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Sample records for alpha folate receptor-expressing

  1. Folate

    Science.gov (United States)

    ... ODS: ods.od.nih.gov/contact Table of Contents What is folate and what does it do? How much folate do I need? What foods provide folate? What kinds of folic acid dietary supplements are available? Am I getting enough ...

  2. Folate receptor {alpha} regulates cell proliferation in mouse gonadotroph {alpha}T3-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Congjun; Evans, Chheng-Orn [Department of Neurosurgery and Laboratory of Molecular Neurosurgery and Biotechnology, Emory University, School of Medicine, Atlanta, Georgia (United States); Stevens, Victoria L. [Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia (United States); Owens, Timothy R. [Emory University, School of Medicine, Atlanta, Georgia (United States); Oyesiku, Nelson M., E-mail: noyesik@emory.edu [Department of Neurosurgery and Laboratory of Molecular Neurosurgery and Biotechnology, Emory University, School of Medicine, Atlanta, Georgia (United States)

    2009-11-01

    We have previously found that the mRNA and protein levels of the folate receptor alpha (FR{alpha}) are uniquely over-expressed in clinically human nonfunctional (NF) pituitary adenomas, but the mechanistic role of FR{alpha} has not fully been determined. We investigated the effect of FR{alpha} over-expression in the mouse gonadotroph {alpha}T3-1 cell line as a model for NF pituitary adenomas. We found that the expression and function of FR{alpha} were strongly up-regulated, by Western blotting and folic acid binding assay. Furthermore, we found a higher cell growth rate, an enhanced percentage of cells in S-phase by BrdU assay, and a higher PCNA staining. These observations indicate that over-expression of FR{alpha} promotes cell proliferation. These effects were abrogated in the same {alpha}T3-1 cells when transfected with a mutant FR{alpha} cDNA that confers a dominant-negative phenotype by inhibiting folic acid binding. Finally, by real-time quantitative PCR, we found that mRNA expression of NOTCH3 was up-regulated in FR{alpha} over-expressing cells. In summary, our data suggests that FR{alpha} regulates pituitary tumor cell proliferation and mechanistically may involve the NOTCH pathway. Potentially, this finding could be exploited to develop new, innovative molecular targeted treatment for human NF pituitary adenomas.

  3. New Roles of Folate Receptor Alpha in Oncogenic Cell Signalling

    DEFF Research Database (Denmark)

    Hansen, Mariann Fagernæs

    I løbet af sine ph.d.-studier har Mariann Fagernæs Hansen undersøgt proteinet Folat Receptoren, der naturligt kan binde folinsyre. Folat Receptoren har betydning for cellevækst og er til stede på overfladen af mange kræftceller. I mange lande tilsættes folinsyre aktivt i f.eks. mel- og morgenmads...

  4. Expansion of microsatellite in the thyroid hormone receptor-alpha1 gene linked to increased receptor expression and less aggressive thyroid cancer

    DEFF Research Database (Denmark)

    Onda, Masamitsu; Li, Daisy; Suzuki, Shinichi;

    2002-01-01

    PURPOSE: The purpose of this study was to determine whether the length of the THRA1 microsatellite, which resides in a noncoding portion of the thyroid hormone receptor-alpha1 gene, affects receptor expression and is linked to clinicopathological parameters in thyroid cancer. EXPERIMENTAL DESIGN:...

  5. Folate Receptor Targeted Alpha-Therapy Using Terbium-149

    Directory of Open Access Journals (Sweden)

    Cristina Müller

    2014-03-01

    Full Text Available Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09 using folate receptor (FR-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq. A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d compared to untreated controls (A: 21 d. Analysis of blood parameters revealed no signs of acute toxicity to the kidneys or liver in treated mice over the time of investigation. These results demonstrated the potential of folate-based α-radionuclide therapy in tumor-bearing mice.

  6. Folate Receptor Targeted Alpha-Therapy Using Terbium-149

    CERN Document Server

    Müller, Cristina; Haller, Stephanie; Dorrer, Holger; Köster, Ulli; Johnston, Karl; Zhernosekov, Konstantin; Türler, Andreas; Schibli, Roger

    2014-01-01

    Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters rev...

  7. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.

    NARCIS (Netherlands)

    Steinfeld, R.; Grapp, M.; Kraetzner, R.; Dreha-Kulaczewski, S.; Helms, G.; Dechent, P.; Wevers, R.A.; Grosso, S.; Gartner, J.

    2009-01-01

    Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specifi

  8. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups

    OpenAIRE

    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 characteristic...

  9. 64Cu-labeled alpha-melanocyte-stimulating hormone analog for microPET imaging of melanocortin 1 receptor expression.

    Science.gov (United States)

    Cheng, Zhen; Xiong, Zhengming; Subbarayan, Murugesan; Chen, Xiaoyuan; Gambhir, Sanjiv Sam

    2007-01-01

    The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor (melanocortin type 1 receptor, or MC1R) plays an important role in the development and growth of melanoma cells. It was found that MC1R was overexpressed on most murine and human melanoma, making it a promising molecular target for melanoma imaging and therapy. Radiolabeled alpha-MSH peptide and its analogs that can specifically bind with MC1R have been extensively explored for developing novel agents for melanoma detection and radionuclide therapy. The goal of this study was to evaluate a 64Cu-labeled alpha-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys(DOTA)-NH2 (DOTA-NAPamide), as a potential molecular probe for microPET imaging of melanoma and MC1R expression in melanoma xenografted mouse models. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated NAPamide was synthesized and radiolabeled with 64Cu (t1/2=12 h) in NH4OAc (0.1 M; pH 5.5) buffered solution for 60 min at 50 degrees C. Cell culture studies reveal rapid and high uptake and internalization of 64Cu-DOTA-NAPamide in B16F10 cells. Over 90% of receptor-bound tracer is internalized at 3 h incubation. A cellular retention study demonstrates that the receptor-bound 64Cu-DOTA-NAPamide is slowly released from the B16F10 cells into the medium; 66% of the radioactivity is still associated with the cells even after 3 h incubation. The biodistribution of 64Cu-DOTA-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16F10 melanoma tumors with high capacity of MC1R and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Tumor uptake values of 64Cu-DOTA-NAPamide are found to be 4.63 +/- 0.45% and 2.49 +/- 0.31% ID/g in B16F10 and A375M xenografted melanoma at 2 h postinjection (pi), respectively. The B16F10 tumor uptake at 2 h pi is further inhibited to 2.29 +/- 0.24% ID/g, while A375M tumor uptake at 2 h pi remains 2.20 +/- 0.41% ID/g with a coinjection of excess

  10. 64Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

    OpenAIRE

    CHENG Zhen; Xiong, Zhengming; Subbarayan, Murugesan; Chen, Xiaoyuan; Gambhir, Sanjiv Sam

    2007-01-01

    The alpha-melanocyte-stimulating hormone (α-MSH) receptor (melanocortin type 1 receptor, or MC1R) plays an important role in the development and growth of melanoma cells. It was found that MC1R was overexpressed on most murine and human melanoma, making it a promising molecular target for melanoma imaging and therapy. Radiolabeled α-MSH peptide and its analogs that can specifically bind with MC1R have been extensively explored for developing novel agents for melanoma detection and radionuclid...

  11. Blocking and binding folate receptor alpha autoantibodies identify novel autism spectrum disorder subgroups

    Directory of Open Access Journals (Sweden)

    Richard Eugene Frye

    2016-03-01

    Full Text Available 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 with 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.

  12. Blocking and Binding Folate Receptor Alpha Autoantibodies Identify Novel Autism Spectrum Disorder Subgroups.

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  14. Exposure to Folate Receptor Alpha Antibodies during Gestation and Weaning Leads to Severe Behavioral Deficits in Rats: A Pilot Study.

    Directory of Open Access Journals (Sweden)

    Jeffrey M Sequeira

    Full Text Available The central nervous system continues to develop during gestation and after birth, and folate is an essential nutrient in this process. Folate deficiency and folate receptor alpha autoantibodies (FRα-AuAb have been associated with pregnancy-related complications and neurodevelopmental disorders. In this pilot study, we investigated the effect of exposure to FRα antibodies (Ab during gestation (GST, the pre-weaning (PRW, and the post weaning (POW periods on learning and behavior in adulthood in a rat model. In the open field test and novel object recognition task, which examine locomotor activity and anxiety-like behavior, deficits in rats exposed to Ab during gestation and pre-weaning (GST+PRW included more time spent in the periphery or corner areas, less time in the central area, frequent self-grooming akin to stereotypy, and longer time to explore a novel object compared to a control group; these are all indicative of increased levels of anxiety. In the place avoidance tasks that assess learning and spatial memory formation, only 30% of GST+PRW rats were able to learn the passive place avoidance task. None of these rats learned the active place avoidance task indicating severe learning deficits and cognitive impairment. Similar but less severe deficits were observed in rats exposed to Ab during GST alone or only during the PRW period, suggesting the extreme sensitivity of the fetal as well as the neonatal rat brain to the deleterious effects of exposure to Ab during this period. Behavioral deficits were not seen in rats exposed to antibody post weaning. These observations have implications in the pathology of FRα-AuAb associated with neural tube defect pregnancy, preterm birth and neurodevelopmental disorders including autism.

  15. Targeted Thiazole Orange Derivative with Folate: Synthesis, Fluorescence and in Vivo Fluorescence Imaging

    OpenAIRE

    Qingyang Meng; Baolian Zhang; Yiqi Wang; Xuening Fei; Yingchun Gu

    2010-01-01

    A Thiazole Orange conjugated with folate derivative was synthesized in two steps. Firstly, folate was coupled with 1-(3-aminopropyl)-4-methylquinolinium bromide to afford folate-methylquinolinium bromide, which then reacted with benzothiazolium to obtain the title folate-conjugated compound. The compound was evaluated by 1H-NMR MS, TG/DTA and fluorescence spectroscopic methods. The title compound could selectively target folate receptor expressing tumors according to the in vivo fluorescence ...

  16. Evaluation of estrogen receptor alpha and beta and progesterone receptor expression and correlation with clinicopathologic factors and proliferative marker Ki-67 in breast cancers

    DEFF Research Database (Denmark)

    Rosa, Fabíola E; Caldeira, José R F; Felipes, Joice;

    2008-01-01

    To elucidate the molecular profile of hormonal steroid receptor status, we analyzed ER-alpha, ER-beta, and PGR mRNA and protein expression in 80 breast carcinomas using reverse transcriptase polymerase chain reaction (RT-PCR), quantitative RT-PCR, and immunohistochemical analysis. Qualitative...... analysis revealed positive expression of ER-alpha, ER-beta, and PGR mRNA in 48%, 59%, and 48% of the breast carcinomas, respectively. ER-alpha, ER-beta, and PGR transcript overexpression was observed in 51%, 0%, and 12% of the cases, respectively, whereas moderate or strong protein expression was detected...... in 68%, 78%, and 49% of the cases, respectively. Tumor grade was negatively correlated with transcript and protein levels of ER-alpha (P = .0169 and P = .0006, respectively) and PGR (P = .0034 and P = .0005, respectively). Similarly, proliferative index Ki-67 was negatively associated with transcript...

  17. Folate bioavailability.

    Science.gov (United States)

    McNulty, Helene; Pentieva, Kristina

    2004-11-01

    The achievement of optimal folate status to prevent neural-tube defects, and possibly other diseases, is hindered by the well-recognised incomplete bioavailability of the natural folates found in foods compared with the synthetic vitamin, folic acid. Folate bioavailability from different foods is considered to be dependent on a number of factors, including the food matrix, the intestinal deconjugation of polyglutamyl folates, the instability of certain labile folates during digestion and the presence of certain dietary constituents that may enhance folate stability during digestion. There is conflicting evidence as to whether the extent of conjugation of polyglutamyl folate (in the absence of specific inhibitors of deconjugation in certain foods) is a limiting factor in folate bioavailability. Estimates of the extent of lower bioavailability of food folates compared with folic acid (relative bioavailability) show great variation, ranging anywhere between 10 and 98%, depending on the methodological approach used. The lack of accurate data on folate bioavailability from natural food sources is of particular concern in those countries in which there is no mandatory folic acid fortification, and therefore a greater reliance on natural food folates as a means to optimise status. Apart from the incomplete bioavailability of food folates, the poor stability of folates in foods (particularly green vegetables) under typical conditions of cooking can substantially reduce the amount of vitamin ingested and thereby be an additional factor limiting the ability of food folates to enhance folate status. A recent workshop convened by the Food Standards Agency concluded that gaining a better understanding of folate bioavailability in representative human diets is a high priority for future research.

  18. ER-alpha-cDNA as part of a bicistronic transcript gives rise to high frequency, long term, receptor expressing cell clones.

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    Michal Shenfeld

    Full Text Available Within the large group of Estrogen Receptor alpha (ERα-negative breast cancer patients, there is a subgroup carrying the phenotype ERα(-, PR(-, and Her2(-, named accordingly "Triple-Negative" (TN. Using cell lines derived from this TN group, we wished to establish cell clones, in which ERα is ectopically expressed, forming part of a synthetic lethality screening system. Initially, we generated cell transfectants expressing a mono-cistronic ERα transcription unit, adjacent to a separate dominant selectable marker transcription unit. However, the yield of ERα expressing colonies was rather low (5-12.5%, and only about half of these displayed stable ectopic ERα expression over time. Generation and maintenance of such cell clones under minimal exposure to the ERα ligand, did not improve yield or expression stability. Indeed, other groups have also reported grave difficulties in obtaining ectopic expression of ERα in ERα-deficient breast carcinoma cells. We therefore switched to transfecting these cell lines with pERα-IRES, a plasmid vector encoding a bicistronic translation mRNA template: ERα Open Reading Frame (ORF being upstream followed by a dominant-positive selectable marker (hygro(R ORF, directed for translation from an Internal Ribosome Entry Site (IRES. Through usage of this bicistronic vector linkage system, it was possible to generate a very high yield of ERα expressing cell clones (50-100%. The stability over time of these clones was also somewhat improved, though variations between individual cell clones were evident. Our successful experience with ERα in this system may serve as a paradigm for other genes where ectopic expression meets similar hardships.

  19. A Comparative Study of Two Folate-Conjugated Gold Nanoparticles for Cancer Nanotechnology Applications

    Energy Technology Data Exchange (ETDEWEB)

    Mansoori, G. Ali, E-mail: mansoori@uic.edu; Brandenburg, Kenneth S. [Department of Bioengineering, University of Illinois at Chicago, 851 S. Morgan St. (MC 063), Chicago, IL 60607 (United States); Shakeri-Zadeh, Ali [Department of Medical Physics, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2010-11-18

    We report a comparative study of synthesis, characteristics and in vitro tests of two folate-conjugated gold nanoparticles (AuNP) differing in linkers and AuNP sizes for selective targeting of folate-receptor positive cancerous cells. The linkers chosen were 4-aminothiophenol (4Atp) and 6-mercapto-1-hexanol (MH) with nanoconjugate products named Folate-4Atp-AuNP and Folate-MH-AuNP. We report the folate-receptor tissue distribution and its endocytosis for targeted nanotechnology. Comparison of the two nanoconjugates’ syntheses and characterization is also reported, including materials and methods of synthesis, UV-visible absorption spectroscopic measurements, Fourier Transform Infra Red (FTIR) measurements, Transmission electron microscopy (TEM) images and size distributions, X-ray diffraction data, elemental analyses and chemical stability comparison. In addition to the analytical characterization of the nanoconjugates, the cell lethality was measured in HeLa (high level of folate receptor expression) and MCF-7 (low level of folate receptor expression) cells. The nanoconjugates themselves, as well as the intense pulsed light (IPL) were not harmful to cell viability. However, upon stimulation of the folate targeted nanoconjugates with the IPL, ~98% cell killing was found in HeLa cells and only ~9% in MCF-7 cells after four hours incubation with the nanoconjugate. This demonstrates that folate targeting is effective in selecting for specific cell populations. Considering the various comparisons made, we conclude that Folate-4Atp-AuNP is superior to Folate-MH-AuNP for cancer therapy.

  20. Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo

    Science.gov (United States)

    Ndong, Christian; Toraya-Brown, Seiko; Kekalo, Katsiaryna; Baker, Ian; Gerngross, Tillman U; Fiering, Steven N; Griswold, Karl E

    2015-01-01

    Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs) to the folate receptor alpha (FOLRα) using an engineered antibody fragment (Ffab). Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy. PMID:25878495

  1. Antibody-mediated targeting of iron oxide nanoparticles to the folate receptor alpha increases tumor cell association in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Ndong C

    2015-04-01

    Full Text Available Christian Ndong,1 Seiko Toraya-Brown,2 Katsiaryna Kekalo,1 Ian Baker,1 Tillman U Gerngross,1,3,4 Steven N Fiering,2,5,6 Karl E Griswold1,3,6 1Thayer School of Engineering, Dartmouth, Hanover, NH, USA; 2Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 3Department of Biological Sciences, Dartmouth, Hanover, NH, USA; 4Department of Chemistry, Dartmouth, Hanover, NH, USA; 5Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 6Norris Cotton Cancer Center, Lebanon, NH, USA Abstract: Active molecular targeting has become an important aspect of nanoparticle development for oncology indications. Here, we describe molecular targeting of iron oxide nanoparticles (IONPs to the folate receptor alpha (FOLRα using an engineered antibody fragment (Ffab. Compared to control nanoparticles targeting the non-relevant botulinum toxin, the Ffab-IONP constructs selectively accumulated on FOLRα-overexpressing cancer cells in vitro, where they exhibited the capacity to internalize into intracellular vesicles. Similarly, Ffab-IONPs homed to FOLRα-positive tumors upon intraperitoneal administration in an orthotopic murine xenograft model of ovarian cancer, whereas negative control particles showed no detectable tumor accumulation. Interestingly, Ffab-IONPs built with custom 120 nm nanoparticles exhibited lower in vitro targeting efficiency when compared to those built with commercially sourced 180 nm nanoparticles. In vivo, however, the two Ffab-IONP platforms achieved equivalent tumor homing, although the smaller 120 nm IONPs were more prone to liver sequestration. Overall, the results show that Ffab-mediated targeting of IONPs yields specific, high-level accumulation within cancer cells, and this fact suggests that Ffab-IONPs could have future utility in ovarian cancer diagnostics and therapy. Keywords: nanoparticle targeting, antibody fragment, biodistribution, ovarian cancer

  2. Folate-deficiency anemia

    Science.gov (United States)

    ... 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) ...

  3. Regulation of fibrinogen receptor expression on human platelets

    Energy Technology Data Exchange (ETDEWEB)

    Shattil, S.J.; Motulsky, H.J.; Insel, P.A.; Brass, L.F.

    1986-03-01

    Platelet aggregation requires the binding of fibrinogen to specific receptors on the plasma membrane glycoprotein IIb-IIIa complex. Although the IIb-IIIa complex is identifiable on the surface of resting platelets, the fibrinogen receptor is expressed only after platelet activation. The authors have developed a monoclonal anti-IIb-IIIa antibody (PAC-1) that binds only to stimulated platelets and only in the presence of Ca. In order to better understand the steps leading to platelet aggregation, the authors used radiolabeled PAC-1 and fibrinogen to examine the effect of the ..cap alpha../sub 2/-adrenergic agonist, epinephrine, on the expression and function of the fibrinogen receptor. The addition of epinephrine to unstirred platelets caused and immediate increase in PAC-1 and fibrinogen binding that was associated with platelet aggregation once the platelets were stirred. Even after prolonged incubation of the platelets with epinephrine, fibrinogen receptor expression could be reversed by adding EGTA, PGl/sub 2/, or the ..cap alpha../sub 2/-adrenergic antagonist, phentolamine. When unstirred platelets were exposed to epinephrine for more than 10 min, the extent of aggregation caused by subsequent stirring was decreased by 70%. Surprisingly, these desensitized platelets bound PAC-1 and fibrinogen normally, indicating that the loss of aggregation was not due to a decrease in fibrinogen receptor expression or function. These studies demonstrate that: (1) fibrinogen receptor expression is dependent on extracellular CA; (2) induction of the fibrinogen receptor by epinephrine requires the continued presence of the agonist; and (3) prolonged stimulation of the platelet by epinephrine can lead to a reduced aggregation response by a mechanism that does not involve a loss of either fibrinogen recepor expression or fibrinogen binding.

  4. Folate-conjugated immunoglobulin targets melanoma tumor cells for NK cell effector functions

    Science.gov (United States)

    Skinner, Cassandra C.; McMichael, Elizabeth L.; Jaime-Ramirez, Alena C.; Abrams, Zachary B.; Lee, Robert J.; Carson, William E.

    2016-01-01

    The folate receptor (FR) is over-expressed on the vascular side of cancerous cells including those of the breast, ovaries, testes, and cervix. We hypothesized that a folate-conjugated immunoglobulin (F-IgG) would bind to the FR that is over-expressed on melanoma tumor cells to target these cells for lysis by natural killer (NK) cells. Folate receptor expression was confirmed in the Mel-39 (human melanoma) cell line by flow cytometry and immunoblot analysis, using KB (human oral epithelial) and F01 (human melanoma) as a positive and negative control, respectively. FR-positive and negative cell lines were treated with F-IgG or control immunoglobulin G (C-IgG) in the presence or absence of cytokines in order to determine NK cell ability to lyse FR-positive cell lines. NK cell activation was significantly upregulated and lysis of Mel 39 tumor cells enhanced following treatment with F-IgG, as compared to C-IgG at all effector:target (E:T) ratios (p<0.01). This trend was further enhanced by NK cell stimulation with the activating cytokine interleukin-12 (IL-12). NK cell production of cytokines such as interferon-gamma (IFN-γ), macrophage inflammatory protein 1 alpha (MIP-1α), and regulated on activation normal T-cell expressed and secreted (RANTES) were also significantly increased in response to co-stimulation with IL-12 stimulation and F-IgG-coated Mel 39 target cells, as compared to controls (p<0.01). In contrast, F-IgG did not bind to the FR-negative cell line F01 and had no significant effect on NK cell lysis or cytokine production. This research indicates the potential use of F-IgG for its ability to induce an immune response from NK cells against FR-positive melanoma tumor cells which can be further enhanced by the addition of cytokines. PMID:27035691

  5. A Comparative Study of Two Folate-Conjugated Gold Nanoparticles for Cancer Nanotechnology Applications

    Directory of Open Access Journals (Sweden)

    Ali Shakeri-Zadeh

    2010-11-01

    Full Text Available We report a comparative study of synthesis, characteristics and in vitro tests of two folate-conjugated gold nanoparticles (AuNP differing in linkers and AuNP sizes for selective targeting of folate-receptor positive cancerous cells. The linkers chosen were 4-aminothiophenol (4Atp and 6-mercapto-1-hexanol (MH with nanoconjugate products named Folate-4Atp-AuNP and Folate-MH-AuNP. We report the folate-receptor tissue distribution and its endocytosis for targeted nanotechnology. Comparison of the two nanoconjugates’ syntheses and characterization is also reported, including materials and methods of synthesis, UV-visible absorption spectroscopic measurements, Fourier Transform Infra Red (FTIR measurements, Transmission electron microscopy (TEM images and size distributions, X-ray diffraction data, elemental analyses and chemical stability comparison. In addition to the analytical characterization of the nanoconjugates, the cell lethality was measured in HeLa (high level of folate receptor expression and MCF-7 (low level of folate receptor expression cells. The nanoconjugates themselves, as well as the intense pulsed light (IPL were not harmful to cell viability. However, upon stimulation of the folate targeted nanoconjugates with the IPL, ~98% cell killing was found in HeLa cells and only ~9% in MCF-7 cells after four hours incubation with the nanoconjugate. This demonstrates that folate targeting is effective in selecting for specific cell populations. Considering the various comparisons made, we conclude that Folate-4Atp-AuNP is superior to Folate-MH-AuNP for cancer therapy.

  6. Folate and Cancer

    Directory of Open Access Journals (Sweden)

    Luciana Yuki Tomita PhD

    2016-07-01

    Full Text Available Folate plays a central role in DNA synthesis and methylation, which are essential for DNA integrity maintenance and gene expression. Folate deficiency may lead to the incorporation of uracil into DNA and chromosome breaks, increasing the risk of cancer. However, conflicting evidence has been observed depending on the type of epidemiological study, dietary or circulating folate, and the type of cancer. New concern has arisen after a mandatory folic acid (FA fortification program adopted for the prevention of neural tube defects in the United States, which suggested an increase in the incidence of colorectal cancer. In the present article, folate status and cancer are under review, and a discussion of the challenge of assessing folate status through food intake, supplement use, FA fortification programs, circulating folate, and the interaction of diet and the polymorphism of the enzyme involved in folate metabolism will be presented.

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

    Science.gov (United States)

    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.

  8. Androgen receptor expression in gastrointestinal stromal tumor.

    Science.gov (United States)

    Lopes, Lisandro F; Bacchi, Carlos E

    2009-03-01

    The aim of this study was to evaluate the expression of estrogen, progesterone, and androgen receptors in a large series of gastrointestinal stromal tumors. Clinical and pathologic data were reviewed in 427 cases of gastrointestinal stromal tumor and the expression of such hormone receptors was investigated by immunohistochemistry using tissue microarray technique. All tumors were negative for estrogen receptor expression. Progesterone and androgen receptors expression was observed in 5.4% and 17.6% of tumors, respectively. We found the higher average age at diagnosis, the lower frequency of tumors located in the small intestine, and the higher frequency of extragastrointestinal tumors to be statistically significant in the group of tumors with androgen receptor expression in contrast to the group showing no androgen receptor expression. There was no statistic difference between such groups regarding sex, tumor size, mitotic count, cell morphology, and risk of aggressive behavior. Considering that the expression of androgen receptors in gastrointestinal stromal tumors is not negligible, further studies are encouraged to establish the role of androgen deprivation therapy for gastrointestinal stromal tumors.

  9. Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression.

    Science.gov (United States)

    Able, Jessica A; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K

    2014-03-01

    Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats.

  10. Human Folate Bioavailability

    Directory of Open Access Journals (Sweden)

    Cornelia M. Witthoft

    2011-04-01

    Full Text Available The vitamin folate is recognized as beneficial health-wise in the prevention of neural tube defects, anemia, cardiovascular diseases, poor cognitive performance, and some forms of cancer. However, suboptimal dietary folate intake has been reported in a number of countries. Several national health authorities have therefore introduced mandatory food fortification with synthetic folic acid, which is considered a convenient fortificant, being cost-efficient in production, more stable than natural food folate, and superior in terms of bioavailability and bioefficacy. Other countries have decided against fortification due to the ambiguous role of synthetic folic acid regarding promotion of subclinical cancers and other adverse health effects. This paper reviews recent studies on folate bioavailability after intervention with folate from food. Our conclusions were that limited folate bioavailability data are available for vegetables, fruits, cereal products, and fortified foods, and that it is difficult to evaluate the bioavailability of food folate or whether intervention with food folate improves folate status. We recommend revising the classical approach of using folic acid as a reference dose for estimating the plasma kinetics and relative bioavailability of food folate.

  11. A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer

    Directory of Open Access Journals (Sweden)

    Kandalaft Lana E

    2012-08-01

    Full Text Available Abstract Purpose In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Rationale Genetically reprogrammed, patient-derived chimeric antigen receptor (CAR-T lymphocytes with the ability to recognize predefined surface antigens with high specificity in a non-MHC restricted manner have shown increasing anti-tumor efficacy in preclinical and clinical studies. Folate receptor-α (FRα is an ovarian cancer-specific tumor target; however, it is expressed at low levels in certain organs with risk for toxicity. Design Here we propose a phase I study testing the feasibility, safety and preliminary activity of FRα-redirected CAR-T cells bearing the CD137 (4-1BB costimulatory domain, administered after lymphodepletion for the treatment of recurrent ovarian cancer. A novel trial design is proposed that maximizes safety features. Innovation This design involves an initial accelerated dose escalation phase of FR-α CAR-T cells followed by a standard 3 + 3 escalation phase. A split-dose approach is proposed to mitigate acute adverse events. Furthermore, infusion of bulk untransduced autologous peripheral blood lymphocytes (PBL is proposed two days after CAR-T cell infusion at the lower dose levels of CAR-T cells, to suppress excessive expansion of CAR-T cells in vivo and mitigate toxicity.

  12. Upregulation of neurokinin-1 receptor expression in the lungs of patients with sarcoidosis.

    LENUS (Irish Health Repository)

    O'Connor, Terence M

    2012-02-03

    Substance P (SP) is a proinflammatory neuropeptide that is secreted by sensory nerves and inflammatory cells. Increased levels of SP are found in sarcoid bronchoalveolar lavage fluid. SP acts by binding to the neurokinin-1 receptor and increases secretion of tumor necrosis factor-alpha in many cell types. We sought to determine neurokinin-1 receptor expression in patients with sarcoidosis compared with normal controls. Neurokinin-1 receptor messenger RNA and protein expression were below the limits of detection by reverse transcriptase-polymerase chain reaction and immunohistochemistry in peripheral blood mononuclear cells of healthy volunteers (n = 9) or patients with stage 1 or 2 pulmonary sarcoidosis (n = 10), but were detected in 1\\/9 bronchoalveolar lavage cells of controls compared with 8\\/10 patients with sarcoidosis (p = 0.012) and 2\\/9 biopsies of controls compared with 9\\/10 patients with sarcoidosis (p = 0.013). Immunohistochemistry localized upregulated neurokinin-1 receptor expression to bronchial and alveolar epithelial cells, macrophages, lymphocytes, and sarcoid granulomas. The patient in whom neurokinin-1 receptor was not detected was taking corticosteroids. Incubation of the type II alveolar and bronchial epithelial cell lines A549 and SK-LU 1 with dexamethasone downregulated neurokinin-1 receptor expression. Upregulated neurokinin-1 receptor expression in patients with sarcoidosis may potentiate substance P-induced proinflammatory cytokine production in patients with sarcoidosis.

  13. Targeted images of KB cells using folate-conjugated gold nanoparticles

    Science.gov (United States)

    Rathinaraj, Pierson; Lee, Kyubae; Park, Soo-Young; Kang, Inn-Kyu

    2015-01-01

    Mercaptosuccinic acid-coated gold (GM) nanoparticles were prepared and characterized by transmission electron microscopy and dynamic light scattering. Folic acid (F) was then conjugated to the GM to preferentially target oral squamous cancer (KB) cells with folate receptors expressed on their membranes and facilitate the transit of the nanoparticles across the cell membrane. Finally, a fluorescence dye (Atto) was conjugated to the nanoparticles to visualize their internalization into KB cells. After culture of the cells in a medium containing GM and folate-conjugated GM (GF), the interaction of surface-modified gold nanoparticles with KB cells was studied.

  14. Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy

    Science.gov (United States)

    Kumar, Ajay; Chelvam, Venkatesh; Sakkarapalayam, Mahalingam; Li, Guo; Sanchez-Cruz, Pedro; Piñero, Natasha S.; Low, Philip S.; Alegria, Antonio E.

    2016-01-01

    Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a constitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered. PMID:27066312

  15. Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles.

    Science.gov (United States)

    Erdoğar, Nazlı; Esendağlı, Güneş; Nielsen, Thorbjorn T; Şen, Murat; Öner, Levent; Bilensoy, Erem

    2016-07-25

    As nanomedicines are gaining momentum in the therapy of cancer, new biomaterials emerge as alternative platforms for the delivery of anticancer drugs with bioavailability problems. In this study, two novel amphiphilic cyclodextrins (FCD-1 and FCD-2) conjugated with folate group to enable active targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD-2 nanoparticles remained within the range of 70-275nm and 125-185nm, respectively. Zeta potential values were neutral and -20mV for FCD-1 and FCD-2 nanoparticles, respectively. Drug release studies showed initial burst release followed by a longer sustained release. Blank nanoparticles had no cytotoxicity against L929 cells. T-47D and ZR-75-1 human breast cancer cells with different levels of folate receptor expression were used to assess anti-cancer efficacy. Through targeting the folate receptor, these nanoparticles were efficiently engulfed by the breast cancer cells. Additionally, breast cancer cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate-dependent mechanism. PMID:27282534

  16. Preparation and Preliminary Biological Evaluation of {sup 177}Lu-DOTA folate as Potential Folate Receptor Targeting Therapeutic Agent

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Kang-Hyuk; Hong, Young-Don; Pyun, Mi-Sun; Lee, So-Young; Felipe, Fenelope; Yoon, Sun-Ha; Choi, Sun-Ju [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2008-10-15

    Folic Acid (FA) and FA derivatives are overexpressed on several tumor cells. The cell-membrane folic acid receptors are known to be responsible for the cellular accumulation of FA and FA analogs, such as methotrexate and folic acid. Folate has been characterized to have high affinity for the folate-receptor positive cells and tissues and considered to be useful as diagnostic imaging and therapeutic agent. In 1940s, Folate analogue, aminopterin, was first used for treatment of leukemia and recently, many folate derivatives were tried for cancer-treatment agent as well as visualization of folate receptor. Many researchers tried to conjugate folic acid with macromolecules or low molecular weight chelators through its alpha or gamma carboxylate. However, despite the reduced binding affinity, FAs are still recognized by the folate receptor. Therefore, we focused to develop folate-based radiopharmaceutical that has the potential to be used as a therapeutic agent. We report here the synthesis and the radiolabeling of {sup 177}Lu-DOTA as well as the biodistribution data of our developed compound.

  17. The intestinal absorption of folates.

    Science.gov (United States)

    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

  18. Folate biofortification of tomato fruit

    OpenAIRE

    Díaz de la Garza, Rocío I; Gregory, Jesse F.; Hanson, Andrew D.

    2007-01-01

    Folate deficiency leads to neural tube defects and other human diseases, and is a global health problem. Because plants are major folate sources for humans, we have sought to enhance plant folate levels (biofortification). Folates are synthesized from pteridine, p-aminobenzoate (PABA), and glutamate precursors. Previously, we increased pteridine production in tomato fruit up to 140-fold by overexpressing GTP cyclohydrolase I, the first enzyme of pteridine synthesis. This strategy increased fo...

