B12 deficiency. The vitamin B12 geometric mean was 186 pmol/L; 30.2% of children were deficient. The mean RBC folate concentration was 13,612 nmol/L; there was no deficiency. Factors associated with vitamin B12 deficiency included: (a) age six to 11 months (adjusted odds ratio (aOR) 1.51; 95% confidence interval (CI): 1.18, 1.92) or 12–17 months (aOR 1.38; 95% CI: 1.10, 1.72) compared to 18–23 months; (b) being stunted (aOR 1.24; 95% CI: 1.03, 1.50) compared to not being stunted; (c) and not eating animal-source foods (aOR 1.85; 95% CI: 1.42, 2.41) compared to eating animal-source foods the previous day. There was a high prevalence of vitamin B12 deficiency, but no folate deficiency. Improving early feeding practices, including the consumption of rich sources of vitamin B12, such as animal-source foods and fortified foods, may help decrease deficiency. PMID:28106733

  8. High Prevalence of Vitamin B12 Deficiency and No Folate Deficiency in Young Children in Nepal.

    PubMed

    Ng'eno, Bernadette N; Perrine, Cria G; Whitehead, Ralph D; Subedi, Giri Raj; Mebrahtu, Saba; Dahal, Pradiumna; Jefferds, Maria Elena D

    2017-01-17

    Many children in low- and middle-income countries may have inadequate intake of vitamin B12 and folate; data confirming these inadequacies are limited. We used biochemical, demographic, behavioral and anthropometric data to describe the folate and vitamin B12 concentrations among six- to 23-month-old Nepalese children. Vitamin B12 (serum B12 < 150 pmol/L) and folate deficiencies (red blood cell (RBC) folate < 226.5 nmol/L) were assessed. We used logistic regression to identify predictors of vitamin B12 deficiency. The vitamin B12 geometric mean was 186 pmol/L; 30.2% of children were deficient. The mean RBC folate concentration was 13,612 nmol/L; there was no deficiency. Factors associated with vitamin B12 deficiency included: (a) age six to 11 months (adjusted odds ratio (aOR) 1.51; 95% confidence interval (CI): 1.18, 1.92) or 12-17 months (aOR 1.38; 95% CI: 1.10, 1.72) compared to 18-23 months; (b) being stunted (aOR 1.24; 95% CI: 1.03, 1.50) compared to not being stunted; (c) and not eating animal-source foods (aOR 1.85; 95% CI: 1.42, 2.41) compared to eating animal-source foods the previous day. There was a high prevalence of vitamin B12 deficiency, but no folate deficiency. Improving early feeding practices, including the consumption of rich sources of vitamin B12, such as animal-source foods and fortified foods, may help decrease deficiency.

  9. Anemias excluding cobalamin and folate deficiencies.

    PubMed

    Dublis, Stephanie; Shah, Shefali; Nand, Sucha; Anderes, Elise

    2014-01-01

    Anemias are one of the commonest maladies affecting humans. They result from either a failure of production by the bone marrow (hypoproliferative), or from premature destruction or loss (hyperproliferative) of red cells. Hypoproliferative anemias typically result from deficiencies of essential nutrients, stem cell abnormalities or deficiency, and infiltrative processes of the bone marrow. In the hyperproliferative forms, the bone marrow function is normal and anemia results from bleeding or shortened erythrocyte lifespan due to hemoglobinopathies, red cell enzyme disorders, membrane defects, or external factors such as antibodies, trauma, or heat injury. The etiology of anemia is frequently obvious, but when obscure, a systematic diagnostic approach frequently yields the answer. It is important to realize that anemias are usually a consequence of another disease process, which must be identified. Without correction of the underlying disease process, the treatment is likely to fail.

  10. 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...

  11. 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...

  12. 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

  13. 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.

  14. Folate deficiency induces neurodegeneration and brain dysfunction in mice lacking uracil DNA glycosylase.

    PubMed

    Kronenberg, Golo; Harms, Christoph; Sobol, Robert W; Cardozo-Pelaez, Fernando; Linhart, Heinz; Winter, Benjamin; Balkaya, Mustafa; Gertz, Karen; Gay, Shanna B; Cox, David; Eckart, Sarah; Ahmadi, Michael; Juckel, Georg; Kempermann, Gerd; Hellweg, Rainer; Sohr, Reinhard; Hörtnagl, Heide; Wilson, Samuel H; Jaenisch, Rudolf; Endres, Matthias

    2008-07-09

    Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls. Folate depletion increased nuclear mutation rates in Ung-/- embryonic fibroblasts, and conferred death of cultured Ung-/- hippocampal neurons. Feeding animals a folate-deficient diet (FD) for 3 months induced degeneration of CA3 pyramidal neurons in Ung-/- but not Ung+/+ mice along with decreased hippocampal expression of brain-derived neurotrophic factor protein and decreased brain levels of antioxidant glutathione. Furthermore, FD induced cognitive deficits and mood alterations such as anxious and despair-like behaviors that were aggravated in Ung-/- mice. Independent of Ung genotype, FD increased plasma homocysteine levels, altered brain monoamine metabolism, and inhibited adult hippocampal neurogenesis. These results indicate that impaired uracil repair is involved in neurodegeneration and neuropsychiatric dysfunction induced by experimental folate deficiency.

  15. Interactions of ethanol and folate deficiency in development of alcoholic liver disease in the micropig.

    PubMed Central

    Halsted, Charles H.; Villanueva, Jesus A.; Devlin, Angela M.; James, S. Jill

    2002-01-01

    Folate deficiency is present in most patients with alcoholic liver disease (ALD), whereas folate regulates and alcoholism perturbs intrahepatic methionine metabolism, and S-adenosyl-methionine prevents the development of experimental ALD. Our studies explored the hypothesis that abnormal methionine metabolism is exacerbated by folate deficiency and promotes the development of ALD in the setting of chronic ethanol exposure. Using the micropig animal model, dietary combinations of folate deficiency and a diet containing 40% of kcal as ethanol were followed by measurements of hepatic methionine metabolism and indices of ALD. Alcoholic liver injury, expressed as steatohepatitis in terminal 14 week liver specimens, was evident in micropigs fed the combined ethanol containing and folate deficient diet but not in micropigs fed each diet separately. Perturbations of methionine metabolism included decreased hepatic S-adenosylmethionine and glutathione with increased products of DNA and lipid oxidation. Thus, the development of ALD is linked to abnormal methionine metabolism and is accelerated in the presence of folate deficiency. PMID:12053707

  16. The Major Facilitative Folate Transporters Solute Carrier 19A1 and Solute Carrier 46A1: Biology and Role in Antifolate Chemotherapy of Cancer

    PubMed Central

    Wilson, Mike R.; Hou, Zhanjun

    2014-01-01

    This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases. PMID:24396145

  17. The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.

    PubMed

    Matherly, Larry H; Wilson, Mike R; Hou, Zhanjun

    2014-04-01

    This review summarizes the biology of the major facilitative membrane transporters, the reduced folate carrier (RFC) (Solute Carrier 19A1) and the proton-coupled folate transporter (PCFT) (Solute Carrier 46A1). Folates are essential vitamins, and folate deficiency contributes to a variety of health disorders. RFC is ubiquitously expressed and is the major folate transporter in mammalian cells and tissues. PCFT mediates the intestinal absorption of dietary folates and appears to be important for transport of folates into the central nervous system. Clinically relevant antifolates for cancer, such as methotrexate and pralatrexate, are transported by RFC, and loss of RFC transport is an important mechanism of methotrexate resistance in cancer cell lines and in patients. PCFT is expressed in human tumors, and is active at pH conditions associated with the tumor microenvironment. Pemetrexed is an excellent substrate for both RFC and PCFT. Novel tumor-targeted antifolates related to pemetrexed with selective membrane transport by PCFT over RFC are being developed. In recent years, there have been major advances in understanding the structural and functional properties and the regulation of RFC and PCFT. The molecular bases for methotrexate resistance associated with loss of RFC transport and for hereditary folate malabsorption, attributable to mutant PCFT, were determined. Future studies should continue to translate molecular insights from basic studies of RFC and PCFT biology into new therapeutic strategies for cancer and other diseases.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  19. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig.

    PubMed

    Halsted, Charles H; Villanueva, Jesus A; Devlin, Angela M; Niemelä, Onni; Parkkila, Seppo; Garrow, Timothy A; Wallock, Lynn M; Shigenaga, Mark K; Melnyk, Stepan; James, S Jill

    2002-07-23

    Alcoholic liver disease is associated with abnormal hepatic methionine metabolism and folate deficiency. Because folate is integral to the methionine cycle, its deficiency could promote alcoholic liver disease by enhancing ethanol-induced perturbations of hepatic methionine metabolism and DNA damage. We grouped 24 juvenile micropigs to receive folate-sufficient (FS) or folate-depleted (FD) diets or the same diets containing 40% of energy as ethanol (FSE and FDE) for 14 wk, and the significance of differences among the groups was determined by ANOVA. Plasma homocysteine levels were increased in all experimental groups from 6 wk onward and were greatest in FDE. Ethanol feeding reduced liver methionine synthase activity, S-adenosylmethionine (SAM), and glutathione, and elevated plasma malondialdehyde (MDA) and alanine transaminase. Folate deficiency decreased liver folate levels and increased global DNA hypomethylation. Ethanol feeding and folate deficiency acted together to decrease the liver SAM/S-adenosylhomocysteine (SAH) ratio and to increase liver SAH, DNA strand breaks, urinary 8-oxo-2'-deoxyguanosine [oxo(8)dG]/mg of creatinine, plasma homocysteine, and aspartate transaminase by more than 8-fold. Liver SAM correlated positively with glutathione, which correlated negatively with plasma MDA and urinary oxo(8)dG. Liver SAM/SAH correlated negatively with DNA strand breaks, which correlated with urinary oxo(8)dG. Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MDA. Steatohepatitis occurred in five of six pigs in FDE but not in the other groups. In summary, folate deficiency enhances perturbations in hepatic methionine metabolism and DNA damage while promoting alcoholic liver injury.

  20. Review of the magnitude of folate and vitamin B12 deficiencies worldwide

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Human deficiencies of folate and vitamin B12 result in adverse effects which may be of public health significance, but the magnitude of these deficiencies is unknown. Therefore, we examine the prevalence data currently available, assess global coverage of surveys, determine the frequency with which...

  1. Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice.

    PubMed

    Wang, Xueqian; Cabrera, Robert M; Li, Yue; Miller, David S; Finnell, Richard H

    2013-03-01

    Folate deficiency has been associated with many adverse clinical manifestations. The blood-brain barrier (BBB), formed by brain capillary endothelial cells, protects the brain from exposure to neurotoxicants. The function of BBB is modulated by multiple ABC transporters, particularly P-glycoprotein. A proton-coupled folate transporter (PCFT)-deficient mouse has been previously described as a model for systemic folate deficiency. Herein, we demonstrate that exposing mouse brain capillaries to the antiepileptic drug, valproic acid (VPA; 5 μM), significantly increased P-glycoprotein transport function in the wild-type animals. A ligand to the aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produced a similar induction of P-glycoprotein, which tightened the BBB, thereby increasing the neuroprotection. However, VPA- or TCDD-induced P-glycoprotein transport was blocked in the PCFT-nullizygous mice, indicating that multiple neuroprotective mechanisms are compromised under folate-deficient conditions. Brain capillaries from S-folinic acid (SFA; 40 mg/kg)-treated PCFT-nullizygous mice exhibited increased P-glycoprotein transport following VPA exposure. This suggests that SFA supplementation restored the normal BBB function. In addition, we show that tight-junction proteins are disintegrated in the PCFT mutant mice. Taken together, these findings strongly suggest that folate deficiency disrupts the BBB function by targeting the transporter and tight junctions, which may contribute to the development of neurological disorders.

  2. Genetics Home Reference: cerebral folate transport deficiency

    MedlinePlus

    ... treatment, these neurological problems worsen over time. Related Information What does it mean if a disorder seems ... have been described in the scientific literature. Related Information What information about a genetic condition can statistics ...

  3. Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter

    PubMed Central

    Borzutzky, Arturo; Crompton, Brian; Bergmann, Anke K.; Giliani, Silvia; Baxi, Sachin; Martin, Madelena; Neufeld, Ellis J.; Notarangelo, Luigi D.

    2009-01-01

    Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the proton-coupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion. PMID:19740703

  4. Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases.

    PubMed

    Kao, Tseng-Ting; Chu, Chia-Yi; Lee, Gang-Hui; Hsiao, Tsun-Hsien; Cheng, Nai-Wei; Chang, Nan-Shan; Chen, Bing-Hung; Fu, Tzu-Fun

    2014-11-01

    Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly. However, the etiology underlying these folate deficiency-associated diseases is not completely understood. In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH). Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis. Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. When folate deficiency was induced in aged fish accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections. Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation. Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.

  5. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss on CBA/Ca Mice

    PubMed Central

    Martínez-Vega, Raquel; Murillo-Cuesta, Silvia; Partearroyo, Teresa; Varela-Moreiras, Gregorio; Varela-Nieto, Isabel; Pajares, María A.

    2016-01-01

    Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after 2-months, corroborates the epidemiological association previously described between vitamin deficiency and this sensory impairment. However, this strain is prone to early hearing loss, and hence we decided to analyze whether the effects exerted by folate deprivation follow the same pattern in a mouse strain such as CBA/Ca, which is resistant to hearing impairment. Here, we show results of a long-term study on hearing carried out on CBA/Ca mice subjected to dietary folate deprivation. Systemic changes included decreased serum folate levels, hyperhomocysteinemia and signs of anemia in the group fed with folate-deficient (FD) diet. Initial signs of hearing loss were detected in this strain after 8-months of vitamin deficiency, and correlated with histological damage in the cochleae. In conclusion, the data presented reinforce the importance of adequate folic acid levels for the auditory system and suggest that the impact of dietary deficiencies may depend on the genetic background. PMID:27630560

  6. 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

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

    PubMed

    Kopp, Markus; Morisset, Rosalie; Koehler, Peter; Rychlik, Michael

    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.

  8. Brief Report: Autistic Symptoms, Developmental Regression, Mental Retardation, Epilepsy, and Dyskinesias in CNS Folate Deficiency

    ERIC Educational Resources Information Center

    Moretti, Paolo; Peters, Sarika U.; del Gaudio, Daniela; Sahoo, Trilochan; Hyland, Keith; Bottiglieri, Teodoro; Hopkin, Robert J.; Peach, Elizabeth; Min, Sang Hee; Goldman, David; Roa, Benjamin; Bacino, Carlos A.; Scaglia, Fernando

    2008-01-01

    We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects…

  9. MATERNAL FOLATE DEFICIENCY AMPLIFIES THE CELLULAR AND TERATOLOGIC EFFECTS OF TOMUDEX

    EPA Science Inventory

    Lau, C., J.E. Andrews, B.E. Grey*, R.G. Hanson*, J.R. Thibodeaux* and J.M. Rogers. Reproductive Toxicology Division, NHEERL, US EPA, ORD, Research Triangle Park, North Carolina. Maternal folate deficiency amplifies the cellular and teratologic effects of Tomudex.
    Maternal fo...

  10. FOLATE DEFICIENCY ENHANCES ARSENIC EFFECTS ON EXPRESSION OF GENES INVOLVED IN EPIDERMAL DIFFERENTIATION

    EPA Science Inventory

    Chronic arsenic exposure in humans is associated with cancers of the skin, lung, and bladder. There is evidence that folate deficiency may increase susceptibility to arsenic¿s effects, including arsenic-induced skin lesions. K6/ODC mice develop skin tumors when exposed to 10 ppm ...

  11. Dioxin mediates downregulation of the reduced folate carrier transport activity via the arylhydrocarbon receptor signalling pathway

    SciTech Connect

    Halwachs, Sandra; Lakoma, Cathleen; Gebhardt, Rolf; Schaefer, Ingo; Seibel, Peter; Honscha, Walther

    2010-07-15

    Dioxins such as 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) are common environmental contaminants known to regulate several genes via activation of the transcription factor aryl hydrocarbon receptor (AhR) associated with the development of numerous adverse biological effects. However, comparatively little is known about the molecular mechanisms by which dioxins display their toxic effects in vertebrates. The 5' untranslated region of the hepatocellular Reduced folate carrier (Rfc1; Slc19a1) exhibits AhR binding sites termed dioxin responsive elements (DRE) that have as yet only been found in the promoter region of prototypical TCDD target genes. Rfc1 mediated transport of reduced folates and antifolate drugs such as methotrexate (MTX) plays an essential role in physiological folate homeostasis and MTX cancer chemotherapy. In order to determine whether this carrier represents a target gene of dioxins we have investigated the influence of TCDD on functional Rfc1 activity in rat liver. Pre-treatment of rats with TCDD significantly diminished hepatocellular Rfc1 uptake activity in a time- and dose-dependent manner. In further mechanistic studies we demonstrated that this reduction was due to TCDD-dependent activation of the AhR signalling pathway. We additionally showed that binding of the activated receptor to DRE motifs in the Rfc1 promoter resulted in downregulation of Rfc1 gene expression and reduced carrier protein levels. As downregulation of pivotal Rfc1 activity results in functional folate deficiency associated with an elevated risk of cardiovascular diseases or carcinogenesis, our results indicate that deregulation of this essential transport pathway represents a novel regulatory mechanism how dioxins display their toxic effects through the Ah receptor.

  12. Dihydrofolate Reductase Deficiency Due to a Homozygous DHFR Mutation Causes Megaloblastic Anemia and Cerebral Folate Deficiency Leading to Severe Neurologic Disease

    PubMed Central

    Cario, Holger; Smith, Desirée E.C.; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

    2011-01-01

    The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate. PMID:21310277

  13. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease.

    PubMed

    Cario, Holger; Smith, Desirée E C; Blom, Henk; Blau, Nenad; Bode, Harald; Holzmann, Karlheinz; Pannicke, Ulrich; Hopfner, Karl-Peter; Rump, Eva-Maria; Ayric, Zuleya; Kohne, Elisabeth; Debatin, Klaus-Michael; Smulders, Yvo; Schwarz, Klaus

    2011-02-11

    The importance of intracellular folate metabolism is illustrated by the severity of symptoms and complications caused by inborn disorders of folate metabolism or by folate deficiency. We examined three children of healthy, distantly related parents presenting with megaloblastic anemia and cerebral folate deficiency causing neurologic disease with atypical childhood absence epilepsy. Genome-wide homozygosity mapping revealed a candidate region on chromosome 5 including the dihydrofolate reductase (DHFR) locus. DHFR sequencing revealed a homozygous DHFR mutation, c.458A>T (p.Asp153Val), in all siblings. The patients' folate profile in red blood cells (RBC), plasma, and cerebrospinal fluid (CSF), analyzed by liquid chromatography tandem mass spectrometry, was compatible with DHFR deficiency. DHFR activity and fluorescein-labeled methotrexate (FMTX) binding were severely reduced in EBV-immortalized lymphoblastoid cells of all patients. Heterozygous cells displayed intermediate DHFR activity and FMTX binding. RT-PCR of DHFR mRNA revealed no differences between wild-type and DHFR mutation-carrying cells, whereas protein expression was reduced in cells with the DHFR mutation. Treatment with folinic acid resulted in the resolution of hematological abnormalities, normalization of CSF folate levels, and improvement of neurological symptoms. In conclusion, the homozygous DHFR mutation p.Asp153Val causes DHFR deficiency and leads to a complex hematological and neurological disease that can be successfully treated with folinic acid. DHFR is necessary for maintaining sufficient CSF and RBC folate levels, even in the presence of adequate nutritional folate supply and normal plasma folate.

  14. Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice

    PubMed Central

    Wang, Xueqian; Cabrera, Robert M.; Li, Yue; Miller, David S.; Finnell, Richard H.

    2013-01-01

    Folate deficiency has been associated with many adverse clinical manifestations. The blood-brain barrier (BBB), formed by brain capillary endothelial cells, protects the brain from exposure to neurotoxicants. The function of BBB is modulated by multiple ABC transporters, particularly P-glycoprotein. A proton-coupled folate transporter (PCFT)-deficient mouse has been previously described as a model for systemic folate deficiency. Herein, we demonstrate that exposing mouse brain capillaries to the antiepileptic drug, valproic acid (VPA; 5 μM), significantly increased P-glycoprotein transport function in the wild-type animals. A ligand to the aryl hydrocarbon receptor, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produced a similar induction of P-glycoprotein, which tightened the BBB, thereby increasing the neuroprotection. However, VPA- or TCDD-induced P-glycoprotein transport was blocked in the PCFT-nullizygous mice, indicating that multiple neuroprotective mechanisms are compromised under folate-deficient conditions. Brain capillaries from S-folinic acid (SFA; 40 mg/kg)-treated PCFT-nullizygous mice exhibited increased P-glycoprotein transport following VPA exposure. This suggests that SFA supplementation restored the normal BBB function. In addition, we show that tight-junction proteins are disintegrated in the PCFT mutant mice. Taken together, these findings strongly suggest that folate deficiency disrupts the BBB function by targeting the transporter and tight junctions, which may contribute to the development of neurological disorders.—Wang, X., Cabrera, R. M., Li, Y., Miller, D. S., Finnell, R. H. Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice. PMID:23212123

  15. Experimental folate and vitamin B12 deficiency does not alter bone quality in rats.

    PubMed

    Herrmann, Markus; Wildemann, Britt; Wagner, Alexandra; Wolny, Martin; Schorr, Heike; Taban-Shomal, Omid; Umanskaya, Natalia; Ross, Steffen; Garcia, Patric; Hübner, Ulrich; Herrmann, Wolfgang

    2009-04-01

    Hyperhomocysteinemia (HHCY) has been linked to fragility fractures and osteoporosis. Folate and vitamin B(12) deficiencies are among the main causes of HHCY. However, the impact of these vitamins on bone health has been poorly studied. This study analyzed the effect of folate and vitamin B(12) deficiency on bone in rats. We used two groups of rats: a control group (Co, n = 10) and a vitamin-deficient group (VitDef, n = 10). VitDef animals were fed for 12 wk with a folate- and vitamin B(12)-free diet. Co animals received an equicaloric control diet. Tissue and plasma concentrations of homocysteine (HCY), S-adenosyl-homocysteine (SAH), and S-adenosyl-methionine (SAM) were measured. Bone quality was assessed by biomechanical testing (maximum force of an axial compression test; F(max)), histomorphometry (bone area/total area; B.Ar./T.Ar.], and the measurement of biochemical bone turnover markers (osteocalcin, collagen I C-terminal cross-laps [CTX]). VitDef animals developed significant HHCY (Co versus VitDef: 6.8 +/- 2.7 versus 61.1 +/- 12.8 microM, p < 0.001) that was accompanied by a high plasma concentration of SAH (Co versus VitDef: 24.1 +/- 5.9 versus 86.4 +/- 44.3 nM, p < 0.001). However, bone tissue concentrations of HCY, SAH, and SAM were similar in the two groups. Fmax, B.Ar./T.Ar., OC, and CTX did not differ between VitDef and Co animals, indicating that bone quality was not affected. Folate and vitamin B(12) deficiency induces distinct HHCY but has no effect on bone health in otherwise healthy adult rats. The unchanged HCY metabolism in bone is the most probable explanation for the missing effect of the vitamin-free diet on bone.

  16. Anaemia, folate, zinc and copper deficiencies among adolescent schoolgirls in eastern Sudan.

    PubMed

    Abdelrahim, Ishraga I; Mahgoub, Hyder M; Mohamed, Ayoub A; Ali, Naji I; Elbashir, Mustafa I; Adam, I

    2009-12-01

    Anaemia is a widespread problem especially in the tropics. Among adolescent girls, it has negative consequences on growth, school performance, morbidity and reproductive performance. A cross-sectional study was conducted to investigate the prevalence of anaemia, iron, folate, zinc and copper deficiencies amongst adolescent schoolgirls in New Halfa, eastern Sudan, and to examine the relationship of these micronutrients with haemoglobin (Hb) levels. Out of 187 adolescent schoolgirls, 181 (96.8%) had anaemia (Hb<12 g/dl); 21% had mild anaemia (Hb 11.0-11.9 g/dl); 66.8.1% had moderate anaemia (Hb 8.0-10.9 g/dl), and 12.1% had severe anaemia (Hb<8 g/dl), respectively. Iron deficiency (S-ferritin<12 μg/l), iron deficiency anaemia (<12 m/dl and S- ferritin<12 μg/l) and folate deficiency (S-folate<3 ng/ml) were prevalent in 17.6%, 16.5% and 69% of these girls, respectively. Nine percent and 5.9% of these girls had zinc (<75 μg/ml) and copper deficiency (<75 μg/ml), respectively. Twenty-six (14%) girls had ≥ 2 micronutrient deficiencies. S-ferritin and zinc were significantly lower in patients with severe anaemia. Haemoglobin levels were significantly positively correlated with zinc levels (r=0.161, P=0.03) and with copper levels (r=0.151, P=0.03). Thus, interventions are required to prevent and control anaemia in this setting. Further research is needed.

  17. 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

  18. Gene-environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function.

    PubMed

    Burren, Katie A; Savery, Dawn; Massa, Valentina; Kok, Robert M; Scott, John M; Blom, Henk J; Copp, Andrew J; Greene, Nicholas D E

    2008-12-01

    Risk of neural tube defects (NTDs) is determined by genetic and environmental factors, among which folate status appears to play a key role. However, the precise nature of the link between low folate status and NTDs is poorly understood, and it remains unclear how folic acid prevents NTDs. We investigated the effect of folate level on risk of NTDs in splotch (Sp(2)(H)) mice, which carry a mutation in Pax3. Dietary folate restriction results in reduced maternal blood folate, elevated plasma homocysteine and reduced embryonic folate content. Folate deficiency does not cause NTDs in wild-type mice, but causes a significant increase in cranial NTDs among Sp(2)(H) embryos, demonstrating a gene-environment interaction. Control treatments, in which intermediate levels of folate are supplied, suggest that NTD risk is related to embryonic folate concentration, not maternal blood folate concentration. Notably, the effect of folate deficiency appears more deleterious in female embryos than males, since defects are not prevented by exogenous folic acid. Folate-deficient embryos exhibit developmental delay and growth retardation. However, folate content normalized to protein content is appropriate for developmental stage, suggesting that folate availability places a tight limit on growth and development. Folate-deficient embryos also exhibit a reduced ratio of s-adenosylmethionine (SAM) to s-adenosylhomocysteine (SAH). This could indicate inhibition of the methylation cycle, but we did not detect any diminution in global DNA methylation, in contrast to embryos in which the methylation cycle was specifically inhibited. Hence, folate deficiency increases the risk of NTDs in genetically predisposed splotch embryos, probably via embryonic growth retardation.

  19. Genetics Home Reference: dopamine transporter deficiency syndrome

    MedlinePlus

    ... Genetics Home Health Conditions dopamine transporter deficiency syndrome dopamine transporter deficiency syndrome Enable Javascript to view the ... boxes. Download PDF Open All Close All Description Dopamine transporter deficiency syndrome is a rare movement disorder. ...

  20. 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.

  1. The transmembrane pH gradient drives uphill folate transport in rabbit jejunum. Direct evidence for folate/hydroxyl exchange in brush border membrane vesicles.

    PubMed Central

    Schron, C M; Washington, C; Blitzer, B L

    1985-01-01

    In rabbit jejunal, but not ileal brush border membrane vesicles, an outwardly directed OH- gradient (pH 7.7 inside, pH 5.5 outside) markedly stimulated the initial velocity of folate (0.1 microM) uptake compared with uptake in the absence of a pH gradient. Under pH gradient conditions, folate was transiently accumulated at a concentration four times that found at equilibrium (over-shoot), implying uphill transport of the vitamin. Equilibrium folate uptake was inversely proportional to medium osmolality, suggesting uptake into an osmotically sensitive space. pH gradient-stimulated folate uptake was markedly reduced by inhibitors of anion exchange (4,4'-diisothiocyano-2,2'-disulfonic acid stilbene; 4-acetamido-4-isothiocyanostilbene-2,2'-disulfonic acid; furosemide), and was saturable (folate Km = 0.19 +/- 0.02 microM; Vmax = 12.8 +/- 0.4 pmol X mg protein-1 X min-1). Imposition of an inside-positive electrical potential did not stimulate folate uptake, suggesting that stimulation by a pH gradient was not due to an induced electrical potential. In contrast, an inwardly directed Na+ or K+ gradient did not stimulate folate uptake. These findings provide evidence for a carrier on the jejunal brush border membrane that mediates folate/OH- exchange (or H+/folate co-transport), and are consonant with the known presence of an outwardly directed OH- gradient in vivo (brush border acid microclimate), an acidic pH optimum for intestinal folate uptake, and the primary role of the jejunum in folate absorption. PMID:4056063

  2. Influence of Physiologic Folate Deficiency on Human Papillomavirus Type 16 (HPV16)-harboring Human Keratinocytes in Vitro and in Vivo*

    PubMed Central

    Xiao, Suhong; Tang, Ying-Sheng; Khan, Rehana A.; Zhang, Yonghua; Kusumanchi, Praveen; Stabler, Sally P.; Jayaram, Hiremagalur N.; Antony, Aśok C.

    2012-01-01

    Although HPV16 transforms infected epithelial tissues to cancer in the presence of several co-factors, there is insufficient molecular evidence that poor nutrition has any such role. Because physiological folate deficiency led to the intracellular homocysteinylation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) and activated a nutrition-sensitive (homocysteine-responsive) posttranscriptional RNA operon that included interaction with HPV16 L2 mRNA, we investigated the functional consequences of folate deficiency on HPV16 in immortalized HPV16-harboring human (BC-1-Ep/SL) keratinocytes and HPV16-organotypic rafts. Although homocysteinylated hnRNP-E1 interacted with HPV16 L2 mRNA cis-element, it also specifically bound another HPV16 57-nucleotide poly(U)-rich cis-element in the early polyadenylation element (upstream of L2̂L1 genes) with greater affinity. Together, these interactions led to a profound reduction of both L1 and L2 mRNA and proteins without effects on HPV16 E6 and E7 in vitro, and in cultured keratinocyte monolayers and HPV16-low folate-organotypic rafts developed in physiological low folate medium. In addition, HPV16-low folate-organotypic rafts contained fewer HPV16 viral particles, a similar HPV16 DNA viral load, and a much greater extent of integration of HPV16 DNA into genomic DNA when compared with HPV16-high folate-organotypic rafts. Subcutaneous implantation of 18-day old HPV16-low folate-organotypic rafts into folate-replete immunodeficient mice transformed this benign keratinocyte-derived raft tissue into an aggressive HPV16-induced cancer within 12 weeks. Collectively, these studies establish a likely molecular linkage between poor folate nutrition and HPV16 and predict that nutritional folate and/or vitamin-B12 deficiency, which are both common worldwide, will alter the natural history of HPV16 infections and also warrant serious consideration as reversible co-factors in oncogenic transformation of HPV16-infected tissues to cancer

  3. Influence of physiologic folate deficiency on human papillomavirus type 16 (HPV16)-harboring human keratinocytes in vitro and in vivo.

    PubMed

    Xiao, Suhong; Tang, Ying-Sheng; Khan, Rehana A; Zhang, Yonghua; Kusumanchi, Praveen; Stabler, Sally P; Jayaram, Hiremagalur N; Antony, Asok C

    2012-04-06

    Although HPV16 transforms infected epithelial tissues to cancer in the presence of several co-factors, there is insufficient molecular evidence that poor nutrition has any such role. Because physiological folate deficiency led to the intracellular homocysteinylation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP-E1) and activated a nutrition-sensitive (homocysteine-responsive) posttranscriptional RNA operon that included interaction with HPV16 L2 mRNA, we investigated the functional consequences of folate deficiency on HPV16 in immortalized HPV16-harboring human (BC-1-Ep/SL) keratinocytes and HPV16-organotypic rafts. Although homocysteinylated hnRNP-E1 interacted with HPV16 L2 mRNA cis-element, it also specifically bound another HPV16 57-nucleotide poly(U)-rich cis-element in the early polyadenylation element (upstream of L2L1 genes) with greater affinity. Together, these interactions led to a profound reduction of both L1 and L2 mRNA and proteins without effects on HPV16 E6 and E7 in vitro, and in cultured keratinocyte monolayers and HPV16-low folate-organotypic rafts developed in physiological low folate medium. In addition, HPV16-low folate-organotypic rafts contained fewer HPV16 viral particles, a similar HPV16 DNA viral load, and a much greater extent of integration of HPV16 DNA into genomic DNA when compared with HPV16-high folate-organotypic rafts. Subcutaneous implantation of 18-day old HPV16-low folate-organotypic rafts into folate-replete immunodeficient mice transformed this benign keratinocyte-derived raft tissue into an aggressive HPV16-induced cancer within 12 weeks. Collectively, these studies establish a likely molecular linkage between poor folate nutrition and HPV16 and predict that nutritional folate and/or vitamin-B(12) deficiency, which are both common worldwide, will alter the natural history of HPV16 infections and also warrant serious consideration as reversible co-factors in oncogenic transformation of HPV16-infected tissues to cancer.

  4. The reduced folate carrier (RFC) is cytotoxic to cells under conditions of severe folate deprivation. RFC as a double edged sword in folate homeostasis.

    PubMed

    Ifergan, Ilan; Jansen, Gerrit; Assaraf, Yehuda G

    2008-07-25

    The reduced folate carrier (RFC), a bidirectional anion transporter, is the major uptake route of reduced folates essential for a spectrum of biochemical reactions and thus cellular proliferation. However, here we show that ectopic overexpression of the RFC, but not of folate receptor alpha, a high affinity unidirectional folate uptake route serving here as a negative control, resulted in an approximately 15-fold decline in cellular viability in medium lacking folates but not in folate-containing medium. Moreover to explore possible mechanisms of adaptation to folate deficiency in various cell lines that express the endogenous RFC, we first determined the gene expression status of the following genes: (a) RFC, (b) ATP-driven folate exporters (i.e. MRP1, MRP5, and breast cancer resistance protein), and (c) folylpoly-gamma-glutamate synthetase and gamma-glutamate hydrolase (GGH), enzymes catalyzing folate polyglutamylation and hydrolysis, respectively. Upon 3-7 days of folate deprivation, semiquantitative reverse transcription-PCR analysis revealed a specific approximately 2.5-fold decrease in RFC mRNA levels in both breast cancer and T-cell leukemia cell lines that was accompanied by a consistent fall in methotrexate influx, serving here as an RFC transport activity assay. Likewise a 2.4-fold decrease in GGH mRNA levels and approximately 19% decreased GGH activity was documented for folate-deprived breast cancer cells. These results along with those of a novel mathematical biomodeling devised here suggest that upon severe short term (i.e. up to 7 days) folate deprivation RFC transport activity becomes detrimental as RFC, but not ATP-driven folate exporters, efficiently extrudes folate monoglutamates out of cells. Hence down-regulation of RFC and GGH may serve as a novel adaptive response to severe folate deficiency.

  5. Preservation of folate transport activity with a low-pH optimum in rat IEC-6 intestinal epithelial cell lines that lack reduced folate carrier function.

    PubMed

    Wang, Yanhua; Rajgopal, Arun; Goldman, I David; Zhao, Rongbao

    2005-01-01

    Intestinal folate transport has been well characterized, and rat small intestinal epithelial (IEC-6) cells have been used as a model system for the study of this process on the cellular level. The major intestinal folate transport activity has a low-pH optimum, and the current paradigm is that this process is mediated by the reduced folate carrier (RFC), despite the fact that this carrier has a neutral pH optimum in leukemia cells. The current study addressed the question of whether constitutive low-pH folate transport activity in IEC-6 cells is mediated by RFC. Two independent IEC-6 sublines, IEC-6/A4 and IEC-6/PT1, were generated by chemical mutagenesis followed by selective pressure with antifolates. In IEC-6/A4 cells, a premature stop resulted in truncation of RFC at Gln(420). A green fluorescent protein (GFP) fusion with the truncated protein was not stable. In IEC-6/PT1 cells, Ser(135) was deleted, and this alteration resulted in the failure of localization of the GFP fusion protein in the plasma membrane. In both cell lines, methotrexate (MTX) influx at neutral pH was markedly decreased compared with wild-type IEC-6 cells, but MTX influx at pH 5.5 was not depressed. Transient transfection of the GFP-mutated RFC constructs into RFC-null HeLa cells confirmed their lack of transport function. These results indicate that in IEC-6 cells, folate transport at neutral pH is mediated predominantly by RFC; however, the folate transport activity at pH 5.5 is RFC independent. Hence, constitutive folate transport activity with a low-pH optimum in this intestinal cell model is mediated by a process entirely distinct from that of RFC.

  6. Wernicke's Encephalopathy, Wet Beriberi, and Polyneuropathy in a Patient with Folate and Thiamine Deficiency Related to Gastric Phytobezoar

    PubMed Central

    Huertas-González, Nuria; Hernando-Requejo, Virgilio; Luciano-García, Zaida; Cervera-Rodilla, Juan Luis

    2015-01-01

    Background. Wernicke's encephalopathy (WE) is an acute neurological disorder resulting from thiamine deficiency. It is mainly related to alcohol abuse but it can be associated with other conditions such as gastrointestinal disorders. This vitamin deficiency can also present with cardiovascular symptoms, called “wet beriberi.” Association with folate deficit worsens the clinical picture. Subject. A 70-year-old man with gastric phytobezoar presented with gait instability, dyspnoea, chest pain associated with right heart failure and pericarditis, and folate deficiency. Furosemide was administered and cardiac symptoms improved but he soon developed vertiginous syndrome, nystagmus, diplopia, dysmetria, and sensitive and motor deficit in all four limbs with areflexia. Results. A cerebral magnetic resonance imaging (MRI) showed typical findings of WE. He was immediately treated with thiamine. Neurological symptoms improved in a few days and abnormal signals disappeared in a follow-up MRI two weeks later. Conclusion. Patients with malabsorption due to gastrointestinal disorders have an increased risk of thiamine deficiency, and folate deficiency can make this vitamin malabsorption worse. An established deficiency mainly shows neurological symptoms, WE, or rarely cardiovascular symptoms, wet beriberi. Early vitamin treatment in symptomatic patients improves prognosis. We recommend administration of prophylactic multivitamins supplements in patients at risk as routine clinical practice. PMID:26697247

  7. Supplementation with vitamin D3 during pregnancy protects against lipopolysaccharide-induced neural tube defects through improving placental folate transportation.

    PubMed

    Chen, Yuan-Hua; Yu, Zhen; Fu, Lin; Xia, Mi-Zhen; Zhao, Mei; Wang, Hua; Zhang, Cheng; Hu, Yong-Fang; Tao, Fang-Biao; Xu, De-Xiang

    2015-05-01

    Several reports demonstrated that maternal lipopolysaccharide (LPS) exposure at middle gestational stage caused neural tube defects (NTDs). This study investigated the effects of supplementation with vitamin D3 (VitD3) during pregnancy on LPS-induced NTDs. Pregnant mice except controls were ip injected with LPS (25 μg/kg) daily from gestational day (GD)8 to GD12. In LPS+VitD3 group, pregnant mice were orally administered with VitD3 (25 μg/kg) before LPS injection. As expected, a 5-day LPS injection resulted in 62.5% (10/16) of dams and 20.3% of fetuses with NTDs. Additional experiment showed that a 5-day LPS injection downregulated placental proton-coupled folate transporter (pcft) and reduced folate carrier 1 (rfc1), 2 major folate transporters in placentas. Consistent with downregulation of placental folate transporters, folate transport from maternal circulation into embryos was disturbed in LPS-treated mice. Interestingly, VitD3 not only inhibited placental inflammation but also attenuated LPS-induced downregulation of placental folate transporters. Correspondingly, VitD3 markedly improved folate transport from maternal circulation into the embryos. Importantly, supplementation with VitD3 during pregnancy protected mice from LPS-induced NTDs. Taken together, these results suggest that supplementation with VitD3 during pregnancy prevents LPS-induced NTDs through inhibiting placental inflammation and improving folate transport from maternal circulation into the embryos.

  8. Questionable Reliability of Homocysteine as the Metabolic Marker for Folate and Vitamin B12 Deficiency in Patients with Chronic Obstructive Pulmonary Disease

    PubMed Central

    Beletić, Anđelo; Mirković, Duško; Dudvarski-Ilić, Aleksandra; Milenković, Branislava; Nagorni-Obradović, Ljudmila; Đorđević, Valentina; Ignjatović, Svetlana; Majkić-Singh, Nada

    2015-01-01

    Summary Background An increased homocysteine (Hcy) concentration may represent a metabolic marker of folate and vitamin B12 deficiency, both significant public health problems. For different reasons, patients with chronic obstructive pulmonary disease (COPD) are prone to these deficiencies. The study evaluates the reliability of Hcy concentration in predicting folate or vitamin B12 deficiency in these patients. Methods A group of 50 COPD patients (28 males/22 females, age (χ̄±SD=49.0±14.5) years was enrolled. A chemiluminescent microparticle immunoassay was applied for homocysteine, folate and vitamin B12 concentration. Kolmogorov-Smirnov, Mann-Whitney U and χ2 tests, Spearman’s correlation and ROC analysis were included in the statistical analysis, with the level of significance set at 0.05. Results Average (SD) concentrations of folate and vitamin B12 were 4.13 (2.16) μg/L and 463.6 (271.0) ng/L, whereas only vitamin B12 correlated with the Hcy level (P=−0.310 (R=0.029)). Gender related differences were not significant and only a borderline significant correlation between age and folate was confirmed (R=0.279 (P=0.047)). The incidence of folate and vitamin B12 deficiency differed significantly (P=0.000 and P<0.000 for folate and vitamin B12 respectively), depending on the cutoff used for classification (4.4, 6.6 and 8.0 μg/L – folate; 203 and 473 ng/L – vitamin B12). ROC analyses failed to show any significance of hyperhomocysteinemia as a predictor of folate or vitamin B12 deficiency. Conclusion Reliability of the Hcy concentration as a biomarker of folate or vitamin B12 depletion in COPD patients is not satisfactory, so their deficiency cannot be predicted by the occurrence of HHcy. PMID:28356857

  9. Folate deficiency and aberrant expression of cell adhesion molecule 1 are potential indicators of prognosis in laryngeal squamous cell carcinoma

    PubMed Central

    Chang, Hao; Ma, Min; Ma, Rui; Zhang, Chao; Zeng, Wei; Xing, Lu Qi

    2016-01-01

    The etiology of laryngeal squamous cell carcinoma (LSCC) has not yet been adequately examined. Therefore, the present study aimed to investigate the association between serum folate deficiency and abnormal expression of the cell adhesion molecule 1 (CADM1) protein in the progression of LSCC. Samples were collected from 60 patients with LSCC and 30 healthy people. Radioimmunoassays and immunohistochemical staining were performed to measure serum folate levels and CADM1 protein expression, respectively. The results demonstrated that CADM1 expression in LSCC specimens was significantly lower than in adjacent normal tissues (χ2=28.229, P<0.001), which was associated with histological differentiation and clinical stage (P=0.010 and 0.020, respectively). Levels of serum folate in patients with LSCC were significantly lower than those observed in healthy individuals (P=0.002). Furthermore, TSLCl expression and serum folate levels were positively correlated in LSCC (r=0.642, P=0.001). Thus, the present study determined that decreased CADM1 protein expression and low levels of serum folate were correlated with an increased severity of LSCC. PMID:28105160

  10. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency.

    PubMed

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-08-10

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28-75 were enrolled in this study from September 2005-December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.

  11. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency

    PubMed Central

    Li, Wen-Xing; Dai, Shao-Xing; Zheng, Jun-Juan; Liu, Jia-Qian; Huang, Jing-Fei

    2015-01-01

    Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk. PMID:26266420

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

    PubMed

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

    2017-04-01

    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

  13. Affinity labeling of the folate-methotrexate transporter from Leishmania donovani

    SciTech Connect

    Beck, J.T.; Ullman, B. )

    1989-08-22

    An affinity labeling technique has been developed to identify the folate-methotrexate transporter of Leishmania donovani promastigotes using activated derivatives of the ligands. These activated derivatives were synthesized by incubating folate and methotrexate with a 10-fold excess of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) for 10 min at ambient temperature in dimethyl sulfoxide. When intact wild-type (DI700) Leishmania donovani or preparations of their membranes were incubated with a 0.4 {mu}M concentration of either activated ({sup 3}H)folate or activated ({sup 3}H)methotrexate, the radiolabeled ligands were covalently incorporated into a polypeptide with a molecular weight of approximately 46,000, as demonstrated by SDS-polyacrylamide gel electrophoresis. No affinity labeling of a 46,000-dalton protein was observed when equimolar concentrations of activated radiolabeled ligands were incubated with intact cells or membranes prepared from a methotrexate-resistant mutant clone of Leishmania donovani, MTXA5, that is genetically defective in folate-methotrexate transport capability. Time course studies indicated that maximal labeling of the 46,000-dalton protein occurred within 5-10 min of incubation of intact cells with activated ligand. These studies provide biochemical evidence that the folate-methotrexate transporter of Leishmania donovani can be identified in crude extracts by an affinity labeling technique and serve as a prerequisite to further analysis of the transport protein by providing a vehicle for subsequent purification of this membrane carrier. Moreover, these investigations suggest that the affinity labeling technique using EDC-activated ligands may be exploitable to analyze other cell surface binding proteins in Leishmania donovani, as well as in other organisms.

  14. Folate and Colorectal Cancer in Rodents: A Model of DNA Repair Deficiency

    PubMed Central

    Rosati, Rita; Ma, Hongzhi; Cabelof, Diane C.

    2012-01-01

    Fortification of grains has resulted in a positive public health outcome vis-a-vis reduced incidence of neural tube defects. Whether folate has a correspondingly beneficial effect on other disease outcomes is less clear. A role for dietary folate in the prevention of colorectal cancer has been established through epidemiological data. Experimental data aiming to further elucidate this relationship has been somewhat equivocal. Studies report that folate depletion increases DNA damage, mutagenesis, and chromosomal instability, all suggesting inhibited DNA repair. While these data connecting folate depletion and inhibition of DNA repair are convincing, we also present data demonstrating that genetic inhibition of DNA repair is protective in the development of preneoplastic colon lesions, both when folate is depleted and when it is not. The purpose of this paper is to (1) give an overview of the data demonstrating a DNA repair defect in response to folate depletion, and (2) critically compare and contrast the experimental designs utilized in folate/colorectal cancer research and the corresponding impact on tissue folate status and critical colorectal cancer endpoints. Our analysis suggests that there is still an important need for a comprehensive evaluation of the impact of differential dietary prescriptions on blood and tissue folate status. PMID:23093960

  15. COMMUNICATION: Folate and S-adenosylmethionine modulate synaptic activity in cultured cortical neurons: acute differential impact on normal and apolipoprotein-deficient mice

    NASA Astrophysics Data System (ADS)

    Serra, Michael; Chan, Amy; Dubey, Maya; Gilman, Vladimir; Shea, Thomas B.

    2008-12-01

    Folate deficiency is accompanied by a decline in the cognitive neurotransmitter acetylcholine and a decline in cognitive performance in mice lacking apolipoprotein E (ApoE-/- mice), a low-density lipoprotein that regulates aspects of lipid metabolism. One direct consequence of folate deficiency is a decline in S-adenosylmethionine (SAM). Since dietary SAM supplementation maintains acetylcholine levels and cognitive performance in the absence of folate, we examined herein the impact of folate and SAM on neuronal synaptic activity. Embryonic cortical neurons from mice expressing or lacking ApoE (ApoE+/+ or -/-, respectively) were cultured for 1 month on multi-electrode arrays, and signaling was recorded. ApoE+/+ cultures displayed significantly more frequent spontaneous signals than ApoE-/- cultures. Supplementation with 166 µm SAM (not normally present in culture medium) increased signal frequency and decreased signal amplitude in ApoE+/+ cultures. SAM also increased the frequency of tightly clustered signal bursts. Folate deprivation reversibly reduced signal frequency in ApoE+/+ cultures; SAM supplementation maintained signal frequency despite folate deprivation. These findings support the importance of dietary supplementation with folate and SAM on neuronal health. Supplementation with 166 µm SAM did not alter signaling in ApoE-/- cultures, which may be a reflection of the reduced SAM levels in ApoE-/- mice. The differential impact of SAM on ApoE+/+ and -/- neurons underscores the combined impact of nutritional and genetic deficiencies on neuronal homeostasis.

  16. Near-elimination of folate-deficiency anemia by mandatory folic acid fortification in older US adults: Reasons for Geographic and Racial Differences in Stroke study 2003–20072,3

    PubMed Central

    Odewole, Oluwaseun A; Williamson, Rebecca S; Zakai, Neil A; Berry, Robert J; Judd, Suzanne E; Qi, Yan Ping; Adedinsewo, Demilade A; Oakley, Godfrey P

    2015-01-01

    Background The United States implemented mandatory folic acid fortification of enriched cereal grains in 1998. Although several studies have documented the resulting decrease in anemia and folate deficiency, to our knowledge, no one has determined the prevalence of folate-deficiency anemia after fortification. Objective We determined the prevalence of folate deficiency and folate-deficiency anemia within a sample of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Design The REGARDS cohort is a prospective cohort of 30,239 black and white participants living in the contiguous United States. We measured serum folate concentrations in a random sample of 1546 REGARDS participants aged ≥50 y with baseline hemoglobin and red blood cell mean corpuscular volume measurements. Folate deficiency was defined as a serum folate concentration <6.6 nmol/L (<3.0 ng/mL), and anemia was defined as a hemoglobin concentration <13 g/dL in men and <12 g/dL in nonpregnant women (WHO criteria). Folate-deficiency anemia was defined as the presence of both folate deficiency and anemia. Results The mean hemoglobin concentration was 13.6 g/dL, and 15.9% of subjects had anemia. The median serum folate concentration was 34.2 nmol/L (15.1 ng/mL), and only 2 of 1546 participants 0.1%) were folate deficient. Both subjects were African American women with markedly elevated C-reactive protein concentrations, macrocytosis, and normal serum cobalamin concentrations; only one subject was anemic. Overall, the prevalence of folate-deficiency anemia was <0.1% (1 of 1546 subjects). Conclusion Our data suggest that, after mandatory folic acid fortification, the prevalence of folate-deficiency anemia is nearly nonexistent in a community-dwelling population in the United States. PMID:23945721

  17. Pediococcus cerevisiae mutant with altered transport of folates.

    PubMed

    Mandelbaum-Shavit, F; Grossowicz, N

    1975-08-01

    A Pediococcus cerevisiae mutant that actively accumulated folate (PteGlu), in contrast to the wild-type, was also found to exhibit changes in the pattern of uptake of 5-methyl-tetrahydrofolate (5-CH3-H4PteGlu) and amethopterin. Most of the 5-CH3-H4PteGlue accumulated through a glucose- and temperature-dependent process, and a concentrative uptake was also found in gluocse-starved cells and in cells incubated at OC. About 75% of the accumulated 5-CH3-H4PteGlu exchanged with amethopterin. In contrast to the wild type, the mutant accumulated both diastereoisomers of 5-CH3-H4PteGlue by glucose-dependent and glucose-independent processes. Amethopterin and PteGlue competitively inhibited the uptake in both processes, with an apparent lower affinity of the carrier for PteGlu than for the analogue. p-Chloromercuribenzoate strongly inhibited the uptake (75%). The p-chloromercuribenzoate-nonsusceptible and temperature-independent uptake was also competed by amethopterin. Metabolic poisons like sodium azide, potassium fluoride, iodoacetate, and 2,4-dimitrophenol inhibited the glucose-dependent process. Uptake, in the absence of glucose, was enhanced by sodium azide and potassium fluoride.

  18. A high prevalence of biochemical evidence of vitamin B12 or folate deficiency does not translate into a comparable prevalence of anemia.

    PubMed

    Metz, Jack

    2008-06-01

    Based on biochemical evidence, a high prevalence of biochemical evidence of vitamin B12 or folate deficiency has been reported in a number of areas in the world. The evidence that these biochemical abnormalities lead to a comparable prevalence of anemia is reviewed. The overall contribution of vitamin B12 deficiency to the global burden of anemia is probably not significant, except perhaps in women and their infants and children in vegetarian communities. In developed countries, folate-deficiency anemia is uncommon. In some developing countries, this anemia is still seen, but there are no comprehensive data on the relative prevalence compared with anemia due to malaria, iron-deficiency, hemoglobinopathy, and HIV disease. It seems unlikely that folate deficiency makes a major contribution to the burden of anemia in developing countries. Iron-deficiency anemia may coexist with vitamin B12 and especially folate deficiency, and may confound the hematological features of the vitamin deficiencies whose prevalence would then be underestimated. Supplementation of the diet of pregnant women with folic acid can virtually eliminate folate-deficiency anemia in these women. There are very few data on the hematological effect of vitamin B12 supplementation or fortification at the population level. The addition of vitamin B12 to the supplementation of the diet of pregnant women with iron and folic acid does not produce an increased hematological response, at least in nonvegetarian populations. There are numerous reports of the effect of folic acid fortification of food on tests of folate status, but only a single published report on the hematological response was found.

  19. Parkinson's Disease and Homocysteine: A Community-Based Study in a Folate and Vitamin B12 Deficient Population

    PubMed Central

    Tiandong, Wang; Yang, Li; Huaxing, Meng; Guowen, Min; Yalan, Fang

    2016-01-01

    Background. Homocysteine (Hcy) levels were higher in patients with Parkinson's disease (PD). This could be partially explained by levodopa treatment. Whether untreated PD patients have higher Hcy levels is contradictory. Methods. A community-based study was conducted using a two-stage approach for subjects ≥ 55 years to find PD patients in 3 towns of Lüliang City. Blood samples were collected. Serum Hcy, folate, and vitamin B12 concentrations were measured. For each untreated PD patient, 5 controls were selected matched with age and sex to evaluate the relationship between Hcy levels and PD. Results. Of 6338 eligible residents, 72.7% participated in the study. 31 PD cases were identified. The crude prevalence of PD for people ≥ 55 years was 0.67%. Blood samples were collected from 1845 subjects, including 17 untreated PD patients. There was no difference for concentrations of serum Hcy, folate, and vitamin B12 between cases and controls (P > 0.05). In univariate and multivariate analysis, there was significant inverse relation between PD and current smoking (P < 0.05). No other factor was significant statistically. Conclusions. The prevalence of PD was comparable to earlier studies in China. Hyperhomocysteinemia was not a risk factor of PD, as well as folate and vitamin B12 deficiency. PMID:27656311

  20. Parkinson's Disease and Homocysteine: A Community-Based Study in a Folate and Vitamin B12 Deficient Population.

    PubMed

    Wei, Zhang; Tiandong, Wang; Yang, Li; Huaxing, Meng; Guowen, Min; Yalan, Fang; Xiaoyuan, Niu

    2016-01-01

    Background. Homocysteine (Hcy) levels were higher in patients with Parkinson's disease (PD). This could be partially explained by levodopa treatment. Whether untreated PD patients have higher Hcy levels is contradictory. Methods. A community-based study was conducted using a two-stage approach for subjects ≥ 55 years to find PD patients in 3 towns of Lüliang City. Blood samples were collected. Serum Hcy, folate, and vitamin B12 concentrations were measured. For each untreated PD patient, 5 controls were selected matched with age and sex to evaluate the relationship between Hcy levels and PD. Results. Of 6338 eligible residents, 72.7% participated in the study. 31 PD cases were identified. The crude prevalence of PD for people ≥ 55 years was 0.67%. Blood samples were collected from 1845 subjects, including 17 untreated PD patients. There was no difference for concentrations of serum Hcy, folate, and vitamin B12 between cases and controls (P > 0.05). In univariate and multivariate analysis, there was significant inverse relation between PD and current smoking (P < 0.05). No other factor was significant statistically. Conclusions. The prevalence of PD was comparable to earlier studies in China. Hyperhomocysteinemia was not a risk factor of PD, as well as folate and vitamin B12 deficiency.

  1. 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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The hypothesis that age- and tissue-specific differences in choline metabolism is differentially affected by folate deficiency (FD) was tested by comparing choline and acetylcholine levels in male Sprague Dawley rats, who were fed for 10 weeks either a control diet or a folate deficient diet startin...

  2. Folate and Vitamin B12 Deficiency Among Nonpregnant Women of Childbearing Age in Guatemala 2009–2010: Prevalence and Identification of Vulnerable Populations

    PubMed Central

    Rosenthal, Jorge; Lopez-Pazos, Eunice; Dowling, Nicole F.; Pfeiffer, Christine M.; Mulinare, Joe; Vellozzi, Claudia; Zhang, Mindy; Lavoie, Donna J; Molina, Roberto; Ramirez, Nicte; Reeve, Mary-Elizabeth

    2015-01-01

    Introduction Information on folate and vitamin B12 deficiency rates in Guatemala is essential to evaluate the current fortification program. The objectives of this study were to describe the prevalence of folate and vitamin B12 deficiencies among women of childbearing age (WCBA) in Guatemala and to identify vulnerable populations at greater risk for nutrient deficiency. Methods A multistage cluster probability study was designed with national and regional representation of nonpregnant WCBA (15–49 years of age). Primary data collection was carried out in 2009–2010. Demographic and health information was collected through face-to-face interviews. Blood samples were collected from 1,473 WCBA for serum and red blood cell (RBC) folate and serum vitamin B12. Biochemical concentrations were normalized using geometric means. Prevalence rate ratios were estimated to assess relative differences among different socioeconomic and cultural groups including ethnicity, age, education level, wealth index and rural versus urban locality. Results National prevalence estimates for deficient serum (<10 nanomoles per liter [nmol/L]) and RBC folate (<340 nmol/L) concentrations were 5.1% (95% CI 3.8, 6.4) and 8.9% (95% CI 6.7, 11.7), respectively; for vitamin B12 deficiency (<148 pmol/L) 18.5% (95% CI 15.6, 21.3). Serum and RBC folate deficiency prevalences were higher for rural areas than for urban areas (8.0% vs. 2.0% and 13.5% vs. 3.9%, respectively). The prevalence of RBC folate deficiency showed wide variation by geographic region (3.2%–24.9%) and by wealth index (4.1%–15.1%). The prevalence of vitamin B12 deficiency also varied among regions (12.3% –26.1%). Conclusions In Guatemala, folate deficiency was more prevalent among indigenous rural and urban poor populations. Vitamin B12 deficiency was widespread among WCBA. Our results suggest the ongoing need to monitor existing fortification programs, in particular regarding its reach to vulnerable populations. PMID:26002178

  3. Two-compartment behavior during transport of folate compounds in L1210 cell plasma membrane vesicles

    SciTech Connect

    Yang, C.H.; Dembo, M.; Sirotnak, F.M.

    1982-01-01

    The transport of (/sup 3/H) 1,L 5-formyltetrahydrofolate, (/sup 3/H) folic acid, and (/sup 3/H)methotrexate by L1210 cell plasma membrane vesicles exhibited multicompartmental behavior. Two separate vesicular compartments (parallel relationship) of approximately equal volume were revealed during measurements of influx and efflux. Flux in one compartment was rapid, saturable, highly temperature-sensitive, and inhibited by pCMBS. Flux in the other compartment exhibited all of the characteristics of passive diffusion. These results imply that our plasma membrane vesicle preparations consist of a mixture of two functional species. Transport of folate into one of these species occurs by passive diffusion alone, whereas transport into the other kind of vesicle occurs by both passive diffusion and carrier-facilitated transport.

  4. Genetics Home Reference: riboflavin transporter deficiency neuronopathy

    MedlinePlus

    ... Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, ... on PubMed Central GeneReview: Riboflavin Transporter Deficiency Neuronopathy Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, ...

  5. 6-Substituted Pyrrolo[2,3-d]pyrimidine Thienoyl Regioisomers as Targeted Antifolates for Folate Receptor α and the Proton-Coupled Folate Transporter in Human Tumors

    PubMed Central

    Wang, Lei; Wallace, Adrianne; Raghavan, Sudhir; Deis, Siobhan M.; Wilson, Mike R.; Yang, Si; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Orr, Steven; George, Christina; O’Connor, Carrie; Hou, Zhanjun; Mitchell-Ryan, Shermaine; Dann, Charles E.; Matherly, Larry H.; Gangjee, Aleem

    2016-01-01

    2-Amino-4-oxo-6-substituted-pyrrolo[2,3-d]-pyrimidine antifolate thiophene regioisomers of AGF94 (4) with a thienoyl side chain and three-carbon bridge lengths [AGF150 (5) and AGF154 (7)] were synthesized as potential antitumor agents. These analogues inhibited proliferation of Chinese hamster ovary (CHO) sublines expressing folate receptors (FRs) α or β (IC50s < 1 nM) or the proton-coupled folate transporter (PCFT) (IC50 < 7 nM). Compounds 5 and 7 inhibited KB, IGROV1, and SKOV3 human tumor cells at subnanomolar concentrations, reflecting both FRα and PCFT uptake. AGF152 (6) and AGF163 (8), 2,4-diamino-5-substituted-furo[2,3-d]pyrimidine thiophene regioisomers, also inhibited growth of FR-expressing CHO and KB cells. All four analogues inhibited glycinamide ribonucleotide formyltransferase (GARFTase). Crystal structures of human GARFTase complexed with 5 and 7 were reported. In severe combined immunodeficient mice bearing SKOV3 tumors, 7 was efficacious. The selectivity of these compounds for PCFT and for FRα and β over the ubiquitously expressed reduced folate carrier is a paradigm for selective tumor targeting. PMID:26317331

  6. Response to Quinlivan: Post-fortification, folate intake in vitamin B12 deficiency is positively related to homocysteine and methylmalonic acid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    With cross-sectional data, causes and effects are difficult to distinguish, and Quinlivan suggests that high circulating concentrations of homcysteine (Hcy), methylmalonic acid (MMA), and folate observed among vitamin B12-deficient survey participants all resulted from a lack of vitamin B12 (1). How...

  7. TRIBROMOMETHANE EXPOSURE AND DIETARY FOLATE DEFICIENCY IN THE FORMATION OF ABERRANT CRYPT FOCI IN THE COLONS OF F344/N RATS

    EPA Science Inventory

    TRIBROMOMETHANE EXPOSURE AND DIETARY FOLATE DEFICIENCY IN THE FORMATION OF ABERRANT CRYPT FOCI IN THE COLONS OF F344/N RATS

    David R. Geter', Tanya M. Moore', Michael H. George', Steve R. Kilburn', Gloria Huggins-Clark', James W. Allen', and Anthony B. DeAngelo' 'National H...

  8. Elevated Homocysteine Level and Folate Deficiency Associated with Increased Overall Risk of Carcinogenesis: Meta-Analysis of 83 Case-Control Studies Involving 35,758 Individuals

    PubMed Central

    Wu, Wei; Guo, Ye; Cui, Wei

    2015-01-01

    Background Results of the association of folate metabolism and carcinogenesis are conflicting. We performed a meta-analysis to examine the effect of the interaction of serum concentration of homocysteine (Hcy), folate, and vitamin B12 and 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism on risk of cancer overall. Method Two reviewers independently searched for all published studies of Hcy and cancer in PubMed, EMBASE-MEDLINE and Chinese databases. Pooled results were reported as odds ratios (ORs) and mean differences and presented with 95% confidence intervals (95% CIs) and 2-sided probability values. Results We identified 83 eligible studies of 15,046 cases and 20,712 controls. High level of Hcy but low level of folate was associated with risk of cancer overall, with little effect by type of cancer or ethnicity. Vitamin B12 level was inversely associated with only urinary-system and gastrointestinal carcinomas and for Asian and Middle Eastern patients. As well, MTHFR C677T, A1298C and G1793A polymorphisms were related to elevated serum level of Hcy, and folate and vitamin B12 deficiency. However, only MTHFR C677T homogeneity/wild-type (TT/CC) polymorphism was positively associated with overall risk of cancer. Conclusion Elevated serum Hcy level and folate deficiency are associated with increased overall risk of cancer. PMID:25985325

  9. Crystal structure of a folate energy-coupling factor transporter from Lactobacillus brevis.

    PubMed

    Xu, Ke; Zhang, Minhua; Zhao, Qin; Yu, Fang; Guo, Hui; Wang, Chengyuan; He, Fangyuan; Ding, Jianping; Zhang, Peng

    2013-05-09

    ATP-binding cassette (ABC) transporters, composed of importers and exporters, form one of the biggest protein superfamilies that transport a variety of substrates across the membrane, powered by ATP hydrolysis. Most ABC transporters are composed of two transmembrane domains and two cytoplasmic nucleotide-binding domains. Also, importers from prokaryotes usually have extra solute-binding proteins in the periplasm that are responsible for the binding of substrates. Structures of importers have been reported that suggested a two-state model for the transport mechanism. Energy-coupling factor (ECF) transporters belong to a new class of ATP-binding cassette importers. Each ECF transporter comprises an energy-coupling module consisting of a transmembrane T protein (EcfT), two nucleotide-binding proteins (EcfA and EcfA'), and another transmembrane substrate-specific binding S protein (EcfS). Despite the similarities with ABC transporters, ECF transporters have different organizational and functional properties. The lack of solute-binding proteins in ECF transporters differentiates them clearly from the canonical ABC importers. Previously reported structures of the EcfS proteins RibU and ThiT clearly demonstrated the binding site of substrate riboflavin and thiamine, respectively. However, the organization of the four different components and the transport mechanism of ECF transporters remain unknown. Here we present the structure of an intact folate ECF transporter from Lactobacillus brevis at a resolution of 3 Å. This structure was captured in an inward-facing, nucleotide-free conformation with no bound substrate. The folate-binding protein FolT is nearly parallel to the membrane and is bound almost entirely by EcfT, which adopts an L shape and connects to EcfA and EcfA' through two coupling helices. Two conserved XRX motifs from the coupling helices of EcfT have a vital role in energy coupling by docking into EcfA-EcfA'. We propose a transport model that involves a

  10. Genetic defects in folate and cobalamin pathways affecting the brain.

    PubMed

    Kirsch, Susanne H; Herrmann, Wolfgang; Obeid, Rima

    2013-01-01

    Folate and cobalamin are necessary for early brain development and function. Deficiency of folate or cobalamin during pregnancy can cause severe malformation in the central nervous system such as neural tube defects. After birth, folate and cobalamin deficiency can cause anemia, failure to thrive, recurrent infections, psychiatric and neurological symptoms. The folate and the homocysteine metabolic pathways interact at a central step where 5-methyltetrahydrofolate donates its methyl group to homocysteine to produce methionine and tetrahydrofolate. Methyl cobalamin and folate interact at this critical step. Both nutrients have a crucial role in DNA synthesis and in delivering S-adenosylmethionine, the universal methyl donor. Severe and mild inherited disorders in folate and cobalamin pathways have been described. The two groups of disorders share some similarities, but differ in the molecular mechanism, metabolic dysregulation, and disease management. This review summarizes selected disorders, including rare and common mutations that affect folate and cobalamin absorption, transport, or dependent enzymes. When the mutations are discovered early enough, many of the described disorders are easily treatable by B vitamin supplementation, which often prevents or reverses the manifestation of the disease. Therefore, the screening for mutations is recommended and should be carried out as early as possible: after occurrence of the first symptoms or when a certain constellations of the folate and cobalamin related markers are measured, such as elevated homocysteine and/or methylmalonic acid.

  11. The Intestinal Absorption of Folates

    PubMed Central

    Visentin, Michele; Diop-Bove, Ndeye; Zhao, Rongbao; Goldman, I. David

    2014-01-01

    The properties of intestinal folate absorption were documented decades ago. However, it was only recently that the proton-coupled folate transporter (PCFT) was identified and its critical role in folate transport across the apical brush-border membrane of the proximal small intestine established by the loss-of-function mutations identified in the PCFT gene in subjects with hereditary folate malabsorption and, more recently, by the Pcft-null mouse. This article reviews the current understanding of the properties of PCFT-mediated transport and how they differ from those of the reduced folate carrier. Other processes that contribute to the transport of folates across the enterocyte, along with the contribution of the enterohepatic circulation, are considered. Important unresolved issues are addressed, including the mechanism of intestinal folate absorption in the absence of PCFT and regulation of PCFT gene expression. The impact of a variety of ions, organic molecules, and drugs on PCFT-mediated folate transport is described. PMID:24512081

  12. A carrier-mediated transport for folate in basolateral membrane vesicles of rat small intestine.

    PubMed Central

    Said, H M; Redha, R

    1987-01-01

    The mechanism of exit of folate from the enterocyte, i.e. transport across the basolateral membrane, is not known. In this study we examined, using basolateral membrane vesicles, the transport of folic acid across the basolateral membrane of rat intestine. Uptake of folic acid by these vesicles represents transport of the substrate into the intravesicular compartment and not binding to the membrane surface. The rate of folic acid transport was linear for the first 1 min of incubation but decreased thereafter, reaching equilibrium after 5 min of incubation. The transport of folic acid was: (1) saturable as a function of concentration with an apparent Km of 0.6 +/- 0.17 microM and Vmax. of 1.01 +/- 0.11 pmol/30 s per mg of protein; (2) inhibited in a competitive manner by the structural analogues 5-methyltetrahydrofolate and methotrexate (Ki = 2 and 1.4 microM, respectively); (4) electroneutral; (5) Na+-independent; (6) sensitive to the effect of the anion exchange inhibitor 4,4'-di-isothiocyanatostilbene-2,2'-disulphonic acid (DIDS). These data indicate the existence of a carrier-mediated transport system for folic acid in rat intestinal basolateral membrane and demonstrate that the transport process is electroneutral, Na+-independent and sensitive to the effect of anion exchange inhibition. PMID:3689340

  13. Carrier-mediated transport of folate in a mutant of Pediococcus cerevisiae.

    PubMed

    Mandelbaum-Shavit, F; Grossowicz, N

    1973-05-01

    A mutant strain of Pediococcus cerevisiae (P. cerevisiae/PteGlu) was isolated which grows on low-folate (PteGlu) concentrations (200 pg/ml). The growth response of the parent and mutant strains to folinate (5-CHO-H(4)PteGlu) was the same. The transport of (14)C-PteGlu by P. cerevisiae/PteGlu was temperature-dependent (Q(10) between 27 C and 37 C was about 2), energy-dependent, and pH-dependent and was inhibited by iodoacetate, 2,4-dinitrophenol, potassium fluoride, and sodium azide. The uptake obeyed saturation kinetics with an apparent K(m) of 6.6 x 10(-6) M and V(max) of 4.0 x 10(-10) mol per min per mg (dry weight). At the steady state the intracellular concentration of PteGlu was 120-fold higher from that of the medium. Reduced folates like 5-CHO-H(4)PteGlu and methyl-tetrahydrofolate (5-CH(3)-H(4)PteGlu) as well as 2,4-diaminoanalogues (amethopterin and aminopterin) were shown to compete for the PteGlue-carrier.

  14. Vitamin B12 Deficiency and Elevated Folate Levels: An Unusual Cause of Generalized Tonic-Clonic Seizure

    PubMed Central

    Lubana, Sandeep Singh; Alfishawy, Mostafa; Singh, Navdeep; Atkinson, Sharon

    2015-01-01

    Patient: Male, 49 Final Diagnosis: Generalized tonic-clonic seizures in the setting of vitamin B12 deficiency and elevated folate levels Symptoms: Seizures Medication: — Clinical Procedure: None Specialty: Neurology Objective: Unknown ethiology Background: Vitamin B12 deficiency leads to abnormal myelination or demyelination, resulting in sub-acute combined degeneration, peripheral neuropathy, and psychiatric problems, including delusions, hallucinations, cognitive changes, depression, and dementia. Vitamin B12 deficiency also leads to brain shrinkage and neurodegenerative disorders. Case Report: We report the case of a 49-year-old man presenting with new-onset seizures one and a half years following subtotal gastrectomy due to stage IV gastric adenocarcinoma. The patient did not have any history of head injury. Laboratory tests were negative for any metabolic derangements. There were no signs of infection. MRI brain and EEG were normal and there were no changes in medications. Conclusions: In case of unexplained new-onset seizures, patients should be tested for vitamin B12 and folic acid levels and these should be done as part of the initial work-up. PMID:26101427

  15. Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription.

    PubMed

    Xie, Qiu; Li, Caihua; Song, Xiaozhen; Wu, Lihua; Jiang, Qian; Qiu, Zhiyong; Cao, Haiyan; Yu, Kaihui; Wan, Chunlei; Li, Jianting; Yang, Feng; Huang, Zebing; Niu, Bo; Jiang, Zhengwen; Zhang, Ting

    2016-12-06

    The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.

  16. Hereditary folate malabsorption: A positively charged amino acid at position 113 of the proton-coupled folate transporter (PCFT/SLC46A1) is required for folic acid binding

    SciTech Connect

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

    2009-08-28

    The proton-coupled folate transporter (PCFT/SLC46A1) mediates intestinal folate uptake at acidic pH. Some loss of folic acid (FA) transport mutations in PCFT from hereditary folate malabsorption (HFM) patients cluster in R113, thereby suggesting a functional role for this residue. Herein, unlike non-conservative substitutions, an R113H mutant displayed 80-fold increase in the FA transport Km while retaining parental Vmax, hence indicating a major fall in folate substrate affinity. Furthermore, consistent with the preservation of 9% of parental transport activity, R113H transfectants displayed a substantial decrease in the FA growth requirement relative to mock transfectants. Homology modeling based on the crystal structures of the Escherichia coli transporter homologues EmrD and glycerol-3-phosphate transporter revealed that the R113H rotamer properly protrudes into the cytoplasmic face of the minor cleft normally occupied by R113. These findings constitute the first demonstration that a basic amino acid at position 113 is required for folate substrate binding.

  17. High Affinity S-Adenosylmethionine Plasma Membrane Transporter of Leishmania Is a Member of the Folate Biopterin Transporter (FBT) Family*

    PubMed Central

    Dridi, Larbi; Ahmed Ouameur, Amin; Ouellette, Marc

    2010-01-01

    S-Adenosylmethionine (AdoMet) is an important methyl group donor that plays a central role in many essential biochemical processes. The parasite Leishmania can both synthesize and transport AdoMet. Leishmania cells resistant to the antifolate methotrexate due to a rearrangement in folate biopterin transporter (FBT) genes were cross-resistant to sinefungin, an AdoMet analogue. FBT gene rearrangements were also observed in Leishmania major cells selected for sinefungin resistance. One of the rearranged FBT genes corresponded to the main AdoMet transporter (AdoMetT1) of Leishmania as determined by gene transfection and gene inactivation experiments. AdoMetT1 was determined to be a high affinity plasma membrane transporter expressed constitutively throughout the growth phases of the parasite. Leishmania cells selected for resistance or naturally insensitive to sinefungin had lower expression of AdoMetT1. A new function in one carbon metabolism, also a pathway of interest for chemotherapeutic interventions, is described for a novel class of membrane proteins found in diverse organisms. PMID:20406813

  18. High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring.

    PubMed

    Bahous, Renata H; Jadavji, Nafisa M; Deng, Liyuan; Cosín-Tomás, Marta; Lu, Jessica; Malysheva, Olga; Leung, Kit-Yi; Ho, Ming-Kai; Pallàs, Mercè; Kaliman, Perla; Greene, Nicholas DE; Bedell, Barry J; Caudill, Marie A; Rozen, Rima

    2017-01-09

    Methylenetetrahydrofolate reductase (MTHFR) generates methyltetrahydrofolate for methylation reactions. Severe MTHFR deficiency results in homocystinuria and neurologic impairment. Mild MTHFR deficiency (677C>T polymorphism) increases risk for complex traits, including neuropsychiatric disorders. Although low dietary folate impacts brain development, recent concerns have focused on high folate intake following food fortification and increased vitamin use. Our goal was to determine whether high dietary folate during pregnancy affects brain development in murine offspring. Female mice were placed on control diet (CD) or folic acid-supplemented diet (FASD) throughout mating, pregnancy and lactation. Three-week-old male pups were evaluated for motor and cognitive function. Tissues from E17.5 embryos, pups and dams were collected for choline/methyl metabolite measurements, immunoblotting or gene expression of relevant enzymes. Brains were examined for morphology of hippocampus and cortex.Pups of FASD mothers displayed short-term memory impairment, decreased hippocampal size and decreased thickness of the dentate gyrus. MTHFR protein levels were reduced in FASD pup livers, with lower concentrations of phosphocholine and glycerophosphocholine in liver and hippocampus, respectively. FASD pup brains showed evidence of altered acetylcholine availability and Dnmt3a mRNA was reduced in cortex and hippocampus. E17.5 embryos and placentas from FASD dams were smaller. MTHFR protein and mRNA were reduced in embryonic liver, with lower concentrations of choline, betaine and phosphocholine. Embryonic brain displayed altered development of cortical layers. In summary, high folate intake during pregnancy leads to pseudo-MTHFR 3 deficiency, disturbed choline/methyl metabolism, embryonic growth delay and memory impairment in offspring. These findings highlight the unintended negative consequences of supplemental folic acid.

  19. Mechanistic target of rapamycin (mTOR) regulates trophoblast folate uptake by modulating the cell surface expression of FR-α and the RFC

    PubMed Central

    Rosario, Fredrick J.; Powell, Theresa L.; Jansson, Thomas

    2016-01-01

    Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal folate uptake. Folate uptake stimulated by insulin + IGF-1 was mediated by mTORC2 but did not involve mTORC1. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of FR-α and RFC transporter isoforms without affecting global protein expression. Inhibition of the ubiquitin ligase Nedd4-2 had no effect on folate transport. In conclusion, we report for the first time that mTORC1/C2 are positive regulators of cellular folate uptake by modulating the cell surface abundance of specific transporter isoforms. We propose that regulation of placental folate transport by mTOR signaling provide a direct link between placental function, gene methylation and fetal programming. PMID:27562465

  20. Mechanistic target of rapamycin (mTOR) regulates trophoblast folate uptake by modulating the cell surface expression of FR-α and the RFC.

    PubMed

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

    2016-08-26

    Folate deficiency in fetal life is strongly associated with structural malformations and linked to intrauterine growth restriction. In addition, limited availability of methyl donors, such as folate, during pregnancy may result in abnormal gene methylation patterns and contribute to developmental programming. The fetus is dependent on placental transfer of folate, however the molecular mechanisms regulating placental folate transport are unknown. We used cultured primary human trophoblast cells to test the hypothesis that mechanistic target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate folate transport by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal folate uptake. Folate uptake stimulated by insulin + IGF-1 was mediated by mTORC2 but did not involve mTORC1. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of FR-α and RFC transporter isoforms without affecting global protein expression. Inhibition of the ubiquitin ligase Nedd4-2 had no effect on folate transport. In conclusion, we report for the first time that mTORC1/C2 are positive regulators of cellular folate uptake by modulating the cell surface abundance of specific transporter isoforms. We propose that regulation of placental folate transport by mTOR signaling provide a direct link between placental function, gene methylation and fetal programming.

  1. Genetics Home Reference: hereditary folate malabsorption

    MedlinePlus

    ... provides instructions for making a protein called the proton-coupled folate transporter (PCFT). PCFT is important for ... A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary ...

  2. Folate biofortification in food crops.

    PubMed

    Strobbe, Simon; Van Der Straeten, Dominique

    2017-03-19

    Folates are essential vitamins in the human diet. Folate deficiency is still very common, provoking disorders such as birth defects and anemia. Biofortification via metabolic engineering is a proven powerful means to alleviate folate malnutrition. A variety of metabolic engineering approaches have been successfully implemented in different crops and tissues. Furthermore, ensuring folate stability is crucial for long-term storage of crop products. However, the current strategies, shown to be successful in rice and tomato, will need to be fine-tuned to enable adequate biofortification of other staples such as potato, wheat and cassava. Thus, there is a need to overcome remaining hurdles in folate biofortification. Overall, biofortification, via breeding or metabolic engineering, will be imperative to effectively combat folate deficiency.

  3. Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children

    PubMed Central

    Zaruma-Torres, Fausto; Lares-Asseff, Ismael; Lima, Aurea; Reyes-Espinoza, Aarón; Loera-Castañeda, Verónica; Sosa-Macías, Martha; Galaviz-Hernández, Carlos; Arias-Peláez, María C.; Reyes-López, Miguel A.; Quiñones, Luis A.

    2016-01-01

    Acute lymphoblastic leukemia (ALL) is a frequent neoplasia occurring in children. The most commonly used drug for the treatment of ALL is methotrexate (MTX), an anti-folate agent. Previous studies suggest that folate transporters play a role in ALL prognosis and that genetic polymorphism of genes encoding folate transporters may increase the risk of ALL. Therefore, the main goal of this study was to determine the associations among six genetic polymorphisms in four genes related with the folate transporter pathway to determine a relationship with the occurrence of ALL in Mexican children. A case-control study was performed in 73 ALL children and 133 healthy children from Northern and Northwestern Mexico. COL18A1 (rs2274808), SLC19A1 (rs2838956), ABCB1 (rs1045642 and rs1128503), and ABCC5 (rs9838667 and rs3792585). Polymorphisms were assayed through qPCR. Our results showed an increased ALL risk in children carrying CT genotype (OR = 2.55, CI 95% 1.11–5.83, p = 0.0001) and TT genotype (OR = 21.05, CI 95% 5.62–78.87, p < 0.0001) of COL18A1 rs2274808; in SLC19A1 rs2838956 AG carriers (OR = 44.69, CI 95% 10.42–191.63, p = 0.0001); in ABCB1 rs1045642 TT carriers (OR = 13.76, CI 95% 5.94–31.88, p = 0.0001); in ABCC5 rs9838667 AC carriers (OR = 2.61, CI 95% 1.05–6.48, p < 0.05); and in ABCC5 rs3792585 CC carriers (OR = 9.99, CI 95% 3.19–31.28, p = 0.004). Moreover, several combinations of genetic polymorphisms were found to be significantly associated with a risk for ALL. Finally, two combinations of ABCC5 polymorphisms resulted in protection from this neoplasia. In conclusion, certain genetic polymorphisms related to the folate transport pathway, particularly COL18A1 rs2274808, SLC19A1 rs2838956, ABCB1 rs1045642, and ABCC5 rs3792585, were associated with an increased risk for ALL in Mexican children. PMID:27547186

  4. C5a receptor signaling prevents folate deficiency-induced neural tube defects in mice.

    PubMed

    Denny, Kerina J; Coulthard, Liam G; Jeanes, Angela; Lisgo, Steven; Simmons, David G; Callaway, Leonie K; Wlodarczyk, Bogdan; Finnell, Richard H; Woodruff, Trent M; Taylor, Stephen M

    2013-04-01

    The complement system is involved in a range of diverse developmental processes, including cell survival, growth, differentiation, and regeneration. However, little is known about the role of complement in embryogenesis. In this study, we demonstrate a novel role for the canonical complement 5a receptor (C5aR) in the development of the mammalian neural tube under conditions of maternal dietary folic acid deficiency. Specifically, we found C5aR and C5 to be expressed throughout the period of neurulation in wild-type mice and localized the expression to the cephalic regions of the developing neural tube. C5aR was also found to be expressed in the neuroepithelium of early human embryos. Ablation of the C5ar1 gene or the administration of a specific C5aR peptide antagonist to folic acid-deficient pregnant mice resulted in a high prevalence of severe anterior neural tube defect-associated congenital malformations. These findings provide a new and compelling insight into the role of the complement system during mammalian embryonic development.

  5. X-linked creatine transporter deficiency: clinical aspects and pathophysiology.

    PubMed

    van de Kamp, Jiddeke M; Mancini, Grazia M; Salomons, Gajja S

    2014-09-01

    Creatine transporter deficiency was discovered in 2001 as an X-linked cause of intellectual disability characterized by cerebral creatine deficiency. This review describes the current knowledge regarding creatine metabolism, the creatine transporter and the clinical aspects of creatine transporter deficiency. The condition mainly affects the brain while other creatine requiring organs, such as the muscles, are relatively spared. Recent studies have provided strong evidence that creatine synthesis also occurs in the brain, leading to the intriguing question of why cerebral creatine is deficient in creatine transporter deficiency. The possible mechanisms explaining the cerebral creatine deficiency are discussed. The creatine transporter knockout mouse provides a good model to study the disease. Over the past years several treatment options have been explored but no treatment has been proven effective. Understanding the pathogenesis of creatine transporter deficiency is of paramount importance in the development of an effective treatment.

  6. Use of a Novel Genetic Mouse Model to Investigate the Role of Folate in Colitis-Associated Colon Cancer

    PubMed Central

    Chapkin, Robert S.; Kamen, Barton A.; Callaway, Evelyn S.; Davidson, Laurie A.; George, Nysia I.; Wang, Naisyin; Lupton, Joanne R.; Finnell, Richard H.

    2009-01-01

    Inflammatory bowel disease (IBD) patients are at high risk for developing folate deficiency and colon cancer. Since it is difficult to study the subtle global and gene-specific epigenetic mechanisms involved in folate-mediated tumor initiation and promotion, we have generated genetically modified mouse models by targeting the reduced folate carrier (RFC1) and folate binding protein (Folbp1) genes. The transgenic mice were fed semi-purified diets for 8 wk containing either normal (2 mg) or deficient (0.1 mg folate/kg diet) levels of folate. Compound heterozygous mice (Folbp1+/−RFC1+/−) mice fed an adequate folate diet exhibited a reduction in plasma folate concentrations compared to heterozygous (Folbp1+/−) and littermate wild-type mice (p<0.05). In contrast, no differences were observed in colonic mucosa. Consumption of a low folate diet significantly reduced (3–4 fold) plasma and tissue folate levels in all animal models, although plasma homocysteine levels were not altered. In order to elucidate the relationship between folate status and inflammation-associated colon cancer, animals were injected with azoxymethane followed by dextran sodium sulphate treatment in the drinking water. Mice were fed a normal folate diet and were terminated 5 wks after carcinogen injection. The number of high multiplicity aberrant crypt foci per cm of colon was significantly elevated (p<0.05) in compound Folbp1+/− RFC1+/− (3.5±0.4) mice as compared to Folbp1+/− (1.9±0.3) and wild-type control mice (1.1±0.1). These data demonstrate that the ablation of two receptor/carrier-mediated pathways for folate transport increases the risk for developing inflammation-associated colon cancer. PMID:18926688

  7. Use of a novel genetic mouse model to investigate the role of folate in colitis-associated colon cancer.

    PubMed

    Chapkin, Robert S; Kamen, Barton A; Callaway, Evelyn S; Davidson, Laurie A; George, Nysia I; Wang, Naisyin; Lupton, Joanne R; Finnell, Richard H

    2009-08-01

    Inflammatory bowel disease (IBD) patients are at high risk for developing folate deficiency and colon cancer. Since it is difficult to study the subtle global and gene-specific epigenetic mechanisms involved in folate-mediated tumor initiation and promotion, we have generated genetically modified mouse models by targeting the reduced folate carrier (RFC1) and folate-binding protein (Folbp1) genes. The transgenic mice were fed semi-purified diets for 8 weeks containing either normal (2 mg) or deficient (0.1 mg folate/kg diet) levels of folate. Compound heterozygous mice (Folbp1(+/-); RFC1(+/-)) fed an adequate folate diet exhibited a reduction in plasma folate concentrations compared to heterozygous (Folbp1(+/-)) and littermate wild-type mice (P<.05). In contrast, no differences were observed in colonic mucosa. Consumption of a low folate diet significantly reduced (three- to fourfold) plasma and tissue folate levels in all animal models, although plasma homocysteine levels were not altered. In order to elucidate the relationship between folate status and inflammation-associated colon cancer, animals were injected with azoxymethane followed by dextran sodium sulphate treatment in the drinking water. Mice were fed a normal folate diet and were terminated 5 weeks after carcinogen injection. The number of high multiplicity aberrant crypt foci per centimeter of colon was significantly elevated (P<.05) in compound Folbp1(+/-); RFC1(+/-) (3.5+/-0.4) mice as compared to Folbp1(+/-) (1.9+/-0.3) and wild-type control mice (1.1+/-0.1). These data demonstrate that the ablation of two receptor/carrier-mediated pathways for folate transport increases the risk for developing inflammation-associated colon cancer.

  8. Glucose transporter type1 (GLUT-1) deficiency.

    PubMed

    Gordon, Neil; Newton, Richard W

    2003-10-01

    Glucose transporter type1 (GLUT-1) deficiency may be rare, but it is a preventable cause of severe learning difficulties; and therefore there is an urgency in making an early diagnosis. Suspicions must be roused when intractable seizures occur in infancy. These may be associated with acquired microcephaly and developmental delay. The finding of low glucose sugar levels in the cerebrospinal fluid, but not in the blood will identify the condition. The gene encoding the GLUT-1 protein is located on the short arm of chromosome 1, and inheritance is by a dominant trait. Patients with this syndrome can have heterozygous mutations, with one allele being a normal wild type and one being mutant. An efficient transport of glucose across the blood-brain barrier is essential as it is such an important fuel for the brain, and this is provided by glucose transporter type1 in the endothelial cells of the brain capillaries. Another minor contribution to the symptomatology of GLUT-1 may be impaired transport of an oxidised form of vitamin C. Treatment with anti-epileptic drugs may be needed, and the ketogenic diet may reduce symptoms, as ketosis can provide an alternative source of fuel for the brain. It has also been suggested that antioxidant thioctic acid may be of benefit. Substances such as caffeine and phenobarbitone should be avoided as they inhibit glucose transport.

  9. [Glucose transporter type 1 (GLUT-1) deficiency].

    PubMed

    Cano, A; Ticus, I; Chabrol, B

    2008-11-01

    Impaired glucose transport across the blood brain barrier results in glucose transporter type 1 (GLUT-1) deficiency syndrome, first described in 1991. It is characterized by infantile seizures refractory to anticonvulsive treatments, microcephaly, delays in mental and motor development, spasticity, ataxia, dysarthria and other paroxysmal neurologic phenomena, often occurring prior to meals. Affected infants are normal at birth following an uneventful pregnancy and delivery. Seizures usually begin between the age of one and four months and can be preceded by apneic episodes or abnormal eyes movements. Patients with atypical presentations such as mental retardation and intermittent ataxia without seizures, or movement disorders characterized by choreoathetosis and dystonia, have also been described. Glucose is the principal fuel source for the brain and GLUT-1 is the only vehicle by which glucose enters the brain. In case of GLUT-1 deficiency, the risk of clinical manifestations is increased in infancy and childhood, when the brain glucose demand is maximal. The hallmark of the disease is a low glucose concentration in the cerebrospinal fluid in a presence of normoglycemia (cerebrospinal fluid/blood glucose ratio less than 0.4). The GLUT-1 defect can be confirmed by molecular analysis of the SCL2A1 gene or in erythrocytes by glucose uptake studies and GLUT-1 immunoreactivity. Several heterozygous mutations, with a majority of de novo mutations, resulting in GLUT-1 haploinsufficiency, have been described. Cases with an autosomal dominant transmission have been established and adults can exhibit symptoms of this deficiency. Ketogenic diet is an effective treatment of epileptic manifestations as ketone bodies serve as an alternative fuel for the developing brain. However, this diet is not effective on cognitive impairment and other treatments are being evaluated. The physiopathology of this disorder is partially unclear and its understanding could explain the clinical

  10. 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

  11. Chromosomal localization of the murine RFC-1 gene encoding a folate transporter and its amplification in an antifolate resistant variant overproducing the transporter.

    PubMed

    Roy, K; Chiao, J H; Spengler, B A; Tolner, B; Yang, C H; Biedler, J L; Sirotnak, F M

    1998-08-01

    A variant of the L1210 cell (L1210/R83) selected in the presence of the lipophilic antifolate, metoprine, and a concentration of the natural diastereoisomer of 5-formyltetrahydrofolate, lL5CHO-folateH4, suboptimum for growth exhibited a 35-fold increase compared to parental L1210 cells in one-carbon, reduced folate transport. This was evidenced by the increase in Vmax for [3H]MTX (methotrexate) influx and a commensurate increase in the amount of the 46 kilodalton (kDa) transport protein and reduced folate carrier (RFC-1) mRNA. The variant is resistant to lipophilic antifolates, but shows collateral sensitivity to classical folate analogues. Karyotype analysis of L1210/R83 cells revealed the presence of several new chromosome abnormalities. One of these was a large, submetacentric marker chromosome comprising a normal #10 and a longer, abnormally banded arm of uncertain origin which exhibited an interstitial, palely staining, HSR-like segment. The results of Southern and Northern blotting showed that the RFC-1 gene copy number and RNA transcript level were markedly increased (30-35 fold) in L1210/R83 cells. Fluorescence in situ hybridization (FISH) analysis revealed that the HSR-like segment in these cells was the site of amplified RFC-1 genes. Independent revertant subclones, obtained following growth in the absence of selection pressure, showed four- to 12-fold decreases in [3H]MTX influx Vmax and in amount of NHS (N-hydroxysuccinimide)-[3H]MTX affinity labeled one-carbon, reduced folate transporter compared to L1210/R83 cells. RFC-1 gene copy number also decreased, and the mean length of the HSR in these revertants declined 1.6- to 5-fold. Based upon genomic nucleotide sequencing, the RFC-1 gene in the normal mouse genome was localized to chromosome 10 in close association with the alpha 1 (Col18a1) collagen gene at 10B3(locus 41cM). The close association of these genes was confirmed by other data showing that the alpha 1 collagen gene was co-amplified in L1210/R

  12. Adult neurogenesis in serotonin transporter deficient mice.

    PubMed

    Schmitt, A; Benninghoff, J; Moessner, R; Rizzi, M; Paizanis, E; Doenitz, C; Gross, S; Hermann, M; Gritti, A; Lanfumey, L; Fritzen, S; Reif, A; Hamon, M; Murphy, D L; Vescovi, A; Lesch, K-P

    2007-09-01

    Serotonin (5-HT) is a regulator of morphogenetic activities during early brain development and neurogenesis, including cell proliferation, migration, differentiation, and synaptogenesis. The 5-HT transporter (5-HTT, SLC6A4) mediates high-affinity reuptake of 5-HT into presynaptic terminals and thereby fine-tunes serotonergic neurotransmission. Inactivation of the 5-HTT gene in mice reduces 5-HT clearance resulting in persistently increased concentrations of synaptic 5-HT. In the present study, we investigated the effects of elevated 5-HT levels on adult neurogenesis in the hippocampus of 5-HTT deficient mice, including stem cell proliferation, survival, and differentiation. Using an in vivo approach, we showed an increase in proliferative capacity of hippocampal adult neural stem cells in aged 5-HTT knockout mice (approximately 14.5 months) compared to wildtype controls. In contrast, in vivo and additional in vitro analyses of younger adult 5-HTT knockout mice (approximately 7 weeks and approximately 3.0 months) did not reveal significant changes in proliferation of neural stem cells or survival of newborn cells. We showed that the cellular fate of newly generated cells in 5-HTT knockout mice is not different with respect to the total number and percentage of neurons or glial cells from wildtype controls. Our findings indicate that elevated synaptic 5-HT concentration throughout early development and later life of 5-HTT deficient mice does not induce adult neurogenesis in adult mice, but that elevated 5-HT levels in aged mice influence stem cell proliferation.

  13. Improving folate (vitamin B9) stability in biofortified rice through metabolic engineering.

    PubMed

    Blancquaert, Dieter; Van Daele, Jeroen; Strobbe, Simon; Kiekens, Filip; Storozhenko, Sergei; De Steur, Hans; Gellynck, Xavier; Lambert, Willy; Stove, Christophe; Van Der Straeten, Dominique

    2015-10-01

    Biofortification of staple crops could help to alleviate micronutrient deficiencies in humans. We show that folates in stored rice grains are unstable, which reduces the potential benefits of folate biofortification. We obtain folate concentrations that are up to 150 fold higher than those of wild-type rice by complexing folate to folate-binding proteins to improve folate stability, thereby enabling long-term storage of biofortified high-folate rice grains.

  14. Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia.

    PubMed

    Farkas, Sanja A; Böttiger, Anna K; Isaksson, Helena S; Finnell, Richard H; Ren, Aiguo; Nilsson, Torbjörn K

    2013-03-01

    The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR's) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.

  15. Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid beta-peptide.

    PubMed

    Pak, Kirk J; Chan, Sic L; Mattson, Mark P

    2003-01-01

    Although damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid beta-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid beta-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid beta-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.

  16. MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring.

    PubMed

    Jadavji, N M; Deng, L; Malysheva, O; Caudill, M A; Rozen, R

    2015-08-06

    Genetic or nutritional disturbances in one-carbon metabolism, with associated hyperhomocysteinemia, can result in complex disorders including pregnancy complications and neuropsychiatric diseases. In earlier work, we showed that mice with a complete deficiency of methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate and homocysteine metabolism, had cognitive impairment with disturbances in choline metabolism. Maternal demands for folate and choline are increased during pregnancy and deficiencies of these nutrients result in several negative outcomes including increased resorption and delayed development. The goal of this study was to investigate the behavioral and neurobiological impact of a maternal genetic deficiency in MTHFR or maternal nutritional deficiency of folate or choline during pregnancy on 3-week-old Mthfr(+/+) offspring. Mthfr(+/+) and Mthfr(+/-) females were placed on control diets (CD); and Mthfr(+/+) females were placed on folate-deficient diets (FD) or choline-deficient diets (ChDD) throughout pregnancy and lactation until their offspring were 3weeks of age. Short-term memory was assessed in offspring, and hippocampal tissue was evaluated for morphological changes, apoptosis, proliferation and choline metabolism. Maternal MTHFR deficiency resulted in short-term memory impairment in offspring. These dams had elevated levels of plasma homocysteine when compared with wild-type dams. There were no differences in plasma homocysteine in offspring. Increased apoptosis and proliferation was observed in the hippocampus of offspring from Mthfr(+/-) mothers. In the maternal FD and ChDD study, offspring also showed short-term memory impairment with increased apoptosis in the hippocampus; increased neurogenesis was observed in ChDD offspring. Choline acetyltransferase protein was increased in the offspring hippocampus of both dietary groups and betaine was decreased in the hippocampus of FD offspring. Our results reveal short-term memory

  17. Folate- and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor α.

    PubMed

    Pourié, Grégory; Martin, Nicolas; Bossenmeyer-Pourié, Carine; Akchiche, Nassila; Guéant-Rodriguez, Rosa Maria; Geoffroy, Andréa; Jeannesson, Elise; El Hajj Chehadeh, Sarah; Mimoun, Khalid; Brachet, Patrick; Koziel, Violette; Alberto, Jean-Marc; Helle, Deborah; Debard, Renée; Leininger, Brigitte; Daval, Jean-Luc; Guéant, Jean-Louis

    2015-09-01

    Deficiency in the methyl donors vitamin B12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor α (ER-α)/Src tyrosine kinase. The influence of impaired ER-α pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-α antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-α and subsequent decreased ER-α/PPAR-γ coactivator 1 α (PGC-1α) interaction in deficiency condition. The impaired ER-α pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4-quinazolinamine, SKI-1, Src-l1) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-α pathway.

  18. Dopamine transporter deficiency syndrome: phenotypic spectrum from infancy to adulthood

    PubMed Central

    Ng, Joanne; Zhen, Juan; Meyer, Esther; Erreger, Kevin; Li, Yan; Kakar, Naseebullah; Ahmad, Jamil; Thiele, Holger; Kubisch, Christian; Rider, Nicholas L.; Holmes Morton, D.; Strauss, Kevin A.; Puffenberger, Erik G.; D’Agnano, Daniela; Anikster, Yair; Carducci, Claudia; Hyland, Keith; Rotstein, Michael; Leuzzi, Vincenzo; Borck, Guntram; Reith, Maarten E. A.

    2014-01-01

    Dopamine transporter deficiency syndrome due to SLC6A3 mutations is the first inherited dopamine ‘transportopathy’ to be described, with a classical presentation of early infantile-onset progressive parkinsonism dystonia. In this study we have identified a new cohort of patients with dopamine transporter deficiency syndrome, including, most significantly, atypical presentation later in childhood with a milder disease course. We report the detailed clinical features, molecular genetic findings and in vitro functional investigations undertaken for adult and paediatric cases. Patients presenting with parkinsonism dystonia or a neurotransmitter profile characteristic of dopamine transporter deficiency syndrome were recruited for study. SLC6A3 mutational analysis was undertaken in all patients. The functional consequences of missense variants on the dopamine transporter were evaluated by determining the effect of mutant dopamine transporter on dopamine uptake, protein expression and amphetamine-mediated dopamine efflux using an in vitro cellular heterologous expression system. We identified eight new patients from five unrelated families with dopamine transporter deficiency syndrome. The median age at diagnosis was 13 years (range 1.5–34 years). Most significantly, the case series included three adolescent males with atypical dopamine transporter deficiency syndrome of juvenile onset (outside infancy) and progressive parkinsonism dystonia. The other five patients in the cohort presented with classical infantile-onset parkinsonism dystonia, with one surviving into adulthood (currently aged 34 years) and labelled as having ‘juvenile parkinsonism’. All eight patients harboured homozygous or compound heterozygous mutations in SLC6A3, of which the majority are previously unreported variants. In vitro studies of mutant dopamine transporter demonstrated multifaceted loss of dopamine transporter function. Impaired dopamine uptake was universally present, and more

  19. Effects of Cu deficiency on photosynthetic electron transport

    SciTech Connect

    Droppa, M.; Terry, N.; Horvath, G.

    1984-04-01

    The role of copper (Cu) in photosynthetic electron transport was explored by using Cu deficiency in sugar beet as an experimental approach. Copper influenced electron transport at two sites in addition to plastocyanin. Under mild deficiency (0.84 nmol of Cu per cm/sup 2/ of leaf area), electron transport between the two photosystems (PS) is inhibited but not electron transport within PS I or PS II measured separately. The chlorophyll/plastoquinone ratio was normal in Cu-deficient plants. However, the breakpoint in the Arrhenius plot of electron transport was shifted towards a higher temperature. It is concluded that Cu is necessary to maintain the appropriate membrane fluidity to ensure the mobility of plastoquinone molecules to transfer electrons between the two photosystems. Under severe deficiency (0.22 nmol of Cu per cm/sup 2/ of leaf area) both PS II and PS I electron transports were inhibited and to the same extent. PS II electron transport activity could not be restored by adding artifical electron donors. Polypeptides with M/sub r/s of 28,000 and 13,500 were missing in Cu-deficient chloroplast membranes. In PS II particles prepared from normal chloroplasts of spinach, 2 atoms of Cu per reaction center are present. We conclude that Cu influences PS II electron transport either directly, by participation in electron transfer as a constituent of an electron carrier, or indirectly, via the polypeptide composition of the membrane in the PS II complex.

  20. Gene expression profiling in the fetal cardiac tissue after folate and low dose trichloroethylene exposure

    PubMed Central

    Caldwell, Patricia T.; Manziello, Ann; Howard, Jamie; Palbykin, Brittany; Runyan, Raymond B.; Selmin, Ornella

    2014-01-01

    Background Previous studies show gene expression alterations in rat embryo hearts and cell lines that correspond to the cardio-teratogenic effects of trichloroethylene (TCE) in animal models. One potential mechanism of TCE teratogenicity may be through altered regulation of calcium homeostatic genes with a corresponding inhibition of cardiac function. It has been suggested that TCE may interfere with the folic acid/methylation pathway in liver and kidney and alter gene regulation by epigenetic mechanisms. According to this hypothesis, folate supplementation in the maternal diet should counteract TCE effects on gene expression in the embryonic heart. Approach To identify transcriptional targets altered in the embryonic heart after exposure to TCE, and possible protective effects of folate, we used DNA microarray technology to profile gene expression in embryonic mouse hearts with maternal TCE exposure and dietary changes in maternal folate. Results Exposure to low doses of TCE (10ppb) caused extensive alterations in transcripts encoding proteins involved in transport, ion channel, transcription, differentiation, cytoskeleton, cell cycle and apoptosis. Exogenous folate did not offset the effects of TCE exposure on normal gene expression and both high and low levels of folate produced additional significant changes in gene expression. Conclusions A mechanism where TCE induces a folate deficiency does not explain altered gene expression patterns in the embryonic mouse heart. The data further suggest that use of folate supplementation, in the presence of this toxin, may be detrimental and non-protective of the developing embryo. PMID:19813261

  1. 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…

  2. Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6–7 linker

    PubMed Central

    Wilson, Mike R.; Hou, Zhanjun; Wilson, Lucas J.; Ye, Jun; Matherly, Larry H.

    2016-01-01

    The proton-coupled folate transporter (PCFT; SLC46A1) is a folate–proton symporter expressed in solid tumors and is used for tumor-targeted delivery of cytotoxic antifolates. Topology modeling suggests that the PCFT secondary structure includes 12 transmembrane domains (TMDs) with TMDs 6 and 7 linked by an intracellular loop (positions 236–265) including His247, implicated as functionally important. Single-cysteine (Cys) mutants were inserted from positions 241 to 251 in Cys-less PCFT and mutant proteins were expressed in PCFT-null (R1–11) HeLa cells; none were reactive with 2-aminoethyl methanethiosulfonate biotin, suggesting that the TMD6–7 loop is intracellular. Twenty-nine single alanine mutants spanning the entire TMD6–7 loop were expressed in R1–11 cells; activity was generally preserved, with the exception of the 247, 250, and 251 mutants, partly due to decreased surface expression. Coexpression of PCFT TMD1–6 and TMD7–12 half-molecules in R1–11 cells partially restored transport activity, although removal of residues 252–265 from TMD7–12 abolished transport. Chimeric proteins, including a nonhomologous sequence from a thiamine transporter (ThTr1) inserted into the PCFT TMD6–7 loop (positions 236–250 or 251–265), were active, although replacement of the entire loop with the ThTr1 sequence resulted in substantial loss of activity. Amino acid replacements (Ala, Arg, His, Gln, and Glu) or deletions at position 247 in wild-type and PCFT–ThTr1 chimeras resulted in differential effects on transport. Collectively, our findings suggest that the PCFT TMD6–7 connecting loop confers protein stability and may serve a unique functional role that depends on secondary structure rather than particular sequence elements. PMID:27514717

  3. When transporters fail to be transported: how to rescue folding-deficient SLC6 transporters

    PubMed Central

    Sucic, Sonja; Kasture, Ameya; Mazhar Asjad, H. M.; Kern, Carina; El-Kasaby, Ali; Freissmuth, Michael

    2017-01-01

    The human dopamine transporter (hDAT) belongs to the solute carrier 6 (SLC6) gene family. Point mutations in hDAT (SLC6A3) have been linked to a syndrome of dopamine transporter deficiency or infantile dystonia/parkinsonism. The mutations impair DAT folding, causing retention of variant DATs in the endoplasmic reticulum and subsequently impair transport activity. The folding trajectory of DAT itself is not understood, though many insights have been gained from studies of folding-deficient mutants of the closely related serotonin transporter (SERT); i.e. their functional rescue by pharmacochaperoning with (nor)ibogaine or heat-shock protein inhibitors. We recently provided a proof-of-principle that folding-deficits in DAT are amenable to rescue in vitro and in vivo. As a model we used the Drosophila melanogaster DAT mutant dDAT-G108Q, which phenocopies the fumin/sleepless DAT-knockout. Treatment with noribogaine and/or HSP70 inhibitor pifithrin-μ restored folding of, and dopamine transport by, dDAT-G108Q, its axonal delivery and normal sleep time in mutant flies. The possibility of functional rescue of misfolded DATs in living flies by pharmacochaperoning grants new therapeutic prospects in the remedy of folding diseases, not only in hDAT, but also in other SLC6 transporters, in particular mutants of the creatine transporter-1, which give rise to X-linked mental retardation.

  4. Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.

    PubMed

    Golani, Lalit K; Wallace-Povirk, Adrianne; Deis, Siobhan M; Wong, Jennifer; Ke, Jiyuan; Gu, Xin; Raghavan, Sudhir; Wilson, Mike R; Li, Xinxin; Polin, Lisa; de Waal, Parker W; White, Kathryn; Kushner, Juiwanna; O'Connor, Carrie; Hou, Zhanjun; Xu, H Eric; Melcher, Karsten; Dann, Charles E; Matherly, Larry H; Gangjee, Aleem

    2016-09-08

    Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.

  5. 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...

  6. Folate deficiency and folic acid supplementation: the prevention of neural-tube defects and congenital heart defects.

    PubMed

    Czeizel, Andrew E; Dudás, Istvan; Vereczkey, Attila; Bánhidy, Ferenc

    2013-11-21

    Diet, particularly vitamin deficiency, is associated with the risk of birth defects. The aim of this review paper is to show the characteristics of common and severe neural-tube defects together with congenital heart defects (CHD) as vitamin deficiencies play a role in their origin. The findings of the Hungarian intervention (randomized double-blind and cohort controlled) trials indicated that periconceptional folic acid (FA)-containing multivitamin supplementation prevented the major proportion (about 90%) of neural-tube defects (NTD) as well as a certain proportion (about 40%) of congenital heart defects. Finally the benefits and drawbacks of three main practical applications of folic acid/multivitamin treatment such as (i) dietary intake; (ii) periconceptional supplementation; and (iii) flour fortification are discussed. The conclusion arrived at is indeed confirmation of Benjamin Franklin's statement: "An ounce of prevention is better than a pound of care".

  7. Vitamin Deficiency Anemia

    MedlinePlus

    Vitamin deficiency anemia Overview By Mayo Clinic Staff Vitamin deficiency anemia is a lack of healthy red blood ... normal amounts of certain vitamins. Vitamins linked to vitamin deficiency anemia include folate, vitamin B-12 and vitamin ...

  8. Increased hippocampal DNA oxidation in serotonin transporter deficient mice.

    PubMed

    Mössner, R; Dringen, R; Persico, A M; Janetzky, B; Okladnova, O; Albert, D; Götz, M; Benninghoff, J; Schmitt, A; Gerlach, M; Riederer, P; Lesch, K P

    2002-05-01

    The serotonin transporter (5HTT) is the molecule responsible for the high-affinity reuptake of 5HT from the synaptic cleft. Mice lacking the 5HTT exhibit highly elevated extracellular concentrations of 5HT. We assessed whether the glutathione detoxification system is altered in 5HTT-deficient mice. While levels of reduced and oxidized glutathione were unchanged, glutathione metabolising enzymes showed a differential pattern of modulation. Glutathione peroxidase was reduced in frontal cortex, brainstem, and cerebellum of 5HTT-deficient mice, though not to a statistically significant extent, while a putative isoform of the detoxifying enzyme glutathione-S-transferase pi was decreased in a number of brain regions, especially in brainstem. At the level of the DNA, we found an increase of oxidative DNA adducts in the hippocampus of 5HTT-deficient mice. Given the importance of the hippocampus in learning and memory, this may be the most important neurochemical consequence of the absence of the 5HTT.

  9. Red cell or serum folate: what to do in clinical practice?

    PubMed

    Farrell, Christopher-John L; Kirsch, Susanne H; Herrmann, Markus

    2013-03-01

    Folate deficiency has been linked to diverse clinical manifestations and despite the importance of accurate assessment of folate status, the best test for routine use is uncertain. Both serum and red cell folate assays are widely available in clinical laboratories; however, red cell folate is the more time-consuming and costly test. This review sought to evaluate whether the red cell assay demonstrated superior performance characteristics to justify these disadvantages. Red cell folate, but not serum folate, measurements demonstrated analytical variation due to sample pre-treatment parameters, oxygen saturation of haemoglobin and haematocrit. Neither marker was clearly superior in characterising deficiency but serum folate more frequently showed the higher correlation with homocysteine, a sensitive marker of deficiency. Similarly, both serum and red cell folate were shown to increase in response to folic acid supplementation. However, serum folate generally gave the greater response and was able to distinguish different supplementation doses. The C677T polymorphism of methylenetetrahydrofolate reductase alters the distribution of folate forms in red cells and may thereby cause further analytical variability in routine red cell folate assays. Overall, serum folate is cheaper and faster to perform than red cell folate, is influenced by fewer analytical variables and provides an assessment of folate status that may be superior to red cell folate.

  10. Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line.

    PubMed

    Diop-Bove, Ndeye Khady; Wu, Julia; Zhao, Rongbao; Locker, Joseph; Goldman, I David

    2009-08-01

    This laboratory recently identified a novel proton-coupled folate transporter (PCFT) that mediates intestinal folate absorption and transport of folates into the central nervous system. The present study focuses on the definition of the minimum transcriptional regulatory region of this gene in HeLa cells and the mechanism(s) underlying the loss of PCFT expression in the methotrexate-resistant HeLa R1-11 cell line. The PCFT transcriptional regulatory controls were localized between -42 and +96 bases from the transcriptional start site using a luciferase-reporter gene system. The promoter is a G + C rich region of 139 nucleotides contained in a CpG island. HeLa R1-11 cells have no mutations in the PCFT open reading frame and its promoter; the transcription/translation machinery is intact because transient transfections in HeLa R1-11 and wild-type HeLa cells produced similar luciferase activities. Hypermethylation at CpG sites within the minimal transcriptional regulatory region was shown in HeLa R1-11 cells as compared with the parental PCFT-competent HeLa cells, using bisulfite conversion and sequence analysis. Treatment with 5-aza-2'-deoxycytidine resulted in a substantial restoration of transport and PCFT mRNA expression and small but significant decreases in methylation in the promoter region. In vitro methylation of the transfected reporter plasmid inhibited luciferase gene expression. Cytogenetics/fluorescence in situ hybridization indicated a loss of half the PCFT gene copies in HeLa R1-11 as compared with PCFT-competent HeLa cells. Taken together, promoter silencing through methylation and gene copy loss accounted for the loss of PCFT activity in antifolate-resistant HeLa R1-11 cells.

  11. Synthesis, biological and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase

    PubMed Central

    Wang, Lei; Desmoulin, Sita Kugel; Cherian, Christina; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Fulterer, Andreas; Chang, Min-Hwang; Mitchell, Shermaine; Stout, Mark; Romero, Michael F.; Hou, Zhanjun; Matherly, Larry H.; Gangjee, Aleem

    2011-01-01

    2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1–3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-α-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with L-glutamate diethyl ester, followed by saponification, afforded 1–3. Compound 3 selectively inhibited proliferation of cells expressing folate receptors (FRs) α or β, or the proton-coupled folate transporter (PCFT), including human tumor cells KB and IGROV1 much more potently than 4. Compound 3 was more inhibitory than 4 toward β-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1, 2 and 4-atom bridge lengths for the activity of this series. PMID:21879757

  12. [Glucose transporter-1 deficiency syndrome can cause various clinical symptoms].

    PubMed

    Larsen, Jan; Stubbings, Vibeke; Møller, Rikke Steensbjerre; Hjalgrim, Helle

    2013-12-09

    Glucose transporter-1 deficiency syndrome (GLUT1-DS) is caused by a decreased function of the glucose transporter GLUT1 protein, which is located in the blood brain barrier. This leads to inadequate glucose levels for brain metabolism and can cause various clinical symptoms including medically intractable epilepsy, developmental delay and complex movement disorders. Ketonic diet is the golden standard for treatment of GLUT1-DS. GLUT1-DS should be suspected in patients with early-onset intractable epilepsy with developmental delay or activity-induced movement disorders with or without epilepsy.

  13. Random mutagenesis of the proton-coupled folate transporter (SLC46A1), clustering of mutations, and the bases for associated losses of function.

    PubMed

    Zhao, Rongbao; Shin, Daniel Sanghoon; Diop-Bove, Ndeye; Ovits, Channa Gila; Goldman, I David

    2011-07-08

    Loss-of-function mutations in the proton-coupled folate transporter (PCFT, SLC46A1) result in the autosomal recessive disorder, hereditary folate malabsorption (HFM). Identification and characterization of HFM mutations provide a wealth of information on the structure-function relationship of this transporter. In the current study, PCR-based random mutagenesis was employed to generate unbiased loss-of-function mutations of PCFT, simulating the spectrum of alterations that might occur in the human disorder. A total of 26 mutations were generated and 4 were identical to HFM mutations. Eleven were base deletion or insertion mutations that led to a frameshift and, along with similar HFM mutations, are predominantly localized to two narrow regions of the pcft gene at the 5'-end. Base substitution mutations identified in the current study and HFM patients were largely distributed across the pcft gene. Elimination of the ATG initiation codon by a one-base substitution (G > A) did not result in a complete lack of translation at the same codon consistent with rare non-ATG translation initiation. Among six missense mutants evaluated, three mutant PCFTs were not detected at the plasma membrane, one mutation resulted in decreased binding to folate substrate, and one had a reduced rate of conformational change associated with substrate translocation. The remaining PCFT mutant had defects in both processes. These results broaden understanding of the regions of the pcft gene prone to base insertion and deletion and inform further approaches to the analysis of the structure-function of PCFT.

  14. Exogenous folates stimulate growth and budding of Candida glabrata

    PubMed Central

    Porzoor, Afsaneh; Macreadie, Ian G.

    2015-01-01

    Folate, vitamin B9, is well recognized as being essential for cell growth. The utilization of folate is common to all cells, but the source of it may be quite different. For example, mammalian cells depend on exogenous uptake of folates, while plants and microbes can synthesize them. There has been little consideration of uptake of folate in microbial cells, and studies on the effects of folates in mammalian cells, where conditions are restricted. This study shows that exogenous folates (folic acid or folinic acid), causes Candida glabrata cells suspended in water alone to undergo two cycles of cell division and to form multiple buds. The effect was limited to cells in the stationary phase and more profound in quiescent cells. These data indicate a novel response of yeast to folates that may increase the utility of yeast as a model to study folate transport and signaling. PMID:28357288

  15. Folate Intake and Markers of Folate Status in Women of Reproductive Age, Pregnant and Lactating Women: A Meta-Analysis

    PubMed Central

    Berti, Cristiana; Fekete, Katalin; Dullemeijer, Carla; Trovato, Monica; Souverein, Olga W.; Cavelaars, Adriënne; Dhonukshe-Rutten, Rosalie; Massari, Maddalena; Decsi, Tamás; van't Veer, Pieter; Cetin, Irene

    2012-01-01

    Background. Pregnant and breastfeeding women are at risk for folate deficiency. Folate supplementation has been shown to be associated with enhanced markers of folate status. However, dose-response analyses for adult women are still lacking. Objective. To assess the dose-response relationship between total folate intake (folic acid plus dietary folate) and markers of folate status (plasma/serum folate, red blood cell folate, and plasma homocysteine); to evaluate potential differences between women in childbearing age, pregnant and lactating women. Methods. Electronic literature searches were carried out on three databases until February 2010. The overall pooled regression coefficient (β) and SE(β) were calculated using meta-analysis on a double-log scale. Results. The majority of data was based on nonpregnant, nonlactating women in childbearingage. The pooled estimate of the relationship between folate intake and serum/plasma folate was 0.56 (95% CI = 0.40–0.72, P < 0.00001); that is, the doubling of folate intake increases the folate level in serum/plasma by 47%. For red blood cell folate, the pooled-effect estimate was 0.30 (95% CI = 0.22–0.38, P < 0.00001), that is, +23% for doubling intake. For plasma-homocysteine it was –0.10 (95% = –0.17 to –0.04, P = 0.001), that is, –7% for doubling the intake. Associations tended to be weaker in pregnant and lactating women. Conclusion. Significant relationships between folate intake and serum/plasma folate, red blood cell folate, and plasma homocysteine were quantified. This dose-response methodology may be applied for setting requirements for women in childbearing age, as well as for pregnant and lactating women. PMID:23024859

  16. Relative bioavailability of folate from the traditional food plant Moringa oleifera L. as evaluated in a rat model.

    PubMed

    Saini, R K; Manoj, P; Shetty, N P; Srinivasan, K; Giridhar, P

    2016-01-01

    Moringa oleifera is an affordable and rich source of dietary folate. Quantification of folate by HPLC showed that 5-formyl-5,6,7,8-tetrahydrofolic acid (502.1 μg/100 g DW) and 5,6,7,8-tetrahydrofolic acid (223.9 μg/100 g DW) as the most dominant forms of folate in M. oleifera leaves. The bioavailability of folate and the effects of folate depletion and repletion on biochemical and molecular markers of folate status were investigated in Wistar rats. Folate deficiency was induced by keeping the animals on a folate deficient diet with 1 % succinyl sulfathiazole (w/w). After the depletion period, animals were repleted with different levels of folic acid and M. oleifera leaves as a source of folate. Feeding the animals on a folate deficient diet for 7 weeks caused a significant (3.4-fold) decrease in serum folate content, compared to non-depleted control animals. Relative bioavailability of folate from dehydrated leaves of M. oleifera was 81.9 %. During folate depletion and repletion, no significant changes in liver glycine N-methyl transferase and 5-methyltetrahydrofolate-homocysteine methyltransferase expression were recorded. In RDA calculations, only 50 % of natural folate is assumed to be bioavailable. Therefore, the bioavailability of folate from Moringa is much higher, suggesting that M. oleifera based food can be used as a significant source of folate.