  19. Cannabinoid-receptor expression in human leukocytes.

    Science.gov (United States)

    Bouaboula, M; Rinaldi, M; Carayon, P; Carillon, C; Delpech, B; Shire, D; Le Fur, G; Casellas, P

    1993-05-15

    Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS), probably through the cannabinoid receptor, which has recently been cloned in rat and human. While numerous reports have also described effects of cannabinoids on the immune system, the observation of both mRNA and cannabinoid receptor has hitherto been exclusively confined to the brain, a reported detection in the testis being the sole example of its presence at the periphery. Here we report the expression of the cannabinoid receptor on human immune tissues using a highly sensitive polymerase-chain-reaction-based method for mRNA quantification. We show that, although present in a much lower abundance than in brain, cannabinoid receptor transcripts are found in human spleen, tonsils and peripheral blood leukocytes. The distribution pattern displays important variations of the mRNA level for the cannabinoid receptor among the main human blood cell subpopulations. The rank order of mRNA levels in these cells is B cells > natural killer cells > or = polymorphonuclear neutrophils > or = T8 cells > monocytes > T4 cells. Cannabinoid-receptor mRNA, which is also found in monocytic, as well as T and B leukemia cell lines but not in Jurkat cells, presents a great diversity of expression on these cells as well, B-cell lines expressing a much higher level than T-cell lines. The cannabinoid receptor PCR products from leukocytes and brain are identical both in size and sequence suggesting a strong similarity between central and peripheral cannabinoid receptors. The expression of this receptor was demonstrated on membranes of the myelomonocytic U937 cells using the synthetic cannabinoid [3H]CP-55940 as ligand. The Kd determined from Scatchard analysis was 0.1 nM and the Bmax for membranes was 525 fmol/mg protein. The demonstration of cannabinoid-receptor expression at both mRNA and protein levels on human leukocytes provides a molecular basis for cannabinoid action on these cells. PMID

  20. Vitamin B12 and Folate Test

    Science.gov (United States)

    ... be limited. Home Visit Global Sites Search Help? 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 ...

  1. Folate Production by Probiotic Bacteria

    Directory of Open Access Journals (Sweden)

    Stefano Raimondi

    2011-01-01

    Full Text Available Probiotic bacteria, mostly belonging to the genera Lactobacillus and Bifidobacterium, confer a number of health benefits to the host, including vitamin production. With the aim to produce folate-enriched fermented products and/or develop probiotic supplements that accomplish folate biosynthesis in vivo within the colon, bifidobacteria and lactobacilli have been extensively studied for their capability to produce this vitamin. On the basis of physiological studies and genome analysis, wild-type lactobacilli cannot synthesize folate, generally require it for growth, and provide a negative contribution to folate levels in fermented dairy products. Lactobacillus plantarum constitutes an exception among lactobacilli, since it is capable of folate production in presence of para-aminobenzoic acid (pABA and deserves to be used in animal trials to validate its ability to produce the vitamin in vivo. On the other hand, several folate-producing strains have been selected within the genus Bifidobacterium, with a great variability in the extent of vitamin released in the medium. Most of them belong to the species B. adolescentis and B. pseudocatenulatum, but few folate producing strains are found in the other species as well. Rats fed a probiotic formulation of folate-producing bifidobacteria exhibited increased plasma folate level, confirming that the vitamin is produced in vivo and absorbed. In a human trial, the same supplement raised folate concentration in feces. The use of folate-producing probiotic strains can be regarded as a new perspective in the specific use of probiotics. They could more efficiently confer protection against inflammation and cancer, both exerting the beneficial effects of probiotics and preventing the folate deficiency that is associated with premalignant changes in the colonic epithelia.

  2. Folate production by probiotic bacteria.

    Science.gov (United States)

    Rossi, Maddalena; Amaretti, Alberto; Raimondi, Stefano

    2011-01-01

    Probiotic bacteria, mostly belonging to the genera Lactobacillus and Bifidobacterium, confer a number of health benefits to the host, including vitamin production. With the aim to produce folate-enriched fermented products and/or develop probiotic supplements that accomplish folate biosynthesis in vivo within the colon, bifidobacteria and lactobacilli have been extensively studied for their capability to produce this vitamin. On the basis of physiological studies and genome analysis, wild-type lactobacilli cannot synthesize folate, generally require it for growth, and provide a negative contribution to folate levels in fermented dairy products. Lactobacillus plantarum constitutes an exception among lactobacilli, since it is capable of folate production in presence of para-aminobenzoic acid (pABA) and deserves to be used in animal trials to validate its ability to produce the vitamin in vivo. On the other hand, several folate-producing strains have been selected within the genus Bifidobacterium, with a great variability in the extent of vitamin released in the medium. Most of them belong to the species B. adolescentis and B. pseudocatenulatum, but few folate producing strains are found in the other species as well. Rats fed a probiotic formulation of folate-producing bifidobacteria exhibited increased plasma folate level, confirming that the vitamin is produced in vivo and absorbed. In a human trial, the same supplement raised folate concentration in feces. The use of folate-producing probiotic strains can be regarded as a new perspective in the specific use of probiotics. They could more efficiently confer protection against inflammation and cancer, both exerting the beneficial effects of probiotics and preventing the folate deficiency that is associated with premalignant changes in the colonic epithelia. PMID:22254078

  3. Folate, alcohol, and liver disease.

    Science.gov (United States)

    Medici, Valentina; Halsted, Charles H

    2013-04-01

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

  4. Folate Production by Probiotic Bacteria

    OpenAIRE

    Stefano Raimondi; Alberto Amaretti; Maddalena Rossi

    2011-01-01

    Probiotic bacteria, mostly belonging to the genera Lactobacillus and Bifidobacterium, confer a number of health benefits to the host, including vitamin production. With the aim to produce folate-enriched fermented products and/or develop probiotic supplements that accomplish folate biosynthesis in vivo within the colon, bifidobacteria and lactobacilli have been extensively studied for their capability to produce this vitamin. On the basis of physiological studies and genome analysis, wild-typ...

  5. Tonotopic changes in GABA receptor expression in guinea pig inferior colliculus after partial unilateral hearing loss.

    Science.gov (United States)

    Dong, S; Rodger, J; Mulders, W H A M; Robertson, D

    2010-06-25

    Immunohistochemistry was used to investigate the topographic distribution of the alpha1 subunit of the GABA receptor (GABRA1) in guinea pig inferior colliculus after treatments that caused a unilateral loss of peripheral neural sensitivity in the high-frequency regions of the cochlea. Both forms of treatment (direct mechanical lesion of the cochlea and acoustic overstimulation) resulted in a significant decrease in GABRA1 labeling in regions of the contralateral inferior colliculus in which high-frequency sound stimuli are represented. This localized region of reduced inhibitory receptor expression corresponds to the region in which hyperactivity of inferior colliculus neurons has been shown to develop after such treatments. The results strengthen the notion of a causal link between reduced GABRA1 expression and neural hyperactivity in central auditory nuclei and provide a possible mechanism for the development of phantom auditory sensations, or tinnitus. PMID:20438718

  6. Dopamine receptor expression and function in corticotroph pituitary tumors

    OpenAIRE

    Pivonello, Rosario; Lamberts, Steven; Ferone, Diego; De Herder, Wouter; Kros, Johan; Caro, M.L.; M. Arvigo; Annunziato, L; Lombardi, Gaetano; Colao, Annamaria; Hofland, Leo

    2004-01-01

    textabstractThe role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D(2) receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion and the in vivo effect of short-term cabergoline treatment on cortisol secretion. D(2) expression was evaluated by receptor-ligand binding, immunohistochemistry, and RT-PCR. A 50% or more decrease in daily urinary ...

  7. Radiosensitization effect of folate-conjugated gold nanoparticles on HeLa cancer cells under orthovoltage superficial radiotherapy techniques

    Science.gov (United States)

    Khoshgard, Karim; Hashemi, Bijan; Arbabi, Azim; Javad Rasaee, Mohammad; Soleimani, Masoud

    2014-05-01

    Due to the high atomic number of gold nanoparticles (GNPs), they are known as new radiosensitizer agents for enhancing the efficiency of superficial radiotherapy techniques by increasing the dose absorbed in tumor cells wherein they can be accumulated selectively. The aim of this study was to compare the effect of various common low energy levels of orthovoltage x-rays and megavoltage γ-rays (Co-60) on enhancing the therapeutic efficiency of HeLa cancer cells in the presence of conjugated folate and non-conjugated (pegylated) GNPs. To achieve this, GNPs with an average diameter of 52 nm were synthesized and conjugated to folic acid molecules. Pegylated GNPs with an average diameter of 47 nm were also synthesized and used as non-conjugated folate GNPs. Cytotoxicity assay of the synthesized folate-conjugated and pegylated GNPs was performed using different levels of nanoparticle concentration incubated with HeLa cells for 24 h. The radiosensitizing effect of both the conjugated and pegylated GNPs on the cells at a concentration of 50 µM was compared using MTT as well as clonogenic assays after exposing them to 2 Gy ionizing radiation produced by an orthovoltage x-ray machine at four different kVps and γ-rays of a Co-60 unit. Significant differences were noted among various irradiated groups with and without the folate conjugation, with an average dose enhancement factor (DEF) of 1.64 ± 0.05 and 1.35 ± 0.05 for the folate-conjugated and pegylated GNPs, respectively. The maximum DEF was obtained with the 180 kVp x-ray beam for both of the GNPs. Folate-conjugated GNPs can significantly enhance the cell killing potential of orthovoltage x-ray energies (especially at 180 kVp) in folate receptor-expressing cancer cells, such as HeLa, in superficial radiotherapy techniques.

  8. Folates in lettuce: a pilot study

    Science.gov (United States)

    Johansson, Madelene; Jägerstad, Margaretha; Frølich, Wenche

    2007-01-01

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

  9. Folate biofortification in food plants

    NARCIS (Netherlands)

    S. Bekaert; S. Storozhenko; P. Mehrshahi; M.J. Bennett; W. Lambert; J.F. Gregory III; K. Schubert; J. Hugenholtz; D. van der Straeten; A.D. Hanson

    2008-01-01

    Folate deficiency is a global health problem affecting many people in the developing and developed world. Current interventions (industrial food fortification and supplementation by folic acid pills) are effective if they can be used but might not be possible in less developed countries. Recent adva

  10. [Modulation of Fcgamma and C3b receptor expression by marine bioglycans in mouse splenocytes].

    Science.gov (United States)

    Zaporozhets, T S

    2003-01-01

    Investigation of polysacharide immunomodulators of marine origin was performed--mitilane, alpha-1,4;1,6-D-glucane, isolated from midia Crenomytilus grayanus, and translam--beta-1,3;1,6-D-glucane isolated from marine algae Laminaria cichorioides were compared. Mechanisms of phagocytes cells activation were investigated. Dose-dependent ability of investigated bioglycanes to facilitate Fc gamma R [symbol: see text] C3bR expression at mice splenocytes was demonstrated in vivo and in vitro. The effect depended on immunomodulator type, incubation conditions, dose, period of incubation in vitro and by splenocytes population used for Fc gamma R and C3bR identification. It was shown that C3bR expression was more enhanced by immunomodulators than Fc gamma R expression. For Fc gamma R induction on lymphocytes membranes the presence of phagocytes cell (macrophages and neutrophils) is obligatory. Mitilane, containing alpha-1,4;1,6-D-glucane and some amount of protein is more effective in stimulation of membrane receptors expression than translam--beta-1,3;1,6-D-glucane. The results of investigation demonstrates the possibility to use marine bioglicanes as activators of Fc gamma R and C3bR activity, that is the base for control of pathological processes, related to immune system. PMID:12914116

  11. Folate deficiency affects histone methylation.

    Science.gov (United States)

    Garcia, Benjamin A; Luka, Zigmund; Loukachevitch, Lioudmila V; Bhanu, Natarajan V; Wagner, Conrad

    2016-03-01

    Formaldehyde is extremely toxic reacting with proteins to crosslinks peptide chains. Formaldehyde is a metabolic product in many enzymatic reactions and the question of how these enzymes are protected from the formaldehyde that is generated has largely remained unanswered. Early experiments from our laboratory showed that two liver mitochondrial enzymes, dimethylglycine dehydrogenase (DMGDH) and sarcosine dehydrogenase (SDH) catalyze oxidative demethylation reactions (sarcosine is a common name for monomethylglycine). The enzymatic products of these enzymes were the demethylated substrates and formaldehyde, produced from the removed methyl group. Both DMGDH and SDH contain FAD and both have tightly bound tetrahydrofolate (THF), a folate coenzyme. THF binds reversibly with formaldehyde to form 5,10-methylene-THF. At that time we showed that purified DMGDH, with tightly bound THF, reacted with formaldehyde generated during the reaction to form 5,10-methylene-THF. This effectively scavenged the formaldehyde to protect the enzyme. Recently, post-translational modifications on histone tails have been shown to be responsible for epigenetic regulation of gene expression. One of these modifications is methylation of lysine residues. The first enzyme discovered to accomplish demethylation of these modified histones was histone lysine demethylase (LSD1). LSD1 specifically removes methyl groups from di- and mono-methylated lysines at position 4 of histone 3. This enzyme contained tightly bound FAD and the products of the reaction were the demethylated lysine residue and formaldehyde. The mechanism of LSD1 demethylation is analogous to the mechanism previously postulated for DMGDH, i.e. oxidation of the N-methyl bond to the methylene imine followed by hydrolysis to generate formaldehyde. This suggested that THF might also be involved in the LSD1 reaction to scavenge the formaldehyde produced. Our hypotheses are that THF is bound to native LSD1 by analogy to DMGDH and SDH and

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

    Science.gov (United States)

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

    2016-08-01

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

  13. Folate in oats and its milling fractions.

    Science.gov (United States)

    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.

  14. Fischer 344 Rat: A Preclinical Model for Epithelial Ovarian Cancer Folate-Targeted Therapy.

    OpenAIRE

    AZAIS, Henri; QUENIAT, Gurvan; Bonner, Caroline; Kerdraon, Olivier; Tardivel, Meryem; Leroux, Bertrand; Frochot, Céline; Betrouni, Nacim; Collinet, Pierre; Mordon, Serge

    2015-01-01

    Objective: Ovarian cancer prognosis remains dire after primary therapy. Recurrence rates are disappointingly high as 60% of women with advanced epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis and residual tumorous cells during surgery is necessary as they are the main predictive factors of recurrences. Folate receptor [alpha] (FR[alpha]) shows promising prospects in targeting ovarian cancero...

  15. In vivo structural activity and optimization studies of folate-tubulysin conjugates.

    Science.gov (United States)

    Reddy, Joseph A; Dorton, Ryan; Dawson, Alicia; Vetzel, Marilynn; Parker, Nikki; Nicoson, Jeffrey S; Westrick, Elaine; Klein, Patrick J; Wang, Yu; Vlahov, Iontcho R; Leamon, Christopher P

    2009-01-01

    Herein we report on the potencies of 4 related folate-conjugated tubulysins constructed with either tubulysin B hydrazide (EC0305), tubulysin A hydrazide (EC0510), the N,O-acetal derivative of natural tubulysins (EC0317) or a tubulysin B ester (EC0302). Our results confirmed that EC0305 is the most favorable conjugate of the group due to its potent antitumor activity [100% cures at 1 micromol/kg, three times a week (TIW) for 2 weeks] and its favorably low toxicity profile. In contrast, the natural tubulysin B drug proved to be inactive against a human nasopharyngeal tumor model when administered at doses near to or greater than the maximum tolerated dose (MTD). When tested against more chemoresistant folate receptor expressing M109 and 4T1-cl2 tumors, EC0305 displayed superior antitumor activity over a previously disclosed folate conjugate of desacetylvinblastine monohydrazide (EC145). These studies demonstrate that EC0305 has significant antiproliferative activity against FR expressing tumors, including those which are generally more chemoresistant, and that EC0305 should be considered for development as a candidate for the treatment of advanced FR-expressing human cancers. PMID:19630399

  16. Vitamin B12, folate and folate-binding proteins in dairy products

    OpenAIRE

    Arkbåge, Karin

    2003-01-01

    Vitamin B12 and folate are two important B vitamins for maintaining good health, being involved in amino acid metabolism and DNA synthesis. Milk and dairy products are good sources of vitamin B12 and folate. Moreover, they are of interest due to their content of folate-binding proteins (FBP), since it was hypothesised that these promote folate bioavailability. Furthermore, fermentation of milk is a way to increase the content of both vitamins. Vitamin analysis in fermented dairy products is c...

  17. Dietary folate and folate vitamers and the risk of prostate cancer in the Netherlands Cohort Study

    NARCIS (Netherlands)

    Verhage, B.A.J.; Cremers, P.; Schouten, L.J.; Goldbohm, R.A.; Brandt, P.A. van den

    2012-01-01

    Purpose: The aim of the present study was to examine the association between intake of folate, and specific folate vitamers, and the risk of advanced and total prostate cancer. Methods: The association between dietary folate and prostate cancer risk was evaluated in The Netherlands Cohort Study (NLC

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

    Science.gov (United States)

    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…

  19. Genes involved in Drosophila glutamate receptor expression and localization

    Directory of Open Access Journals (Sweden)

    Featherstone David E

    2005-06-01

    Full Text Available Abstract Background A clear picture of the mechanisms controlling glutamate receptor expression, localization, and stability remains elusive, possibly due to an incomplete understanding of the proteins involved. We screened transposon mutants generated by the ongoing Drosophila Gene Disruption Project in an effort to identify the different types of genes required for glutamate receptor cluster development. Results To enrich for non-silent insertions with severe disruptions in glutamate receptor clustering, we identified and focused on homozygous lethal mutants in a collection of 2185 BG and KG transposon mutants generated by the BDGP Gene Disruption Project. 202 lethal mutant lines were individually dissected to expose glutamatergic neuromuscular junctions, stained using antibodies that recognize neuronal membrane and the glutamate receptor subunit GluRIIA, and viewed using laser-scanning confocal microscopy. We identified 57 mutants with qualitative differences in GluRIIA expression and/or localization. 84% of mutants showed loss of receptors and/or clusters; 16% of mutants showed an increase in receptors. Insertion loci encode a variety of protein types, including cytoskeleton proteins and regulators, kinases, phosphatases, ubiquitin ligases, mucins, cell adhesion proteins, transporters, proteins controlling gene expression and protein translation, and proteins of unknown/novel function. Expression pattern analyses and complementation tests, however, suggest that any single mutant – even if a mutant gene is uniquely tagged – must be interpreted with caution until the mutation is validated genetically and phenotypically. Conclusion Our study identified 57 transposon mutants with qualitative differences in glutamate receptor expression and localization. Despite transposon tagging of every insertion locus, extensive validation is needed before one can have confidence in the role of any individual gene. Alternatively, one can focus on the

  20. Bioavailability of folate from fortified milk products

    NARCIS (Netherlands)

    Verwei, M.

    2004-01-01

    The gap between actual intake and recommended intake of folate could be bridged by the consumption of fortified food products. Milk is considered as a potential food matrix for folate fortification in countries (such as the«

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  1. Folate and brain function in the elderly

    Science.gov (United States)

    PURPOSE OF REVIEW: Over the past several decades, folate has emerged as an important nutrient in several key conditions of concern to the elderly. Subclinical levels of folate inadequacy can have significant negative impacts on health in older individuals. RECENT FINDINGS: Serum and red blood cell...

  2. Folate and age-related disease

    NARCIS (Netherlands)

    Durga, J.

    2004-01-01

    Aging is associated with increased risk of cardiovascular and neurodegenerative disorders and an increase in their risk factors, such as decreased concentrations of folate and increased concentrations of homocysteine. The association of folate and homocysteine with age-related disease and, most impo

  3. Prostaglandin F receptor expression in intrauterine tissues of pregnant rats

    Science.gov (United States)

    Kanca, Halit; Yar, Atiye Seda; Helvacioğlu, Fatma; Menevşe, Sevda; Çalgüner, Engin; Erdoğan, Deniz

    2014-01-01

    In this investigation, we studied the expression and localization of rat prostaglandin F (FP) receptor in uterine tissues of rats on gestational Days 10, 15, 18, 20, 21, 21.5 and postpartal Days 1 and 3 using Western blotting analysis, real-time PCR, and immunohistochemistry. A high level of immunoreactivity was observed on gestational Days 20, 21, and 21.5 with the most significant signals found on Day 20. FP receptor protein was expressed starting on gestational Day 15, and a fluctuating unsteady increase was observed until delivery. Uterine FP receptor mRNA levels were low between Days 10 and 18 of gestation (p < 0.05). The transcript level increased significantly on Day 20 and peaked on Day 21.5 just before labor (p < 0.05). There was a positive correlation between FP receptor mRNA expression and serum estradiol levels (rs = 0.78; p < 0.01) along with serum estradiol/progesterone ratios (rs = 0.79; p < 0.01). In summary, we observed an increase FP receptor expression in rat uterus with advancing gestation, a marked elevation of expression at term, and a concominant decrease during the postpartum period. These findings indicate a role for uterine FP receptors in the mediation of uterine contractility at term. PMID:24136214

  4. Serotonin receptors expressed in Drosophila mushroom bodies differentially modulate larval locomotion.

    Directory of Open Access Journals (Sweden)

    Bryon Silva

    Full Text Available Drosophila melanogaster has been successfully used as a simple model to study the cellular and molecular mechanisms underlying behaviors, including the generation of motor programs. Thus, it has been shown that, as in vertebrates, CNS biogenic amines (BA including serotonin (5HT participate in motor control in Drosophila. Several evidence show that BA systems innervate an important association area in the insect brain previously associated to the planning and/or execution of motor programs, the Mushroom Bodies (MB. The main objective of this work is to evaluate the contribution of 5HT and its receptors expressed in MB to motor behavior in fly larva. Locomotion was evaluated using an automated tracking system, in Drosophila larvae (3(rd-instar exposed to drugs that affect the serotonergic neuronal transmission: alpha-methyl-L-dopa, MDMA and fluoxetine. In addition, animals expressing mutations in the 5HT biosynthetic enzymes or in any of the previously identified receptors for this amine (5HT1AR, 5HT1BR, 5HT2R and 5HT7R were evaluated in their locomotion. Finally, RNAi directed to the Drosophila 5HT receptor transcripts were expressed in MB and the effect of this manipulation on motor behavior was assessed. Data obtained in the mutants and in animals exposed to the serotonergic drugs, suggest that 5HT systems are important regulators of motor programs in fly larvae. Studies carried out in animals pan-neuronally expressing the RNAi for each of the serotonergic receptors, support this idea and further suggest that CNS 5HT pathways play a role in motor control. Moreover, animals expressing an RNAi for 5HT1BR, 5HT2R and 5HT7R in MB show increased motor behavior, while no effect is observed when the RNAi for 5HT1AR is expressed in this region. Thus, our data suggest that CNS 5HT systems are involved in motor control, and that 5HT receptors expressed in MB differentially modulate motor programs in fly larvae.

  5. Quantifying folate bioavailability: a critical appraisal of methods

    NARCIS (Netherlands)

    Boonstra, A.; Verhoef, P.; West, C.E.

    2004-01-01

    Purpose of review Dietary reference intakes for folate rely on a good estimate of folate bioavailability from the general diet. In this review, current methods for quantifying the bioavailability of dietary folate and specific folate vitamers in humans are reviewed. Emphasis is on isotopic labeling

  6. Increased production of folate by metabolic engineering of Lactococcus lactis

    NARCIS (Netherlands)

    Sybesma, W.F.H.; Starrenburg, M.; Kleerebezem, M.; Mierau, I.; Vos, de W.M.; Hugenholtz, J.

    2003-01-01

    The dairy starter bacterium Lactococcus lactis is able to synthesize folate and accumulates large amounts of folate, predominantly in the polyglutamyl form. Only small amounts of the produced folate are released in the extracellular medium. Five genes involved in folate biosynthesis were identified

  7. HUMAN ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTORS EXPRESSED IN XENOPUS OOCYTES ARE INHIBITED BY TRICHLOROETHYLENE.

    Science.gov (United States)

    Trichloroethylene (TCE) is a volatile organic solvent (VOC) that is used as a metal degreasing agent and in paints and glue. In addition to being a commonly abused inhalant, run-off from hazardous waste sites contain enough TCE and other VOCs to contaminate ground water and near...

  8. Protein expression in response to folate stress in Escherichia coli.

    OpenAIRE

    Huang, E Y; Mohler, A M; Rohlman, C E

    1997-01-01

    Interruption of folate metabolism by trimethoprim results in the elevated expression of folate stress proteins in Escherichia coli. E. coli grown in culture medium supplemented with the folate-dependent metabolites glycine, methionine, and the purine nucleoside inosine shows reduced expression of folate stress proteins. The folate stress proteins include the universal stress protein, the ferric uptake regulatory repressor, and possibly, lipoamide dehydrogenase, the L protein component of the ...

  9. DMPD: G-protein-coupled receptor expression, function, and signaling in macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17456803 G-protein-coupled receptor expression, function, and signaling in macropha...2007 Apr 24. (.png) (.svg) (.html) (.csml) Show G-protein-coupled receptor expression, function, and signali...ng in macrophages. PubmedID 17456803 Title G-protein-coupled receptor expression,

  10. Dopamine receptor expression and function in corticotroph pituitary tumors.

    Science.gov (United States)

    Pivonello, Rosario; Ferone, Diego; de Herder, Wouter W; Kros, Johan M; De Caro, Maria Laura Del Basso; Arvigo, Marica; Annunziato, Lucio; Lombardi, Gaetano; Colao, Annamaria; Hofland, Leo J; Lamberts, Steven W J

    2004-05-01

    The role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D(2) receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion and the in vivo effect of short-term cabergoline treatment on cortisol secretion. D(2) expression was evaluated by receptor-ligand binding, immunohistochemistry, and RT-PCR. A 50% or more decrease in daily urinary cortisol levels was considered a significant clinical response. At receptor-ligand binding, specific binding of [(125)I]epidepride was found in 80% of cases. At immunohistochemistry, specific D(2) immunostaining was found in 75% of cases. D(2) expression was found in 83.3% of cases (D(2long) in 40%, D(2short) in 20%, and both in 40%) by RT-PCR. Significant in vitro inhibition of ACTH secretion was found in 100% of D(2)-positive cases, but not in 100% of D(2)-negative cases by either bromocriptine or cabergoline. A significant in vivo inhibition of cortisol secretion after 3-month cabergoline treatment was found in 60%, although a normalization of cortisol secretion was found in 40% of cases. All cabergoline-responsive cases were associated with D(2) expression, whereas all noncabergoline-responsive cases but one were not associated with D(2) expression. In conclusion, functional D(2) receptors were expressed in approximately 80% of corticotroph pituitary tumors. The effectiveness of cabergoline in normalizing cortisol secretion in 40% of cases supports its therapeutic use in the management of Cushing's disease. PMID:15126577

  11. Folate Metabolism and Human Reproduction

    Science.gov (United States)

    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

  12. [Dairy products as source of folates].

    Science.gov (United States)

    Kowalska, Marika; Cichosz, Grazyna

    2014-04-01

    Dairy products, especially yoghurts and blue cheeses, are underestimated source of folates in human diet. Though foliates content in dairy products is lower than in vegetables and cereals, nevertheless their bioavailability and stability is much better. High folate stability results from presence of hydro- and lipophylic antioxidants efficiently protecting folates and other bioactive compounds against oxidation processes on synergic way. On the other hand, high bioavailability is a consequence of folic appearing in milk mainly in form of mono glutamates and also of a presence of a protein ready to bind folates (FBP--folic binding protein). FBP makes easier folates transport through cell membranes. Moreover, present in milk sphingolipids and cholesterol stimulate activity of FBP. Mould cheeses and milk fermented beverages contain the highest amount of folates. However, cottage cheese contain considerable amount of folic binding protein. Regular consumption of milk fermented beverages and eating them together with vegetables and fruits rich in folates is a chance to increase covering of folic demand. PMID:24868906

  13. Folate and Alzheimer: when time matters.

    Science.gov (United States)

    Hinterberger, Margareta; Fischer, Peter

    2013-01-01

    Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and β-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (≥ 2 years RCT; ≥ 4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably "misleading"(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies-epidemiologic and interventional-starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for-like neural tube defects-hopefully declining AD incidence and disproving safety concerns. PMID:22627695

  14. Functional coating of liposomes using a folate–polymer conjugate to target folate receptors

    OpenAIRE

    Watanabe K.; Kaneko M; Maitani Y

    2012-01-01

    Kazuo Watanabe, Makoto Kaneko, Yoshie MaitaniInstitute of Medical Chemistry, Hoshi University, Tokyo, JapanAbstract: Folate-polymer-coated liposomes were developed for targeted chemotherapy using doxorubicin (DXR) as a model drug. Folate-poly(L-lysine) (F–PLL) conjugates with a folate modification degree of 16.7 mol% on epsilon amino groups of PLL were synthesized. DXR-loaded anionic liposomes were coated with F–PLL, and the cellular association of F–PLL-coated l...

  15. Epidermal growth factor receptor expression in triple negative and nontriple negative breast carcinomas

    Directory of Open Access Journals (Sweden)

    Arathi A Changavi

    2015-01-01

    Conclusion: EGFR is an important marker to stratify patients with breast cancer according to molecular classification. Its expression correlated positively with young age, higher SBR grade, necrosis, lymphocytic infiltrate and inversely with hormonal receptor expression.

  16. Hypothyroidism Affects D2 Receptor-mediated Breathing without altering D2 Receptor Expression

    OpenAIRE

    Schlenker, Evelyn H; Rio, Rodrigo Del; Schultz, Harold D.

    2014-01-01

    Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age- matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a periphera...

  17. Chemokine receptor expression by inflammatory T cells in EAE.

    Science.gov (United States)

    Mony, Jyothi Thyagabhavan; Khorooshi, Reza; Owens, Trevor

    2014-01-01

    Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS). The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS). The CCL20 receptor CCR6 has been reported to be selectively expressed by CD4(+) T cells that produce the cytokine IL-17 (Th17 cells). Th17 cells and interferon-gamma (IFNγ)-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE). We have assessed whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4(+) T cells produced IFNγ in flow cytometric cytokine assays, whereas less than 1% produced IL-17. About 1% of CD4(+) T cells produced both cytokines. CCR6 was expressed by Th1, Th1+17 and by Th17 cells, but not by CD8(+) T cells. CD8(+) T cells expressed CXCR3, which was also expressed by CD4(+) T cells, with no correlation to cytokine profile. Messenger RNA for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6(+) and CXCR3(+) CD4(+) T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8(+) T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double immunofluorescence. Consistent with flow cytometry data some but not all CD4(+) T cells expressed CCR6 within infiltrates. CD4-negative CCR6(+) cells included macrophage/microglial cells. Thus we have for the first time directly studied CD4(+) and CD8(+) T cells in the CNS of mice with peak EAE, and determined IFNγ and IL17 expression by cells expressing CCR6 and CXCR3. We show that neither CCR6 or CXCR3 align with CD4 T cell subsets, and Th1 or mixed Th1+17 predominate in EAE.

  18. Neurotrophin receptors expression and JNK pathway activation in human astrocytomas

    International Nuclear Information System (INIS)

    Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane – receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (~1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor grade

  19. Chemokine receptor expression by inflammatory T cells in EAE

    Directory of Open Access Journals (Sweden)

    Jyothi Thyagabhavan Mony

    2014-07-01

    Full Text Available Chemokines direct cellular infiltration to tissues, and their receptors and signaling pathways represent targets for therapy in diseases such as multiple sclerosis (MS. The chemokine CCL20 is expressed in choroid plexus, a site of entry of T cells to the central nervous system (CNS. The CCL20 receptor CCR6 has been reported to be selectively expressed by CD4+ T cells that produce the cytokine IL-17 (Th17 cells. Th17 cells and interferon-gamma (IFNγ-producing Th1 cells are implicated in induction of MS and its animal model experimental autoimmune encephalomyelitis (EAE. We have assessed whether CCR6 identifies specific inflammatory T cell subsets in EAE. Our approach was to induce EAE, and then examine chemokine receptor expression by cytokine-producing T cells sorted from CNS at peak disease. About 7% of CNS-infiltrating CD4+ T cells produced IFNγ in flow cytometric cytokine assays, whereas less than 1% produced IL-17. About 7.7% of CD4+ T cells produced both cytokines. CCR6 was expressed by Th1, Th1+17 and by Th17 cells, but not by CD8+ T cells. CD8+ T cells expressed CXCR3, which was also expressed by CD4+ T cells, with no correlation to cytokine profile. Messenger RNA for IFNγ, IL-17A, and the Th1 and Th17-associated transcription factors T-bet and RORγt was detected in both CCR6+ and CXCR3+ CD4+ T cells. IFNγ, but not IL-17A mRNA expression was detected in CD8+ T cells in CNS. CCR6 and CD4 were co-localized in spinal cord infiltrates by double immunofluorescence. Consistent with flow cytometry data some but not all CD4+ T cells expressed CCR6 within infiltrates. CD4-negative CCR6+ cells included macrophage/microglial cells. Thus we have for the first time directly studied CD4+ and CD8+ T cells in the CNS of mice with peak EAE, and determined IFNγ and IL17 expression by cells expressing CCR6 and CXCR3. We show that neither CCR6 or CXCR3 align with CD4 T cell subsets, and Th1 or mixed Th1+17 predominate in EAE.

  20. Genetics Home Reference: hereditary folate malabsorption

    Science.gov (United States)

    ... Children Living with Inherited Metabolic Diseases (CLIMB) National Organization for Rare Disorders (NORD): Megaloblastic ... Andrews NC. When is a heme transporter not a heme transporter? When it's a folate transporter. Cell Metab. 2007 Jan;5(1):5-6. Citation ...