  17. Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts.

    PubMed

    VanderMeer, Julia E; Carter, Tonia C; Pangilinan, Faith; Mitchell, Adam; Kurnat-Thoma, Emma; Kirke, Peadar N; Troendle, James F; Molloy, Anne M; Munger, Ronald G; Feldkamp, Marcia L; Mansilla, Maria A; Mills, James L; Murray, Jeff C; Brody, Lawrence C

    2016-04-01

    Many folate-related genes have been investigated for possible causal roles in neural tube defects (NTDs) and oral clefts. However, no previous reports have examined the major gene responsible for folate uptake, the proton-coupled folate transporter (SLC46A1). We tested for association between these birth defects and single nucleotide polymorphisms in the SLC46A1 gene. The NTD study population included 549 complete and incomplete case-family triads, and 999 controls from Ireland. The oral clefts study population comprised a sample from Utah (495 complete and incomplete case-family triads and 551 controls) and 221 Filipino multiplex cleft families. There was suggestive evidence of increased NTD case risk with the rs17719944 minor allele (odds ratio (OR): 1.29; 95% confidence intervals (CI): [1.00-1.67]), and decreased maternal risk of an NTD pregnancy with the rs4795436 minor allele (OR: 0.62; [0.39-0.99]). In the Utah sample, the rs739439 minor allele was associated with decreased case risk for cleft lip with cleft palate (genotype relative risk (GRR): 0.56 [0.32-0.98]). Additionally, the rs2239907 minor allele was associated with decreased case risk for cleft lip with cleft palate in several models, and with cleft palate only in a recessive model (OR: 0.41; [0.20-0.85]). These associations did not remain statistically significant after correcting for multiple hypothesis testing. Nominal associations between SLC46A1 polymorphisms and both Irish NTDs and oral clefts in the Utah population suggest some role in the etiology of these birth defects, but further investigation in other populations is needed.

  18. Folate metabolic pathways in Leishmania.

    PubMed

    Vickers, Tim J; Beverley, Stephen M

    2011-01-01

    Trypanosomatid parasitic protozoans of the genus Leishmania are autotrophic for both folate and unconjugated pteridines. Leishmania salvage these metabolites from their mammalian hosts and insect vectors through multiple transporters. Within the parasite, folates are reduced by a bifunctional DHFR (dihydrofolate reductase)-TS (thymidylate synthase) and by a novel PTR1 (pteridine reductase 1), which reduces both folates and unconjugated pteridines. PTR1 can act as a metabolic bypass of DHFR inhibition, reducing the effectiveness of existing antifolate drugs. Leishmania possess a reduced set of folate-dependent metabolic reactions and can salvage many of the key products of folate metabolism from their hosts. For example, they lack purine synthesis, which normally requires 10-formyltetrahydrofolate, and instead rely on a network of purine salvage enzymes. Leishmania elaborate at least three pathways for the synthesis of the key metabolite 5,10-methylene-tetrahydrofolate, required for the synthesis of thymidylate, and for 10-formyltetrahydrofolate, whose presumptive function is for methionyl-tRNAMet formylation required for mitochondrial protein synthesis. Genetic studies have shown that the synthesis of methionine using 5-methyltetrahydrofolate is dispensable, as is the activity of the glycine cleavage complex, probably due to redundancy with serine hydroxymethyltransferase. Although not always essential, the loss of several folate metabolic enzymes results in attenuation or loss of virulence in animal models, and a null DHFR-TS mutant has been used to induce protective immunity. The folate metabolic pathway provides numerous opportunities for targeted chemotherapy, with strong potential for 'repurposing' of compounds developed originally for treatment of human cancers or other infectious agents.

  19. [Molecular genetic studies of mitochondrial ornithine transporter deficiency (HHH syndrome)].

    PubMed

    Tsujino, S; Miyamoto, T; Kanazawa, N

    2001-11-01

    Mitochondrial ornithine transporter deficiency has been called HHH syndrome, because this disorder is characterized by three biochemical abnormalities; hyperornithinemia, hyperammonemia, and homocitrullinuria, and presents with various neurological symptoms; mental retardation, spastic paraparesis with pyramidal signs, cerebellar ataxia and episodic disturbance of consciousness or coma due to hyperammonemia. We identified four mutations in the mitochondrial ornithine transporter gene (ORNT1) of Japanese patients with HHH syndrome. These include a nonsense mutation (R179X), associated with exon skipping, missense mutations (G27E, P126R), and an insertion of AAC between codons 228 and 229, leading to an insertion of amino acid Asn. Especially, R179X was detected 4 of 7 Japanese patients (8 of 14 alleles), implying that this is a common mutation in Japanese population.

  20. Zebrafish as a model for monocarboxyl transporter 8-deficiency.

    PubMed

    Vatine, Gad David; Zada, David; Lerer-Goldshtein, Tali; Tovin, Adi; Malkinson, Guy; Yaniv, Karina; Appelbaum, Lior

    2013-01-04

    Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor retardation characterized by neurological impairment and abnormal thyroid hormone (TH) levels. Mutations in the TH transporter, monocarboxylate transporter 8 (MCT8), are associated with AHDS. MCT8 knock-out mice exhibit impaired TH levels; however, they lack neurological defects. Here, the zebrafish mct8 gene and promoter were isolated, and mct8 promoter-driven transgenic lines were used to show that, similar to humans, mct8 is primarily expressed in the nervous and vascular systems. Morpholino-based knockdown and rescue experiments revealed that MCT8 is strictly required for neural development in the brain and spinal cord. This study shows that MCT8 is a crucial regulator during embryonic development and establishes the first vertebrate model for MCT8 deficiency that exhibits a neurological phenotype.

  1. Rice folate enhancement through metabolic engineering has an impact on rice seed metabolism, but does not affect the expression of the endogenous folate biosynthesis genes.

    PubMed

    Blancquaert, Dieter; Van Daele, Jeroen; Storozhenko, Sergei; Stove, Christophe; Lambert, Willy; Van Der Straeten, Dominique

    2013-11-01

    Folates are key-players in one-carbon metabolism in all organisms. However, only micro-organisms and plants are able to synthesize folates de novo and humans rely entirely on their diet as a sole folate source. As a consequence, folate deficiency is a global problem. Although different strategies are currently implemented to fight folate deficiency, up until now, all of them have their own drawbacks. As an alternative and complementary means to those classical strategies, folate biofortification of rice by metabolic engineering was successfully achieved a couple of years ago. To gain more insight into folate biosynthesis regulation and the effect of folate enhancement on general rice seed metabolism, a transcriptomic study was conducted in developing transgenic rice seeds, overexpressing 2 genes of the folate biosynthetic pathway. Upon folate enhancement, the expression of 235 genes was significantly altered. Here, we show that rice folate biofortification has an important effect on folate dependent, seed developmental and plant stress response/defense processes, but does not affect the expression of the endogenous folate biosynthesis genes.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  3. In vitamin B12 deficiency, higher serum folate is assoicated with increased total homocysteine (tHcy) and methlmalonic acid (MMA) concentrations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In a recent study of older participants (age >/= 60 y) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B-12 status was associated with higher prevalence of cognitive impairment and anemia than other combina...

  4. Thiamine transporter-2 deficiency: outcome and treatment monitoring

    PubMed Central

    2014-01-01

    Background The clinical characteristics distinguishing treatable thiamine transporter-2 deficiency (ThTR2) due to SLC19A3 genetic defects from the other devastating causes of Leigh syndrome are sparse. Methods We report the clinical follow-up after thiamine and biotin supplementation in four children with ThTR2 deficiency presenting with Leigh and biotin-thiamine-responsive basal ganglia disease phenotypes. We established whole-blood thiamine reference values in 106 non-neurological affected children and monitored thiamine levels in SLC19A3 patients after the initiation of treatment. We compared our results with those of 69 patients with ThTR2 deficiency after a review of the literature. Results At diagnosis, the patients were aged 1 month to 17 years, and all of them showed signs of acute encephalopathy, generalized dystonia, and brain lesions affecting the dorsal striatum and medial thalami. One patient died of septicemia, while the remaining patients evidenced clinical and radiological improvements shortly after the initiation of thiamine. Upon follow-up, the patients received a combination of thiamine (10–40 mg/kg/day) and biotin (1–2 mg/kg/day) and remained stable with residual dystonia and speech difficulties. After establishing reference values for the different age groups, whole-blood thiamine quantification was a useful method for treatment monitoring. Conclusions ThTR2 deficiency is a reversible cause of acute dystonia and Leigh encephalopathy in the pediatric years. Brain lesions affecting the dorsal striatum and medial thalami may be useful in the differential diagnosis of other causes of Leigh syndrome. Further studies are needed to validate the therapeutic doses of thiamine and how to monitor them in these patients. PMID:24957181

  5. Folate status and neural tube defects.

    PubMed

    Molloy, A M; Mills, J L; Kirke, P N; Weir, D G; Scott, J M

    1999-01-01

    Periconceptional folic acid supplementation prevents approximately 70% of neural tube defects (NTDs). While most women carrying affected fetuses do not have deficient blood folate levels, the risk of having an NTD affected child is inversely correlated with pregnancy red cell folate levels. Current research is focused on the discovery of genetic abnormalities in folate related enzymes which might explain the role of folate in NTD prevention. The first candidate gene to emerge was the C677T variant of 5,10-methylenetetrahydrofolate reductase. Normal subjects who are homozygous for the mutation (TT) have red cell folate status some 20% lower than expected. It is now established that the prevalence of the TT genotype is significantly higher among spina bifida cases and their parents. Nevertheless, our studies show that the variant does not account for the reduced blood folate levels in many NTD affected mothers. We conclude that low maternal folate status may in itself be the most important risk factor for NTDs and that food fortification may be the only population strategy of benefit in the effort to eliminate NTDs.

  6. Natural variation of folate content and composition in spinach (Spinacia oleracea) germplasm.

    PubMed

    Shohag, M J I; Wei, Yan-yan; Yu, Ning; Zhang, Jie; Wang, Kai; Patring, Johan; He, Zhen-li; Yang, Xiao-e

    2011-12-14

    Breeding to increase folate levels in edible parts of plants, termed folate biofortification, is an economical approach to fight against folate deficiency in humans, especially in the developing world. Germplasm with elevated folates are a useful genetic source for both breeding and direct use. Spinach is one of the well-know vegetables that contains a relatively high amount of folate. Currently, little is known about how much folate, and their composition varies in different spinach accessions. The aim of this study was to investigate natural variation in the folate content and composition of spinach genotypes grown under controlled environmental conditions. The folate content and composition in 67 spinach accessions were collected from the United States Department of Agriculture (USDA) and Asian Vegetable Research and Development Center (AVRDC) germplasm collections according to their origin, grown under control conditions to screen for natural diversity. Folates were extracted by a monoenzyme treatment and analyzed by a validated liquid chromatography (LC) method. The total folate content ranged from 54.1 to 173.2 μg/100 g of fresh weight, with 3.2-fold variation, and was accession-dependent. Four spinach accessions (PI 499372, NSL 6095, PI 261787, and TOT7337-B) have been identified as enriched folate content over 150 μg/100 g of fresh weight. The folate forms found were H(4)-folate, 5-CH(3)-H(4)-folate, and 5-HCO-H(4)-folate, and 10-CHO-folic acid also varied among different accessions and was responsible for variation in the total folate content. The major folate vitamer was represented by 5-CH(3)-H(4)-folate, which on average accounted for up to 52% of the total folate pool. The large variation in the total folate content and composition in diverse spinach accessions demonstrates the great genetic potential of diverse genotypes to be exploited by plant breeders.

  7. Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

    PubMed Central

    Li, Chao; Ni, Juan; Liu, Yao-Xian; Wang, Han; Liang, Zi-Qing; Wang, Xu

    2017-01-01

    Background/Aims Folic acid (FA) is a core micronutrient involved in DNA synthesis/methylation, and the metabolism of FA is responsible for genomic stability. MicroRNAs may affect gene expression during folate metabolism when cellular homeostasis is changed. This study aimed to reveal the relationship between FA deficiency and the expression of miR-22-p/miR-149-5p and the targeted regulation of miR-22-3p/miR-149-5p on the key folate metabolic gene Methylenetetrahydrofolate reductase (MTHFR). Methods Normal (HL-7702 cells) and cancerous (QGY-7703 cells) human hepatocytes were intervened in modified RPMI 1640 with FA deficiency for 21 days. The interaction between MTHFR and the tested miRNAs was verified by Dual-Luciferase Reporter Assays. The changes in the expression of miR-22-3p/miR-149-5p in response to FA deficiency were detected by Poly (A) Tailing RT-qPCR, and the expression of MTHFR at both the transcriptional and translational levels was determined by RT-qPCR and Western blotting, respectively. Result MiR-22-3p/miR-149-5p directly targeted the 3’UTR sequence of the MTHFR gene. FA deficiency led to an upregulation of miR-22-3p/miR-149-5p expression in QGY-7703/HL-7702 cells, while the transcription of MTHFR was decreased in QGY-7703 cells but elevated in HL-7702 cells. Western blotting showed that FA deficiency resulted in a decline of the MTHFR protein in QGY-7703 cells, whereas in HL-7702 cells, the MTHFR protein level remained constant. Conclusion The results suggested that miR-22-3p/miR-149-5p exert different post-transcriptional effects on MTHFR under conditions of FA deficiency in normal and cancerous human hepatocytes. The results also implied that miR-22-3p/miR-149-5p might exert anticancer effects in cases of long-term FA deficiency. PMID:28045918

  8. Folate and homocysteine levels in pregnancy.

    PubMed

    Megahed, M A; Taher, I M

    2004-01-01

    This study aims to determine serum folate and plasma homocysteine levels in healthy pregnant women following a live birth and compare them with healthy non-pregnant women. Fifty healthy gravid multiparous women are included in the study and 25 normal non-pregnant female subjects act as controls (group I). The pregnant women are divided into two groups according to interpregnancy interval: group II (six months or less); group III (18-24 months). Venous blood samples are analysed for red blood cell folate and homocysteine, vitamin B12, serum folate and albumin, and serum aminotransferases (ALT and AST). There was a significant decrease in red cell folate and serum folate in group II compared to the control group (P<0.001). Serum vitamin B12 showed no significant difference. Plasma homocysteine and serum albumin showed significant decreases in both groups II and III compared to the control group. (P<0.001) There was significant positive correlation between homocysteine and serum albumin in the three studied groups. (r=0.42, P<0.001; r=0.45, P<0.001; r=0.51, P<0.001, respectively). There was significant negative correlation between red cell folate and homocysteine in the three studied groups. (r=-0.48, P<0.001; r=-0.53, P<0.001; r=-0.49, P<0.001, respectively). Two cases in group II showed signs of intrauterine growth retardation. The results suggest that pregnant females with short interpregnancy intervals are more likely to develop folate deficiency. Educational strategies are required to increase folate awareness among women to promote the benefits of folic acid supplementation. Mandatory folate fortification of foods should be defined and monitored.

  9. Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency.

    PubMed

    Kobayashi, Yu; Tohyama, Jun; Akiyama, Tomoyuki; Magara, Shinichi; Kawashima, Hideshi; Akasaka, Noriyuki; Nakashima, Mitsuko; Saitsu, Hirotomo; Matsumoto, Naomichi

    2017-03-01

    Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy. Nerve conduction studies revealed both axonal degeneration and demyelinating features. A diagnosis of cerebral folate deficiency was confirmed by a homozygous c.466T>G (p.W156G) mutation in FOLR1, coupled with extremely low cerebrospinal fluid levels of 5-methyltetrahydrofolate. Her symptoms, neuroradiological findings, and polyneuropathy were alleviated by oral folinic acid treatment in conjunction with intravenous and intramuscular administration therapy. Our patient shows that folinic acid therapy can ameliorate the clinical symptoms, white matter disturbances, cortical insults, and peripheral neuropathy of cerebral folate deficiency caused by FOLR1 mutation. It is important to recognize these clinical symptoms and make a precise diagnosis early on, because cerebral folate deficiency is treatable.

  10. Consequences of monocarboxylate transporter 8 deficiency for renal transport and metabolism of thyroid hormones in mice.

    PubMed

    Trajkovic-Arsic, Marija; Visser, Theo J; Darras, Veerle M; Friesema, Edith C H; Schlott, Bernhard; Mittag, Jens; Bauer, Karl; Heuer, Heike

    2010-02-01

    Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by high-serum T(3) and low-serum T(4) levels is also found in mice mutants deficient in MCT8 although the cause of these abnormalities is still unknown. Here we describe the consequences of MCT8 deficiency for renal thyroid hormone transport, metabolism, and function by studying MCT8 null mice and wild-type littermates. Whereas serum and urinary parameters do not indicate a strongly altered renal function, a pronounced induction of iodothyronine deiodinase type 1 expression together with increased renal T(3) and T(4) content point to a general hyperthyroid state of the kidneys in the absence of MCT8. Surprisingly, accumulation of peripherally injected T(4) and T(3) into the kidneys was found to be enhanced in the absence of MCT8, indicating that MCT8 deficiency either directly interferes with the renal efflux of thyroid hormones or activates indirectly other renal thyroid hormone transporters that preferentially mediate the renal uptake of thyroid hormones. Our findings indicate that the enhanced uptake and accumulation of T(4) in the kidneys of MCT8 null mice together with the increased renal conversion of T(4) into T(3) by increased renal deiodinase type 1 activities contributes to the generation of the low-serum T(4) and the increase in circulating T(3) levels, a hallmark of MCT8 deficiency.

  11. A Dual-Targeting Octaguanidine-Doxorubicin Conjugate Transporter for Inducing Caspase-Mediated Apoptosis on Folate-Expressing Cancer Cells.

    PubMed

    Nair, Jyothi B; Joseph, Manu M; Mohapatra, Saswat; Safeera, M; Ghosh, Surajit; Sreelekha, T T; Maiti, Kaustabh Kumar

    2016-04-05

    An efficient synthetic framework was assembled (G8-FKE-FA-Dox), consisting of a lysosome-targeting octaguanidine molecular transporter with a cathepsin B (cath B)-specific peptide substrate, folic acid, and the potent chemotherapeutic drug doxorubicin (Dox). Because the folate receptor (FR) and cath B are overexpressed in malignant cells, this transporter conjugate successfully executed lysosome-mediated transport of Dox to FR-positive tumor cells, illustrating this framework as an excellent targeted drug delivery system (TDDS). G8-FKE-FA-Dox was shown to exhibit selective toxicity toward FR-overexpressing cancer cells, with an IC50 value superior to that of the USFDA-approved Lipodox(TM) and proportional to that of free Dox via selective induction of apoptosis by the activation of caspases 8, 9, and 3. This TDDS was observed to be nontoxic to red blood cells and lymphocytes at neutral pH. Furthermore the tumor-targeting dissemination pattern of this system was revealed by monitoring the in vivo biodistribution of the carrier (G8-FKE-FA-FL) in normal and FR-overexpressing tumor-bearing mice.

  12. 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.

  13. Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.

    PubMed

    Kishimoto, Kenji; Kobayashi, Ryoji; Sano, Hirozumi; Suzuki, Daisuke; Maruoka, Hayato; Yasuda, Kazue; Chida, Natsuko; Yamada, Masafumi; Kobayashi, Kunihiko

    2014-07-01

    Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency.

  14. Folate and MMA predict cognitive impairment in elderly stroke survivors: A cross sectional study.

    PubMed

    Pascoe, Michaela C; Linden, Thomas

    2016-09-30

    Elderly stroke survivors are at risk of malnutrition and long-term cognitive impairment. Vitamin B-related metabolites, folate and methylmalonic acid, have been implicated in cognitive function. We conducted a study exploring the relationship between blood folate, methylmalonic acid and post-stroke cognitive impairment. This is a cross sectional study of elderly Swedish patients (n=149) 20 months post-stroke, assessed using the Mini Mental State Examination, serum blood levels of methylmalonic acid and red blood cell levels of folate. Linear modeling indicated that low levels of blood folate and elevated methylmalonic acid significantly contributed to cognitive impairment in stroke survivors. Half of the stroke survivors were shown to have folate deficiency at 20 months after stroke. Folate deficiency is common long term after stroke and both low folate and elevated methylmalonic acid appear to be associated with long term cognitive impairment, in elderly Swedish stroke survivors.

  15. The transport of indole-3-acetic Acid in boron- and calcium-deficient sunflower hypocotyl segments.

    PubMed

    Tang, P M; Dela Fuente, R K

    1986-06-01

    Transfer of sunflower (Helianthus annuus L. cv Russian Mammoth) seedlings from complete nutrient solution to solutions deficient in either boron or calcium resulted in a steady decline in the rate of auxin transport, compared to seedlings that remained in the complete solution. In seedlings transferred to solutions deficient in both B and Ca, the decline in auxin transport was greater than seedlings deficient in only one element. The transfer of B- or Ca-deficient seedlings back to the complete solution prevented further decline in auxin transport, but auxin transport did not increase to the same level as seedlings maintained in complete solution. The significant reduction in auxin transport during the early stages of B or Ca deficiency was not related to (a) reduced growth rate of the hypocotyl, (b) increased acropetal movement of auxin, or (c) lack of respiratory substrates in the hypocotyl. In addition, no difference was found in the water-extractable total and ionic Ca in B-deficient and control nondeficient hypocotyls, indicating a direct effect of B on auxin transport, rather than indirectly by affecting Ca absorption. The rate of auxin transport in hypocotyls deficient in either B or Ca, was inversely correlated with K(+) leakage and rate of respiration. The data presented strongly support the view that there are separate sites for B and Ca in the basipetal transport of the plant hormone indoleacetic acid.

  16. Hepatic folate metabolism in the chronic alcoholic monkey

    SciTech Connect

    Tamura, T.; Romero, J.J.; Watson, J.E.; Gong, E.J.; Halsted, C.H.

    1981-05-01

    To assess the role of altered hepatic folate metabolism in the pathogenesis of the folate deficiency of chronic alcoholism, the hepatic metabolism of a tracer dose of /sup 3/H-PteGlu was compared in monkeys given 50% of energy as ethanol for 2 years and in control monkeys. Long-term ethanol feeding resulted in mild hepatic injury, with a significant decrease in hepatic folate levels. Chromatographic studies of liver biopsies obtained after the tracer dose indicated that the processes of reduction, methylation, and formylation of reduced folate and the synthesis of polyglutamyl folates were not affected by long-term ethanol feeding. Hepatic tritium levels were significantly decreased in the ethanol-fed group. These studies suggest that the decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decreased ability to retain folates in the liver, whereas reduction and further metabolism of folates is not affected.

  17. Homogeneous assay for whole blood folate using photon upconversion.

    PubMed

    Arppe, Riikka; Mattsson, Leena; Korpi, Krista; Blom, Sami; Wang, Qi; Riuttamäki, Terhi; Soukka, Tero

    2015-02-03

    Red blood cell folate is measured for folate deficiency diagnosis, because it reflects the long-term folate level in tissues, whereas serum folate only represents the dietary intake. Direct homogeneous assay from whole blood would be ideal but conventional fluorescence techniques in blood suffer from high background and strong absorption of light at ultraviolet and visible wavelengths. In this study, a new photon upconversion-based homogeneous assay for whole blood folate is introduced based on resonance energy transfer from upconverting nanophosphor donor coated with folate binding protein to a near-infrared fluorescent acceptor dye conjugated to folate analogue. The sensitized acceptor emission is measured at 740 nm upon 980 nm excitation. Thus, optically transparent wavelengths are utilized for both donor excitation and sensitized acceptor emission to minimize the sample absorption, and anti-Stokes detection completely eliminates the Stokes-shifted autofluorescence. The IC50 value of the assay was 6.0 nM and the limit of detection (LOD) was 1 nM. The measurable concentration range was 2 orders of magnitude between 1.0-100 nM, corresponding to 40-4000 nM folate in the whole blood sample. Recoveries of added folic acid were 112%-114%. A good correlation was found when compared to a competitive heterogeneous assay based on the DELFIA-technology. The introduced assay provides a simple and fast method for whole blood folate measurement.

  18. [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.

  19. Folate Deficiency Triggered Apoptosis of Synoviocytes: Role of Overproduction of Reactive Oxygen Species Generated via NADPH Oxidase/Mitochondrial Complex II and Calcium Perturbation.

    PubMed

    Hsu, Hung-Chih; Chang, Wen-Ming; Wu, Jin-Yi; Huang, Chin-Chin; Lu, Fung-Jou; Chuang, Yi-Wen; Chang, Pey-Jium; Chen, Kai-Hua; Hong, Chang-Zern; Yeh, Rang-Hui; Liu, Tsan-Zon; Chen, Ching-Hsein

    2016-01-01

    Despite a plethora of literature has documented that osteoarthritis (OA) is veritably associated with oxidative stress-mediated chondrocyte death and matrix degradation, yet the possible involvement of synoviocyte abnormality as causative factor of OA has not been thoroughly investigated. For this reason, we conduct the current studies to insight into how synoviocytes could respond to an episode of folate-deprived (FD) condition. First, when HIG-82 synoviocytes were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature mediated through FD-evoked overproduction of reactive oxygen species (ROS) and drastically released of cytosolic calcium (Ca2+) concentrations. Next, we uncovered that FD-evoked ROS overproduction could only be strongly suppressed by either mitochondrial complex II inhibitors (TTFA and carboxin) or NADPH oxidase (NOX) inhibitors (AEBSF and apocynin), but not by mitochondrial complex I inhibitor (rotenone) and mitochondrial complex III inhibitor (antimycin A). Interestingly, this selective inhibition of FD-evoked ROS by mitochondrial complex II and NOX inhibitors was found to correlate excellently with the suppression of cytosolic Ca2+ release and reduced the magnitude of the apoptotic TUNEL-positive cells. Taken together, we present the first evidence here that FD-triggered ROS overproduction in synoviocytes is originated from mitochondrial complex II and NOX. Both elevated ROS in tandem with cytosolic Ca2+ overload serve as final arbitrators for apoptotic lethality of synoviocytes cultivated under FD condition. Thus, folate supplementation may be beneficial to patients with OA.

  20. Photoaffinity analogues of methotrexate as folate antagonist binding probes. 2. Transport studies, photoaffinity labeling, and identification of the membrane carrier protein for methotrexate from murine L1210 cells

    SciTech Connect

    Price, E.M.; Freisheim, J.H.

    1987-07-28

    A membrane-derived component of the methotrexate/one-carbon-reduced folate transport system in murine L1210 cells has been identified by using a photoaffinity analogue of methotrexate. The compound, a radioiodinated 4-azidosalicylyl derivative of the lysine analogue of methotrexate, is transported into murine L1210 cells in a temperature-dependent, sulfhydryl reagent inhibitable manner with a K/sub t/ of 506 +/- 79 nM and a V/sub max/ of 17.9 +/- 4.2 pmol min/sup -1/ (mg of total cellular protein)/sup -1/. Uptake of the iodinated compound at 200 nM is inhibited by low amounts of methotrexate. The parent compounds of the iodinated photoprobe inhibit (/sup 3/H)methotrexate uptake, with the uniodinated 4-azidosalicylyl derivative exhibiting a K/sub i/ of 66 +/- 21 nM. UV irradiation, at 4 /sup 0/C, of a cell suspension that had been incubated with the probe results in the covalent modification of a 46K-48K protein. This can be demonstrated when the plasma membranes from the labeled cells are analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Labeling of this protein occurs half-maximally at a reagent concentration that correlates with the K/sub t/ for transport of the iodinated compound. Protection against labeling of this protein by increasing amounts of methotrexate parallels the concentration dependence of inhibition of photoprobe uptake by methotrexate. Evidence that, in the absence of irradiation and at 37/sup 0/C, the iodinated probe is actually internalized is demonstrated by the labeling of two soluble proteins (M/sub r/ 38K and 21K) derived from the cell homogenate supernatant.

  1. 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.

  2. A single amino acid difference within the folate transporter encoded by the murine RFC-1 gene selectively alters its interaction with folate analogues. Implications for intrinsic antifolate resistance and directional orientation of the transporter within the plasma membrane of tumor cells.

    PubMed

    Roy, K; Tolner, B; Chiao, J H; Sirotnak, F M

    1998-01-30

    The apparent Km, but not Vmax, for influx of methotrexate (MTX) mediated through the plasma membrane of S180 cells by the one-carbon, reduced folate transporter as well as the KD for binding to the transporter were 4-fold higher than in L1210 cells correlating with the greater intrinsic resistance of the former to this folate analogue. In contrast, no difference was observed between each cell type with regard to efflux of [3H]MTX mediated by this same transporter in ATP-depleted cells. The difference in influx Km in the case of this 10-methyl substituted N1O analogue of folic acid was not seen with more effective permeants, such as the unsubstituted N1O aminopterin or C1O analogues. Thus, values for influx Km for aminopterin, which were 1-1.2 microM in each cell type, increased as a result of substitution at N1O (MTX) 3-fold in L1210 cells but 12-fold in S180 cells. Nucleotide sequencing of reverse transcriptase-polymerase chain reaction-generated cDNA and of polymerase chain reaction-generated genomic DNA identified a single nucleotide difference between each cell type at +890 within exon 3 of the RFC-1 gene. This was in the form of a G (L1210 cells) to A (S180 cells) transition. Codon 297, the site of this transition, encodes either Ser or Asn in L1210 or S180 cells, respectively, which is located between the seventh and eight membrane-spanning helices. This amino acid difference had no effect on the electrophoretic mobility or amount of the transporter in each cell type that was shown by Western blotting with anti-RFC-1 peptide antibodies to migrate as 46 kDa in each case. Proof that this nucleotide difference alone accounted for the alteration in influx between each cell type was obtained by S180 RFC-1 cDNA versus L1210 RFC-1 cDNA transfection of an L1210 cell variant with undetectable MTX influx and RFC-1 gene expression. In this case, the higher Km for MTX influx associated with S180 cells was duplicated only in the S180 RFC-1 transfectants. These results

  3. Clinical utility of folate-containing oral contraceptives

    PubMed Central

    Lassi, Zohra S; Bhutta, Zulfiqar A

    2012-01-01

    Folate is a generic term for a water-soluble B-complex vitamin which plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth. Pregnant and lactating women are at increased risk of folic acid deficiency because generally their dietary folate is insufficient to meet their physiological requirements and the metabolic demands of the growing fetus. The evidence pertaining to the reduction of the risk of neural tube defects (NTDs) due to folate is so compelling that supplementation with 400 μg of folic acid to all women trying to conceive until 12 weeks of pregnancy has been recommended by every relevant authority. A recent Cochrane review has also found protective effects of folate supplementation in occurrence and reoccurrence of NTDs. Despite food fortification and targeted public health campaigns promoting folic acid supplementation, 4,300,000 new cases occur each year worldwide resulting in an estimated 41,000 deaths and 2.3 million disability-adjusted life years (DALYS). This article will review the burden and risk factors of NTDS, and the role of folate in preventing NTDs. It will also describe different modes of supplementing folate and the newer evidence of the effectiveness of adding folate in oral contraceptives for raising serum and red blood cell folate levels. PMID:22570577

  4. Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet

    SciTech Connect

    Tryndyak, Volodymyr P.; Latendresse, John R.; Montgomery, Beverly; Ross, Sharon A.; Beland, Frederick A.; Rusyn, Ivan; Pogribny, Igor P.

    2012-07-01

    MicroRNAs (miRNAs) are a class of small, conserved, tissue-specific regulatory non-coding RNAs that modulate a variety of biological processes and play a fundamental role in the pathogenesis of major human diseases, including nonalcoholic fatty liver disease (NAFLD). However, the association between inter-individual differences in susceptibility to NAFLD and altered miRNA expression is largely unknown. In view of this, the goals of the present study were (i) to determine whether or not individual differences in the extent of NAFLD-induced liver injury are associated with altered miRNA expression, and (ii) assess if circulating blood miRNAs may be used as potential biomarkers for the noninvasive evaluation of the severity of NAFLD. A panel of seven genetically diverse strains of inbred male mice (A/J, C57BL/6J, C3H/HeJ, 129S/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) were fed a choline- and folate-deficient (CFD) diet for 12 weeks. This diet induced liver injury in all mouse strains; however, the extent of NAFLD-associated pathomorphological changes in the livers was strain-specific, with A/J, C57BL/6J, and C3H/HeJ mice being the least sensitive and WSB/EiJ mice being the most sensitive. The morphological changes in the livers were accompanied by differences in the levels of hepatic and plasma miRNAs. The levels of circulating miR-34a, miR-122, miR-181a, miR-192, and miR-200b miRNAs were significantly correlated with a severity of NAFLD-specific liver pathomorphological features, with the strongest correlation occurring with miR-34a. These observations suggest that the plasma levels of miRNAs may be used as biomarkers for noninvasive monitoring the extent of NAFLD-associated liver injury and susceptibility to NAFLD. -- Highlights: ► Choline- and folate-deficiency induces a strain-specific fatty liver injury in mice. ► The extent of liver pathology was accompanied by the changes in microRNA expression. ► The levels of circulating microRNAs mirror the magnitude of

  5. Iatrogenic nutritional deficiencies.

    PubMed

    Young, R C; Blass, J P

    1982-01-01

    This article catalogs the nutritional deficiencies inadvertently introduced by certain treatment regimens. Specifically, the iatrogenic effects on nutrition of surgery, hemodialysis, irradiation, and drugs are reviewed. Nutritional problems are particularly frequent consequences of surgery on the gastrointestinal tract. Gastric surgery can lead to deficiencies of vitamin B12, folate, iron, and thiamine, as well as to metabolic bone disease. The benefits of small bowel bypass are limited by the potentially severe nutritional consequences of this procedure. Following bypass surgery, patients should be monitored for signs of possible nutritional probems such as weight loss, neuropathy, cardiac arrhythmias, loss of stamina, or changes in mental status. Minimal laboratory tests should include hematologic evaluation, B12, folate, iron, albumin, calcium, phosphorus, alkaline phosphatase, transaminases, sodium, potassium, chloride, and carbon dioxide levels. Roentgenologic examination of the bone should also be obtained. Loss of bone substance is a major consequence of many forms of treatment, and dietary supplementation with calcium is warranted. Patients undergoing hemodialysis have shown carnitine and choline deficiencies, potassium depletion, and hypovitaminosis, as well as osteomalacia. Chronic drug use may alter intake, synthesis, absorption, transport, storage, metabolism, or excretion of nutrients. Patients vary markedly in the metabolic effects of drugs, and recommendations for nutrition must be related to age, sex, reproductive status, and genetic endowment. Moreover, the illness being treated can itself alter nutritional requirements and the effect of the treatment on nutrient status. The changes in nutritional levels induced by use of estrogen-containing oral contraceptives (OCs) are obscure; however, the effects on folate matabolism appear to be of less clinical import than previously suggested. Reduction in pyridoxine and serum vitamin B12 levels has been

  6. Potential role of folate in pre-eclampsia.

    PubMed

    Singh, Mansi Dass; Thomas, Philip; Owens, Julie; Hague, William; Fenech, Michael

    2015-10-01

    Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review was to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia.

  7. Mathematical Modelling of Folate Metabolism

    PubMed Central

    Panetta, John C.; Paugh, Steven W.

    2013-01-01

    Folate metabolism is a complex biological process that is influenced by many variables including transporters, co-factors and enzymes. Mathematical models provide a useful tool to evaluate this complex system and to elucidate hypotheses that would be otherwise untenable to test in vitro or in vivo. Forty years of model development and refinement along with enhancements in technology have led to systematic improvement in our biological understanding from these models. However, increased complexity does not always lead to increased understanding, and a balanced approach to modelling the system is often advantageous. This approach should address questions about sensitivity of the model to variation and incorporate genomic data. The folate model is a useful platform for investigating the effects of antifolates on the folate pathway. The utility of the model is demonstrated through interrogation of drug resistance, drug-drug interactions, drug selectivity, and drug doses and schedules. Mathematics can be used to create models with the ability to design and improve rationale therapeutic interventions. PMID:23703958

  8. Update on cobalamin, folate, and homocysteine.

    PubMed

    Carmel, Ralph; Green, Ralph; Rosenblatt, David S; Watkins, David

    2003-01-01

    Three topics affecting cobalamin, folate, and homocysteine that have generated interest, activity, and advances in recent years are discussed. These are: (I). the application of an expanded variety of tools to the diagnosis of cobalamin deficiency, and how these affect and are affected by our current understanding of deficiency; (II). the nature of the interaction between homocysteine and vascular disease, and how the relationship is affected by vitamins; and (III). the improved understanding of relevant genetic disorders and common genetic polymorphisms, and how these interact with environmental influences. The diagnostic approach to cobalamin deficiency now allows better diagnosis of difficult and atypical cases and more confident rejection of the diagnosis when deficiency does not exist. However, the process has also become a complex and sometimes vexing undertaking. Part of the difficulty derives from the lack of a diagnostic gold standard among the many available tests, part from the overwhelming numerical preponderance of patients with subclinical deficiency (in which isolated biochemical findings exist without clinical signs or symptoms) among the cobalamin deficiency states, and part from the decreased availability of reliable tests to identify the causes of a patient's cobalamin deficiency and thus a growing deemphasis of that important part of the diagnostic process. In Section I, Dr. Carmel discusses the tests, the diagnostic issues, and possible approaches to the clinical evaluation. It is suggested no single algorithm fits all cases, some of which require more biochemical proof than others, and that differentiating between subclinical and clinical deficiency, despite their overlap, may be a helpful and practical point of departure in the evaluation of patients encountered in clinical practice. The arguments for and against a suggested expansion of the cobalamin reference range are also weighed. The epidemiologic data suggest that homocysteine elevation

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

    PubMed Central

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

    2013-01-01

    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. PMID:23934049

  10. 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.

  11. Folate nutrition and blood-brain barrier dysfunction.

    PubMed

    Stover, Patrick J; Durga, Jane; Field, Martha S

    2017-04-01

    Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.

  12. Folate and neural tube defects: The role of supplements and food fortification

    PubMed Central

    Ami, Noam; Bernstein, Mark; Boucher, François; Rieder, Michael; Parker, Louise

    2016-01-01

    Periconceptional folic acid significantly reduces the risk of neural tube defects. It is difficult to achieve optimal levels of folate by diet alone, even with fortification of flour, especially because flour consumption in Canada is slightly decreasing. Intermittent concerns have been raised concerning possible deleterious effects of folate supplementation, including the masking of symptoms of vitamin B12 deficiency and an association with cancer, especially colorectal cancer. Both concerns have been disproved. The Canadian Paediatric Society endorses the following steps to enhance folate intake in women of child-bearing age: encouraging the consumption of folate-rich foods such as leafy vegetables, increasing the level of folate food fortification, taking a supplement containing folate and B12, and providing free folate supplementation to disadvantaged women of child-bearing age. These recommendations are consistent with those of the Society of Obstetricians and Gynaecologists of Canada. PMID:27398055

  13. Folate and neural tube defects: The role of supplements and food fortification.

    PubMed

    Ami, Noam; Bernstein, Mark; Boucher, François; Rieder, Michael; Parker, Louise

    2016-04-01

    Periconceptional folic acid significantly reduces the risk of neural tube defects. It is difficult to achieve optimal levels of folate by diet alone, even with fortification of flour, especially because flour consumption in Canada is slightly decreasing. Intermittent concerns have been raised concerning possible deleterious effects of folate supplementation, including the masking of symptoms of vitamin B12 deficiency and an association with cancer, especially colorectal cancer. Both concerns have been disproved. The Canadian Paediatric Society endorses the following steps to enhance folate intake in women of child-bearing age: encouraging the consumption of folate-rich foods such as leafy vegetables, increasing the level of folate food fortification, taking a supplement containing folate and B12, and providing free folate supplementation to disadvantaged women of child-bearing age. These recommendations are consistent with those of the Society of Obstetricians and Gynaecologists of Canada.

  14. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling, and folate uptake in human colonic epithelial cell lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell...

  15. [Folate, vitamin B12 and human health].

    PubMed

    Brito, Alex; Hertrampf, Eva; Olivares, Manuel; Gaitán, Diego; Sánchez, Hugo; Allen, Lindsay H; Uauy, Ricardo

    2012-11-01

    During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared functions and intertwined metabolic pathways that define the size of the "methyl donor" pool utilized in multiple metabolic pathways; these include DNA methylation and synthesis of nucleic acids. In Chile, folate deficiency is virtually nonexistent, while vitamin B12 deficiency affects approximately 8.5-51% depending on the cut-off value used to define deficiency. Folate is found naturally mainly in vegetables or added as folic acid to staple foods. Vitamin B12 in its natural form is present only in foods of animal origin, which is why deficit is more common among strict vegetarians and populations with a low intake of animal foods. Poor folate status in vulnerable women of childbearing age increases the risk of neural tube birth defects, so the critical time for the contribution of folic acid is several months before conception since neural tube closure occurs during the first weeks of life. The absorption of vitamin B12 from food is lower in older adults, who are considered to have higher risk of gastric mucosa atrophy, altered production of intrinsic factor and acid secretion. Deficiency of these vitamins is associated with hematological disorders. Vitamin B12 deficiency can also induce clinical and sub-clinical neurological and of other disorders. The purpose of this review is to provide an update on recent advances in the basic and applied knowledge of these vitamins relative to human health.

  16. Maternal bile acid transporter deficiency promotes neonatal demise

    PubMed Central

    Zhang, Yuanyuan; Li, Fei; Wang, Yao; Pitre, Aaron; Fang, Zhong-ze; Frank, Matthew W.; Calabrese, Christopher; Krausz, Kristopher W.; Neale, Geoffrey; Frase, Sharon; Vogel, Peter; Rock, Charles O.; Gonzalez, Frank J.; Schuetz, John D.

    2015-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition. PMID:26416771

  17. The role of folate metabolism in orofacial development and clefting.

    PubMed

    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

    2015-09-01

    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.

  18. Present and future of folate biofortification of crop plants.

    PubMed

    Blancquaert, Dieter; De Steur, Hans; Gellynck, Xavier; Van Der Straeten, Dominique

    2014-03-01

    Improving nutritional health is one of the major socio-economic challenges of the 21st century, especially with the continuously growing and ageing world population. Folate deficiency is an important and underestimated problem of micronutrient malnutrition affecting billions of people worldwide. More and more countries are adapting policies to fight folate deficiency, mostly by fortifying foods with folic acid. However, there is growing concern about this practice, calling for alternative or complementary strategies. In addition, fortification programmes are often inaccessible to remote and poor populations where folate deficiency is most prevalent. Enhancing folate content in staple crops by metabolic engineering is a promising, cost-effective strategy to eradicate folate malnutrition worldwide. Over the last decade, major progress has been made in this field. Nevertheless, engineering strategies have thus far been implemented on a handful of plant species only and need to be transferred to highly consumed staple crops to maximally reach target populations. Moreover, successful engineering strategies appear to be species-dependent, hence the need to adapt them in order to biofortify different staple crops with folate.

  19. Glucose Transporter Type 1 Deficiency Syndrome with Carbohydrate-Responsive Symptoms but without Epilepsy

    ERIC Educational Resources Information Center

    Koy, Anne; Assmann, Birgit; Klepper, Joerg; Mayatepek, Ertan

    2011-01-01

    Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female…

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

    PubMed

    Xue, J; Zempleni, J

    2013-11-01

    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 signalling 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 signalling.

  1. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing.

    PubMed

    Scaglione, Francesco; Panzavolta, Giscardo

    2014-05-01

    1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency.

  2. Parental vitamin deficiency affects the embryonic gene expression of immune-, lipid transport- and apolipoprotein genes

    PubMed Central

    Skjærven, Kaja H.; Jakt, Lars Martin; Dahl, John Arne; Espe, Marit; Aanes, Håvard; Hamre, Kristin; Fernandes, Jorge M. O.

    2016-01-01

    World Health Organization is concerned for parental vitamin deficiency and its effect on offspring health. This study examines the effect of a marginally dietary-induced parental one carbon (1-C) micronutrient deficiency on embryonic gene expression using zebrafish. Metabolic profiling revealed a reduced 1-C cycle efficiency in F0 generation. Parental deficiency reduced the fecundity and a total of 364 genes were differentially expressed in the F1 embryos. The upregulated genes (53%) in the deficient group were enriched in biological processes such as immune response and blood coagulation. Several genes encoding enzymes essential for the 1-C cycle and for lipid transport (especially apolipoproteins) were aberrantly expressed. We show that a parental diet deficient in micronutrients disturbs the expression in descendant embryos of genes associated with overall health, and result in inherited aberrations in the 1-C cycle and lipid metabolism. This emphasises the importance of parental micronutrient status for the health of the offspring. PMID:27731423

  3. Parental vitamin deficiency affects the embryonic gene expression of immune-, lipid transport- and apolipoprotein genes

    NASA Astrophysics Data System (ADS)

    Skjærven, Kaja H.; Jakt, Lars Martin; Dahl, John Arne; Espe, Marit; Aanes, Håvard; Hamre, Kristin; Fernandes, Jorge M. O.

    2016-10-01

    World Health Organization is concerned for parental vitamin deficiency and its effect on offspring health. This study examines the effect of a marginally dietary-induced parental one carbon (1-C) micronutrient deficiency on embryonic gene expression using zebrafish. Metabolic profiling revealed a reduced 1-C cycle efficiency in F0 generation. Parental deficiency reduced the fecundity and a total of 364 genes were differentially expressed in the F1 embryos. The upregulated genes (53%) in the deficient group were enriched in biological processes such as immune response and blood coagulation. Several genes encoding enzymes essential for the 1-C cycle and for lipid transport (especially apolipoproteins) were aberrantly expressed. We show that a parental diet deficient in micronutrients disturbs the expression in descendant embryos of genes associated with overall health, and result in inherited aberrations in the 1-C cycle and lipid metabolism. This emphasises the importance of parental micronutrient status for the health of the offspring.

  4. Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: B vitamins such as folate, vitamin B-6, and vitamin B-12 are coenzymes that are important for DNA integrity and stability. Deficiency in these B vitamins may promote tumor carcinogenesis. Objective: We prospectively evaluated plasma concentrations of folate, pyridoxal 5'-phosphate (PLP; ...

  5. Folate and vitamin B12 status in Latin America and the Caribbean: An update

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: The current magnitude of folate and vitamin B12 deficiency in Latin America and the Caribbean is uncertain. Objective: To summarize data on plasma or serum vitamin B12 and folate concentrations in Latin America and the Caribbean reported since 1990, a period that covers the era before an...

  6. Folate Augmentation of Treatment – Evaluation for Depression (FolATED): protocol of a randomised controlled trial

    PubMed Central

    Roberts, Seren Haf; Bedson, Emma; Hughes, Dyfrig; Lloyd, Keith; Moat, Stuart; Pirmohamed, Munir; Slegg, Gary; Tranter, Richard; Whitaker, Rhiannon; Wilkinson, Clare; Russell, Ian

    2007-01-01

    Background Clinical depression is common, debilitating and treatable; one in four people experience it during their lives. The majority of sufferers are treated in primary care and only half respond well to active treatment. Evidence suggests that folate may be a useful adjunct to antidepressant treatment: 1) patients with depression often have a functional folate deficiency; 2) the severity of such deficiency, indicated by elevated homocysteine, correlates with depression severity, 3) low folate is associated with poor antidepressant response, and 4) folate is required for the synthesis of neurotransmitters implicated in the pathogenesis and treatment of depression. Methods/Design The primary objective of this trial is to estimate the effect of folate augmentation in new or continuing treatment of depressive disorder in primary and secondary care. Secondary objectives are to evaluate the cost-effectiveness of folate augmentation of antidepressant treatment, investigate how the response to antidepressant treatment depends on genetic polymorphisms relevant to folate metabolism and antidepressant response, and explore whether baseline folate status can predict response to antidepressant treatment. Seven hundred and thirty patients will be recruited from North East Wales, North West Wales and Swansea. Patients with moderate to severe depression will be referred to the trial by their GP or Psychiatrist. If patients consent they will be assessed for eligibility and baseline measures will be undertaken. Blood samples will be taken to exclude patients with folate and B12 deficiency. Some of the blood taken will be used to measure homocysteine levels and for genetic analysis (with additional consent). Eligible participants will be randomised to receive 5 mg of folic acid or placebo. Patients with B12 deficiency or folate deficiency will be given appropriate treatment and will be monitored in the 'comprehensive cohort study'. Assessments will be at screening, randomisation

  7. Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet.

    PubMed

    Haberlandt, Edda; Karall, Daniela; Jud, Veronika; Baumgartner, Sara Sigl; Zotter, Sibylle; Rostasy, Kevin; Baumann, Matthias; Scholl-Buergi, Sabine

    2014-04-01

    This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient.

  8. Deficiencies of Serum Ferritin and Vitamin B12, but not Folate, are Common in Adolescent Girls Residing in a Slum in Delhi.

    PubMed

    Gupta Bansal, Priyanka; Singh Toteja, Gurudayal; Bhatia, Neena; Kishore Vikram, Naval; Siddhu, Anupa; Kumar Garg, Ashok; Kumar Roy, Ashok

    2015-01-01

    Anemia among adolescent girls is one of the major challenges faced by India. The present study was undertaken to assess the prevalence of anemia and status of other hematological parameters among adolescent girls (11 - 18 years) residing in an urban slum of Delhi. A total of 794 adolescent girls were recruited for the study. The prevalence of anemia was estimated using the cyanmethemoglobin method. Serum levels of ferritin, folic acid and vitamin B12 were estimated for anemic subjects. The prevalence of anemia was reported as 58.7 %, with 31.6 %, 25.7 % and 1.4 % of subjects being mild, moderate and severely anemic. Hemoglobin levels of subjects who had attained menarche were found to be significantly lower than those who had not attained menarche. The prevalence of serum ferritin, folic acid and vitamin B12 deficiency among those who were anemic was reported as 41.1 %, 5.0 % and 63.3 % respectively. A total of 23.5 % anemic subjects had concomitant micronutrient deficiencies of serum vitamin B12 and ferritin. The results indicate that supplemental iron and vitamin B12 may better address the burden of anemia in adolescent girls in Delhi.

  9. Dietary folate and APC mutations in sporadic colorectal cancer.

    PubMed

    de Vogel, Stefan; van Engeland, Manon; Lüchtenborg, Margreet; de Bruïne, Adriaan P; Roemen, Guido M J M; Lentjes, Marjolein H F M; Goldbohm, R Alexandra; van den Brandt, Piet A; de Goeij, Anton F P M; Weijenberg, Matty P

    2006-12-01

    Folate deficiency has been associated with colorectal cancer risk and may be involved in colorectal carcinogenesis through increased chromosome instability, gene mutations, and aberrant DNA methylation. Within the Netherlands Cohort Study on diet and cancer, we investigated the associations between dietary folate intake and colorectal cancer risk with (APC(+)) and without (APC(-)) truncating APC mutations, accounting for hMLH1 expression and K-ras mutations. In total, 528 cases and 4200 subcohort members were available for data analyses of the study cohort (n = 120,852) from a follow-up period between 2.3 and 7.3 y after baseline. Adjusted gender-specific incidence rate ratios (RR) over tertiles of folate intake were calculated in case-cohort analyses for colon and rectal cancer. Although relatively high folate intake was not associated with overall colorectal cancer risk, it reduced the risk of APC(-)colon tumors in men (RR 0.58, 95% CI 0.32-1.05, P(trend) = 0.06 for the highest vs. lowest tertile of folate intake). In contrast, it was positively associated with APC(+) colon tumors in men (highest vs. lowest tertile: RR 2.77, 95% CI 1.29-5.95, P(trend) = 0.008) and was even stronger when the lack of hMLH1 expression and K-ras mutations were excluded (RR 3.99, 95% CI 1.43-11.14, P(trend) = 0.007). Such positive associations were not observed among women; nor was folate intake associated with rectal cancer when APC mutation status was taken into account. Relatively high folate consumption reduced the risk of APC(-) colon tumors, but folate intake was positively associated with APC(+) colon tumors among men. These opposite results may indicate that folate enhances colorectal carcinogenesis through a distinct APC mutated pathway.

  10. Urinary folate excretion in chronic ethanol- and diet-treated rats

    SciTech Connect

    Collins, T.D.; McMartin, K.E.; Bairnsfather, L.

    1986-03-05

    Acute ethanol treatment of rats produces a marked increase in urinary folate excretion, which accumulates in correlation with the duration of ethanol treatment. In order to study the role of excess urinary folate excretion in the development of folate deficiency by chronic ethanol feeding, groups of male Sprague-Dawley rats were maintained for four months on one of the following liquid diets: ethanol, pair-fed control, ethanol minus folic acid, and pair-fed control minus folic acid. A fifth group was provided a control chow diet ad libitum. Blood ethanol levels were generally maintained between 80-150 mg/dl at various times of the day. Decrease in plasma and tissue folate levels occurred within four weeks in all liquid diet groups compared to chow rats and within two weeks for urinary folate levels. Greater effects were generally observed in both folate-deficient groups than in the control or ethanol group. Acute ethanol treatment of rats from the various diet groups produced increases in urinary folate excretion in all groups except the ethanol minus folic acid diet group. When the folate system of rats are compromised by dietary deprivation and/or chronic ethanol treatment, these results suggest that urinary folate excretion is greatly reduced as a conservation measure.

  11. Purine transport by malpighian tubules of pteridine-deficient eye color mutants of Drosophila melanogaster.

    PubMed

    Sullivan, D T; Bell, L A; Paton, D R; Sullivan, M C

    1979-06-01

    Uptakes of guanine into Malpighian tubules of wild-type Drosophila and the eye color mutants white (w), brown (bw), and pink-peach (pp) have been compared. Tubules for each of these mutants are unable to concentrate guanine intracellularly. The transport of xanthine and riboflavin is also deficient in w tubules. The transport of guanosine, adenine, hypoxanthine, and guanosine monophosphate is similar in wild-type and white Malpighian tubules. These data and other information about these mutants make it likely that these pteridine-deficient eye color mutants do not produce pigments because of the inability to transport a pteridine precursor. This view supports the hypothesis that mutants which lack both pteridine and ommochromes do so because precursors to both classes of pigments share a common transport system.

  12. Zinc transporter 7 deficiency affects lipid synthesis in adipocytes by inhibiting insulin-dependent Akt activity and glucose uptake

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice deficient for zinc transporter 7 (Znt7) are mildly zinc deficient, accompanied with low body weight gain and body fat accumulation. To investigate the underlying mechanism of Znt7 deficiency in body adiposity, we investigated fatty acid composition and insulin sensitivity in visceral (epididyma...

  13. No relation between folate and homocysteine levels and depression in early pregnant women.

    PubMed

    Watanabe, Hiroko; Suganuma, Nobuhiko; Hayashi, Ayako; Hirowatari, Yumiko; Hirowatari, Tsuneharu; Ohsawa, Masami

    2010-12-01

    The objective in this study was to evaluate the association between folate and homocysteine (Hcy) levels and depressive symptoms in early pregnancy. A cross-sectional study was conducted with 86 pregnant women in the first trimester. A Japanese version of the Center for Epidemiologic Studies Depression (CES-D) scale was used to screen for depression. Non-fasting blood samples were collected from the women to measure folate and Hcy levels. Fifty-three (61.6%) women scored at or above a clinical cut-off of 16, and were classified with depression. In logistic regression analyses, no significant associations were observed between the incidence of depression in the first trimester and elevated Hcy and deficiencies of serum folate, folate intake, vitamin B6 intake and vitamin B12 intake. Folate and Hcy concentrations, and folate consumption, may not be protective against depression in early pregnancy.

  14. Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect?

    PubMed

    Cecil, K M; Salomons, G S; Ball, W S; Wong, B; Chuck, G; Verhoeven, N M; Jakobs, C; DeGrauw, T J

    2001-03-01

    Recent reports highlight the utility of in vivo magnetic resonance spectroscopy (MRS) techniques to recognize creatine deficiency syndromes affecting the central nervous system (CNS). Reported cases demonstrate partial reversibility of neurologic symptoms upon restoration of CNS creatine levels with the administration of oral creatine. We describe a patient with a brain creatine deficiency syndrome detected by proton MRS that differs from published reports. Metabolic screening revealed elevated creatine in the serum and urine, with normal levels of guanidino acetic acid. Unlike the case with other reported creatine deficiency syndromes, treatment with oral creatine monohydrate demonstrated no observable increase in brain creatine with proton MRS and no improvement in clinical symptoms. In this study, we report a novel brain creatine deficiency syndrome most likely representing a creatine transporter defect.

  15. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency

    NASA Technical Reports Server (NTRS)

    Shannon, J. R.; Flattem, N. L.; Jordan, J.; Jacob, G.; Black, B. K.; Biaggioni, I.; Blakely, R. D.; Robertson, D.

    2000-01-01

    BACKGROUND: Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. METHODS: In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic norepinephrine spillover and clearance, and we sequenced the norepinephrine-transporter gene and evaluated its function. RESULTS: The patient had a high mean plasma norepinephrine concentration while standing, as compared with the mean (+/-SD) concentration in normal subjects (923 vs. 439+/-129 pg per milliliter [5.46 vs. 2.59+/-0.76 nmol per liter]), reduced systemic norepinephrine clearance (1.56 vs. 2.42+/-0.71 liters per minute), impairment in the increase in the plasma norepinephrine concentration after the administration of tyramine (12 vs. 56+/-63 pg per milliliter [0.07 vs. 0.33+/-0.37 pmol per liter]), and a disproportionate increase in the concentration of plasma norepinephrine relative to that of dihydroxyphenylglycol. Analysis of the norepinephrine-transporter gene revealed that the proband was heterozygous for a mutation in exon 9 (encoding a change from guanine to cytosine at position 237) that resulted in more than a 98 percent loss of function as compared with that of the wild-type gene. Impairment of synaptic norepinephrine clearance may result in a syndrome characterized by excessive sympathetic activation in response to physiologic stimuli. The mutant allele in the proband's family segregated with the postural heart rate and abnormal plasma catecholamine homeostasis. CONCLUSIONS: Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic

  16. Familial orthostatic tachycardia due to norepinephrine transporter deficiency

    NASA Technical Reports Server (NTRS)

    Robertson, D.; Flattem, N.; Tellioglu, T.; Carson, R.; Garland, E.; Shannon, J. R.; Jordan, J.; Jacob, G.; Blakely, R. D.; Biaggioni, I.