  1. Folate Deficiency in Chronic Pancreatitis

    Directory of Open Access Journals (Sweden)

    Gopalakrishna Rajesh

    2010-07-01

    Full Text Available Dear Sir, While there has been a spurt of interest in genetic alterations associated with pancreatitis in the past few years, interest in the role of environmental factors has largely focused on alcoholism and smoking with insufficient attention being paid to the contributions of nutritional deficiency, and the role of environmental toxins in the pathogenesis of pancreatitis. Braganza and Dormandy [1] argue convincingly about the role played by cytochrome P450 monooxygenases (especially CYP1A enzyme induction by xenobiotics and the resultant oxidative stress, as also the now increasingly recognized reductive stress posed by the metabolites in initiating pancreatic injury. Their article underlines the important part played by the deficiency of methyl and thiol molecules in different stages of the progression of pancreatic damage. Furthermore, they attempt to establish a link between environmental and genetic factors and bring in a holistic view on the etiopathogenesis of chronic pancreatitis. We have recently demonstrated lower plasma methionine levels in two cohorts of chronic pancreatitis patients; one of tropical chronic pancreatitis and the other, of alcoholic chronic pancreatitis as compared to healthy controls [2] which suggests that deficiency of methyl groups may be a factor in various forms of pancreatitis. Similarly, we have shown lower red cell glutathione levels in chronic pancreatitis patients with tropical chronic pancreatitis and alcoholic chronic pancreatitis, indicating deficiency of thiol molecules. In addition, we have demonstrated significantly higher levels of plasma total homocysteine in chronic pancreatitis patients than in healthy controls. Moreover, our study has shown that there is a deficiency of red cell folate in the majority of chronic pancreatitis patients, more so in tropical chronic pancreatitis; and that folate deficiency appeared to be the key factor in hyperhomocysteinemia in chronic pancreatitis patients

  2. Folate status and health: challenges and opportunities.

    Science.gov (United States)

    Obeid, Rima; Oexle, Konrad; Rißmann, Anke; Pietrzik, Klaus; Koletzko, Berthold

    2016-04-01

    Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia. PMID:25825915

  3. The role of the cell cycle in the cellular uptake of folate-modified poly(l-amino acid) micelles in a cell population

    Science.gov (United States)

    Tang, Jihui; Liu, Ziwei; Ji, Fenqi; Li, Yao; Liu, Junjie; Song, Jian; Li, Jun; Zhou, Jianping

    2015-12-01

    Nanoparticles are widely recognized as a vehicle for tumor-targeted therapies. There are many factors that can influence the uptake of nanoparticles, such as the size of the nanoparticles, and/or their shape, elasticity, surface charge and even the cell cycle phase. However, the influence of the cell cycle on the active targeting of a drug delivery system has been unknown until now. In this study, we initially investigated the folate receptor α (FR-α) expression in different phases of HeLa cells by flow cytometric and immunocytochemical methods. The results obtained showed that FR-α expression was cell cycle-dependent, i.e. the S cells' folate receptor expression was the highest as the cell progressed through its cycle. Then, we used folate modified poly(l-amino acid) micelles (FA-PM) as an example to investigate the influence of the cell cycle on the active targeting drug delivery system. The results obtained indicated that the uptake of FA-PM by cells was influenced by the cell cycle phase, and the S cells took up the greatest number of folate conjugated nanoparticles. Our findings suggest that future studies on ligand-mediated active targeting preparations should consider the cell cycle, especially when this system is used for a cell cycle-specific drug.

  4. Dietary folate and folate vitamers and the risk of pancreatic cancer in the Netherlands cohort study

    NARCIS (Netherlands)

    Keszei, A.P.; Verhage, B.A.J.; Heinen, M.M.; Goldbohm, R.A.; Brandt, P.A. van den

    2009-01-01

    An association between high intake of folate and reduced risk of cancer has been suggested by previous research. However, epidemiologic data from cohort studies regarding the relationship between dietary folate and pancreatic cancer are sparse and inconsistent. We examined the association between di

  5. Study on folate receptor PET imaging agent 18F-flurophenethyl folate

    International Nuclear Information System (INIS)

    This work is aimed at synthesizing an 18F-labelled folate derivative that can be used as folate-receptor induced tumor PET imaging agent. Under the optimal reaction and testing specification formulated during the cold-labeling experiments, 18F labeling of folic acid was achieved in three steps of 18F pre-labeling,bromination and esterification. The receptor binding property of the newly-synthesized folate radio-derivative was studied through β-lactoglobulin binding test. Tumor-bearing nude mice injected with the new compound were used to study whether the derivative can accumulate within tumor issue. Preliminary studies in vitro and in vivo showed that this new PET agent still possessed receptor binding qualities of folic acid. 18F-flurophenethyl folate remained good affinity and specificity with β-lactoglobulin. Accumulation of activities in tumor tissues was found in tumor-bearing nude mice. A new folate receptor ligand: 18F-flurophenethyl folate was synthesized,with high yield and good stability. Since the pre-labeling method was used, the fluorine labeling was not directly imposed upon folic acid.In this way, the structure destruction, which happens in high temperature reaction of folic acid, can be avoided. The synthesized folate derivative remained the binding structural quality of folic acid and could bind with the folate-binding protein: β-lactoglobulin. Through the folate receptors located on tumor tissues, 18F-flurophenethyl folate accumulated in the tumor tissue, exhibiting its potential as a tumor PET imaging agent. (authors)

  6. Aberrant folate status in schizophrenic patients: what is the evidence?

    NARCIS (Netherlands)

    Muntjewerff, J.W.; Blom, H.J.

    2005-01-01

    A vast amount of case reports, open studies and, to a lesser extent, case-control studies have been published on the topic of psychopathology and folate deficiency. These studies reported a high incidence of serum folate deficiency in patients with various psychiatric disorders. Folate deficiency se

  7. Identiifcation of QTLs Underlying Folate Content in Milled Rice

    Institute of Scientific and Technical Information of China (English)

    DONG Wei; CHENG Zhi-jun; XU Jian-long; ZHENG Tian-qing; WANG Xiao-le; ZHANG Hong-zheng; WANG Jie; WAN Jian-min

    2014-01-01

    Understanding the genetic mechanism underlying folate biosynthesis and accumulation in rice would be beneifcial for breeding high folate content varieties as a cost-effective approach to addressing widespread folate deifciency in developing countries. In this study, the inheritance of rice grain folate content was investigated in the Lemont/Teqing recombinant inbred lines and the Koshihikari/Kasalath//Koshihikari backcross inbred lines. 264 F12 recombinant inbred lines (RILs) and 182 BC1F10 backcross inbred lines (BILs) with their parents planted in randomized complete blocks with two replicates in 2010, and RILs harvested in 2008 were used for QTL detection using inclusive composite interval mapping (ICIM) method. In the RIL population, two QTLs, denoted by qQTF-3-1and qQTF-3-2(QTF, quantitative total folate), explaining 7.8% and 11.1-15.8% of the folate content variation were detected in one or two years, respectively. In the BIL population, a QTL, denoted by qQTF-3-3,was detected, explaining 25.3% of the variation in folate content. All the positive alleles for higher folate content were from the high-folate parents, i.e., Teqing and Kasalath. The known putative folate biosynthesis genes do not underlie the QTLs detected in this study andtherefore may be novel loci affecting folate content in milled rice. QTLs identiifed in this study have potential value for marker assisted breeding for high-folate rice variety.

  8. Folate Metabolism and the Risk of Down Syndrome

    Science.gov (United States)

    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…

  9. The glycophospholipid-linked folate receptor internalizes folate without entering the clathrin-coated pit endocytic pathway

    OpenAIRE

    1990-01-01

    The folate receptor, also known as the membrane folate-binding protein, is maximally expressed on the surface of folate-depleted tissue culture cells and mediates the high affinity accumulation of 5- methyltetrahydrofolic acid in the cytoplasm of these cells. Recent evidence suggests that this receptor recycles during folate internalization and that it is anchored in the membrane by a glycosyl- phosphatidylinositol linkage. Using quantitative immunocytochemistry, we now show that (a) this rec...

  10. How well do blood folate concentrations predict dietary folate intakes in a sample of Canadian lactating women exposed to high levels of folate? An observational study

    Directory of Open Access Journals (Sweden)

    Sherwood Kelly L

    2007-10-01

    Full Text Available Abstract Background In 1998, mandatory folic acid fortification of white flour and select cereal grain products was implemented in Canada with the intention to increase dietary folate intakes of reproducing women. Folic acid fortification has produced a dramatic increase in blood folate concentrations among reproductive age women, and a reduction in neural tube defect (NTD-affected pregnancies. In response to improved blood folate concentrations, many health care professionals are asking whether a folic acid supplement is necessary for NTD prevention among women with high blood folate values, and how reliably high RBC folate concentrations predict folate intakes shown in randomized controlled trials to be protective against NTDs. The objective of this study was to determine how predictive blood folate concentrations and folate intakes are of each other in a sample of well-educated lactating Canadian women exposed to high levels of synthetic folate. Methods The relationship between blood folate concentrations and dietary folate intakes, determined by weighed food records, were assessed in a sample of predominantly university-educated lactating women (32 ± 4 yr at 4-(n = 53 and 16-wk postpartum (n = 55. Results Median blood folate concentrations of all participants were well above plasma and RBC folate cut-off levels indicative of deficiency (6.7 and 317 nmol/L, respectively and all, except for 2 subjects, were above the cut-off for NTD-risk reduction (>906 nmol/L. Only modest associations existed between total folate intakes and plasma (r = 0.46, P P nd quartile of intake did not differ from that of women consuming >410 μg/d (3rd and 4th quartile. Conclusion Folate intakes, estimated by food composition tables, and blood folate concentrations are not predictive of each other in Canadian lactating women exposed to high levels of folate. Synthetic intakes > 151–410 μg/d in these women produced little additional benefit in terms of maximizing

  11. Studies on folate binding and a radioassay for serum and whole blood folate using goat milk as binding agent

    International Nuclear Information System (INIS)

    Preparations of cow, goat, buffalo, and human milk in addition to pig plasma were tested for folate binding properties. Of these, only pig plasma and goat milk showed sufficient binding to enable use as binding agents in a radioassay for serum and whole blood folate. The binding of folate by cow mild preparations in particular was found to be very poor. (orig.)

  12. Estrogen and Progesterone hormone receptor expression in oral cavity cancer

    Science.gov (United States)

    Biegner, Thorsten; Teriete, Peter; Hoefert, Sebastian; Krimmel, Michael; Munz, Adelheid; Reinert, Siegmar

    2016-01-01

    Background Recent studies have shown an increase in the incidence of oral squamous cell carcinoma (OSCC) in younger patients. The hypothesis that tumors could be hormonally induced during pregnancy or in young female patients without the well-known risk factors alcohol or tobacco abuse seems to be plausible. Material and Methods Estrogen Receptor alpha (ERα) and Progesterone Receptor (PR) expression were analyzed in normal oral mucosa (n=5), oral precursor lesions (simple hyperplasia, n=11; squamous intraepithelial neoplasia, SIN I-III, n=35), and OSCC specimen. OSCCs were stratified in a young female (n=7) study cohort and older patients (n=46). In the young female study cohort three patients (n=3/7) developed OSCC during or shortly after pregnancy. Breast cancer tissues were used as positive control for ERα and PR expression. Results ERα expression was found in four oral precursor lesions (squamous intraepithelial neoplasia, SIN I-III, n=4/35, 11%) and in five OSCC specimen (n=5/46, 11%). The five ERα positive OSCC samples were older male patients. All patients within the young female study cohort were negatively stained for both ERα and PR. Conclusions ER expression could be regarded as a seldom risk factor for OSCC. PR expression seems to be not relevant for the development of OSCC. Key words:Oral squamous cell carcinoma, estrogen receptor, progesterone receptor, hormone receptor. PMID:27475696

  13. Intracellular folate distribution in cultured fibroblasts from patients with the fragile X syndrome.

    OpenAIRE

    Popovich, B W; Rosenblatt, D S; Cooper, B. A.; Vekemans, M

    1983-01-01

    Altered folate metabolism has been suggested as a possible reason for expression of the fragile X chromosome in low-folate medium. However, there were no significant differences in the total folate content or in the distribution of folate cofactors between fibroblasts from patients with the fragile X chromosome and those of controls both before and after a period of folate starvation. Fragile X and control fibroblasts lose folate at an equivalent rate. Insofar as folate content and distributi...

  14. Assessing the Association between Natural Food Folate Intake and Blood Folate Concentrations: A Systematic Review and Bayesian Meta-Analysis of Trials and Observational Studies

    OpenAIRE

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

  15. Effect of germination and thermal treatments on folates in rye.

    Science.gov (United States)

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

    2006-12-13

    Effects of germination conditions and thermal processes on folate contents of rye were investigated. Total folate contents were determined microbiologically with Lactobacillus rhamnosus (ATCC 7469) as the growth indicator organism, and individual folates were determined by high-performance liquid chromatography after affinity chromatographic purification. Germination increased the folate content by 1.7-3.8-fold, depending on germination temperature, with a maximum content of 250 micro g/100 g dry matter. Hypocotylar roots with their notably high folate concentrations (600-1180 micro g/100 g dry matter) contributed 30-50% of the folate contents of germinated grains. Germination altered the proportions of folates, increasing the proportion of 5-methyltetrahydrofolate and decreasing the proportion of formylated folate compounds. Thermal treatments (extrusion, autoclaving and puffing, and IR and toasting) resulted in significant folate losses. However, folate levels in grains that were germinated and then were heat processed were higher than for native (nongerminated) grains. Opportunities to optimize rye processing to enhance folate levels in rye-based foods are discussed. PMID:17147441

  16. Soluble triggering receptor expressed on myeloid cells 1: a biomarker for bacterial meningitis

    NARCIS (Netherlands)

    R.M. Determann; M. Weisfelt; J. de Gans; A. van der Ende; M.J. Schultz; D. van de Beek

    2006-01-01

    Objective: To evaluate whether soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in CSF can serve as a biomarker for the presence of bacterial meningitis and outcome in patients with this disease. Design: Retrospective study of diagnostic accuracy. Setting and patients: CSF was coll

  17. Androgen, estrogen and progesterone receptor expression in the human uterus during the menstrual cycle

    NARCIS (Netherlands)

    Mertens, HJMM; Heineman, MJ; Theunissen, PHMH; de Jong, FH; Evers, JLH

    2001-01-01

    Cyclic changes in steroid receptor expression in endometrial cells are considered a reflection of its differential functions. Besides estrogen and progestogens, androgens have also been suggested to affect the biological function of the female reproductive tract. We investigated the distribution and

  18. Preclinical evaluation of radiolabeled DOTA-derivatized cyclic minigastrin analogs for targeting cholecystokinin receptor expressing malignancies.

    NARCIS (Netherlands)

    Guggenberg, E. von; Rangger, C.; Sosabowski, J.; Laverman, P.; Reubi, J.C.; Virgolini, I.J.; Decristoforo, C.

    2012-01-01

    PURPOSE: Targeting of cholecystokinin receptor expressing malignancies such as medullary thyroid carcinoma is currently limited by low in vivo stability of radioligands. To increase the stability, we have developed and preclinically evaluated two cyclic 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraa

  19. Iron and Folate-Deficiency Anaemias.

    Science.gov (United States)

    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…

  20. Folate, vitamin B12 and human health

    Science.gov (United States)

    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...

  1. Methylenetetrahydrofolate Reductase Activity and Folate Metabolism

    Directory of Open Access Journals (Sweden)

    Nursen Keser

    2014-04-01

    Full Text Available Folate is a vital B vitamin which is easily water-soluble. It is a natural source which is found in the herbal and animal foods. Folate has important duties in the human metabolism, one of them is the adjustment of the level of plasma homocysteine. Reduction in MTHFR (methylenetetrahydrofolate reductase,which is in charge of the metabolism of homocysteine activity affects the level of homocysteine. Therefore MTHFR is an important enzyme in folate metabolism. Some of the mutations occurring in the MTHFR gene is a risk factor for various diseases and may be caused the hyperhomocysteinemia or the homocystinuria, and they also may lead to metabolic problems. MTHFR is effective in the important pathways such as DNA synthesis, methylation reactions and synthesis of RNA. C677T and A1298C are the most commonly occurring polymorphisms in the gene of MTHFR. The frequency of these polymorphisms show differences in the populations. MTHFR, folate distribution, metabolism of homocysteine and S-adenosylmethionine, by the MTHFR methylation the genetic defects have the potential of affecting the risk of disease in the negative or positive way.

  2. Validation of a food frequency questionnaire to assess folate intake of Dutch elderly people

    NARCIS (Netherlands)

    Rest, van de O.; Durga, J.; Verhoef, P.; Boonstra, A.; Brants, H.A.M.

    2007-01-01

    Folate is required for 1-carbon metabolism and deficiency in folate leads to megaloblastic anemia. Low levels of folate have been associated with increased risk of vascular disease. To investigate whether RDA of folate are met, habitual folate intake needs to be assessed reliably. We developed a FFQ

  3. Memory consolidation and amnesia modify 5-HT6 receptors expression in rat brain: an autoradiographic study.

    Science.gov (United States)

    Meneses, A; Manuel-Apolinar, L; Castillo, C; Castillo, E

    2007-03-12

    Traditionally, the search for memory circuits has been centered on examinations of amnesic and AD patients, cerebral lesions and, neuroimaging. A complementary alternative might be the use of autoradiography with radioligands. Indeed, ex vivo autoradiographic studies offer the advantage to detect functionally active receptors altered by pharmacological tools and memory formation. Hence, herein the 5-HT(6) receptor antagonist SB-399885 and the amnesic drugs scopolamine or dizocilpine were used to manipulate memory consolidation and 5-HT(6) receptors expression was determined by using [(3)H]-SB-258585. Thus, memory consolidation was impaired in scopolamine and dizocilpine treated groups relative to control vehicle but improved it in SB-399885-treated animals. SB-399885 improved memory consolidation seems to be associated with decreased 5-HT(6) receptors expression in 15 out 17 brain areas. Scopolamine or dizocilpine decreased 5-HT(6) receptors expression in nine different brain areas and increased it in CA3 hippocampus or other eight areas, respectively. In brain areas thought to be in charge of procedural memory such basal ganglia (i.e., nucleus accumbens, caudate putamen, and fundus striate) data showed that relative to control animals amnesic groups showed diminished (scopolamine) or augmented (dizocilpine) 5-HT(6) receptor expression. SB-399885 showing improved memory displayed an intermediate expression in these same brain regions. A similar intermediate expression occurs with regard to amygdala, septum, and some cortical areas in charge of explicit memory storage. However, relative to control group amnesic and SB-399885 rats in the hippocampus, region where explicit memory is formed, showed a complex 5-HT(6) receptors expression. In conclusion, these results indicate neural circuits underlying the effects of 5-HT(6) receptor antagonists in autoshaping task and offer some general clues about cognitive processes in general. PMID:17267053

  4. Folate inadequacy in the diet of pregnant women

    Directory of Open Access Journals (Sweden)

    Lívia de Castro Crivellenti

    2014-06-01

    Full Text Available OBJECTIVE: To estimate food and dietary folate inadequacies in the diets of adult pregnant women. METHODS: A prospective study was conducted with 103 healthy pregnant adult users of the Public Health Care System of Ribeirão Preto, São Paulo, Brazil. The present study included the 82 women with complete food intake data during pregnancy, which were collected by three 24-hour dietary recalls. Food folate (folate naturally present in foods and dietary folate (food folate plus folate from fortified wheat flour and cornmeal inadequacies were determined, using the Estimated Average Requirement as cutoff. RESULTS: The diets of 100% and 94% of the pregnant women were inadequate in food folate and dietary folate, respectively. However, fortified foods increased the medium availability of the nutrient by 87%. CONCLUSION: The large number of pregnant women consuming low-folate diets was alarming. Nationwide population studies are needed to confirm the hypothesized high prevalence of low-folate diets among pregnant women.

  5. Influence of folic acid-fortified foods on folate status in a folate depletion-repletion rat model.

    Science.gov (United States)

    O'Leary, K; Sheehy, P J

    2001-04-01

    An increasing number of foods fortified with varying levels of folic acid are appearing in the market place, targeted either at the general population or at specific consumer groups. Although it is assumed that the folate in these products should be highly bioavailable, there is a need to carry out studies to ascertain that this is, in fact, the case. The present study investigated the ability of selected folic acid-fortified foods (targeted at different types of consumer) to increase the folate status of folate-deficient rats. Forty-two weanling male rats (Wistar strain) were fed a folate-deficient diet containing 1 % succinyl sulfathiazole (w/w) for 28 d. Following depletion, seven rats were randomly assigned to each of five repletion diets containing folic acid, Complan, Slim Fast, Opti-Fuel2 or Cola Coa calculated to provide 200 microg folate/kg of each diet. Calculations were based on folate information from the product labels. After a further 28 d, plasma, liver and kidney folate concentrations were determined by microbiological assay. Plasma homocysteine was measured by HPLC as a functional indicator of folate status. The folate content of the foods was measured by tri-enzyme extraction followed by microbiological assay. Our analyses suggest that there may be considerable inaccuracies on the part of the manufacturers in relation to the folate declarations on the product labels. Despite this, the four foods evaluated were highly effective in elevating plasma, liver and kidney folate and lowering plasma homocysteine concentrations in rats. These results lend support to the policy of food fortification with folic acid as a means of raising the folate status of the population, and in particular to the fortification of specific foods which may target areas of the population where increased folate status is most needed.

  6. Comparison of albumin receptors expressed on bovine and human group G streptococci.

    OpenAIRE

    Raeder, R; Otten, R. A.; Boyle, M D

    1991-01-01

    The albumin receptor expressed by bovine group G streptococci was extracted and affinity purified. The protein was characterized for species reactivity, and monospecific antibodies were prepared to the purified receptor. The bovine group G albumin receptor was compared functionally, antigenically, and for DNA homology with the albumin-binding protein expressed by human group G streptococci. In agreement with previous reports, the albumin-binding activity of human strains was mediated by a uni...

  7. Repeated Stress Causes Cognitive Impairment by Suppressing Glutamate Receptor Expression and Function in Prefrontal Cortex

    OpenAIRE

    Yuen, Eunice Y; Wei, Jing; Liu, Wenhua; ZHONG, PING; Li, Xiangning; Yan, Zhen

    2012-01-01

    Chronic stress could trigger maladaptive changes associated with stress-related mental disorders, however, the underlying mechanisms remain elusive. In this study, we found that exposing juvenile male rats to repeated stress significantly impaired the temporal order recognition memory, a cognitive process controlled by prefrontal cortex (PFC). Concomitantly, significantly reduced AMPAR- and NMDAR-mediated synaptic transmission and glutamate receptor expression were found in PFC pyramidal neur...

  8. Lentils (Lens culinaris L.), a rich source of folates.

    Science.gov (United States)

    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. PMID:23865478

  9. Plasticity in D1-like receptor expression is associated with different components of cognitive processes.

    Directory of Open Access Journals (Sweden)

    Christina Herold

    Full Text Available Dopamine D1-like receptors consist of D1 (D1A and D5 (D1B receptors and play a key role in working memory. However, their possibly differential contribution to working memory is unclear. We combined a working memory training protocol with a stepwise increase of cognitive subcomponents and real-time RT-PCR analysis of dopamine receptor expression in pigeons to identify molecular changes that accompany training of isolated cognitive subfunctions. In birds, the D1-like receptor family is extended and consists of the D1A, D1B, and D1D receptors. Our data show that D1B receptor plasticity follows a training that includes active mental maintenance of information, whereas D1A and D1D receptor plasticity in addition accompanies learning of stimulus-response associations. Plasticity of D1-like receptors plays no role for processes like response selection and stimulus discrimination. None of the tasks altered D2 receptor expression. Our study shows that different cognitive components of working memory training have distinguishable effects on D1-like receptor expression.

  10. Oxygen Modulates Human Decidual Natural Killer Cell Surface Receptor Expression and Interactions with Trophoblasts1

    Science.gov (United States)

    Wallace, Alison E.; Goulwara, Sonu S.; Whitley, Guy S.; Cartwright, Judith E.

    2014-01-01

    Decidual natural killer (dNK) cells have been shown to both promote and inhibit trophoblast behavior important for decidual remodeling in pregnancy and have a distinct phenotype compared to peripheral blood NK cells. We investigated whether different levels of oxygen tension, mimicking the physiological conditions of the decidua in early pregnancy, altered cell surface receptor expression and activity of dNK cells and their interactions with trophoblast. dNK cells were isolated from terminated first-trimester pregnancies and cultured in oxygen tensions of 3%, 10%, and 21% for 24 h. Cell surface receptor expression was examined by flow cytometry, and the effects of secreted factors in conditioned medium (CM) on the trophoblast cell line SGHPL-4 were assessed in vitro. SGHPL-4 cells treated with dNK cell CM incubated in oxygen tensions of 10% were significantly more invasive (P oxygen tensions of 3% or 21%. After 24 h, a lower percentage of dNK cells expressed CD56 at 21% oxygen (P oxygen (P oxygen tensions, with large patient variation. This study demonstrates dNK cell phenotype and secreted factors are modulated by oxygen tension, which induces changes in trophoblast invasion and endovascular-like differentiation. Alterations in dNK cell surface receptor expression and secreted factors at different oxygen tensions may represent regulation of function within the decidua during the first trimester of pregnancy. PMID:25232021

  11. Inhibition of epidermal growth factor receptor expression by RNA interference in A549 cells

    Institute of Scientific and Technical Information of China (English)

    MinZHANG; XinZHANG; Chun-xueBAI; JieCHEN; MinQWEI

    2004-01-01

    AIM: To investigate the biological features of A549 cells in which epidermal growth factor (EGF) receptors expression were suppressed by RNA interference (RNAi). METHODS: A549 cells were transfected using short small interfering RNAs (siRNAs) formulated with Lipofectamine 2000. The EGF receptor numbers were determined by Western blotting and flowcytometry. The antiproliferative effects of sequence specific double stranded RNA (dsRNA) were assessed using cell count, colony assay and scratch assay. The chemosensitivity of transfected cells to cisplatin was measured by MTT. RESULTS: Sequence specific dsRNA-EGFR down-regulated EGF receptor expression dramatically. Compared with the control group, dsRNA-EGFR reduced the cell number by 85.0 %, decreased the colonies by 63.3 %, inhibited the migration by 87.2 %, and increased the sensitivity of A549 to cisplatin by four-fold. CONCLUSION: Sequence specific dsRNA-EGFR were capable of suppressing EGF receptor expression, hence significantly inhibiting cellular proliferation and motility, and enhancing chemosensitivity of A549 cells to cisplatin. The successful application of dsRNA-EGFR for inhibition of proliferation in EGF receptor overexpressing cells can help extend the list of available therapeutic modalities in the treatment of non-small-cell lung carcinoma (NSCLC).

  12. Effects of chemotherapy agents on Sphingosine-1-Phosphate receptors expression in MCF-7 mammary cancer cells.

    Science.gov (United States)

    Ghosal, P; Sukocheva, O A; Wang, T; Mayne, G C; Watson, D I; Hussey, D J

    2016-07-01

    Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in the regulation of cell proliferation and cancer progression. Increased expression of S1P receptors has been detected in advanced breast tumours with poor prognosis suggesting that S1P receptors might control tumour response to chemotherapy. However, it remains unclear how the levels of S1P receptor expression are influenced by chemotherapy agents. Western immunoblotting, PCR analysis and fluorescent microscopy techniques were used in this study to analyze expression patterns of S1P receptors 2 and 3 (S1P2/S1P3) in MCF-7 breast adenocarcinoma cells treated by Tamoxifen (TAM) and/or Medroxyprogesterone acetate (MPA). We found that TAM/MPA induce downregulation of S1P3 receptors, but stimulate expression of S1P2. According to cell viability and caspase activity analyses, as expected, TAM activated apoptosis. We also detected TAM/MPA-induced autophagy marked by formation of macroautophagosomes and increased level of Beclin 1. Combined application of TAM and MPA resulted in synergistic apoptosis- and autophagy-stimulating effects. Assessed by fluorescent microscopy with autophagosome marker LAMP-2, changes in S1P receptor expression coincided with activation of autophagy, suggestively, directing breast cancer cells towards death. Further studies are warranted to explore the utility of manipulation of S1P2 and S1P3 receptor expression as a novel treatment approach. PMID:27261597

  13. A Comparison of Iron and Folate with Folate Alone in Hematologic Recovery of Children Treated for Acute Malaria

    OpenAIRE

    Gara, Samuel N.; Madaki, Aboi J.K.; THACHER, Tom D

    2010-01-01

    Concern has been raised that iron supplementation for treatment of acute malaria may worsen the severity of malaria. We compared the effect of iron and folate with folate alone on hematologic recovery in children treated for acute malaria. We randomized 82 children 6–60 months of age from Nigeria with smear-positive malaria and anemia (hematocrit < 33%) to receive iron (2 mg/kg/day) plus folate (5 mg/day) or folate alone in addition to antimalarial drugs. The mean ± SD hematocrit at baseline ...

  14. Physiological responses to folate overproduction in Lactobacillus plantarum WCFS1

    Directory of Open Access Journals (Sweden)

    de Vos Ric CH

    2010-12-01

    Full Text Available Abstract 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.

  15. Human folate metabolism using 14C-accelerator mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Clifford, A. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Arjomand, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Duecker, S. R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Johnson, H. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Schneider, P. D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Zulim, R. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bucholz, B. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Vogel, J. S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    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.

  16. Lentils (Lens culinaris L.), a rich source of folates

    Science.gov (United States)

    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...

  17. Modulation of folate production in lactic acid bacteria

    NARCIS (Netherlands)

    Wegkamp, H.B.A.

    2008-01-01

    Food fortification has proven to be very useful in reducing health problems associated with mal-intake of essential nutrients, such as the B-vitamin folate. Folate is used as one-carbon donor/acceptor in several biochemical processes like synthesis of DNA, RNA and some amino acids. Sufficient intake

  18. Metabolic engineering of folate production in lactic acid bacteria

    NARCIS (Netherlands)

    Sybesma, W.F.H.

    2003-01-01

    Folate is an essential compound in the human diet. Folate deficiency occurs frequently among certain population groups even in highly developed countries and may increase the risks for several diseases like neural tube defects, cardiovascular diseases and certain forms of cancer. The dairy starter b

  19. Proper Maternal Folate Level May Reduce Child Obesity Risk

    Science.gov (United States)

    ... 13, 2016 Proper maternal folate level may reduce child obesity risk NIH-funded study suggests an optimal level ... folate may mitigate the effect of a mother’s obesity on her child’s health.” The study, published online in JAMA Pediatrics, ...

  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

    Directory of Open Access Journals (Sweden)

    Claire M. Marchetta

    2015-04-01

    Full Text Available 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.

  1. Disruption of the folate pathway in zebrafish causes developmental defects

    Directory of Open Access Journals (Sweden)

    Lee Marina S

    2012-04-01

    Full Text Available Abstract Background Folic acid supplementation reduces the risk of neural tube defects and congenital heart defects. The biological mechanisms through which folate prevents birth defects are not well understood. We explore the use of zebrafish as a model system to investigate the role of folate metabolism during development. Results We first identified zebrafish orthologs of 12 human folate metabolic genes. RT-PCR and in situ analysis indicated maternal transcripts supply the embryo with mRNA so that the embryo has an intact folate pathway. To perturb folate metabolism we exposed zebrafish embryos to methotrexate (MTX, a potent inhibitor of dihydrofolate reductase (Dhfr an essential enzyme in the folate metabolic pathway. Embryos exposed to high doses of MTX exhibited developmental arrest prior to early segmentation. Lower doses of MTX resulted in embryos with a shortened anterior-posterior axis and cardiac defects: linear heart tubes or incomplete cardiac looping. Inhibition of dhfr mRNA with antisense morpholino oligonucleotides resulted in embryonic lethality. One function of the folate pathway is to provide essential one-carbon units for dTMP synthesis, a rate-limiting step of DNA synthesis. After 24 hours of exposure to high levels of MTX, mutant embryos continue to incorporate the thymidine analog BrdU. However, additional experiments indicate that these embryos have fewer mitotic cells, as assayed with phospho-histone H3 antibodies, and that treated embryos have perturbed cell cycles. Conclusions Our studies demonstrate that human and zebrafish utilize similar one-carbon pathways. Our data indicate that folate metabolism is essential for early zebrafish development. Zebrafish studies of the folate pathway and its deficiencies could provide insight into the underlying etiology of human birth defects and the natural role of folate in development.

  2. Prostate-specific antigen and hormone receptor expression in male and female breast carcinoma

    Directory of Open Access Journals (Sweden)

    Cohen Cynthia

    2010-09-01

    Full Text Available Abstract Background Prostate carcinoma is among the most common solid tumors to secondarily involve the male breast. Prostate specific antigen (PSA and prostate-specific acid phosphatase (PSAP are expressed in benign and malignant prostatic tissue, and immunohistochemical staining for these markers is often used to confirm the prostatic origin of metastatic carcinoma. PSA expression has been reported in male and female breast carcinoma and in gynecomastia, raising concerns about the utility of PSA for differentiating prostate carcinoma metastasis to the male breast from primary breast carcinoma. This study examined the frequency of PSA, PSAP, and hormone receptor expression in male breast carcinoma (MBC, female breast carcinoma (FBC, and gynecomastia. Methods Immunohistochemical staining for PSA, PSAP, AR, ER, and PR was performed on tissue microarrays representing six cases of gynecomastia, thirty MBC, and fifty-six FBC. Results PSA was positive in two of fifty-six FBC (3.7%, focally positive in one of thirty MBC (3.3%, and negative in the five examined cases of gynecomastia. PSAP expression was absent in MBC, FBC, and gynecomastia. Hormone receptor expression was similar in males and females (AR 74.1% in MBC vs. 67.9% in FBC, p = 0.62; ER 85.2% vs. 68.5%, p = 0.18; and PR 51.9% vs. 48.2%, p = 0.82. Conclusions PSA and PSAP are useful markers to distinguish primary breast carcinoma from prostate carcinoma metastatic to the male breast. Although PSA expression appeared to correlate with hormone receptor expression, the incidence of PSA expression in our population was too low to draw significant conclusions about an association between PSA expression and hormone receptor status in breast lesions.

  3. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  4. Role of GABA Release From Leptin Receptor-Expressing Neurons in Body Weight Regulation

    OpenAIRE

    Xu, Yuanzhong; O'Brien, William G.; Lee, Cheng-Chi; Myers, Martin G.; Tong, Qingchun

    2012-01-01

    It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neur...

  5. Chemokine receptor expression on B cells and effect of interferon-beta in multiple sclerosis

    DEFF Research Database (Denmark)

    Sørensen, Torben Lykke; Roed, Hanne; Sellebjerg, Finn

    2002-01-01

    We investigated the B-cell expression of chemokine receptors CXCR3, CXCR5 and CCR5 in the blood and cerebrospinal fluid (CSF) from patients in relapse of multiple sclerosis (MS) and in neurological controls. Chemokine receptor expression was also studied in interferon-beta-treated patients...... with relapsing-remitting or secondary progressive MS. We observed significantly higher expression of CXCR3 on B cells in the CSF in active MS than in controls. Patients with active MS also had higher B-cell expression of CCR5 in blood. No major differences between RRMS and SPMS patients were detected...

  6. The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy?

    DEFF Research Database (Denmark)

    Husemoen, LL; Toft, U.; Fenger, Mogens;

    2006-01-01

    aimed at examining the association between atopy and markers of impaired folate metabolism, i.e. MTHFR(C677T) genotype, plasma total homocysteine, and dietary intakes of methionine, folates, and vitamins B12, B6, and B2. METHODS: Cross-sectional population-based study of 1,671 male and female residents.......12, 95% CI 0.98-1.29). CONCLUSIONS: The results suggest that an impaired folate metabolism may be causally related to the development of atopy.......BACKGROUND: Deficiency of folate has been associated with several disorders characterized by enhanced activation of the cellular immune system (non-allergic th1 type immune response). Whether folate status is also associated with atopic disease (allergic th2 type immune response) is unknown. We...

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

    Science.gov (United States)

    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.

  8. TREM-2 Receptor Expression Increases with 25(OHD Vitamin Serum Levels in Patients with Pulmonary Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Maria Bucova

    2015-01-01

    Full Text Available TREM-1 and TREM-2 molecules are members of the TREM transmembrane glycoproteins. In our previous study we identified increased expressions of TREM-1 and TREM-2 receptors in pulmonary sarcoidosis (PS. Only a few studies concerning the association between vitamin D and TREM receptor expression can be found. The aim of our current study was to determine the association between the levels of an inactive form of 25(OHD vitamin and TREM-1 and TREM-2 receptor expressions. We have detected low levels of 25(OHD vitamin in 79% of PS patients. Only 21% of patients had normal serum level of 25(OHD vitamin with values clustered within the low-normal range. The most striking findings were the increased TREM-2 expressions on myeloid cells surfaces in BALF of PS patients with normal 25(OHD vitamin serum levels compared with those with its decreased levels. The total number of TREM-2 positive cells was 5.7 times higher and the percentage of TREM-2 positive cells was also significantly increased in BALF of PS patients with normal compared to PS patients with low 25(OHD vitamin serum levels. A significant correlation between total TREM-2 expression and vitamin D levels has been detected too. However, we have not detected similar differences in TREM-1expression and 25(OHD vitamin serum levels.

  9. Platelet receptor expression and shedding: glycoprotein Ib-IX-V and glycoprotein VI.

    Science.gov (United States)

    Gardiner, Elizabeth E; Andrews, Robert K

    2014-04-01

    Quantity, quality, and lifespan are 3 important factors in the physiology, pathology, and transfusion of human blood platelets. The aim of this review is to discuss the proteolytic regulation of key platelet-specific receptors, glycoprotein(GP)Ib and GPVI, involved in the function of platelets in hemostasis and thrombosis, and nonimmune or immune thrombocytopenia. The scope of the review encompasses the basic science of platelet receptor shedding, practical aspects related to laboratory analysis of platelet receptor expression/shedding, and clinical implications of using the proteolytic fragments as platelet-specific biomarkers in vivo in terms of platelet function and clearance. These topics can be relevant to platelet transfusion regarding both changes in platelet receptor expression occurring ex vivo during platelet storage and/or clinical use of platelets for transfusion. In this regard, quantitative analysis of platelet receptor profiles on blood samples from individuals could ultimately enable stratification of bleeding risk, discrimination between causes of thrombocytopenia due to impaired production vs enhanced clearance, and monitoring of response to treatment prior to change in platelet count.

  10. Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

    DEFF Research Database (Denmark)

    Xu, Cang-Bao; Zheng, Jian-Pu; Zhang, Wei;

    2014-01-01

    -regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signal pathways are involved in this process. Rat mesenteric artery segments were organ cultured in the presence and absence of LDL with or without inhibitors for MAPK kinase 1 and 2 (MEK1/2), p38 and transcription. The upregulation...... of the ET(B) receptor mRNA and protein expressions, and activation of ERK1/2 and p38 MAPK. Blockage of ERK1/2 and p38 MAPK signal pathways using MEK1/2 inhibitors (PD98059 and U0126) or p38 inhibitors (SB203580 and SB239063) significantly abolished the LDL-induced upregulation of vasoconstrictive ET......(B) receptor expression. Actinomycin D (general transcriptional inhibitor) almost completely inhibited the LDL effects. In conclusion, LDL induces upregulation of vasoconstrictive ET(B) receptor expression through activation of ERK1/2 and p38 MAPK signal pathway-dependent transcriptional mechanisms....

  11. Drugs and vitamin B12 and folate metabolism.

    Science.gov (United States)

    Lindenbaum, J

    1983-01-01

    Deficiency of either folic acid or vitamin B12 may interfere with DNA synthesis and result in megaloblastic anemia or other conditions. These 2 vitamins have dissimilar molecular structures and are present in different foods; they are also absorbed and metabolized differently. In 201 consecutive cases of megaloblastic anemia, for 90% the cause was alcoholism and poor diet; 0.5% (1 case) was related to oral contraceptives (OCs). Megaloblastic anemia due to folate deficiency has occasionally been reported in patients with inflammatory bowel disease and has been attributed to poor diet, impaired absorption, and increased tissue utilization of folate. Sulfasalazine, a compound containing a sulfa drug and a salicylate that is broken down to its active components by the gut flora, is widely used in the treatment of inflammatory bowel disease and has been shown to impair the absorption of folic acid, polyglutamyl folate, and methyl-tetrahydrofolic acid in patients with these disorders. There is also evidence suggesting an interaction between anticonvulsant drugs and folate balance. A number of cases of megaloblastic anemia due to folate deficiency have been reported in women taking OCs. While in some cases no apparent cause for the megaloblastic anemia other than contraceptive therapy was demonstrated, in many patients other underlying disorders that were likely to disturb folate balance such as celiac disease, decreased dietary vitamin intake, and the administration of other drugs known to affect folate status have also been present. There is no convincing evidence that sex steroids affect folate absorption; about 20% of women taking OCs were found to have mild megaloblastic changes on Papanicolaou smears. These changes disappered after folic acid therapy, suggesting that OCs may cause an increased demand for folate limited to the reproductive system. Another finding is of low serum cobalamin levels in women using OCs; this appears however to be a laboratory abnormality

  12. [Treatable Dementia due to Vitamin B12 and Folate Deficiency].

    Science.gov (United States)

    Yoshizawa, Toshihiro

    2016-04-01

    Vitamin deficiency is one of the major causes of treatable dementia. Specifically, patients suffering from dementia frequentry display low serum levels of vitamin B(12). There is a close metabolic interaction between folate and vitamin B(12). Folate deficiency causes various neuropsychiatric symptoms, which resemble those observed in vitamin B(12) deficiency. This review summarizes, the basic pathophysiology of vitamin B(12) and folate deficiency, its clinical diagnosis, associated neuropsychiatric symptoms such as subacute combined degeneration and dementia, and epidemiological studies of cognitive decline and brain atrophy. PMID:27056859

  13. Preparation and characterization of folate-poly(ethylene glycol)-grafted-trimethylchitosan for intracellular transport of protein through folate receptor-mediated endocytosis.

    Science.gov (United States)

    Zheng, Yu; Song, Xiangrong; Darby, Michael; Liang, Yufeng; He, Ling; Cai, Zheng; Chen, Qiuhong; Bi, Yueqi; Yang, Xiaojuan; Xu, Jiapeng; Li, Yuanbo; Sun, Yiyi; Lee, Robert J; Hou, Shixiang

    2010-01-01

    To develop a receptor-mediated intracellular delivery system that can transport therapeutic proteins to specific tumor cells, folate-poly(ethylene glycol)-grafted-trimethylchitosan (folate-PEG-g-TMC) was synthesized. Nano-scaled spherical polyelectrolyte complexes between the folate-PEG-g-TMC and fluorescein isothiocyanate conjugated bovine serum albumin (FITC-BSA) were prepared under suitable weight ratio of copolymer to FITC-BSA by ionic interaction between the positively charged copolymers and the negatively charged FITC-BSA. Intracellular uptake of FITC-BSA was specifically enhanced in SKOV3 cells (folate receptor over-expressing cell line) through folate receptor-mediated endocytosis compared with A549 cells (folate receptor deficient cell line). Folate-PEG-g-TMC shows promise for intracellular transport of negatively charged therapeutic proteins into folate receptor over-expressing tumor cells.

  14. Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate.

    Science.gov (United States)

    Junyaprasert, Varaporn Buraphacheep; Dhanahiranpruk, Sirithip; Suksiriworapong, Jiraphong; Sripha, Kittisak; Moongkarndi, Primchanien

    2015-12-01

    Folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-FOL) decorated methotrexate (MTX)-conjugated nanoparticles were developed for targeted delivery of MTX to folate receptor-expressed tumor cells. The synthesis of TPGS-FOL followed 3-step process. Firstly, the terminal hydroxyl group of TPGS was converted to sulfonyl chloride using mesyl chloride in comparison with nosyl and tosyl chlorides. The highest conversion efficiency and yield were obtained by mesyl chloride due to the formation of higher reactive intermediate in a presence of triethylamine. Secondly, the substitution of sulfonyl group by sodium azide produced considerably high yield with conversion efficiency of over 90%. Lastly, the coupling reaction of azido-substituted TPGS and propargyl folamide by click reaction resulted in 96% conjugation efficiency without polymer degradation. To fabricate the folate receptor-targeted nanoparticles, 10 and 20%mol MTX-conjugated PEGylated poly(ϵ-caprolactone) nanoparticles were decorated with TPGS-FOL. The size and size distribution of MTX-conjugated nanoparticles relatively increased with %MTX. The MTX release from the nanoparticles was accelerated in acidic medium with an increase of %MTX but retarded in physiological pH medium. The decoration of TPGS-FOL onto the nanoparticles slightly enlarged the size and size distribution of the nanoparticles; however, it did not affect the surface charge. The cytotoxicity and cellular uptake of MCF-7 cells demonstrated that 10% MTX-conjugated nanoparticles and FOL-decorated nanoparticles possessed higher toxicity and uptake efficiency than 20% MTX-conjugated nanoparticles and undecorated nanoparticles, respectively. The results indicated that FOL-10% MTX-conjugated nanoparticles exhibited potential targeted delivery of MTX to folate receptor-expressed cancer cells.

  15. Dynamics of antifolate transport via the reduced folate carrier and the membrane folate receptor in murine leukaemia cells in vitro and in vivo

    NARCIS (Netherlands)

    Mauritz, Robert; Peters, Godefridus; Kathmann, Ietje; Teshale, Habte; Noordhuis, Paul; Comijn, Elizabeth; Pinedo, Herbert; Jansen, Gerrit

    Murine L1210 leukaemia cells expressing either the reduced folate carrier (RFC) or the membrane folate receptor (MFR) were studied in vitro and in vivo to assess the dynamics of membrane transport of two categories antifolates; folate-based inhibitors of dihydrofolate reductase (methotrexate, edatre

  16. Megalin binds and mediates cellular internalization of folate binding protein

    DEFF Research Database (Denmark)

    Birn, Henrik; Zhai, Xiaoyue; Holm, Jan;

    2005-01-01

    Folate is an essential vitamin involved in a number of biological processes. High affinity folate binding proteins (FBPs) exist both as glycosylphosphatidylinositol-linked, membrane associated folate binding proteins and as soluble FBPs in plasma and some secretory fluids such as milk, saliva...... to bind and mediate cellular uptake of FBP. Surface plasmon resonance analysis shows binding of bovine and human milk FBP to immobilized megalin, but not to low density lipoprotein receptor related protein. Binding of (125)I-labeled folate binding protein (FBP) to sections of kidney proximal tubule, known...... to express high levels of megalin, is inhibitable by excess unlabeled FBP and by receptor associated protein, a known inhibitor of binding to megalin. Immortalized rat yolk sac cells, representing an established model for studying megalin-mediated uptake, reveal (125)I-labeled FBP uptake which is inhibited...

  17. Dietary folate and APC mutations in sporadic colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Engeland, M. van; Lüchtenborg, M.; Bruïne, A.P. de; Roemen, G.M.J.M.; Lentjes, M.H.F.M.; Goldbohm, R.A.; Brandt, P.A. van den; Goeij, A.F.P.M. de; Weijenberg, M.P.

    2006-01-01

    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

  18. Temporal development of GABA agonist induced alterations in ultrastructure and GABA receptor expression in cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Hansen, G H; Belhage, B; Schousboe, A;

    1987-01-01

    The temporal development of the effect of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) on the ultrastructure composition and GABA receptor expression in cerebellar granule cells was investigated by quantitative electron microscopy (morphometric analysis) and GABA binding assays...... exposed to THIP (150 microM) for 3 hr low affinity GABA receptors were induced. These findings show that the effect of THIP on the ultrastructure composition and GABA receptor expression in cultured cerebellar granule cells may be interrelated and moreover it is likely that the turn-over of GABA receptors...

  19. Temporal development of GABA agonist induced alterations in ultrastructure and GABA receptor expression in cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Hansen, Gert Helge; Belhage, B; Schousboe, A;

    1987-01-01

    The temporal development of the effect of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) on the ultrastructure composition and GABA receptor expression in cerebellar granule cells was investigated by quantitative electron microscopy (morphometric analysis) and GABA binding assays. It was...... exposed to THIP (150 microM) for 3 hr low affinity GABA receptors were induced. These findings show that the effect of THIP on the ultrastructure composition and GABA receptor expression in cultured cerebellar granule cells may be interrelated and moreover it is likely that the turn-over of GABA receptors...

  20. Vitamin B12 and folate depletion in cognition: A review

    OpenAIRE

    Moretti Rita; Torre Paola; Antonello Rodolfo; Cattaruzza Tatiana; Cazzato Giuseppe; Bava Antonio

    2004-01-01

    In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in ne...

  1. Transferrin receptor expression and role in transendothelial transport of transferrin in cultured brain endothelial monolayers

    DEFF Research Database (Denmark)

    Hersom, Maria; Helms, Hans Christian; Pretzer, Natasia;

    2016-01-01

    across the endothelial cells by transcytosis. The aim of the present study was to investigate transferrin receptor expression and role in transendothelial transferrin transport in cultured bovine brain endothelial cell monolayers. Transferrin receptor mRNA and protein levels were investigated...... in endothelial mono-cultures and co-cultures with astrocytes, as well as in freshly isolated brain capillaries using qPCR, immunocytochemistry and Western blotting. Transendothelial transport and luminal association of holo-transferrin was investigated using [125I]holo-transferrin or [59Fe......]-transferrin. Transferrin receptor mRNA expression in all cell culture configurations was lower than in freshly isolated capillaries, but the expression slightly increased during six days of culture. The mRNA expression levels were similar in mono-cultures and co-cultures. Immunostaining demonstrated comparable transferrin...

  2. Dynamic T-lymphocyte chemokine receptor expression induced by interferon-beta therapy in multiple sclerosis

    DEFF Research Database (Denmark)

    Krakauer, M; Sorensen, P S; Khademi, M;

    2006-01-01

    as these influence central nervous system (CNS) transmigration and inflammation. At 'steady state' (>/=1 day after the most recent IFN-beta injection), IFN-beta treatment increased CD4(+) T-cell surface expression of CC chemokine receptor (CCR)4, CCR5 and CCR7 after 3 months of treatment, whereas that of CXC...... and immunoregulatory genes. In conclusion, IFN-beta treatment caused 'steady-state' increases of several chemokine receptors relevant for CD4(+) T-lymphocyte trafficking and function, possibly facilitating lymphocyte migration into the CNS. An important therapeutic effect of IFN-beta treatment may be the normalization...... of a decreased Th2-related CD4(+) T-cell CCR4 expression in MS patients. Surface chemokine receptor expression and CXCL10 varied according to the timing of blood sampling in relation to the most recent IFN-beta injection. Thus, it is imperative to distinguish acute effects of IFN-beta from steady-state effects....

  3. Endothelin-1 and endothelin-3 regulate endothelin receptor expression in rat coronary arteries

    DEFF Research Database (Denmark)

    Skovsted, Gry Freja; Kilic, Semsi; Edvinsson, Lars

    2015-01-01

    . Organ culture significantly up-regulated ETB receptors and down-regulated ETA receptor expression. Co-incubation with ET-1 (1 nM) or ET-3 (100 nM) induced further down-regulation of the ETA receptor mRNA, while the function and protein level of ETA remained unchanged. ET-3 (100 nM) further up-regulated......In ischaemic hearts, endothelin (ET) levels are increased, and vasoconstrictor responses to ET-1 are greatly enhanced. We previously reported that ETB receptors are up-regulated in the smooth muscle layer of coronary arteries after myocardial ischaemia-reperfusion and that the MEK-ERK1/2 signalling...... pathway is involved in ETB receptor up-regulation. Whether ETs are directly involved in receptor regulation has not been determined. We suggest that ET-1 and ET-3 alter the expression/activity of ET receptors in coronary vascular smooth muscle cells. Vasoconstrictor responses were studied in endothelium...

  4. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Directory of Open Access Journals (Sweden)

    Anshula eSamarajeewa

    2014-11-01

    Full Text Available The serotonin (5-HT type 7 receptor is expressed throughout the CNS including cortical neurons. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA-induced toxicity. The tropomyosin-related kinase B (TrkB receptor is one of the receptors for brain-derived neurotrophic factor (BDNF and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins towards the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands.

  5. Notch receptor expression in neurogenic regions of the adult zebrafish brain.

    Directory of Open Access Journals (Sweden)

    Vanessa de Oliveira-Carlos

    Full Text Available The adult zebrash brain has a remarkable constitutive neurogenic capacity. The regulation and maintenance of its adult neurogenic niches are poorly understood. In mammals, Notch signaling is involved in stem cell maintenance both in embryonic and adult CNS. To better understand how Notch signaling is involved in stem cell maintenance during adult neurogenesis in zebrafish we analysed Notch receptor expression in five neurogenic zones of the adult zebrafish brain. Combining proliferation and glial markers we identified several subsets of Notch receptor expressing cells. We found that 90 [Formula: see text] of proliferating radial glia express notch1a, notch1b and notch3. In contrast, the proliferating non-glial populations of the dorsal telencephalon and hypothalamus rarely express notch3 and about half express notch1a/1b. In the non-proliferating radial glia notch3 is the predominant receptor throughout the brain. In the ventral telencephalon and in the mitotic area of the optic tectum, where cells have neuroepithelial properties, notch1a/1b/3 are expressed in most proliferating cells. However, in the cerebellar niche, although progenitors also have neuroepithelial properties, only notch1a/1b are expressed in a high number of PCNA [Formula: see text] cells. In this region notch3 expression is mostly in Bergmann glia and at low levels in few PCNA [Formula: see text] cells. Additionally, we found that in the proliferation zone of the ventral telencephalon, Notch receptors display an apical high to basal low gradient of expression. Notch receptors are also expressed in subpopulations of oligodendrocytes, neurons and endothelial cells. We suggest that the partial regional heterogeneity observed for Notch expression in progenitor cells might be related to the cellular diversity present in each of these neurogenic niches.

  6. Expression of soluble triggering receptor expression on myeloid cells-1 in pleural effusion

    Institute of Scientific and Technical Information of China (English)

    HUANG Lu-ying; SHI Huan-zhong; LIANG Qiu-li; WU Yan-bin; QIN Xue-jun; CHEN Yi-qiang

    2008-01-01

    Background Tdggedng receptors expressed on myeloid cells(TREM)proteins are a family of cell surface receptors expressed broadly by cells of the myeloid lineage.The aim of this study was to investigate the clinical significance of soluble TREM-1(sTREM-1)in pleural effusions,and to determine the effects of pneumonia on pleural sTREM-1 concentrations.Methods PleuraI fluid was collected from 109 patients who presented to the respiratory institute (35 with malignant pleural effusion,31 with tuberculous pleural effusion,21 with bacteriaI pleural effusion,and 22 with transudate).The concentrations of sTREM-1,tumor necrosis factor-o(TNF-α)and interleukin-1β(IL-1β)were determined jn effusion and serum samples by enzyme Iinked immunosorbent assay(ELISA).Results The concentrations of sTREM-1 in bacterial pleural effusion were significantly higher than those in malignant.tuberculous,and transudative groups(all P<0.001).An sTREM-1 cutoff value of 768.1 ng/L had a sensitivity of 86%and a specificity of 93%.Pleural sTREM-1 Ievels were positively correlated with Ievels of TNF-α and IL-1β.Patients with complicating bacterial pneumonia did not have elevated concentration of STREM-1 jn pleural effusion when compared with patients without pneumonia.Conclusions Determination of pleural sTREM-1 may improve the ability of clinicians to differentiate pleural effusion patients of bacterial origin from those with other etiologies.The occurrence of bacterial pneumonia did not affect pleural sTREM-1 concentrations.

  7. 5-HT7 receptor activation promotes an increase in TrkB receptor expression and phosphorylation

    Science.gov (United States)

    Samarajeewa, Anshula; Goldemann, Lolita; Vasefi, Maryam S.; Ahmed, Nawaz; Gondora, Nyasha; Khanderia, Chandni; Mielke, John G.; Beazely, Michael A.

    2014-01-01

    The serotonin (5-HT) type 7 receptor is expressed throughout the CNS including the cortex and hippocampus. We have previously demonstrated that the application of 5-HT7 receptor agonists to primary hippocampal neurons and SH-SY5Y cells increases platelet-derived growth factor (PDGF) receptor expression and promotes neuroprotection against N-methyl-D-aspartate-(NMDA)-induced toxicity. The tropomyosin-related kinase B (TrkB) receptor is one of the receptors for brain-derived neurotrophic factor (BDNF) and is associated with neurodevelopmental and neuroprotective effects. Application of LP 12 to primary cerebral cortical cultures, SH-SY5Y cells, as well as the retinal ganglion cell line, RGC-5, increased both the expression of full length TrkB as well as its basal phosphorylation state at tyrosine 816. The increase in TrkB expression and phosphorylation was observed as early as 30 min after 5-HT7 receptor activation. In addition to full-length TrkB, kinase domain-deficient forms may be expressed and act as dominant-negative proteins toward the full length receptor. We have identified distinct patterns of TrkB isoform expression across our cell lines and cortical cultures. Although TrkB receptor expression is regulated by cyclic AMP and Gαs-coupled GPCRs in several systems, we demonstrate that, depending on the model system, pathways downstream of both Gαs and Gα12 are involved in the regulation of TrkB expression by 5-HT7 receptors. Given the number of psychiatric and degenerative diseases associated with TrkB/BDNF deficiency and the current interest in developing 5-HT7 receptor ligands as pharmaceuticals, identifying signaling relationships between these two receptors will aid in our understanding of the potential therapeutic effects of 5-HT7 receptor ligands. PMID:25426041

  8. Biomarkers of Nutrition for Development-Folate Review.

    Science.gov (United States)

    Bailey, Lynn B; Stover, Patrick J; McNulty, Helene; Fenech, Michael F; Gregory, Jesse F; Mills, James L; Pfeiffer, Christine M; Fazili, Zia; Zhang, Mindy; Ueland, Per M; Molloy, Anne M; Caudill, Marie A; Shane, Barry; Berry, Robert J; Bailey, Regan L; Hausman, Dorothy B; Raghavan, Ramkripa; Raiten, Daniel J

    2015-07-01

    The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development. PMID:26451605

  9. Erythrocyte folate, plasma folate and plasma homocysteine during normal pregnancy and postpartum: a longitudinal study comprising 404 danish women

    DEFF Research Database (Denmark)

    Milman, N; Byg, KE; Hvas, Anne-Mette;

    2006-01-01

    OBJECTIVE: To assess folate and homocysteine status during normal pregnancy and postpartum in a longitudinal setting. METHODS: This study, performed in 1995-1996, comprised 404 healthy pregnant Danish Caucasian women residential in Copenhagen County. Women taking folic acid tablets or vitamin B12...... injections were not included. Dietary multivitamin supplements containing folic acid 100 microg or vitamin B12 1 microg, taken by 34%, were discontinued at inclusion. Participants had normal renal function. Folate status [erythrocyte (Ery-) folate, plasma (P-) folate, P-homocysteine] was measured at 18, 32...... new guidelines for folic acid supplement since 1997, only 13% of pregnant women followed the guidelines in 2003. The official recommendations for periconceptional folic acid supplement should be reconsidered and reinforced....

  10. Development of new folate-based PET radiotracers: preclinical evaluation of {sup 68}Ga-DOTA-folate conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Fani, Melpomeni; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); University Hospital Freiburg, Clinic for Nuclear Medicine, Freiburg (Germany); Wang, Xuejuan [University Hospital Basel, Division of Radiological Chemistry, Basel (Switzerland); Nicolas, Guillaume [University Hospital Basel, Department of Nuclear Medicine, Basel (Switzerland); Medina, Christelle; Raynal, Isabelle; Port, Marc [Guerbet, Research Department, Aulnay-sous-Bois (France)

    2011-01-15

    A number of {sup 111}In- and {sup 99m}Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A {sup 68}Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of {sup 68}Ga from a generator. The aim of the study was to develop a new {sup 68}Ga-folate-based PET radiotracer. Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{l_brace}2-[2-(3-amino-propoxy)-ethoxy]-ethoxy{r_brace}-propylamine as a spacer, respectively. Both conjugates were labelled with {sup 67/68}Ga. Binding affinity, internalization and externalization studies were performed using the FR-positive KB cell line. Biodistribution and PET/CT imaging studies were performed in nude mice, on a folate-deficient diet, bearing KB and HT1080 (FR-negative) tumours, concurrently. The new radiotracers were evaluated comparatively to the reference molecule {sup 111}In-DTPA-folate ({sup 111}In-P3139). The K{sub d} values of {sup 67/68}Ga-P3026 (4.65 {+-} 0.82 nM) and {sup 67/68}Ga-P1254 (4.27 {+-} 0.42 nM) showed high affinity for the FR. The internalization rate followed the order {sup 67/68}Ga-P3026 >{sup 67/68}Ga-P1254 >{sup 111}In-P3139, while almost double cellular retention was found for {sup 67/68}Ga-P3026 and {sup 67/68}Ga-P1254, compared to {sup 111}In-P3139. The biodistribution data of {sup 67/68}Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to {sup 111}In-P3139. PET/CT images, performed with {sup 68}Ga-P3026, showed high uptake in the kidneys and clear visualization of the FR-positive tumours. The DOTA-folate conjugates can be efficiently labelled with {sup 68}Ga in labelling yields and specific activities which allow clinical application. The characteristics of the {sup 67/68}Ga-DOTA-folates are comparable to {sup 111}In-DTPA-folate

  11. An unusual role of folate in the self-assembly of heparin-folate conjugates into nanoparticles

    Science.gov (United States)

    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

  12. Association between folate intake, serum folate levels and the risk of lung cancer: a systematic review and meta-analysis

    Institute of Scientific and Technical Information of China (English)

    DAI Wei-min; YANG Bo; CHU Xiang-yang; WANG Yu-qi; ZHAO Ming; CHEN Li; ZHANG Guo-qing

    2013-01-01

    Background Folate plays a critical role in nucleotide synthesis and DNA methylation,and was considered to be associated with anti-carcinogenesis.Results from studies that concern the relationship between the folate intake or serum folate levels and lung cancer risk showed no consistency,which requires our further comprehensive metaanalysis.Methods Systematic literature search was conducted to identify the relevant studies (published prior to February 2013)according to standard protocol.Estimated effects were calculated under both random-effects and fixed-effects models.Heterogeneity between studies and publication bias were also evaluated.Results A total of 4390 cases and 6138 controls from 6 case-control studies revealed a significant overall inverse association between folate intake and lung cancer risk (OR =0.74,95% Cl =0.65-0.84,P< 0.001).Summary of 1438 cases and 2582 controls from 4 case-control studies and 44 cases out of a cohort of 1988 participants suggested a marginal association without significance (OR =0.78,95% Cl =0.60-1.02,P =0.075) between high serum folate levels and less lung cancer susceptibility; however,subgroup analysis about population-based case-control studies showed that high serum folate levels significantly associated with the reduced lung cancer risk (OR =0.76,95% Cl =0.58-1.00,P =0.048).Conclusion Higher folate intake can be a protective factor against lung cancer risk,and higher serum folate level is probably associated with reduced lung cancer risk in marginal manner,though more studies are warranted to confirm these associations.

  13. Coefficient Alpha

    OpenAIRE

    Panayiotis Panayides

    2013-01-01

    Heavy reliance on Cronbach’s alpha has been standard practice in many validation studies. However, there seem to be two misconceptions about the interpretation of alpha. First, alpha is mistakenly considered as an indication of unidimensionality and second, that the higher the value of alpha the better. The aim of this study is to clarify these misconceptions with the use of real data from the educational setting. Results showed that high alpha values can be obtained in multidimensional scale...

  14. Some nutritional effects of folate-binding protein in bovine milk on the bioavailability of folate to rats

    Energy Technology Data Exchange (ETDEWEB)

    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.

  15. Determination of the folate content in cladodes of nopal (Opuntia ficus indica) by microbiological assay utilizing Lactobacillus casei (ATCC 7469) and enzyme-linked immunosorbent assay.

    Science.gov (United States)

    Ortiz-Escobar, Tania Breshkovskaya; Valverde-González, Maria Elena; Paredes-López, Octavio

    2010-05-26

    Prickly pear cactus has been an important food source in Mexico since ancient times due to its economical and ecological benefits and potential nutraceutical value. Nevertheless, studies on the nutritional aspects and health benefits have been scarce. The purpose of this study was to assess, apparently for the first time, the folate contents of cladodes of nopal by a microbiological assay, using Lactobacillus casei (ATCC 7469) in extracts that were enzymatically treated to release the bound vitamin, employing single, dual, and trienzymatic procedures, and using the enzyme-linked immunosorbent assay (ELISA). We used Opuntia cladodes of different length sizes. The microbiological assay showed some differences among enzyme treatments and sizes of nopal; the trienzyme treatment (alpha-amylase-protease-conjugase) was more efficient in determining the folate content in nopal, giving 5.0 ng/g in the small size cladodes at 54 h of testing time, while ELISA showed no significant differences in the folate content among sizes of cladodes (5.5-5.62 ng/g at 0 min testing time). Both techniques may be used for the assessment of folate content in cladodes, but ELISA is more rapid and reliable. PMID:20441169

  16. Determination of the folate content in cladodes of nopal (Opuntia ficus indica) by microbiological assay utilizing Lactobacillus casei (ATCC 7469) and enzyme-linked immunosorbent assay.

    Science.gov (United States)

    Ortiz-Escobar, Tania Breshkovskaya; Valverde-González, Maria Elena; Paredes-López, Octavio

    2010-05-26

    Prickly pear cactus has been an important food source in Mexico since ancient times due to its economical and ecological benefits and potential nutraceutical value. Nevertheless, studies on the nutritional aspects and health benefits have been scarce. The purpose of this study was to assess, apparently for the first time, the folate contents of cladodes of nopal by a microbiological assay, using Lactobacillus casei (ATCC 7469) in extracts that were enzymatically treated to release the bound vitamin, employing single, dual, and trienzymatic procedures, and using the enzyme-linked immunosorbent assay (ELISA). We used Opuntia cladodes of different length sizes. The microbiological assay showed some differences among enzyme treatments and sizes of nopal; the trienzyme treatment (alpha-amylase-protease-conjugase) was more efficient in determining the folate content in nopal, giving 5.0 ng/g in the small size cladodes at 54 h of testing time, while ELISA showed no significant differences in the folate content among sizes of cladodes (5.5-5.62 ng/g at 0 min testing time). Both techniques may be used for the assessment of folate content in cladodes, but ELISA is more rapid and reliable.

  17. Triggering receptor expressed on myeloid cells-2 fine-tunes inflammatory responses in murine Gram-negative sepsis

    DEFF Research Database (Denmark)

    Schmidt Thøgersen, Mariane; Gawish, Riem; Martins, Rui;

    2015-01-01

    During infections, TLR-mediated responses require tight regulation to allow for pathogen removal, while preventing overwhelming inflammation and immunopathology. The triggering receptor expressed on myeloid cells (TREM)-2 negatively regulates inflammation by macrophages and impacts on phagocytosi...... overwhelming inflammation while preserving antibacterial-effector functions....

  18. Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

    NARCIS (Netherlands)

    D. Chadha; T.D. Pache; F.J. Huikeshoven (Frans); A.O. Brinkmann (Albert); Th.H. van der Kwast (Theo)

    1994-01-01

    textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsex

  19. Muscle Plasticity and β2-Adrenergic Receptors: Adaptive Responses of β2-Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

    OpenAIRE

    Shogo Sato; Ken Shirato; Kaoru Tachiyashiki; Kazuhiko Imaizumi

    2011-01-01

    We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented ...