    2001-01-01

    Orthostatic intolerance (OI) or postural tachycardia syndrome (POTS) is a syndrome primarily affecting young females, and is characterized by lightheadedness, palpitations, fatigue, altered mentation, and syncope primarily occurring with upright posture and being relieved by lying down. There is typically tachycardia and raised plasma norepinephrine levels on upright posture, but little or no orthostatic hypotension. The pathophysiology of OI is believed to be very heterogeneous. Most studies of the syndrome have focused on abnormalities in norepinephrine release. Here the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to the pathophysiology in some patients with OI was tested. In a proband with significant orthostatic symptoms and tachycardia, disproportionately elevated plasma norepinephrine with standing, impaired systemic, and local clearance of infused tritiated norepinephrine, impaired tyramine responsiveness, and a dissociation between stimulated plasma norepinephrine and DHPG elevation were found. Studies of NET gene structure in the proband revealed a coding mutation that converts a highly conserved transmembrane domain Ala residue to Pro. Analysis of the protein produced by the mutant cDNA in transfected cells demonstrated greater than 98% reduction in activity relative to normal. NE, DHPG/NE, and heart rate correlated with the mutant allele in this family. CONCLUSION: These results represent the first identification of a specific genetic defect in OI and the first disease linked to a coding alteration in a Na+/Cl(-)-dependent neurotransmitter transporter. Identification of this mechanism may facilitate our understanding of genetic causes of OI and lead to the development of more effective therapeutic modalities.

  17. Aminoglycoside-resistant mutants of Pseudomonas aeruginosa deficient in cytochrome d, nitrite reductase, and aerobic transport.

    PubMed Central

    Bryan, L E; Kwan, S

    1981-01-01

    Two gentamicin-resistant mutants of Pseudomonas aeruginosa PAO 503 were selected after ethyl methane sulfonate mutagenesis. Mutant PAO 2403 had significantly increased resistance to aminoglycoside but not to other antibiotics. Mutant PAO 2402 showed a similar spectrum of resistance but of lower magnitude. Both mutants showed no detectable cytochrome d and had a high frequency of reversion to a fully wild-type phenotype. PAO 2403 had a marked decrease and PAO 2402 had a moderate decrease in nitrite reductase activity. Both mutants had reduced uptake of gentamicin and dihydrostreptomycin. Mutant PAO 2403 showed a general decrease in transport rate of cationic compounds, whereas mutant PAO 2402 had only deficient glucose transport. Both mutants showed enhanced rates of glutamine transport and no change in glutamic acid transport. Other components of electron transport and oxidative phosphorylation were normal. These mutants involve ferrocytochrome C551 oxidoreductase formed only on anaerobic growth but illustrate transport defects in aerobically grown cells. PMID:6791588

  18. Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome.

    PubMed

    Klepper, Jörg; Diefenbach, Sonja; Kohlschütter, Alfried; Voit, Thomas

    2004-03-01

    The ketogenic diet (KD), established to treat intractable childhood epilepsy, has emerged as the principal treatment of GLUT1 deficiency syndrome (OMIM 606777). This defect of glucose transport into the brain results in hypoglycorrhachia causing epilepsy, developmental delay, and a complex motor disorder in early childhood. Ketones provided by a high-fat, low-carbohydrate diet serve as an alternative fuel to the brain. Glucose, lactate, lipids, and ketones in blood and cerebrospinal fluid were investigated in five GLUT1-deficient patients before and on the KD. Hypoglycorrhachia was detected in the non-ketotic and ketotic state. In ketosis, lactate concentrations in the cerebrospinal fluid increased moderately. The CSF/blood ratio for acetoacetate was higher compared to beta-hydroxybutyrate. Free fatty acids did not enter the brain in significant amounts. Blood concentrations of essential fatty acids determined in 18 GLUT1-deficient patients on the KD were sufficient in all age groups. The effects of the KD in GLUT1 deficiency syndrome, particularly the course of blood lipids, are discussed in an illustrative case. In this syndrome, the KD effectively restores brain energy metabolism. Ketosis does not influence impaired GLUT1-mediated glucose transport into brain: hypoglycorrhachia, the biochemical hallmark of the disease, can be identified in GLUT1-deficient patients on a KD. The effects of ketosis on the concentrations of glucose, lactate, ketones, and fatty acids in blood and cerebrospinal fluid in this entity are discussed in view of previous data on ketosis in man.

  19. Folate and alcohol consumption and the risk of lung cancer

    SciTech Connect

    Bandera, E.V.; Graham, S.; Freudenheim, J.L.; Marshall, J.R.; Haughey, B.P.; Swanson, M.; Brasure, J.; Wilkinson, G. )

    1991-03-11

    Because both folate deficiency and alcohol intake have been hypothesized to be lung cancer risk factors, the authors examined the effect of folate and alcohol consumption on risk of lung cancer in a case-control study conducted 1980-1984. Usual dietary intake of 450 histologically confirmed lung cancer cases and 902 controls, all Western New York residents, was ascertained using a modified food frequency questionnaire. Folate intake was not associated with lung cancer risk. After adjusting for age, cigarette smoking, education, and carotene intake, the odds ratio (OR) for the highest category of folate intake was 1.59 in males and 1.34 in females. There was some indication of a protective effect of folate only among women who never smoked. There was a suggestion of a positive association of alcohol intake with lung cancer risk in males, independent of age, education, cigarette smoking, and carotene. Consumers of more than 9 beers per month had an OR of 1.51 compared to non-drinkers. In both sexes, there was an indication of an interaction between beer ingestion and cigarette smoking. While folate intake did not appear to affect risk of lung cancer, the association of alcohol intake with risk independent of cigarette smoking deserves further inquiry.

  20. LRP2 mediates folate uptake in the developing neural tube.

    PubMed

    Kur, Esther; Mecklenburg, Nora; Cabrera, Robert M; Willnow, Thomas E; Hammes, Annette

    2014-05-15

    The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2) is a multifunctional cell-surface receptor expressed in the embryonic neuroepithelium. Loss of LRP2 in the developing murine central nervous system (CNS) causes impaired closure of the rostral neural tube at embryonic stage (E) 9.0. Similar neural tube defects (NTDs) have previously been attributed to impaired folate metabolism in mice. We therefore asked whether LRP2 might be required for the delivery of folate to neuroepithelial cells during neurulation. Uptake assays in whole-embryo cultures showed that LRP2-deficient neuroepithelial cells are unable to mediate the uptake of folate bound to soluble folate receptor 1 (sFOLR1). Consequently, folate concentrations are significantly reduced in Lrp2(-/-) embryos compared with control littermates. Moreover, the folic-acid-dependent gene Alx3 is significantly downregulated in Lrp2 mutants. In conclusion, we show that LRP2 is essential for cellular folate uptake in the developing neural tube, a crucial step for proper neural tube closure.

  1. Intakes of Folate and Vitamin B12 and Biomarkers of Status in the Very Old: The Newcastle 85+ Study.

    PubMed

    Mendonça, Nuno; Mathers, John C; Adamson, Ashley J; Martin-Ruiz, Carmen; Seal, Chris J; Jagger, Carol; Hill, Tom R

    2016-09-28

    Very old adults are at increased risk of folate and vitamin B12 deficiencies due to reduced food intake and gastrointestinal absorption. The main aim was to determine the association between folate and vitamin B12 intake from total diets and food groups, and status. Folate or vitamin B12 intakes (2 × 24 h multiple pass recalls) and red blood cell (RBC) folate or plasma vitamin B12 (chemiluminescence immunoassays) concentrations were available at baseline for 731 participants aged 85 from the Newcastle 85+ Study (North-East England). Generalized additive and binary logistic models estimated the associations between folate and vitamin B12 intakes from total diets and food groups, and RBC folate and plasma B12. Folate intake from total diets and cereal and cereal products was strongly associated with RBC folate (p < 0.001). Total vitamin B12 intake was weakly associated with plasma vitamin B12 (p = 0.054) but those with higher intakes from total diets or meat and meat products were less likely to have deficient status. Women homozygous for the FUT2 G allele had higher concentrations of plasma vitamin B12. Cereals and cereal products are a very important source of folate in the very old. Higher intakes of folate and vitamin B12 lower the risk of "inadequate" status.

  2. Intakes of Folate and Vitamin B12 and Biomarkers of Status in the Very Old: The Newcastle 85+ Study

    PubMed Central

    Mendonça, Nuno; Mathers, John C.; Adamson, Ashley J.; Martin-Ruiz, Carmen; Seal, Chris J.; Jagger, Carol; Hill, Tom R.

    2016-01-01

    Very old adults are at increased risk of folate and vitamin B12 deficiencies due to reduced food intake and gastrointestinal absorption. The main aim was to determine the association between folate and vitamin B12 intake from total diets and food groups, and status. Folate or vitamin B12 intakes (2 × 24 h multiple pass recalls) and red blood cell (RBC) folate or plasma vitamin B12 (chemiluminescence immunoassays) concentrations were available at baseline for 731 participants aged 85 from the Newcastle 85+ Study (North-East England). Generalized additive and binary logistic models estimated the associations between folate and vitamin B12 intakes from total diets and food groups, and RBC folate and plasma B12. Folate intake from total diets and cereal and cereal products was strongly associated with RBC folate (p < 0.001). Total vitamin B12 intake was weakly associated with plasma vitamin B12 (p = 0.054) but those with higher intakes from total diets or meat and meat products were less likely to have deficient status. Women homozygous for the FUT2 G allele had higher concentrations of plasma vitamin B12. Cereals and cereal products are a very important source of folate in the very old. Higher intakes of folate and vitamin B12 lower the risk of “inadequate” status. PMID:27690091

  3. Folate and vitamin B12: function and importance in cognitive development.

    PubMed

    Troen, Aron M

    2012-01-01

    The importance of the B vitamins folate and vitamin B12 for healthy neurological development and function is unquestioned. Folate and vitamin B12 are required for biological methylation and DNA synthesis. Vitamin B12 also participates in the mitochondrial catabolism of odd-chain fatty acids and some amino acids. Inborn errors of their metabolism and severe nutritional deficiencies cause serious neurological and hematological pathology. Poor folate and vitamin B12 status short of clinical deficiency is associated with increased risk of cognitive impairment, depression, Alzheimer's disease and stroke among older adults and increased risk of neural tube defects among children born to mothers with low folate status. Folate supplementation and food fortification are known to reduce incident neural tube defects, and B vitamin supplementation may have cognitive benefit in older adults. Less is known about folate and vitamin B12 requirements for optimal brain development and long-term cognitive health in newborns, children and adolescents. While increasing suboptimal nutritional status has observed benefits, the long-term effects of high folate intake are uncertain. Several observations of unfavorable health indicators in children and adults exposed to high folic acid intake make it imperative to achieve a more precise definition of folate and B12 requirements for brain development and function.

  4. Vitamin B12 and Folate Test

    MedlinePlus

    ... AACC products and services. Advertising & Sponsorship: Policy | Opportunities Vitamin B12 and Folate Share this page: Was this ... as: Cobalamin; Folic Acid; RBC Folate Formal name: Vitamin B12; Folate Related tests: Complete Blood Count , Methylmalonic ...

  5. The effect of ethanol on the urinary excretion and differential metabolism of folate compounds

    SciTech Connect

    Eisenga, B.H.

    1989-01-01

    In rats chronically fed ethanol and folate-containing diets for 12 weeks, urinary folate excretion was increased. However, no significant tissue depletion was noted unless rats were fed folate deficient diets. In rats fed folate-deficient diets urinary folate excretion was dramatically decreased at two weeks, when tissue folate stores were replete. After 16 weeks of diet treatment, the urinary excretion of an intraperitoneal dose of {sup 3}H-PteGlu was not altered in folate-deficient rats. Although acute ethanol administration (oral or intravenous) increased endogenous folate excretion that of {sup 3}H-PteGlu was not significantly altered, nor was the fractional excretion of {sup 3}H-label. To clarify this effect, the metabolism of {sup 3}H-PteGlu was studied. HPLC analysis of urine showed extensive metabolism of {sup 3}H-PteGlu to other folate substrates. Oral ethanol-treatment increased the fractional excretion of endogenous 5-CH{sub 3}-H{sub 4}PteGlu with no increase in urinary excretion or fractional excretion of other {sup 3}H-labeled derivatives. After infusion of tritium labeled 5-CH{sub 3}-H{sub 4}PteGlu, ethanol treatment increased the fractional excretion of endogenous and {sup 3}H-5-CH{sub 3}-H{sub 4}PteGlu, but not that of other folates. There was rapid uptake of {sup 3}H-label by the kidney with only 10% of the urinary {sup 3}H-label as {sup 3}H-5-CH{sub 3}-H{sub 4}PteGlu.

  6. Mammalian folylpoly-. gamma. -glutamate synthetase. 4. In vitro and in vivo metabolism of folates and analogues and regulation of folate homeostasis

    SciTech Connect

    Cook, J.D.; Cichowicz, D.J.; George, S.; Lawler, Ann; Shane, B.

    1987-01-27

    The regulation of folate and folate analogue metabolism was studied in vitro by using purified hog liver folylpolyglutamate synthetase as a model system and in vivo in cultured mammalian cells. The types of folylpolyglutamates that accumulate in vivo in hog liver, and changes in cellular folate levels and folylpolyglutamate distributions caused by physiological and nutritional factors such as changes in growth rates and methionine, folate, and vitamin B/sub 12/ status, can be mimicked in vitro by using purified enzyme. (/sup 3/H)Folylpolyglutamate distributions can be explained solely in terms of the substrate specificity of folylpolyglutamate synthetase and can be modeled by using kinetic parameters obtained with purified enzyme. Low levels of folylpolyglutamate synthetase activity are normally required for the cellular metabolism of folates to retainable polyglutamate forms, and consequently folate retention and concentration, while higher levels of activity are required for the synthesis of the long chain length derivatives that are found in mammalian tissues. The synthesis of very long chain derivatives, which requires tetrahydrofolate polyglutamates as substrates, is a very slow process in vivo. The slow metabolism of 5-methyltetrahydrofolate to retainable polyglutamate forms causes the decreased tissue retention of folate in B/sub 12/ deficiency. Although cellular folylpolyglutamate distributions change in response to nutritional and physiological modulations, it is unlikely that these changes play a regulatory role in one-carbon metabolism as folate distributions respond only slowly.

  7. Two iron-regulated cation transporters from tomato complement metal uptake-deficient yeast mutants.

    PubMed

    Eckhardt, U; Mas Marques, A; Buckhout, T J

    2001-03-01

    Although iron deficiency poses severe nutritional problems to crop plants, to date iron transporters have only been characterized from the model plant Arabidopsis thaliana. To extend our molecular knowledge of Fe transport in crop plants, we have isolated two cDNAs (LeIRT1 and LeIRT2) from a library constructed from roots of iron-deficient tomato (Lycopersicon esculentum) plants, using the Arabidopsis iron transporter cDNA, IRTI, as a probe. Their deduced polypeptides display 64% and 62% identical amino acid residues to the IRT1 protein, respectively. Transcript level analyses revealed that both genes were predominantly expressed in roots. Transcription of LeIRT2 was unaffected by the iron status of the plant, while expression of LeIRT1 was strongly enhanced by iron limitation. The growth defect of an iron uptake-deficient yeast (Saccharomyces cerevisiae) mutant was complemented by LeIRT1 and LeIRT2 when ligated to a yeast expression plasmid. Transport assays revealed that iron uptake was restored in the transformed yeast cells. This uptake was temperature-dependent and saturable, and Fe2+ rather than Fe3+ was the preferred substrate. A number of divalent metal ions inhibited Fe2+ uptake when supplied at 100-fold or 10-fold excess. Manganese, zinc and copper uptake-deficient yeast mutants were also rescued by the two tomato cDNAs, suggesting that their gene products have a broad substrate range. The gene structure was determined by polymerase chain reaction experiments and, surprisingly, both genes are arranged in tandem with a tail-to-tail orientation.

  8. Targeting the Proton-Coupled Folate Transporter for Selective Delivery of 6-Substituted Pyrrolo[2,3-d]Pyrimidine Antifolate Inhibitors of De Novo Purine Biosynthesis in the Chemotherapy of Solid TumorsS⃞

    PubMed Central

    Desmoulin, Sita Kugel; Wang, Yiqiang; Wu, Jianmei; Stout, Mark; Hou, Zhanjun; Fulterer, Andreas; Chang, Min-Hwang; Romero, Michael F.; Cherian, Christina; Gangjee, Aleem

    2010-01-01

    The proton-coupled folate transporter (PCFT) is a folate-proton symporter with an acidic pH optimum, approximating the microenvironments of solid tumors. We tested 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with one to six carbons in the bridge region for inhibition of proliferation in isogenic Chinese hamster ovary (CHO) and HeLa cells expressing PCFT or reduced folate carrier (RFC). Only analogs with three and four bridge carbons (N-{4-[3-2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)propyl]benzoyl}-l-glutamic acid (compound 2) and N-{4-[4-2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]-pyrimidin-6-yl)butyl]benzoyl}*-l-glutamic acid (compound 3), respectively) were inhibitory, with 2 ≫ 3. Activity toward RFC-expressing cells was negligible. Compound 2 and pemetrexed (Pmx) competed with [3H]methotrexate for PCFT transport in PCFT-expressing CHO (R2/hPCFT4) cells from pH 5.5 to 7.2; inhibition increased with decreasing pH. In Xenopus laevis oocytes microinjected with PCFT cRNA, uptake of 2, like that of Pmx, was electrogenic. Cytotoxicity of 2 toward R2/hPCFT4 cells was abolished in the presence of adenosine or 5-amino-4-imidazolecarboxamide, suggesting that glycinamide ribonucleotide formyltransferase (GARFTase) in de novo purine biosynthesis was the primary target. Compound 2 decreased GTP and ATP pools by ∼50 and 75%, respectively. By an in situ GARFTase assay, 2 was ∼20-fold more inhibitory toward intracellular GARFTase than toward cell growth or colony formation. Compound 2 irreversibly inhibited clonogenicity, although this required at least 4 h of exposure. Our results document the potent antiproliferative activity of compound 2, attributable to its efficient cellular uptake by PCFT, resulting in inhibition of GARFTase and de novo purine biosynthesis. Furthermore, they establish the feasibility of selective chemotherapy drug delivery via PCFT over RFC, a process that takes advantage of a unique biological feature of solid tumors. PMID

  9. Iron, folate, and vitamin B12 nutrition in pregnancy: a study of 1 000 women from southern India*

    PubMed Central

    Yusufji, D.; Mathan, V. I.; Baker, S. J.

    1973-01-01

    As part of a WHO collaborative programme the prevalence of anaemia was studied and the serum concentrations of iron, folate, and vitamin B12 were measured in 1 000 pregnant women from southern India. The results of the study show a high prevalence of anaemia, resulting from iron and folate deficiency with iron deficiency predominating. Interrelationships between these nutrients and their effect on pregnancy and the fetus were investigated. The results indicate that, in comparison with populations in developed countries, there was a high prevalence of iron and vitamin B12 deficiency in the community, but the state of folate nutrition was similar to that found elsewhere. PMID:4541142

  10. Performance, serum biochemical responses, and gene expression of intestinal folate transporters of young and older laying hens in response to dietary folic acid supplementation and challenge with Escherichia coli lipopolysaccharide.

    PubMed

    Jing, M; Munyaka, P M; Tactacan, G B; Rodriguez-Lecompte, J C; O, K; House, J D

    2014-01-01

    The present study was conducted to investigate the effects of dietary folic acid (FA) supplementation on performance, serum biochemical indices, and mRNA abundance of intestinal folate transporters in young and older laying hens after acute lipopolysaccharide (LPS) challenge. Two experiments were conducted separately involving 48 Shaver White young laying hens (24 wk of age) in experiment 1 and 48 Shaver White older laying hens (58 wk of age) in experiment 2. Birds were fed 2 diets in a complete randomized design. The diets were wheat-soybean meal based, with or without supplemental 4 mg of FA/kg of diet. Birds were fed for 8 wk, during which time feed consumption and egg production were monitored. At the end of each feeding experiment, 6 hens from each dietary treatment were injected intravenously with 8 mg/kg of BW of either Escherichia coli LPS or sterile saline. Four hours after injection, blood and intestinal samples were collected for further analysis. Compared with the control, dietary FA supplementation increased egg weight and egg mass and decreased serum glucose levels in the young laying hens, and reduced serum uric acid in the older laying hens (P < 0.05). Relative to saline injection, plasma homocysteine, serum calcium, and phosphorus levels were found to be lower in both young and older laying hens after LPS challenge (P < 0.05). Other serum biochemical variables and the mRNA expression of 2 folate transport genes in the small and large intestine were differentially affected by LPS challenge, and some of those responses varied with the age of the birds. Additionally, interactions between diet and LPS challenge were specifically found in the older laying hens. In summary, in addition to improving production performance, there were effects of dietary FA supplementation and its interaction with LPS challenge on biochemical constituents, and age played a role in the development of responses to diet and bacterial LPS infections.

  11. Folate levels modulate oncogene-induced replication stress and tumorigenicity

    PubMed Central

    Lamm, Noa; Maoz, Karin; Bester, Assaf C; Im, Michael M; Shewach, Donna S; Karni, Rotem; Kerem, Batsheva

    2015-01-01

    Chromosomal instability in early cancer stages is caused by replication stress. One mechanism by which oncogene expression induces replication stress is to drive cell proliferation with insufficient nucleotide levels. Cancer development is driven by alterations in both genetic and environmental factors. Here, we investigated whether replication stress can be modulated by both genetic and non-genetic factors and whether the extent of replication stress affects the probability of neoplastic transformation. To do so, we studied the effect of folate, a micronutrient that is essential for nucleotide biosynthesis, on oncogene-induced tumorigenicity. We show that folate deficiency by itself leads to replication stress in a concentration-dependent manner. Folate deficiency significantly enhances oncogene-induced replication stress, leading to increased DNA damage and tumorigenicity in vitro. Importantly, oncogene-expressing cells, when grown under folate deficiency, exhibit a significantly increased frequency of tumor development in mice. These findings suggest that replication stress is a quantitative trait affected by both genetic and non-genetic factors and that the extent of replication stress plays an important role in cancer development. PMID:26197802

  12. The Vacuolar Manganese Transporter MTP8 Determines Tolerance to Iron Deficiency-Induced Chlorosis in Arabidopsis.

    PubMed

    Eroglu, Seckin; Meier, Bastian; von Wirén, Nicolaus; Peiter, Edgar

    2016-02-01

    Iron (Fe) deficiency is a widespread nutritional disorder on calcareous soils. To identify genes involved in the Fe deficiency response, Arabidopsis (Arabidopsis thaliana) transfer DNA insertion lines were screened on a high-pH medium with low Fe availability. This approach identified METAL TOLERANCE PROTEIN8 (MTP8), a member of the Cation Diffusion Facilitator family, as a critical determinant for the tolerance to Fe deficiency-induced chlorosis, also on soil substrate. Subcellular localization to the tonoplast, complementation of a manganese (Mn)-sensitive Saccharomyces cerevisiae yeast strain, and Mn sensitivity of mtp8 knockout mutants characterized the protein as a vacuolar Mn transporter suitable to prevent plant cells from Mn toxicity. MTP8 expression was strongly induced on low-Fe as well as high-Mn medium, which were both strictly dependent on the transcription factor FIT, indicating that high-Mn stress induces Fe deficiency. mtp8 mutants were only hypersensitive to Fe deficiency when Mn was present in the medium, which further suggested an Mn-specific role of MTP8 during Fe limitation. Under those conditions, mtp8 mutants not only translocated more Mn to the shoot than did wild-type plants but suffered in particular from critically low Fe concentrations and, hence, Fe chlorosis, although the transcriptional Fe deficiency response was up-regulated more strongly in mtp8. The diminished uptake of Fe from Mn-containing low-Fe medium by mtp8 mutants was caused by an impaired ability to boost the ferric chelate reductase activity, which is an essential process in Fe acquisition. These findings provide a mechanistic explanation for the long-known interference of Mn in Fe nutrition and define the molecular processes by which plants alleviate this antagonism.

  13. Effects of anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency syndrome in vitro.

    PubMed

    Klepper, Jörg; Flörcken, Anne; Fischbarg, Jorge; Voit, Thomas

    2003-02-01

    Facilitative type-1 glucose transporter (GLUT1) deficiency syndrome is caused by a defect of glucose transport into brain, resulting in an epileptic encephalopathy. Seizures respond effectively to a ketogenic diet, but a subgroup of patients require add-on anticonvulsant therapy or do not tolerate the diet. With the exception of barbiturates, which have been shown to inhibit GLUT1 function, no anticonvulsants have been investigated for possible interactions with GLUT1. Kinetic analyses of (14)C-labeled 3-O-methyl glucose (3OMG) uptake into erythroctes were performed in 11 patients and 30 controls. For in vitro inhibition studies, zero-trans influx of 3OMG (5 mmol/L) into erythrocytes was determined following preincubation with diazepam, carbamazepine, phenytoin, and chloralhydrate. In addition, the effects of ethanol on cell lysis and 3OMG transport into erythrocytes were determined. In patients, mean 3OMG influx was 53% of controls. Ethanol, diazepam, and chloralhydrate significantly inhibited GLUT1 function. Erythrocyte cell lysis was evident at concentrations of 2.5% ethanol. Diazepam, chloralhydrate, and ethanol are inhibitors of GLUT1 function in vitro and might potentiate the effects of GLUT1-mediated glucose transport in patients with GLUT1 deficiency syndrome. In contrast, no inhibitory effects were observed for carbamazepine and phenytoin, indicating that these substances might be preferable for additional seizure control in this disorder.

  14. Folate status of young Canadian women after folic acid fortification of grain products.

    PubMed

    Shuaibi, Aysheh M; House, James D; Sevenhuysen, Gustaaf P

    2008-12-01

    Women of childbearing age are advised to consume folic acid-containing supplements. Whether this remains necessary after folic acid fortification of the food supply in North America has yet to be determined. The objectives of this study were to assess folate intakes and the contribution of folic acid to the diets of women of childbearing age in the post-folic acid fortification era. Using a cross-sectional study design, fasting blood samples were obtained from 95 women (aged 18 to 25 years), and the samples were analyzed for serum and red blood cell folate, as well for total homocysteine. Dietary and supplemental folate intakes were assessed. The biochemical evidence showed that no women were folate deficient, but only 14% reached red blood cell folate concentrations associated with significant reductions in neural tube defect risk. Mean dietary intake of food folic acid was 96+/-64 microg/day, supplemental folic acid was 94+/-189 microg/day, natural folate was 314+/-134 microg/day, and the total intake, as dietary folate equivalents, was 646+/-368 microg dietary folate equivalents/day. Therefore, intakes of folic acid from fortified foods are within the level originally predicted for the fortification efforts; however, only 17% of participants met the special recommendation for women capable of becoming pregnant (400 microg folic acid daily from supplements, fortified foods, or both in addition to consuming food folate from a varied diet). These data suggest that women of childbearing age are achieving positive folate status in the postfortification era, but it may not be sufficient to achieve red blood cell folate concentrations associated with a significant reduction in neural tube defect risk. Even with food fortification, women of childbearing age should be advised to take a folic acid-containing supplement on a daily basis.

  15. Phospholipid transfer protein deficiency in mice impairs macrophage reverse cholesterol transport in vivo

    PubMed Central

    Si, Yanhong; Zhang, Ying; Chen, Xiaofeng; Zhai, Lei; Zhou, Guanghai; Yu, Ailing; Cao, Haijun

    2016-01-01

    Phospholipid transfer protein is expressed in various cell types and secreted into plasma, where it transfers phospholipids between lipoproteins and modulates the composition of high-density lipoprotein particles. Phospholipid transfer protein deficiency in vivo can lower high-density lipoprotein cholesterol level significantly and impact the biological quality of high-density lipoprotein. Considering high-density lipoprotein was a critical determinant for reverse cholesterol transport, we investigated the role of systemic phospholipid transfer protein deficiency in macrophage reverse cholesterol transport in vivo. After the littermate phospholipid transfer protein KO and WT mice were fed high-fat diet for one month, they were injected intraperitoneally with 3H-cholesterol-labeled and acLDL-loaded macrophages. Then the appearance of 3H-tracer in plasma, liver, bile, intestinal wall, and feces over 48 h was determined. Plasma lipid analysis indicated phospholipid transfer protein deficiency lowered total cholesterol, high-density lipoprotein-C and apolipoprotein A1 levels significantly but increased triglyceride level in mice. The isotope tracing experiment showed 3H-cholesterol of plasma was decreased by 68% for male and 62% for female, and 3H-tracer of bile was decreased by 37% for male and 21% for female in phospholipid transfer protein KO mice compared with WT mice. However, there was no difference in liver, and 3H-tracer of intestinal wall was increased by 43% for male and 27% for female. Finally, 3H-tracer of fecal excretion in phospholipid transfer protein KO mice was reduced significantly by 36% for male and 43% for female during 0–24 h period, but there was no significant difference during 24–48 h period. Meanwhile, Western Blot analysis showed the expressions of reverse cholesterol transport -related protein liver X receptor α (LXRα), ATP binding cassette transporter A1, and cholesterol 7α-hydroxylase A1 were upregulated in liver of

  16. Enhancing pterin and para-aminobenzoate content is not sufficient to successfully biofortify potato tubers and Arabidopsis thaliana plants with folate.

    PubMed

    Blancquaert, Dieter; Storozhenko, Sergei; Van Daele, Jeroen; Stove, Christophe; Visser, Richard G F; Lambert, Willy; Van Der Straeten, Dominique

    2013-09-01

    Folates are important cofactors in one-carbon metabolism in all living organisms. Since only plants and micro- organisms are capable of biosynthesizing folates, humans depend entirely on their diet as a folate source. Given the low folate content of several staple crop products, folate deficiency affects regions all over the world. Folate biofortification of staple crops through enhancement of pterin and para-aminobenzoate levels, precursors of the folate biosynthesis pathway, was reported to be successful in tomato and rice. This study shows that the same strategy is not sufficient to enhance folate content in potato tubers and Arabidopsis thaliana plants and concludes that other steps in folate biosynthesis and/or metabolism need to be engineered to result in substantial folate accumulation. The findings provide a plausible explanation why, more than half a decade after the proof of concept in rice and tomato, successful folate biofortification of other food crops through enhancement of para-aminobenzoate and pterin content has not been reported thus far. A better understanding of the folate pathway is required in order to determine an engineering strategy that can be generalized to most staple crops.

  17. Alterations in Adhesion, Transport, and Membrane Characteristics in an Adhesion-Deficient Pseudomonad

    PubMed Central

    DeFlaun, M. F.; Oppenheimer, S. R.; Streger, S.; Condee, C. W.; Fletcher, M.

    1999-01-01

    A stable adhesion-deficient mutant of Burkholderia cepacia G4, a soil pseudomonad, was selected in a sand column assay. This mutant (ENV435) was compared to the wild-type strain by examining the adhesion of the organisms to silica sand and their transport through two aquifer sediments that differed in their sand, silt, and clay contents. We compared the longitudinal transport of the wild type and the adhesion mutant to the transport of a conservative chloride tracer in 25-cm-long glass columns. The transport of the wild-type strain was severely retarded compared to the transport of the conservative tracer in a variety of aquifer sediments, while the adhesion mutant and the conservative tracer traveled at similar rates. An intact sediment core study produced similar results; ENV435 was transported at a faster rate and in much greater numbers than G4. The results of hydrophobic interaction chromatography revealed that G4 was significantly more hydrophobic than ENV435, and polyacrylamide gel electrophoresis revealed significant differences in the lipopolysaccharide O-antigens of the adhesion mutant and the wild type. Differences in this cell surface polymer may explain the decreased adhesion of strain ENV435. PMID:9925613

  18. Folate receptor alpha is necessary for neural plate cell apical constriction during Xenopus neural tube formation.

    PubMed

    Balashova, Olga A; Visina, Olesya; Borodinsky, Laura N

    2017-03-02

    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-α (FRα) impairs neural tube formation and leads to NTDs. FRα knockdown in neural plate cells only is necessary and sufficient to induce NTDs. FRα-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 for folate receptor interacting with cell adhesion molecules, thus regulating apical cell membrane remodeling and cytoskeletal dynamics necessary for neural plate folding. Further studies in this organism may unveil novel cellular and molecular events mediated by folate and lead to new means for preventing NTDs.

  19. Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World

    PubMed Central

    Stamm, Rosemary A.; Houghton, Lisa A.

    2013-01-01

    Folate is a B-vitamin with particular importance during reproduction due to its role in the synthesis and maintenance of DNA. Folate is well known for its role in preventing neural tube defects (NTDs) during the periconceptional period. There is also an increased need for folate throughout pregnancy to support optimal growth and development of the fetus and blood volume expansion and tissue growth of the mother. During lactation, women are at risk of folate deficiency due to increased demands to accommodate milk folate levels. Nutrient Intake Values (NIVs) for folate have been calculated to take into account additional needs during pregnancy and lactation. However, these values vary widely between countries. For example, the folate requirement that is set to meet the needs of almost all healthy women during pregnancy varies from 300 µg/day in the United Kingdom to 750 µg/day in Mexico. Currently, there is no accepted standardized terminology or framework for establishing NIVs. This article reviews country-specific NIVs for folate during pregnancy and lactation and the basis for setting these reference values. PMID:24084052

  20. 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

  1. Polymorphisms in 1-carbon metabolism, epigenetics and folate-related pathologies.

    PubMed

    Stover, Patrick J

    2011-01-01

    Folate-mediated 1-carbon metabolism is a network of interconnected metabolic pathways necessary for the synthesis of purine nucleotides, thymidylate and the remethylation of homocysteine to methionine. Disruptions in this pathway influence both DNA synthesis and stability and chromatin methylation, and result from nutritional deficiencies and common gene variants. The mechanisms underlying folate-associated pathologies and developmental anomalies have yet to be established. This review focuses on the relationships among folate-mediated 1-carbon metabolism, chromatin methylation and human disease, and the role of gene-nutrient interactions in modifying epigenetic processes.

  2. Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy.

    PubMed

    Terrill, Jessica R; Grounds, Miranda D; Arthur, Peter G

    2015-09-01

    The amino acid taurine is essential for the function of skeletal muscle and administration is proposed as a treatment for Duchenne Muscular Dystrophy (DMD). Taurine homeostasis is dependent on multiple processes including absorption of taurine from food, endogenous synthesis from cysteine and reabsorption in the kidney. This study investigates the cause of reported taurine deficiency in the dystrophic mdx mouse model of DMD. Levels of metabolites (taurine, cysteine, cysteine sulfinate and hypotaurine) and proteins (taurine transporter [TauT], cysteine deoxygenase and cysteine sulfinate dehydrogenase) were quantified in juvenile control C57 and dystrophic mdx mice aged 18 days, 4 and 6 weeks. In C57 mice, taurine content was much higher in both liver and plasma at 18 days, and both cysteine and cysteine deoxygenase were increased. As taurine levels decreased in maturing C57 mice, there was increased transport (reabsorption) of taurine in the kidney and muscle. In mdx mice, taurine and cysteine levels were much lower in liver and plasma at 18 days, and in muscle cysteine was low at 18 days, whereas taurine was lower at 4: these changes were associated with perturbations in taurine transport in liver, kidney and muscle and altered metabolism in liver and kidney. These data suggest that the maintenance of adequate body taurine relies on sufficient dietary intake of taurine and cysteine availability and metabolism, as well as retention of taurine by the kidney. This research indicates dystrophin deficiency not only perturbs taurine metabolism in the muscle but also affects taurine metabolism in the liver and kidney, and supports targeting cysteine and taurine deficiency as a potential therapy for DMD.

  3. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice.

    PubMed

    Dumitrescu, Alexandra M; Liao, Xiao-Hui; Weiss, Roy E; Millen, Kathleen; Refetoff, Samuel

    2006-09-01

    Mutations of the X-linked thyroid hormone (TH) transporter (monocarboxylate transporter, MCT8) produce in humans unusual abnormalities of thyroid function characterized by high serum T3 and low T4 and rT3. The mechanism of these changes remains obscure and raises questions regarding the regulation of intracellular availability and metabolism of TH. To study the pathophysiology of MCT8 deficiency, we generated Mct8 knockout mice. Male mice deficient in Mct8 (Mct8(-/y)) replicate the thyroid abnormalities observed in affected men. TH deprivation and replacement with L-T3 showed that suppression of TSH required higher serum levels T3 in Mct8(-/y) than wild-type (WT) littermates, indicating hypothalamus and/or thyrotroph resistance to T3. Furthermore, T4 is required to maintain the high serum T3 level because the latter was not different between the two genotypes during administration of T3. Mct8(-/y) mice have 2.3-fold higher T3 content in liver associated with 6.1- and 3.1-fold increase in deiodinase 1 mRNA and enzymatic activity, respectively. The relative T3 excess in liver of Mct8(-/y) mice produced a decrease in serum cholesterol (79 +/- 18 vs. 137 +/- 38 mg/dl in WT) and an increase in alkaline phosphatase (107 +/- 23 vs. 58 +/- 3 U/liter in WT) levels. In contrast, T3 content in cerebrum was 1.8-fold lower in Mct8(-/y) mice, associated with a 1.6- and 10.6-fold increase in D2 mRNA and enzymatic activity, respectively, as previously observed in TH-deprived WT mice. We conclude that cell-specific differences in intracellular TH content due to differences in contribution of the various TH transporters are responsible for the unusual clinical presentation of this defect, in contrast to TH deficiency.

  4. In vivo vitamin C deficiency in guinea pigs increases ascorbate transporters in liver but not kidney and brain.

    PubMed

    Søgaard, Ditte; Lindblad, Maiken M; Paidi, Maya D; Hasselholt, Stine; Lykkesfeldt, Jens; Tveden-Nyborg, Pernille

    2014-07-01

    Moderate vitamin C (vitC) deficiency (plasma concentrations less than 23 μmol/L) affects as much as 10% of adults in the Western World and has been associated with an increased mortality in disease complexes such as cardiovascular disease and the metabolic syndrome. The distribution of vitC within the body is subjected to complex and nonlinear pharmacokinetics and largely depends on the sodium-dependent vitC-specific transporters, sodium-dependent vitamin C transporter 1 (SVCT1) and sodium-dependent vitamin C transporter 2 (SVCT2). Although currently not established, it is likely to expect that a state of deficiency may affect the expression of these transporters to preserve vitC concentrations in specific target tissues. We hypothesized that diet-induced states of vitC deficiency lead to alterations in the messenger RNA (mRNA) and/or protein expression of vitC transporters, thereby regulating vitC tissue distribution. Using guinea pigs as a validated model, this study investigated the effects of a diet-induced vitC deficiency (100 mg vitC/kg feed) or depletion (0 mg vitC/kg feed) on the expression of transporters SVCT1 and SVCT2 in selected tissues and the transport from plasma to cerebrospinal fluid (CSF). In deficient animals, SVCT1 was increased in the liver, whereas a decreased SVCT1 expression but increased SVCT2 mRNA in livers of depleted animals suggests a shift in transporter expression as response to the diet. In CSF, a constant plasma:CSF ratio shows unaltered vitC transport irrespective of dietary regime. The study adds novel information to the complex regulation maintaining vitC homeostasis in vivo during states of deficiency.

  5. Endo-Lysosomal Dysfunction in Human Proximal Tubular Epithelial Cells Deficient for Lysosomal Cystine Transporter Cystinosin

    PubMed Central

    Van Den Heuvel, Lambertus; Pastore, Anna; Dijkman, Henry; De Matteis, Maria Antonietta; Levtchenko, Elena N.

    2015-01-01

    Nephropathic cystinosis is a lysosomal storage disorder caused by mutations in the CTNS gene encoding cystine transporter cystinosin that results in accumulation of amino acid cystine in the lysosomes throughout the body and especially affects kidneys. Early manifestations of the disease include renal Fanconi syndrome, a generalized proximal tubular dysfunction. Current therapy of cystinosis is based on cystine-lowering drug cysteamine that postpones the disease progression but offers no cure for the Fanconi syndrome. We studied the mechanisms of impaired reabsorption in human proximal tubular epithelial cells (PTEC) deficient for cystinosin and investigated the endo-lysosomal compartments of cystinosin-deficient PTEC by means of light and electron microscopy. We demonstrate that cystinosin-deficient cells had abnormal shape and distribution of the endo-lysosomal compartments and impaired endocytosis, with decreased surface expression of multiligand receptors and delayed lysosomal cargo processing. Treatment with cysteamine improved surface expression and lysosomal cargo processing but did not lead to a complete restoration and had no effect on the abnormal morphology of endo-lysosomal compartments. The obtained results improve our understanding of the mechanism of proximal tubular dysfunction in cystinosis and indicate that impaired protein reabsorption can, at least partially, be explained by abnormal trafficking of endosomal vesicles. PMID:25811383

  6. Altered microtubule dynamics and vesicular transport in mouse and human MeCP2-deficient astrocytes

    PubMed Central

    Delépine, Chloé; Meziane, Hamid; Nectoux, Juliette; Opitz, Matthieu; Smith, Amos B.; Ballatore, Carlo; Saillour, Yoann; Bennaceur-Griscelli, Annelise; Chang, Qiang; Williams, Emily Cunningham; Dahan, Maxime; Duboin, Aurélien; Billuart, Pierre; Herault, Yann; Bienvenu, Thierry

    2016-01-01

    Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder, characterized by normal post-natal development followed by a sudden deceleration in brain growth with progressive loss of acquired motor and language skills, stereotypic hand movements and severe cognitive impairment. Mutations in the methyl-CpG-binding protein 2 (MECP2) cause more than 95% of classic cases. Recently, it has been shown that the loss of Mecp2 from glia negatively influences neurons in a non-cell-autonomous fashion, and that in Mecp2-null mice, re-expression of Mecp2 preferentially in astrocytes significantly improved locomotion and anxiety levels, restored respiratory abnormalities to a normal pattern and greatly prolonged lifespan compared with globally null mice. We now report that microtubule (MT)-dependent vesicle transport is altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared with control wild-type littermates. Similar observation has been made in human MECP2 p.Arg294* iPSC-derived astrocytes. Importantly, administration of Epothilone D, a brain-penetrant MT-stabilizing natural product, was found to restore MT dynamics in Mecp2-deficient astrocytes and in MECP2 p.Arg294* iPSC-derived astrocytes in vitro. Finally, we report that relatively low weekly doses of Epothilone D also partially reversed the impaired exploratory behavior in Mecp2308/y male mice. These findings represent a first step toward the validation of an innovative treatment for RTT. PMID:26604147

  7. Intestinal folate binding protein (FBP) and folate absorption in the suckling rat

    SciTech Connect

    Mason, J.B.; Selhub, J.

    1986-03-01

    The folate in milk is bound to high affinity FBPs but it is unknown whether this binding affects intestinal transport of milk folate in the suckling rat. The authors examined the FBP activity of segments of the GI tract in fed and fasting states. Under fed conditions, the FBP activity in the mucosa of the stomach and proximal small intestine were similar (0.28 and 0.32 pMole folic acid binding/mg protein, N.S.). Both demonstrated less activity than the mucosa of the distal small intestine (1.31 pMole/mg protein, P < .001). A 6 hr fast produced no change in the FBP activity in the stomach or proximal small intestine but resulted in a 42% decrease in the distal small intestine (p < .01). Intestinal transport of unbound and FB-bound H/sup 3/pteryolmonoglutamate (H/sup 3/PGA) was examined in suckling rats by the intestinal loop model. Unbound H/sup 3/PGA demonstrated greater lumenal disappearance in the proximal segment of the small intestine compared to the distal segment (79% vs. 56%, P < .001) whereas the bound H/sup 3/PGA demonstrated greater lumenal disappearance in the distal segment (36% vs. 21%, p < .005). That porton of FBP activity in the distal small intestine that disappears with fasting may represent FBP absorbed from the lumen of the intestine. The FBP-bound folate in milk appears to be absorbed in the suckling rat by a mechanism that favors the distal small intestine and is different from the mechanism responsible for absorption of the unbound folate.

  8. Implication of homocysteine in diabetes and impact of folate and vitamin B12 in diabetic population.

    PubMed

    Mursleen, M Tahir; Riaz, Samreen

    2016-12-13

    Diabetes mellitus is an acutely debilitating ailment affecting a large population of the world. At present, over 415 million people around the world including 7 million people in Pakistan suffering from diabetes. Homocysteine is an amino acid that is inversely related to vitamin B12 and folate, and raised level of homocysteine is implicated in many adverse health conditions. In this study, the potential role of homocysteine in diabetes and the epidemiology of hyperhomocysteinaemia, and vitamin B12 and folate deficiency is reviewed along with the impact of folate and vitamin B12 in regulation of homocysteine level. Deficiency of vitamin B12 and folate is rare in developed countries and the countries which adopted fortification programs, but deficiency of these vitamins is found to be highly prevalent in developing world, particularly in Pakistan. Several studies have found an association of high homocysteine levels and diabetes, but a few studies found contrary results. Hence, further epidemiological studies are recommended for homocysteine involvement in diabetes and vitamin B12 and folate deficiency, so that an urgent action can be taken to control the hyperhomocysteinaemia and consequently the ever increasing burden of disease and specifically diabetes.

  9. Glucose transporter type 1 deficiency syndrome (Glut1DS): methylxanthines potentiate GLUT1 haploinsufficiency in vitro.

    PubMed

    Ho, Y Y; Yang, H; Klepper, J; Fischbarg, J; Wang, D; De Vivo, D C

    2001-08-01

    Methylxanthines such as caffeine and theophylline are known to inhibit glucose transport. We have studied such inhibition in the glucose transporter type 1 deficiency syndrome (Glut1DS) by erythrocyte glucose transport assays. Data from four patients with individual mutations in the GLUT1 gene are discussed: patient 1 (hemizygosity), 3 (S66F), 15 (368Ins23), and 17 (R333W). Zero-trans influx of (14)C-labeled 3-O-methyl glucose (3-OMG) into erythrocytes of patients is reduced (patient 1, 51%; 3, 45%; 15, 31%; 17, 52%) compared with maternal controls. Inhibition studies on patients 1, 3, 17, and maternal controls show an IC(50) for caffeine of approximately 1.5 mM both in controls (n = 3) and patients (n = 3) at 5 mM 3-OMG concentration. In the same two groups, kinetic studies show that 3 mM caffeine significantly decreases V(max) (p < 0.005), whereas the decrease in K(m) is significant (p < 0.01) only in the three controls and one patient (patient 3). Kinetic data from individual patients permit us to speculate that the interactions between caffeine and Glut1 are influenced by the mutation. Three mM caffeine also inhibits the transport of dehydroascorbic acid (DHA), another substrate for Glut1. The combined effects of caffeine (3 mM) and phenobarbital (10 mM) on glucose transport, as determined in patient 15 and the maternal control, show no additive or synergistic inhibition. These data indicate that caffeine and phenobarbital have similar Glut1 inhibitory properties in these two subjects. Our study suggests that Glut1DS patients may have a reduced safety margin for methylxanthines. Consumption of methylxanthine-containing products may aggravate the neurologic symptoms associated with the Glut1DS.

  10. Status of serum vitamin B12 and folate in patients with inflammatory bowel disease in China

    PubMed Central

    Huang, Shaozhong; Ma, Jiayi; Zhu, Mingming

    2017-01-01

    Background/Aims Inflammatory bowel disease (IBD) primarily involves the intestinal tract and can affect vitamin absorption. This study was designed to assess the prevalence of vitamin B12 and folate deficiencies in patients with IBD, and to identify the risk factors associated with abnormal serum vitamin B12 and folate levels. Methods We evaluated the medical records of 195 patients with Crohn's disease (CD) and 62 patients with ulcerative colitis (UC), and selected 118 healthy subjects for the control group. Results There were more CD patients with vitamin B12 deficiency than UC patients (14.9% vs. 3.2%, P=0.014) and controls (14.9% vs. 4.2%, P=0.003). The prevalence of folate deficiency was higher in CD patients than in controls (13.3% vs. 3.4%, P=0.004). There were no significant differences in the serum vitamin B12 and folate statuses of the UC and control groups. Patients with prior ileal or ileocolic resection showed a higher prevalence of abnormal vitamin B12 levels than those without prior resection (n=6/16, n=23/179; P=0.018). A disease duration within 5 years was a risk factor of abnormal folate levels in CD patients. Conclusions This study showed that vitamin B12 and folate deficiencies were more common in patients with CD than in UC patients and controls. Prior ileal or ileocolonic resection was a risk factor of serum vitamin B12 abnormalities, and a disease duration within 5 years was a risk factor of low serum folate levels in CD patients. PMID:28239320

  11. SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation

    PubMed Central

    Park, Julien H.; Hogrebe, Max; Grüneberg, Marianne; DuChesne, Ingrid; von der Heiden, Ava L.; Reunert, Janine; Schlingmann, Karl P.; Boycott, Kym M.; Beaulieu, Chandree L.; Mhanni, Aziz A.; Innes, A. Micheil; Hörtnagel, Konstanze; Biskup, Saskia; Gleixner, Eva M.; Kurlemann, Gerhard; Fiedler, Barbara; Omran, Heymut; Rutsch, Frank; Wada, Yoshinao; Tsiakas, Konstantinos; Santer, René; Nebert, Daniel W.; Rust, Stephan; Marquardt, Thorsten

    2015-01-01

    SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders. PMID:26637979

  12. Quantitation of 5HT3 receptors in forebrain of serotonin transporter deficient mice.

    PubMed

    Mössner, R; Schmitt, A; Hennig, T; Benninghoff, J; Gerlach, M; Riederer, P; Deckert, J; Lesch, K P

    2004-01-01

    Mice deficient in the serotonin transporter (5HTT) display highly elevated extracellular 5HT levels. 5HT exerts ist effects via at least fourteen different cloned 5HT receptors located pre- and postsynaptically. In contrast to the other 5HT receptors, the 5HT3 receptor is a ionotropic receptor with ligand-gated cation channel function. Since G-protein-coupled 5HT receptors show extensive adaptive changes in 5HTT-deficient mice, we investigated whether 5HT3 receptors are also altered in these mice. Using quantitative autoradiography, we found that 5HT3 receptors are upregulated in frontal cortex (+46%), parietal cortex (+42%), and in stratum oriens of the CA3 region of the hippocampus (+18%) of 5HTT knockout mice. Changes in 5HT3 receptor mRNA expression, as determined by quantitative in situ hybridisation, were less pronounced. The adaptive changes of 5HT3 receptor expression constitute a part of the complex regulatory pattern of 5HT receptors in 5HTT knockout mice.

  13. SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.

    PubMed

    Park, Julien H; Hogrebe, Max; Grüneberg, Marianne; DuChesne, Ingrid; von der Heiden, Ava L; Reunert, Janine; Schlingmann, Karl P; Boycott, Kym M; Beaulieu, Chandree L; Mhanni, Aziz A; Innes, A Micheil; Hörtnagel, Konstanze; Biskup, Saskia; Gleixner, Eva M; Kurlemann, Gerhard; Fiedler, Barbara; Omran, Heymut; Rutsch, Frank; Wada, Yoshinao; Tsiakas, Konstantinos; Santer, René; Nebert, Daniel W; Rust, Stephan; Marquardt, Thorsten

    2015-12-03

    SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit. The variants c.112G>C (p.Gly38Arg) and c.1019T>A (p.Ile340Asn) were identified in SLC39A8. A second individual with the variants c.97G>A (p.Val33Met) and c.1004G>C (p.Ser335Thr) on the paternal allele and c.610G>T (p.Gly204Cys) on the maternal allele was identified among a group of unresolved case subjects with CDG. These data demonstrate that variants in SLC39A8 impair the function of manganese-dependent enzymes, most notably β-1,4-galactosyltransferase, a Golgi enzyme essential for biosynthesis of the carbohydrate part of glycoproteins. Impaired galactosylation leads to a severe disorder with deformed skull, severe seizures, short limbs, profound psychomotor retardation, and hearing loss. Oral galactose supplementation is a treatment option and results in complete normalization of glycosylation. SLC39A8 deficiency links a trace element deficiency with inherited glycosylation disorders.

  14. Divalent metal transporter 1 (Dmt1) Mediates Copper Transport in the Duodenum of Iron-Deficient Rats and When Overexpressed in Iron-Deprived HEK-293 Cells12

    PubMed Central

    Jiang, Lingli; Garrick, Michael D.; Garrick, Laura M.; Zhao, Lin; Collins, James F.

    2013-01-01

    Intracellular copper-binding proteins (metallothionein I/II) and a copper exporter (Menkes copper-transporting ATPase) are upregulated in duodenal enterocytes from iron-deficient rats, consistent with copper accumulation in the intestinal mucosa. How copper enters enterocytes during iron deficiency is, however, not clear. Divalent metal transporter 1 (Dmt1), the predominant iron importer in the mammalian duodenum, also transports other metal ions, possibly including copper. Given this possibility and that Dmt1 expression is upregulated by iron deprivation, we sought to test the hypothesis that Dmt1 transports copper during iron deficiency. Two model systems were utilized: the Belgrade (b) rat, expressing mutant Dmt1, and an inducible Dmt1-overexpression cell culture system. Mutant rats (b/b) were fed a semipurified, AIN93G-based control diet and phenotypically normal littermates (+/b) were fed control or iron-deficient diets for ∼14 wk. An everted gut sleeve technique and a colorimetric copper quantification assay were utilized to assess duodenal copper transport. The control diet-fed +/b rats had normal hematological parameters, whereas iron-deprived +/b and b/b rats were iron deficient and Dmt1 mRNA and protein levels increased. Importantly, duodenal copper transport was similar in the control +/b and b/b rats; however, it significantly increased (∼4-fold) in the iron-deprived +/b rats. Additional experiments in Dmt1 overexpressing HEK-293 cells showed that copper (64Cu) uptake was stimulated (∼3-fold) in the presence of an iron chelator. Dmt1 transcript stabilization due to a 3′ iron-responsive element was also documented, likely contributing to increased transport activity. In summary, these studies suggest that Dmt1 enhances copper uptake into duodenal enterocytes during iron deprivation. PMID:24089420

  15. The Arabidopsis COPT6 transport protein functions in copper distribution under copper-deficient conditions.

    PubMed

    Garcia-Molina, Antoni; Andrés-Colás, Nuria; Perea-García, Ana; Neumann, Ulla; Dodani, Sheel C; Huijser, Peter; Peñarrubia, Lola; Puig, Sergi

    2013-08-01

    Copper (Cu), an essential redox active cofactor, participates in fundamental biological processes, but it becomes highly cytotoxic when present in excess. Therefore, living organisms have established suitable mechanisms to balance cellular and systemic Cu levels. An important strategy to maintain Cu homeostasis consists of regulating uptake and mobilization via the conserved family of CTR/COPT Cu transport proteins. In the model plant Arabidopsis thaliana, COPT1 protein mediates root Cu acquisition, whereas COPT5 protein functions in Cu mobilization from intracellular storage organelles. The function of these transporters becomes critical when environmental Cu bioavailability diminishes. However, little is know about the mechanisms that mediate plant Cu distribution. In this report, we present evidence supporting an important role for COPT6 in Arabidopsis Cu distribution. Similarly to COPT1 and COPT2, COPT6 fully complements yeast mutants defective in high-affinity Cu uptake and localizes to the plasma membrane of Arabidopsis cells. Whereas COPT2 mRNA is only up-regulated upon severe Cu deficiency, COPT6 transcript is expressed under Cu excess conditions and displays a more gradual increase in response to decreases in environmental Cu levels. Consistent with COPT6 expression in aerial vascular tissues and reproductive organs, copt6 mutant plants exhibit altered Cu distribution under Cu-deficient conditions, including increased Cu in rosette leaves but reduced Cu levels in seeds. This altered Cu distribution is fully rescued when the wild-type COPT6 gene is reintroduced into the copt6 mutant line. Taken together, these findings highlight the relevance of COPT6 in shoot Cu redistribution when environmental Cu is limited.

  16. Delivery of orally supplemented alpha-tocotrienol to vital organs of rats and tocopherol-transport protein deficient mice.

    PubMed

    Khanna, Savita; Patel, Viren; Rink, Cameron; Roy, Sashwati; Sen, Chandan K

    2005-11-15

    The natural vitamin E tocotrienol (TCT) possesses biological properties not shared by tocopherols (TCP). Nanomolar alpha-TCT, not alpha-TCP, is potently neuroprotective (JBC 275:13049; 278:43508). Tocopherol-transport protein (TTP) represents the primary mechanism for maintaining normal alpha-TCP concentrations in plasma and extrahepatic tissues. TTP primarily transports alpha-TCP and has low affinity for alpha-TCT. There are no studies that have investigated tissue delivery of alpha-TCT when orally gavaged on a long-term basis. A long-term study was conducted to examine the effects of alpha-TCT or alpha-TCP supplementation, either alone or in combination, on tissue levels. Rats were maintained on a vitamin E-deficient diet and gavaged with alpha-TCT or alpha-TCP alone or in combination. Five generations of rats were studied over 60 weeks. TTP-deficient mice were supplemented with TCT and bred to examine tissue delivery of oral alpha-TCT. Orally supplemented alpha-TCT was effectively delivered to most tissues over time. When co-supplemented, alpha-TCP outcompeted alpha-TCT for transport systems delivering vitamin E to tissues. To evaluate the significance of TTP in alpha-TCT delivery to tissues, tissue levels of alpha-TCT in supplemented TTP-deficient mice were studied. alpha-TCT was transported to several vital organs in TTP-deficient mice. alpha-TCT restored fertility in TTP-deficient mice. In sum, orally supplemented alpha-TCT was successfully delivered to several vital organs. The transport efficiency of alpha-TCT to tissues may be maximized by eliminating the co-presence of alpha-TCP in the oral supplement. Examination of whether alpha-TCT may benefit humans suffering from neurological disorders because of congenital TTP deficiency is warranted.

  17. Salicylic acid-induced elicitation of folates in coriander (Coriandrum sativum L.) improves bioaccessibility and reduces pro-oxidant status.

    PubMed

    Puthusseri, Bijesh; Divya, Peethambaran; Lokesh, Veeresh; Neelwarne, Bhagyalakshmi

    2013-01-15

    Foliage of Coriandrum sativum is a rich source of natural folates amenable for enhancement through salicylic acid-mediated elicitation, thereby holding a great promise for natural-mode alleviation of this vitamin (B(9)) deficiency. In the present study we report salicylic acid-mediated differential elicitation of different forms of folates - 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and 10-formyltetrahydrofolate - their stabilities during microwave-drying and bioaccessibilities from fresh and dried foliage. The first two compounds nearly doubled and the third increased sixfold post-elicitation, with all three showing concomitant increase in bioaccessibilities. Although a slight decrease in bioaccessibility was observed in dried foliage, over twofold increase of each form of folate upon elicitation would deliver much higher levels of natural folates from this traditional culinary foliage, which is widely used in many cuisines. Elicitor-mediated folate enhancement also imparted reduction of oxidative status and the enhancement of antioxidant enzyme activities in coriander foliage.