  20. Prospects in folate receptor-targeted radionuclide therapy

    Directory of Open Access Journals (Sweden)

    Cristina eMüller

    2013-09-01

    Full Text Available Targeted radionuclide therapy is based on systemic application of particle-emitting radiopharmaceuticals which are directed towards a specific tumor-associated target. Accumulation of the radiopharmaceutical in targeted cancer cells results in high doses of absorbed radiation energy whereas toxicity to non-targeted healthy tissue is limited. This strategy has found widespread application in the palliative treatment of neuroendocrine tumors using somatostatin-based radiopeptides. The folate receptor (FR has been identified as a target associated with a variety of frequent tumor types (e.g. ovarian, lung, brain, renal and colorectal cancer. In healthy organs and tissue FR-expression is restricted to only a few sites such as for instance the kidneys. This demonstrates why FR-targeting is an attractive strategy for the development of new therapy concepts. Due to its high FR-binding affinity (KD < 10-9 M the vitamin folic acid has emerged as an almost ideal targeting agent. Therefore, a variety of folic acid radioconjugates for nuclear imaging have been developed. However, in spite of the large number of cancer patients who could benefit of a folate-based radionuclide therapy, a therapeutic concept with folate radioconjugates has not yet been envisaged for clinical application. The reason is the generally high accumulation of folate radioconjugates in the kidneys where emission of particle-radiation may result in damage to the renal tissue. Therefore, the design of more sophisticated folate radioconjugates providing improved tissue distribution profiles are needed.This review article summarizes recent developments with regard to a therapeutic application of folate radioconjugates. A new construct of a folate radioconjugate and an application protocol which makes use of a pharmacological interaction allowed the first preclinical therapy experiments with radiofolates. These results raise hope for future application of such new concepts also in the

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

    Science.gov (United States)

    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. PMID:26471523

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

    Science.gov (United States)

    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.

  3. Vitamin B12 And Folate Deficiency In a Hospital Population

    Directory of Open Access Journals (Sweden)

    Wadia RS

    2001-01-01

    Full Text Available This is a study of B12 and folate deficiency in a hospital population. We studied the incidence of their deficiency by evaluating blood levels in every tenth hospital admission. Among the 450 patients chosen, 417 had normal levels of both, 2 had deficiency of folate alone (folate < 3ng.ml, 3 had B12 deficiency alone (B12<200pg/mland 11 had deficiency of both (total 3.5%. In addition 12 had borderline b12 level(200-300pg/ml, 2 had borderline folate level (3-4ng/ml(0.44%and 3 had borderline levels for both (0.66% . Thus 33% had definite or borderline deficiency. This deficiency was more common in the elderly and in patients on vegetarian diet (5.7% definite deficiency, 8.8% borderline levels compared to those on a non-vegetarian diet. During the 2 1/2 years of the study a total of 99 definite deficiency and 69 borderline deficiency were seen. In the definite deficiency group, 22.3% had neuropathy, 6.1% had evidence of myelopathy, 18.2% had neuropsychiatric changes (memory defect, dementia, behavioural abnormalities, depression and 4.1% had cerebellar signs. The neurologic findings in the borderline group were almost similar (neuropathy 29%, myelopathy 8.6% and neuropsychiatric changes 18.4%. High mean corpuscular volume (MCV> 95 was seen in 69% of those with both B12 and folate deficiency, 43.4% with B12 deficiency and 61.15 with folate deficiency. Hypersegmented polymorphs were seen in 21.7% with B12 deficiency, 27.5% with folate both B12 and folate deficiency had either megaloblastosis or dimorphic picture. It is to be noted that B12 and folate deficiency in this population was more frequent than we previously considered and reliance on haematologic parameters will miss half to one third of all cases. As expected B12 deficiency is more frequent in vegetarians than non-vegetarians.

  4. Biocompatibility of folate-modified chitosan nanoparticles

    Institute of Scientific and Technical Information of China (English)

    Subhankari Prasad Chakraborty; Sumanta Kumar Sahu; Panchanan Pramanik; Somenath Roy

    2012-01-01

    Objective: To evaluate the acute toxicity of carboxymethyl chitosan-2, 2’ ethylenedioxy bis-ethylamine-folate (CMC-EDBE-FA) and as well as possible effect on microbial growth and in vitro cell cyto-toxicity. Methods: CMC-EDBE-FA was prepared on basis of carboxymethyl chitosan tagged with folic acid by covalently linkage through 2, 2’ ethylenedioxy bis-ethylamine. In vivo acute toxicity, in vitro cyto-toxicity and antimicrobial activity of CMC-EDBE-FA nanoparticle were determined. Results: Vancomycin exhibited the antibacterial activity against vancomycin sensitive Staphylococcus aureus, but CMC-EDBE-FA nanoparticle did not give any antibacterial activity as evidenced by minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), disc agar diffusion (DAD) and killing kinetic assay. Further, the CMC-EDBE-FA nanoparticle showed no signs of in vivo acute toxicity up to a dose level of 1000 mg/kg p.o., and as well as in vitro cyto-toxicity up to 250 μg/mL. Conclusions: These findings suggest that CMC-EDBE-FA nanoparticle is expected to be safe for biomedical applications.

  5. Peptide Anchor for Folate-Targeted Liposomal Delivery.

    Science.gov (United States)

    Nogueira, Eugénia; Mangialavori, Irene C; Loureiro, Ana; Azoia, Nuno G; Sárria, Marisa P; Nogueira, Patrícia; Freitas, Jaime; Härmark, Johan; Shimanovich, Ulyana; Rollett, Alexandra; Lacroix, Ghislaine; Bernardes, Gonçalo J L; Guebitz, Georg; Hebert, Hans; Moreira, Alexandra; Carmo, Alexandre M; Rossi, Juan Pablo F C; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

    2015-09-14

    Specific folate receptors are abundantly overexpressed in chronically activated macrophages and in most cancer cells. Directed folate receptor targeting using liposomes is usually achieved using folate linked to a phospholipid or cholesterol anchor. This link is formed using a large spacer like polyethylene glycol. Here, we report an innovative strategy for targeted liposome delivery that uses a hydrophobic fragment of surfactant protein D linked to folate. Our proposed spacer is a small 4 amino acid residue linker. The peptide conjugate inserts deeply into the lipid bilayer without affecting liposomal integrity, with high stability and specificity. To compare the drug delivery potential of both liposomal targeting systems, we encapsulated the nuclear dye Hoechst 34580. The eventual increase in blue fluorescence would only be detectable upon liposome disruption, leading to specific binding of this dye to DNA. Our delivery system was proven to be more efficient (2-fold) in Caco-2 cells than classic systems where the folate moiety is linked to liposomes by polyethylene glycol. PMID:26241560

  6. Cerebrospinal fluid folate and cobalamin levels in febrile convulsion.

    Science.gov (United States)

    Osifo, B O; Lukanmbi, F A; Familusi, J B

    1985-05-01

    Folate and cobalamin parameters were studied in the serum and cerebrospinal fluid of 40 febrile paediatric patients. Eighteen of these children were in a state of febrile convulsion while the remaining 22 were non-convulsing. The serum folate concentration of all the patients was higher than that of the control group but the highest value was found in the convulsing children. There was no significant difference in the CSF folate levels between the two groups of patients. The serum cobalamin levels of the patients were significantly lower than those of the control children and the lowest mean was observed in the convulsing state. On the other hand, there was no difference in the CSF cobalamin between the convulsing and non-convulsing children. These results confirm that there is an effective blood-brain barrier system for folate even when serum folate levels are higher than normal. There is also a definite decrease in serum cobalamin during pyrexia but this decrease is more apparent in the convulsing state. The role of cobalamin metabolism in convulsion is not clear. PMID:4009203

  7. Vitamin B12 and folate depletion in cognition: A review

    Directory of Open Access Journals (Sweden)

    Moretti Rita

    2004-07-01

    Full Text Available In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in neurophysiology. Results are quite controversial and there is an open debate in literature, considering that the potential and differential role of folate and B12 vitamin in memory acquisition and cognitive development is not completely understood or accepted. What is not clear is the fact that vitamin B12 and folate deficiency deteriorate a pre-existing not overt pathological situation or can be dangerous even in normal subjects. Even more intriguing is the interaction between B12 and folate, and their role in developing hyperhomocysteinemia. The approach to the rehabilitation of the deficiency with adequate vitamin supplementation is very confusing. Some authors suggest it, even in chronic situations, others deny any possible role. Starting from these quite confusing perspectives, the aim of this review is to report and categorize the data obtained from the literature. Despite the plausible biochemical mechanism, further studies, based on clinical, neuropsychological, laboratory and (lastly pathological features will be necessary to better understand this fascinating biochemical riddle.

  8. Synthesis of folate- pegylated polyester nanoparticles encapsulating ixabepilone for targeting folate receptor overexpressing breast cancer cells.

    Science.gov (United States)

    Siafaka, P; Betsiou, M; Tsolou, A; Angelou, E; Agianian, B; Koffa, M; Chaitidou, S; Karavas, E; Avgoustakis, K; Bikiaris, D

    2015-12-01

    The aim of this study was the preparation of novel polyester nanoparticles based on folic acid (FA)-functionalized poly(ethylene glycol)-poly(propylene succinate) (PEG-PPSu) copolymer and loaded with the new anticancer drug ixabepilone (IXA). These nanoparticles may serve as a more selective (targeted) treatment of breast cancer tumors overexpressing the folate receptor. The synthesized materials were characterized by (1)H-NMR, FTIR, XRD and DSC. The nanoparticles were prepared by a double emulsification and solvent evaporation method and characterized with regard to their morphology by scanning electron microscopy, drug loading with HPLC-UV and size by dynamic light scattering. An average size of 195 nm and satisfactory drug loading efficiency (3.5%) were observed. XRD data indicated that IXA was incorporated into nanoparticles in amorphous form. The nanoparticles exhibited sustained drug release properties in vitro. Based on in vitro cytotoxicity studies, the blank FA-PEG-PPSu nanoparticles were found to be non-toxic to the cells. Fluorescent nanoparticles were prepared by conjugating Rhodanine B to PEG-PPSu, and live cell, fluorescence, confocal microscopy was applied in order to demonstrate the ability of FA-PEG-PPSu nanoparticles to enter into human breast cancer cells expressing the folate receptor.

  9. Determination of folate concentrations in diverse potato germplasm using a trienzyme extraction and microbiological assay

    Science.gov (United States)

    We determined total folate concentrations of potato tubers from 67 cultivars, advanced breeding lines, or wild species. Folates were extracted by a tri-enzyme treatment and analyzed by using a Lactobacillus rhamnosus microbiological assay. Folate concentrations varied from 521 ± 96 to 1373 ± 230 ng/...

  10. Controlles modulation of folate polyglutamyl tail length by metabolic engineering of Lactococcus lactis

    NARCIS (Netherlands)

    Sybesma, W.F.H.; Born, van den E.; Starrenburg, M.; Mierau, I.; Kleerebezem, M.; Vos, de W.M.; Hugenholtz, J.

    2003-01-01

    The dairy starter bacterium Lactococcus lactis is able to synthesize folate and accumulates >90% of the produced folate intracellularly, predominantly in the polyglutamyl form. Approximately 10% of the produced folate is released into the environment. Overexpression of folC in L. lactis led to an

  11. Folate metabolism in the human colon: cellular responses identified through in vitro studies

    NARCIS (Netherlands)

    Pellis, E.P.M.

    2006-01-01

    Low folate intake influences the risk of not only neural tube defects and vascular diseases, but also colorectal tumours. Folate forms have different roles in the one-carbon metabolism. This includes DNA synthesis and methylation reactions. Folate is present as 5'-methyltetrahydrofolate (MTHF) in th

  12. Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats

    NARCIS (Netherlands)

    J.G. LeBlanc; W. Sybesma; M. Starrenburg; F. Sesma; W.M. de Vos; G. Savoy de Giori; J. Hugenholtz

    2010-01-01

    Objective: The aim of this study was to establish the bioavailability of different folates produced by engineered Lactococcus lactis strains using a rodent depletion-repletion bioassay. Methods: Rats were fed a folate-deficient diet, which produces a reversible subclinical folate deficiency, supplem

  13. Atopy, asthma, and lung function in relation to folate and vitamin B(12) in adults

    DEFF Research Database (Denmark)

    Thuesen, B H; Husemoen, L L N; Ovesen, L;

    2010-01-01

    Recent studies suggested low serum folate and impaired folate metabolism as potential risk factors for development of asthma and atopic disease, but the results are inconsistent. The aim of this study was to investigate the relations of markers of folate and vitamin B12 (B12) deficiency with diff...

  14. Combinatorial activation and repression by seven transcription factors specify Drosophila odorant receptor expression.

    Directory of Open Access Journals (Sweden)

    Shadi Jafari

    Full Text Available The mechanism that specifies olfactory sensory neurons to express only one odorant receptor (OR from a large repertoire is critical for odor discrimination but poorly understood. Here, we describe the first comprehensive analysis of OR expression regulation in Drosophila. A systematic, RNAi-mediated knock down of most of the predicted transcription factors identified an essential function of acj6, E93, Fer1, onecut, sim, xbp1, and zf30c in the regulation of more than 30 ORs. These regulatory factors are differentially expressed in antennal sensory neuron classes and specifically required for the adult expression of ORs. A systematic analysis reveals not only that combinations of these seven factors are necessary for receptor gene expression but also a prominent role for transcriptional repression in preventing ectopic receptor expression. Such regulation is supported by bioinformatics and OR promoter analyses, which uncovered a common promoter structure with distal repressive and proximal activating regions. Thus, our data provide insight into how combinatorial activation and repression can allow a small number of transcription factors to specify a large repertoire of neuron classes in the olfactory system.

  15. Vascular endothelial growth factor and its receptor expression during the process of fracture healing

    Institute of Scientific and Technical Information of China (English)

    CHU Tong-wei; LIU Yu-gang; WANG Zheng-guo; ZHU Pei-fang; LIU Da-wei

    2008-01-01

    Objective: To study the expression regularity of vascular endothelial growth factor (VEGF) during the process of fracture healing, and the type of VEGF receptor expressed in the vascular endothelial cells of the fracture site.Methods: The fracture model was made in the middle part of left radius in 35 rabbits. The specimens from the fracture site were harvested at 8, 24, 72 hours and 1, 3, 5, 8 weeks, and then fixed, decalcified, and sectioned frozenly to detect the expression of VEGF and its receptor at the fracture site by in situ hybridization and immunochemical assays. Results: VEGF mRNA and VEGF expression was detected in many kinds of cells at the fracture site during 8hours to 8 weeks after fracture. Flt1 receptor of VEGF was found in the vascular endothelial cells at the fracture site during 8 hours to 8 weeks after fracture, and strong expression of flk1 receptor was detected from 3 days to 3 weeks after fracture. Conclusions: The expression of VEGF and flt1 receptor appears during the whole course of fracture healing, especially from 1 to 3 weeks. Flk1 receptor is highly expressed in a definite period after fracture. VEGF is proved to be involved in the vascular reconstruction and fracture healing.

  16. A short review of twin pregnancy and how oxytocin receptor expression may differ in multiple pregnancy.

    Science.gov (United States)

    Turton, Peter; Neilson, James P; Quenby, Siobhan; Burdyga, Theodor; Wray, Susan

    2009-05-01

    During a multiple pregnancy, the mother and her fetuses are exposed to a variety of risks during both pregnancy and labour. The most notable of these risks is that of pre-term labour and its associated sequelae. Whilst much research has been directed towards understanding the mechanisms of uterine contractility, very little research has focussed on how contractility in multiple pregnancy differs from contractility in the singleton pregnancy. The aim of this paper is to review the changing prevalence and risks of a twin pregnancy, as well as reviewing what is known about myometrium from multiple pregnancies. The paper ends by discussing how oxytocin receptor expression may differ in twin pregnancy, based on the evidence of animal models, as well as presenting our own evidence of how oxytocin affects myometrium from twin pregnancies. We highlight the lack of the basic information needed to characterize human myometrium in twin pregnancies. Of particular note is the lack of supporting data for the hypothesis that stretch is responsible for earlier activation of the uterus in multiple pregnancy. New hypotheses based on increased experimental work are called for. Such information may throw light on specific mechanisms leading to the increased incidence of pre-term delivery in twins. PMID:19303192

  17. Serum estrogen levels and hippocampus β-estrogen receptor expressions in patients with epilepsy

    International Nuclear Information System (INIS)

    Objective: To investigate the relationship between serum estrogen (estrodial) levels estrogen β-receptor expressions in hippocampus and occurrence of seizure attack in patients of both sexes. Methods: The serum estrodial (E2) levels were detected in 8male and 9 female epileptic patients with radioimmunoassay. β-estrgen receptor (β-ER) in hippocampus were blotted with immuno-histochemical method in the 27 specimens from epilepsy surgery. Results: Few differences of E2 levels were found between those in epileptics and non-epileptics (n=30 as controls) (P>0.05). However the β-ER expression in hippocampus was significantly up-regulated in specimens from 8 female patients with catamenial epilepsy (P<0.05) as compared with that in the other 19 surgical specinens of this study and 27 other surgical specimen with different non-epileptic diseases as controls. Conclusion: Serum estrogen is not responsible for occurrence of seizure attack in patients with epilepsy. But the increased expression of β-estrogen receptors in hippocampus may be closely related with seizure in catamenial epilepsy. (authors)

  18. Characterization of a thyroid hormone receptor expressed in human kidney and other tissues

    International Nuclear Information System (INIS)

    A cDNA encoding a specific form of thyroid hormone receptor expressed in human liver, kidney, placenta, and brain was isolated from a human kidney library. Identical clones were found in human placenta and HepG2 cDNA libraries. The cDNA encodes a 490-amino acid protein. When expressed and translated in vitro, the protein products binds triiodothyronine with K/sub a/ of 2.3 /times/ 109 M/sup /minus/1/. This protein, designated human thyroid hormone receptor type α2 (hTRα2), has the same domain structure as other members of the v-erbA-related superfamily of receptor genes. It is similar to thyroid hormone receptor type α described in chicken and rat and less similar to human thyroid hormone receptor type β (formerly referred to as c-erbAβ) from placenta. However, it is distinguished from these receptors by an extension of the C-terminal hormone binding domain making it 80 amino acids longer than rat thyroid hormone receptor type α1. Different sizes of mRNA found in liver and kidney suggest that there may be tissue-specific processing of the primary transcript of this gene. Identification of human thyroid hormone receptor type α2 indicates that two or more forms of thyroid hormone receptor exist in human tissues and may explain the normal variation in thyroid hormone responsiveness of various organs and the selective tissue abnormalities found in the thyroid hormone resistance syndromes

  19. A short review of twin pregnancy and how oxytocin receptor expression may differ in multiple pregnancy.

    Science.gov (United States)

    Turton, Peter; Neilson, James P; Quenby, Siobhan; Burdyga, Theodor; Wray, Susan

    2009-05-01

    During a multiple pregnancy, the mother and her fetuses are exposed to a variety of risks during both pregnancy and labour. The most notable of these risks is that of pre-term labour and its associated sequelae. Whilst much research has been directed towards understanding the mechanisms of uterine contractility, very little research has focussed on how contractility in multiple pregnancy differs from contractility in the singleton pregnancy. The aim of this paper is to review the changing prevalence and risks of a twin pregnancy, as well as reviewing what is known about myometrium from multiple pregnancies. The paper ends by discussing how oxytocin receptor expression may differ in twin pregnancy, based on the evidence of animal models, as well as presenting our own evidence of how oxytocin affects myometrium from twin pregnancies. We highlight the lack of the basic information needed to characterize human myometrium in twin pregnancies. Of particular note is the lack of supporting data for the hypothesis that stretch is responsible for earlier activation of the uterus in multiple pregnancy. New hypotheses based on increased experimental work are called for. Such information may throw light on specific mechanisms leading to the increased incidence of pre-term delivery in twins.

  20. Effects of Dexamethasone on glucocorticoid receptor expression in a human ovarian carcinoma cell line 3AO

    Institute of Scientific and Technical Information of China (English)

    徐明娟; 宋亮年; 王昭梅

    2003-01-01

    Objective To observe the effects of Dexamethasone (Dex), a synthetic glucocorticoid, on glucocorticoid receptor expression in the human ovarian carcinoma cell line 3AO. The molecular mechanism of glucocorticoid (GC) on 3AO cells was also studied.Methods The expression and regulation of the glucocorticoid receptor in 3AO cells was studied by utilizing radioligand binding assay and quantitative RT-PCR. Results High affinity and low capacity GR existed in 3AO cells, in addition, GR binding activity was down-regulated by Dex in a time-dependent manner, to a level about 28.34% of control following 24 hours treatment, with a concomitant decrease in GR mRNA. The induction of alkaline phosphatase (AKP) activity by Dex was reversed by RU486, a potent glucocorticoid antagonist.Conclusion In 3AO cells, functional GR which can be down-regulated by Dex at the protein and mRNA level, exists suggesting that the regulating effects of Dex on GR occur at least partially at the GR mRNA level, and that the cellular effects of Dex on 3AO cells might be mediated by GR.

  1. The progesterone and estrogen modify the uterine prolactin and prolactin receptor expression of hyperprolactinemic mice.

    Science.gov (United States)

    do Amaral, Vinícius Cestari; Carvalho, Kátia Candido; Maciel, Gustavo Arantes Rosa; Simoncini, Tommaso; da Silva, Priscilla Ludovico; Marcondes, Rodrigo Rodrigues; Soares, José Maria; Baracat, Edmund Chada

    2015-02-01

    The aim of this study was to evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin (PRL) and PRL receptor's expression in the uterus of mice. For this purpose, 49 Swiss mice were divided into the following groups: GrSS (non-ovariectomized mice given vehicle); GrMET (non-ovariectomized mice treated with metoclopramide); OvSS (ovariectomized mice given vehicle); OvMET (ovariectomized mice treated with metoclopramide); OvMET+17βE (ovariectomized mice treated with metoclopramide and 17β estradiol); OvMET+MP (ovariectomized mice treated with metoclopramide and micronized progesterone); OvMET+17βE+MP (ovariectomized mice treated with metoclopramide and a solution of 17β estradiol and micronized progesterone). Immunohistochemical analyzes were evaluated semi-quantitatively. Our results showed that GrMET, OvMET+MP, and OvMET+17βE+MP presented strong PRL expression. OvMET and OvMET+17βE presented mild reaction, while GrSS and OvSS presented weak reaction. Concerning PRL receptor, OvMET+MP and OvMET+17βE+MP showed strong reaction; GrMET, OvSS, and OvMET+17βE showed mild reaction; and GrSS and OvMET showed weak reaction. These findings suggest that progesterone alone or in combination with estrogen may increase the expression of uterine PRL and PRL receptor.

  2. Detergent activation of the binding protein in the folate radioassay

    International Nuclear Information System (INIS)

    A minor cow's whey protein associated with β-lactoglobulin is used as binding protein in the competitive radioassay for serum and erythrocyte folate. Seeking to optimize the assay, we tested the performance of binder solutions of increasing purity. The folate binding protein was isolated from cow's whey by means of CM-Sepharose CL-6B cation-exchange chromatography, and further purified on a methotrexate-AH-Sepharose 4B affinity matrix. In contrast to β-lactoglobulin, the purified protein did not bind folate unless the detergents cetyltrimethylammonium (10 mmol/Ll) or Triton X-100 (1 g/L) were present. Such detergent activation was not needed in the presence of serum. There seems to be a striking analogy between these phenomena and the well-known reactivation of certain purified membrane-derived enzymes by surfactants

  3. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    Energy Technology Data Exchange (ETDEWEB)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Roskams, Tania [Department of Morphology and Molecular Pathology, University of Leuven (Belgium); Oben, Jude A., E-mail: j.oben@ucl.ac.uk [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Department of Gastroenterology and Hepatology, Guy' s and St Thomas' Hospital, London SE1 7EH (United Kingdom)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cigarette smoke may induce liver fibrosis via nicotine receptors. Black-Right-Pointing-Pointer Nicotine induces proliferation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Nicotine activates hepatic fibrogenic pathways. Black-Right-Pointing-Pointer Nicotine receptor antagonists attenuate HSC proliferation. Black-Right-Pointing-Pointer Nicotinic receptor antagonists may have utility as novel anti-fibrotic agents. -- Abstract: Background and aims: Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine - which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH). Methods: hHSC were isolated from healthy human livers and nAChR expression analyzed - RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-{alpha}2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-{beta}1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH). Results: hHSCs express muscle type ({alpha}1, {beta}1, delta and epsilon) and neuronal type ({alpha}3, {alpha}6, {alpha}7, {beta}2 and {beta}4) nAChR subunits at the mRNA level. Among these subunits, {alpha}3, {alpha}7, {beta}1 and {epsilon} were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-{alpha}2 and TGF-{beta}1 mRNA expression were significantly upregulated by nicotine and inhibited by

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

    Science.gov (United States)

    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. PMID:26787970

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

    Science.gov (United States)

    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.

  6. Hematological studies on iron- and folate-requirements in pregnancy

    Directory of Open Access Journals (Sweden)

    Taguchi,Hirokuni

    1974-04-01

    Full Text Available Hematological changes and serum iron, vitamin B12 and folate levels after administration of iron plus folic acid were com· pared with changes and levels after supplement of iron alone in 100 pregnant women. No hematological benefits by adding folic acid was revealed. It is concluded that folic acid deficiency in pregnant women is mild and routine supplementation of folic acid is not necessary except for proved cases of folate deficiency. As to the reason why folic acid deficiency is so mild and megaloblastic anemia is so rare in Japan, uniformity of dietary habits, i. e. boiled rice as basic food, was discussed.

  7. Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors.

    Science.gov (United States)

    Pivonello, Rosario; Ferone, Diego; de Herder, Wouter W; de Krijger, Ronald R; Waaijers, Marlijn; Mooij, Diana M; van Koetsveld, Peter M; Barreca, Antonina; De Caro, Maria Laura del Basso; Lombardi, Gaetano; Colao, Annamaria; Lamberts, Steven W J; Hofland, Leo J

    2004-09-01

    Dopamine is known to play a role in the modulation of aldosterone and catecholamine secretion from the adrenal gland, where dopamine receptors (DR), in particular the DR type 2 (D(2)), have been found to be expressed. DR expression has also been demonstrated in some types of benign adrenal tumors. The aims of the current study were to evaluate DR expression and D(2) localization in the normal adrenal gland and in different types of benign and malignant adrenal tumors, as well as to evaluate the in vitro effects of the dopamine agonists bromocriptine and cabergoline on hormone secretion in nontumoral adrenal cells. Adrenal tissues from 25 patients, subjected to adrenal surgery for different diseases, were studied. These included three normal adrenals; five adrenal hyperplasias; four aldosterone-secreting, two cortisol-secreting, and two clinically nonfunctioning adrenal adenomas; two aldosterone-secreting, two cortisol-secreting, and two androgen-secreting adrenal carcinomas; and three pheochromocytomas. In all tissues, DR and D(2) isoform (D(2long) and D(2short)) expression was evaluated by RT-PCR. D(2) localization was also evaluated by immunohistochemistry using a specific polyclonal antibody, whereas D(2)-like receptor expression was evaluated by receptor-ligand binding study, using the radiolabeled D(2) analog (125)I-epidepride. The effects of bromocriptine and cabergoline on baseline and ACTH and/or angiotensin II-stimulated aldosterone, cortisol, and androstenedione secretion were evaluated in cell cultures derived from five different adrenal hyperplasia. At RT-PCR, both D(1)-like and D(2)-like receptors were expressed in all normal and hyperplastic adrenals. D(2) and D(4) were expressed in aldosterone- and cortisol-secreting adenomas, cortisol-secreting carcinomas, and clinically nonfunctioning adenomas, whereas no DR was expressed in aldosterone- and androgen-secreting carcinomas. D(2), D(4), and D(5) were expressed in pheochromocytomas. In all D(2

  8. High Cell Surface Death Receptor Expression Determines Type I Versus Type II Signaling*

    Science.gov (United States)

    Meng, Xue Wei; Peterson, Kevin L.; Dai, Haiming; Schneider, Paula; Lee, Sun-Hee; Zhang, Jin-San; Koenig, Alexander; Bronk, Steve; Billadeau, Daniel D.; Gores, Gregory J.; Kaufmann, Scott H.

    2011-01-01

    Previous studies have suggested that there are two signaling pathways leading from ligation of the Fas receptor to induction of apoptosis. Type I signaling involves Fas ligand-induced recruitment of large amounts of FADD (FAS-associated death domain protein) and procaspase 8, leading to direct activation of caspase 3, whereas type II signaling involves Bid-mediated mitochondrial perturbation to amplify a more modest death receptor-initiated signal. The biochemical basis for this dichotomy has previously been unclear. Here we show that type I cells have a longer half-life for Fas message and express higher amounts of cell surface Fas, explaining the increased recruitment of FADD and subsequent signaling. Moreover, we demonstrate that cells with type II Fas signaling (Jurkat or HCT-15) can signal through a type I pathway upon forced receptor overexpression and that shRNA-mediated Fas down-regulation converts cells with type I signaling (A498) to type II signaling. Importantly, the same cells can exhibit type I signaling for Fas and type II signaling for TRAIL (TNF-α-related apoptosis-inducing ligand), indicating that the choice of signaling pathway is related to the specific receptor, not some other cellular feature. Additional experiments revealed that up-regulation of cell surface death receptor 5 levels by treatment with 7-ethyl-10-hydroxy-camptothecin converted TRAIL signaling in HCT116 cells from type II to type I. Collectively, these results suggest that the type I/type II dichotomy reflects differences in cell surface death receptor expression. PMID:21865165

  9. A sensitive electrochemiluminescence cytosensor for quantitative evaluation of epidermal growth factor receptor expressed on cell surfaces

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Yanjuan; Zhang, Shaolian; Wen, Qingqing; Huang, Hongxing; Yang, Peihui, E-mail: typh@jnu.edu.cn

    2015-06-30

    Highlights: • EGF-cytosensor was used for evaluating EGFR expression level on cell surfaces. • CdSQDs and EGF were coated on magnetic beads (MBs) for ECL-probe. • Good sensitivity was achieved due to the signal amplification of ECL-probe. - Abstract: A sensitive electrochemiluminescence (ECL) strategy for evaluating the epidermal growth factor receptor (EGFR) expression level on cell surfaces was designed by integrating the specific recognition of EGFR expressed on MCF-7 cell surfaces with an epidermal growth factor (EGF)-funtionalized CdS quantum dots (CdSQDs)-capped magnetic bead (MB) probe. The high sensitivity of ECL probe of EGF-funtionalized CdSQD-capped-MB was used for competitive recognition with EGFR expressed on cell surfaces with recombinant EGFR protein. The changes of ECL intensity depended on both the cell number and the expression level of EGFR receptor on cell surfaces. A wide linear response to cells ranging from 80 to 4 × 10{sup 6} cells mL{sup −1} with a detection limit of 40 cells mL{sup −1} was obtained. The EGF-cytosensor was used to evaluate EGFR expression levels on MCF-7 cells, and the average number of EGFR receptor on single MCF-7 cells was 1.35 × 10{sup 5} with the relative standard deviation of 4.3%. This strategy was further used for in-situ and real-time evaluating EGFR receptor expressed on cell surfaces in response to drugs stimulation at different concentration and incubation time. The proposed method provided potential applications in the detection of receptors on cancer cells and anticancer drugs screening.

  10. Neural endocannabinoid CB1 receptor expression, social status, and behavior in male European starlings.

    Science.gov (United States)

    DeVries, M Susan; Cordes, Melissa A; Rodriguez, Jonathan D; Stevenson, Sharon A; Riters, Lauren V

    2016-08-01

    Many species modify behavior in response to changes in resource availability or social status; however, the neural mechanisms underlying these modifications are not well understood. Prior work in male starlings demonstrates that status-appropriate changes in behavior involve brain regions that regulate social behavior and vocal production. Endocannabinoids are ubiquitously distributed neuromodulators that are proposed to play a role in adjusting behavior to match social status. As an initial step to provide insight into this hypothesis we observed flocks of male starlings in outdoor aviaries during the breeding season. We used quantitative real-time PCR to measure expression of endocannabinoid CB1 receptors in brain regions involved in social behavior and motivation (lateral septum [LS], ventral tegmental area [VTA], medial preoptic nucleus [POM]) and vocal behavior (Area X and robust nucleus of the arcopallium; RA). Males with nesting sites sang to females and displaced other males more than males without nesting sites. They also had higher levels of CB1 receptor expression in LS and RA. CB1 expression in LS correlated positively with agonistic behaviors. CB1 expression in RA correlated positively with singing behavior. CB1 in VTA also correlated positively with singing when only singing birds were considered. These correlations nicely map onto the well-established role of LS in agonistic behavior and the known role of RA in song production and VTA in motivation and song production. Studies are now needed to precisely characterize the role of CB1 receptors in these regions in the production of status-appropriate social behaviors. PMID:27206544

  11. Reduced retinoids and retinoid receptors' expression in pancreatic cancer: A link to patient survival.

    Science.gov (United States)

    Bleul, Tim; Rühl, Ralph; Bulashevska, Svetlana; Karakhanova, Svetlana; Werner, Jens; Bazhin, Alexandr V

    2015-09-01

    Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers in the world. All-trans retinoic acid (ATRA) is the major physiologically active form of vitamin A, regulating expression of many genes. Disturbances of vitamin A metabolism are prevalent in some cancer cells. The main aim of this work was to investigate deeply the components of retinoid signaling in PDAC compared to in the normal pancreas and to prove the clinical importance of retinoid receptor expression. For the study, human tumor tissues obtained from PDAC patients and murine tumors from the orthotopic Panc02 model were used for the analysis of retinoids, using high performance liquid chromatography mass spectrometry and real-time RT-PCR gene expression analysis. Survival probabilities in univariate analysis were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for the multivariate analysis. In this work, we showed for the first time that the ATRA and all-trans retinol concentration is reduced in PDAC tissue compared to their normal counterparts. The expression of RARα and β as well as RXRα and β are down-regulated in PDAC tissue. This reduced expression of retinoid receptors correlates with the expression of some markers of differentiation and epithelial-to-mesenchymal transition as well as of cancer stem cell markers. Importantly, the expression of RARα and RXRβ is associated with better overall survival of PDAC patients. Thus, reduction of retinoids and their receptors is an important feature of PDAC and is associated with worse patient survival outcomes.