  18. Enhancement of folate content and its stability using food grade elicitors in coriander (Coriandrum sativum L.).

    PubMed

    Puthusseri, Bijesh; Divya, Peethambaran; Lokesh, Veeresh; Neelwarne, Bhagyalakshmi

    2012-06-01

    Folate (vitamin B₉) content was evaluated in 10 varieties of coriander with the aim of enhancing its concentration and stability, because of three reasons: 1) coriander is among a few widely used greens in the world and suits many cuisines, 2) folate deficiency is prevalent in developing countries causing anaemia, infant mortality and neural tube closure defects, and 3) natural folate is preferred due to doubts about health risks associated with the synthetic form. In C. sativum, the highest folate content of 1,577 μg/100 g DW was found in var. GS4 Multicut foliage of mature plants (marketable stage) with an insignificantly higher content (1,599.74 μg/100 g DW) at flowering, which is a stage not preferred in markets. In callus cultures treated with plant growth regulators (GRs) (6-benzylaminopurine, kinetin and abscisic acid) substantial increase in folate occurred after 6 h, whereas elicitors (methyl jasmonate and salicylic acid) caused rapid 2-fold increase of folate, particularly in response to salicylic acid. Based on these observations, foliar applications were done for in vivo plants, where salicylic acid (250 μM, 24 h) also enhanced folate level by 2-folds (3,112.33 μg/100 g DW), although the content varied with diurnal rhythms. Stability of folates in treated coriander foliage was 10 % higher than in untreated foliage when stored at 25 °C and 4 °C. This study has established for the first time that coriander foliage is rich in folates, which can be doubled by elicitation and impart 10 % more stability than control during processing and storage.

  19. Lifestyle and genetic determinants of folate and vitamin B12 levels in a general adult population.

    PubMed

    Thuesen, Betina H; Husemoen, Lise Lotte N; Ovesen, Lars; Jørgensen, Torben; Fenger, Mogens; Linneberg, Allan

    2010-04-01

    Danish legislation regarding food fortification has been very restrictive resulting in few fortified food items on the Danish market. Folate and vitamin B12 deficiency is thought to be common due to inadequate intakes but little is known about the actual prevalence of low serum folate and vitamin B12 in the general population. The aim of the present study was to evaluate the folate and vitamin B12 status of Danish adults and to investigate associations between vitamin status and distinct lifestyle and genetic factors. The study included a random sample of 6784 individuals aged 30-60 years. Information on lifestyle factors was obtained by questionnaires and blood samples were analysed for serum folate and vitamin B12 concentrations and several genetic polymorphisms. The overall prevalence of low serum folate ( < 6.8 nmol/l) was 31.4 %. Low serum folate was more common among men than women and the prevalence was lower with increasing age. Low serum folate was associated with smoking, low alcohol intake, high coffee intake, unhealthy diet, and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR)-C677T polymorphism. The overall prevalence of low serum vitamin B12 ( < 148 pmol/l) was 4.7 %. Low serum vitamin B12 was significantly associated with female sex, high coffee intake, low folate status, and the TT genotype of the MTHFR-C677T polymorphism. In conclusion, low serum folate was present in almost a third of the adult population in the present study and was associated with several lifestyle factors whereas low serum concentrations of vitamin B12 were less common and only found to be associated with a few lifestyle factors.

  20. Neural tube defects: pathogenesis and folate metabolism.

    PubMed

    Pulikkunnel, Scaria T; Thomas, S V

    2005-02-01

    Neural tube defects (NTDs) are a group of congenital malformations with worldwide distribution and complex aetio-pathogenesis. Animal studies indicate that there may be four sites of initiation of neural tube closure (NTC). Selective involvement of these sites may lead to defects varying from anencephaly to spina bifida. The NTC involves formation of medial and dorsolateral hinge points, convergent extension and a zipper release process. Proliferation and migration of neuroectodermal cells and its morphological changes brought about by microfilaments and other cytoskeletal proteins mediate NTC. Genetic, nutritional and teratogenic mechanisms have been implicated in the pathogenesis of NTDs. Folate is an important component in one carbon metabolism that provides active moieties for synthesis of nucleic acids and proteins. Several gene defects affecting enzymes and proteins involved in transport and metabolism of folate have been associated with NTDs. It may be possible in future, to identify individuals at higher risk of NTDs by genetic studies. Epidemiological and clinical studies have shown that dietary supplementation or food fortification with folic acid would reduce the incidence of NTDs. The protective effect of folic acid may be by overcoming these metabolic blocks through unidentified mechanisms. Genetic and biochemical studies on foetal cells may supplement currently available prenatal tests to diagnose NTDs. Antiepileptic drugs (AEDs), particularly valproate and carbamazepine have been shown to increase the risk of NTDs by possibly increasing the oxidative stress and deranging the folate metabolism. Accordingly, it is recommended that all women taking AEDs may use 1-5 mg folic acid daily in the pre conception period and through pregnancy.

  1. FOLATE CONTENT IN SELECT DRY BEAN GENOTYPES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dry edible beans are a good natural source of folate (½-cup serving of cooked beans provide 35% daily value of folate). Recognized healthful benefits of folate in the human diet include reduced birth defects, decreased plasma homocysteine level which is a risk factor in cardiovascular disease, reduc...

  2. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism.

    PubMed

    Reed, Michael C; Nijhout, H Frederik; Neuhouser, Marian L; Gregory, Jesse F; Shane, Barry; James, S Jill; Boynton, Alanna; Ulrich, Cornelia M

    2006-10-01

    Impaired folate-mediated 1-carbon metabolism has been linked to multiple disease outcomes. A better understanding of the nutritional and genetic influences on this complex biochemical pathway is needed to comprehend their impact on human health. To this end, we created a mathematical model of folate-mediated 1-carbon metabolism. The model uses published data on folate enzyme kinetics and regulatory mechanisms to simulate the impact of genetic and nutritional variation on critical aspects of the pathway. We found that the model predictions match experimental data, while providing novel insights into pathway kinetics. Our primary observations were as follows: 1) the inverse association between folate and homocysteine is strongest at very low folate concentrations, but there is no association at high folate concentrations; 2) the DNA methylation reaction rate is relatively insensitive to changes in folate pool size; and 3) as folate concentrations become very high, enzyme velocities decrease. With regard to polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), the modeling predicts that decrease MTHFR activity reduces concentrations of S-adenosylmethionine and 5-methyltetrahydrofolate, as well as DNA methylation, while modestly increasing S-adenosylhomocysteine and homocysteine concentrations and thymidine or purine synthesis. Decreased folate together with a simulated vitamin B-12 deficiency results in decreases in DNA methylation and purine and thymidine synthesis. Decreased MTHFR activity superimposed on the B-12 deficiency appears to reverse the declines in purine and thymidine synthesis. These mathematical simulations of folate-mediated 1-carbon metabolism provide a cost-efficient approach to in silico experimentation that can complement and help guide laboratory studies.

  3. Generation of boron-deficiency-tolerant tomato by overexpressing an Arabidopsis thaliana borate transporter AtBOR1.

    PubMed

    Uraguchi, Shimpei; Kato, Yuichi; Hanaoka, Hideki; Miwa, Kyoko; Fujiwara, Toru

    2014-01-01

    Nutrient deficiency in soil poses a widespread agricultural problem. Boron (B) is an essential micronutrient in plants, and its deficiency causes defects in both vegetative and reproductive growth in various crops in the field. In Arabidopsis thaliana, increased expression of a major borate transporter gene AtBOR1 or boric acid channel gene AtNIP5;1 improves plant growth under B-deficient conditions. In this study, we examined whether high expression of a borate transporter gene increases B accumulation in shoots and improves the growth of tomato plant, a model of fruit-bearing crops, under B-deficient conditions. We established three independent transgenic tomato plants lines expressing AtBOR1 using Agrobacterium-mediated transformation of tomato (Solanum lycopersicum L. cv. Micro-Tom). Reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed that two lines (Line 1 and Line 2) more strongly expressed AtBOR1 than Line 3. Wild-type plants and the transgenic plants were grown hydroponically under B-sufficient and B-deficient conditions. Wild-type and Line 3 (weakly expressing transgenic line) showed a defect in shoot growth under B-deficient conditions, especially in the development of new leaves. However, seedlings of Line 1 and Line 2, the transgenic lines showing strong AtBOR1 expression, did not show the B-deficiency phenotype in newly developing leaves. In agreement with this phenotype, shoot biomass under low-B conditions was higher in the strongly expressing AtBOR1 line. B concentrations in leaves or fruits were also higher in Line 2 and Line 1. The present study demonstrates that strong expression of AtBOR1 improved growth in tomato under B-deficient conditions.

  4. Generation of boron-deficiency-tolerant tomato by overexpressing an Arabidopsis thaliana borate transporter AtBOR1

    PubMed Central

    Uraguchi, Shimpei; Kato, Yuichi; Hanaoka, Hideki; Miwa, Kyoko; Fujiwara, Toru

    2014-01-01

    Nutrient deficiency in soil poses a widespread agricultural problem. Boron (B) is an essential micronutrient in plants, and its deficiency causes defects in both vegetative and reproductive growth in various crops in the field. In Arabidopsis thaliana, increased expression of a major borate transporter gene AtBOR1 or boric acid channel gene AtNIP5;1 improves plant growth under B-deficient conditions. In this study, we examined whether high expression of a borate transporter gene increases B accumulation in shoots and improves the growth of tomato plant, a model of fruit-bearing crops, under B-deficient conditions. We established three independent transgenic tomato plants lines expressing AtBOR1 using Agrobacterium-mediated transformation of tomato (Solanum lycopersicum L. cv. Micro-Tom). Reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed that two lines (Line 1 and Line 2) more strongly expressed AtBOR1 than Line 3. Wild-type plants and the transgenic plants were grown hydroponically under B-sufficient and B-deficient conditions. Wild-type and Line 3 (weakly expressing transgenic line) showed a defect in shoot growth under B-deficient conditions, especially in the development of new leaves. However, seedlings of Line 1 and Line 2, the transgenic lines showing strong AtBOR1 expression, did not show the B-deficiency phenotype in newly developing leaves. In agreement with this phenotype, shoot biomass under low-B conditions was higher in the strongly expressing AtBOR1 line. B concentrations in leaves or fruits were also higher in Line 2 and Line 1. The present study demonstrates that strong expression of AtBOR1 improved growth in tomato under B-deficient conditions. PMID:24744768

  5. 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

  6. Preliminary Evidence of Apathetic-Like Behavior in Aged Vesicular Monoamine Transporter 2 Deficient Mice

    PubMed Central

    Baumann, Aron; Moreira, Carlos G.; Morawska, Marta M.; Masneuf, Sophie; Baumann, Christian R.; Noain, Daniela

    2016-01-01

    Apathy is considered to be a core feature of Parkinson’s disease (PD) and has been associated with a variety of states and symptoms of the disease, such as increased severity of motor symptoms, impaired cognition, executive dysfunction and dementia. Apart from the high prevalence of apathy in PD, which is estimated to be about 40%, the underlying pathophysiology remains poorly understood and current treatment approaches are unspecific and proved to be only partially effective. In animal models, apathy has been sub-optimally modeled, mostly by means of pharmacological and stress-induced methods, whereby concomitant depressive-like symptoms could not be ruled out. In the context of PD only a few studies on toxin-based models (i.e., 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)) claimed to have determined apathetic symptoms in animals. The assessment of apathetic symptoms in more elaborated and multifaceted genetic animal models of PD could help to understand the pathophysiological development of apathy in PD and eventually advance specific treatments for afflicted patients. Here we report the presence of behavioral signs of apathy in 12 months old mice that express only ~5% of the vesicular monoamine transporter 2 (VMAT2). Apathetic-like behavior in VMAT2 deficient (LO) mice was evidenced by impaired burrowing and nest building skills, and a reduced preference for sweet solution in the saccharin preference test, while the performance in the forced swimming test was normal. Our preliminary results suggest that VMAT2 deficient mice show an apathetic-like phenotype that might be independent of depressive-like symptoms. Therefore VMAT2 LO mice could be a useful tool to study the pathophysiological substrates of apathy and to test novel treatment strategies for apathy in the context of PD. PMID:27917116

  7. Selenium, Folate, and Colon Cancer

    PubMed Central

    Connelly-Frost, Alexandra; Poole, Charles; Satia, Jessie A.; Kupper, Lawrence L.; Millikan, Robert C.; Sandler, Robert S.

    2009-01-01

    Background Selenium is an essential trace element which has been implicated in cancer risk; however, study results have been inconsistent with regard to colon cancer. Our objectives were to 1) investigate the association between selenium and colon cancer 2) evaluate possible effect measure modifiers and 3) evaluate potential biases associated with the use of post-diagnostic serum selenium measures Methods The North Carolina Colon Cancer Study is a large population-based, case-control study of colon cancer in North Carolina between 1996 and 2000 (n=1,691). Nurses interviewed patients about diet and lifestyle and drew blood specimens which were used to measure serum selenium. Results Individuals who had both high serum selenium (>140 mcg/L) and high reported folate (>354 mcg/day), had a reduced relative risk of colon cancer (OR=0.5, 95% CI=0.4,0.8). The risk of colon cancer for those with high selenium and low folate was approximately equal to the risk among those with low selenium and low folate (OR=1.1, 95% CI=0.7,1.5) as was the risk for those with low selenium and high folate (OR=0.9, 95% CI=0.7–1.2). We did not find evidence of bias due to weight loss, stage at diagnosis, or time from diagnosis to selenium measurement. Conclusion High levels of serum selenium and reported folate jointly were associated with a substantially reduced risk of colon cancer. Folate status should be taken into account when evaluating the relation between selenium and colon cancer in future studies. Importantly, weight loss, stage at diagnosis, or time from diagnosis to blood draw did not appear to produce strong bias in our study. PMID:19235033

  8. Nutritional Deficiencies and Phospholipid Metabolism

    PubMed Central

    Gimenez, María S.; Oliveros, Liliana B.; Gomez, Nidia N.

    2011-01-01

    Phospholipids are important components of the cell membranes of all living species. They contribute to the physicochemical properties of the membrane and thus influence the conformation and function of membrane-bound proteins, such as receptors, ion channels, and transporters and also influence cell function by serving as precursors for prostaglandins and other signaling molecules and modulating gene expression through the transcription activation. The components of the diet are determinant for cell functionality. In this review, the effects of macro and micronutrients deficiency on the quality, quantity and metabolism of different phospholipids and their distribution in cells of different organs is presented. Alterations in the amount of both saturated and polyunsaturated fatty acids, vitamins A, E and folate, and other micronutrients, such as zinc and magnesium, are discussed. In all cases we observe alterations in the pattern of phospholipids, the more affected ones being phosphatidylcholine, phosphatidylethanolamine and sphingomyelin. The deficiency of certain nutrients, such as essential fatty acids, fat-soluble vitamins and some metals may contribute to a variety of diseases that can be irreversible even after replacement with normal amount of the nutrients. Usually, the sequelae are more important when the deficiency is present at an early age. PMID:21731449

  9. Molecular cloning and tissue distribution of reduced folate carrier and effect of dietary folate supplementation on the expression of reduced folate carrier in laying hens.

    PubMed

    Jing, M; Tactacan, G B; Rodriguez-Lecompte, J C; Kroeker, A; House, J D

    2009-09-01

    The reduced folate carrier (RFC) has been postulated to be a major entity for folate transport activity in humans and other mammals. However, there are limited reports of the importance of RFC in an avian system. In the current study, therefore, the molecular cloning and tissue distribution of RFC, as well as the effect of dietary folate supplementation on the expression of this transporter, were investigated in the chicken. Shaver White laying hens (n=8 per diet) received 3 wheat-based diets containing the following: 1) no supplemental folate, 2) folic acid (10.00 mg/kg), or 3) 5-methyltetrahydrofolate (11.30 mg/kg) for 21 d. The mRNA expression levels were analyzed by quantitative real-time PCR. The results showed that the cloned partial RFC cDNA containing the full coding region from duodenum was 99% homologous to the reference gene available in GenBank. A broad expression profile of RFC transcripts was observed, with RFC mRNA detected in the brain, liver, kidney, spleen, lung, intestine, ovary, and testis, as well as other tissues. Real-time PCR analysis revealed that no significant differences (P>0.05) due to diet were found in the mRNA levels of RFC in the duodenum and cecum. However, compared with the basal diet, jejunal mRNA levels of RFC were decreased (P<0.05) in hens fed with the 5-methyltetrahydrofolate diet, but the reduction did not reach significance (P=0.077) in the hens fed the folic acid diet. Overall, the current study demonstrated that the RFC cDNA containing the full coding region was successfully cloned from the duodenum of laying hens. The wide tissue distribution of RFC transcripts is suggestive of an important role of RFC in the process of folate transport in the chicken. Moreover, dietary folate supplementation could downregulate the jejunal mRNA expression of RFC. Such findings will lay the foundation of future work involving the RFC in avian systems, including laying hens.

  10. An Arabidopsis ABC Transporter Mediates Phosphate Deficiency-Induced Remodeling of Root Architecture by Modulating Iron Homeostasis in Roots.

    PubMed

    Dong, Jinsong; Piñeros, Miguel A; Li, Xiaoxuan; Yang, Haibing; Liu, Yu; Murphy, Angus S; Kochian, Leon V; Liu, Dong

    2017-02-13

    The remodeling of root architecture is a major developmental response of plants to phosphate (Pi) deficiency and is thought to enhance a plant's ability to forage for the available Pi in topsoil. The underlying mechanism controlling this response, however, is poorly understood. In this study, we identified an Arabidopsis mutant, hps10 (hypersensitive to Pi starvation 10), which is morphologically normal under Pi sufficient condition but shows increased inhibition of primary root growth and enhanced production of lateral roots under Pi deficiency. hps10 is a previously identified allele (als3-3) of the ALUMINUM SENSITIVE3 (ALS3) gene, which is involved in plant tolerance to aluminum toxicity. Our results show that ALS3 and its interacting protein AtSTAR1 form an ABC transporter complex in the tonoplast. This protein complex mediates a highly electrogenic transport in Xenopus oocytes. Under Pi deficiency, als3 accumulates higher levels of Fe(3+) in its roots than the wild type does. In Arabidopsis, LPR1 (LOW PHOSPHATE ROOT1) and LPR2 encode ferroxidases, which when mutated, reduce Fe(3+) accumulation in roots and cause root growth to be insensitive to Pi deficiency. Here, we provide compelling evidence showing that ALS3 cooperates with LPR1/2 to regulate Pi deficiency-induced remodeling of root architecture by modulating Fe homeostasis in roots.

  11. New insights into erythropoiesis: the roles of folate, vitamin B12, and iron.

    PubMed

    Koury, Mark J; Ponka, Prem

    2004-01-01

    Erythropoiesis is the process in which new erythrocytes are produced. These new erythrocytes replace the oldest erythrocytes (normally about one percent) that are phagocytosed and destroyed each day. Folate, vitamin B12, and iron have crucial roles in erythropoiesis. Erythroblasts require folate and vitamin B12 for proliferation during their differentiation. Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis, and causes erythroblast apoptosis, resulting in anemia from ineffective erythropoiesis. Erythroblasts require large amounts of iron for hemoglobin synthesis. Large amounts of iron are recycled daily with hemoglobin breakdown from destroyed old erythrocytes. Many recently identified proteins are involved in absorption, storage, and cellular export of nonheme iron and in erythroblast uptake and utilization of iron. Erythroblast heme levels regulate uptake of iron and globin synthesis such that iron deficiency causes anemia by retarded production rates with smaller, less hemoglobinized erythrocytes.

  12. A Humanized Mouse Model for the Reduced Folate Carrier

    PubMed Central

    Patterson, David; Graham, Christine; Cherian, Christina; Matherly, Larry H.

    2008-01-01

    The ubiquitously expressed reduced folate carrier (RFC) or SLC19A1 is recognized to be an essential transport system for folates in mammalian cells and tissues. In addition to its generalized role as a folate transporter, RFC provides specialized tissue functions including absorption across intestinal/colonic epithelia, transport across the basolateral membrane of renal proximal tubules, transplacental transport of folates, and folate transport across the blood-brain barrier. The human RFC (hRFC) gene is regulated by 5 major upstream non-coding regions (designated A1/A2, A, B, C, and D), each transcribed from a unique promoter. Altogether, at least 14 distinct hRFC transcripts can be envisaged in which different 5’ untranslated regions (UTRs) are fused to a common splice acceptor region (positions -1 to -49) within the first coding exon with a common 1776 bp coding sequence. The 5’ non-coding regions are characterized by alternate transcription start sites, multiple splice forms, and selective tissue distributions. Alternate 5’UTRs impact mRNA stabilities and translation efficiencies, and result in synthesis of modified hRFC proteins translated from upstream AUGs. In this report, we describe production and characterization of transgenic mice (TghRFC1) containing a functional hRFC gene and of humanized mice in which the mRFC gene is inactivated and an active hRFC gene has been introduced. The mice appear to be healthy and to breed well. Analysis of tissue specificity of expression in both the TghRFC1 and humanized hRFC mice by real-time RT-PCR demonstrates that the hRFC gene is expressed with a specificity closely resembling that seen in human tissues. For the humanized hRFC mice, levels of B and A1/A2 5’UTRs predominated in all mice/tissues, thus resembling results in normal human tissues. Lower levels of A and C 5’UTRs were also detected. The availability of humanized mouse models for hRFC will permit investigators to address critical unanswered

  13. Duodenal expression of iron transport molecules in patients with hereditary hemochromatosis or iron deficiency

    PubMed Central

    Dostalikova-Cimburova, Marketa; Kratka, Karolina; Balusikova, Kamila; Chmelikova, Jitka; Hejda, Vaclav; Hnanicek, Jan; Neubauerova, Jitka; Vranova, Jana; Kovar, Jan; Horak, Jiri

    2012-01-01

    Abstract Disturbances of iron metabolism are observed in chronic liver diseases. In the present study, we examined gene expression of duodenal iron transport molecules and hepcidin in patients with hereditary hemochromatosis (HHC) (treated and untreated), involving various genotypes (genotypes which represent risk for HHC were examined), and in patients with iron deficiency anaemia (IDA). Gene expressions of DMT1, ferroportin, Dcytb, hephaestin, HFE and TFR1 were measured in duodenal biopsies using real-time PCR and Western blot. Serum hepcidin levels were measured using ELISA. DMT1, ferroportin and TFR1 mRNA levels were significantly increased in post-phlebotomized hemochromatics relative to controls. mRNAs of all tested molecules were significantly increased in patients with IDA compared to controls. The protein expression of ferroportin was increased in both groups of patients but not significantly. Spearman rank correlations showed that DMT1 versus ferroportin, Dcytb versus hephaestin and DMT1 versus TFR1 mRNAs were positively correlated regardless of the underlying cause, similarly to protein levels of ferroportin versus Dcytb and ferroportin versus hephaestin. Serum ferritin was negatively correlated with DMT1 mRNA in investigated groups of patients, except for HHC group. A decrease of serum hepcidin was observed in IDA patients, but this was not statistically significant. Our data showed that although untreated HHC patients do not have increased mRNA levels of iron transport molecules when compared to normal subjects, the expression is relatively increased in relation to body iron stores. On the other hand, post-phlebotomized HHC patients had increased DMT1 and ferroportin mRNA levels possibly due to stimulated erythropoiesis after phlebotomy. PMID:21973163

  14. Impact of monocarboxylate transporter-8 deficiency on the hypothalamus-pituitary-thyroid axis in mice.

    PubMed

    Trajkovic-Arsic, Marija; Müller, Julia; Darras, Veerle M; Groba, Claudia; Lee, Sooyeon; Weih, Debra; Bauer, Karl; Visser, Theo J; Heuer, Heike

    2010-10-01

    In patients, inactivating mutations in the gene encoding the thyroid hormone-transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels.

  15. Astroglial Glutamate Transporter Deficiency Increases Synaptic Excitability and Leads to Pathological Repetitive Behaviors in Mice

    PubMed Central

    Aida, Tomomi; Yoshida, Junichi; Nomura, Masatoshi; Tanimura, Asami; Iino, Yusuke; Soma, Miho; Bai, Ning; Ito, Yukiko; Cui, Wanpeng; Aizawa, Hidenori; Yanagisawa, Michiko; Nagai, Terumi; Takata, Norio; Tanaka, Kenji F; Takayanagi, Ryoichi; Kano, Masanobu; Götz, Magdalena; Hirase, Hajime; Tanaka, Kohichi

    2015-01-01

    An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLASTCreERT2/+/GLT1flox/flox, iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors. PMID:25662838

  16. Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.

    PubMed

    Aida, Tomomi; Yoshida, Junichi; Nomura, Masatoshi; Tanimura, Asami; Iino, Yusuke; Soma, Miho; Bai, Ning; Ito, Yukiko; Cui, Wanpeng; Aizawa, Hidenori; Yanagisawa, Michiko; Nagai, Terumi; Takata, Norio; Tanaka, Kenji F; Takayanagi, Ryoichi; Kano, Masanobu; Götz, Magdalena; Hirase, Hajime; Tanaka, Kohichi

    2015-06-01

    An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.

  17. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS).

    PubMed

    Pearson, Toni S; Akman, Cigdem; Hinton, Veronica J; Engelstad, Kristin; De Vivo, Darryl C

    2013-04-01

    Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.

  18. Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency.

    PubMed

    Vos, Melissa; Geens, Ann; Böhm, Claudia; Deaulmerie, Liesbeth; Swerts, Jef; Rossi, Matteo; Craessaerts, Katleen; Leites, Elvira P; Seibler, Philip; Rakovic, Aleksandar; Lohnau, Thora; De Strooper, Bart; Fendt, Sarah-Maria; Morais, Vanessa A; Klein, Christine; Verstreken, Patrik

    2017-03-06

    PINK1 is mutated in Parkinson's disease (PD), and mutations cause mitochondrial defects that include inefficient electron transport between complex I and ubiquinone. Neurodegeneration is also connected to changes in lipid homeostasis, but how these are related to PINK1-induced mitochondrial dysfunction is unknown. Based on an unbiased genetic screen, we found that partial genetic and pharmacological inhibition of fatty acid synthase (FASN) suppresses toxicity induced by PINK1 deficiency in flies, mouse cells, patient-derived fibroblasts, and induced pluripotent stem cell-derived dopaminergic neurons. Lower FASN activity in PINK1 mutants decreases palmitate levels and increases the levels of cardiolipin (CL), a mitochondrial inner membrane-specific lipid. Direct supplementation of CL to isolated mitochondria not only rescues the PINK1-induced complex I defects but also rescues the inefficient electron transfer between complex I and ubiquinone in specific mutants. Our data indicate that genetic or pharmacologic inhibition of FASN to increase CL levels bypasses the enzymatic defects at complex I in a PD model.

  19. A parametric study of golf car and personal transport vehicle braking stability and their deficiencies.

    PubMed

    Seluga, Kristopher J; Baker, Lowell L; Ojalvo, Irving U

    2009-07-01

    This paper describes research and parametric analyses of braking effectiveness and directional stability for golf cars, personal transport vehicles (PTVs) and low speed vehicles (LSVs). It is shown that current designs, which employ brakes on only the rear wheels, can lead to rollovers if the brakes are applied while traveling downhill. After summarizing the current state of existing safety standards and brake system designs, both of which appear deficient from a safety perspective, a previously developed dynamic simulation model is used to identify which parameters have the greatest influence on the vehicles' yaw stability. The simulation results are then used to parametrically quantify which combination of these factors can lead to yaw induced rollover during hard braking. Vehicle velocity, steering input, path slope and tire friction are all identified as important parameters in determining braking stability, the effects of which on rollover propensity are presented graphically. The results further show that when vehicles are equipped with front brakes or four-wheel brakes, the probability of a yaw induced rollover is almost entirely eliminated. Furthermore, the parametric charts provided may be used as an aid in developing guidelines for golf car and PTV path design if rear brake vehicles are used.

  20. Folate in oats and its milling fractions.

    PubMed

    Edelmann, Minnamari; Kariluoto, Susanna; Nyström, Laura; Piironen, Vieno

    2012-12-01

    Total folate content in oat varieties from three harvesting years (2006-2008), and in oats milling fractions, was determined using microbiological assay. Furthermore, folate vitamer distribution in milling fractions were examined with the UPLC method, which was taken in use and validated. The total folate content of the cultivars varied moderately within each year. The average content in the 2008 samples was 685ng/gdm. The UPLC method proved fast and sensitive for determining seven folate monoglutamates in cereal samples. Folate content in fractions, which are normally discarded, such as flour from oat cutting and flaking, were 1.5- to 2.5-fold higher than in native grain. The main folate vitamers found in the oat fractions were 5-CH(3)-H(4)folate, 5-HCO-H(4)folate, and 5,10-CH(+)-H(4)folate. The UPLC results more closely matched the microbiological results compared to those that are usually achieved with HPLC methods. This study illustrates that oats and, especially, by-products of milling are good sources of folate.

  1. Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: a treatable cause of Leigh syndrome.

    PubMed

    Ortigoza-Escobar, Juan Darío; Molero-Luis, Marta; Arias, Angela; Oyarzabal, Alfonso; Darín, Niklas; Serrano, Mercedes; Garcia-Cazorla, Angels; Tondo, Mireia; Hernández, María; Garcia-Villoria, Judit; Casado, Mercedes; Gort, Laura; Mayr, Johannes A; Rodríguez-Pombo, Pilar; Ribes, Antonia; Artuch, Rafael; Pérez-Dueñas, Belén

    2016-01-01

    Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid.

  2. Arabidopsis copper transport protein COPT2 participates in the cross talk between iron deficiency responses and low-phosphate signaling.

    PubMed

    Perea-García, Ana; Garcia-Molina, Antoni; Andrés-Colás, Nuria; Vera-Sirera, Francisco; Pérez-Amador, Miguel A; Puig, Sergi; Peñarrubia, Lola

    2013-05-01

    Copper and iron are essential micronutrients for most living organisms because they participate as cofactors in biological processes, including respiration, photosynthesis, and oxidative stress protection. In many eukaryotic organisms, including yeast (Saccharomyces cerevisiae) and mammals, copper and iron homeostases are highly interconnected; yet, such interdependence is not well established in higher plants. Here, we propose that COPT2, a high-affinity copper transport protein, functions under copper and iron deficiencies in Arabidopsis (Arabidopsis thaliana). COPT2 is a plasma membrane protein that functions in copper acquisition and distribution. Characterization of the COPT2 expression pattern indicates a synergic response to copper and iron limitation in roots. We characterized a knockout of COPT2, copt2-1, that leads to increased resistance to simultaneous copper and iron deficiencies, measured as reduced leaf chlorosis and improved maintenance of the photosynthetic apparatus. We propose that COPT2 could play a dual role under iron deficiency. First, COPT2 participates in the attenuation of copper deficiency responses driven by iron limitation, possibly to minimize further iron consumption. Second, global expression analyses of copt2-1 versus wild-type Arabidopsis plants indicate that low-phosphate responses increase in the mutant. These results open up new biotechnological approaches to fight iron deficiency in crops.

  3. Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize.

    PubMed

    Marasas, Walter F O; Riley, Ronald T; Hendricks, Katherine A; Stevens, Victoria L; Sadler, Thomas W; Gelineau-van Waes, Janee; Missmer, Stacey A; Cabrera, Julio; Torres, Olga; Gelderblom, Wentzel C A; Allegood, Jeremy; Martínez, Carolina; Maddox, Joyce; Miller, J David; Starr, Lois; Sullards, M Cameron; Roman, Ana Victoria; Voss, Kenneth A; Wang, Elaine; Merrill, Alfred H

    2004-04-01

    Fumonisins are a family of toxic and carcinogenic mycotoxins produced by Fusarium verticillioides (formerly Fusarium moniliforme), a common fungal contaminant of maize. Fumonisins inhibit ceramide synthase, causing accumulation of bioactive intermediates of sphingolipid metabolism (sphinganine and other sphingoid bases and derivatives) as well as depletion of complex sphingolipids, which interferes with the function of some membrane proteins, including the folate-binding protein (human folate receptor alpha). Fumonisin causes neural tube and craniofacial defects in mouse embryos in culture. Many of these effects are prevented by supplemental folic acid. Recent studies in LMBc mice found that fumonisin exposure in utero increases the frequency of developmental defects and administration of folate or a complex sphingolipid is preventive. High incidences of neural tube defects (NTD) occur in some regions of the world where substantial consumption of fumonisins has been documented or plausibly suggested (Guatemala, South Africa, and China); furthermore, a recent study of NTD in border counties of Texas found a significant association between NTD and consumption of tortillas during the first trimester. Hence, we propose that fumonisins are potential risk factors for NTD, craniofacial anomalies, and other birth defects arising from neural crest cells because of their apparent interference with folate utilization.

  4. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia.

    PubMed

    Fernández-Murray, J Pedro; Prykhozhij, Sergey V; Dufay, J Noelia; Steele, Shelby L; Gaston, Daniel; Nasrallah, Gheyath K; Coombs, Andrew J; Liwski, Robert S; Fernandez, Conrad V; Berman, Jason N; McMaster, Christopher R

    2016-01-01

    Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia.

  5. Glycine and Folate Ameliorate Models of Congenital Sideroblastic Anemia

    PubMed Central

    Dufay, J. Noelia; Steele, Shelby L.; Gaston, Daniel; Nasrallah, Gheyath K.; Coombs, Andrew J.; Liwski, Robert S.; Fernandez, Conrad V.; Berman, Jason N.; McMaster, Christopher R.

    2016-01-01

    Sideroblastic anemias are acquired or inherited anemias that result in a decreased ability to synthesize hemoglobin in red blood cells and result in the presence of iron deposits in the mitochondria of red blood cell precursors. A common subtype of congenital sideroblastic anemia is due to autosomal recessive mutations in the SLC25A38 gene. The current treatment for SLC25A38 congenital sideroblastic anemia is chronic blood transfusion coupled with iron chelation. The function of SLC25A38 is not known. Here we report that the SLC25A38 protein, and its yeast homolog Hem25, are mitochondrial glycine transporters required for the initiation of heme synthesis. To do so, we took advantage of the fact that mitochondrial glycine has several roles beyond the synthesis of heme, including the synthesis of folate derivatives through the glycine cleavage system. The data were consistent with Hem25 not being the sole mitochondrial glycine importer, and we identify a second SLC25 family member Ymc1, as a potential secondary mitochondrial glycine importer. Based on these findings, we observed that high levels of exogenous glycine, or 5-aminolevulinic acid (5-Ala) a metabolite downstream of Hem25 in heme biosynthetic pathway, were able to restore heme levels to normal in yeast cells lacking Hem25 function. While neither glycine nor 5-Ala could ameliorate SLC25A38 congenital sideroblastic anemia in a zebrafish model, we determined that the addition of folate with glycine was able to restore hemoglobin levels. This difference is likely due to the fact that yeast can synthesize folate, whereas in zebrafish folate is an essential vitamin that must be obtained exogenously. Given the tolerability of glycine and folate in humans, this study points to a potential novel treatment for SLC25A38 congenital sideroblastic anemia. PMID:26821380

  6. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport

    SciTech Connect

    Rebouche, C.J.; Engel, A.G.

    1984-03-01

    The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-(methyl-3H)carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and ''other tissues'') was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-(methyl-3H)carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.

  7. Compliance with Iron-Folate Supplement and Associated Factors among Antenatal Care Attendant Mothers in Misha District, South Ethiopia: Community Based Cross-Sectional Study

    PubMed Central

    Arega Sadore, Abinet; Abebe Gebretsadik, Lakew; Aman Hussen, Mamusha

    2015-01-01

    Background. In Ethiopia, higher proportions of pregnant women are anemic. Despite the efforts to reduce iron deficiency anemia during pregnancy, only few women took an iron supplement as recommended. Thus, this study aimed to assess compliance with iron-folate supplement and associated factors among antenatal care attendant mothers in Misha district, South Ethiopia. Method. Community based cross-sectional study supported with in-depth interview was conducted from March 1 to March 30, 2015. The sample size was determined using single population proportion to 303. Simple random sampling technique was used to select the study participants. Bivariate and multivariable logistic regression analyses were employed to identify factors associated with compliance to iron-folate supplement. Results. The compliance rate was found to be 39.2%. Mothers knowledge of anemia (AOR = 4.451, 95% CI = (2.027,9.777)), knowledge of iron-folate supplement (AOR = 3.509, 95% CI = (1.442,8.537)), and counseling on iron-folate supplement (AOR = 4.093, 95% CI = (2.002,8.368)) were significantly associated with compliance to iron-folate supplement. Conclusions. Compliance rate of iron-folate supplementation during pregnancy remains very low. This study showed that providing women with clear instructions about iron-folate tablet intake and educating them on the health benefits of the iron-folate tablets can increase compliance with iron-folate supplementation. PMID:26839573

  8. Professor John Scott, folate and neural tube defects.

    PubMed

    Hoffbrand, A Victor

    2014-02-01

    John Scott (1940-2013) was born in Dublin where he was to spend the rest of his career, both as an undergraduate and subsequently Professor of Biochemistry and Nutrition at Trinity College. His research with the talented group of scientists and clinicians that he led has had a substantial impact on our understanding of folate metabolism, mechanisms of its catabolism and deficiency. His research established the leading theory of folate involvement with vitamin B12 in the pathogenesis of vitamin B12 neuropathy. He helped to establish the normal daily intake of folate and the increased requirements needed either in food or as a supplement before and during pregnancy to prevent neural tube defects. He also suggested a dietary supplement of vitamin B12 before and during pregnancy to reduce the risk of neural tube defects. It would be an appropriate epitaph if fortification of food with folic acid became mandatory in the UK and Ireland, as it is in over 70 other countries.

  9. [Folate and folic acid intake estimation and food enrichment requirements].

    PubMed

    Olivares Martínez, Ana Belén; Ros Berruezo, Gaspar; Bernal Cava, M José; Martínez Graciá, Carmen; Periago Castón, M Jesús

    2005-03-01

    The term "folate" is a generic way to name the different forms derived from folic acid, one of the B vitamins (specifically B9 vitamin). They are essential in the metabolism when they act as cofactors in the transfer reactions of one carbon. However, only plants and microorganisms are able to synthesize them de novo, in such a way that both animals and human beings have to intake them through their diet. Folic acid is widely spread in nature, mainly in vegetables, liver ans cereals. However, nowadays, the lack of folates in the diet is one of the most common nutritional deficiencies in the world, and it has serious consequences on human health. There is evidence that even in developed countries folate intake is usually low; and even, is some cases, below optima levels. The authorities in several countries have adapted different norms related to folic acid, fortifying staple food such as dairy products or cereals, mandatory (U.S.A., Canada or Chile) or voluntary (most of the European countries).

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  11. Folate and vitamin B12 status and dietary intake of anaemic adolescent schoolgirls in the delta region of Myanmar.

    PubMed

    Htet, Min Kyaw; Fahmida, Umi; Thurnham, David I; Hlaing, Lwin Mar; Akib, Arwin; Utomo, Budi; Houghton, Lisa A

    2016-07-01

    The aim of the present study was to assess the prevalence of deficiency of folate and vitamin B12 and, simultaneously, the nutrient intake adequacy of folate, vitamin B12, iron, vitamin A, vitamin C, vitamin B6 and calcium in 391 adolescent anaemic (Hb<120 g/l) schoolgirls living in the delta region of Myanmar (Burma). Dietary intakes were assessed using a 3 d estimated food record. The distribution of observed intakes calculated from the food records were adjusted for usual intakes, and the prevalence of inadequacy was estimated using the estimated average requirement cut-point method. Median (first, third quartile) serum folate and vitamin B12 concentrations were 6·5 (4·6, 8·5) nmol/l and 612·8 (443·2, 795·2) pmol/l, respectively. The prevalence of folate deficiency defined as <6·8 nmol/l was 54 %; however, vitamin B12 deficiency defined as <148 pmol/l was negligible (<1 %). The prevalence of inadequate intake of folate was high (100 %) as was the prevalence of inadequate intakes of vitamin A, vitamin C, vitamin B6 and calcium, ranging from 60 to 100 %. Red meat or poultry was rarely consumed, but fish was consumed on a daily basis. Green leafy vegetables were also consumed frequently but consumption of dairy products was uncommon. Folate deficiency was high, and the prevalence of inadequate intake of folate among other key micronutrients was relatively common in this sample of anaemic adolescent schoolgirls. Appropriate strategies such as food fortification and dietary diversification are needed to improve the micronutrient status of these young women to ensure optimal health and future reproductive success.

  12. The Vacuolar Manganese Transporter MTP8 Determines Tolerance to Iron Deficiency-Induced Chlorosis in Arabidopsis1[OPEN

    PubMed Central

    2016-01-01

    Iron (Fe) deficiency is a widespread nutritional disorder on calcareous soils. To identify genes involved in the Fe deficiency response, Arabidopsis (Arabidopsis thaliana) transfer DNA insertion lines were screened on a high-pH medium with low Fe availability. This approach identified METAL TOLERANCE PROTEIN8 (MTP8), a member of the Cation Diffusion Facilitator family, as a critical determinant for the tolerance to Fe deficiency-induced chlorosis, also on soil substrate. Subcellular localization to the tonoplast, complementation of a manganese (Mn)-sensitive Saccharomyces cerevisiae yeast strain, and Mn sensitivity of mtp8 knockout mutants characterized the protein as a vacuolar Mn transporter suitable to prevent plant cells from Mn toxicity. MTP8 expression was strongly induced on low-Fe as well as high-Mn medium, which were both strictly dependent on the transcription factor FIT, indicating that high-Mn stress induces Fe deficiency. mtp8 mutants were only hypersensitive to Fe deficiency when Mn was present in the medium, which further suggested an Mn-specific role of MTP8 during Fe limitation. Under those conditions, mtp8 mutants not only translocated more Mn to the shoot than did wild-type plants but suffered in particular from critically low Fe concentrations and, hence, Fe chlorosis, although the transcriptional Fe deficiency response was up-regulated more strongly in mtp8. The diminished uptake of Fe from Mn-containing low-Fe medium by mtp8 mutants was caused by an impaired ability to boost the ferric chelate reductase activity, which is an essential process in Fe acquisition. These findings provide a mechanistic explanation for the long-known interference of Mn in Fe nutrition and define the molecular processes by which plants alleviate this antagonism. PMID:26668333

  13. Homocysteine, folate and pregnancy outcomes.

    PubMed

    Kim, M W; Hong, S-C; Choi, J S; Han, J-Y; Oh, M-J; Kim, H J; Nava-Ocampo, A; Koren, G

    2012-08-01

    The purpose of this study is to evaluate the relationship between maternal and/or cord blood folate/homocysteine concentrations and adverse pregnancy outcomes. The study population included a random sample of singleton pregnant women in whom we measured total homocysteine and folic acid in maternal or cord blood at deliveries. A total of 227 pregnant women were enrolled. The concentration of folate in maternal blood tended to be significantly lower in pre-term birth than in full-term delivery group (median (95% CI), 14.4 (3.6-73) vs 25 (7.3-105.5) p < 0.01). The total homocysteine in maternal and cord blood was significantly higher in the pre-eclampsia than in the normotensive group (7.9 (1.7-28.2) vs 5.9 (1.8-14.6) μmol/ml, p < 0.05; and 5.8 (2.6-14.4) vs 4.2 (0.7-7.9) ng/ml, p < 0.05, respectively). Lower maternal serum folate concentration is associated with pre-term delivery and higher maternal plasma homocysteine concentration with pre-eclampsia.

  14. RNA sequencing of creatine transporter (SLC6A8) deficient fibroblasts reveals impairment of the extracellular matrix.

    PubMed

    Nota, Benjamin; Ndika, Joseph D T; van de Kamp, Jiddeke M; Kanhai, Warsha A; van Dooren, Silvy J M; van de Wiel, Mark A; Pals, Gerard; Salomons, Gajja S

    2014-09-01

    Creatine transporter (SLC6A8) deficiency is the most common cause of cerebral creatine syndromes, and is characterized by depletion of creatine in the brain. Manifestations of this X-linked disorder include intellectual disability, speech/language impairment, behavior abnormalities, and seizures. At the moment, no effective treatment is available. In order to investigate the molecular pathophysiology of this disorder, we performed RNA sequencing on fibroblasts derived from patients. The transcriptomes of fibroblast cells from eight unrelated individuals with SLC6A8 deficiency and three wild-type controls were sequenced. SLC6A8 mutations with different effects on the protein product resulted in different gene expression profiles. Differential gene expression analysis followed by gene ontology term enrichment analysis revealed that especially the expression of genes encoding components of the extracellular matrix and cytoskeleton are altered in SLC6A8 deficiency, such as collagens, keratins, integrins, and cadherins. This suggests an important novel role for creatine in the structural development and maintenance of cells. It is likely that the (extracellular) structure of brain cells is also impaired in SLC6A8-deficient patients, and future studies are necessary to confirm this and to reveal the true functions of creatine in the brain.

  15. Glucose transport 1 deficiency presenting as infantile spasms with a mutation identified in exon 9 of SLC2A1

    PubMed Central

    Lee, Hyun Hee

    2016-01-01

    Glucose transport 1 (GLUT-1) deficiency is a rare syndrome caused by mutations in the glucose transporter 1 gene (SLC2A1) and is characterized by early-onset intractable epilepsy, delayed development, and movement disorder. De novo mutations and several hot spots in N34, G91, R126, R153, and R333 of exons 2, 3, 4, and 8 of SLC2A1 are associated with this condition. Seizures, one of the main clinical features of GLUT-1 deficiency, usually develop during infancy. Most patients experience brief and subtle myoclonic jerk and focal seizures that evolve into a mixture of different types of seizures, such as generalized tonic-clonic, absence, myoclonic, and complex partial seizures. Here, we describe the case of a patient with GLUT-1 deficiency who developed infantile spasms and showed delayed development at 6 months of age. She had intractable epilepsy despite receiving aggressive antiepileptic drug therapy, and underwent a metabolic workup. Cerebrospinal fluid (CSF) examination showed CSF-glucose-to-blood-glucose ratio of 0.38, with a normal lactate level. Bidirectional sequencing of SLC2A1 identified a missense mutation (c.1198C>T) at codon 400 (p.Arg400Cys) of exon 9. PMID:28018440

  16. Redefining the Pediatric Phenotype of X-Linked Monocarboxylate Transporter 8 (MCT8) Deficiency: Implications for Diagnosis and Therapies.

    PubMed

    Matheus, Maria Gisele; Lehman, Rebecca K; Bonilha, Leonardo; Holden, Kenton R

    2015-10-01

    X-linked monocarboxylate transporter 8 (MCT8) deficiency results from a loss-of-function mutation in the monocarboxylate transporter 8 gene, located on chromosome Xq13.2 (Allan-Herndon-Dudley syndrome). Affected boys present early in life with neurodevelopment delays but have pleasant dispositions and commonly have elevated serum triiodothyronine. They also have marked axial hypotonia and quadriparesis but surprisingly little spasticity early in their disease course. They do, however, have subtle involuntary movements, most often dystonia. The combination of hypotonia and dystonia presents a neurorehabilitation challenge and explains why spasticity-directed therapies have commonly produced suboptimal responses. Our aim was to better define the spectrum of motor disability and to elucidate the neuroanatomic basis of the motor impairments seen in MCT8 deficiency using clinical observation and brain magnetic resonance imaging (MRI) in a cohort of 6 affected pediatric patients. Our findings identified potential imaging biomarkers and suggest that rehabilitation efforts targeting dystonia may be more beneficial than those targeting spasticity in the prepubertal pediatric MCT8 deficiency population.

  17. Folate and vitamin B12 levels in levodopa-treated Parkinson's disease patients: their relationship to clinical manifestations, mood and cognition.

    PubMed

    Triantafyllou, Nikolaos I; Nikolaou, Chrysoula; Boufidou, Fotini; Angelopoulos, Elias; Rentzos, Michael; Kararizou, Evangelia; Evangelopoulos, Maria-Eleftheria; Vassilopoulos, Dimitrios

    2008-01-01

    We tested the hypothesis that mood, clinical manifestations and cognitive impairment of levodopa-treated Parkinson's disease (PD) patients are associated with vitamin B12 and folate deficiency. To this end, we performed this cross-sectional study by measuring serum folate and vitamin B12 blood levels in 111 consecutive PD patients. Levodopa-treated PD patients showed significantly lower serum levels of folate and vitamin B12 than neurological controls, while depressed patients had significantly lower serum folate levels as compared to non-depressed. Cognitively impaired PD patients exhibited significantly lower serum vitamin B12 levels as compared to cognitively non-impaired. In conclusion, lower folate levels were associated with depression, while lower vitamin B12 levels were associated with cognitive impairment. The effects of vitamin supplementation merit further attention and investigation.

  18. Alcoholic Myelopathy and Nutritional Deficiency

    PubMed Central

    Koike, Haruki; Nakamura, Tomohiko; Ikeda, Shohei; Takahashi, Mie; Kawagashira, Yuichi; Iijima, Masahiro; Katsuno, Masahisa; Sobue, Gen

    2017-01-01

    A patient with chronic alcoholism presented with myelopathy and low serum folate and cobalamin levels. A 42-year-old alcoholic man had gait disturbance for 4 months. A neurological examination revealed marked spasticity with increased deep tendon reflexes and extensor plantar responses of the lower limbs. His cobalamin level was decreased and his serum folate level was particularly low. His plasma ammonia level was not increased. Abstinence and folic acid and cobalamin supplementation stopped the progression of his neurological deficits. This case indicates that nutritional deficiency should be monitored closely in patients with chronic alcoholism who present with myelopathy. PMID:28049986

  19. Red blood cell folate levels in pregnant women with a history of mood disorders: a case series

    PubMed Central

    Yaremco, Elyse; Inglis, Angela; Innis, Sheila M.; Hippman, Catriona; Carrion, Prescilla; Lamers, Yvonne; Honer, William G.; Austin, Jehannine

    2014-01-01

    Objective Maternal folate supplementation reduces offspring risk for neural tube defects (NTDs) and other congenital abnormalities. Maternal red blood cell (RBC) folate concentrations of >906nmol/L have been associated with the lowest risk of having an NTD affected pregnancy. Mood disorders (e.g. depression, bipolar disorder) are common among women and can be associated with folate deficiency. Thus, pregnant women with histories of mood disorders may be prone to RBC folate levels insufficient to provide optimal protection against NTDs. While previous studies have assessed RBC folate concentrations in pregnant women from the general population, none have looked specifically at a group of pregnant women who have a history of a mood disorder. Methods We collected data about RBC folate concentrations and folic acid supplement intake during early pregnancy (<161days gestation) from n=24 women with histories of mood disorders. We also collected information about offspring congenital abnormalities and birthweight. Results Among women with histories of mood disorders, the mean RBC folate concentration was 674 nmol/L (range: 362 –1105nmol/L). Only 12.5% (n=3) of the women had an RBC folate concentrations >906nmol/L, despite all participants reporting current daily use of folic acid supplements. Data regarding offspring were available for 22 women: birthweights ranged from 2296g to 4819g, and congenital abnormalities were identified in two (hypoplastic left heart, annular pancreas). Conclusion Data from this exploratory case series suggest a need for future larger scale controlled studies investigating RBC folate concentrations in early pregnancy and offspring outcomes among women with and without histories of mood disorders. PMID:23760977

  20. Sulla carnosa modulates root invertase activity in response to the inhibition of long-distance sucrose transport under magnesium deficiency.

    PubMed

    Farhat, N; Smaoui, A; Maurousset, L; Porcheron, B; Lemoine, R; Abdelly, C; Rabhi, M

    2016-11-01

    Being the principal product of photosynthesis, sucrose is involved in many metabolic processes in plants. As magnesium (Mg) is phloem mobile, an inverse relationship between Mg shortage and sugar accumulation in leaves is often observed. Mg deficiency effects on carbohydrate contents and invertase activities were determined in Sulla carnosa Desf. Plants were grown hydroponically at different Mg concentrations (0.00, 0.01, 0.05 and 1.50 mM Mg) for one month. Mineral analysis showed that Mg contents were drastically diminished in shoots and roots mainly at 0.01 and 0.00 mM Mg. This decline was adversely associated with a significant increase of sucrose, fructose and mainly glucose in shoots of plants exposed to severe deficiency. By contrast, sugar contents were severely reduced in roots of these plants indicating an alteration of carbohydrate partitioning between shoots and roots of Mg-deficient plants. Cell wall invertase activity was highly enhanced in roots of Mg-deficient plants, while the vacuolar invertase activity was reduced at 0.00 mM Mg. This decrease of vacuolar invertase activity may indicate the sensibility of roots to Mg starvation resulting from sucrose transport inhibition. (14) CO2 labeling experiments were in accordance with these findings showing an inhibition of sucrose transport from source leaves to sink tissues (roots) under Mg depletion. The obtained results confirm previous findings about Mg involvement in photosynthate loading into phloem and add new insights into mechanisms evolved by S. carnosa to cope with Mg shortage in particular the increase of the activity of cell wall invertase.

  1. Lipid peroxidation and electrogenic ion transport in the jejunum of the vitamin E deficient rat.

    PubMed Central

    Lindley, K J; Goss-Sampson, M A; Muller, D P; Milla, P J

    1994-01-01

    Increased concentrations of reactive oxygen species in children with depleted antioxidant defences have been implicated in a cycle of malnutrition, malabsorption, and infection leading to protracted diarrhoea. A rat model of chronic vitamin E deficiency has been used to study the effects of antioxidant depletion on jejunal structure and function in vitro. Basal intestinal short circuit current (Isc), a measure of net electrogenic ion movement across the intestinal epithelium, was greater in chronically vitamin E deficient jejuna than controls, as was the electrogenic secretory response to aminophylline and Escherichia coli STa but not to bethanechol. The galactose stimulated current was also greater in vitamin E deficient jejuna. Indices of lipid peroxidation (concentrations of thiobarbituric acid reactive substances and malondialdehyde) were increased in the vitamin E deficient small bowel. Small intestinal brush border membranes from vitamin E deficient animals displayed changes in both static and dynamic components of membrane fluidity measured by steady state fluorescence polarography. The results of these studies support the hypothesis that oxidative stress in subjects with compromised antioxidant defences results in small intestinal hypersecretion, which could predispose to or perpetuate protracted diarrhoea. Images Figure 5 PMID:8307446

  2. Results of an international round robin for serum and whole-blood folate.

    PubMed

    Gunter, E W; Bowman, B A; Caudill, S P; Twite, D B; Adams, M J; Sampson, E J

    1996-10-01

    Because of the increasing significance of folate nutriture to public health, a "round robin" interlaboratory comparison study was conducted to assess differences among methods. Twenty research laboratories participated in a 3-day analysis of six serum and six whole-blood pools. Overall means, SDs, and CVs derived from these results were compared within and across method types. Results reported for serum and whole-blood folate demonstrated overall CVs of 27.6% and 35.7%, respectively, across pools and two- to ninefold differences in concentrations between methods, with the greatest variation occurring at critical low folate concentrations. Although results for serum pools were less variable than those for whole-blood pools, substantial intermethod variation still occurred. The overall results underscore the urgent need for developing and validating reference methods for serum and whole-blood folate and for properly characterized reference materials. For evaluating study or clinical data, method-specific reference ranges (established with clinical confirmation of values for truly folate-deficient individuals) must be used.

  3. Folate levels and polyglutamylation profiles of papaya (Carica papaya cv. Maradol) during fruit development and ripening.

    PubMed

    Ramos-Parra, Perla A; García-Salinas, Carolina; Hernández-Brenes, Carmen; de la Garza, Rocío I Díaz

    2013-04-24

    Folates are essential micronutrients for humans, and their deficiency causes several detrimental effects on human health. Papaya fruit is an important natural source of some micronutrients. This paper presents a first complete characterization of folate derivatives accumulated in cv. Maradol papaya during fruit development and ripening processes. During postharvest ripening, the fruit accumulated up to 24.5% of the daily folate recommended dietary allowance (RDA) for an adult in a 1 cup (145 g) portion. Tetrahydrofolate (THF) and 5-methyl-THF were the predominant folate classes observed. Surprisingly, an unusually long polyglutamylation profile of tentatively up to 17 glutamates linked to 5-methyl-THF was detected; to the authors' knowledge, this very long polyglutamyl tail has not been reported for any organism, and it is probably characteristic of this plant species. This polyglutamylation degree changed throughout fruit development and ripening, showing the largest differences at the onset of ripening. This work raises questions about the functional role of folate derivatives in fruit development.

  4. Folate status in type 2 diabetic patients with and without retinopathy

    PubMed Central

    Malaguarnera, Giulia; Gagliano, Caterina; Salomone, Salvatore; Giordano, Maria; Bucolo, Claudio; Pappalardo, Antonino; Drago, Filippo; Caraci, Filippo; Avitabile, Teresio; Motta, Massimo

    2015-01-01

    Background Folate deficiency is associated with cardiovascular disease, megaloblastic anemia, and with hyperhomocysteinemia. This study has been undertaken to investigate the role of folate status during the progression of the diabetic retinopathy. Methods We measured the plasma levels of homocysteine, folic acid, and red cell folate in 70 diabetic type 2 patients with nonproliferative diabetic retinopathy (NPDR), 65 with proliferative diabetic retinopathy (PDR), 96 without diabetic retinopathy, and 80 healthy subjects used as a control group. Results We found higher plasma levels of homocysteine in the NPDR group compared to the control group (P<0.001) and in the PDR group compared to control group (P<0.001) and NPDR group (P<0.01). The severity of diabetic retinopathy was associated with lower folic acid and red cell folate levels, and a significant difference was observed between PDR and NPDR groups (P<0.05). Conclusion The folate status could play a role in the development and progression of diabetic retinopathy. PMID:26300625

  5. Transgenic petunia with the iron(III)-phytosiderophore transporter gene acquires tolerance to iron deficiency in alkaline environments.

    PubMed

    Murata, Yoshiko; Itoh, Yoshiyuki; Iwashita, Takashi; Namba, Kosuke

    2015-01-01

    Iron is an essential nutrient for all plants. However, terrestrial plants often suffer from iron deficiency in alkaline soil due to its extremely low solubility. Alkaline soil accounts for about 30% of all cultivated ground in the world. Plants have evolved two distinct strategies, I and II, for iron uptake from the soil. Dicots and non-graminaceous monocots use Strategy I, which is primarily based on the reduction of iron(III) to iron(II) and the uptake of iron(II) by the iron-regulated transporter, IRT1. In contrast, graminaceous plants use Strategy II to efficiently acquire insoluble iron(III). Strategy II comprises the synthesis and secretion of iron-chelating phytosiderophores, such as mugineic acids and the Yellow Stripe 1 transporter proteins of the iron(III)-phytosiderophore complex. Barley, which exhibits the highest tolerance to iron deficiency in alkaline soil among graminaceous plants, utilizes mugineic acids and the specific iron(III)-mugineic acids transporter, HvYS1. In this study, we established the transgenic plant Petunia hybrida, which originally had only Strategy I, by introducing the HvYS1 transporter gene derived from barley. When the transgenic plants were grown hydroponically in media containing the iron(III)-2'-deoxymugineic acid complex, free 2'-deoxymugineic acid and its iron(III) complex were detected in the root extract of the transgenic plant by electrospray ionization-Fourier transform-ion cyclotron resonance mass spectrometry. The growth of the transgenic petunia was significantly better than that of the control host in alkaline conditions. Consequently, the transgenic plant acquired a significantly enhanced tolerance to alkaline hydroponic media in the presence of the iron(III)-2'-deoxymugineic acid complex. Furthermore, the flower color of the transgenic plant deepened. The results showed that iron-phytosiderophore complexes and their transporters can potentially be utilized to overcome the worldwide iron uptake problems to diverse

  6. 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

  7. Expression and cellular localization of ZIP1 transporter under zinc-deficiency in wild emmer wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Zinc (Zn) deficiency is a common problem leading to severe decreases in grain yield and has detrimental effects on nutritional quality in cereals. Wild emmer wheat, Triticum turgidum ssp. dicoccoides, exhibits a potential genetic resource for wheat improvement due to its compatibility with modern wh...