  12. Role of soluble triggering receptor expressed on myeloid cells in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Michalis Tzivras; Vassilios Koussoulas; Evangelos J Giamarellos-Bourboulis; Dimitrios Tzivras; Thomas Tsaganos; Pantelis Koutoukas; Helen Giamarellou; Athanasios Archimandritis

    2006-01-01

    AIM: To investigate the probable role of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the pathogenesis of inflammatory bowel disease (IBD).METHODS: Fifty-eight patients were enrolled; nineteen healthy volunteers served as controls; 8 patients were diagnosed with Crohn's disease, and 31 with ulcerative colitis. Clinical and endoscopic activity indexes of patients with Crohn's disease and ulcerative colitis respectively were estimated. Upon admission blood was sampled;sTREM-1 and TNFα were measured by an immunoassay and malondialdehyde (MDA) by the thiobarbitourate assay, after passage through an HPLC system.RESULTS: Median ± SE of TNFα of controls, patients with Crohn's disease and patients with ulcerative colitis were 6.02 ± 3.94, 7.98 ± 5.08 (P = NS vs controls), and 8.45±4.15 ng/L (P = 0.018 vs controls) respectively.Respective values of sTREM-1 were 53.31 ± 32.93,735.10 ± 197.17 (P = 0.008 vs controls) and 435.82 ±279.71 ng/L (P = 0.049 vs controls), sTREM-1 was positively correlated with Crohn's disease activity index and clinical and endoscopic activity indexes of ulcerative colitis (P = 0.002, 0.001 and 0.009, respectively), sTREM-1 of patients with ulcerative colitis was positively correlated with TNFα (P = 0.001).CONCLUSION: sTREM-1 seems to behave as a novel mediator in IBD in correlation with the degree of the inflammatory reaction of the intestinal mucosa.

  13. Epstein-Barr virus receptor expression on human CD8+ (cytotoxic/suppressor) T lymphocytes.

    Science.gov (United States)

    Sauvageau, G; Stocco, R; Kasparian, S; Menezes, J

    1990-02-01

    In 1977 we showed that cells of a human lymphocytic leukaemia-derived T line (Molt-4) have receptors for Epstein-Barr virus (EBV). More recently, EBV-positive human T cell lymphomas have been recognized and human T cell lines containing the EBV genome have been established in vitro. To understand better the interaction of EBV with T cells, we decided to determine first whether human peripheral blood T lymphocytes express receptors for EBV. Using flow cytometry we examined the binding of both lymphocyte-transforming (B95-8) and non-transforming (P3HR-1) strains of EBV to T lymphocyte subpopulations, using a double labelling technique with T cell-specific phycoerythrinated monoclonal antibodies (Leu 2a) and fluoresceinated viral preparation. Our results suggest that, in general, about 50% of the CD8+ (or suppressor/cytotoxic) T cell subpopulation from both EBV-seropositive and -seronegative individuals can bind EBV. EBV receptor expression on these T cells was about 10 and 51 times less than that on Molt-4 and Raji (an EBV receptor-positive B cell line) cells, respectively. The specificity of this binding was demonstrated by the inhibition of attachment of viral preparations preincubated with a monoclonal antibody directed against the viral ligand (gp240/350), and by preincubating these target T cells with unlabelled virus. We were unable to detect EBV-induced antigens in infected T cells, suggesting that, as in Molt-4 cells, virus internalization may not occur in fresh T cells and/or that the virus receptor may not be completely functional. We were also unable to detect C3d (or CR2) receptors on these T cells, or to inhibit virus attachment by treating the targets with an anti-CR2 monoclonal antibody (OKB7), suggesting that the EBV receptor on CD8+ peripheral blood lymphocytes is different from that on B cells. PMID:2155291

  14. Changes of epidermal mu-opiate receptor expression and nerve endings in chronic atopic dermatitis.

    Science.gov (United States)

    Bigliardi-Qi, M; Lipp, B; Sumanovski, L T; Buechner, S A; Bigliardi, P L

    2005-01-01

    There is increasing evidence that neuropeptides such as a substance P, neurotrophins or beta-endorphin, an endogenous agonist for mu-opioid receptor, are involved in the pathogenesis of atopic dermatitis in which mental stress and scratching deteriorate the disease. mu-Opioid receptor, a G-protein-coupled receptor, can be downregulated and internalized by agonists and other factors in vitro. In this study, we investigated the regulation of mu-opioid receptor and nerve endings in atopic dermatitis patients. Skin biopsies from atopic dermatitis patients revealed a significant downregulation of mu-opiate receptor expression in epidermis of atopic dermatitis. Permeabilization of the skin showed that the receptor in keratinocytes from atopic dermatitis is internalized. The mRNA expression pattern of the mu-opiate receptor is different in epidermis taken from patients with chronic atopic dermatitis compared to normal skin. In atopic dermatitis, the mRNA is concentrated in the subcorneal layers of the epidermis and in normal skin in the suprabasal layers. Staining of the nerve endings using protein gene product 9.5 shows a different pattern of epidermal nerve endings in normal skin compared to atopic dermatitis. In normal skin, the epidermal nerve endings are rather thick. However, in atopic dermatitis, the epidermal nerve endings are thin and run straight through the epidermis. Based on these observations and combining the 'intensity' and 'pattern' hypothesis, we propose a new theory especially for histamine-unrelated, peripheral induction of chronic pruritus. We suggest that 'itch' is elicited in the epidermal unmyelinated nerve C-fibers and 'pain' in the dermal unmyelinated nerve fibers. The downregulation of the opioid receptor in the epidermis contributes to the chronic itching. We call this new hypothesis the 'layer hypothesis'.

  15. Association of haemolytic uraemic syndrome with dysregulation of chemokine receptor expression in circulating monocytes.

    Science.gov (United States)

    Ramos, Maria Victoria; Ruggieri, Matias; Panek, Analia Cecilia; Mejias, Maria Pilar; Fernandez-Brando, Romina Jimena; Abrey-Recalde, Maria Jimena; Exeni, Andrea; Barilari, Catalina; Exeni, Ramon; Palermo, Marina Sandra

    2015-08-01

    Haemolytic uraemic syndrome (HUS) is the major complication of Escherichia coli gastrointestinal infections that are Shiga toxin (Stx) producing. Monocytes contribute to HUS evolution by producing cytokines that sensitize endothelial cells to Stx action and migration to the injured kidney. As CC chemokine receptors (CCRs) are involved in monocyte recruitment to injured tissue, we analysed the contribution of these receptors to the pathogenesis of HUS. We analysed CCR1, CCR2 and CCR5 expression in peripheral monocytes from HUS patients during the acute period, with healthy children as controls. We observed an increased expression of CCRs per cell in monocytes from HUS patients, accompanied by an increase in the absolute number of monocytes CCR1+, CCR2+ and CCR5+. It is interesting that prospective analysis confirmed that CCR1 expression positively correlated with HUS severity. The evaluation of chemokine levels in plasma showed that regulated on activation of normal T-cell-expressed and -secreted (RANTES) protein was reduced in plasma from patients with severe HUS, and this decrease correlated with thrombocytopenia. Finally, the expression of the higher CCRs was accompanied by a loss of functionality which could be due to a mechanism for desensitization to compensate for altered receptor expression. The increase in CCR expression correlates with HUS severity, suggesting that the dysregulation of these receptors might contribute to an increased risk of renal damage. Activated monocytes could be recruited by chemokines and then receptors could be dysregulated. The dysregulation of CCRs and their ligands observed during the acute period suggests that a chemokine pathway would participate in HUS development.

  16. The association between atopy and factors influencing folate metabolism: is low folate status causally related to the development of atopy?

    DEFF Research Database (Denmark)

    Husemoen, LL; Toft, U.; Fenger, Mogens;

    2006-01-01

    aimed at examining the association between atopy and markers of impaired folate metabolism, i.e. MTHFR(C677T) genotype, plasma total homocysteine, and dietary intakes of methionine, folates, and vitamins B12, B6, and B2. METHODS: Cross-sectional population-based study of 1,671 male and female residents...... homocysteine was measured by fluorescent polarization immunoassay. Dietary vitamin intakes were estimated from a semi-quantitative food frequency questionnaire. RESULTS: The prevalence of atopy was associated with MTHFR(C677T) genotype. TT individuals had a significantly higher risk of atopy compared with CC...

  17. Effect of dietary folic acid supplementation on egg folate content and the performance and folate status of two strains of laying hens.

    Science.gov (United States)

    Hebert, K; House, J D; Guenter, W

    2005-10-01

    Enrichment of eggs with folate is possible when dietary folic acid levels are increased. However, development of optimal strategies for the production of folate-enriched eggs requires knowledge as to differences due to strain of bird and a greater understanding of the factors limiting egg folate deposition. To this end, a study was designed to determine the response of two leghorn strains that differ in production performance. Hyline W36 and W98 hens (n = 6 per diet) received a barley-based ration containing 0, 2, 4, 8, 16, 32, 64, or 128 mg/kg of crystalline folic acid for 21 d. Response criteria included production parameters, measures of blood folate status, and egg folate content. Significant (P folic acid through a reduction in plasma homocysteine concentrations, suggesting that this strain has a higher requirement for folate than the W36 strain. Overall, egg folate content is maximized when crystalline folic acid is supplemented to the diet at 2 mg/kg or higher. Higher levels of egg folate are not achieved due to the saturation of the precursor pool for egg folate deposition.

  18. CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency.

    Science.gov (United States)

    Torres, A; Newton, S A; Crompton, B; Borzutzky, A; Neufeld, E J; Notarangelo, L; Berry, G T

    2015-01-01

    Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease. PMID:26006721

  19. Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.

    Science.gov (United States)

    Nogueira, Eugénia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrícia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonçalo J L; Moreira, Alexandra; Stockinger, Hannes; Burnet, Michael; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Bismuth, Georges; Cavaco-Paulo, Artur

    2015-12-01

    Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance. PMID:26510317

  20. Enhancing Methotrexate Tolerance with Folate Tagged Liposomes in Arthritic Mice.

    Science.gov (United States)

    Nogueira, Eugénia; Lager, Franck; Le Roux, Delphine; Nogueira, Patrícia; Freitas, Jaime; Charvet, Celine; Renault, Gilles; Loureiro, Ana; Almeida, Catarina R; Ohradanova-Repic, Anna; Machacek, Christian; Bernardes, Gonçalo J L; Moreira, Alexandra; Stockinger, Hannes; Burnet, Michael; Carmo, Alexandre M; Gomes, Andreia C; Preto, Ana; Bismuth, Georges; Cavaco-Paulo, Artur

    2015-12-01

    Methotrexate is the first line of treatment of rheumatoid arthritis. Since many patients become unresponsive to methotrexate treatment, only very expensive biological therapies are effective and increased methotrexate tolerance strategies need to be identified. Here we propose the encapsulation of methotrexate in a new liposomal formulation using a hydrophobic fragment of surfactant protein conjugated to a linker and folate to enhance their tolerance and efficacy. In this study we aim to evaluate the efficiency of this system to treat rheumatoid arthritis, by targeting folate receptor β present at the surface of activated macrophages, key effector cells in this pathology. The specificity of our liposomal formulation to target folate receptor β was investigated both in vitro as in vivo using a mouse model of arthritis (collagen-induced arthritis in DBA/1J mice strain). In both systems, the liposomal constructs were shown to be highly specific and efficient in targeting folate receptor β. These liposomal formulations also significantly increase the clinical benefit of the encapsulated methotrexate in vivo in arthritic mice, together with reduced expression of CD39 and CD73 ectonucleotidases by joint-infiltrating macrophages. Thus, our formulation might be a promising cost effective way to treat rheumatoid arthritis and delay or reduce methotrexate intolerance.

  1. Research goals for folate and related B vitamin in Europe

    NARCIS (Netherlands)

    Finglas, P.M.; Meer, K. de; Molloy, A.; Verhoef, P.; Pietrzik, K.; Powers, H.J.; Straeten, D. van der; Jägerstad, M.; Varela-Moreiras, G.; Vliet, T. van; Havenaar, R.; Buttriss, J.; Wright, A.J.A.

    2006-01-01

    In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, f

  2. Bioavailability of folate from processed spinach in humans

    NARCIS (Netherlands)

    Castenmiller, J.J.M.; Poll, van de C.J.; West, C.E.; Brouwer, I.A.; Thomas, C.M.G.; Dusseldorp, van M.

    2000-01-01

    The effect of the food matrix and dietary fibre on the bioavailability of folate is not known. In a controlled, 3-week dietary intervention study, 28 men and 42 women were divided into six groups to receive either a control diet (n = 10), or the control diet plus 20 g/MJ per day (n = 12 per group) o

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

    Science.gov (United States)

    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...

  4. Causes of Vitamin B12 and Folate Deficiency

    Science.gov (United States)

    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...

  5. Hyperhomocysteinemia in ulcerative colitis is related to folate levels

    Institute of Scientific and Technical Information of China (English)

    Petros Zezos; Georgia Papaioannou; Nikolaos Nikolaidis; Themistoclis Vasiliadis; Olga Giouleme; Nikolaos Evgenidis

    2005-01-01

    AIM: To study the prevalence and clinical significance of hyperhomocysteinemia (hHcys), an independent factor for arterial and venous thrombosis, in a group of patients with ulcerative colitis (UC).METHODS: Fasting homocysteine (Hcys), folate, and vitamin B12 serum levels were measured in 40 UC patients and 50 healthy controls. Clinical data regarding UC were gathered.RESULTS: Median serum Hcys levels in UC patients were similar to those in controls (12.26 μmol/L vs 12.32 μmol/L), but the prevalence of hHcys was higher in UC patients than in controls (30% vs 10%, P= 0.028). UC significantly increased the risk of hHcys (adjusted odds ratio: 4.125;95% CI: 1.26-13.44). Multivariate regression analysis showed that male sex, folate and vitamin B12 deficiency or lower serum values were significant independent predictors of higher Hcys levels in UC patients (r2 = 0.4; P<0.001).CONCLUSION: hHcys is common in UC patients and it is related to folate and vitamin B12 deficiency or lower serum values. It would be reasonable for patients with UC to receive folate and vitamin B complex supplements as a prophylactic measure.

  6. Causes of vitamin B12 and folate deficiency.

    Science.gov (United States)

    Allen, Lindsay H

    2008-06-01

    This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor vitamin 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 vegetarians (vegans) are at risk for vitamin B12 deficiency, evidence now indicates that low intakes of animal-source foods, such as occur in some lacto-ovo vegetarians and many less-industrialized countries, cause vitamin B12 depletion. Malabsorption of the vitamin is most commonly observed as food-bound cobalamin malabsorption due to gastric atrophy in the elderly, and probably as a result of Helicobacter pylori infection. There is growing evidence that gene polymorphisms in transcobalamins affect plasma vitamin B12 concentrations. The primary cause of folate deficiency is low intake of sources rich in the vitamin, such as legumes and green leafy vegetables, and the consumption of these foods may explain why folate status can be adequate in relatively poor populations. Other situations in which the risk of folate deficiency increases include lactation and alcoholism.

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

    NARCIS (Netherlands)

    Blancquaert, D.; Storozhenko, S.; Daele, W.; Stove, C.; Visser, R.G.F.; Lambert, W.; Straeten, van der D.

    2013-01-01

    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 af

  8. DNA methylation and folate metabolism in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Shun Shi Zhu; Shu Dong Xiao; Zhi Ping Chen; Yao Shi; Jing Yuan Fang; Rong Rong Li; Joel B Masor

    2000-01-01

    AIM To investigate DNA methylation status in gastric cancer and its relationship with folate metabolism.METHODS Serum before operation, the gastric mucosa from the lesion, and the surrounding area inpatients with gastric cancer and the remote normal-appearing mucosa of the resected stomach were collectedrespectively. The serum folate, mucosal tissue folate, S-adenosylmethionine ( SAM ), S-adenosylhomocysteine (SAH), and the DNA methylation levels were determined.RESULTS The tissue folate was significantly lower than that in ulcers, especially in the surrounding andnormal mucosa (0.38±0.13, 0.50±0.17 vs 0.53±0.50, 0.79±0.82ng/mg protein, P < 0.01), and itdecreased gradually in the lesion areas. The DNA methylation status showed similar decreasing trend incancers compared with the methylation increasing trend in ulcers. The SAM level ascended in the lesion areaswith a higher. concentration in cancer mueosa (63.5±43.0 vs 25.9±11.9nmol/g tissue, P < 0.01 ). Theaccumulation of SAH in the surrounding and normal mucosa of cancers was observed (17.3±24.6, 15.5±8.6vs 14.6±4.2, 10.0±1.9nmol/g tissue, P < 0.05 - 0.01). There were significantly negative correlationsbetween tissue folate and the SAM and SAH levels in the three areas.CONCLUSION Patients with gastric cancer have the regional folate deficiency in the stomach mucosa,although the serum folate level remains normal. This disturbs the local SAM and SAH metabolism withaccumulation of SAH and DNA hypomethylation which has been known as an important molecularmechanism for carcinogenesis. Folic acid can modulate DNA methylation status by its effect in one-carbongroup metabolism and thus affect the process of the carcinogenesis. Therefore, this may be an access for theprevention of gastric cancer.

  9. Electroacupuncture diminishes P2X2 and P2X3 purinergic receptor expression in dorsal root ganglia of rats with visceral hypersensitivity

    Institute of Scientific and Technical Information of China (English)

    Zhijun Weng; Luyi Wu; Yuan Lu; Lidong Wang; Linying Tan; Ming Dong; Yuhu Xin

    2013-01-01

    Electroacupuncture at Shangjuxu (ST37) and Tianshu (ST25) can improve visceral hypersensitivity in rats. Colorectal distension was used to establish a rat model of chronic visceral hypersensitivity. Immunohistochemistry was used to detect P2X2 and P2X3 receptor expression in dorsal root ganglia from rats with chronic visceral hypersensitivity. Results demonstrated that abdominal withdrawal reflex scores obviously increased following establishment of the model, indicating visceral hypersensitivity. Simultaneously, P2X2 and P2X3 receptor expression increased in dorsal root ganglia. After bilateral electroacupuncture at Shangjuxu and Tianshu, abdominal withdrawal reflex scores and P2X2 and P2X3 receptor expression decreased in rats with visceral hypersensitivity. These results indicated that electroacupuncture treatment improved visceral hypersensitivity in rats with irritable bowel syndrome by reducing P2X2 and P2X3 receptor expression in dorsal root ganglia.

  10. Laying hens can convert high doses of folic acid added to the feed into natural folates in eggs providing a novel source of food folate.

    Science.gov (United States)

    Hoey, Leane; McNulty, Helene; McCann, Elizabeth M E; McCracken, Kelvin J; Scott, John M; Marc, Barbara Blaznik; Molloy, Anne M; Graham, Ciaren; Pentieva, Kristina

    2009-01-01

    There are few good sources of natural food folates apart from green leafy vegetables and these may have a limited potential to increase folate status because of substantial losses that can occur during cooking. Fortified foods can overcome this but are controversial because of safety concerns regarding chronic exposure to high-dose folic acid (FA; the synthetic form). The aim of the present study was to develop eggs with an enriched natural folate content and minimal unmetabolised FA. Forty-eight, 30-week-old laying hens were randomised to receive the basal feed (formulated to provide 1 mg folate/kg feed) to which had been added one of the following FA levels (0, 2, 4, 8, 16, 32 mg/kg feed). Total folate was measured in eggs collected throughout the 12-week study period and the FA content estimated at 12 weeks. Results showed that the maximal egg folate content was achieved by adding 16 mg FA/kg feed. At this optimal dose, the total folate content per egg was 75 microg (compared with 32 microg in a regular egg) of which FA represented at most 10%, a level which would probably be converted into natural folates by humans after ingestion. The results demonstrate that it is possible to use synthetic FA at high doses to produce novel animal foods enriched with natural folates in a cost-efficient process. Such foods may be particularly relevant to European populations without access to FA fortification and therefore dependent on natural food folate sources for the primary prevention of folate-related disease.

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

    Directory of Open Access Journals (Sweden)

    J Pedro Fernández-Murray

    2016-01-01

    Full Text Available 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.

  12. Buffett's Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting...

  13. Folate: a key to optimizing health and reducing disease risk in the elderly.

    Science.gov (United States)

    Rampersaud, Gail C; Kauwell, Gail P A; Bailey, Lynn B

    2003-02-01

    Inadequate folate status is associated with an increased risk for chronic diseases that may have a negative impact on the health of the aging population. Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Inadequate folate status may result in hyperhomocysteinemia, a significant risk factor for atherosclerotic vascular disease, changes in DNA that may result in pro-carcinogenic effects and increased risk for cognitive dysfunction. Folate status may be negatively influenced by inadequate intake, genetic polymorphisms and interactions with various drugs. In the US, folic acid is now added to enriched grain products and continues to be included in the majority of ready-to-eat breakfast cereals. Recent data indicate that the folate status in the US population has improved significantly, presumably due to the effects of fortification. Folic acid (not food folate) intake in excess of the Tolerable Upper Intake Level may mask the diagnosis of a vitamin B(12) deficiency, which is more prevalent in the elderly than younger individuals. When folic acid supplements are recommended, a multivitamin that includes vitamin B(12) should also be advised. To safely and effectively increase folate intake in the elderly, naturally occurring folate-rich food sources should be promoted. Folate-rich foods include orange juice, dark green leafy vegetables, asparagus, strawberries and legumes. These foods are also excellent sources of other health-promoting nutrients associated with chronic disease risk reduction.

  14. Exploring Folate Diversity in Wild and Primitive Potatoes for Modern Crop Improvement.

    Science.gov (United States)

    Robinson, Bruce R; Sathuvalli, Vidyasagar; Bamberg, John; Goyer, Aymeric

    2015-01-01

    Malnutrition is one of the world's largest health concerns. Folate (also known as vitamin B₉) is essential in the human diet, and without adequate folate intake, several serious health concerns, such as congenital birth defects and an increased risk of stroke and heart disease, can occur. Most people's folate intake remains sub-optimal, even in countries that have a folic acid food fortification program in place. Staple crops, such as potatoes, represent an appropriate organism for biofortification through traditional breeding based on their worldwide consumption and the fact that modern cultivars only contain about 6% of the daily recommended intake of folate. To start breeding potatoes with enhanced folate content, high folate potato material must be identified. In this study, 250 individual plants from 77 accessions and 10 Solanum species were screened for their folate content using a tri-enzyme extraction and microbial assay. There was a 10-fold range of folate concentrations among individuals. Certain individuals within the species Solanum tuberosum subsp. andigenum, Solanum vernei and Solanum boliviense have the potential to produce more than double the folate concentrations of commercial cultivars, such as Russet Burbank. Our results show that tapping into the genetic diversity of potato is a promising approach to increase the folate content of this important crop. PMID:26670256

  15. Folate receptor beta as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients

    NARCIS (Netherlands)

    J.W. van der Heijden; R. Oerlemans; B.A.C. Dijkmans; H. Qi; C.J. van der Laken; W.F. Lems; A.L. Jackman; M.C. Kraan; P.P. Tak; M. Ratnam; G. Jansen

    2009-01-01

    OBJECTIVE: To determine the expression of folate receptor beta (FRbeta) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FRbeta than methotrexat

  16. Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus.

    Science.gov (United States)

    Wiater, M F; Mukherjee, S; Li, A-J; Dinh, T T; Rooney, E M; Simasko, S M; Ritter, S

    2011-11-01

    Sleep and feeding rhythms are highly coordinated across the circadian cycle, but the brain sites responsible for this coordination are unknown. We examined the role of neuropeptide Y (NPY) receptor-expressing neurons in the mediobasal hypothalamus (MBH) in this process by injecting the targeted toxin, NPY-saporin (NPY-SAP), into the arcuate nucleus (Arc). NPY-SAP-lesioned rats were initially hyperphagic, became obese, exhibited sustained disruption of circadian feeding patterns, and had abnormal circadian distribution of sleep-wake patterns. Total amounts of rapid eye movement sleep (REMS) and non-REMS (NREMS) were not altered by NPY-SAP lesions, but a peak amount of REMS was permanently displaced to the dark period, and circadian variation in NREMS was eliminated. The phase reversal of REMS to the dark period by the lesion suggests that REMS timing is independently linked to the function of MBH NPY receptor-expressing neurons and is not dependent on NREMS pattern, which was altered but not phase reversed by the lesion. Sleep-wake patterns were altered in controls by restricting feeding to the light period, but were not altered in NPY-SAP rats by restricting feeding to either the light or dark period, indicating that disturbed sleep-wake patterns in lesioned rats were not secondary to changes in food intake. Sleep abnormalities persisted even after hyperphagia abated during the static phase of the lesion. Results suggest that the MBH is required for the essential task of integrating sleep-wake and feeding rhythms, a function that allows animals to accommodate changeable patterns of food availability. NPY receptor-expressing neurons are key components of this integrative function.

  17. Internalization of FLAG-MOR in low or high receptor expressing mouse pituitary AtT20 cell lines

    International Nuclear Information System (INIS)

    Full text: Receptor endocytosis is a process that contributes to the desensitization of receptor mediated functional responses. We subcloned FLAG-tagged μopioid receptors (MOR)in mouse pituitary AtT20 cells and selected for a high and a low receptor expressing cell line. Using [3 H ]Naloxone binding to cell membranes,we were able to determine cell receptor number from Scatchard analysis. The high expressing cell line had 37,000 receptors/cell and the low expressing cell line had 8000 receptors/cell. Mouse AtT20 cells have endogenous calcium currents (ICa). (ICa) was reversibly inhibited by μ-opioid agonists in both cell lines. Inhibition of ICa by 1 μM DAMGO was 26 ±3% and 17 ±2% in high and low receptor cell lines, respectively. The selective MOR antagonist CTAP (1 μM)blocked DAMGO mediated inhibition of ICa .Endocytosis of FLAG-MOR was examined using immunohistochemistry and confocal microscopy. Opioid ligands of differing intrinsic efficacies were examined on FLAG-MOR endocytosis. Internalization of FLAG-MOR by 20 minute incubation at 37deg C following 10 μM DAMGO or 10 μM methadone binding at 4 deg C,resulted in an increase in intracellular immunoreactivity for high and low receptor expressing cells. Morphine (10 μM) and the opioid receptor antagonist,naloxone (1 μM), did not cause an increase in cytosolic immunoreactivity after a 20 minute incubation in either cell line. Comparison of time courses for receptor endocytosis and receptor mediated ICa desensitization for high and low receptor expressing cell lines will be discussed. Copyright (1998) Australian Neuroscience Society

  18. Effect of Exercise Training on Adiponectin Receptor Expression and Insulin Resistance in Mice Fed a High Fat Diet

    OpenAIRE

    Naglaa Fathy Alhusseini; Nasr Arafat Belacy; Enas Mohammed Kasem; Mona Maher Allam

    2010-01-01

    Problem statement: Adiponectin is an adipocyte secreted hormones, exerts its effects via the specific receptors. AdipoR1 and adipoR2 and plays a pivotal role in lipid and glucose metabolism. Approach: We investigated the effect of increased physical activities on insulin resistance and if this effect is modulated through adiponectin receptor expression. Results: We also assessed the effect of High Fat Diet (HFD) on adipoRs expression. Mice were subjected to 16 weeks of HFD protocol then to 4,...

  19. Alpha fetoprotein

    Science.gov (United States)

    Fetal alpha globulin; AFP ... Greater than normal levels of AFP may be due to: Cancer in testes , ovaries, biliary (liver secretion) tract, stomach, or pancreas Cirrhosis of the liver Liver cancer ...

  20. Folylpoly-γ-glutamate synthetase: A key determinant of folate homeostasis and antifolate resistance in cancer.

    Science.gov (United States)

    Raz, Shachar; Stark, Michal; Assaraf, Yehuda G

    2016-09-01

    Mammalians are devoid of autonomous biosynthesis of folates and hence must obtain them from the diet. Reduced folate cofactors are B9-vitamins which play a key role as donors of one-carbon units in the biosynthesis of purine nucleotides, thymidylate and amino acids as well as in a multitude of methylation reactions including DNA, RNA, histone and non-histone proteins, phospholipids, as well as intermediate metabolites. The products of these S-adenosylmethionine (SAM)-dependent methylations are involved in the regulation of key biological processes including transcription, translation and intracellular signaling. Folate-dependent one-carbon metabolism occurs in several subcellular compartments including the cytoplasm, mitochondria, and nucleus. Since folates are essential for DNA replication, intracellular folate cofactors play a central role in cancer biology and inflammatory autoimmune disorders. In this respect, various folate-dependent enzymes catalyzing nucleotide biosynthesis have been targeted by specific folate antagonists known as antifolates. Currently, antifolates are used in drug treatment of multiple human cancers, non-malignant chronic inflammatory disorders as well as bacterial and parasitic infections. An obligatory key component of intracellular folate retention and intracellular homeostasis is (anti)folate polyglutamylation, mediated by the unique enzyme folylpoly-γ-glutamate synthetase (FPGS), which resides in both the cytoplasm and mitochondria. Consistently, knockout of the FPGS gene in mice results in embryonic lethality. FPGS catalyzes the addition of a long polyglutamate chain to folates and antifolates, hence rendering them polyanions which are efficiently retained in the cell and are now bound with enhanced affinity by various folate-dependent enzymes. The current review highlights the crucial role that FPGS plays in maintenance of folate homeostasis under physiological conditions and delineates the plethora of the molecular mechanisms

  1. Type 1 chemokine receptor expression in Chagas' disease correlates with morbidity in cardiac patients.

    Science.gov (United States)

    Gomes, Juliana A S; Bahia-Oliveira, Lilian M G; Rocha, Manoel Otávio C; Busek, Solange C U; Teixeira, Mauro M; Silva, João Santana; Correa-Oliveira, Rodrigo

    2005-12-01

    Chemokines and chemokine receptors (CKRs) control the migration of leukocytes during the inflammatory process and are important immunological markers of type 1 (CCR5 and CXCR3) and type 2 (CCR3 and CCR4) responses. The coexpression of CKRs (CCR2, CCR3, CCR5, CXCR3, and CXCR4) and intracellular cytokines (interleukin-10 [IL-10], IL-4, tumor necrosis factor alpha [TNF-alpha], and gamma interferon [IFN-gamma]) on T CD4+ and CD8+ peripheral cells from individuals with indeterminate (IND) or cardiac (CARD) clinical forms of Chagas' disease after in vitro stimulation with Trypanosoma cruzi antigens, were evaluated in this study. The percentage of T CD4+ and CD8+ cells coexpressing CCR5 and IFN-gamma, CXCR3 and IFN-gamma, and CXCR3 and TNF-alpha were higher in CARD than in IND individuals; on the other hand, the percentage of T CD4+ or CD8+ cells coexpressing CCR3 and IL-10 or coexpressing CCR3 and IL-4 were lower in CARD individuals than in IND individuals. In addition, a significant positive correlation between the expression of CCR5 or CXCR3 and IFN-gamma was observed in CARD individuals contrasting with a significant positive correlation between the expression of CCR3 and IL-4 and of CCR3 and IL-10 in IND patients. These results reinforce the hypothesis that a T. cruzi-exacerbated specific type 1 immune response developed by CARD chagasic patients is associated with the development of heart pathology.

  2. Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation.

    Science.gov (United States)

    Chaudhari, Snehal N; Mukherjee, Madhumati; Vagasi, Alexandra S; Bi, Gaofeng; Rahman, Mohammad M; Nguyen, Christine Q; Paul, Ligi; Selhub, Jacob; Kipreos, Edward T

    2016-07-11

    Here we describe an in vitro primary culture system for Caenorhabditis elegans germline stem cells. This culture system was used to identify a bacterial folate as a positive regulator of germ cell proliferation. Folates are a family of B-complex vitamins that function in one-carbon metabolism to allow the de novo synthesis of amino acids and nucleosides. We show that germ cell proliferation is stimulated by the folate 10-formyl-tetrahydrofolate-Glun both in vitro and in animals. Other folates that can act as vitamins to rescue folate deficiency lack this germ cell stimulatory activity. The bacterial folate precursor dihydropteroate also promotes germ cell proliferation in vitro and in vivo, despite its inability to promote one-carbon metabolism. The folate receptor homolog FOLR-1 is required for the stimulation of germ cells by 10-formyl-tetrahydrofolate-Glun and dihydropteroate. This work defines a folate and folate-related compound as exogenous signals to modulate germ cell proliferation. PMID:27404357

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

    Directory of Open Access Journals (Sweden)

    Rita Rosati

    2012-01-01

    Full Text Available 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.

  4. Design and optimization of novel paclitaxel-loaded folate-conjugated amphiphilic cyclodextrin nanoparticles

    DEFF Research Database (Denmark)

    Erdoğar, Nazlı; Esendağlı, Güneş; Nielsen, Thorbjorn T;

    2016-01-01

    targeting to folate positive breast tumors were introduced. The objective of this study was to develop and characterize new folated-CD nanoparticles via 3(2) factorial design for optimal final parameters. Full physicochemical characterization studies were performed. Blank and paclitaxel loaded FCD-1 and FCD...... cells became more sensitive to cytotoxic and/or cytostatic effects of PCX delivered by FCD-1 and FCD-2. In conclusion, these novel folate-conjugated cyclodextrin nanoparticles can therefore be considered as promising alternative systems for safe and effective delivery of paclitaxel with a folate...

  5. Vitamin B12 and folate levels in long-term vegans.

    Science.gov (United States)

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

    1990-06-01

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

  6. MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum.

    Science.gov (United States)

    Rijpma, Sanna R; van der Velden, Maarten; Bilos, Albert; Jansen, Robert S; Mahakena, Sunny; Russel, Frans G M; Sauerwein, Robert W; van de Wetering, Koen; Koenderink, Jan B

    2016-02-01

    Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway.

  7. Insilco analysis of functionally important residues in folate receptors

    OpenAIRE

    Ramamoorthy, Kalidoss; Potala, Sirisha; Verma, Rama Shanker

    2007-01-01

    Lack of crystal structure data of folate binding proteins has left so many questions unanswered (for example, important residues in active site, binding domain, important amino acid residues involved in interactions between ligand and receptor). With sequence alignment and PROSITE motif identification, we attempted to answer evolutionarily significant residues that are of functional importance for ligand binding and that form catalytic sites. We have analyzed 46 different FRs and FBP sequence...