  8. Paradoxical impact of two folate receptors, FRα and RFC, in ovarian cancer: effect on cell proliferation, invasion and clinical outcome.

    PubMed

    Siu, Michelle K Y; Kong, Daniel S H; Chan, Hoi Yan; Wong, Esther S Y; Ip, Philip P C; Jiang, LiLi; Ngan, Hextan Y S; Le, Xiao-Feng; Cheung, Annie N Y

    2012-01-01

    Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.

  9. 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.

  10. Folate Metabolism and Human Reproduction

    PubMed Central

    Thaler, C. J.

    2014-01-01

    Folate metabolism affects ovarian function, implantation, embryogenesis and the entire process of pregnancy. In addition to its well-established effect on the incidence of neural tube defects, associations have been found between reduced folic acid levels and increased homocysteine concentrations on the one hand, and recurrent spontaneous abortions and other complications of pregnancy on the other. In infertility patients undergoing IVF/ICSI treatment, a clear correlation was found between plasma folate concentrations and the incidence of dichorionic twin pregnancies. In patients supplemented with 0.4 mg/d folic acid undergoing ovarian hyperstimulation and oocyte pick-up, carriers of the MTHFR 677T mutation were found to have lower serum estradiol concentrations at ovulation and fewer oocytes could be retrieved from them. It appears that these negative effects can be compensated for in full by increasing the daily dose of folic acid to at least 0.8 mg. In carriers of the MTHFR 677TT genotype who receive appropriate supplementation, AMH concentrations were found to be significantly increased, which could indicate a compensatory mechanism. AMH concentrations in homozygous carriers of the MTHFR 677TT genotype could even be overestimated, as almost 20 % fewer oocytes are retrieved from these patients per AMH unit compared to MTHFR 677CC wild-type individuals. PMID:25278626

  11. Assessment of the value of a competitive protein binding radioassay of folic acid in the detection of folic acid deficiency.

    PubMed Central

    Bain, B J; Wickramasinghe, S N; Broom, G N; Litwinczuk, R A; Sims, J

    1984-01-01

    The diagnostic value of the Becton Dickinson Radioassay Kit (125I) for the the assay of red cell folate has been investigated. The assay was acceptable with regards to precision but was non-linear with changing packed cell volume. Sensitivity of the assay was satisfactory, with 24 of 25 folate deficient patients giving red cell folate values which fell below the reference range. Specificity of the assay in the detection of folate deficiency was less satisfactory. As with microbiological assays, a considerable proportion of vitamin B12 deficient patients had low red cell folate values. In addition, low concentrations were found in 12% of patients who were unlikely to be deficient in either vitamin B12 or folic acid. PMID:6470170

  12. Strigolactones are involved in phosphate- and nitrate-deficiency-induced root development and auxin transport in rice.

    PubMed

    Sun, Huwei; Tao, Jinyuan; Liu, Shangjun; Huang, Shuangjie; Chen, Si; Xie, Xiaonan; Yoneyama, Koichi; Zhang, Yali; Xu, Guohua

    2014-12-01

    Strigolactones (SLs) or their derivatives have recently been defined as novel phytohormones that regulate root development. However, it remains unclear whether SLs mediate root growth in response to phosphorus (P) and nitrogen (N) deficiency. In this study, the responses of root development in rice (Oryza sativa L.) to different levels of phosphate and nitrate supply were investigated using wild type (WT) and mutants defective in SL synthesis (d10 and d27) or insensitive to SL (d3). Reduced concentration of either phosphate or nitrate led to increased seminal root length and decreased lateral root density in WT. Limitation of either P or N stimulated SL production and enhanced expression of D10, D17, and D27 and suppressed expression of D3 and D14 in WT roots. Mutation of D10, D27, or D3 caused loss of sensitivity of root response to P and N deficiency. Application of the SL analogue GR24 restored seminal root length and lateral root density in WT and d10 and d27 mutants but not in the d3 mutant, suggesting that SLs were induced by nutrient-limiting conditions and led to changes in rice root growth via D3. Moreover, P or N deficiency or GR24 application reduced the transport of radiolabelled indole-3-acetic acid and the activity of DR5::GUS auxin reporter in WT and d10 and d27 mutants. These findings highlight the role of SLs in regulating rice root development under phosphate and nitrate limitation. The mechanisms underlying this regulatory role involve D3 and modulation of auxin transport from shoots to roots.

  13. Deficiency in the divalent metal transporter 1 augments bleomycin-induced lung injury

    EPA Science Inventory

    Exposure to bleomycin can result in an inflammatory lung injury. The biological effect of this anti-neoplastic agent is dependent on its coordination of iron with subsequent oxidant generation. In lung cells, divalent metal transporter 1 (DMT1) can participate in metal transport ...

  14. Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation?

    PubMed

    Breimer, Lars H; Nilsson, Torbjörn K

    2012-05-01

    It is now 30 years since the first publications stating that supplementation with folate could prevent neural tube defects appeared and 20 years since the definitive data, including prevention of other birth defects. Since then epidemiological studies and animal experiments have identified folate as a molecule at the crossroads of neural development. Fortification of food has greatly reduced the incidence of spina bifida. Much interest has focussed on long-term sequelae in children born to mothers severely deprived of folate (and other nutrients) such as during the Dutch Hunger Winter of 1944 and in poor parts of the world. In addition, deficiency in folate and B12 are increasingly discussed as a possible contributing factor in dementia and congenital orofacial and heart malformations. The year 2011 saw the publication of a study that implicated low folate intake in poorer school performance of adolescents as judged by school marks. This has enormous social implications but needs confirmation from other settings. This review assesses the current state of evidence and sets the data in context of whether folate has a role in the development and plasticity of the nervous system even after birth, with particular emphasis on childhood and adolescence.

  15. Nutri-epigenomic Studies Related to Neural Tube Defects: Does Folate Affect Neural Tube Closure Via Changes in DNA Methylation?

    PubMed

    Rochtus, Anne; Jansen, Katrien; Van Geet, Chris; Freson, Kathleen

    2015-01-01

    Neural tube defects (NTDs), affecting 1-2 per 1000 pregnancies, are severe congenital malformations that arise from the failure of neurulation during early embryonic development. The methylation hypothesis suggests that folate prevents NTDs by stimulating cellular methylation reactions. Folate is central to the one-carbon metabolism that produces pyrimidines and purines for DNA synthesis and for the generation of the methyldonor S-adenosyl-methionine. This review focuses on the relation between the folate-mediated one-carbon metabolism, DNA methylation and NTDs. Studies will be discussed that investigated global or locus-specific DNA methylation differences in patients with NTDs. Folate deficiency may increase NTD risk by decreasing DNA methylation, but to date, human studies vary widely in study design in terms of analyzing different clinical subtypes of NTDs, using different methylation quantification assays and using DNA isolated from diverse types of tissues. Some studies have focused mainly on global DNA methylation differences while others have quantified specific methylation differences for imprinted genes, transposable elements and DNA repair enzymes. Findings of global DNA hypomethylation and LINE-1 hypomethylation suggest that epigenetic alterations may disrupt neural tube closure. However, current research does not support a linear relation between red blood cell folate concentration and DNA methylation. Further studies are required to better understand the interaction between folate, DNA methylation changes and NTDs.

  16. Interaction between γ-radiation and dietary folate starvation metabolically reprograms global hepatic histone H3 methylation at lysine 4 and lysine 27 residues.

    PubMed

    Batra, Vipen; Devasagayam, Thomas Paul Asir

    2012-03-01

    The objective of the present study was to investigate the regulatory control of histone H3 methylation at lysine 4 (H3K4) and lysine 27 (H3K27) residues in response to the effect of folate deficiency and gamma (γ)-radiation. Male Swiss mice maintained on folate sufficient diet (FSD) and folate free diet (FFD) based on AIN-93M formula, were subjected to 2-4 Gy total body γ-irradiation. There was a significant decrease in liver folate levels with concomitant depletion of S-adenosylmethionine (SAM) reserves. Folate deficiency and γ-radiation together induced H3K4 histone methyltransferase (H3K4HMTase) and suppressed H3K27 histone methyltransferase (H3K27HMTase) activities in a dose and time dependent manner. Our studies suggested radiation induced metabolic reprogramming of H3K4/H3K27 methylation patterns in FFD animals. We showed that radiation toxicity diverted one-carbon (C1) flux in FFD fed animals towards H3K4 methylation. Present work on methylation pattern of histone lysine residues gains particular importance as methylation of H3K4 residues is associated with euchromatin while methylated H3K27 residues promote gene silencing. In conclusion, our study suggests that maintenance of genomic histone methylation under γ-radiation stress might be a very dynamic, progressive process that could be modulated by dietary folate deficiency leading to formation of epigenetically reprogrammed cells.

  17. Knock-out of Arabidopsis metal transporter gene IRT1 results in iron deficiency accompanied by cell differentiation defects.

    PubMed

    Henriques, Rossana; Jásik, Ján; Klein, Markus; Martinoia, Enrico; Feller, Urs; Schell, Jeff; Pais, Maria S; Koncz, Csaba

    2002-11-01

    IRT1 and IRT2 are members of the Arabidopsis ZIP metal transporter family that are specifically induced by iron deprivation in roots and act as heterologous suppressors of yeast mutations inhibiting iron and zinc uptake. Although IRT1 and IRT2 are thought to perform redundant functions as root-specific metal transporters, insertional inactivation of the IRT1 gene alone results in typical symptoms of iron deficiency causing severe leaf chlorosis and lethality in soil. The irt1 mutation is characterized by specific developmental defects, including a drastic reduction of chloroplast thylakoid stacking into grana and lack of palisade parenchyma differentiation in leaves, reduced number of vascular bundles in stems, and irregular patterns of enlarged endodermal and cortex cells in roots. Pulse labeling with 59Fe through the root system shows that the irt1 mutation reduces iron accumulation in the shoots. Short-term labeling with 65Zn reveals no alteration in spatial distribution of zinc, but indicates a lower level of zinc accumulation. In comparison to wild-type, the irt1 mutant responds to iron and zinc deprivation by altered expression of certain zinc and iron transporter genes, which results in the activation of ZIP1 in shoots, reduction of ZIP2 transcript levels in roots, and enhanced expression of IRT2 in roots. These data support the conclusion that IRT1 is an essential metal transporter required for proper development and regulation of iron and zinc homeostasis in Arabidopsis.

  18. A Protein Kinase C phosphorylation motif in GLUT1 affects glucose transport and is mutated in GLUT1 deficiency syndrome

    PubMed Central

    Lee, Eunice E.; Ma, Jing; Sacharidou, Anastasia; Mi, Wentao; Salato, Valerie K.; Nguyen, Nam; Jiang, Youxing; Pascual, Juan M.; North, Paula E.; Shaul, Philip W.; Mettlen, Marcel; Wang, Richard C.

    2015-01-01

    Summary Protein Kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through in-vitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify Serine 226 in GLUT1 as a PKC phosphorylation site. Phosphorylation of S226 is required for the rapid increase in glucose uptake and enhanced cell surface localization of GLUT1 induced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Endogenous GLUT1 is phosphorylated on S226 in primary endothelial cells in response to TPA or VEGF. Several naturally-occurring, pathogenic mutations that cause GLUT1 deficiency syndrome disrupt this PKC phosphomotif, impair the phosphorylation of S226 in vitro, and block TPA-mediated increases in glucose uptake. We demonstrate that the phosphorylation of GLUT1 on S226 regulates glucose transport and propose that this modification is important in the physiological regulation of glucose transport. PMID:25982116

  19. A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome.

    PubMed

    Lee, Eunice E; Ma, Jing; Sacharidou, Anastasia; Mi, Wentao; Salato, Valerie K; Nguyen, Nam; Jiang, Youxing; Pascual, Juan M; North, Paula E; Shaul, Philip W; Mettlen, Marcel; Wang, Richard C

    2015-06-04

    Protein kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through in vitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify serine 226 in GLUT1 as a PKC phosphorylation site. Phosphorylation of S226 is required for the rapid increase in glucose uptake and enhanced cell surface localization of GLUT1 induced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Endogenous GLUT1 is phosphorylated on S226 in primary endothelial cells in response to TPA or VEGF. Several naturally occurring, pathogenic mutations that cause GLUT1 deficiency syndrome disrupt this PKC phosphomotif, impair the phosphorylation of S226 in vitro, and block TPA-mediated increases in glucose uptake. We demonstrate that the phosphorylation of GLUT1 on S226 regulates glucose transport and propose that this modification is important in the physiological regulation of glucose transport.

  20. Low folate and selenium in the mouse maternal diet alters liver gene expression patterns in the offspring after weaning.

    PubMed

    Barnett, Matthew P G; Bermingham, Emma N; Young, Wayne; Bassett, Shalome A; Hesketh, John E; Maciel-Dominguez, Anabel; McNabb, Warren C; Roy, Nicole C

    2015-05-08

    During pregnancy, selenium (Se) and folate requirements increase, with deficiencies linked to neural tube defects (folate) and DNA oxidation (Se). This study investigated the effect of a high-fat diet either supplemented with (diet H), or marginally deficient in (diet L), Se and folate. Pregnant female mice and their male offspring were assigned to one of four treatments: diet H during gestation, lactation and post-weaning; diet L during gestation, lactation and post-weaning; diet H during gestation and lactation but diet L fed to offspring post-weaning; or diet L during gestation and lactation followed by diet H fed to offspring post-weaning. Microarray and pathway analyses were performed using RNA from colon and liver of 12-week-old male offspring. Gene set enrichment analysis of liver gene expression showed that diet L affected several pathways including regulation of translation (protein biosynthesis), methyl group metabolism, and fatty acid metabolism; this effect was stronger when the diet was fed to mothers, rather than to offspring. No significant differences in individual gene expression were observed in colon but there were significant differences in cell cycle control pathways. In conclusion, a maternal low Se/folate diet during gestation and lactation has more effects on gene expression in offspring than the same diet fed to offspring post-weaning; low Se and folate in utero and during lactation thus has persistent metabolic effects in the offspring.

  1. Nutritional Intake and Status of Cobalamin and Folate among Non-Pregnant Women of Reproductive Age in Bhaktapur, Nepal

    PubMed Central

    Chandyo, Ram K.; Ulak, Manjeswori; Sommerfelt, Halvor; Schneede, Jørn; Ueland, Per M.; Strand, Tor A.

    2016-01-01

    Cobalamin and folate are especially important for women of childbearing age due to their ubiquitous role in fetal growth and development. Population-based data on cobalamin and folate status are lacking from Nepal, where diets are mostly vegetarian. The objectives of the study were to investigate cobalamin and folate intake and status, and to explore associations with socio-demographics, anthropometrics, anemia, and dietary habits. Following a random selection of geographical clusters, we collected blood samples from 500 non-pregnant women and 24-h dietary recalls and food frequency questionnaires from a subsample of 379 women. Twenty percent of the women did not consume any food containing cobalamin during the days recalled, and in 72% nutritional cobalamin intake was <1 μg/day. Eighty-four percent of the women had cobalamin intake lower than the estimated average requirement (EAR) (<2 μg/day). In contrast, only 12% of the women had a folate intake less than 100 μg per day, whereas 62% had intake between 100 and 320 μg. Low plasma cobalamin (<150 pmol/L) was found in 42% of the women, most of whom (88%) also had elevated levels of methylmalonic acid. Our results indicated a high prevalence of nutritional cobalamin deficiency, while folate deficiency was uncommon. PMID:27338469

  2. Low Folate and Selenium in the Mouse Maternal Diet Alters Liver Gene Expression Patterns in the Offspring after Weaning

    PubMed Central

    Barnett, Matthew P.G.; Bermingham, Emma N.; Young, Wayne; Bassett, Shalome A.; Hesketh, John E.; Maciel-Dominguez, Anabel; McNabb, Warren C.; Roy, Nicole C.

    2015-01-01

    During pregnancy, selenium (Se) and folate requirements increase, with deficiencies linked to neural tube defects (folate) and DNA oxidation (Se). This study investigated the effect of a high-fat diet either supplemented with (diet H), or marginally deficient in (diet L), Se and folate. Pregnant female mice and their male offspring were assigned to one of four treatments: diet H during gestation, lactation and post-weaning; diet L during gestation, lactation and post-weaning; diet H during gestation and lactation but diet L fed to offspring post-weaning; or diet L during gestation and lactation followed by diet H fed to offspring post-weaning. Microarray and pathway analyses were performed using RNA from colon and liver of 12-week-old male offspring. Gene set enrichment analysis of liver gene expression showed that diet L affected several pathways including regulation of translation (protein biosynthesis), methyl group metabolism, and fatty acid metabolism; this effect was stronger when the diet was fed to mothers, rather than to offspring. No significant differences in individual gene expression were observed in colon but there were significant differences in cell cycle control pathways. In conclusion, a maternal low Se/folate diet during gestation and lactation has more effects on gene expression in offspring than the same diet fed to offspring post-weaning; low Se and folate in utero and during lactation thus has persistent metabolic effects in the offspring. PMID:26007332

  3. Folate Protects Hepatocytes of Hyperhomocysteinemia Mice from Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-activated Endoplasmic Reticulum Stress.

    PubMed

    Yang, Anning; Sun, Yue; Mao, Caiyan; Yang, Songhao; Huang, Min; Deng, Mei; Ding, Ning; Yang, Xiaoling; Zhang, Minghao; Jin, Shaoju; Jiang, Yideng; Huang, Ying

    2017-02-23

    Folate deficiency is a known risk factor for liver injury; however, the underlying mechanism remains unclear. In this study, we employed a high homocysteine-induced liver injury model of Apolipoprotein E-deficient (ApoE(-/-) ) mice fed high-methionine diet and found that high homocysteine induced endoplasmic reticulum (ER) stress and liver cell apoptosis by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression; observations that were attenuated with supplementation of dietary folate. The regulation on CFTR expression was mediated by CFTR promoter methylation and trimethylation of lysine 27 on histone H3 (H3K27me3). Mechanistically, folate inhibited homocysteine-induced CFTR promoter methylation and H3K27me3, which resulted in upregulation of CFTR expression, and reduced ER stress and liver cell apoptosis. Further study showed that folate inhibited the expression of DNA methyltransferase 1 and enhancer of zeste homolog 2, downregulated the cellular concentrations of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) and upregulated the SAM/SAH ratio, leading to the inhibition of Hcy-induced DNA hypermethylation and H3K27me3 in CFTR promoter. In conclusion, our results provide insight into the protective role of folate in homocysteine-induced ER stress and liver cell apoptosis through the regulation of CFTR expression. This article is protected by copyright. All rights reserved.

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

    PubMed

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

    2016-08-01

    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.

  5. Altered folate metabolism modifies cell proliferation and progesterone secretion in human placental choriocarcinoma JEG-3 cells.

    PubMed

    Moussa, Carolyne; Ross, Nikia; Jolette, Philippe; MacFarlane, Amanda J

    2015-09-28

    Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nM) demonstrated 13% (P<0.001) and 26% (P<0.001) lower proliferation, 5.5% (P=0.025) and 7.5% (P=0.004) lower invasion capacity, and 5 to 7.5% (P=0.004-0.025) lower viability compared with control (20 nM) or supplemented (100 nM) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17.7% (P<0.0001) lower proliferation and 61% (P=0.014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10.3% (P=0.001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.

  6. Compilation of a standardised international folate database for EPIC.

    PubMed

    Nicolas, Geneviève; Witthöft, Cornelia M; Vignat, Jérôme; Knaze, Viktoria; Huybrechts, Inge; Roe, Mark; Finglas, Paul; Slimani, Nadia

    2016-02-15

    This paper describes the methodology applied for compiling an "international end-user" folate database. This work benefits from the unique dataset offered by the European Prospective Investigation into Cancer and Nutrition (EPIC) (N=520,000 subjects in 23 centres). Compilation was done in four steps: (1) identify folate-free foods then find folate values for (2) folate-rich foods common across EPIC countries, (3) the remaining "common" foods, and (4) "country-specific" foods. Compiled folate values were concurrently standardised in terms of unit, mode of expression and chemical analysis, using information in national food composition tables (FCT). 43-70% total folate values were documented as measured by microbiological assay. Foods reported in EPIC were either matched directly to FCT foods, treated as recipes or weighted averages. This work has produced the first standardised folate dataset in Europe, which was used to calculate folate intakes in EPIC; a prerequisite to study the relation between folate intake and diseases.

  7. Albumin-Folate Conjugates for Drug-targeting in Photodynamic Therapy.

    PubMed

    Butzbach, Kathrin; Rasse-Suriani, Federico A O; Gonzalez, M Micaela; Cabrerizo, Franco M; Epe, Bernd

    2016-07-01

    Photodynamic therapy (PDT) is based on the cytotoxicity of photosensitizers in the presence of light. Increased selectivity and effectivity of the treatment is expected if a specific uptake of the photosensitizers into the target cells, often tumor cells, can be achieved. An attractive transporter for that purpose is the folic acid receptor α (FRα), which is overexpressed on the surface of many tumor cells and mediates an endocytotic uptake. Here, we describe the synthesis and photobiological characterization of polar β-carboline derivatives as photosensitizers covalently linked to folate-tagged albumin as the carrier system. The particles were taken up by KB (human carcinoma) cells within <90 min and then co-localized with a lysosomal marker. FRα antibodies prevented the uptake and also the corresponding conjugate without folate was not taken up. Accordingly, a folate-albumin-β-carbolinium conjugate proved to be phototoxic, while the corresponding albumin-β-carbolinium conjugates without FA were nontoxic, both with and without irradiation. An excess of free folate as competitor for the FRα-mediated uptake completely inhibited the photocytotoxicity. Interestingly, the albumin conjugates are devoid of photodynamic activity under cell-free conditions, as shown for DNA as a target. Thus, phototoxicity requires cellular uptake and lysosomal degradation of the conjugates. In conclusion, albumin-folate conjugates appear to be promising vehicles for a tumor cell targeted PDT.

  8. Effect of cisplatin on intracellular folate compounds in L1210 cells

    SciTech Connect

    Vitols, K.S.; Monteiano, Y.D.

    1987-05-01

    The biologically active form of the anticancer agent Cisplatin, cis-diamminediaquaplatinum(II)-ion, reacts rapidly with tetrahydrofolate at pH 7 and 37/sup 0/C to form a stable complex. The purified platinum-tetrahydrofolate derivative has also been shown to inhibit the dihydrofolate reductase and the folate transport system of L1210 cells. To determine whether platinum-tetrahydrofolate complex formation would be observed under in vivo conditions, intracellular folates of L1210 cells were labeled by growth on (/sup 3/H)folate and then analyzed by reverse phase HPLC. No evidence for the intracellular formation of platinum tetrahydrofolate was found in cells grown for 48 in the presence of 10/sup -7/ M Cisplatin. The profile of intracellular folate monoglutamates, however, was distinctly different. The level of 5,10-methenyltetrahydrofolate was decreased, and increases were seen in the levels of tetrahydrofolate and its 5-formyl and 10-formyl derivatives. These changes in intracellular folates are compared to those seen when L1210 cells are treated with the antifolate drug, Methotrexate, and the implications for cell kill are examined.

  9. Connexin-deficiency affects expression levels of glial glutamate transporters within the cerebrum.

    PubMed

    Unger, Tina; Bette, Stefanie; Zhang, Jiong; Theis, Martin; Engele, Jürgen

    2012-01-06

    The glial glutamate transporter subtypes, GLT-1/EAAT-2 and GLAST/EAAT-1 clear the bulk of extracellular glutamate and are severely dysregulated in various acute and chronic brain diseases. Despite the previous identification of several extracellular factors modulating glial glutamate transporter expression, our knowledge of the regulatory network controlling glial glutamate transport in health and disease still remains incomplete. In studies with cultured cortical astrocytes, we previously obtained evidence that glial glutamate transporter expression is also affected by gap junctions/connexins. To assess whether gap junctions would likewise control the in vivo expression of glial glutamate transporters, we have now assessed their expression levels in brains of conditional Cx43 knockout mice, total Cx30 knockouts, as well as Cx43/Cx30 double knockouts. We found that either knocking out Cx30, Cx43, or both increases GLT-1/EAAT-2 protein levels in the cerebral cortex to a similar extent. By contrast, GLAST/EAAT-1 protein levels maximally increased in cerebral cortices of Cx30/Cx43 double knockouts, implying that gap junctions differentially affect the expression of GLT-1/EAAT-2 and GLAST/EAAT-1. Quantitative PCR analysis further revealed that increases in glial glutamate transporter expression are brought about by transcriptional and translational/posttranslational processes. Moreover, GLT-1/EAAT-2- and GLAST/EAAT-1 protein levels remained unchanged in the hippocampi of Cx43/Cx30 double knockouts when compared to Cx43fl/fl controls, indicating brain region-specific effects of gap junctions on glial glutamate transport. Since astrocytic gap junction coupling is affected in various forms of brain injuries, our findings point to gap junctions/connexins as important regulators of glial glutamate turnover in the diseased cerebral cortex.

  10. Micronutrient status in female university students: iron, zinc, copper, selenium, vitamin B12 and folate.

    PubMed

    Fayet-Moore, Flavia; Petocz, Peter; Samman, Samir

    2014-11-13

    Young women are at an increased risk of micronutrient deficiencies, particularly due to higher micronutrient requirements during childbearing years and multiple food group avoidances. The objective of this study was to investigate biomarkers of particular micronutrients in apparently healthy young women. Female students (n = 308; age range 18-35 year; Body Mass Index 21.5 ± 2.8 kg/m2; mean ± SD) were recruited to participate in a cross-sectional study. Blood samples were obtained from participants in the fasted state and analysed for biomarkers of iron status, vitamin B12, folate, homocysteine, selenium, zinc, and copper. The results show iron deficiency anaemia, unspecified anaemia, and hypoferritinemia in 3%, 7% and 33.9% of participants, respectively. Low vitamin B12 concentrations (<120 pmol/L) were found in 11.3% of participants, while 4.7% showed sub-clinical deficiency based on serum methylmalonic acid concentrations >0.34 μmol/L. Folate concentrations below the reference range were observed in 1.7% (serum) or 1% (erythrocytes) of participants, and 99.7% of the participant had erythrocyte-folate concentrations >300 nmol/L. Serum zinc concentrations <10.7 μmol/L were observed in 2% of participants. Serum copper and selenium concentrations were below the reference range in 23% and 11% of participants, respectively. Micronutrient deficiencies including iron and vitamin B12, and apparent excess of folate are present in educated Australian female students of childbearing age, including those studying nutrition. The effects of dietary behaviours and food choices on markers of micronutrient status require further investigation.

  11. Direct evidence in vivo of impaired macrophage-specific reverse cholesterol transport in ATP-binding cassette transporter A1-deficient mice.

    PubMed

    Calpe-Berdiel, Laura; Rotllan, Noemi; Palomer, Xavier; Ribas, Vicent; Blanco-Vaca, Francisco; Escolà-Gil, Joan Carles

    2005-12-30

    The ATP-binding cassette transporter A1 (ABCA1) is a key regulator of high-density lipoprotein (HDL) metabolism. There is strong evidence that ABCA1 is a key regulator of reverse cholesterol transport (RCT). However, this could not be proved in vivo since hepatobiliary cholesterol transport was unchanged in ABCA1-deficient mice (ABCA1-/-). We used ABCA1-/- mice to test the hypothesis that ABCA1 is a critical determinant of macrophage-specific RCT. Although this cell-specific RCT only accounts for a tiny part of total RCT, it is widely accepted that it may have a major impact on atherosclerosis susceptibility. [(3)H]cholesterol-labeled endogenous macrophages were injected intraperitoneally into wild-type ABCA1+/+, ABCA1+/- and ABCA1-/- mice maintained on a chow diet. A direct relationship was observed between ABCA1 gene dose and plasma [(3)H]cholesterol at 24 and 48 h after the injection of tracer into the mice. Forty-eight hours after this injection, ABCA1-/- mice had significantly reduced [(3)H]cholesterol in liver (2.8-fold), small intestine enterocytes (1.7-fold) and feces (2-fold). To our knowledge, this is the first direct in vivo quantitative evidence that ABCA1 is a critical determinant of macrophage-specific RCT.

  12. Human concentrative nucleoside transporter 3 transfection with ultrasound and microbubbles in nucleoside transport deficient HEK293 cells greatly increases gemcitabine uptake.

    PubMed

    Paproski, Robert J; Yao, Sylvia Y M; Favis, Nicole; Evans, David; Young, James D; Cass, Carol E; Zemp, Roger J

    2013-01-01

    Gemcitabine is a hydrophilic clinical anticancer drug that requires nucleoside transporters to cross plasma membranes and enter cells. Pancreatic adenocarcinomas with low levels of nucleoside transporters are generally resistant to gemcitabine and are currently a clinical problem. We tested whether transfection of human concentrative nucleoside transporter 3 (hCNT3) using ultrasound and lipid stabilized microbubbles could increase gemcitabine uptake and sensitivity in HEK293 cells made nucleoside transport deficient by pharmacologic treatment with dilazep. To our knowledge, no published data exists regarding the utility of using hCNT3 as a therapeutic gene to reverse gemcitabine resistance. Our ultrasound transfection system--capable of transfection of cell cultures, mouse muscle and xenograft CEM/araC tumors--increased hCNT3 mRNA and (3)H-gemcitabine uptake by >2,000- and 3,400-fold, respectively, in dilazep-treated HEK293 cells. Interestingly, HEK293 cells with both functional human equilibrative nucleoside transporters and hCNT3 displayed 5% of (3)H-gemcitabine uptake observed in cells with only functional hCNT3, suggesting that equilibrative nucleoside transporters caused significant efflux of (3)H-gemcitabine. Efflux assays confirmed that dilazep could inhibit the majority of (3)H-gemcitabine efflux from HEK293 cells, suggesting that hENTs were responsible for the majority of efflux from the tested cells. Oocyte uptake transport assays were also performed and provided support for our hypothesis. Gemcitabine uptake and efflux assays were also performed on pancreatic cancer AsPC-1 and MIA PaCa-2 cells with similar results to that of HEK293 cells. Using the MTS proliferation assay, dilazep-treated HEK293 cells demonstrated 13-fold greater resistance to gemcitabine compared to dilazep-untreated HEK293 cells and this resistance could be reversed by transfection of hCNT3 cDNA. We propose that transfection of hCNT3 cDNA using ultrasound and microbubbles may be a

  13. Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport

    PubMed Central

    Ferreirinha, Fatima; Quattrini, Angelo; Pirozzi, Marinella; Valsecchi, Valentina; Dina, Giorgia; Broccoli, Vania; Auricchio, Alberto; Piemonte, Fiorella; Tozzi, Giulia; Gaeta, Laura; Casari, Giorgio; Ballabio, Andrea; Rugarli, Elena I.

    2004-01-01

    In several neurodegenerative diseases, axonal degeneration occurs before neuronal death and contributes significantly to patients’ disability. Hereditary spastic paraplegia (HSP) is a genetically heterogeneous condition characterized by selective degeneration of axons of the corticospinal tracts and fasciculus gracilis. HSP may therefore be considered an exemplary disease to study the local programs mediating axonal degeneration. We have developed a mouse model for autosomal recessive HSP due to mutations in the SPG7 gene encoding the mitochondrial ATPase paraplegin. Paraplegin-deficient mice are affected by a distal axonopathy of spinal and peripheral axons, characterized by axonal swelling and degeneration. We found that mitochondrial morphological abnormalities occurred in synaptic terminals and in distal regions of axons long before the first signs of swelling and degeneration and correlated with onset of motor impairment during a rotarod test. Axonal swellings occur through massive accumulation of organelles and neurofilaments, suggesting impairment of anterograde axonal transport. Retrograde axonal transport is delayed in symptomatic mice. We speculate that local failure of mitochondrial function may affect axonal transport and cause axonal degeneration. Our data suggest that a timely therapeutic intervention may prevent the loss of axons. PMID:14722615

  14. Ex-ante evaluation of biotechnology innovations: the case of folate biofortified rice in China.

    PubMed

    De Steur, Hans; Blancquaert, Dieter; Gellynck, Xavier; Lambert, Willy; Van Der Straeten, Dominique

    2012-12-01

    In order to valorize novel biotechnology innovations, there is a need to evaluate ex-ante their market potential. A case in point is biofortification, i.e. the enhancement of the micronutrient content of staple crops through conventional or genetic breeding techniques. In a recent article in Nature Biotechnology, for example, De Steur et al. (2010) demonstrated the large potential consumer health benefits of folate biofortified rice as a means to reduce folate deficiency and Neural-Tube Defects. By focusing on a Chinese high-risk region of Neural-Tube Defects, the current study defines the potential cost-effectiveness of this genetically modified crop where the need to improve folate intake levels is highest. Building on the Disability-Adjusted Life Years (DALY) approach, both the potential health impacts and costs of its implementation are measured and benchmarked against similar innovations. The results show that this transgenic crop could be a highly cost-effective product innovation (US$ 120.34 - US$ 40.1 per DALY saved) to alleviate the large health burden of folate deficiency and reduce the prevalence of neural-tube birth defects. When compared with other biofortified crops and target regions, folate biofortified rice in China has a relatively high health impact and moderate cost-effectiveness. This research further supports the need for, and importance of ex-ante evaluation studies in order to adequately market and, thus, valorize biotechnology innovations. Although the cost-effectiveness analysis enables to illustrate the market potential of innovative agricultural biotechnology research, further research is required to address policy issues on transgenic biofortification, such as biosafety regulatory requirements.

  15. Serum vitamin B12 and folate concentrations and the effect of the Mediterranean diet on vulnerable populations.

    PubMed

    Balcı, Yasemin Işık; Ergin, Ahmet; Karabulut, Aysun; Polat, Aziz; Doğan, Mustafa; Küçüktaşcı, Kazım

    2014-02-01

    Low vitamin B12 and folate levels in expectant mothers may lead to low stores in babies. The aim of this study was to determine the frequencies of vitamin B12 and folate deficiencies in pregnant women and neonates, and to assess the effect of maternal vitamin status on babies' vitamin levels in the Aegean region of Turkey, where the Mediterranean diet (mainly fresh fruits and vegetables) is adopted. We studied 72 pregnant women and their singleton-term babies. Venous blood samples of expectant mothers were collected 1 h before delivery and cord blood of babies were obtained at birth. The mean vitamin B12 in maternal and cord blood serum was 163.1 ± 72.0 pg/mL and 146.2 ± 102.5 pg/mL, and the mean folate, 9.8 ± 4.8 ng/mL and 15.8 ± 3.8 ng/mL, respectively. There were statistically significant correlation between maternal and cord blood serum vitamin B12 (r = 0.61, P = .04) and folate levels (r = 0.65, P < .001). 70.8% of the mothers and 83.9% of the babies were vitamin B12 deficient (<200 pg/mL). Neither group showed folate deficiency. The mean level of vitamin B12 in mothers significantly varied by the type of diet (241.6 (72.1) pg/mL versus 155.9 (68.2) pg/mL; P = .012). Vitamin B12 deficiency in pregnant women and neonates may be a public health problem in our community. The Mediterranean diet in these vulnerable groups may be an aggravating factor for vitamin B12 deficiency. Prenatal screening of all expectant mothers, prenatal supplementation of vitamin B12, and an increase in animal-source food intake may improve expectant mother's vitamin B12 level.

  16. The nitrate transporter NRT2.1 functions in the ethylene response to nitrate deficiency in Arabidopsis.

    PubMed

    Zheng, Dongchao; Han, Xiao; An, Y I; Guo, Hongwei; Xia, Xinli; Yin, Weilun

    2013-07-01

    The ethylene signalling pathway is closely associated with complex environmental stresses. Previous studies have reported impact of high nitrate (HN) availability on ethylene biosynthesis and regulation of ethylene on nitrate transporter 2.1 (NRT2.1) expression. However, molecular interaction between NRT2.1 transcript levels and the ethylene signalling pathway under nitrate deficiency is still elusive. Here, we report a low nitrate (LN) treatment-induced rapid burst of ethylene production and regulated expression of ethylene signalling components CTR1, EIN3 and EIL1 in wild-type Arabidopsis thaliana (Col-0) seedlings, and enhanced ethylene response reporter EBS:GUS activity in both Col-0 and the ethylene mutants ein3-1eil1-1 and ctr1-1. LN treatment also caused up-regulation of NRT2.1 expression, which was responsible for an enhanced high-affinity nitrate uptake. Comparison of ethylene production and EBS:GUS activity between nrt1.1, nrt2.1 mutants and Col-0 indicated that this up-regulation of NRT2.1 expression caused a positive effect on ethylene biosynthesis and signalling under LN treatment. On the other hand, ethylene down-regulated NRT2.1 expression and reduced the high-affinity nitrate uptake. Together, these findings uncover a negative feedback loop between NRT2.1 expression and ethylene biosynthesis and signalling under nitrate deficiency, which may contribute to finely tuning of plant nitrate acquisition during exploring dynamic soil conditions.

  17. Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3.

    PubMed

    Pfaender, Stefanie; Sauer, Ann Katrin; Hagmeyer, Simone; Mangus, Katharina; Linta, Leonhard; Liebau, Stefan; Bockmann, Juergen; Huguet, Guillaume; Bourgeron, Thomas; Boeckers, Tobias M; Grabrucker, Andreas M

    2017-03-27

    Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3αβ knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract.

  18. Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3

    PubMed Central

    Pfaender, Stefanie; Sauer, Ann Katrin; Hagmeyer, Simone; Mangus, Katharina; Linta, Leonhard; Liebau, Stefan; Bockmann, Juergen; Huguet, Guillaume; Bourgeron, Thomas; Boeckers, Tobias M.; Grabrucker, Andreas M.

    2017-01-01

    Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3αβ knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract. PMID:28345660

  19. Altered postnatal development of cortico-hippocampal neuronal electric activity in mice deficient for the mitochondrial aspartate-glutamate transporter.

    PubMed

    Gómez-Galán, Marta; Makarova, Julia; Llorente-Folch, Irene; Saheki, Takeyori; Pardo, Beatriz; Satrústegui, Jorgina; Herreras, Oscar

    2012-02-01

    The deficiency in the mitochondrial aspartate/glutamate transporter Aralar/AGC1 results in a loss of the malate-aspartate NADH shuttle in the brain neurons, hypomyelination, and additional defects in the brain metabolism. We studied the development of cortico/hippocampal local field potential (LFP) in Aralar/AGC1 knockout (KO) mice. Laminar profiles of LFP, evoked potentials, and unit activity were recorded under anesthesia in young (P15 to P22) Aralar-KO and control mice as well as control adults. While LFP power increased 3 to 7 times in both cortex and hippocampus of control animals during P15 to P22, the Aralar-KO specimens hardly progressed. The divergence was more pronounced in the CA3/hilus region. In parallel, spontaneous multiunit activity declined severely in KO mice. Postnatal growth of hippocampal-evoked potentials was delayed in KO mice, and indicated abnormal synaptic and spike electrogenesis and reduced output at P20 to P22. The lack of LFP development in KO mice was accompanied by the gradual appearance of epileptic activity in the CA3/hilus region that evolved to status epilepticus. Strikingly, CA3 bursts were poorly conducted to the CA1 field. We conclude that disturbed substrate supply to neuronal mitochondria impairs development of cortico-hippocampal LFPs. Aberrant neuronal electrogenesis and reduced neuron output may explain circuit dysfunction and phenotype deficiencies.

  20. Protective effect of mesoporous silica particles on encapsulated folates.

    PubMed

    Ruiz-Rico, María; Daubenschüz, Hanna; Pérez-Esteve, Édgar; Marcos, María D; Amorós, Pedro; Martínez-Máñez, Ramón; Barat, José M

    2016-08-01

    Mesoporous silica particles (MSPs) are considered suitable supports to design gated materials for the encapsulation of bioactive molecules. Folates are essential micronutrients which are sensitive to external agents that provoke nutritional deficiencies. Folates encapsulation in MSPs to prevent degradation and to allow their controlled delivery is a promising strategy. Nevertheless, no information exists about the protective effect of MSPs encapsulation to prevent their degradation. In this work, 5-formyltetrahydrofolate (FO) and folic acid (FA) were entrapped in MSPs functionalized with polyamines, which acted as pH-dependent molecular gates. The stability of free and entrapped vitamins after acidic pH, high temperature and light exposure was studied. The results showed the degradation of FO after high temperature and acidic pH, whereas entrapped FO displayed enhanced stability. Free FA was degraded by light, but MSPs stabilized the vitamin. The obtained results point toward the potential use of MSPs as candidates to enhance stability and to improve the bioavailability of functional biomolecules.

  1. 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.

  2. Abnormal N-Glycosylation of a Novel Missense Creatine Transporter Mutant, G561R, Associated with Cerebral Creatine Deficiency Syndromes Alters Transporter Activity and Localization.

    PubMed

    Uemura, Tatsuki; Ito, Shingo; Ohta, Yusuke; Tachikawa, Masanori; Wada, Takahito; Terasaki, Tetsuya; Ohtsuki, Sumio

    2017-01-01

    Cerebral creatine deficiency syndromes (CCDSs) are caused by loss-of-function mutations in creatine transporter (CRT, SLC6A8), which transports creatine at the blood-brain barrier and into neurons of the central nervous system (CNS). This results in low cerebral creatine levels, and patients exhibit mental retardation, poor language skills and epilepsy. We identified a novel human CRT gene missense mutation (c.1681 G>C, G561R) in Japanese CCDSs patients. The purpose of the present study was to evaluate the reduction of creatine transport in G561R-mutant CRT-expressing 293 cells, and to clarify the mechanism of its functional attenuation. G561R-mutant CRT exhibited greatly reduced creatine transport activity compared to wild-type CRT (WT-CRT) when expressed in 293 cells. Also, the mutant protein is localized mainly in intracellular membrane fraction, while WT-CRT is localized in plasma membrane. Western blot analysis revealed a 68 kDa band of WT-CRT protein in plasma membrane fraction, while G561R-mutant CRT protein predominantly showed bands at 55, 110 and 165 kDa in crude membrane fraction. The bands of both WT-CRT and G561R-mutant CRT were shifted to 50 kDa by N-glycosidase treatment. Our results suggest that the functional impairment of G561R-mutant CRT was probably caused by incomplete N-linked glycosylation due to misfolding during protein maturation, leading to oligomer formation and changes of cellular localization.

  3. Immobilized purified folate-binding protein: binding characteristics and use for quantifying folate in erythrocytes

    SciTech Connect

    Hansen, S.I.; Holm, J.; Nexo, E.

    1987-08-01

    Purified folate-binding protein from cow's milk was immobilized on monodisperse polymer particles (Dynospheres) activated by rho-toluenesulfonyl chloride. Leakage from the spheres was less than 0.1%, and the binding properties were similar to those of the soluble protein with regard to dissociation, pH optimum for binding pteroylglutamic acid, and specificity for binding various folate derivatives. We used the immobilized folate-binding protein as binding protein in an isotope-dilution assay for quantifying folate in erythrocytes. The detection limit was 50 nmol/L and the CV over a six-month period was 2.3% (means = 1.25 mumol/L, n = 15). The reference interval, for folate measured in erythrocytes of 43 blood donors, was 0.4-1.5 mumol/L.

  4. Summary of Vadose -- Zone Conceptual Models for Flow and Contaminant Transport and 1999 - 2003 Progress on Resolving Deficiencies in Understanding the Vadose Zone at the INEEL

    SciTech Connect

    Robert C. Starr; Dana L. Dettmers; Brennon R. Orr; Thomas R. Wood

    2003-12-01

    The thick vadose zone that underlies the Idaho National Engineering and Environmental Laboratory has been recognized both as an avenue through which contaminants disposed at or near the ground surface can migrate to groundwater in the underlying Eastern Snake River Plain aquifer, and as a barrier to the movement of contaminants into the aquifer. Flow and contaminant transport in the vadose zone at the INEEL is complicated by the highly heterogeneous nature of the geologic framework and by the variations in the behavior of different contaminants in the subsurface. The state of knowledge concerning flow and contaminant transport in the vadose zone at and near the INEEL IN 1999 was summarized in Deficiencies in Vadose Zone Understanding at the Idaho National Engineering and Environmental Laboratory (Wood et al., 2000). These authors identified deficiencies in knowledge of flow and contaminant transport processes in the vadose zone, and provided recommendations for additional work that should be conducted to address these deficiencies. In the period since (Wood et al., 2000) was prepared, research has been published that, to some degree, address these deficiencies. This document provides a bibliography of reports, journal articles, and conference proceedings published 1999 through mid-2003 that are relevant to the vadose zone at or near the INEEL and provides a brief description of each work. Publications that address specific deficiencies or recommendations are identified, and pertinent information from selected publications is presented.

  5. Lipid absorption defects in intestine-specific microsomal triglyceride transfer protein and ATP-binding cassette transporter A1-deficient mice.

    PubMed

    Iqbal, Jahangir; Parks, John S; Hussain, M Mahmood

    2013-10-18

    We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92-95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and carnitine palmitoyltransferase 1α (CPT1α). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations.

  6. 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.

  7. [Folate and iron in fertile age women from a Venezuelan community affected by incidence of neural tube defects].

    PubMed

    Mariela, Montilva; Jham, Papale; Nieves, García-Casal María; Yelitza, Berné; Yudith, Ontiveros; Lourdes, Durán

    2010-06-01

    The objective of this transversal study was to determine folate and iron nutritional status of women in fertile age from Municipio Jiménez, Lara State, Venezuela. The sampling was probabilistic by conglomerates from the urban and rural areas, selecting 15 conglomerates from which women between 12 and 45 years (269), were studied. After signing informed consent, participating were interviewed for personal data, antecedents related to folate and iron, socioeconomic data (Graffar-Mendez Castellano method and unsatisfied basic needs). In blood sample was determined Hemoglobin, and Erythrocytic Folate (FE). Serum was obtained to determine Ferritin and Serum Folate (FS). 53.53% of the sample presented low FS levels, 10.78% were FS deficient. Severe FE deficiency was present in 80.7% of the cases, moderate deficiency affected 5.9%. For both tests, median was higher for women in treatment with Acido Fólico or pregnant (p = 0.000), median for FE was higher for adults (p = 0.001) and in non poor women (p = 0.011). There were no significant differences for coffee, alcohol, anticonceptive consumption, urban or rural resident or socioeconomic strata. The prevalence of anemia was 11.2% being significantly more frequent in adults than in adolescents (p = 0.029) and in urban women (p = 0.042). Low ferritin were found in 37.3% of the sample, the effect of different variables was not statistically significant. In conclusion, there is a high prevalence of iron and folate deficiencies in women of fertile age from Municipio Jiménez, which could constitute a conditioning factor for the appearance of neural tube defects.

  8. [Serum folate and homocysteine concentrations in women smoking during pregnancy and in umbilical cord blood of newborns].

    PubMed

    Ambroszkiewicz, Jadwiga; Chełchowska, Magdalena; Lewandowski, Leszek; Gajewska, Joanna; Laskowska-Klita, Teresa

    2007-01-01

    In metabolism of homocysteine several enzymes and vitamin cofactors are involves. Genetic abnormalities in these enzymes or nutritional deficiency vitamins, especially of folate may lead to hyperhomocysteinemia, a known risk factor for some pregnancy complications. High maternal homocysteine and low folate levels correlate with low birth weight. Maternal smoking affected significantly total homocysteine concentration in infants. Studies in this area are still scarce and report on limited number of patients. The aim of our study was to assess serum folate and total homocysteine (tHcy) concentrations in smoking pregnant women and in their newborn infants as compared with nonsmoking. The study consisted of 57 pregnant women, who qualified into two groups: smoking (n=28) and nonsmoking (n=29). The serum concentrations of folate were determined by electrochemiluninescent method and tHcy by fluorescence polarization immunoassay. We shown, that serum homocysteine concentrations were significantly higher in smoking as compared with nonsmoking pregnant women (p<0.05) as well as in umbilical cord blood of their newborns (p<0.001). The folate levels were comparable in serum both groups of mothers, but in infants born to smoking women were lower by 20%. In addition, the maternal serum levels of homocysteine and folate showed a significant positive correlation's with these parameters in newborns. Average birth weight infants born to smoking mother was significantly lower than nonsmoking cigarettes (p<0.05). It seems that tobacco smoking during pregnancy affected folate and homocysteine levels in serum of mothers and their infants. Smoking exposure is also associate with reduced birth weight.

  9. Folate receptors and neural tube closure.

    PubMed

    Saitsu, Hirotomo

    2017-02-28

    Neural tube defects (NTD) are among the most common human congenital malformations, affecting 0.5-8/1000 of live births. Human clinical trials have shown that periconceptional folate supplementation significantly decreases the occurrence of NTD in offspring. However, the mechanism by which folate acts on NTD remains largely unknown. Folate receptor (Folr) is one of the three membrane proteins that mediate cellular uptake of folates. Recent studies suggest that mouse Folr1 (formerly referred to as Fbp1) is essential for neural tube closure. Therefore, we examined spatial and temporal expression patterns of Folr1 in developing mouse embryos, showing a close association between Folr1 and anterior neural tube closure. Transient transgenic analysis was performed using lacZ as a reporter; we identified a 1.1-kb enhancer that directs lacZ expression in the neural tube and optic vesicle in a manner that is similar to endogenous Folr1. The 1.1-kb enhancer sequences were highly conserved between humans and mice, suggesting that human FOLR1 is associated with anterior neural tube closure in humans. Several experimental studies in mice and human epidemiological and genetics studies have suggested that folate receptor abnormalities are involved in a portion of human NTDs, although the solo defect of FOLR1 did not cause NTD.

  10. Quantitative description of the interaction between folate and the folate-binding protein from cow's milk

    PubMed Central

    2004-01-01

    A detailed study has been carried out on the dependence of folate binding on the concentration of FBP (folate-binding protein) at pH 5.0, conditions selected to prevent complications arising from the pre-existing self-association of the acceptor. In contrast with the mandatory requirement that reversible interaction of ligand with a single acceptor site should exhibit a unique, rectangular hyperbolic binding curve, results obtained by ultrafiltration for the FBP–folate system required description in terms of (i) a sigmoidal relationship between concentrations of bound and free folate and (ii) an inverse dependence of affinity on FBP concentration. These findings have been attributed to the difficulties in determining the free ligand concentration in the FBP–folate mixtures for which reaction is essentially stoichiometric. This explanation also accounts for the similar published behaviour of the FBP–folate system at neutral pH, which had been attributed erroneously to acceptor self-association, a phenomenon incompatible with the experimental findings because of its prediction of a greater affinity for folate with increasing FBP concentration. PMID:15142039

  11. Abnormal folate metabolism in foetuses affected by neural tube defects.

    PubMed

    Dunlevy, Louisa P E; Chitty, Lyn S; Burren, Katie A; Doudney, Kit; Stojilkovic-Mikic, Taita; Stanier, Philip; Scott, Rosemary; Copp, Andrew J; Greene, Nicholas D E

    2007-04-01

    Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs.

  12. Natural variation in folate levels among tomato (Solanum lycopersicum) accessions.

    PubMed

    Upadhyaya, Pallawi; Tyagi, Kamal; Sarma, Supriya; Tamboli, Vajir; Sreelakshmi, Yellamaraju; Sharma, Rameshwar

    2017-02-15

    Folate content was estimated in tomato (Solanum lycopersicum) accessions using microbiological assay (MA) and by LC-MS. The MA revealed that in red-ripe fruits folate levels ranged from 4 to 60μg/100g fresh weight. The LC-MS estimation of red-ripe fruits detected three folate forms, 5-CH3-THF, 5-CHO-THF, 5,10-CH(+)THF and folate levels ranged from 14 to 46μg/100g fresh weight. In mature green and red ripe fruit, 5-CH3-THF was the most abundant folate form. Comparison of LC-MS with MA revealed that MA inaccurately estimates folate levels. The accumulation of folate forms and their distribution varied among accessions. The single nucleotide polymorphism was examined in the key genes of the folate pathway to understand its linkage with folate levels. Despite the significant variation in folate levels among tomato accessions, little polymorphism was found in folate biosynthesis genes. Our results indicate that variation in folate level is governed by a more complex regulation at cellular homeostasis level.

  13. Neuronal injury: folate to the rescue?

    PubMed Central

    Kronenberg, Golo; Endres, Matthias

    2010-01-01

    Strong epidemiological evidence indicates that derangement of single-carbon metabolism has detrimental effects for proper CNS functioning. Conversely, a role for folate supplementation in the treatment and prevention of neurodegenerative and neuropsychiatric disorders remains to be established. In this issue of the JCI, in an elegant series of experiments in rodents, Iskandar and colleagues demonstrate a crucial role of folate in the regeneration of afferent spinal neurons after injury. Probing sequential steps in folate metabolism, from cellular entry to DNA methylation, the authors show that axonal regeneration relies upon the integrity of DNA methylation pathways. These findings provide the first demonstration of an epigenetic mechanism contributing to neurorepair and suggest that manipulation of the methylation milieu may offer promising new therapeutic avenues to promote regeneration. PMID:20424316

  14. Neuronal injury: folate to the rescue?

    PubMed

    Kronenberg, Golo; Endres, Matthias

    2010-05-01

    Strong epidemiological evidence indicates that derangement of single-carbon metabolism has detrimental effects for proper CNS functioning. Conversely, a role for folate supplementation in the treatment and prevention of neurodegenerative and neuropsychiatric disorders remains to be established. In this issue of the JCI, in an elegant series of experiments in rodents, Iskandar and colleagues demonstrate a crucial role of folate in the regeneration of afferent spinal neurons after injury. Probing sequential steps in folate metabolism, from cellular entry to DNA methylation, the authors show that axonal regeneration relies upon the integrity of DNA methylation pathways. These findings provide the first demonstration of an epigenetic mechanism contributing to neurorepair and suggest that manipulation of the methylation milieu may offer promising new therapeutic avenues to promote regeneration.

  15. Components of the folate metabolic pathway and ADHD core traits: an exploration in eastern Indian probands.

    PubMed

    Saha, Tanusree; Chatterjee, Mahasweta; Sinha, Swagata; Rajamma, Usha; Mukhopadhyay, Kanchan

    2017-03-02

    We investigated role of the folate-homocysteine metabolic pathway in the etiology of attention-deficit hyperactivity disorder (ADHD) due to its importance in maintaining DNA integrity as well as neurotransmission. Functional gene variants in MTR (rs1805087), CBS (rs5742905), MTHFR (rs1801133 & rs1801131), MTHFD (rs2236225), RFC1 (rs1051266), plasma vitamin B12, folate and homocysteine were analyzed. rs1805087 'A' showed strong association with ADHD. Vitamin B12 deficiency of ADHD probands (P=0.01) correlated with rs1801133 'T' and rs1805087'GG'. Mild hyperhomocysteinemia (P=0.05) in the probands was associated with rs1805087 'AA'. Probands having rs1805087 'GG' and rs1051266 'G' was more inattentive. Hyperactivity-impulsivity score revealed association with rs5742905 'TT' and rs2236225 'CC', while rs1801133 'CC' showed association with inattentiveness and hyperactivity-impulsivity. rs1801131 exhibited strong synergistic interaction with rs1051266 and rs2236225. This indicated that the folate-homocysteine pathway gene variants may affect ADHD etiology through mild hyperhomocysteinemia and vitamin B12 deficiency, factors known to be associated with cognitive deficit.Journal of Human Genetics advance online publication, 2 March 2017; doi:10.1038/jhg.2017.23.

  16. 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...

  17. [Treatment with levodopa can affect latent vitamin B 12 and folic acid deficiency. Patients with Parkinson disease runt the risk of elevated homocysteine levels].

    PubMed

    Lökk, Johan

    2003-08-28

    There is a well-known interaction between vitamin B12, folate, and homocysteine. More unknown is the fact that this interaction might be affected by long-term treatment with levo-dopa in patients with Parkinson's disease. An increase in homocysteine levels and tissue deficiency of vitamin B12 and folate may occur. The responsible doctor should be liberal in checking vitamin B12 and folate status and supplement with appropriate vitamins when needed.

  18. Update of nutrient-deficiency anemia in elderly patients.

    PubMed

    Andrès, Emmanuel; Federici, Laure; Serraj, Khalid; Kaltenbach, Georges

    2008-11-01

    Anemia, defined as a hemoglobin level < 13 g/dL in men and < 12 g/dL in women, is an important healthcare concern among the elderly. Nutrient-deficiency anemia represents one third of all anemias in elderly patients. About two thirds of nutrient-deficiency anemia is associated with iron deficiency and most of those cases are the result of chronic blood loss from gastrointestinal lesions. The remaining cases of nutrient-deficiency anemia are usually associated with vitamin B12, most frequently related to food-cobalamin malabsorption, and/or folate deficiency and are easily treated (nutrient-deficiency replacement).

  19. Potential application of a glucose-transport-deficient mutant of Schizosaccharomyces pombe for removing gluconic acid from grape must.

    PubMed

    Peinado, Rafael A; Moreno, Juan J; Medina, Manuel; Mauricio, Juan C

    2005-02-23

    Musts from rotten grapes typically contain high levels of gluconic acid, which can raise severe problems in winemaking processes. In this work, the ability of the glucose-transport-deficient mutant YGS-5 of Schizosaccharomyces pombe to completely or partly remove gluconic acid from a synthetic glucose-containing medium and the potential use of this yeast strain for the same purpose in musts and wines were examined. Surprisingly, the S. pombe YGS-5 strain successfully removed 93% of the initial gluconic acid (2.5 gL(-1)) and 80% of the initial malic acid (1.0 gL(-1)) within 30 h after inoculation. Also, the yeast strain produced no volatile compounds other than those obtained in fermentations conducted with the wine yeast Saccharomyces cerevisiae. S. pombe YGS-5 could thus be used to remove gluconic acid present in musts from rotten grapes. On the basis of these results, various ways of using S. pombe YGS-5 to treat musts containing gluconic acid in order to solve the problems due to the high gluconic acid concentrations in botrytized grape must are proposed.

  20. Brain microvasculature defects and Glut1 deficiency syndrome averted by early repletion of the glucose transporter-1 protein

    PubMed Central

    Tang, Maoxue; Gao, Guangping; Rueda, Carlos B.; Yu, Hang; Thibodeaux, David N.; Awano, Tomoyuki; Engelstad, Kristin M.; Sanchez-Quintero, Maria-Jose; Yang, Hong; Li, Fanghua; Li, Huapeng; Su, Qin; Shetler, Kara E.; Jones, Lynne; Seo, Ryan; McConathy, Jonathan; Hillman, Elizabeth M.; Noebels, Jeffrey L.; De Vivo, Darryl C.; Monani, Umrao R.