  8. Ecdysone receptor expression in developing and adult mushroom bodies of the ant Camponotus japonicus.

    Science.gov (United States)

    Nemoto, Michie; Hara, Kenji

    2007-09-01

    Mushroom bodies (MBs) are insect brain centers involved in sensory integration and memory formation. In social Hymenoptera, MBs are large and comprise larger number of Kenyon cells and have repeatedly been implied to underlie the social behaviors. In the present study, to facilitate our understanding of the neural basis of social behaviors, two complementary DNAs (cDNAs) encoding presumed ecdysone receptor isoforms (CjEcR-A and CjEcR-alpha) were identified in the developing brains of the carpenter ant Camponotus japonicus. Sequence comparison indicated that these CjEcR proteins had common DNA- and hormone-binding domains linked to different N-terminal regions. The alignment of the distinct regions with other insects EcRs indicated that CjEcR-A is the ant homologue of EcR-A, and CjEcR-alpha has a novel type of A/B region. Immunohistochemical analyses of the MBs of C. japonicus with the common region antibody demonstrated that these CjEcRs appear in all neuroblasts, neurons, and glia cells during neurogenesis, whereas expression is confined to the neurons, disappearing in the glia cells in newly emerged workers. Less expression was observed in the forager MBs. These findings suggest that CjEcRs are involved in maturation and development of ant MBs. PMID:17703321

  9. Ecdysone receptor expression in developing and adult mushroom bodies of the ant Camponotus japonicus.

    Science.gov (United States)

    Nemoto, Michie; Hara, Kenji

    2007-09-01

    Mushroom bodies (MBs) are insect brain centers involved in sensory integration and memory formation. In social Hymenoptera, MBs are large and comprise larger number of Kenyon cells and have repeatedly been implied to underlie the social behaviors. In the present study, to facilitate our understanding of the neural basis of social behaviors, two complementary DNAs (cDNAs) encoding presumed ecdysone receptor isoforms (CjEcR-A and CjEcR-alpha) were identified in the developing brains of the carpenter ant Camponotus japonicus. Sequence comparison indicated that these CjEcR proteins had common DNA- and hormone-binding domains linked to different N-terminal regions. The alignment of the distinct regions with other insects EcRs indicated that CjEcR-A is the ant homologue of EcR-A, and CjEcR-alpha has a novel type of A/B region. Immunohistochemical analyses of the MBs of C. japonicus with the common region antibody demonstrated that these CjEcRs appear in all neuroblasts, neurons, and glia cells during neurogenesis, whereas expression is confined to the neurons, disappearing in the glia cells in newly emerged workers. Less expression was observed in the forager MBs. These findings suggest that CjEcRs are involved in maturation and development of ant MBs.

  10. Mathematical modeling of folate-related processes in human placenta

    Directory of Open Access Journals (Sweden)

    Dotsenko V. A.

    2014-03-01

    Full Text Available Aim. Description the folate-related processes in the human placenta using the stoichiometric model and investigation the system’s behavior under various conditions. Methods. The model is based on the stoichiometry of the reactions of the folate-related processes at steady state conditions and constructed using CellNetAnalyzer. Behavior of the system is described by elementary flux modes and control-effective fluxes depending on the activity of methylenetetrahydrofolate reductase and methionine synthase and input methionine flux. Results. Change in methylenetetrahydrofolate reductase activity causes a decrease in fluxes through the main routes of homocysteine elimination and increases the need for 5-methyltetrahydrofolate. Methionine synthase inactivation reduces 5-methyltetrahydrofolate consumption and increases the flux through the taurine syn-thesis. Lack of methionine leads to increased 5-methyltetrahydrofolate consumption, reduced homocysteine concentration and reduces the fluxes through the methionine cycle. Conclusions. Analysis of model functioning has shown the compliance of system’s functioning changes with the clinic parameters. There is evidence that the homocysteine level as a marker of folate-related processes functioning of is not sufficient to justify the therapy.

  11. Muscle Plasticity and β2-Adrenergic Receptors: Adaptive Responses of β2-Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

    Directory of Open Access Journals (Sweden)

    Shogo Sato

    2011-01-01

    Full Text Available We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented by the downregulation of the receptor. Endurance training improves oxidative performance partly by increasing β2-adrenergic receptor density in exercise-recruited slow-twitch muscles. However, excessive stimulation of β2-adrenergic receptors negates their beneficial effects. Although the preventive effects of β2-adrenergic receptor stimulation on atrophy induced by muscle disuse and catabolic hormones or drugs are observed, these catabolic conditions decrease β2-adrenergic receptor expression in slow-twitch muscles. These findings present evidence against the use of β2-adrenergic agonists in therapy for muscle wasting and weakness. Thus, β2-adrenergic receptors in the skeletal muscles play an important physiological role in the regulation of protein and energy balance.

  12. TREM-2 Receptor Expression Increases with 25(OH)D Vitamin Serum Levels in Patients with Pulmonary Sarcoidosis.

    Science.gov (United States)

    Bucova, Maria; Suchankova, Magda; Tibenska, Elena; Tedlova, Eva; Demian, Juraj; Majer, Ivan; Novosadova, Helena; Tedla, Miroslav

    2015-01-01

    TREM-1 and TREM-2 molecules are members of the TREM transmembrane glycoproteins. In our previous study we identified increased expressions of TREM-1 and TREM-2 receptors in pulmonary sarcoidosis (PS). Only a few studies concerning the association between vitamin D and TREM receptor expression can be found. The aim of our current study was to determine the association between the levels of an inactive form of 25(OH)D vitamin and TREM-1 and TREM-2 receptor expressions. We have detected low levels of 25(OH)D vitamin in 79% of PS patients. Only 21% of patients had normal serum level of 25(OH)D vitamin with values clustered within the low-normal range. The most striking findings were the increased TREM-2 expressions on myeloid cells surfaces in BALF of PS patients with normal 25(OH)D vitamin serum levels compared with those with its decreased levels. The total number of TREM-2 positive cells was 5.7 times higher and the percentage of TREM-2 positive cells was also significantly increased in BALF of PS patients with normal compared to PS patients with low 25(OH)D vitamin serum levels. A significant correlation between total TREM-2 expression and vitamin D levels has been detected too. However, we have not detected similar differences in TREM-1expression and 25(OH)D vitamin serum levels. PMID:26166951

  13. Prenatal stress alters diazepam withdrawal syndrome and 5HT1A receptor expression in the raphe nuclei of adult rats.

    Science.gov (United States)

    Lakehayli, S; Said, N; El Khachibi, M; El Ouahli, M; Nadifi, S; Hakkou, F; Tazi, A

    2016-08-25

    Early-life events have long-term effects on brain structures and cause behavioral alterations that persist into adulthood. The present experiments were designed to investigate the effects of prenatal stress on diazepam-induced withdrawal syndrome and serotonin-1A (5HT1A) receptor expression in the raphe nuclei of adult offspring. The results of the present study reveal that maternal exposure to chronic footshock stress increased the anxiety-like behavior in the prenatally stressed (PS) animals withdrawn from chronic diazepam (2.5mg/kg/day i.p for 1week). Moreover, prenatal stress induced a down-regulation of 5HT1A mRNA in the raphe nuclei of adult offspring. To our knowledge, this study is the first to demonstrate that maternal exposure to chronic footshock stress enhances diazepam withdrawal symptoms and alters 5HT1A receptor gene expression in the raphe nuclei of adult offspring. Thus, more studies are needed to clarify the mechanisms underlying the decrease of 5HT1A receptors expression in the raphe nuclei of PS rats. PMID:27235743

  14. TREM-2 Receptor Expression Increases with 25(OH)D Vitamin Serum Levels in Patients with Pulmonary Sarcoidosis.

    Science.gov (United States)

    Bucova, Maria; Suchankova, Magda; Tibenska, Elena; Tedlova, Eva; Demian, Juraj; Majer, Ivan; Novosadova, Helena; Tedla, Miroslav

    2015-01-01

    TREM-1 and TREM-2 molecules are members of the TREM transmembrane glycoproteins. In our previous study we identified increased expressions of TREM-1 and TREM-2 receptors in pulmonary sarcoidosis (PS). Only a few studies concerning the association between vitamin D and TREM receptor expression can be found. The aim of our current study was to determine the association between the levels of an inactive form of 25(OH)D vitamin and TREM-1 and TREM-2 receptor expressions. We have detected low levels of 25(OH)D vitamin in 79% of PS patients. Only 21% of patients had normal serum level of 25(OH)D vitamin with values clustered within the low-normal range. The most striking findings were the increased TREM-2 expressions on myeloid cells surfaces in BALF of PS patients with normal 25(OH)D vitamin serum levels compared with those with its decreased levels. The total number of TREM-2 positive cells was 5.7 times higher and the percentage of TREM-2 positive cells was also significantly increased in BALF of PS patients with normal compared to PS patients with low 25(OH)D vitamin serum levels. A significant correlation between total TREM-2 expression and vitamin D levels has been detected too. However, we have not detected similar differences in TREM-1expression and 25(OH)D vitamin serum levels.

  15. Cranial irradiation modulates hypothalamic-pituitary-adrenal axis activity and corticosteroid receptor expression in the hippocampus of juvenile rat.

    Science.gov (United States)

    Velickovic, Natasa; Djordjevic, Ana; Drakulic, Dunja; Stanojevic, Ivana; Secerov, Bojana; Horvat, Anica

    2009-01-01

    Glucocorticoids, essential for normal hypothalamic-pituitary-adrenal (HPA) axis activity, exert their action on the hippocampus through two types of corticosteroid receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Recent studies report that exposure of juvenile rats to cranial irradiation adversely affects HPA axis stability leading to its activation along with radiation- induced inflammation. This study was aimed to examine the acute effects of radiation on HPA axis activity and hippocampal corticosteroid receptor expression in 18-day-old rats. Since immobilization was part of irradiation procedure, both irradiated and sham-irradiated animals were exposed to this unavoidable stress. Our results demonstrate that the irradiated rats exhibited different pattern of corticosteroid receptor expression and hormone levels compared to respective controls. These differences included upregulation of GR protein in the hippocampus with a concomitant elevation of GR mRNA and an increase in circulating level of corticosterone. In addition, the expression of MR, both at the level of protein and gene expression, was not altered. Taken together, this study demonstrates that cranial irradiation in juvenile rats leads to enhanced HPA axis activity and increased relative GR/MR ratio in hippocampus. The present paper intends to show that neuroendocrine response of normal brain tissue to localized irradiation comprise both activation of HPA axis and altered corticosteroid receptor balance, probably as consequence of innate immune activation.

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

    Science.gov (United States)

    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. PMID:27276031

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

    Science.gov (United States)

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

    2011-05-01

    Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. PMID:21315145

  18. $\\alpha_s$ review (2016)

    CERN Document Server

    d'Enterria, David

    2016-01-01

    The current world-average of the strong coupling at the Z pole mass, $\\alpha_s(m^2_{Z}) = 0.1181 \\pm 0.0013$, is obtained from a comparison of perturbative QCD calculations computed, at least, at next-to-next-to-leading-order accuracy, to a set of 6 groups of experimental observables: (i) lattice QCD "data", (ii) $\\tau$ hadronic decays, (iii) proton structure functions, (iv) event shapes and jet rates in $e^+e^-$ collisions, (v) Z boson hadronic decays, and (vi) top-quark cross sections in p-p collisions. In addition, at least 8 other $\\alpha_s$ extractions, usually with a lower level of theoretical and/or experimental precision today, have been proposed: pion, $\\Upsilon$, W hadronic decays; soft and hard fragmentation functions; jets cross sections in pp, e-p and $\\gamma$-p collisions; and photon F$_2$ structure function in $\\gamma\\,\\gamma$ collisions. These 14 $\\alpha_s$ determinations are reviewed, and the perspectives of reduction of their present uncertainties are discussed.

  19. Folate receptor α regulates cell proliferation in mouse gonadotroph αT3-1 cells

    International Nuclear Information System (INIS)

    We have previously found that the mRNA and protein levels of the folate receptor alpha (FRα) are uniquely over-expressed in clinically human nonfunctional (NF) pituitary adenomas, but the mechanistic role of FRα has not fully been determined. We investigated the effect of FRα over-expression in the mouse gonadotroph αT3-1 cell line as a model for NF pituitary adenomas. We found that the expression and function of FRα were strongly up-regulated, by Western blotting and folic acid binding assay. Furthermore, we found a higher cell growth rate, an enhanced percentage of cells in S-phase by BrdU assay, and a higher PCNA staining. These observations indicate that over-expression of FRα promotes cell proliferation. These effects were abrogated in the same αT3-1 cells when transfected with a mutant FRα cDNA that confers a dominant-negative phenotype by inhibiting folic acid binding. Finally, by real-time quantitative PCR, we found that mRNA expression of NOTCH3 was up-regulated in FRα over-expressing cells. In summary, our data suggests that FRα regulates pituitary tumor cell proliferation and mechanistically may involve the NOTCH pathway. Potentially, this finding could be exploited to develop new, innovative molecular targeted treatment for human NF pituitary adenomas.

  20. Effect of Exercise Training on Adiponectin Receptor Expression and Insulin Resistance in Mice Fed a High Fat Diet

    Directory of Open Access Journals (Sweden)

    Naglaa Fathy Alhusseini

    2010-01-01

    Full Text Available Problem statement: Adiponectin is an adipocyte secreted hormones, exerts its effects via the specific receptors. AdipoR1 and adipoR2 and plays a pivotal role in lipid and glucose metabolism. Approach: We investigated the effect of increased physical activities on insulin resistance and if this effect is modulated through adiponectin receptor expression. Results: We also assessed the effect of High Fat Diet (HFD on adipoRs expression. Mice were subjected to 16 weeks of HFD protocol then to 4, 6 and 8 weeks of exercise training. Following the experimental protocol the fasting plasma glucose, insulin and index of Homeostasis Model Assessment of insulin Resistance (HOMA-R were evaluated. The mRNA expression of adiponectin receptors genes were also analyzed using reverse transcription RT-PCR. The consumption of high fat diet by the mice for 16 weeks resulted in a significant increase in weight associated with insulin resistance and associated with significant decrease in adiponectin receptors R1 and R2 expression in both liver and skeletal muscle. Exercise training for 4 weeks resulted in a significant improvement in the insulin resistance state, significant increase in expression of AdipoR1 and AdipoR2 in both liver and skeletal muscles. On increasing duration of exercise training for 6 weeks and 8 weeks there was significant improvement in insulin resistance and significant increase in the expression of AdipoR1 in liver, AdipoR1 and AdipoR2 in muscle, whereas liver AdipoR2 expression was significantly decreased. Conclusion/Recommendations: we conclude that the exercise training improves insulin sensitivity and up-regulates mRNA expression of AdipoR1 in both skeletal muscle and liver in mice and AdiopR2 in muscle and this suggests that the insulin sensitizing effect of exercise training may be mediated even partially through increased adiponectin receptor expression and up regulation of adiponectin receptors reaches certain level and increasing the

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

    NARCIS (Netherlands)

    Park, J.Y.; Nicolas, G.; Freisling, H.; Biessy, C.; Scalbert, A.; Romieu, I.; Chajes, V.; Chuang, S.C.; Ericson, U.; Wallstrom, P.; Ros, M.M.; Peeters, P.H.M.; Mattiello, A.; Palli, D.; Huerta, J.M.; Amiano, P.; Halkjaer, J.; Dahm, C.C.; Trichopoulou, A.; Orfanos, P.; Teucher, B.; Feller, S.; Skeie, G.; Engeset, D.; Boutron-Ruault, M.C.; Clavel-Chapelon, F.; Crowe, F.; Khaw, K.T.; Vineis, P.; Slimani, N.

    2012-01-01

    Folate plays an important role in the synthesis and methylation of DNA as a cofactor in one-carbon metabolism. Inadequate folate intake has been linked to adverse health events. However, comparable information on dietary folate intake across European countries has never been reported. The objective

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

    Science.gov (United States)

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

  3. Effect of folate-binding protein on intestinal transport of folic acid and 5-methyltetrahydrofolate across Caco-2 cells

    NARCIS (Netherlands)

    Verwei, M.; Berg, H. van den; Havenaar, R.; Groten, J.P.

    2005-01-01

    Background: Milk products are a potential matrix for fortification with synthetic folic acid or natural 5-methyltetrahydrofolate (5-CH 3-H4folate) to enhance the daily folate intake. In milk, folate occurs bound to folatebinding proteins (FBP). Our previous studies with an in vitro gastrointestinal

  4. Effects of dietary folic acid level and symbiotic folate production on fitness and development in the fruit fly Drosophila melanogaster.

    Science.gov (United States)

    Blatch, Sydella A; Meyer, Kyle W; Harrison, Jon F

    2010-01-01

    Folic acid is a vitamin for probably all animals. When converted to folate forms, it is used in DNA synthesis and amino acid metabolism. Literature suggests insects must consume folates, folates do not affect others, is a toxin for some, and that a few insects synthesize it. It has been reported that Drosophila melanogaster does not consistently need dietary folate because it can synthesize it. This seems unlikely since animals generally lack this ability. More likely, folates thought to have been made by the fly came from microbial symbionts. We aimed to clarify how dietary folic acid affects fitness and development in fruit flies and whether flies may receive folates from microbial symbionts. We found larvae were more viable and developed faster with increasing dietary folic acid, with the surprising exception that larvae fed nearly-zero folic acid developed faster. Their body folate levels did not significantly differ from those that consumed up to 600 times more folic acid. However, these flies fed little folate only achieved normal body folate levels and development times when antibiotics were excluded from the diet. When flies consumed near-zero folates with antibiotics, their body folate levels decreased and development was prolonged. An assay for the endosymbiont Wolbachia in flies used to generate the experimental flies did not show presence of these bacteria. Our data suggest D. melanogaster can harbor unknown bacterial symbiont(s) that provide essential folates to their host when it is scarce in the diet, allowing the fruit fly to maintain growth and development.

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

    Science.gov (United States)

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

    2012-03-01

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

  6. Ordering folate assays is no longer justified for investigation of anemias, in folic acid fortified countries

    Directory of Open Access Journals (Sweden)

    von Kuster Kenneth

    2010-01-01

    Full Text Available Abstract Background Since 1998, in the countries where there is mandatory fortification of grain products with folic acid, folate deficiency has become very rare. Consequently, we decided to find out whether there is any justification for ordering folate assays for investigation of anemias. Methods We reviewed serum folate (SF and red cell folate (RF data at two teaching hospitals in Canada. At the Health Sciences Centre (HSC the folate data for the year 2001 were analyzed and the medical records of those with low SF or low RF were reviewed. At St. Boniface General Hospital(SBGHall folate data between January 1996 and Dec 31,2004 were analyzed and the medical records of all who had low RF between January 1,1999 and December 31,2004 were reviewed. Results In 2001, at HSC, 11 out of 2154(0.5%SF were low( Conclusion In countries where there is mandatory fortification of grain products with folic acid, folate deficiency to the degree that could cause anemia is extremely rare. Ordering folate assays for investigation of anemias, in these countries, is waste of time and money. The result of these tests is more likely to mislead the physicians than to provide any useful information.

  7. Bioavailability of Food Folates is 80% of that of folic acid 1-3

    NARCIS (Netherlands)

    Winkels, R.M.; Brouwer, I.A.; Siebelink, E.; Katan, M.B.; Verhoef, P.

    2007-01-01

    Background: The bioavailability of natural food folates is lower than that of synthetic folic acid, but no agreement exists as to the extent of the difference. Objective: In a 4-wk dietary intervention study, we determined the aggregate bioavailability of food folates from fruit, vegetables, and liv

  8. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk

    DEFF Research Database (Denmark)

    Holmes, Michael V; Newcombe, Paul; Hubacek, Jaroslav A;

    2011-01-01

    The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias wa...

  9. Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model

    Directory of Open Access Journals (Sweden)

    Virk Bhupinder

    2012-07-01

    Full Text Available Abstract Background Gut microbes influence animal health and thus, are potential targets for interventions that slow aging. Live E. coli provides the nematode worm Caenorhabditis elegans with vital micronutrients, such as folates that cannot be synthesized by animals. However, the microbe also limits C. elegans lifespan. Understanding these interactions may shed light on how intestinal microbes influence mammalian aging. Results Serendipitously, we isolated an E. coli mutant that slows C. elegans aging. We identified the disrupted gene to be aroD, which is required to synthesize aromatic compounds in the microbe. Adding back aromatic compounds to the media revealed that the increased C. elegans lifespan was caused by decreased availability of para-aminobenzoic acid, a precursor to folate. Consistent with this result, inhibition of folate synthesis by sulfamethoxazole, a sulfonamide, led to a dose-dependent increase in C. elegans lifespan. As expected, these treatments caused a decrease in bacterial and worm folate levels, as measured by mass spectrometry of intact folates. The folate cycle is essential for cellular biosynthesis. However, bacterial proliferation and C. elegans growth and reproduction were unaffected under the conditions that increased lifespan. Conclusions In this animal:microbe system, folates are in excess of that required for biosynthesis. This study suggests that microbial folate synthesis is a pharmacologically accessible target to slow animal aging without detrimental effects.

  10. Folate concentration dependent transport activity of the Multidrug Resistance Protein 1 (ABCC1).

    NARCIS (Netherlands)

    Hooijberg, J.H.; Jansen, G.; Assaraf, Y.G.; Kathmann, I.; Pieters, R.; Laan, AC; Veerman, A.J.P.; Kaspers, G.J.L.; Peters, G.J.

    2004-01-01

    The Multidrug Resistance Protein MRP1 (ABCC1) can confer resistance to a variety of therapeutic drugs. In addition, MRP1/ABCC1 mediates cellular export of natural folates, such as folic acid and l-leucovorin. In this study we determined whether cellular folate status affected the functional activity

  11. Identification of Genes Encoding the Folate- and Thiamine-Binding Membrane Proteins in Firmicutes

    NARCIS (Netherlands)

    Eudes, Aymerick; Erkens, Guus B.; Slotboom, Dirk J.; Rodionov, Dmitry A.; Naponelli, Valeria; Hanson, Andrew D.

    2008-01-01

    Genes encoding high-affinity folate- and thiamine-binding proteins (FolT, ThiT) were identified in the Lactobacillus casei genome, expressed in Lactococcus lactis, and functionally characterized. Similar genes occur in many Firmicutes, sometimes next to folate or thiamine salvage genes. Most thiT ge

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

    Science.gov (United States)

    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...

  13. HIV and other predictors of serum folate, serum ferritin, and hemoglobin in pregnancy

    DEFF Research Database (Denmark)

    Friis, Henrik; Gomo, E; Kæstel, Pernille;

    2001-01-01

    BACKGROUND: Folate and iron status and hemoglobin concentrations are important to maternal and infant health. OBJECTIVE: Our goal was to identify predictors of serum folate, serum ferritin, and hemoglobin. DESIGN: This was a cross-sectional study of 1669 pregnant women (22-35 wk of gestation) in ...

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

    Directory of Open Access Journals (Sweden)

    Lisa A. Houghton

    2013-09-01

    Full Text Available 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.

  15. Peptide fingerprinting of folate-responsive proteins in human B lymphoblasts and orofacial clefting

    NARCIS (Netherlands)

    Bliek, B.J.; Guzel, C.; Klein, A. de; Stingl, C.; Luider, T.M.; Lindemans, J.; Steegers, E.A.P.; Steegers-Theunissen, R.P.M.

    2012-01-01

    BACKGROUND: Maternal periconceptional use of folic acid contributes to the prevention of neural crest-related congenital malformations including orofacial clefts. The underlying biological pathways affected by folic acid,however, are still not clarified. In an explorative study, we identify folate-r

  16. Effect of freezing technology and storage conditions on folate content in selected vegetables.

    Science.gov (United States)

    Czarnowska, Marta; Gujska, Elzbieta

    2012-12-01

    Folates (B vitamins) are essential for the proper function of many bodily processes. Although a rich natural source are vegetables, the literature lacks data on the effect of the pre-treatment and freezing technologies used in vegetable processing and frozen storage time on the folate content in these materials. Moreover, since folates are very unstable nutrients, the amount available in processed and stored foods can be significantly lower than in raw products. In tested vegetables (green beans, yellow beans, peas, cauliflower, broccoli and spinach), one folate form was identified, 5-methyltetrahydrofolate (5-CH₃-H₄folate). It was observed that pre-treatment and freezing technology significantly (p peas). In all analyzed samples, the 5-CH₃-H₄folate content decreased with the time of frozen storage. In frozen cauliflower, the 5-CH₃-H₄folate loss exceeded 95 % compared to the fresh product just after the third month of frozen storage. Meanwhile, in green and yellow beans, significant 5-CH₃-H₄folate losses (at the level of 75 % and 95 %, respectively) were observed no earlier than after the 9th month of frozen storage. PMID:22983767

  17. Betaine and folate status as cooperative determinants of plasma homocysteine in humans.

    NARCIS (Netherlands)

    Holm, P.I.; Ueland, P.M.; Vollset, S.E.; Midttun, O.; Blom, H.J.; Keijzer, M.B.; Heijer, M. den

    2005-01-01

    OBJECTIVE: Two published studies have demonstrated that betaine in the circulation is a determinant of plasma total homocysteine, but none had sufficient power to investigate the possible effect modification by folate status. METHODS AND RESULTS: We measured homocysteine, betaine, folate, vitamin B(

  18. Effects of cultivation conditions on folate production by lactic acid bacteria

    NARCIS (Netherlands)

    Sybesma, W.; Starrenburg, M.; Tijsseling, L.; Hoefnagel, M.H.N.; Hugenholtz, J.

    2003-01-01

    A variety of lactic acid bacteria were screened for their ability to produce folate intracellularly and/or extracellularly. Lactococcus lactis, Streptococcus thermophilus, and Leuconostoc spp. all produced folate, while most Lactobacillus spp., with the exception of Lactobacillus plantarum, were not

  19. Folate composition of ten types of mushrooms determined by liquid chromatography-mass spectrometry

    Science.gov (United States)

    White button, crimini, shiitake, maitake, enoki, oyster, chanterelle, morel, portabella, and uv-treated portabella mushrooms were sampled from U.S. retail outlets and major producers. Folate (5-methyltetrahydrofolate [5MTHF], 10-formyl folate [10FF], 5-formyltetrahydrofolate [5FTHF]) was analyzed u...

  20. Analysis of Chemokines and Receptors Expression Profile in the Myelin Mutant Taiep Rat

    Directory of Open Access Journals (Sweden)

    Guadalupe Soto-Rodriguez

    2015-01-01

    Full Text Available Taiep rat has a failure in myelination and remyelination processes leading to a state of hypomyelination throughout its life. Chemokines, which are known to play a role in inflammation, are also involved in the remyelination process. We aimed to demonstrate that remyelination-stimulating factors are altered in the brainstem of 1- and 6-month-old taiep rats. We used a Rat RT2 Profiler PCR Array to assess mRNA expression of 84 genes coding for cytokines, chemokines, and their receptors. We also evaluated protein levels of CCL2, CCR1, CCR2, CCL5, CCR5, CCR8, CXCL1, CXCR2, CXCR4, FGF2, and VEGFA by ELISA. Sprague-Dawley rats were used as a control. PCR Array procedure showed that proinflammatory cytokines were not upregulated in the taiep rat. In contrast, some mRNA levels of beta and alpha chemokines were upregulated in 1-month-old rats, but CXCR4 was downregulated at their 6 months of age. ELISA results showed that CXCL1, CCL2, CCR2, CCR5, CCR8, and CXCR4 protein levels were decreased in brainstem at the age of 6 months. These results suggest the presence of a chronic neuroinflammation process with deficiency of remyelination-stimulating factors (CXCL1, CXCR2, and CXCR4, which might account for the demyelination in the taiep rat.

  1. Folate status, folate-related genes and serum miR-21 expression: Implications for miR-21 as a biomarker

    Directory of Open Access Journals (Sweden)

    Emma Louise Beckett

    2015-12-01

    General significance: This study demonstrates that serum miR-21 expression correlates with folate status and related genetic status. This may have consequences for the proposed use of miR-21 as a colorectal cancer biomarker.

  2. Folate and neural tube defects - Recommendations from a Danish working group

    DEFF Research Database (Denmark)

    Rasmussen, Lone Banke; Andersen, Niels Lyhne; Andersson, G.;

    1998-01-01

    in Denmark will decrease if the folate intake in fertile women increases. All women planning pregnancy should receive dietary counselling. Women who do not eat according to the Nordic Nutrition Recommendations. and women a with an increased risk due to diseases are recommended a supplement of 400 mu g folic......A working group was established to evaluate the need for an increased folate intake in Danish women to decrease the risk of neural tube defects (NTDs). NTD are birth defects a which include anencephaly, encephalocele and spina bifida. In Denmark the incidence is about 1.4 per 1,000 pregnancies......, in the few studies which calculate folate intake from the diet, a lower risk of NTD with higher intake of folate from the diet has been found. The folate intake can be increased by the diet, by folic acid supplements or by fortification of food a with folic acid. It is concluded that the incidence of NTDs...

  3. The assay of thyrotropin receptor antibodies with human TSH/LH-CG chimeric receptor expressed on chinese hamster ovary cells

    Energy Technology Data Exchange (ETDEWEB)

    Yi, Ka Hee; Kim, Chang Min [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    1996-12-01

    TSH/LH-CG chimera cDNA is transfected to CHO-K1 cell to obtain the chimeric receptor expressed on the cell surface. The optimal conditions for TSAb and TSBAb measurements are determined using chimeric receptors and under these conditions activity of TSAb and TSBAb in the sera of the Graves` patients. The results obtained are compared to those of TSAb assays using FRTL5 cells CHO-TSHR cells which have wild type human TSH receptor. The transfection procedure of chimeric receptor gene to CHO-K1 cells are on going. The optimal conditions for TSAb and TSBAb measurement using chimeric receptor will be determined after success of transfection procedure. If this study is successfully completed, not only the heterogeneity of Graves. IgG but also pathogenesis of Graves` disease will be elucidated. (author). 25 refs.

  4. Biodistribution of 111In-pentetreotide and dosimetric considerations with respect to somatostatin receptor expressing tumor burden

    International Nuclear Information System (INIS)

    The general features of the biodistribution of the labeled somatostatin analog 111In-pentretreotide are already known. We describe some details of 111In-pentretreotide accumulation in the thyroid gland, mammae, spleen and gastrointenstinal tract with respect to endocrine parameters, kinetics and time of imaging. In addition, dose estimations were performed for liver, spleen and kidney in patients without neuroendocrine tumor load and in patients with large tumors positive for somatostatin receptors. The overall absorbed dose turned out to be within the range reported previously. However, in patients with extensive tumor burden the radiation dose in liver, spleen and kidney tended to be lower than in patients without such malignancy. The dependence of estimated organ doses on the presence of somatostatin receptor-expressing tumors will have to be considered if radiotherapy with suitable labeled somatostatin analogs becomes available. (orig.)

  5. Synthesis of platelet-activating factor and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Yin-Ying Lu; Chun-Ping Wang; Lin Zhou; Yan Chen; Shu-Hui Su; Yong-Yi Feng; Yong-Ping Yang

    2008-01-01

    AIM:To determine the platelet-activating factor (PAF)synthesis and its receptor expression in Kupffer cells in rat carbon tetrachloride-induce dcirrhosis.METHODS:Kupffer cells,isolated from the livers of control and CCl4-induced cirrhotic rats,were placed in serum-free medium overnight.PAF saturation binding,ET-1 saturation and competition binding were assayed.ET-1 induced PAF synthesis,mRNA expression of PAF,preproendothelin-1,endothelin A (ETA) and endothelin B (ETB) receptors were also determined.RESULTS:A two-fold increase of PAF synthesis (1.42±0.14 vs 0.66±0.04 pg/μg DNA) and a 1.48-fold increase of membrane-bound PAF (1.02±0.06 vs 0.69±0.07 Pg/μg DNA) were observed in activated Kupffer cells of cirrhotic rats.The application of ET-1 to Kupffer cells induced PAF synthesis in a concentration-dependent manner in both cirrhotic and normal rats via ETB receptor,but PAF synthesis in the activated Kupffer cells was more effective than that in the normal Kupffer cells.In activated Kupffer cells,PAF receptor expression and PAF binding capacity were markedly enhanced.Activated Kupffer cells raised the [125I]-ET-1 binding capacity,but changed neither the affinity of the receptors,nor the expression of ETA receptor.CONCLUSION:Kupffer cells in the course of CCl4-induced cirrhosis are the main source of increased PAF.ET-1 is involved endogenously in stimulating the PAF synthesis in activated Kupffer cells via ETB receptor by paracrine.ETA receptor did not appear in activated Kupffer cells,which may exacerbate the hepatic and extrahepatic complications of cirrhosis.

  6. Risperidone regulates Dopamine D2-like receptors expression in rat brain in a time-dependent manner

    Directory of Open Access Journals (Sweden)

    Ni Peiyan

    2015-03-01

    Full Text Available Background and Objectives: Antipsychotics can elicit dopamine super-sensitivity by up-regulation of D2-like receptors (DRD2, DRD3, and DRD4 expression. Nevertheless, the expression profile of dopamine D2-like receptors in different brain regions and peripheral blood mononuclear cells (PBMCs, and changes following risperidone administration were still unclear. In this study, we would investigate the expression of D2-like receptors mRNA in different brain regions and the peripheral blood mononuclear cells (PBMCs in rats after 2, 6 weeks risperidone administration. Methods: The experimental rats were given risperidone (0.25mg/kg/day, i.p., and the control rats were given 0.9% NaCl. The rats were sacrificed at 0 week, 2 weeks and 6 weeks after the drug administration. Expression of the dopamine D2-like receptors was quantified by Real-time PCR method. Results: Dopamine D2-like receptors expressed in all the examined regions of rat brain. Their expression significantly increased 2weeks after risperidone administration in different brain regions. However, the changed expression of DRD2 and DRD3 turned back to the basal level 6weeks later, while the increased DRD4 expression remained in left parietal cortex. Meanwhile, DRD2 and DRD3 but not DRD4 expressed in PBMCs, however, the risperidone could not affect their expression. Conclusions: The risperidone could change the dopamine D2-like receptors expression in a time-dependent manner in different brain regions, which might guide the clinical use in the near future.