    2017-01-01

    Haploinsufficiency of the SLC2A1 gene and paucity of its translated product, the glucose transporter-1 (Glut1) protein, disrupt brain function and cause the neurodevelopmental disorder, Glut1 deficiency syndrome (Glut1 DS). There is little to suggest how reduced Glut1 causes cognitive dysfunction and no optimal treatment for Glut1 DS. We used model mice to demonstrate that low Glut1 protein arrests cerebral angiogenesis, resulting in a profound diminution of the brain microvasculature without compromising the blood–brain barrier. Studies to define the temporal requirements for Glut1 reveal that pre-symptomatic, AAV9-mediated repletion of the protein averts brain microvasculature defects and prevents disease, whereas augmenting the protein late, during adulthood, is devoid of benefit. Still, treatment following symptom onset can be effective; Glut1 repletion in early-symptomatic mutants that have experienced sustained periods of low brain glucose nevertheless restores the cerebral microvasculature and ameliorates disease. Timely Glut1 repletion may thus constitute an effective treatment for Glut1 DS. PMID:28106060

  1. 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.

  2. Synthetic High-Density Lipoprotein-Like Nanocarrier Improved Cellular Transport of Lysosomal Cholesterol in Human Sterol Carrier Protein-Deficient Fibroblasts.

    PubMed

    Nam, Da-Eun; Kim, Ok-Kyung; Park, Yoo Kyoung; Lee, Jeongmin

    2016-01-01

    Sterol carrier protein-2 (SCP-2), which is not found in tissues of people with Zellweger syndrome, facilitates the movement of cholesterol within cells, resulting in abnormal accumulation of cholesterol in SCP-2-deficient cells. This study investigated whether synthetic high-density lipoprotein-like nanocarrier (sHDL-NC) improves the cellular transport of lysosomal cholesterol to plasma membrane in SCP-2-deficient fibroblasts. Human SCP-2-deficient fibroblasts were incubated with [(3)H-cholesterol]LDL as a source of cholesterol and sHDL-NC. The cells were fractionated by centrifugation permit tracking of [(3)H]-cholesterol from lysosome into plasma membrane. Furthermore, cellular content of cholesteryl ester as a storage form and mRNA expression of low-density lipoprotein (LDL) receptor were measured to support the cholesterol transport to plasma membrane. Incubation with sHDL-NC for 8 h significantly increased uptake of [(3)H]-cholesterol to lysosome by 53% and further enhanced the transport of [(3)H]-cholesterol to plasma membrane by 32%. Treatment with sHDL-NC significantly reduced cellular content of cholesteryl ester and increased mRNA expression of LDL receptor (LDL-R). In conclusion, sHDL-NC enables increased transport of lysosomal cholesterol to plasma membrane. In addition, these data were indirectly supported by decreased cellular content of cholesteryl ester and increased gene expression of LDL-R. Therefore, sHDL-NC may be a useful vehicle for transporting cholesterol, which may help to prevent accumulation of cholesterol in SCP-2-deficient fibroblasts.

  3. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups

    PubMed Central

    Frye, Richard E.; Delhey, Leanna; Slattery, John; Tippett, Marie; Wynne, Rebecca; Rose, Shannon; Kahler, Stephen G.; Bennuri, Sirish C.; Melnyk, Stepan; Sequeira, Jeffrey M.; Quadros, Edward

    2016-01-01

    Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in autism spectrum disorder (ASD). They disrupt the transportation of folate across the blood-brain barrier by binding to the FRα. Children with ASD and FRAAs have been reported to respond well to treatment with a form of folate known as folinic acid, suggesting that they may be an important ASD subgroup to identify and treat. There has been no investigation of whether they manifest unique behavioral and physiological characteristics. Thus, in this study we measured both blocking and binding FRAAs, physiological measurements including indices of redox and methylation metabolism and inflammation as well as serum folate and B12 concentrations and measurements of development and behavior in 94 children with ASD. Children positive for the binding FRAA were found to have higher serum B12 levels as compared to those negative for binding FRAAs while children positive for the blocking FRAA were found to have relatively better redox metabolism and inflammation markers as compared to those negative for blocking FRAAs. In addition, ASD children positive for the blocking FRAA demonstrated better communication on the Vineland Adaptive Behavior Scale, stereotyped behavior on the Aberrant Behavioral Checklist and mannerisms on the Social Responsiveness Scale. This study suggests that FRAAs are associated with specific physiological and behavioral characteristics in children with ASD and provides support for the notion that these biomarkers may be useful for subgrouping children with ASD, especially with respect to targeted treatments. PMID:27013943

  4. Comparative genomics of bacterial and plant folate synthesis and salvage: predictions and validations

    PubMed Central

    de Crécy-Lagard, Valérie; El Yacoubi, Basma; de la Garza, Rocío Díaz; Noiriel, Alexandre; Hanson, Andrew D

    2007-01-01

    Background Folate synthesis and salvage pathways are relatively well known from classical biochemistry and genetics but they have not been subjected to comparative genomic analysis. The availability of genome sequences from hundreds of diverse bacteria, and from Arabidopsis thaliana, enabled such an analysis using the SEED database and its tools. This study reports the results of the analysis and integrates them with new and existing experimental data. Results Based on sequence similarity and the clustering, fusion, and phylogenetic distribution of genes, several functional predictions emerged from this analysis. For bacteria, these included the existence of novel GTP cyclohydrolase I and folylpolyglutamate synthase gene families, and of a trifunctional p-aminobenzoate synthesis gene. For plants and bacteria, the predictions comprised the identities of a 'missing' folate synthesis gene (folQ) and of a folate transporter, and the absence from plants of a folate salvage enzyme. Genetic and biochemical tests bore out these predictions. Conclusion For bacteria, these results demonstrate that much can be learnt from comparative genomics, even for well-explored primary metabolic pathways. For plants, the findings particularly illustrate the potential for rapid functional assignment of unknown genes that have prokaryotic homologs, by analyzing which genes are associated with the latter. More generally, our data indicate how combined genomic analysis of both plants and prokaryotes can be more powerful than isolated examination of either group alone. PMID:17645794

  5. “Wigglesworthia morsitans” Folate (Vitamin B9) Biosynthesis Contributes to Tsetse Host Fitness

    PubMed Central

    Snyder, Anna K.

    2015-01-01

    Closely related ancient endosymbionts may retain minor genomic distinctions through evolutionary time, yet the biological relevance of these small pockets of unique loci remains unknown. The tsetse fly (Diptera: Glossinidae), the sole vector of lethal African trypanosomes (Trypanosoma spp.), maintains an ancient and obligate mutualism with species belonging to the gammaproteobacterium Wigglesworthia. Extensive concordant evolution with associated Wigglesworthia species has occurred through tsetse species radiation. Accordingly, the retention of unique symbiont loci between Wigglesworthia genomes may prove instrumental toward host species-specific biological traits. Genome distinctions between “Wigglesworthia morsitans” (harbored within Glossina morsitans bacteriomes) and the basal species Wigglesworthia glossinidia (harbored within Glossina brevipalpis bacteriomes) include the retention of chorismate and downstream folate (vitamin B9) biosynthesis capabilities, contributing to distinct symbiont metabolomes. Here, we demonstrate that these W. morsitans pathways remain functionally intact, with folate likely being systemically disseminated through a synchronously expressed tsetse folate transporter within bacteriomes. The folate produced by W. morsitans is demonstrated to be pivotal for G. morsitans sexual maturation and reproduction. Modest differences between ancient symbiont genomes may still play key roles in the evolution of their host species, particularly if loci are involved in shaping host physiology and ecology. Enhanced knowledge of the Wigglesworthia-tsetse mutualism may also provide novel and specific avenues for vector control. PMID:26025907

  6. Subcellular distribution of folate and folate binding protein in renal proximal tubules

    SciTech Connect

    Sharkey, C.; Hjelle, J.T.; Selhub, J.

    1986-03-01

    High affinity folate binding protein (FBP) found in brush border membranes derived from renal cortices is thought to be involved in the renal conservation of folate. To examine the mechanisms of folate recovery, the subcellular distribution of FBP and /sup 3/H-folate in rabbit renal proximal tubules (PT) was examined using analytical cell fractionation techniques. Tubules contain 3.41 +/- 0.32 picomoles FBP/mg protein (X +/- S.D.; n = 5). Postnuclear supernates (PNS) of PT were layered atop Percoll-sucrose gradients, centrifuged, fractions collected and assayed for various marker enzymes and FBP. Pooled fractions from such gradients were subsequently treated with digitonin and centrifuged in a stoichiometric manner with the activity of the microvillar enzyme, alanylaminopeptidase (AAP); excess FBP distributed with more buoyant particles. Infusion of /sup 3/H-folate into rabbit kidneys followed by tubule isolation and fractionation revealed a time dependent shift in distribution of radiolabel from the AAP-rich gradient fractions to a region containing more buoyant particles; radiolevel was not associated with lysosomal markers. EM-radioautography revealed grains over intracellular vesicles. These results are consistent with the hypothesis that folate is recovered by a process involving receptor-mediated endocytosis or transcytosis.

  7. Folate and neurological function: epidemiology perspective

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This book chapter reviews and summarizes published literature on the relationship between folate status and Alzheimer’s disease, age-related cognitive impairment, and depression. Much of this research was motivated by the hypothesis that high circulating levels of the sulfur-containing amino acid ho...

  8. Exploring the folate pathway in Plasmodium falciparum.

    PubMed

    Hyde, John E

    2005-06-01

    As in centuries past, the main weapon against human malaria infections continues to be intervention with drugs, despite the widespread and increasing frequency of parasite populations that are resistant to one or more of the available compounds. This is a particular problem with the lethal species of parasite, Plasmodium falciparum, which claims some two million lives per year as well as causing enormous social and economic problems. Amongst the antimalarial drugs currently in clinical use, the antifolates have the best defined molecular targets, namely the enzymes dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), which function in the folate metabolic pathway. The products of this pathway, reduced folate cofactors, are essential for DNA synthesis and the metabolism of certain amino acids. Moreover, their formation and interconversions involve a number of other enzymes that have not as yet been exploited as drug targets. Antifolates are of major importance as they currently represent the only inexpensive regime for combating chloroquine-resistant malaria, and are now first-line drugs in a number of African countries. Aspects of our understanding of this pathway and antifolate drug resistance are reviewed here, with a particular emphasis on approaches to analysing the details of, and balance between, folate biosynthesis by the parasite and salvage of pre-formed folate from exogenous sources.

  9. Folate, vitamin B12 and human health

    Technology Transfer Automated Retrieval System (TEKTRAN)

    During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared func...

  10. UK Policy on Folate Fortification of Foods

    ERIC Educational Resources Information Center

    Malcolm, Alan

    2004-01-01

    The UK Food Standards Agency has decided not to recommend fortification of foods with folate, the family of vitamins associated with the prevention of neural tube defects in babies. This is a change in attitude from previous recommendations made by a series of committees and reports in the UK. Notably, it differs from US policy on the matter. The…

  11. 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.

  12. Vitamin B-12 and folate status in relation to decline in scores on the Mini-Mental State Examination in the Framingham Heart Study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Biochemical evidence of low vitamin B-12 status is common in seniors, but its clinical relevance is unclear. Vitamin B-12 deficiency can result in rapid, irreversible cognitive decline – a phenomenon that has been linked to high folate status. Our objective was to investigate the cognitive significa...

  13. Higher maternal plasma folate but not vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10- year-old children in South India.

    PubMed

    Veena, Sargoor R; Krishnaveni, Ghattu V; Srinivasan, Krishnamachari; Wills, Andrew K; Muthayya, Sumithra; Kurpad, Anura V; Yajnik, Chittaranjan S; Fall, Caroline H D

    2010-05-01

    Folate and vitamin B-12 are essential for normal brain development. Few studies have examined the relationship of maternal folate and vitamin B-12 status during pregnancy and offspring cognitive function. To test the hypothesis that lower maternal plasma folate and vitamin B-12 concentrations and higher plasma homocysteine concentrations during pregnancy are associated with poorer neurodevelopment, 536 children (aged 9-10 y) from the Mysore Parthenon birth cohort underwent cognitive function assessment during 2007-2008 using 3 core tests from the Kaufman Assessment Battery, and additional tests measuring learning, long-term storage/retrieval, attention and concentration, and visuo-spatial and verbal abilities. Maternal folate, vitamin B-12, and homocysteine concentrations were measured at 30 +/- 2 wk gestation. During pregnancy, 4% of mothers had low folate concentrations (<7 nmol/L), 42.5% had low vitamin B-12 concentrations (<150 pmol/L), and 3% had hyperhomocysteinemia (>10 micromol/L). The children's cognitive test scores increased by 0.1-0.2 SD per SD increase across the entire range of maternal folate concentrations (P < 0.001 for all), with no apparent associations at the deficiency level. The associations with learning, long-term storage/retrieval, visuo-spatial ability, attention, and concentration were independent of the parents' education, socioeconomic status, religion, and the child's sex, age, current size, and folate and vitamin B-12 concentrations. There were no consistent associations of maternal vitamin B-12 and homocysteine concentrations with childhood cognitive performance. In this Indian population, higher maternal folate, but not vitamin B-12, concentrations during pregnancy predicted better childhood cognitive ability. It also suggests that, in terms of neurodevelopment, the concentration used to define folate deficiency may be set too low.

  14. 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.

  15. Deficiency of Calcium-Independent Phospholipase A2 Beta Induces Brain Iron Accumulation through Upregulation of Divalent Metal Transporter 1

    PubMed Central

    Beck, Goichi; Shinzawa, Koei; Hayakawa, Hideki; Baba, Kousuke; Yasuda, Toru; Sumi-Akamaru, Hisae; Tsujimoto, Yoshihide; Mochizuki, Hideki

    2015-01-01

    Mutations in PLA2G6 have been proposed to be the cause of neurodegeneration with brain iron accumulation type 2. The present study aimed to clarify the mechanism underlying brain iron accumulation during the deficiency of calcium-independent phospholipase A2 beta (iPLA2β), which is encoded by the PLA2G6 gene. Perl’s staining with diaminobenzidine enhancement was used to visualize brain iron accumulation. Western blotting was used to investigate the expression of molecules involved in iron homeostasis, including divalent metal transporter 1 (DMT1) and iron regulatory proteins (IRP1 and 2), in the brains of iPLA2β-knockout (KO) mice as well as in PLA2G6-knockdown (KD) SH-SY5Y human neuroblastoma cells. Furthermore, mitochondrial functions such as ATP production were examined. We have discovered for the first time that marked iron deposition was observed in the brains of iPLA2β-KO mice since the early clinical stages. DMT1 and IRP2 were markedly upregulated in all examined brain regions of aged iPLA2β-KO mice compared to age-matched wild-type control mice. Moreover, peroxidized lipids were increased in the brains of iPLA2β-KO mice. DMT1 and IRPs were significantly upregulated in PLA2G6-KD cells compared with cells treated with negative control siRNA. Degeneration of the mitochondrial inner membrane and decrease of ATP production were observed in PLA2G6-KD cells. These results suggest that the genetic ablation of iPLA2β increased iron uptake in the brain through the activation of IRP2 and upregulation of DMT1, which may be associated with mitochondrial dysfunction. PMID:26506412

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

    PubMed

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

    2015-07-01

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

  17. Development and preclinical evaluation of new (124)I-folate conjugates for PET imaging of folate receptor-positive tumors.

    PubMed

    AlJammaz, I; Al-Otaibi, B; Al-Rumayan, F; Al-Yanbawi, S; Amer, S; Okarvi, S M

    2014-07-01

    In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [(124)I]-SIB- and [(124)I]-SIP-folate conjugates using a straightforward and two-step simple reactions. Radiochemical yields for [(124)I]-SIB- and [(124)I]-SIP-folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30-40min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for (124)I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [(124)I]-SIP-folate conjugate over [(124)I]-SIB-folate conjugate. Biodistribution studies of [(124)I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [(124)I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment.

  18. Folate bioavailability: UK Food Standards Agency workshop report.

    PubMed

    Sanderson, Peter; McNulty, Helene; Mastroiacovo, Pierpaolo; McDowell, Ian F W; Melse-Boonstra, Alida; Finglas, Paul M; Gregory, Jess F

    2003-08-01

    The UK Food Standards Agency convened a group of expert scientists to review current research investigating folate bioavailability. The workshop aimed to overview current research and establish priorities for future research. Discrepancies were observed in the evidence base for folate bioavailability, especially with regard to the relative bioavailability of natural folates compared with folic acid. A substantial body of evidence shows folic acid to have superior bioavailability relative to food folates; however, the exact relative bioavailability still needs to be determined, and in particular with regard to mixed diets. The bioavailability of folate in a mixed diet is probably not a weighted average of that in the various foods consumed; thus the workshop considered that assessment of folate bioavailability of whole diets should be a high priority for future research.

  19. Quantification of folate metabolites in serum using ultraperformance liquid chromatography tandem mass spectrometry.

    PubMed

    Wang, Xiuwei; Zhang, Ting; Zhao, Xin; Guan, Zhen; Wang, Zhen; Zhu, Zhiqiang; Xie, Qiu; Wang, Jianhua; Niu, Bo

    2014-07-01

    Folate deficiency is considered a risk factor for many diseases such as cancer, congenital heart disease and neural tube defects (NTDs). There is a pressing need for more methods of detecting folate and its main metabolites in the human body. Here, we developed a simple, fast and sensitive ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS) method for the simultaneous quantifications of folate metabolites including folic acid, 5-methyltetrahydrofolate (5-MeTHF), 5-formyltetrahydrofolate (5-FoTHF), homocysteine (Hcy), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). The method was validated by determining the linearity (r(2)>0.998), sensitivity (limit of detection ranged from 0.05 to 0.200ng/mL), intra- and inter-day precision (both CV<6%) and recovery (each analyte was >90%). The total analysis time was 7min. Serum samples of NTD-affected pregnancies and controls from a NTD high-risk area in China were analyzed by this method, the NTD serum samples showed lower concentrations of 5-MeTHF (P<0.05) and 5-FoTHF (P<0.05), and higher concentrations of Hcy (P<0.05) and SAH (P<0.05) compared with serum samples from controls, consistent with a previous study. These results showed that the method is sensitive and reliable for simultaneous determination of six metabolites, which might indicate potential risk factors for NTDs, aid early diagnosis and provide more insights into the pathogenesis of NTDs.

  20. Lentils (Lens culinaris L.), a rich source of folates.

    PubMed

    Sen Gupta, Debjyoti; Thavarajah, Dil; Knutson, Phil; Thavarajah, Pushparajah; McGee, Rebecca J; Coyne, Clarice J; Kumar, Shiv

    2013-08-14

    The potential for genetic biofortification of U.S.-grown lentils ( Lens culinaris L.) with bioavailable folate has not been widely studied. The objectives of this study were (1) to determine the folate concentration of 10 commercial lentil cultivars grown in Minot and McLean counties, North Dakota, USA, in 2010 and 2011, (2) to determine the genotype (G) × environmental (E) interactions for folate concentration in lentil cultivars, and (3) to compare the folate concentration of other pulses [field peas ( Pisum sativum L.) and chickpea ( Cicer arietinum L.)] grown in the United States. Folate concentration in lentil cultivars ranged from 216 to 290 μg/100 g with a mean of 255 μg/100 g. In addition, lentil showed higher folate concentration compared to chickpea (42-125 μg/100 g), yellow field pea (41-55 μg/100 g), and green field pea (50-202 μg/100 g). A 100 g serving of lentils could provide a significant amount of the recommended daily allowance of dietary folates (54-73%) for adults. A significant year × location interaction on lentil folate concentration was observed; this indicates that possible location sourcing may be required for future lentil folate research.

  1. Strigolactones are transported through the xylem and play a key role in shoot architectural response to phosphate deficiency in nonarbuscular mycorrhizal host Arabidopsis.

    PubMed

    Kohlen, Wouter; Charnikhova, Tatsiana; Liu, Qing; Bours, Ralph; Domagalska, Malgorzata A; Beguerie, Sebastien; Verstappen, Francel; Leyser, Ottoline; Bouwmeester, Harro; Ruyter-Spira, Carolien

    2011-02-01

    The biosynthesis of the recently identified novel class of plant hormones, strigolactones, is up-regulated upon phosphate deficiency in many plant species. It is generally accepted that the evolutionary origin of strigolactone up-regulation is their function as a rhizosphere signal that stimulates hyphal branching of arbuscular mycorrhizal fungi. In this work, we demonstrate that this induction is conserved in Arabidopsis (Arabidopsis thaliana), although Arabidopsis is not a host for arbuscular mycorrhizal fungi. We demonstrate that the increase in strigolactone production contributes to the changes in shoot architecture observed in response to phosphate deficiency. Using high-performance liquid chromatography, column chromatography, and multiple reaction monitoring-liquid chromatography-tandem mass spectrometry analysis, we identified two strigolactones (orobanchol and orobanchyl acetate) in Arabidopsis and have evidence of the presence of a third (5-deoxystrigol). We show that at least one of them (orobanchol) is strongly reduced in the putative strigolactone biosynthetic mutants more axillary growth1 (max1) and max4 but not in the signal transduction mutant max2. Orobanchol was also detected in xylem sap and up-regulated under phosphate deficiency, which is consistent with the idea that root-derived strigolactones are transported to the shoot, where they regulate branching. Moreover, two additional putative strigolactone-like compounds were detected in xylem sap, one of which was not detected in root exudates. Together, these results show that xylem-transported strigolactones contribute to the regulation of shoot architectural response to phosphate-limiting conditions.

  2. Clinical studies of intestinal folate conjugases.

    PubMed

    Halsted, C H; Beer, W H; Chandler, C J; Ross, K; Wolfe, B M; Bailey, L; Cerda, J J

    1986-03-01

    Clinical differences between the two human intestinal mucosal folate conjugases were assessed by measurement of their activities in normal individuals and in patients with chronic diarrhea of differing causes. Intracellular folate conjugase (ICFC) was 15-fold more active than brush border folate conjugase (BBFC) in jejunal mucosa from seven obese patients undergoing elective gastric bypass surgery. The activity of ICFC was similar among normal volunteers and patients with diarrhea of unknown origin (DUO), gluten-sensitive enteropathy (GSE), inflammatory bowel disease (IBD), and the short bowel syndrome (IBD-SBS). By contrast, BBFC, sucrase, and lactase were decreased significantly in GSE, and BBFC was increased in IBD-SBS. The activity of BBFC correlated with lactase and with sucrase in the normal subjects and in patients with DUO, whereas no correlations were found with the activity of ICFC in any group. Our clinical studies confirm that ICFC and BBFC are different enzymes. ICFC is not affected by intestinal disease, whereas the activity of jejunal BBFC, like that of other brush border enzymes, is decreased by mucosal injury and is also capable of adapting to distal small intestinal disease or surgical resection.

  3. Vitamin paradox in obesity: Deficiency or excess?

    PubMed Central

    Zhou, Shi-Sheng; Li, Da; Chen, Na-Na; Zhou, Yiming

    2015-01-01

    Since synthetic vitamins were used to fortify food and as supplements in the late 1930s, vitamin intake has significantly increased. This has been accompanied by an increased prevalence of obesity, a condition associated with diabetes, hypertension, cardiovascular disease, asthma and cancer. Paradoxically, obesity is often associated with low levels of fasting serum vitamins, such as folate and vitamin D. Recent studies on folic acid fortification have revealed another paradoxical phenomenon: obesity exhibits low fasting serum but high erythrocyte folate concentrations, with high levels of serum folate oxidation products. High erythrocyte folate status is known to reflect long-term excess folic acid intake, while increased folate oxidation products suggest an increased folate degradation because obesity shows an increased activity of cytochrome P450 2E1, a monooxygenase enzyme that can use folic acid as a substrate. There is also evidence that obesity increases niacin degradation, manifested by increased activity/expression of niacin-degrading enzymes and high levels of niacin metabolites. Moreover, obesity most commonly occurs in those with a low excretory reserve capacity (e.g., due to low birth weight/preterm birth) and/or a low sweat gland activity (black race and physical inactivity). These lines of evidence raise the possibility that low fasting serum vitamin status in obesity may be a compensatory response to chronic excess vitamin intake, rather than vitamin deficiency, and that obesity could be one of the manifestations of chronic vitamin poisoning. In this article, we discuss vitamin paradox in obesity from the perspective of vitamin homeostasis. PMID:26322161

  4. Vitamin paradox in obesity: Deficiency or excess?

    PubMed

    Zhou, Shi-Sheng; Li, Da; Chen, Na-Na; Zhou, Yiming

    2015-08-25

    Since synthetic vitamins were used to fortify food and as supplements in the late 1930s, vitamin intake has significantly increased. This has been accompanied by an increased prevalence of obesity, a condition associated with diabetes, hypertension, cardiovascular disease, asthma and cancer. Paradoxically, obesity is often associated with low levels of fasting serum vitamins, such as folate and vitamin D. Recent studies on folic acid fortification have revealed another paradoxical phenomenon: obesity exhibits low fasting serum but high erythrocyte folate concentrations, with high levels of serum folate oxidation products. High erythrocyte folate status is known to reflect long-term excess folic acid intake, while increased folate oxidation products suggest an increased folate degradation because obesity shows an increased activity of cytochrome P450 2E1, a monooxygenase enzyme that can use folic acid as a substrate. There is also evidence that obesity increases niacin degradation, manifested by increased activity/expression of niacin-degrading enzymes and high levels of niacin metabolites. Moreover, obesity most commonly occurs in those with a low excretory reserve capacity (e.g., due to low birth weight/preterm birth) and/or a low sweat gland activity (black race and physical inactivity). These lines of evidence raise the possibility that low fasting serum vitamin status in obesity may be a compensatory response to chronic excess vitamin intake, rather than vitamin deficiency, and that obesity could be one of the manifestations of chronic vitamin poisoning. In this article, we discuss vitamin paradox in obesity from the perspective of vitamin homeostasis.

  5. A Dominant Negative Heterozygous G87R Mutation in the Zinc Transporter, ZnT-2 (SLC30A2), Results in Transient Neonatal Zinc Deficiency

    PubMed Central

    Lasry, Inbal; Seo, Young Ah; Ityel, Hadas; Shalva, Nechama; Pode-Shakked, Ben; Glaser, Fabian; Berman, Bluma; Berezovsky, Igor; Goncearenco, Alexander; Klar, Aharon; Levy, Jacob; Anikster, Yair; Kelleher, Shannon L.; Assaraf, Yehuda G.

    2012-01-01

    Zinc is an essential mineral, and infants are particularly vulnerable to zinc deficiency as they require large amounts of zinc for their normal growth and development. We have recently described the first loss-of-function mutation (H54R) in the zinc transporter ZnT-2 (SLC30A2) in mothers with infants harboring transient neonatal zinc deficiency (TNZD). Here we identified and characterized a novel heterozygous G87R ZnT-2 mutation in two unrelated Ashkenazi Jewish mothers with infants displaying TNZD. Transient transfection of G87R ZnT-2 resulted in endoplasmic reticulum-Golgi retention, whereas the WT transporter properly localized to intracellular secretory vesicles in HC11 and MCF-7 cells. Consequently, G87R ZnT-2 showed decreased stability compared with WT ZnT-2 as revealed by Western blot analysis. Three-dimensional homology modeling based on the crystal structure of YiiP, a close zinc transporter homologue from Escherichia coli, revealed that the basic arginine residue of the mutant G87R points toward the membrane lipid core, suggesting misfolding and possible loss-of-function. Indeed, functional assays including vesicular zinc accumulation, zinc secretion, and cytoplasmic zinc pool assessment revealed markedly impaired zinc transport in G87R ZnT-2 transfectants. Moreover, co-transfection experiments with both mutant and WT transporters revealed a dominant negative effect of G87R ZnT-2 over the WT ZnT-2; this was associated with mislocalization, decreased stability, and loss of zinc transport activity of the WT ZnT-2 due to homodimerization observed upon immunoprecipitation experiments. These findings establish that inactivating ZnT-2 mutations are an underlying basis of TNZD and provide the first evidence for the dominant inheritance of heterozygous ZnT-2 mutations via negative dominance due to homodimer formation. PMID:22733820

  6. Sodium deficiency effect on the transport properties of La0.8Na0.2-x□xMnO3 manganites

    NASA Astrophysics Data System (ADS)

    Elghoul, N.; Wali, M.; Kraiem, S.; Rahmouni, H.; Dhahri, E.; Khirouni, K.

    2015-12-01

    Effect of sodium deficiency on the transport properties of La0.8Na0.2-x□xMnO3 manganites is investigated using impedance spectroscopy technique. In the whole explored temperature range (77-700 K), conductivity measurements show the appearance of a metal-semiconductor transition for all investigated samples. Also, a saturation region is observed in σ (T) curves. It is found that conduction mechanism is governed by hopping process. The conductivity of the material decreases with increasing sodium deficiency. The transition temperature and the activation energy values inferred from grain boundary resistance and conductivity analysis are closed to each other. Such result confirms the contribution of grain boundary on the electrical conductivity. The variation of the Average Normalized Change (ANC) and its derivative with temperature gives important information about the available density of trapped charge states. The obtained results explain the observed saturation region in conductivity at high temperature region.

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

    SciTech Connect

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

    1987-09-01

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

  8. Human folate metabolism using 14C-accelerator mass spectrometry

    SciTech Connect

    Clifford, A. J.; Arjomand, A.; Duecker, S. R.; Johnson, H.; Schneider, P. D.; Zulim, R. A.; Bucholz, B. A.; Vogel, J. S.

    1999-03-25

    Folate is a water soluble vitamin required for optimal health, growth and development. It occurs naturally in various states of oxidation of the pteridine ring and with varying lengths to its glutamate chain. Folates function as one-carbon donors through methyl transferase catalyzed reactions. Low-folate diets, especially by those with suboptimal methyltransferase activity, are associated with increased risk of neural tube birth defects in children, hyperhomocysteinemic heart disease, and cancer in adults. Rapidly dividing (neoplastic) cells have a high folate need for DNA synthesis. Chemical analogs of folate (antifolates) that interfere with folate metabolism are used as therapeutic agents in cancer treatment. Although much is known about folate chemistry, metabolism of this vitamin in vivo in humans is not well understood. Since folate levels in blood and tissues are very low and methods to measure them are inadequate, the few previous studies that have examined folate metabolism used large doses of radiolabeled folic acid in patients with Hodgkin's disease and cancer (Butterworth et al. 1969, Krumdieck et al. 1978). A subsequent protocol using deuterated folic acid was also insufficiently sensitive to trace a physiologic folate dose (Stites et al. 1997). Accelerator mass spectrometry (AMS) is an emerging bioanalytical tool that overcomes the limitations of traditional mass spectrometry and of decay counting of long lived radioisotopes (Vogel et al. 1995). AMS can detect attomolar concentrations of 14 C in milligram-sized samples enabling in vivo radiotracer studies in healthy humans. We used AMS to study the metabolism of a physiologic 80 nmol oral dose of 14 C-folic acid (1/6 US RDA) by measuring the 14 C-folate levels in serial plasma, urine and feces samples taken over a 150-day period after dosing a healthy adult volunteer.

  9. Physiological responses to folate overproduction in Lactobacillus plantarum WCFS1

    PubMed Central

    2010-01-01

    Background Using a functional genomics approach we addressed the impact of folate overproduction on metabolite formation and gene expression in Lactobacillus plantarum WCFS1. We focused specifically on the mechanism that reduces growth rates in folate-overproducing cells. Results Metabolite formation and gene expression were determined in a folate-overproducing- and wild-type strain. Differential metabolomics analysis of intracellular metabolite pools indicated that the pool sizes of 18 metabolites differed significantly between these strains. The gene expression profile was determined for both strains in pH-regulated chemostat culture and batch culture. Apart from the expected overexpression of the 6 genes of the folate gene cluster, no other genes were found to be differentially expressed both in continuous and batch cultures. The discrepancy between the low transcriptome and metabolome response and the 25% growth rate reduction of the folate overproducing strain was further investigated. Folate production per se could be ruled out as a contributing factor, since in the absence of folate production the growth rate of the overproducer was also reduced by 25%. The higher metabolic costs for DNA and RNA biosynthesis in the folate overproducing strain were also ruled out. However, it was demonstrated that folate-specific mRNAs and proteins constitute 8% and 4% of the total mRNA and protein pool, respectively. Conclusion Folate overproduction leads to very little change in metabolite levels or overall transcript profile, while at the same time the growth rate is reduced drastically. This shows that Lactobacillus plantarum WCFS1 is unable to respond to this growth rate reduction, most likely because the growth-related transcripts and proteins are diluted by the enormous amount of gratuitous folate-related transcripts and proteins. PMID:21167023

  10. Zea mays Fe deficiency-related 4 (ZmFDR4) functions as an iron transporter in the plastids of monocots.

    PubMed

    Zhang, Xiu-Yue; Zhang, Xi; Zhang, Qi; Pan, Xiao-Xi; Yan, Luo-Chen; Ma, Xiao-Juan; Zhao, Wei-Zhong; Qi, Xiao-Ting; Yin, Li-Ping

    2017-04-01

    Iron (Fe)-homeostasis in the plastids is closely associated with Fe transport proteins that prevent Fe from occurring in its toxic free ionic forms. However, the number of known protein families related to Fe transport in the plastids (about five) and the function of iron in non-green plastids is limited. In the present study, we report the functional characterization of Zea mays Fe deficiency-related 4 (ZmFDR4), which was isolated from a differentially expressed clone of a cDNA library of Fe deficiency-induced maize roots. ZmFDR4 is homologous to the bacterial FliP superfamily, coexisted in both algae and terrestrial plants, and capable of restoring the normal growth of the yeast mutant fet3fet4, which possesses defective Fe uptake systems. ZmFDR4 mRNA is ubiquitous in maize and is inducible by iron deficiency in wheat. Transient expression of the 35S:ZmFDR4-eGFP fusion protein in rice protoplasts indicated that ZmFDR4 maybe localizes to the plastids envelope and thylakoid. In 35S:c-Myc-ZmFDR4 transgenic tobacco, immunohistochemistry and immunoblotting confirmed that ZmFDR4 is targeted to both the chloroplast envelope and thylakoid. Meanwhile, ultrastructure analysis indicates that ZmFDR4 promotes the density of plastids and accumulation of starch grains. Moreover, Bathophenanthroline disulfonate (BPDS) colorimetry and inductively coupled plasma mass spectrometry (ICP-MS) indicate that ZmFDR4 is related to Fe uptake by plastids and increases seed Fe content. Finally, 35S:c-Myc-ZmFDR4 transgenic tobacco show enhanced photosynthetic efficiency. Therefore, the results of the present study demonstrate that ZmFDR4 functions as an iron transporter in monocot plastids and provide insight into the process of Fe uptake by plastids.

  11. Iron Deficiency Induces a Partial Inhibition of the Photosynthetic Electron Transport and a High Sensitivity to Light in the Diatom Phaeodactylum tricornutum.

    PubMed

    Roncel, Mercedes; González-Rodríguez, Antonio A; Naranjo, Belén; Bernal-Bayard, Pilar; Lindahl, Anna M; Hervás, Manuel; Navarro, José A; Ortega, José M

    2016-01-01

    Iron limitation is the major factor controlling phytoplankton growth in vast regions of the contemporary oceans. In this study, a combination of thermoluminescence (TL), chlorophyll fluorescence, and P700 absorbance measurements have been used to elucidate the effects of iron deficiency in the photosynthetic electron transport of the marine diatom P. tricornutum. TL was used to determine the effects of iron deficiency on photosystem II (PSII) activity. Excitation of iron-replete P. tricornutum cells with single turn-over flashes induced the appearance of TL glow curves with two components with different peaks of temperature and contributions to the total signal intensity: the B band (23°C, 63%), and the AG band (40°C, 37%). Iron limitation did not significantly alter these bands, but induced a decrease of the total TL signal. Far red excitation did not increase the amount of the AG band in iron-limited cells, as observed for iron-replete cells. The effect of iron deficiency on the photosystem I (PSI) activity was also examined by measuring the changes in P700 redox state during illumination. The electron donation to PSI was substantially reduced in iron-deficient cells. This could be related with the important decline on cytochrome c 6 content observed in these cells. Iron deficiency also induced a marked increase in light sensitivity in P. tricornutum cells. A drastic increase in the level of peroxidation of chloroplast lipids was detected in iron-deficient cells even when grown under standard conditions at low light intensity. Illumination with a light intensity of 300 μE m(-2) s(-1) during different time periods caused a dramatic disappearance in TL signal in cells grown under low iron concentration, this treatment not affecting to the signal in iron-replete cells. The results of this work suggest that iron deficiency induces partial blocking of the electron transfer between PSII and PSI, due to a lower concentration of the electron donor cytochrome c 6. This

  12. Iron Deficiency Induces a Partial Inhibition of the Photosynthetic Electron Transport and a High Sensitivity to Light in the Diatom Phaeodactylum tricornutum

    PubMed Central

    Roncel, Mercedes; González-Rodríguez, Antonio A.; Naranjo, Belén; Bernal-Bayard, Pilar; Lindahl, Anna M.; Hervás, Manuel; Navarro, José A.; Ortega, José M.

    2016-01-01

    Iron limitation is the major factor controlling phytoplankton growth in vast regions of the contemporary oceans. In this study, a combination of thermoluminescence (TL), chlorophyll fluorescence, and P700 absorbance measurements have been used to elucidate the effects of iron deficiency in the photosynthetic electron transport of the marine diatom P. tricornutum. TL was used to determine the effects of iron deficiency on photosystem II (PSII) activity. Excitation of iron-replete P. tricornutum cells with single turn-over flashes induced the appearance of TL glow curves with two components with different peaks of temperature and contributions to the total signal intensity: the B band (23°C, 63%), and the AG band (40°C, 37%). Iron limitation did not significantly alter these bands, but induced a decrease of the total TL signal. Far red excitation did not increase the amount of the AG band in iron-limited cells, as observed for iron-replete cells. The effect of iron deficiency on the photosystem I (PSI) activity was also examined by measuring the changes in P700 redox state during illumination. The electron donation to PSI was substantially reduced in iron-deficient cells. This could be related with the important decline on cytochrome c6 content observed in these cells. Iron deficiency also induced a marked increase in light sensitivity in P. tricornutum cells. A drastic increase in the level of peroxidation of chloroplast lipids was detected in iron-deficient cells even when grown under standard conditions at low light intensity. Illumination with a light intensity of 300 μE m-2 s-1 during different time periods caused a dramatic disappearance in TL signal in cells grown under low iron concentration, this treatment not affecting to the signal in iron-replete cells. The results of this work suggest that iron deficiency induces partial blocking of the electron transfer between PSII and PSI, due to a lower concentration of the electron donor cytochrome c6. This

  13. Folate contents in human milk and casein-based and soya-based formulas, and folate status in Korean infants.

    PubMed

    Han, Young-Hee; Yon, Miyong; Han, Heon-Seok; Kim, Kwang-Yup; Tamura, Tsunenobu; Hyun, Taisun H

    2009-06-01

    We assessed folate nutritional status from birth to 12 months in fifty-one infants who were fed human milk (HM; n 20), casein-based formula (CBF; n 12) or soya-based formula (SBF; n 19). Folate contents in ninety-five HM samples obtained from twenty mothers for the first 6-month period and twelve CBF and nineteen SBF samples were measured by bioassay after trienzyme extraction. Folate intake was estimated by weighing infants before and after feeding in the HM group and by collecting formula intake records in the formula-fed groups. After solid foods were introduced, all foods consumed were included to estimate folate intake. Serum folate and total homocysteine (tHcy) concentrations were determined at 5 and 12 months of age, and infant growth was monitored for the first 12 months. Mean HM folate contents ranged from 201 to 365 nmol/l with an overall mean of 291 nmol/l, and the contents peaked at 2 months postpartum. HM folate contents were higher than those reported in North America. Folate contents in CBF and SBF were markedly higher than those in HM and those claimed on the product labels. The overall folate intakes in formula-fed infants were significantly higher than those in HM-fed infants, and this was associated with significantly higher folate and lower tHcy in formula-fed infants than HM-fed infants at 5 months. At 12 months, serum folate was significantly higher in the SBF group than the other groups, whereas serum tHcy and overall growth were similar among all groups.

  14. Nutrigenetics in cancer research--folate metabolism and colorectal cancer.

    PubMed

    Ulrich, Cornelia M

    2005-11-01

    The B vitamin folate is essential for one-carbon transfer reactions, including those related to the methylation of DNA or other substrates and nucleotide synthesis. Epidemiologic and experimental studies implicate low-folate intakes in elevated risk of colorectal neoplasia and suggest that biologic mechanisms underlying this relation include disturbances in DNA methylation patterns or adverse effects on DNA synthesis and repair. With the completion of the Human Genome Project, a vast amount of data on inherited genetic variability has become available. This genetic information can be used in studies of molecular epidemiology to provide information on multiple aspects of folate metabolism. First, studies linking polymorphisms in folate metabolism to an altered risk of cancer provide evidence for a causal link between this pathway and colorectal carcinogenesis. Second, studies on genetic characteristics can help clarify whether certain individuals may benefit from higher or lower intakes of folate or nutrients relevant to folate metabolism. Third, studies on genetic polymorphisms can generate hypotheses regarding possible biologic mechanisms that connect this pathway to carcinogenesis. Last, genetic variability in folate metabolism may predict survival after a cancer diagnosis, possibly via pharmacogenetic effects. To solve the puzzle of the folate-cancer relation, a transdisciplinary approach is needed that integrates knowledge from epidemiology, clinical studies, experimental nutrition, and mathematical modeling. This review illustrates knowledge that can be gained from molecular epidemiology in the context of nutrigenetics, and the questions that this approach can answer or raise.

  15. Lentils (Lens culinaris L.), a rich source of folates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Pulses contain folates in the form of reduced tetrahydrofolate which is the biologically active form absorbed in the jejunum. Genetic biofortification potential of US-grown lentils (Lens culinaris L.) with the bioavailable form of folate has not been widely studied. The objectives of this study wer...

  16. The role of methionine in the intracellular accumulation and function of folates

    SciTech Connect

    Scott, J.M.; McKenna, B.; McGing, P.; Molloy, A.; Dinn, J.; Weir, D.G.

    1983-01-01

    It is suggested that mammalian cells have evolved to respond to methionine deficiency since in such circumstances vital methylation reactions are put at risk, due to decreased levels of S-adenosyl-methionine. Decreased cellular homocysteine, as a result of decreased methionine, would also restrict cell division by decreased conversion of plasma 5-CH3-H/sub 4/PteGlu into intracellular polyglutamates. Cobalamin deficiency, either nutritional or due to exposure to the Co(I)cobalamin inactivating agent nitrous oxide, prevents the demethylation of 5-CH3-H/sub 4/PteGlu, which even in the presence of adequate amounts of homocysteine and methionine prevents rapidly proliferating cells from converting enough of the plasma 5-CH3-H/sub 4/ PteGlu into folylpolyglutamate forms to permit normal DNA biosynthesis and cell replication. This, together with the trapping of the cellular folate cofactors in the 5-CH3-H/sub 4/PteGlu form, results in megaloblastic changes occurring in tissues such as the marrow. The vital role of the methylation reactions was demonstrated by exposing monkeys to nitrous oxide which inactivated their methionine synthetase. The resultant ataxia and severe demyelination was prevented and diminished by methionine supplementation. When methionine synthetase was similarly inactivated in mice it was shown that while 5-CH3-H/sub 4/PteGlu enters mammalian cells, it is not converted into a polyglutamyl form and subsequently leaves the cell unmetabolised. In similar experiments in rats methionine was found to have only a small effect in restoring folylpolyglutamate biosynthesis. It was found that a decrease in the deoxythymidine salvage pathway by methionine has led others to the mistaken conclusion that methionine has an 'anti-folate' effect in bone marrow, i.e. that it decreases folate availability for thymidylate synthetase.

  17. Co-occurrence of anemia, marginal vitamin B6, and folate status and depressive symptoms in older adults.

    PubMed

    Pan, Wen-Harn; Chang, Yi-Ping; Yeh, Wen-Ting; Guei, Yu-Shu; Lin, Bi-Fong; Wei, Ien-Lan; Yang, Feili Lo; Liaw, Yung-Po; Chen, Kuan-Ju; Chen, Wei J

    2012-09-01

    Although nutrient deficiencies are thought to play roles in the development of depression, observational studies have yielded inconsistent results. This study aimed to investigate whether multiple marginal nutrient deficiencies are associated with symptoms of depression in community-dwelling older Taiwanese. Data from 1371 elderly adults recruited from the Elderly Nutrition and Health Survey in Taiwan was used in this study. Depressive symptom scores on depressed mood and emotions affecting daily life were derived from the Medical Outcomes Study Short Form-36 (SF-36). Hemoglobin, serum ferritin, plasma vitamins B(6), B(12), and folate concentration, and erythrocyte transketolase and glutathione reductase activation coefficients were measured. After adjusting for age, gender, cognitive function, physical activity, disease history, and medication in the multivariate analysis, anemia, and marginal B(6) deficiency were significantly associated with the presence of depression symptoms, respectively. In addition, co-occurrence of vitamin B(6) with low folate level and co-occurrence of anemia either with low vitamin B(6) or with folate level were all associated with the depressive mood and with depressive emotions defined by SF-36 (odds ratios [OR] in the range of 2.32-7.13, all P values ≤.05). The magnitude of the ORs is larger when the number of deficiencies increased. Elderly people with coexisting marginal deficiencies of nutrients involved in the S-adenosylmethionine and hemoglobin production were more likely to experience depressed mood and emotion that affect daily activity. Examining status of these nutrients is worthy of consideration for older adults with depressed symptoms.

  18. Enhanced receptor-mediated endocytosis and cytotoxicity of a folic acid-desacetylvinblastine monohydrazide conjugate in a pemetrexed-resistant cell line lacking folate-specific facilitative carriers but with increased folate receptor expression.

    PubMed

    Zhao, Rongbao; Diop-Bove, Ndeye; Goldman, I David

    2014-02-01

    The reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptors (FR) are folate-specific transporters. Antifolates currently in the clinic, such as pemetrexed, methotrexate, and pralatrexate, are transported into tumor cells primarily via RFC. Folic acid conjugated to cytotoxics, a new class of antineoplastics, are transported into cells via FR-mediated endocytosis. To better define the role of PCFT in antifolate resistance, a methotrexate-resistant cell line, M160-8, was selected from a HeLa subline in which the RFC gene was deleted and PCFT was highly overexpressed. These cells were cross-resistant to pemetrexed. PCFT function and the PCFT mRNA level in M160-8 cells were barely detectable, and FR-α function and mRNA level were increased as compared with the parent cells. While pemetrexed rapidly associated with FR and was internalized within endosomes in M160-8 cells, consistent with FR-mediated transport, subsequent pemetrexed and (6S)-5-formyltetrahydrofolate export into the cytosol was markedly impaired. In contrast, M160-8 cells were collaterally sensitive to EC0905, a folic acid-desacetylvinblastine monohydrazide conjugate also transported by FR-mediated endocytosis. However, in this case a sulfhydryl bond is cleaved to release the lipophilic cytotoxic moiety into the endosome, which passively diffuses out of the endosome into the cytosol. Hence, resistance to pemetrexed in M160-8 cells was due to entrapment of the drug within the endosome due to the absence of PCFT under conditions in which the FR cycling function was intact.

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

    PubMed

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

    2015-02-01

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

  20. 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 Central

    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.

    2015-01-01

    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. PMID:25867949

  1. Folate content and retention in selected raw and processed foods.

    PubMed

    Bassett, M N; Sammán, N C

    2010-09-01

    Adequate intake of folate reduced the risk of abnormalities in early embryonic brain development such as the risk of malformations of the embryonic brain/spinal cord, collectively referred to as neural tube defects (NTDs). Folate is extremely sensitive to destruction by heat, oxidation and UV light. The purpose of this study was to evaluate the use of different extraction procedures and enzymatic treatment to determine folate concentrations in variety of foods using a microbiological assay (MA) with Lactobacillus rhamnosus as the test organism. This study also aimed to evaluate the retention of folate in foods after using different cooking processes. Nine of the most commonly consumed foods in Argentina and that contain folate were analyzed: broccoli, spinach, potato, lentil, soy (raw and boiled); hen whole egg and yolks (raw, boiled and fried); beef liver (raw and cooked); strawberry (raw) and white bread. For this study, rat plasma (RP) and human plasma (HP) conjugases together with acetate and phosphate buffers were tested. In extraction step for all analyses, RP conjugase was selected since it was easily available in our laboratory and small quantities were required. The acetate buffer was chosen since better growth and more reproducible results were obtained in the different conditions assayed. The results allowed the foods to be grouped into (a) rich sources of folate: hen eggs, yolks, spinach, soybean (raw) and strawberry (100 and 350 microg/100 g fresh weight (FW); (b) good sources of folate: broccoli (raw), soybean (boiled), lentils (raw) and potato (56 to 83 microg/100 g FW) and c) moderate sources of folate: broccoli, lentils (boiled), white breads, onions and beef liver (15 to 30 microg/100g FW). The folate retention was in the range 14-99% according to both type of food and method of processing. Contents and losses of folate vary widely according to type of food and cooking method.

  2. Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness.

    PubMed

    Jackson, Maria D; Tulloch-Reid, Marshall K; McFarlane-Anderson, Norma; Watson, Alexis; Seers, Vestra; Bennett, Franklyn I; Egleston, Brian; Ragin, Camille

    2013-03-01

    Little is known about the role of folate and polymorphisms associated with folate metabolism on prostate cancer risk in populations of African origin. We examined the relationship between serum folate and prostate cancer and whether any association was modified by genetic polymorphisms for folate metabolism. The study was case-control in design and consisted of 218 men 40-80 years old with newly diagnosed, histologically confirmed prostate cancer and 236 cancer-free men attending the same urology clinics in Jamaica, March 2005-July 2007. Serum folate was measured by an immunoassay method and genomic DNA evaluated for MTHR (C677T and A1298C), MTRR A66G, and MTR A2756G polymorphisms. Mean serum folate concentration was higher among cases (12.3 ± 4.1 nmol/L) than controls (9.7 ± 4.2 nmol/L). Serum folate concentration showed a positive association with prostate cancer (OR, 4.41; CI, 2.52-7.72 per 10 nmol/L) regardless of grade. No interactions were observed between genotype and folate concentration, but a weak gene effect was observed for MTHFR A1298C and low-grade prostate cancer. Larger studies to investigate the role of gene-gene/gene-diet interactions in Black men are needed.

  3. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 ...

  5. The Involvement of OsPHO1;1 in the Regulation of Iron Transport Through Integration of Phosphate and Zinc Deficiency Signaling

    PubMed Central

    Saenchai, Chorpet; Bouain, Nadia; Kisko, Mushtak; Prom-u-thai, Chanakan; Doumas, Patrick; Rouached, Hatem

    2016-01-01

    Plants survival depends on their ability to cope with multiple nutrient stresses that often occur simultaneously, such as the limited availability of essential elements inorganic phosphate (Pi), zinc (Zn), and iron (Fe). Previous research has provided information on the genes involved in efforts by plants to maintain homeostasis when a single nutrient (Pi, Zn, or Fe) is depleted. Recent findings on nutritional stress suggest that plant growth capacity is influenced by a complex tripartite interaction between Pi, Zn, and Fe homeostasis. However, despite its importance, how plants integrate multiple nutritional stimuli into complex developmental programs, and which genes are involved in this tripartite (Pi ZnFe) interaction is still not clear. The aim of this study was to examine the physiological and molecular responses of rice (Oriza sativa L.) to a combination of Pi, Zn, and/or Fe deficiency stress conditions. Results showed that Fe deficiency had the most drastic single-nutrient effect on biomass, while the Zn deficiency-effect depended on the presence of Pi in the medium. Interestingly, the observed negative effect of Fe starvation was alleviated by concomitant Pi or PiZn depletion. Members of the OsPHO1 family showed a differential transcriptional regulation in response PiZnFe combinatory stress conditions. Particularly, the transcripts of the OsPHO1;1 sense and its natural antisense cis-NatPHO1;1 showed the highest accumulation under PiZn deficiency. In this condition, the Ospho1;1 mutants showed over-accumulation of Fe in roots compared to wild type plants. These data reveal coordination between pathways involved in Fe transport and PiZn signaling in rice which involves the OsPHO1; 1, and support the hypothesis of a genetic basis for Pi, Zn, and Fe signaling interactions in plants. PMID:27092147

  6. The Involvement of OsPHO1;1 in the Regulation of Iron Transport Through Integration of Phosphate and Zinc Deficiency Signaling.

    PubMed

    Saenchai, Chorpet; Bouain, Nadia; Kisko, Mushtak; Prom-U-Thai, Chanakan; Doumas, Patrick; Rouached, Hatem

    2016-01-01

    Plants survival depends on their ability to cope with multiple nutrient stresses that often occur simultaneously, such as the limited availability of essential elements inorganic phosphate (Pi), zinc (Zn), and iron (Fe). Previous research has provided information on the genes involved in efforts by plants to maintain homeostasis when a single nutrient (Pi, Zn, or Fe) is depleted. Recent findings on nutritional stress suggest that plant growth capacity is influenced by a complex tripartite interaction between Pi, Zn, and Fe homeostasis. However, despite its importance, how plants integrate multiple nutritional stimuli into complex developmental programs, and which genes are involved in this tripartite (Pi ZnFe) interaction is still not clear. The aim of this study was to examine the physiological and molecular responses of rice (Oriza sativa L.) to a combination of Pi, Zn, and/or Fe deficiency stress conditions. Results showed that Fe deficiency had the most drastic single-nutrient effect on biomass, while the Zn deficiency-effect depended on the presence of Pi in the medium. Interestingly, the observed negative effect of Fe starvation was alleviated by concomitant Pi or PiZn depletion. Members of the OsPHO1 family showed a differential transcriptional regulation in response PiZnFe combinatory stress conditions. Particularly, the transcripts of the OsPHO1;1 sense and its natural antisense cis-NatPHO1;1 showed the highest accumulation under PiZn deficiency. In this condition, the Ospho1;1 mutants showed over-accumulation of Fe in roots compared to wild type plants. These data reveal coordination between pathways involved in Fe transport and PiZn signaling in rice which involves the OsPHO1; 1, and support the hypothesis of a genetic basis for Pi, Zn, and Fe signaling interactions in plants.

  7. Duodenal active transport of calcium and phosphate in vitamin D-deficient rats: effects of nephrectomy, Cestrum diurnum, and 1alpha,25-dihydroxyvitamin D3.

    PubMed

    Walling, M W; Kimberg, D V; Wasserman, R H; Feinberg, R R

    1976-05-01

    Both the methanol:chloroform extractable material from the leaves of the Solanaceous plant, Cestrum diurnum (C.d.), and a 270 ng dose of 1alpha, 25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) increased the active absorption of calcium and phosphate across the proximal duodenum, studied in vitro, from sham-operated and nephrectomized (NPX) vitamin D-deficient rats. In these studies, conducted 24 h after surgery, the uremic state in the NPX animals markedly diminished the intestinal transport response to 1alpha,25-(OH)2D3 and also lowered baseline transport values across duodenum from the NPX vitamin D-deficient controls. Both C.d. and 1alpha, 25-(OH)2D3 elevated plasma Ca levels equally well in the sham-operated and NPX groups. The stimulation of intestinal Ca absorption in NPX animals indicates that, like the leaves of the South American plant, Solanum glaucophyllum, C.d. contains materials which can function in an analogous manner to compounds in the vitamin D group that have either a 1alpha hydroxyl group or its steric equivalent.

  8. Night blindness due to vitamin A deficiency associated with copper deficiency myelopathy secondary to bowel bypass surgery.

    PubMed

    AlHassany, Ali Abdul Jabbar

    2014-04-29

    We present an interesting case of combined vitamin A and copper deficiency after a history of gastric bypass surgery where symptoms improved after parenteral copper and vitamin A treatment. Gastric bypass surgery as a cause of fat soluble vitamin deficiency is generally under-reported. Copper deficiency has been reported after gastric bypass surgery. Vitamin A deficiency after gastric bypass surgery has also been reported in the literature, but the reported cases again fall below the actual figures. B12 and folate deficiencies can produce a type of myelopathy similar to that produced by copper deficiency, and differentiation on the basis of laboratory tests, neurophysiology and improvement of symptoms after replacement therapy might be the hallmark of diagnosis. Combinations of vitamin deficiencies were previously reported, but no cases of combined vitamin A and copper deficiency could be found in the literature.

  9. Acute effects of ethanol on renal folate clearance in rats

    SciTech Connect

    Eisenga, B.H.; McMartin, K.E.

    1986-03-05

    Studies of the renal clearance of folic acid in primates demonstrate net reabsorption of folate by a saturable system. The acute administration of ethanol to rats causes a significant increase in urinary folate excretion. The mechanism for this effect is unknown and thus the effect of acute administration of ethanol on the renal absorption and urinary clearance of folate was studied in rats. Folic acid was administered to male Sprague-Dawley rats via continuous intravenous infusion in doses ranging from 3-75 micromoles/kg and renal clearance relative to inulin was determined. The effects of various dose levels of ethanol on these parameters were then determined. At a dose of 15 micromoles/kg, the renal clearance of folate relative to that of inulin was about 0.65 mg/min. At a plasma ethanol level about 100 mg/dl, the renal clearance of folate was not markedly altered. These results suggests that there is net reabsorption of folate in the rat kidney and that moderate doses of ethanol have little effect on renal effect on renal folate reabsorption.

  10. 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.

  11. Folate receptor targeted liposomes encapsulating anti-cancer drugs.

    PubMed

    Chaudhury, Anumita; Das, Surajit

    2015-01-01

    Among all available lipid based nanoparticulate systems, the success of liposomal drug delivery system is evident by the number of liposomal products available in the market or under advanced stages of preclinical and clinical trials. Liposome has the ability to deliver chemotherapeutic agents to the targeted tissues or even inside the cancerous cells by enhanced intracellular penetration or improved tumour targeting. In the last decade, folate receptor mediated tumour targeting has emerged as an attractive alternative method of active targeting of cancer cells through liposomes due to its numerous advantages over other targeting methods. Folate receptors, also known as folate binding proteins, allow the binding and internalization of folate or folic acid into the cells by a method called folate receptor mediated endocytosis. They have restricted presence in normal cells and are mostly expressed during malignant transformation. In this review article, folate receptor targeting capability of liposomes has been described. This review article has focussed on the different cancer drugs which have been encapsulated in folate receptor targeted liposomes and their in vitro as well as in vivo efficacies in several tumour models.

  12. Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure.

    PubMed

    Anderson, Joel G; Fordahl, Steven C; Cooney, Paula T; Weaver, Tara L; Colyer, Christa L; Erikson, Keith M

    2009-07-24

    Manganese (Mn) is an essential trace element, but overexposure is characterized by Parkinson's like symptoms in extreme cases. Previous studies have shown that Mn accumulation is exacerbated by dietary iron deficiency (ID) and disturbances in norepinephrine (NE) have been reported. Because behaviors associated with Mn neurotoxicity are complex, the goal of this study was to examine the effects of Mn exposure and ID-associated Mn accumulation on NE uptake in synaptosomes, extracellular NE concentrations, and expression of NE transport and receptor proteins. Sprague-Dawley rats were assigned to four dietary groups: control (CN; 35 mg Fe/kg diet), iron-deficient (ID; 6 mg Fe/kg diet), CN with Mn exposure (via the drinking water; 1 g Mn/L) (CNMn), and ID with Mn (IDMn). (3)H-NE uptake decreased significantly (R=-0.753, p=0.001) with increased Mn concentration in the locus coeruleus, while decreased Fe was associated with decreased uptake of (3)H-NE in the caudate putamen (R=0.436, p=0.033) and locus coeruleus (R=0.86; p<0.001). Extracellular concentrations of NE in the caudate putamen were significantly decreased in response to Mn exposure and ID (p<0.001). A diverse response of Mn exposure and ID was observed on mRNA and protein expression of NE transporter (NET) and alpha(2) adrenergic receptor. For example, elevated brain Mn and decreased Fe caused an approximate 50% decrease in NET and alpha(2) adrenergic receptor protein expression in several brain regions, with reductions in mRNA expression also observed. These data suggest that Mn exposure results in a decrease in NE uptake and extracellular NE concentrations via altered expression of transport and receptor proteins.

  13. Refractory epileptic seizures due to vitamin B6 deficiency in a patient with Parkinson's disease under duodopa® therapy.

    PubMed

    Skodda, Sabine; Müller, Thomas

    2013-02-01

    Levodopa/carbidopa intestinal gel (LCIG) infusion for the treatment of advanced Parkinson's disease (PD) has been suspected to provoke polyneuropathy in conjunction with vitamin B6, B12 and folate deficiency and elevated homocysteine levels. We describe a PD patient under LCIG therapy developing refractory epileptic seizures obviously promoted by vitamin B6 deficiency.

  14. Synthesis and biological assessment of folate-accepted developer (99m)Tc-DTPA-folate-polymer.

    PubMed

    Chen, Fei; Shao, Kejing; Zhu, Bao; Jiang, Mengjun

    2016-05-15

    A novel cancer-targetable folate-poly(2-hydroxyethyl methacrylate) (PFDH) copolymer containing DTPA segment was prepared by conventional chemical synthesis and labeled with (99m)Tc subsequently. The (99m)Tc-labled PFDH could be produced easily with high radiochemical yield of 91% and radiochemical purity of 95%. The LogP octanol-water value for the (99m)Tc-labled PFDH was -2.19 and the radiotracer was stable in phosphate-buffered saline and human serum for 2h (>95% in PBS or ∼90% in human serum). To investigate (99m)Tc-labled PFDH tumor targeting, the in vitro and in vivo stability, cell uptake, in vivo biodistribution, and SPECT imaging were evaluated, respectively. These preliminary results strongly suggest that the novel folate conjugated dendrimer maybe developed to be potential for delivery of therapeutic radionuclides.

  15. Intracellular transport of MHC class II and associated invariant chain in antigen presenting cells from AP-3-deficient mocha mice.

    PubMed

    Sevilla, L M; Richter, S S; Miller, J

    2001-06-15

    MHC class II-restricted antigen presentation requires trafficking of newly synthesized class II-invariant chain complexes from the trans-Golgi network to endosomal, peptide-loading compartments. This transport is mediated by dileucine-like motifs within the cytosolic tail of the invariant chain. Although these signals have been well characterized, the cytosolic proteins that interact with these dileucine signals and mediate Golgi sorting and endosomal transport have not been identified. Recently, an adaptor complex, AP-3, has been identified that interacts with dileucine motifs and mediates endosomal/lysosomal transport in yeast, Drosophila, and mammals. In this report, we have assessed class II-invariant chain trafficking in a strain of mice (mocha) which lacks expression of AP-3. Our studies demonstrate that the lack of AP-3 does not affect the kinetics of invariant chain degradation, the route of class II-invariant chain transport, or the rate and extent of class II-peptide binding as assessed by the generation of SDS-stable dimers. The possible role of other known or unknown adaptor complexes in class II-invariant chain transport is discussed.

  16. Transport properties and photo electrochemical characterization of oxygen-deficient ASnO 3- δ (A=Ca, Sr and Ba)

    NASA Astrophysics Data System (ADS)

    Zidi, N.; Omeiri, S.; Hadjarab, B.; Bouguelia, A.; Akroun, A.; Trari, M.

    2010-08-01

    The deficient stannate BaSnO 3- δ, prepared at 980 °C in sealed tube, crystallizes in an ideal perovskite structure. The oxide exhibits a blue color, the bandgap is found to be 2.65 eV and the transition is directly allowed. The non-stoichiometry could not be measured, indicating no appreciable oxygen deficiency. Nevertheless, the transport properties were found to change markedly with the heat treatment. BaSnO 3- δ behaves as degenerate SC with a conductivity σ300 K (=1.63 Ω -1 cm -1) and where the level Ef drops above mobility edge to delocalized states. The electric balance leads to a simultaneous reduction of Sn 4+ inducing n-type behavior. The thermal variation of the thermopower indicates an electron mobility μ300 K (=0.013 cm 2 V -1 s -1) thermally activated. The metal-insulating transition is considered of Anderson type due to the random potential to oxygen vacancies. A predominant variable range hopping is predicted from the non-linearity of Ln σ versus T-1 plot. The capacitance measurement ( C-2- V), measured in KOH media, shows a linear behavior from which a flat band potential Vfb (=-0.67 VSCE) and a density ND (=7.59×10 20 cm -3) are determined. The deficient stannates CaSnO 3 and SrSnO 3 are reported for a comparative purpose. The decrease of Eg is ascribed to the increase of the conduction band width when going from Ba to Ca.

  17. Structure and electrical and transport properties of cation-deficient samples of perovskite ferrocuprates RBaCuFeO5 + δ ( R = Y, La)

    NASA Astrophysics Data System (ADS)

    Klyndyuk, A. I.; Chizhova, E. A.

    2008-04-01

    The structure, thermal expansion, and electrical properties of cation-deficient ferrocuprates RBaCuFeO5 + δ ( R = Y, La), which are p-type semiconductors, are investigated. The linear thermal expansion coefficient of the yttrium-barium ferrocuprate decreases upon formation of vacancies in the A sublattice (Y, Ba), while the unit cell parameters remain practically unchanged upon the formation of vacancies in different sublattices (Y, Ba, Cu/Fe) of the crystal structure. From analyzing the results of the thermopower measurements, it is assumed that the YBaCuFeO5 + δ ferrocuprate is actually a “nanocomposite” consisting of nanoregions of the Y2Cu2O5 and BaFeO3 - δ phases. The lanthanum deficiency brings about an increase in the LaBaCuFeO5 + δ unit cell while leaving very nearly unaffected its linear thermal expansion coefficient and electrical properties. The formation of cation vacancies in extended [Ba(Cu,Fe)2O5] blocks of the LaBaCuFeO5 + δ phase gives rise to tetragonal distortion of its cubic structure, a decrease in the linear thermal expansion coefficient, and an increase in the electrical resistivity of the samples, the latter resulting primarily from an increase in the carrier transport energy in (Cu,Fe)O2 layers of LaBaCuFeO5 + δ.

  18. Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain

    PubMed Central

    Marin-Valencia, Isaac; Good, Levi B; Ma, Qian; Malloy, Craig R; Pascual, Juan M

    2013-01-01

    It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-13C3]heptanoate was examined in the normal mouse brain and in G1D by 13C-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in 13C, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and 13C enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism. PMID:23072752

  19. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles.

    PubMed

    Kantheti, P; Qiao, X; Diaz, M E; Peden, A A; Meyer, G E; Carskadon, S L; Kapfhamer, D; Sufalko, D; Robinson, M S; Noebels, J L; Burmeister, M

    1998-07-01

    The mouse mutant mocha, a model for the Hermansky-Pudlak storage pool deficiency syndrome, is characterized by defective platelets, coat and eye color dilution, lysosomal abnormalities, inner ear degeneration, and neurological deficits. Here, we show that mocha is a null allele of the delta subunit of the adaptor-like protein complex AP-3, which is associated with coated vesicles budding from the trans-Golgi network, and that AP-3 is missing in mocha tissues. In mocha brain, the ZnT-3 transporter is reduced, resulting in a lack of zinc-associated Timm historeactivity in hippocampal mossy fibers. Our results demonstrate that the AP-3 complex is responsible for cargo selection to lysosome-related organelles such as melanosomes and platelet dense granules as well as to neurotransmitter vesicles.

  20. Urine screening for patients with developmental disabilities detected a patient with creatine transporter deficiency due to a novel missense mutation in SLC6A8.

    PubMed

    Kato, Hidekazu; Miyake, Fuyu; Shimbo, Hiroko; Ohya, Makoto; Sugawara, Hidenori; Aida, Noriko; Anzai, Rie; Takagi, Mariko; Okuda, Mitsuko; Takano, Kyoko; Wada, Takahito; Iai, Mizue; Yamashita, Sumimasa; Osaka, Hitoshi

    2014-08-01

    Creatine transporter deficiency (CTD) is an example of X-linked intellectual disability syndromes, caused by mutations in SLC6A8 on Xq28. Although this is the second most frequent genetic cause of intellectual disabilities in Europe or America after Fragile X syndrome, information on the morbidity of this disease is limited in Japan. Using the HPLC screening method we have established recently, we examined samples of urine of 105 patients (73 males and 32 females) with developmental disabilities at our medical center. And we have found a family with three ID boys with a novel missense mutation in SLC6A8. This is the second report of a Japanese family case of CTD. A systematic diagnostic system of this syndrome should be established in Japan to enable us to estimate its frequency and treatment.

  1. Oral contraceptives: effect of folate and vitamin B12 metabolism.

    PubMed Central

    Shojania, A. M.

    1982-01-01

    Women who use oral contraceptives have impaired folate metabolism as shown by slightly but significantly lower levels of folate in the serum and the erythrocytes and an increased urinary excretion of formiminoglutamic acid. The vitamin B12 level in their serum is also significantly lower than that of control groups. However, there is no evidence of tissue depletion of vitamin B12 associated with the use of oral contraceptives. The causes and clinical significance of the impairment of folate and vitamin B12 metabolism in these women is discussed in this review of the literature. Clinicians are advised to ensure that women who shop taking "the pill" because they wish to conceive have adequate folate stores before becoming pregnant. PMID:7037144

  2. Targeting folate receptor alpha for cancer treatment

    PubMed Central

    Josephs, Debra H.; Ilieva, Kristina M.; Pellizzari, Giulia; Opzoomer, James; Bloomfield, Jacinta; Fittall, Matthew; Grigoriadis, Anita; Figini, Mariangela; Canevari, Silvana; Spicer, James F.; Tutt, Andrew N.; Karagiannis, Sophia N.

    2016-01-01

    Promising targeted treatments and immunotherapy strategies in oncology and advancements in our understanding of molecular pathways that underpin cancer development have reignited interest in the tumor-associated antigen Folate Receptor alpha (FRα). FRα is a glycosylphosphatidylinositol (GPI)-anchored membrane protein. Its overexpression in tumors such as ovarian, breast and lung cancers, low and restricted distribution in normal tissues, alongside emerging insights into tumor-promoting functions and association of expression with patient prognosis, together render FRα an attractive therapeutic target. In this review, we summarize the role of FRα in cancer development, we consider FRα as a potential diagnostic and prognostic tool, and we discuss different targeted treatment approaches with a specific focus on monoclonal antibodies. Renewed attention to FRα may point to novel individualized treatment approaches to improve the clinical management of patient groups that do not adequately benefit from current conventional therapies. PMID:27248175

  3. Neural tube defects, folate, and immune modulation.

    PubMed

    Denny, Kerina J; Jeanes, Angela; Fathe, Kristin; Finnell, Richard H; Taylor, Stephen M; Woodruff, Trent M

    2013-09-01

    Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored.

  4. Estimated carrier frequency of creatine transporter deficiency in females in the general population using functional characterization of novel missense variants in the SLC6A8 gene.

    PubMed

    DesRoches, Caro-Lyne; Patel, Jaina; Wang, Peixiang; Minassian, Berge; Salomons, Gajja S; Marshall, Christian R; Mercimek-Mahmutoglu, Saadet

    2015-07-10

    Creatine transporter deficiency (CRTR-D) is an X-linked inherited disorder of creatine transport. All males and about 50% of females have intellectual disability or cognitive dysfunction. Creatine deficiency on brain proton magnetic resonance spectroscopy and elevated urinary creatine to creatinine ratio are important biomarkers. Mutations in the SLC6A8 gene occur de novo in 30% of males. Despite reports of high prevalence of CRTR-D in males with intellectual disability, there are no true prevalence studies in the general population. To determine carrier frequency of CRTR-D in the general population we studied the variants in the SLC6A8 gene reported in the Exome Variant Server database and performed functional characterization of missense variants. We also analyzed synonymous and intronic variants for their predicted pathogenicity using in silico analysis tools. Nine missense variants were functionally analyzed using transient transfection by site-directed mutagenesis with In-Fusion HD Cloning in HeLa cells. Creatine uptake was measured by liquid chromatography tandem mass spectrometry for creatine measurement. The c.1654G>T (p.Val552Leu) variant showed low residual creatine uptake activity of 35% of wild type transfected HeLa cells and was classified as pathogenic. Three variants (c.808G>A; p.Val270Met, c.942C>G; p.Phe314Leu and c.952G>A; p.Ala318Thr) were predicted to be pathogenic based on in silico analysis, but proved to be non-pathogenic by our functional analysis. The estimated carrier frequency of CRTR-D was 0.024% in females in the general population. We recommend functional studies for all novel missense variants by transient transfection followed by creatine uptake measurement by liquid chromatography tandem mass spectrometry as fast and cost effective method for the functional analysis of missense variants in the SLC6A8 gene.

  5. Epigenetic Mechanisms of Folate Nutrition in Breast Cancer

    DTIC Science & Technology

    2011-04-01

    decrease the incidence of neural tube defects (NTDs). While this action was successful in lowering NTD incidence, recent epidemiological studies are...much easier to target folate and one carbon metabolism in different ways such as inhibiting key enzymes with either miRNA or drugs. This is the...4 1     Introduction: This training grant focuses on one carbon and folate metabolism and the effects of perturbing one

  6. Epigenetic Mechanisms of Folate Nutrition in Breast Cancer

    DTIC Science & Technology

    2012-04-01

    unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be...10-1-0235 Epigenetic Mechanisms of Folate Nutrition in Breast Cancer Rebecca Lobo University of California, Davis Davis, CA 95618 The most...and MDA-MB-231 (human) and Met1 and DB-7 (mouse). We are currently working in the two human cell lines MCF7 and MDA-MB- 231. Making cells folate

  7. Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome.

    PubMed

    Wirth, Eva K; Roth, Stephan; Blechschmidt, Cristiane; Hölter, Sabine M; Becker, Lore; Racz, Ildiko; Zimmer, Andreas; Klopstock, Thomas; Gailus-Durner, Valerie; Fuchs, Helmut; Wurst, Wolfgang; Naumann, Thomas; Bräuer, Anja; de Angelis, Martin Hrabé; Köhrle, Josef; Grüters, Annette; Schweizer, Ulrich

    2009-07-29

    Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

  8. Plasma homocysteine levels correlated to interactions between folate status and methylene tetrahydrofolate reductase gene mutation in women with unexplained recurrent pregnancy loss.

    PubMed

    Kumar, K S D; Govindaiah, V; Naushad, S E; Devi, R R; Jyothy, A

    2003-01-01

    Hyperhomocysteinaemia, a risk factor for recurrent pregnancy loss, is related either to a hereditary defect within the methionine-homocysteine pathway or it might be acquired as a result of deficiencies of vitamin B(12) and folate (B(9)). Because hyperhomocysteinaemia seems to be determined by both genetic and environmental factors, the current study was undertaken to find out the interactions between folate status and MTHFR mutation on the homocysteine concentration in 24 women experiencing unexplained three or more consecutive recurrent pregnancy losses. The median fasting total plasma homocysteine concentration in the study group was 10.23 micro mol/l compared to 8.95 micro mol/l; P = 0.096 in the controls. Elevated homocysteine levels > 18 micro mol/l, which was considered to be a risk factor for recurrent early pregnancy loss, was found in four women in the study group and none among the controls. Lower red cell folate levels (normal range >/= 160 ng/ml) were observed in nine (37.5%) women among the study group, compared to five (20.84%) women among controls. The mean +/- SD red cell folate levels in the study group was found to be 154.37 +/- 37.07, while in the controls it was 159.0 +/- 28.97. In the present study six women in the study group and two among controls were found to be carriers for the C677T MTHFR mutation. None were homozygous for the mutant (TT) allele. The highest values of homocysteine concentration were found in women experiencing recurrent pregnancy loss with both the CT genotype and folate deficiency. Identification of hyperhomocysteinaemia in women with recurrent pregnancy loss may help in therapeutic normalisation and might permit a normal birth.

  9. Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: protection by methionine and aggravation by folates

    SciTech Connect

    van der Westhuyzen, J.; Fernandes-Costa, F.; Metz, J.

    1982-11-01

    Nitrous oxide, which inactivates cobalamin when administered to fruit bats, results in severe neurological impairment leading to ataxia, paralysis and death. This occurs after about 6 weeks in animals depleted of cobalamin by dietary restriction, and after about 10 weeks in cobalamin replete bats. Supplementation of the diet with pteroylglutamic acid caused acceleration of the neurological impairment--the first unequivocal demonstration of aggravation of the neurological lesion in cobalamin deficiency by pteroylglutamic acid. The administration of formyltetrahydropteroylglutamic acid produced similar aggravation of the neurological lesion. Supplementation of the diet with methionine protected the bats from neurological impairment, but failed to prevent death. Methionine supplementation protected against the exacerbating effect of folate, preventing the development of neurological changes. These findings lend support to the hypothesis that the neurological lesion in cobalamin deficiency may be related to a deficiency in the methyl donor S-adenosylmethionine which follows diminished synthesis of methionine.

  10. Dietary strategies for improving folate status in institutionalized elderly persons.

    PubMed

    Bermejo, Laura M; Aparicio, Aránzazu; Rodríguez-Rodríguez, Elena; López-Sobaler, M; Andrés, Pedro; Ortega, Rosa M

    2009-06-01

    The aim of this work was to compare the efficacy of two strategies designed to improve folate status: increasing the intake of vegetables, and the consumption of a folic acid-fortified food. Residents (126) from three old people's homes in the Madrid region (Spain) were studied. To each centre a dietary intervention was assigned to be followed for 6 months: (1) the consumption of margarine fortified with 200 microg folic acid/10 g portion (centre M), (2) increasing the consumption of vegetables to three servings per day (centre V), (3) control (centre C). At the beginning and end of the intervention period the subjects' intakes, serum and erythrocyte concentrations of folate were measured. The use of fortified margarine (centre M) led to a significant increase in folate intake (260.9 microg/d), serum concentration (10.3 (sd 8.3) nmol/l) and erythrocyte concentration (638.4 nmol/l). At centre V the increase in total vegetable intake achieved was very poor; these foods met with very poor acceptance, although the intake of certain vegetables particularly rich in folate improved. Therefore, the intake of this vitamin increased a little (26.7 (sd 33.0) microg/d); erythrocyte folate concentration also increased somewhat (460.5 nmol/l), althought less than centre M. The daily consumption of margarine fortified with folic acid was the more effective strategy for improving the folate status of the study subjects.

  11. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  12. Relative Dominance of Physical versus Chemical Effects on the Transport of Adhesion-Deficient Bacteria in Intact Cores from South Oyster, Virginia

    SciTech Connect

    Dong, Hailang; Onstott, Tullis C.; Deflaun, Mary F.; Fuller, Mark E.; Scheibe, Timothy D. ); Streger, Sheryl H.; Rothmel, Randi K.; Mailloux, Brian J.

    2002-03-01

    Bacterial transport experiments were conducted using intact sediment cores collected near South Oyster, VA to delineate the relative importance of physical and chemical heterogeneity in controlling transport of an adhesion-deficient bacterial strain. The sediments consisted of quartz and feldspar with a variable amount of clay and metal hydroxide coatings on the grains. A nonmotile, gram-negative indigenous groundwater strain, designated as Comamonas sp. DA001, was injected into the cores along with a conservative tracer bromide (Br). Bacterial breakthrough preceded the arrival of Br. This differential advection phenomenon can be accounted for by reduction of the effective porosity for the bacteria relative to Br. The distribution of cells remaining in the core was highly variable, ranging from nearly uniform concentrations to exponentially decreasing concentrations. The fraction of bacterial retention in the core was positively correlated with the abundance of the metal hydroxides and negatively correlated with grain size. Because grain size was correlated with the abundance of the metal hydroxide coatings, it was difficult to separate the effects of grain size and mineralogy. The fraction of the bacterial retention accounted for by the effect of grain size exhibited no correlation with the abundance of the metal hydroxides, indicating that the bacterial retention was primarily controlled by grain size. Reasons for the lack of influence of mineralogy on bacterial retention include (1) the slightly negatively charged bacterial surfaces; (2) insufficient heterogeneity of sediment surface properties; and (3) the masking of the positive charge of the metal hydroxide surfaces by adsorbed organic carbon (up to 1180 ppm). This study demonstrates that the laboratory based bacterial transport experiments are effective in delineating physical versus chemical controlling factors, and provide an important link to field-based bacterial transport studies.

  13. An unusual role of folate in the self-assembly of heparin-folate conjugates into nanoparticles.

    PubMed

    Wang, Jianquan; Ma, Daoshuang; Lu, Qian; Wu, Shaoxiong; Lee, Gee Young; Lane, Lucas A; Li, Bin; Quan, Li; Wang, Yiqing; Nie, Shuming

    2015-10-07

    Tumor targeting agents including antibodies, peptides, and small molecules, are often used to improve the delivery efficiency of nanoparticles. Despite numerous studies investigating the abilities of targeting agents to increase the accumulation of nanosized therapeutics within diseased tissues, little attention has been focused on how these ligands can affect the self-assembly of the nanoparticle's modified polymer constituents upon chemical conjugation. Here we present an actively tumor targeted nanoparticle constructed via the self-assembly of a folate modified heparin. Folate conjugation unexpectedly allowed the self-assembly of heparin, where a majority of the folate molecules (>80%) resided inside the core of the nanoparticle. The folate-heparin nanoparticles could also physically encapsulate lipophilic fluorescent dyes, enabling the use of the constructs as activatable fluorescent probes for targeted in vivo tumor imaging.

  14. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis.

    PubMed

    Ganz, Ariel B; Shields, Kelsey; Fomin, Vlad G; Lopez, Yusnier S; Mohan, Sanjay; Lovesky, Jessica; Chuang, Jasmine C; Ganti, Anita; Carrier, Bradley; Yan, Jian; Taeswuan, Siraphat; Cohen, Vanessa V; Swersky, Camille C; Stover, Julie A; Vitiello, Gerardo A; Malysheva, Olga V; Mudrak, Erika; Caudill, Marie A

    2016-10-01

    Although single nucleotide polymorphisms (SNPs) in folate-mediated pathways predict susceptibility to choline deficiency during severe choline deprivation, it is unknown if effects persist at recommended intakes. Thus, we used stable isotope liquid chromatography-mass spectrometry (LC-MS) methodology to examine the impact of candidate SNPs on choline metabolism in a long-term, randomized, controlled feeding trial among pregnant, lactating, and nonpregnant (NP) women consuming 480 or 930 mg/d choline (22% as choline-d9, with d9 indicating a deuterated trimethyl amine group) and meeting folate-intake recommendations. Variants impairing folate metabolism, methylenetetrahydrofolate reductase (MTHFR) rs1801133, methionine synthase (MTR) rs1805087 [wild-type (WT)], MTR reductase (MTRR) rs1801394, and methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase (MTHFD1) rs2236225, influenced choline dynamics, frequently through interactions with reproductive state and choline intake, with fewer genotypic alterations observed among pregnant women. Women with these variants partitioned more dietary choline toward phosphatidylcholine (PC) biosynthesis via the cytidine diphosphate (CDP)-choline pathway at the expense of betaine synthesis even when use of betaine as a methyl donor was increased. Choline intakes of 930 mg/d restored partitioning of dietary choline between betaine and CDP-PC among NP (MTHFR rs1801133 and MTR rs1805087 WT) and lactating (MTHFD1 rs2236225) women with risk genotypes. Overall, our findings indicate that loss-of-function variants in folate-metabolizing enzymes strain cellular PC production, possibly via impaired folate-dependent phosphatidylethanolamine-N-methyltransferase (PEMT)-PC synthesis, and suggest that women with these risk genotypes may benefit from choline intakes exceeding current recommendations.-Ganz, A. B., Shields, K., Fomin, V. G., Lopez, Y. S., Mohan, S., Lovesky, J., Chuang, J. C

  15. Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism

    PubMed Central

    Cabreiro, Filipe; Au, Catherine; Leung, Kit-Yi; Vergara-Irigaray, Nuria; Cochemé, Helena M.; Noori, Tahereh; Weinkove, David; Schuster, Eugene; Greene, Nicholas D.E.; Gems, David

    2013-01-01

    Summary The biguanide drug metformin is widely prescribed to treat type 2 diabetes and metabolic syndrome, but its mode of action remains uncertain. Metformin also increases lifespan in Caenorhabditis elegans cocultured with Escherichia coli. This bacterium exerts complex nutritional and pathogenic effects on its nematode predator/host that impact health and aging. We report that metformin increases lifespan by altering microbial folate and methionine metabolism. Alterations in metformin-induced longevity by mutation of worm methionine synthase (metr-1) and S-adenosylmethionine synthase (sams-1) imply metformin-induced methionine restriction in the host, consistent with action of this drug as a dietary restriction mimetic. Metformin increases or decreases worm lifespan, depending on E. coli strain metformin sensitivity and glucose concentration. In mammals, the intestinal microbiome influences host metabolism, including development of metabolic disease. Thus, metformin-induced alteration of microbial metabolism could contribute to therapeutic efficacy—and also to its side effects, which include folate deficiency and gastrointestinal upset. PaperClip PMID:23540700

  16. Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations.

    PubMed

    Stanger, Olaf; Fowler, Brian; Piertzik, Klaus; Huemer, Martina; Haschke-Becher, Elisabeth; Semmler, Alexander; Lorenzl, Stefan; Linnebank, Michael

    2009-09-01

    In Europe, neuropsychiatric diseases currently make up approximately a third of the total burden of disease. In 2004, 27% of the overall population was affected by at least one of the most frequent neuropsychiatric diseases such as Alzheimer's dementia, Parkinson's disease, stroke or depression. The annual costs of care exceed those of cancer, cardiovascular conditions and diabetes. In order to delay the onset or course of neurodegenerative diseases, the available potential should be utilized. As well as improving quality of life of patients and relatives, this may reduce the great financial burden caused by neurodegenerative disorders. However, the availability of established drugs or therapeutic agents is very limited. This paper reviews the state of current knowledge as to how homocysteine metabolism is relevant for neurodegenerative and other neuropsychiatric diseases, with particular emphasis on the evidence for prophylactic and therapeutic strategies. In the European countries, many people do not take the recommended daily minimum amount of folate and vitamin B12. Deficiency of these vitamins and secondary changes in the concentrations of associated metabolites, such as methylmalonic acid and homocysteine, may contribute to the onset and progression of neuropsychiatric diseases. This paper reviews the evidence regarding whether substitution of folate and vitamin B12 is beneficial, for example, in cerebrovascular disease, dementia and depression.

  17. An unusual role of folate in the self-assembly of heparin-folate conjugates into nanoparticles

    NASA Astrophysics Data System (ADS)

    Wang, Jianquan; Ma, Daoshuang; Lu, Qian; Wu, Shaoxiong; Lee, Gee Young; Lane, Lucas A.; Li, Bin; Quan, Li; Wang, Yiqing; Nie, Shuming

    2015-09-01

    Tumor targeting agents including antibodies, peptides, and small molecules, are often used to improve the delivery efficiency of nanoparticles. Despite numerous studies investigating the abilities of targeting agents to increase the accumulation of nanosized therapeutics within diseased tissues, little attention has been focused on how these ligands can affect the self-assembly of the nanoparticle's modified polymer constituents upon chemical conjugation. Here we present an actively tumor targeted nanoparticle constructed via the self-assembly of a folate modified heparin. Folate conjugation unexpectedly allowed the self-assembly of heparin, where a majority of the folate molecules (>80%) resided inside the core of the nanoparticle. The folate-heparin nanoparticles could also physically encapsulate lipophilic fluorescent dyes, enabling the use of the constructs as activatable fluorescent probes for targeted in vivo tumor imaging.Tumor targeting agents including antibodies, peptides, and small molecules, are often used to improve the delivery efficiency of nanoparticles. Despite numerous studies investigating the abilities of targeting agents to increase the accumulation of nanosized therapeutics within diseased tissues, little attention has been focused on how these ligands can affect the self-assembly of the nanoparticle's modified polymer constituents upon chemical conjugation. Here we present an actively tumor targeted nanoparticle constructed via the self-assembly of a folate modified heparin. Folate conjugation unexpectedly allowed the self-assembly of heparin, where a majority of the folate molecules (>80%) resided inside the core of the nanoparticle. The folate-heparin nanoparticles could also physically encapsulate lipophilic fluorescent dyes, enabling the use of the constructs as activatable fluorescent probes for targeted in vivo tumor imaging. Electronic supplementary information (ESI) available: NMR spectra and fluorescent images of HF-488 with cancer

  18. Magnetic, specific heat and electrical transport properties of oxygen-deficient nanosized rutile TiO2‑δ

    NASA Astrophysics Data System (ADS)

    Tran, Vinh Hung; Thi Quynh Hoa, Nguyen

    2017-03-01

    An oxygen-deficient nanosized {{TiO}}2-δ , δ ∼ 0.7 sample was synthesized by a solvothermal method, and was characterized to have both ∼3 nm amorphous solid and ∼36–46 nm diameter rutile nanowires. Physical properties of the sample were investigated by measuring magnetic, specific heat, electrical resistance and magnetoresitance properties. DC magnetization M(H) data confirm ferromagnetic behavior previously reported for undoped TiO2. Furthermore, M(T) dependence follows the power-law relation M{(T)\\propto (1-T/{T}C)}β in the near-critical regime, yielding Curie temperature {T}C ∼ 415 K and critical exponent β = 0.2. Moreover, our results of AC magnetic susceptibility measurements suggest an additional phase transition at {T}* ∼ 310 K, presumably due to spin orientation. The metallic-like electrical resistance exhibits a distinct drop below {T}* with a strong thermal hysteresis in the temperature range 225–275 K. Specific heat in the temperature range 20–300 K is well described by the sum of contributions from acoustic phonons with Debye temperature 605 K and optical phonons with Einstein temperature 113 K. Below 10 K the specific heat divulges a large excess, which can be interpreted as an additional contribution originating from soft potentials.

  19. 99mTc-Tetraethylenepentamine-Folate--a new 99mTc-based folate derivative for the detection of folate receptor positive tumors: synthesis and biological evaluation.

    PubMed

    Panwar, Puja; Shrivastava, Vibha; Tandon, Vibha; Mishra, Pushpa; Chuttani, Krishna; Sharma, Rakesh Kumar; Chandra, Ramesh; Mishra, Anil K

    2004-10-01

    A new radiopharmaceutical, 99mTc-Tetraethylenepentamine(TEPA)-Folate has been synthesized introducing TEPA to the gamma-carboxyl group of folic acid. This binds with 99mTc high efficiency at ambient temperature. The resulting 99mTc-N5-Folate is stable under physiological conditions at least for 24 h after radiocomplexation. TEPA is a known open chain pentamine (N5) chelator, its four-nitrogen act as the binding site for 99mTc. The folate membrane receptor binding of the 99mTc-TEPA-Folate by established human tumor cell lines (KB, U-87MG and MDA-MB-468) showed Kd in microM range in normal DMEM (10% serum, 10 microM folic acid). The blood kinetic studies showed more than 70% clearance within five minutes from the circulation. The KB cell line tumors in mice were readily identifiable in the gamma images and revealed major accumulation of radiotracer in liver, kidneys and intestines. High tumor uptake was shown in the tumor bearing nude mice; tumorto-blood ratios reached 2.68 +/- 0.52 and 5.5 +/- 1.47 at 1 and 4 h after post injection respectively. Surviving fractions as obtained in clonogenic assay were 1.02 +/- 0.07 and 1.03 +/- 0.05 in U-87MG and MDA-MB-468 cell lines respectively. The 99mTc-N5-Folate conjugate have promising utility as a receptor specific radiopharmaceutical for imaging neoplastic tissues known to over express folate-binding protein.

  20. Some nutritional effects of folate-binding protein in bovine milk on the bioavailability of folate to rats

    SciTech Connect

    Tani, M.; Iwai, K.

    1984-04-01

    The excretions of folate compounds into both the urine and bile were investigated in rats after the administration of pteroylglutamic acid (PteGlu) with or without the folate-binding protein (FBP) prepared from bovine milk. When the sample solution, containing either free or bound (/sup 3/H)PteGlu (i.e., bound to the FBP from milk), was delivered to rats intragastrically via oral intubation, the amounts of (/sup 3/H)PteGlu excreted into the feces did not change. On the other hand, the urinary excretion of /sup 3/H-labeled folate compounds, especially (/sup 3/H)5-methyltetrahydrofolic acid (5-CH/sub 3/-H/sub 4/PteGlu), after the administration of bound (/sup 3/H)PteGlu was significantly lower (P less than 0.01) than that after the administration of free (/sup 3/H)PteGlu. The urinary excretion of (/sup 3/H)5-CH/sub 3/-H/sub 4/PteGlu was directly proportional to the initial amount of free (/sup 3/H)PteGlu administered. The similar effect of FBP was also observed when the biliary excretion of /sup 3/H-labeled folate compounds was investigated in situ. Furthermore, the incorporation of (/sup 3/H)PteGlu into folate-requiring intestinal microorganisms was considerably reduced when it was bound to FBP. These results suggest that milk FBP has some nutritional effects on the bioavailability of folate in vivo.

  1. Nitric oxide and glutathione impact the expression of iron uptake- and iron transport-related genes as well as the content of metals in A. thaliana plants grown under iron deficiency

    PubMed Central

    Koen, Emmanuel; Szymańska, Katarzyna; Klinguer, Agnès; Dobrowolska, Grażyna; Besson-Bard, Angélique; Wendehenne, David

    2012-01-01

    Mounting evidence indicate that nitric oxide (NO) acts as a signaling molecule mediating iron deficiency responses through the upregulation of the expression of iron uptake-related genes. Accordingly, NO donors such as nitrosoglutathione (GSNO) were reported to improve the fitness of plants grown under iron deficiency. Here, we showed that glutathione, a by-product of GSNO, triggered the upregulation of the expression of iron uptake- and transport-related gene and an increase of iron concentration in Arabidopsis thaliana seedlings facing iron deficiency. Furthermore, we provided evidence that under iron deficiency, NO released by GSNO did not improve the root iron concentration but impacted the content of copper. Collectively, our data highlight the complexity of interpreting data based on the use of NO donors when investigating the role of NO in iron homeostasis. PMID:22902693

  2. Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy

    PubMed Central

    Colomina, Jose M.; Cavallé-Busquets, Pere; Fernàndez-Roig, Sílvia; Solé-Navais, Pol; Fernandez-Ballart, Joan D.; Ballesteros, Mónica; Ueland, Per M.; Meyer, Klaus; Murphy, Michelle M.

    2016-01-01

    The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine) single nucleotide polymorphism (SNP) on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW) throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI): 28.3, 33.5). In participants with normal-high plasma folate status (>13.4 nmol/L), least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L) was lower in the GA (2.35 [2.23, 2.47]) versus GG (2.58 [2.46, 2.70]) genotype at ≤12 GW (p < 0.05) and in the GA (2.08 [1.97, 2.19]) and AA (1.94 [1.75, 2.16]) versus GG (2.29 [2.18, 2.40]) genotypes at 15 GW (p < 0.05). No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L) (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038). PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01)). Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (β coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy) and the AA compared to GG genotype was associated with lower pDMG (β coefficients [SEM] ranging from −0.11 [0.06], p = 0.055 to −0.23 [0.06], p < 0.001). Conclusion: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele. PMID:27735840

  3. Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.

    PubMed

    Trotier-Faurion, Alexandra; Dézard, Sophie; Taran, Frédéric; Valayannopoulos, Vassili; de Lonlay, Pascale; Mabondzo, Aloïse

    2013-06-27

    The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.

  4. Neural Tube Defect Induction by Fumonisin B1 in LM/Bc Mice Fed Folate Deficient or Folate Replete Diets

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides and F. proliferatum. FB1 is found in corn-based foods and evidence suggests that it is a risk factor for neural tube defects (NTD). The mechanism(s) underlying NTD induction by FB1 in the sensitive LM/Bc mouse model is not well...

  5. Wheat rolls fortified with microencapsulated L-5-methyltetrahydrofolic acid or equimolar folic acid increase blood folate concentrations to a similar extent in healthy men and women.

    PubMed

    Green, Timothy J; Liu, Yazheng; Dadgar, Samira; Li, Wangyang; Böhni, Ruth; Kitts, David D

    2013-06-01

    Mandatory folic acid fortification of grains such as wheat flour has been introduced in several countries to reduce the incidence of neural tube defects. There are concerns, however, that folic acid could mask the hematologic signs of vitamin B-12 deficiency and lead to other adverse health outcomes in the population. Calcium L-5-methyltetrahydrofolic acid (L-5-MTHF), a synthetic form of reduced folate, should not mask vitamin B-12 deficiency and may be safer than folic acid. Unfortunately, L-5-MTHF is not stable in most food matrices such as bread. Microencapsulation of L-5-MTHF with sodium ascorbate and a modified starch is effective at preventing loss of the vitamin during baking and storage. Our aim was to assess the efficacy of wheat rolls fortified with microencapsulated L-5-MTHF or equimolar folic acid compared with wheat rolls containing no added folate (placebo) at increasing blood folate concentrations during 16 wk. Healthy men and women aged 18-45 y (n = 45) were randomly assigned to consume wheat rolls that contained L-5-MTHF (452 μg/d), the molar equivalent of folic acid (400 μg/d), or placebo. At 16 wk, the mean (95% CI) erythrocyte folate was 0.48 (0.27, 0.71) and 0.37 (0.17, 0.57) μmol/L higher in the L-5-MTHF (P < 0.001) and folic acid wheat roll (P = 0.001) groups, respectively, than in the placebo group. Likewise, the mean plasma folate was 23 (12, 34) and 23 (12, 34) nmol/L higher in the L-5-MTHF (P < 0.001) and folic acid wheat roll (P < 0.001) groups, respectively, than in the placebo group. There were no significant differences in blood folate concentrations between the L-5-MTHF and folic acid wheat roll groups. Both microencapsulated L-5-MTHF and folic acid-fortified wheat rolls increased blood folate concentrations compared with placebo.

  6. Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8.

    PubMed

    Horn, Sigrun; Kersseboom, Simone; Mayerl, Steffen; Müller, Julia; Groba, Claudia; Trajkovic-Arsic, Marija; Ackermann, Tobias; Visser, Theo J; Heuer, Heike

    2013-02-01

    The monocarboxylate transporter 8 (MCT8) plays a critical role in mediating the uptake of thyroid hormones (THs) into the brain. In patients, inactivating mutations in the MCT8 gene are associated with a severe form of psychomotor retardation and abnormal serum TH levels. Here, we evaluate the therapeutic potential of the TH analog 3,5,3',5'-tetraiodothyroacetic acid (tetrac) as a replacement for T(4) in brain development. Using COS1 cells transfected with TH transporter and deiodinase constructs, we could show that tetrac, albeit not being transported by MCT8, can be metabolized to the TH receptor active compound 3,3',5-triiodothyroacetic acid (triac) by type 2 deiodinase and inactivated by type 3 deiodinase. Triac in turn is capable of replacing T(3) in primary murine cerebellar cultures where it potently stimulates Purkinje cell development. In vivo effects of tetrac were assessed in congenital hypothyroid Pax8-knockout (KO) and Mct8/Pax8 double-KO mice as well as in Mct8-KO and wild-type animals after daily injection of tetrac (400 ng/g body weight) during the first postnatal weeks. This treatment was sufficient to promote TH-dependent neuronal differentiation in the cerebellum, cerebral cortex, and striatum but was ineffective in suppressing hypothalamic TRH expression. In contrast, TSH transcript levels in the pituitary were strongly down-regulated in response to tetrac. Based on our findings we propose that tetrac administration offers the opportunity to provide neurons during the postnatal stage with a potent TH receptor agonist, thereby eventually reducing the neurological damage in patients with MCT8 mutations without deteriorating the thyrotoxic situation in peripheral tissues.

  7. Perturbed rhythmic activation of signaling pathways in mice deficient for Sterol Carrier Protein 2-dependent diurnal lipid transport and metabolism.

    PubMed

    Jouffe, Céline; Gobet, Cédric; Martin, Eva; Métairon, Sylviane; Morin-Rivron, Delphine; Masoodi, Mojgan; Gachon, Frédéric

    2016-04-21

    Through evolution, most of the living species have acquired a time keeping system to anticipate daily changes caused by the rotation of the Earth. In all of the systems this pacemaker is based on a molecular transcriptional/translational negative feedback loop able to generate rhythmic gene expression with a period close to 24 hours. Recent evidences suggest that post-transcriptional regulations activated mostly by systemic cues play a fundamental role in the process, fine tuning the time keeping system and linking it to animal physiology. Among these signals, we consider the role of lipid transport and metabolism regulated by SCP2. Mice harboring a deletion of the Scp2 locus present a modulated diurnal accumulation of lipids in the liver and a perturbed activation of several signaling pathways including PPARα, SREBP, LRH-1, TORC1 and its upstream regulators. This defect in signaling pathways activation feedbacks upon the clock by lengthening the circadian period of animals through post-translational regulation of core clock regulators, showing that rhythmic lipid transport is a major player in the establishment of rhythmic mRNA and protein expression landscape.

  8. Perturbed rhythmic activation of signaling pathways in mice deficient for Sterol Carrier Protein 2-dependent diurnal lipid transport and metabolism

    PubMed Central

    Jouffe, Céline; Gobet, Cédric; Martin, Eva; Métairon, Sylviane; Morin-Rivron, Delphine; Masoodi, Mojgan; Gachon, Frédéric

    2016-01-01

    Through evolution, most of the living species have acquired a time keeping system to anticipate daily changes caused by the rotation of the Earth. In all of the systems this pacemaker is based on a molecular transcriptional/translational negative feedback loop able to generate rhythmic gene expression with a period close to 24 hours. Recent evidences suggest that post-transcriptional regulations activated mostly by systemic cues play a fundamental role in the process, fine tuning the time keeping system and linking it to animal physiology. Among these signals, we consider the role of lipid transport and metabolism regulated by SCP2. Mice harboring a deletion of the Scp2 locus present a modulated diurnal accumulation of lipids in the liver and a perturbed activation of several signaling pathways including PPARα, SREBP, LRH-1, TORC1 and its upstream regulators. This defect in signaling pathways activation feedbacks upon the clock by lengthening the circadian period of animals through post-translational regulation of core clock regulators, showing that rhythmic lipid transport is a major player in the establishment of rhythmic mRNA and protein expression landscape. PMID:27097688

  9. Insights into metabolic mechanisms underlying folate-responsive neural tube defects: a minireview.

    PubMed

    Beaudin, Anna E; Stover, Patrick J

    2009-04-01

    Neural tube defects (NTDs), including anencephaly and spina bifida, arise from the failure of neurulation during early embryonic development. Neural tube defects are common birth defects with a heterogenous and multifactorial etiology with interacting genetic and environmental risk factors. Although the mechanisms resulting in failure of neural tube closure are unknown, up to 70% of NTDs can be prevented by maternal folic acid supplementation. However, the metabolic mechanisms underlying the association between folic acid and NTD pathogenesis have not been identified. This review summarizes our current understanding of the mechanisms by which impairments in folate metabolism might ultimately lead to failure of neural tube closure, with an emphasis on untangling the relative contributions of nutritional deficiency and genetic risk factors to NTD pathogenesis.

  10. Deficiency of the ferrous iron transporter FeoAB is linked with metronidazole resistance in Bacteroides fragilis

    PubMed Central

    Veeranagouda, Yaligara; Husain, Fasahath; Boente, Renata; Moore, Jane; Smith, C. Jeffrey; Rocha, Edson R.; Patrick, Sheila; Wexler, Hannah M.

    2014-01-01

    Background Metronidazole is the most commonly used antimicrobial for Bacteroides fragilis infections and is recommended for prophylaxis of colorectal surgery. Metronidazole resistance is increasing and the mechanisms of resistance are not clear. Methods A transposon mutant library was generated in B. fragilis 638R (BF638R) to identify the genetic loci associated with resistance to metronidazole. Results Thirty-two independently isolated metronidazole-resistant mutants had a transposon insertion in BF638R_1421 that encodes the ferrous transport fusion protein (feoAB). Deletion of feoAB resulted in a 10-fold increased MIC of metronidazole for the strain. The metronidazole MIC for the feoAB mutant was similar to that for the parent strain when grown on media supplemented with excess iron, suggesting that the increase seen in the MIC of metronidazole was due to reduced cellular iron transport in the feoAB mutant. The furA gene repressed feoAB transcription in an iron-dependent manner and disruption of furA resulted in constitutive transcription of feoAB, regardless of whether or not iron was present. However, disruption of feoAB also diminished the capacity of BF638R to grow in a mouse intraperitoneal abscess model, suggesting that inorganic ferrous iron assimilation is essential for B. fragilis survival in vivo. Conclusions Selection for feoAB mutations as a result of metronidazole treatment will disable the pathogenic potential of B. fragilis and could contribute to the clinical efficacy of metronidazole. While mutations in feoAB are probably not a direct cause of clinical resistance, this study provides a key insight into intracellular metronidazole activity and the link with intracellular iron homeostasis. PMID:25028451

  11. TRANSPORT

    EPA Science Inventory

    Presentation outline: transport principles, effective solubility; gasoline composition; and field examples (plume diving).
    Presentation conclusions: MTBE transport follows from - phyiscal and chemical properties and hydrology. Field examples show: MTBE plumes > benzene plu...

  12. 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.

  13. Suppression of placental metallothionein 1 and zinc transporter 1 mRNA expressions contributes to fetal heart malformations caused by maternal zinc deficiency.

    PubMed

    Liu, Chaobin; He, Xiaoyu; Hong, Xinru; Kang, Fenhong; Chen, Suqing; Wang, Qing; Chen, Xiaoqiu; Hu, Dian; Sun, Qinghua

    2014-12-01

    Zinc has been implicated to have a protective role against heart malformations during fetal development. Metallothionein 1 (MT-1) and zinc transporter 1 (ZnT-1) are two major metabolic factors that are associated with zinc metabolism. The present work aimed to investigate the association of placental MT-1 and ZnT-1 expressions with fetal heart malformations resulting from maternal zinc deficiency. Sprague-Dawley female rats were randomly divided into five groups of extremely low-zinc, low-zinc, moderately low-zinc, marginally low-zinc and normal zinc (n = 9-12), and were fed diets with controlled zinc content at 1.0 ± 0.3, 8.4 ± 1.8, 15.4 ± 2.8, 22.4 ± 4.1 and 29.4 ± 5.3 [mean ± standard deviation (SD)] mg of zinc/kg, respectively, from day 25 of preconception until day 19 of gestation. The female rats were bred, their fetuses were harvested at day 19 of gestation after killing the dams, and fetal hearts were morphologically examined. Zinc concentration and alkaline phosphatase (ALP) activity in maternal venous blood sera were tested, and MT-1 and ZnT-1 mRNA expressions in the placenta were assayed. Zinc concentrations and ALP activities in the blood were low in all zinc-deficient diet groups in a dose-dependent fashion. The incidences of heart malformations were increased, and the levels of placental MT-1 and ZnT-1 mRNA expressions were decreased in the extremely low-zinc, low-zinc and moderately low-zinc groups compared with the normal zinc group. Specifically, mRNA levels of placental MT-1 or ZnT-1 were significantly decreased and were lower than the specific threshold values in the fetuses with heart malformations but not in the fetuses without heart malformations in all the groups. These data indicate that maternal zinc deficiency resulted in an elevated incidence of fetal heart malformations, which was associated with significant decreases in placental MT-1 and ZnT-1 mRNA expressions to the levels below the threshold values that may be a

  14. Serum concentrations of vitamin B12 and folate in British male omnivores, vegetarians, and vegans: results from a cross-sectional analysis of the EPIC-Oxford cohort study

    PubMed Central

    Gilsing, Anne MJ; Crowe, Francesca L; Lloyd-Wright, Zouë; Sanders, Thomas AB; Appleby, Paul N; Allen, Naomi E; Key, Timothy J

    2010-01-01

    Background/Objectives Vegans and to a lesser extent vegetarians have low average circulating concentrations of vitamin B12; however, the relation between factors such as age or time on these diets and vitamin B12 concentrations is not clear. The objectives were to investigate differences in serum vitamin B12 and folate concentrations between omnivores, vegetarians and vegans and to ascertain whether vitamin B12 concentrations differed by age and time on the diet. Subjects/Methods A cross-sectional analysis involving 689 men (226 omnivores, 231 vegetarians and 232 vegans) from the European Prospective Investigation into Cancer and Nutrition Oxford cohort. Results Mean serum vitamin B12 was highest among omnivores (281, 95% CI: 270-292 pmol/l), intermediate in vegetarians (182, 95% CI: 175-189 pmol/l), and lowest in vegans (122, 95% CI: 117-127 pmol/l). Fifty-two percent of vegans, 7% of vegetarians and one omnivore were classified as vitamin B12 deficient (defined as serum vitamin B12 < 118 pmol/l). There was no significant association between age or duration of adherence to a vegetarian or a vegan diet and serum vitamin B12. In contrast, folate concentrations were highest among vegans, intermediate in vegetarians, and lowest in omnivores, but only two men (both omnivores) were categorised as folate deficient (defined as serum folate < 6.3 nmol/l). Conclusion Vegans have lower vitamin B12 concentrations, but higher folate concentrations, than vegetarians and omnivores. Half of the vegans were categorised as vitamin B12 deficient and would be expected to have a higher risk of developing clinical symptoms related to vitamin B12 deficiency. PMID:20648045

  15. Intestinal transport of zinc and folic acid: a mutual inhibitory effect

    SciTech Connect

    Ghishan, F.K.; Said, H.M.; Wilson, P.C.; Murrell, J.E.; Greene, H.L.

    1986-02-01

    Recent observations suggest an inverse relationship between folic acid intake and zinc nutriture and indicate an interaction between folic acid and zinc at the intestinal level. To define that interaction, we designed in vivo and in vitro transport studies in which folic acid transport in the presence of zinc, as well as zinc transport in the presence of folic acid was examined. These studies show that zinc transport is significantly decreased when folate is present in the intestinal lumen. Similarly folic acid transport is significantly decreased with the presence of zinc. To determine whether this intestinal inhibition is secondary to zinc and folate-forming complexes, charcoal-binding studies were performed. These studies indicate that zinc and folate from complexes at pH 2.0, but that at pH 6.0, these complexes dissolve. Therefore, our studies suggest that under normal physiological conditions a mutual inhibition between folate and zinc exists at the site of intestinal transport.

  16. [Methylenetetrahydrofolate reductase deficiency-induced schizophrenia in a school-age boy].

    PubMed

    Wang, Qiao; Liu, Jing; Liu, Yu-Peng; Li, Xi-Yuan; Ma, Yan-Yan; Wu, Tong-Fei; Ding, Yuan; Song, Jin-Qing; Wang, Yu-Jie; Yang, Yan-Ling

    2014-01-01

    Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.

  17. Focal Thalamic Degeneration from Ethanol and Thiamine Deficiency is Associated with Neuroimmune Gene Induction, Microglial Activation, and Lack of Monocarboxylic Acid Transporters

    PubMed Central

    Qin, Liya; Crews, Fulton T

    2014-01-01

    Background Wernicke's encephalopathy-Korsakoff syndrome (WE-KS) is common in alcoholics, caused by thiamine deficiency (TD; vitamin B1) and associated with lesions to the thalamus (THAL). Although TD alone can cause WE, the high incidence in alcoholism suggests that TD and ethanol (EtOH) interact. Methods Mice in control, TD, or EtOH groups alone or combined were studied after 5 or 10 days of treatment. THAL and entorhinal cortex (ENT) histochemistry and mRNA were assessed. Results Combined EtOH-TD treatment for 5 days (EtOH-TD5) showed activated microglia, proinflammatory gene induction and THAL neurodegeneration that was greater than that found with TD alone (TD5), whereas 10 days resulted in marked THAL degeneration and microglial-neuroimmune activation in both groups. In contrast, 10 days of TD did not cause ENT degeneration. Interestingly, in ENT, TD10 activated microglia and astrocytes more than EtOH-TD10. In THAL, multiple astrocytic markers were lost consistent with glial cell loss. TD blocks glucose metabolism more than acetate. Acetate derived from hepatic EtOH metabolism is transported by monocarboxylic acid transporters (MCT) into both neurons and astrocytes that use acetyl-CoA synthetase (AcCoAS) to generate cellular energy from acetate. MCT and AcCoAS expression in THAL is lower than ENT prompting the hypothesis that focal THAL degeneration is related to insufficient MCT and AcCoAS in THAL. To test this hypothesis, we administered glycerin triacetate (GTA) to increase blood acetate and found it protected the THAL from TD-induced degeneration. Conclusions Our findings suggest that EtOH potentiates TD-induced THAL degeneration through neuroimmune gene induction. The findings support the hypothesis that TD deficiency inhibits global glucose metabolism and that a reduced ability to process acetate for cellular energy results in THAL focal degeneration in alcoholics contributing to the high incidence of Wernicke-Korsakoff syndrome in alcoholism. PMID

  18. A Program of Nutritional Education in Schools Reduced the Prevalence of Iron Deficiency in Students

    PubMed Central

    García-Casal, María Nieves; Landaeta-Jiménez, Maritza; Puche, Rafael; Leets, Irene; Carvajal, Zoila; Patiño, Elijú; Ibarra, Carlos

    2011-01-01

    The objective was to determine the prevalence of iron, folates and retinol deficiencies in school children and to evaluate the changes after an intervention of nutritional education. The project was developed in 17 schools. The sample included 1,301 children (678 males and 623 females). A subsample of 480 individuals, was randomly selected for drawing blood for biochemical determinations before and after the intervention of nutritional education, which included in each school: written pre and post-intervention tests, 6 workshops, 2 participative talks, 5 game activities, 1 cooking course and 1 recipe contest. Anthropometrical and biochemical determinations included weight, height, body-mass index, nutritional status, hematocrit, serum ferritin, retinol and folate concentrations. There was high prevalence of iron (25%), folates (75%) and vitamin A (43%) deficiencies in school children, with a low consumption of fruit and vegetables, high consumption of soft drinks and snacks and almost no physical activity. The nutritional education intervention produced a significant reduction in iron deficiency prevalence (25 to 14%), and showed no effect on vitamin A and folates deficiencies. There was a slight improvement in nutritional status. This study shows, through biochemical determinations, that nutritional education initiatives and programs have an impact improving nutritional health in school children. PMID:21547083

  19. Synthesis of folate receptor-targeted photosensitizers for photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Fang, Yanyan; Wang, Xiaopu; Zou, Qianli; Zhao, Yuxia; Wu, Feipeng

    2014-11-01

    A series of amphiphilic benzylidene cycloalkanes ketone photosensitizers C1-C4 with or without folate receptor-targeted agent were designed and synthesized. Their photophysical properties and in vitro photodynamic therapy (PDT) effects were studied. The results showed that all compounds exhibited appropriate lipid-water partition coefficients and high reactive oxygen yields. The introduction of the folate receptor-targeted agent had no obvious influence on the basic photophysical & photochemical properties of C2 and C4 compared to those of their corresponding prototype compounds (C1 and C3). In vitro studies were carried out using MCF-7 cells (FR+), Hela cells (FR+) and A549 cells (FR-), which represented different levels of folate receptor (FR) expression. All of C1-C4 showed low dark toxicity and superior PDT effects compared with the clinical drug PSD-007 (a mixture of porphyrins). What's more, folate receptor-targeted photosensitizers (C2 and C4) achieved higher accumulation and more excellent PDT effects in MCF-7 cells (FR+) and Hela cells (FR+) than photosensitizers (C1 and C3) without folate receptor-targeted agent and PSD-007. The photocytotoxicity of these photosensitizers showed no obvious differences in A549 cells (FR-).

  20. 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

  1. Plasma folate levels in men with type 2 diabetes.

    PubMed

    Sakuta, Hidenari; Suzuki, Takashi; Yasuda, Hiroko; Ito, Teizo

    2005-09-01

    Limited data suggest that folate levels are higher in patients with type 2 diabetes than in subjects with normal glucose tolerance (NGT). We compared the fasting plasma folate, glucose (FPG), body mass index (BMI), and supplementary vitamin use among male subjects with NGT, those with impaired glucose tolerance (IGT), those with newly diagnosed type 2 diabetes, and those with previously diagnosed type 2 diabetes. Plasma folate of patients with newly diagnosed diabetes and that of patients with previously diagnosed diabetes was significantly higher than that of NGT subjects (p < 0.001). Prevalence of vitamin use was lower in newly diagnosed or previously diagnosed diabetic patients compared with non-diabetic subjects. Self-rated vegetable intake was similar among the four groups. FPG, BMI, triglycerides, and systolic blood pressure correlated with plasma folate levels independently of lifestyle factors studied. These results suggest that plasma folate levels are elevated in male diabetic patients independently of health-conscious behavior that is recommended for diabetic people.

  2. Mechanisms of photodoping in oxygen-deficient YBa2Cu3Ox films studied by in situ transport measurements

    NASA Astrophysics Data System (ADS)

    Stockinger, C.; Markowitsch, W.; Lang, W.; Kula, W.; Sobolewski, Roman

    1998-04-01

    In situ studies of the superconducting and normal-state transport properties in partially oxygen-depleted, metallic YBa2Cu3Ox (Tc,mid~52 K) thin films exposed to long-term white-light illumination (photodoping) are reported. We observed that the effects of photoexcitation strongly depended on the temperature at which the photodoping was performed. The Hall number increased during the illumination in the entire tested temperature range from 70 to 290 K, with the strongest increase near room temperature, whereas, the Hall mobility increased steadily only upon low-temperature illumination. At temperatures above 250 K, it showed an abrupt initial increase followed by a long-term decrease. At high temperatures, the Hall quantities react on the impact of light excitation independently from each other, which strongly suggests that both the photoassisted oxygen ordering and charge-transfer mechanisms contribute to photodoping, the former acting mainly on the mobility, while the latter on the density of charge carriers. The photoinduced enhancement of the superconducting transition temperature Tc exhibited essentially the same temperature dependence as the enhancement of the Hall number, being largest (ΔTc~2.6 K) for the illumination performed at high temperatures. Thus, the Tc enhancement results from the change of the density more likely than of the mobility of the charge carriers.

  3. N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice.

    PubMed

    Cao, L; Li, L; Zuo, Z

    2012-09-18

    Oxidative stress contributes significantly to brain aging. Animals lacking glutamate transporter type 3 (EAAT3) have a decreased level of glutathione, the major intracellular anti-oxidant, in neurons, and present with early onset of brain aging including brain atrophy and cognitive impairment at 11 months of age. Here, 12-month-old male EAAT3 knockout mice received intraperitoneal injection of N-acetylcysteine (NAC) at 150 mg/kg once every day for 4 weeks. NAC is a membrane permeable cysteine precursor that can work as a substrate for glutathione synthesis. EAAT3 knockout mice that received saline injection or did not receive any injection were also included in the study. EAAT3 knockout mice had significantly less freezing behavior than age- and gender-matched wild-type mice in context- and tone-related fear conditioning tests. The knockout mice also had decreased levels of glutathione and increased levels of 4-hydroxy-2-nonenal and proteins containing nitrotyrosine, indicators of oxidative stress, in the cerebral cortex and hippocampus. NAC but not saline injection attenuated these behavioral and biochemical changes in the EAAT3 knockout mice. These results suggest that improvement of anti-oxidative capacity in neurons reverses the existing cognitive impairment in aging brains, implying a potential role of glutathione replacement in cognitive improvement of aging population.

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