  7. Post-transcriptional regulation of dopamine D1 receptor expression in caudate-putamen of cocaine-sensitized mice.

    Science.gov (United States)

    Tobón, Krishna E; Catuzzi, Jennifer E; Cote, Samantha R; Sonaike, Adenike; Kuzhikandathil, Eldo V

    2015-07-01

    The dopamine D1 receptor is centrally involved in mediating the effects of cocaine and is essential for cocaine-induced locomotor sensitization. Changes in D1 receptor expression have been reported in various models of cocaine addiction; however, the mechanisms that mediate these changes in D1 receptor expression are not well understood. Using preadolescent drd1a-EGFP mice and a binge cocaine treatment protocol we demonstrate that the D1 receptor is post-transcriptionally regulated in the caudate-putamen of cocaine-sensitized animal. While cocaine-sensitized mice express high levels of steady-state D1 receptor mRNA, the expression of D1 receptor protein is not elevated. We determined that the post-transcriptional regulation of D1 receptor mRNA is rapidly attenuated and D1 receptor protein levels increase within 30 min when the sensitized mice are challenged with cocaine. The rapid increase in D1 receptor protein levels requires de novo protein synthesis and correlates with the cocaine-induced hyperlocomotor activity in the cocaine-sensitized mice. The increase in D1 receptor protein levels in the caudate-putamen inversely correlated with the levels of microRNA 142-3p and 382, both of which regulate D1 receptor protein expression. The levels of these two microRNAs decreased significantly within 5 min of cocaine challenge in sensitized mice. The results provide novel insights into the previously unknown rapid kinetics of D1 receptor protein expression which occurs in a time scale that is comparable to the expression of immediate early genes. Furthermore, the results suggest a potential novel role for inherently labile microRNAs in regulating the rapid expression of D1 receptor protein in cocaine-sensitized animals. PMID:25900179

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

    Science.gov (United States)

    Min, Jin-Young; Min, Kyoung-Bok

    2016-03-21

    Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality. PMID:27003215

  9. The Binding of Folic Acid and 5-Methyltetrahydrofolate to Folate-Binding Proteins during Gastric Passage Differs in a Dynamic in Vitro Gastrointestinal Model

    NARCIS (Netherlands)

    Verwei, M.; Arkbåge, K.; Mocking, H.; Havenaar, R.; Groten, J.

    2004-01-01

    Despite its low natural folate concentration, milk is responsible for 10-15% of the daily folate intake in countries with a high dairy consumption. Milk products can be considered as a potential matrix for folate fortification, e.g., with synthetic folic acid, to enhance the daily intake of folate.

  10. Heterogeneous estrogen receptor expression in circulating tumor cells suggests diverse mechanisms of fulvestrant resistance.

    Science.gov (United States)

    Paoletti, Costanza; Larios, Jose M; Muñiz, Maria C; Aung, Kimberly; Cannell, Emily M; Darga, Elizabeth P; Kidwell, Kelley M; Thomas, Dafydd G; Tokudome, Nahomi; Brown, Martha E; Connelly, Mark C; Chianese, David A; Schott, Anne F; Henry, N Lynn; Rae, James M; Hayes, Daniel F

    2016-08-01

    Fulvestrant is a dose dependent selective estrogen receptor (ER) down-regulator (SERD) used in ER-positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch(®) system. Clinical data are limited to a subset of patients with ER-positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10). CTCs were enumerated and phenotyped for ER and B-cell lymphoma (BCL2) using the CellSearch(®) CXC kit. In preclinical modeling, tamoxifen and AIs resulted in stabilized ER expression, whereas fulvestrant eliminated it. Five of seven patients progressing on fulvestrant had ≥5CTC/7.5 ml WB. Two of these five, treated with 500 mg/month fulvestrant, had no detectable CTC-expression of ER and BCL2 (an ER regulated gene). Three patients had heterogeneous CTC-ER and BCL2 expression indicating incomplete degradation of the ER target by fulvestrant. Two of these patients received 250 mg/month whereas the third patient received 500 mg/month fulvestrant. Her cancer harbored a mutation (Y537S) in the estrogen receptor alpha gene (ESR1). All seven ER positive patients progressing on AIs had heterogeneous CTC-ER expression. These results suggest heterogeneous mechanisms of resistance to fulvestrant, including insufficient dosage, ESR1 mutation, or conversion to dependence on non-ER pathways. CTC enumeration, phenotyping, and genotyping might identify patients who would benefit from fulvestrant dose escalation versus switching to alternative therapies. PMID:27178224

  11. Some More Comments on 'Folate Deficiency in Chronic Pancreatitis'

    Directory of Open Access Journals (Sweden)

    Conrad Wagner

    2010-11-01

    Full Text Available GNMT: glycine N-methyltransferase; SAH: Sadenosylhomocysteine; SAM: S-adenosylmethionine Dear Sir, The comprehensive review by Braganza and Dormandy on micronutrient therapy for chronic pancreatitis included emphasis on the role of methyl group and thiol metabolism [1]. I am writing to expand on the comments expressed in the letter by Rajesh et al. [2] and the reply by Dr. Braganza [3] in the July issue of JOP. Journal of the Pancreas (Online. These have served to highlight the results reported by Girish et al. in which they suggest that a deficiency of methyl groups may be a factor in the development of pancreatitis [4]. In their letter, Rajesh et al. cite our paper showing that pancreatic secretion in rats is compromised in folate deficiency [2]. There is a close relationship between folate and methyl group metabolism. Folate is required for the de novo synthesis of methyl groups. The ratio of Sadenosylmethionine (SAM to S-adenosylhomocysteine (SAH is regulated by the enzyme glycine Nmethyltransferase (GNMT under the control of a specific form of folate [5]. GNMT is very abundant in the exocrine cells of the pancreas [6] and in a subsequent publication we showed that SAM plays an important role in the secretory process from pancreatic exocrine cells [7]. In that paper we provided evidence that SAM might be needed for carboxymethylation of G proteins that are needed in the process of exocytosis. It should also be noted that the process of exocytosis involves the fusion and regeneration of membranes that are generated in the Golgi and the rough endoplasmic reticulum [8]. Tissues that are actively involved in exocrine secretion may then have an increased requirement for synthesis of phosphatidylcholine, an important component of the plasma membrane. There are two pathways that are used for the synthesis of phosphatidylcholine. The major pathway in most tissues utilizes preformed choline reacting with cytidine triphosphate to eventually form

  12. The $\\alpha-\\alpha$ fishbone potential revisited

    CERN Document Server

    Day, J P; Elhanafy, M; Smith, E; Woodhouse, R; Papp, Z

    2011-01-01

    The fishbone potential of composite particles simulates the Pauli effect by nonlocal terms. We determine the $\\alpha-\\alpha$ fishbone potential by simultaneously fitting to two-$\\alpha$ resonance energies, experimental phase shifts and three-$\\alpha$ binding energies. We found that essentially a simple gaussian can provide a good description of two-$\\alpha$ and three-$\\alpha$ experimental data without invoking three-body potentials.

  13. Alpha One Foundation

    Science.gov (United States)

    ... Tested Find Support Find Doctor What Is Alpha-1? Alpha-1 Antitrypsin Deficiency (Alpha-1) is a ... results for inhaled augmentation More News Our Number One Goal: Find a cure for Alpha-1. Website ...

  14. Folate-targeted gadolinium-lipid-based nanoparticles as a bimodal contrast agent for tumor fluorescent and magnetic resonance imaging.

    Science.gov (United States)

    Nakamura, Taro; Kawano, Kumi; Shiraishi, Kouichi; Yokoyama, Masayuki; Maitani, Yoshie

    2014-01-01

    To enhance tumor magnetic resonance imaging (MRI) signals via the selective accumulation of contrast agents, we prepared folate-modified gadolinium-lipid-based nanoparticles as MRI contrast agents. Folate-modified nanoparticles were comprised of polyethylene glycol (PEG)-lipid, gadolinium diethylenetriamine pentaacetic acid lipid, cationic cholesterol derivatives, folate-conjugated PEG-lipid, and Cy7-PEG-lipid. Folate receptor-mediated cellular nanoparticle association was examined in KB cells, which overexpress the folate receptor. The biodistribution of nanoparticles after their intravenous injection into KB tumor-bearing mice was measured. Mice were imaged through in vivo fluorescence imaging and MRI 24 h after nanoparticle injection, and the intensity enhancement of the tumor MRI signal was evaluated. Increased cellular association of folate-modified nanoparticles was inhibited by excess free folic acid, indicating that nanoparticle association was folate receptor-mediated. Irrespective of folate modification, the amount of nanoparticles in blood 24 h after injection was ca. 10% of the injected dose. Compared with non-modified nanoparticles, folate-modified nanoparticles exhibited significant accumulation in tumor tissues without altering other biodistribution, as well as enhanced tumor fluorescence and MRI signal intensity. The results support the feasibility of MRI- and in vivo fluorescence imaging-based tumor visualization using folate-modified nanoparticles and provide opportunities to develop folate targeting-based imaging applications.

  15. Nucleus Accumbens Dopamine D2-Receptor Expressing Neurons Control Behavioral Flexibility in a Place Discrimination Task in the IntelliCage

    Science.gov (United States)

    Macpherson, Tom; Morita, Makiko; Wang, Yanyan; Sasaoka, Toshikuni; Sawa, Akira; Hikida, Takatoshi

    2016-01-01

    Considerable evidence has demonstrated a critical role for the nucleus accumbens (NAc) in the acquisition and flexibility of behavioral strategies. These processes are guided by the activity of two discrete neuron types, dopamine D1- or D2-receptor expressing medium spiny neurons (D1-/D2-MSNs). Here we used the IntelliCage, an automated…

  16. Folate targeted polymeric 'green' nanotherapy for cancer

    Energy Technology Data Exchange (ETDEWEB)

    Narayanan, Sreeja; Binulal, N S; Mony, Ullas; Manzoor, Koyakutty; Nair, Shantikumar; Menon, Deepthy, E-mail: deepthymenon@aims.amrita.edu [Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi-682 041, Kerala (India)

    2010-07-16

    The concept of 'green' chemotherapy by employing targeted nanoparticle mediated delivery to enhance the efficacy of phytomedicines is reported. Poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulating a well known nutraceutical namely, grape seed extract (GSE)-'NanoGSE'-was prepared by a nanoprecipitation technique. The drug-loaded nanoparticles of size {approx} 100 nm exhibited high colloidal stability at physiological pH. Molecular receptor targeting of this nanophytomedicine against folate receptor over-expressing cancers was demonstrated in vitro by conjugation with a potential cancer targeting ligand, folic acid (FA). Fluorescence microscopy and flow cytometry data showed highly specific cellular uptake of FA conjugated NanoGSE on folate receptor positive cancer cells. Studies were also conducted to investigate the efficiency of targeted (FA conjugated) versus non-targeted (non-FA conjugated) nanoformulations in causing cancer cell death. The IC{sub 50} values were lowered by a factor of {approx} 3 for FA-NanoGSE compared to the free drug, indicating substantially enhanced bioavailability to the tumor cells, sparing the normal ones. Receptor targeting of FA-NanoGSE resulted in a significant increase in apoptotic index, which was also quantified by flow cytometry and fluorescence microscopy. This in vitro study provides a basis for the use of nanoparticle mediated delivery of anticancer nutraceuticals to enhance bioavailability and effectively target cancer by a 'green' approach.

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

    Science.gov (United States)

    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. PMID:27235728

  18. Evaluation of Serum Homocysteine, High-Sensitivity CRP, and RBC Folate in Patients with Alopecia Areata

    Science.gov (United States)

    Yousefi, Maryam; Namazi, Mohammad Reza; Rahimi, Hoda; Younespour, Shima; Ehsani, Amir Houshang; Shakoei, Safoura

    2014-01-01

    Introduction: Alopecia areata (AA) is a common type of hair loss with an autoimmune basis. As the role of homocysteine (Hcys), folate, and CRP has been considered in some autoimmune diseases. Objectives: To evaluate homocysteine, folate and CRP level in AA. Methods: This study was performed on 29 patients who had AA for at least 6 months affecting more than 20% of scalp, and 32 healthy controls. Levels of serum Hcys, blood high-sensitivity CRP, and RBC folate were measured in all subjects. Results: The mean level of RBC folate was significantly lower in the patient group than that in controls (P < 0.001). Also, the level of RBC folate was significantly lower in patients with extensive forms of disease (alopecia totalis/alopecia universalis) in comparison with more localized form (patchy hair loss) (P < 0.05). Patients with higher “Severity of Alopecia Total” (SALT) score had lower RBC folate, as well. Serum Hcys and blood high-sensitivity CRP levels did not show a significant difference in two groups. Conclusion: Patients with alopecia areata have lower level of RBC folate which is in negative correlation with both severity and extension of AA. PMID:25484412

  19. Evaluation of serum homocysteine, high-sensitivity CRP, and RBC folate in patients with alopecia areata

    Directory of Open Access Journals (Sweden)

    Maryam Yousefi

    2014-01-01

    Full Text Available Introduction: Alopecia areata (AA is a common type of hair loss with an autoimmune basis. As the role of homocysteine (Hcys, folate, and CRP has been considered in some autoimmune diseases. Objectives: To evaluate homocysteine, folate and CRP level in AA. Methods: This study was performed on 29 patients who had AA for at least 6 months affecting more than 20% of scalp, and 32 healthy controls. Levels of serum Hcys, blood high-sensitivity CRP, and RBC folate were measured in all subjects. Results: The mean level of RBC folate was significantly lower in the patient group than that in controls (P < 0.001. Also, the level of RBC folate was significantly lower in patients with extensive forms of disease (alopecia totalis/alopecia universalis in comparison with more localized form (patchy hair loss (P < 0.05. Patients with higher "Severity of Alopecia Total" (SALT score had lower RBC folate, as well. Serum Hcys and blood high-sensitivity CRP levels did not show a significant difference in two groups. Conclusion: Patients with alopecia areata have lower level of RBC folate which is in negative correlation with both severity and extension of AA.

  20. Maternal Prepregnancy Folate Intake and Risk of Spontaneous Abortion and Stillbirth

    Science.gov (United States)

    Gaskins, Audrey J.; Rich-Edwards, Janet W.; Hauser, Russ; Williams, Paige L.; Gillman, Matthew W.; Ginsburg, Elizabeth S.; Missmer, Stacey A.; Chavarro, Jorge E.

    2014-01-01

    Objective To evaluate prospectively the relationship between prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Methods Women in the Nurses’ Health Study-II who self-reported a pregnancy between 1992 and 2009 were included in this analysis. Dietary folate and supplement use was assessed every 4 years, starting in 1991, by a food-frequency questionnaire. Pregnancies were self-reported, with case pregnancies lost spontaneously (spontaneous abortion 851μg/day) had a relative risk (RR) of spontaneous abortion of 0.91 (95% CI 0.82,1.02) after multivariable adjustment (P-trend=0.04). This association was primarily attributable to intake of folate from supplements. Compared to women without supplemental folate intake (0μg/day), those in the highest category (>730μg/day) had a RR of spontaneous abortion of 0.80 (95% CI 0.71,0.90) after multivariable adjustment (P-trend=<0.001). The association of prepregnancy supplemental folate with risk of spontaneous abortion was consistent across gestational period of loss. A similar inverse trend was observed with the risk of stillbirth, which fell short of conventional significance (P-trend=0.06). Conclusions Higher intake of folate from supplements was associated with reduced risk of spontaneous abortion. Women at risk of pregnancy should use supplemental folate for neural tube defect prevention and because it may decrease the risk of spontaneous abortion,. PMID:24901281

  1. Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Tristan Montier

    2013-01-01

    Full Text Available Since recombinant viral vectors have been associated with serious side effects, such as immunogenicity and oncogenicity, synthetic delivery systems represent a realistic alternative for achieving efficacy in gene therapy. A major challenge for non-viral nanocarriers is the optimization of transgene expression in the targeted cells. This goal can be achieved by fine-tuning the chemical carriers and the adding specific motifs to promote cellular penetration. Our study focuses on the development of novel folate-based complexes that contain varying quantities of folate motifs. After controlling for their physical properties, neutral folate-modified lipid formulations were compared in vitro to lipoplexes leading to comparable expression levels. In addition, no cytotoxicity was detected, unlike what was observed in the cationic controls. Mechanistically, the delivery of the transgene appeared to be, in part, due to endocytosis mediated by folate receptor targeting. This mechanism was further validated by the observation that adding free folate into the medium decreased luciferase expression by 50%. In vivo transfection with the folate-modified MM18 lipid, containing the highest amount of FA-PEG570-diether co-lipid (w:w; 90:10, at a neutral charge ratio, gave luciferase transgene expression. These studies indicate that modification of lipids with folate residues could enhance non-toxic, cell-specific gene delivery.

  2. B12 Vitamin and Folat Prevelance of Children and Adolescents in Diyarbakır

    Directory of Open Access Journals (Sweden)

    Kahraman Öncel

    2006-01-01

    Full Text Available The most common cause of megaloblastic anemia in childhood are vitamin B12 and folat deficiency. Folat and vitamin B12 play a role in DNA synthessis in gastrointestinal, urogenital,nerves and hemotopoetic cells. The diagnosis of megaloblastic anemia is easy and the treatment cost is low.In this study, the prevalence of vitamin B12 and folat deficiencies in 889 students were determined. Vitamin B12 and folat levels in blood samples were measured via RİAThe average age were betwen 12 and 22 years. Of this students 294(%33,1 were female and 595 (%66,9 were male. The incidence of vitamin B12 deficiency was found to be 2.2%, while folat deficiency was 21.8%. The mean vitamin B12 level was 331,51±144,05 pg/mL (325,60±138,91 in pg/mL male, 343,48±153,48 pg/mL in female, the mean folat level was 5,42±2,12 ng/ml (5,23±2,11 ng/ml in male, 5,80±2,10 ng/ml in female.The prevelance of folat deficiency in our region was higher than other countries, possibly due to low socioeconomical status, improper or inadequate food intake and low educational status.

  3. A mathematical model of microbial folate biosynthesis and utilisation: implications for antifolate development.

    Science.gov (United States)

    Salcedo-Sora, J Enrique; Mc Auley, Mark T

    2016-03-01

    The metabolic biochemistry of folate biosynthesis and utilisation has evolved into a complex network of reactions. Although this complexity represents challenges to the field of folate research it has also provided a renewed source for antimetabolite targets. A range of improved folate chemotherapy continues to be developed and applied particularly to cancer and chronic inflammatory diseases. However, new or better antifolates against infectious diseases remain much more elusive. In this paper we describe the assembly of a generic deterministic mathematical model of microbial folate metabolism. Our aim is to explore how a mathematical model could be used to explore the dynamics of this inherently complex set of biochemical reactions. Using the model it was found that: (1) a particular small set of folate intermediates are overrepresented, (2) inhibitory profiles can be quantified by the level of key folate products, (3) using the model to scan for the most effective combinatorial inhibitions of folate enzymes we identified specific targets which could complement current antifolates, and (4) the model substantiates the case for a substrate cycle in the folinic acid biosynthesis reaction. Our model is coded in the systems biology markup language and has been deposited in the BioModels Database (MODEL1511020000), this makes it accessible to the community as a whole. PMID:26794619

  4. Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations.

    Science.gov (United States)

    Alpers, David H

    2016-07-01

    The systems involving folate and cobalamin have several features in common: 1) their dietary forms require luminal digestion for absorption; 2) intestinal bacteria in the upper intestine synthesize and utilize both vitamins, creating possible competition for the nutrients; 3) there is one major intestinal brush border protein essential for absorption; 4) both are subject to extensive entero-hepatic circulation. Finally, human mutations have confirmed the role of specific transporters and receptors in these processes. There are other features, however, that distinguish the metabolism of these vitamins: 1) upper intestinal bacteria tend to produce folate, while cobalamin (cbl) utilization is more common; 2) cbl absorption requires a luminal binding protein, but folate does not; 3) folate absorption can occur throughout the small bowel, but the cbl receptor, cubilin, is restricted to the distal half of the small bowel; 4) movement into cells uses transporters, exchangers, and symporters, whereas cbl is transferred by receptor-mediated endocytosis; 5) folate is carried in the blood mostly in red blood cells, whereas cbl is carried on specific binding-proteins; 6) folate can enter cells via multiple systems, but cbl uptake into all tissues use the transcobalamin receptor (TC-R), with the asialoglycoprotein receptor (ASGP-R) present in hepatocytes for uptake of haptocorrin-cbl (HC-cbl) complexes. In summary, the systems for absorption and distribution of folate and cobalamin are complex. These complexities help to explain the variable clinical responses after oral administration of the vitamins, especially when provided as supplements. PMID:26586110

  5. Self-assembled liquid-crystalline folate nanoparticles for in vitro controlled release of doxorubicin.

    Science.gov (United States)

    Misra, Rahul; Mohanty, Sanat

    2015-02-01

    Liquid-crystalline folate nanoparticles are ordered in structure which offers several advantages like high encapsulation of drugs, controlled release rates, biocompatible in nature. Moreover, it facilitates the cellular uptake of nanodrugs without any extra step of folate ligand based targeting. The size of these nanocarriers as well as the release profiles of drugs from these nano-carriers can be controlled precisely. Folate molecules self-assemble in ordered stacks and columns even at low concentration of 0.1wt%. Doxorubicin molecules get intercalated within the folate stacks and are developed into nanoparticles. These nanoparticles are composed of highly ordered folate self-assembly which encapsulate doxorubicin molecules. These drug molecules can be released in a controlled manner by disrupting this assembly in the environment of monovalent cations. The ordered structure of folate nanoparticles offers low drug losses of about 4-5%, which is significant in itself. This study reports the size-control method of forming doxorubicin encapsulated folate nanoparticles as well as the parameters to control the release rates of doxorubicin through liquid-crystalline folate nanoparticles. It has been demonstrated that doxorubicin release rates can be controlled by controlling the size of the nanoparticles, cross-linking cation and cross-linking concentration. The effect of different factors like drug loading, release medium, and pH of the medium on doxorubicin release rates was also studied. Moreover, this study also addresses the comparative in vitro cytotoxic performance of Doxorubicin loaded folate nanoparticles and cellular uptake of nano-carriers on cancer and normal cell line. PMID:25661378

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

    DEFF Research Database (Denmark)

    Thuesen, Betina H; Husemoen, Lise Lotte N; Ovesen, Lars;

    2009-01-01

    12 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.......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...

  7. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study.

    Science.gov (United States)

    Steenweg-de Graaff, Jolien; Ghassabian, Akhgar; Jaddoe, Vincent W V; Tiemeier, Henning; Roza, Sabine J

    2015-06-01

    In a population-based study, we examined the associations of maternal plasma folate concentrations at 13 weeks of gestation and prenatal folic acid supplement use with autistic traits in the offspring at the age of six years. Parent-reported autistic traits were assessed using the Social Responsiveness Scale short form. Maternal folate was not associated with autistic traits in the offspring. In contrast, prenatal folic acid use was associated with less child autistic traits. Future research should focus on the timing of the potential effect of prenatal folate on the development of autistic traits in combination with clinical diagnosis of autism in the offspring. PMID:25085472

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

    Science.gov (United States)

    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

  9. Identification and molecular docking studies for novel inverse agonists of SREB, super conserved receptor expressed in brain.

    Science.gov (United States)

    Yanai, Toshihiro; Kurosawa, Aya; Nikaido, Yoshiaki; Nakajima, Nozomi; Saito, Tamio; Osada, Hiroyuki; Konno, Ayumu; Hirai, Hirokazu; Takeda, Shigeki

    2016-07-01

    The identification of novel synthetic ligands for G protein-coupled receptors (GPCRs) is important not only for understanding human physiology, but also for the development of novel drugs, especially for orphan GPCRs for which endogenous ligands are unknown. One of the orphan GPCR subfamilies, Super conserved Receptor Expressed in Brain (SREB), consists of GPR27, GPR85 and GPR173 and is expressed in the central nervous system. We report herein the identification of inverse agonists for the SREB family without their agonists. We carried out an in vitro screening of 5472 chemical compounds from the RIKEN NPDepo chemical library. The binding of [(35) S]GTPγS to the GPR173-Gsα fusion protein expressed in Sf9 cells was measured and resulted in the identification of 8 novel GPR173 inverse agonists. The most potent compound showed an IC50 of approximately 8 μm. The identified compounds were also antagonists for other SREB members, GPR27 and GPR85. These results indicated that the SREB family could couple Gs-type G proteins, and SREB-Gsα fusion proteins showed significant constitutive activities. Moreover, a molecular model of GPR173 was constructed using the screening results. The combination of computational and biological methods will provide a unique approach to ligand identification for orphan GPCRs and brain research. PMID:27184081

  10. Evidence for estrogen receptor expression in germ cell and somatic cell subpopulations in the ovary of the newly hatched chicken.

    Science.gov (United States)

    Méndez, M C; Chávez, B; Echeverría, O; Vilchis, F; Vázquez Nin, G H; Pedernera, E

    1999-10-01

    Estrogens are involved in the gonadal morphogenesis of vertebrates, and almost all hormonal effects of 17beta-estradiol are mediated through specific receptors. At the time of sexual differentiation in the chicken, or even before, there is evidence of the presence of estrogen receptors and the secretion of 17beta-estradiol. However, no information is available regarding the cellular types that express the estrogen receptor in the immature chick ovary. The present study analyzes estrogen receptor expression in germ and somatic cells of the ovary in the newly hatched chicken. Highly purified cell subpopulations of germ and somatic cells were evaluated for specific 17beta-estradiol nuclear binding. In addition, the estrogen receptor was localized at the ultrastructural level by the immunogold technique. Finally, reverse transcription and polymerase chain reaction procedures detected a steady-state level of mRNA for the estrogen receptor. Somatic cells including typical steroidogenic cells showed specific 17beta-estradiol nuclear binding, displayed the estrogen receptor, and possessed estrogen receptor transcripts. The same result was observed in primary oocytes, together with the ultrastructural localization of estrogen receptor in extended chromatin filaments. Our experimental data support the hypothesis that estrogens are involved in the function of somatic and germ cells subpopulations in the immature chicken ovary. PMID:10555548

  11. Characterization of the effects of four HTR3B polymorphisms on human 5-HT3AB receptor expression and signalling

    DEFF Research Database (Denmark)

    Krzywkowski, Karen Margrethe; Davies, Paul A.; Irving, Andrew J.;

    2008-01-01

    BACKGROUND: 5-Hydroxytryptamine 3 (5-HT3) receptors mediate the fast excitatory neurotransmission of serotonin. In this study, we have characterized the effects of four naturally occurring, nonsynonymous variants of the human 5-HT3B subunit on expression and signalling properties of heteromeric 5......-HT3AB receptors. METHODS AND RESULTS: 5-HT3AB receptor signalling was studied in a fluorescence-based cell membrane potential assay and by electrophysiology. Expression levels of cotransfected epitope-tagged 5-HT3A and 5-HT3B subunits were determined using enzyme-linked immunosorbent assay...... and immunocytochemistry. In cells coexpressing 5-HT3A and 5-HT3B(I143T) subunits, cell surface expression levels of 5-HT3B in particular, and also 5-HT3A were markedly reduced compared with those of wild-type (WT) 5-HT3AB receptor-expressing cells. Electrophysiological recordings on cells coexpressing 5-HT3A and 5-HT3B...

  12. Dietary folate, methionine, riboflavin, and vitamin B-6 and risk of sporadic colorectal cancer

    NARCIS (Netherlands)

    Vogel, S. de; Dindore, V.; Engeland, M. van; Goldbohm, R.A.; Brandt, P.A. van den; Weijenberg, M.P.

    2008-01-01

    Adequate intake of folate, methionine, riboflavin, and vitamin B-6 may prevent aberrant DNA methylation and thereby protect against colorectal cancer (CRC). However, previous epidemiological studies investigating associations between dietary intakes of these nutrients and CRC have been inconsistent.

  13. Effects of septal nucleus lesion on dopamine D2 receptor expression in the prefrontal lobe, striatum, and brainstem in a rat model of schizophrenia

    Institute of Scientific and Technical Information of China (English)

    Xin Li; Shuande Li

    2008-01-01

    BACKGROUND: It has been demonstrated that the septal nucleus is involved in the pathogenesis of schizophrenia. Based on autopsies of schizophrenia patients, studies have shown a reduced number of septal nucleus neurons and gila. In addition, experimental rat models of schizophrenia have shown increased dopamine receptor D2 binding sites in the basal ganglia, septal nuclei, and substantia nigra. Previous studies have demonstrated that the septal nucleus modulates dopamine metabolic disorder and dopamine D2 receptor balance.OBJECTIVE: Dopamine D2 receptor expression in a rat model of schizophrenia, combined with antipsychotic drugs, was analyzed in the prefrontal lobe, striatum, and brainstem. In situ hybridization was used to observe the effects of stereotactic septal nucleus lesions on dopamine D2 receptor expression in the brains of methylamphetamine-treated rats. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed in the Laboratory of General Institute of Psychosurgery, Third Hospital of Chinese PLA from November 2005 to June 2006. MATERIALS: A total of 120 healthy, adult Sprague Dawley rats, weighing approximately 200 g, were included. Methylamphetamine (Sigma, USA) and an in situ hybridization detection kit for dopamine D2 receptor (Boster, China) were also used for this study. METHODS: All rats were randomly allocated to the following 4 groups, with 30 rats in each group: normal control, simple administration, septal nucleus lesion, and sham-operated groups. In the normal control group, rats were not administered or lesioned. In the remaining 3 groups, rats were intraperitoneally administered 10 mg/kg methylamphetamine, once per day, for 15 successive days to establish a schizophrenia model. Following successful model establishment, rats from the septal nucleus lesion group were subjected to stereotactic septal nucleus lesions. The cranial bone was exposed in rats from the sham-operated group, and the septal nucleus was not

  14. The interplay between DNA methylation, folate and neurocognitive development.

    Science.gov (United States)

    Irwin, Rachelle E; Pentieva, Kristina; Cassidy, Tony; Lees-Murdock, Diane J; McLaughlin, Marian; Prasad, Girijesh; McNulty, Helene; Walsh, Colum P

    2016-06-01

    DNA methylation provides an attractive possible means for propagating the effects of environmental inputs during fetal life and impacting subsequent adult mental health, which is leading to increasing collaboration between molecular biologists, nutritionists and psychiatrists. An area of interest is the potential role of folate, not just in neural tube closure in early pregnancy, but in later major neurodevelopmental events, with consequences for later sociocognitive maturation. Here, we set the scene for recent discoveries by reviewing the major events of neural development during fetal life, with an emphasis on tissues and structures where dynamic methylation changes are known to occur. Following this, we give an indication of some of the major classes of genes targeted by methylation and important for neurological and behavioral development. Finally, we highlight some cognitive disorders where methylation changes are implicated as playing an important role. PMID:27319574

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

    Directory of Open Access Journals (Sweden)

    Zhang L

    2012-01-01

    Full Text Available Lin Zhang1*, Weiwei Zhu2*, Chunfen Yang1, Hongxia Guo1, Aihua Yu1, Jianbo Ji3, Yan Gao1, Min Sun1, Guangxi Zhai11Department of Pharmaceutical Engineering, College of Pharmacy, Shandong University, Jinan; 2Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai; 3Department of Pharmacology, College of Pharmacy, Shandong University, Jinan, China*These authors contributed equally to the workBackground: The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells.Methods: Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research.Results: The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor® EL, 32.5% Transcutol® HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100. The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular

  16. Quantitative flux analysis reveals folate-dependent NADPH production

    Science.gov (United States)

    Fan, Jing; Ye, Jiangbin; Kamphorst, Jurre J.; Shlomi, Tomer; Thompson, Craig B.; Rabinowitz, Joshua D.

    2014-06-01

    ATP is the dominant energy source in animals for mechanical and electrical work (for example, muscle contraction or neuronal firing). For chemical work, there is an equally important role for NADPH, which powers redox defence and reductive biosynthesis. The most direct route to produce NADPH from glucose is the oxidative pentose phosphate pathway, with malic enzyme sometimes also important. Although the relative contribution of glycolysis and oxidative phosphorylation to ATP production has been extensively analysed, similar analysis of NADPH metabolism has been lacking. Here we demonstrate the ability to directly track, by liquid chromatography-mass spectrometry, the passage of deuterium from labelled substrates into NADPH, and combine this approach with carbon labelling and mathematical modelling to measure NADPH fluxes. In proliferating cells, the largest contributor to cytosolic NADPH is the oxidative pentose phosphate pathway. Surprisingly, a nearly comparable contribution comes from serine-driven one-carbon metabolism, in which oxidation of methylene tetrahydrofolate to 10-formyl-tetrahydrofolate is coupled to reduction of NADP+ to NADPH. Moreover, tracing of mitochondrial one-carbon metabolism revealed complete oxidation of 10-formyl-tetrahydrofolate to make NADPH. As folate metabolism has not previously been considered an NADPH producer, confirmation of its functional significance was undertaken through knockdown of methylenetetrahydrofolate dehydrogenase (MTHFD) genes. Depletion of either the cytosolic or mitochondrial MTHFD isozyme resulted in decreased cellular NADPH/NADP+ and reduced/oxidized glutathione ratios (GSH/GSSG) and increased cell sensitivity to oxidative stress. Thus, although the importance of folate metabolism for proliferating cells has been long recognized and attributed to its function of producing one-carbon units for nucleic acid synthesis, another crucial function of this pathway is generating reducing power.

  17. Polymorphisms in 1-Carbon Metabolism, Epigenetics and Folate-Related Pathologies

    OpenAIRE

    Stover, Patrick J.

    2012-01-01

    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 focuse...

  18. Premarital screening of 466 Mediterranean women for serum ferritin, vitamin B12, and folate concentrations

    OpenAIRE

    Karabulut, Aysun; GÜLER, ÖMER TOLGA; KARAHAN, HATİCE TUBA; ÖZKAN, SEVGİ; KOYUNCU, HASAN; DEMİRCİLER, İBRAHİM

    2015-01-01

    Background/aim: Iron, folate, and vitamin B12 serum levels are closely related with dietary habits and have an essential role in the healthy development of a fetus. We aimed to investigate hemoglobin, ferritin, folate, and vitamin B12 levels in preconceptional women in an area where a plant-based diet referred to as Mediterranean cuisine is commonly used. Materials and methods: The study population included 466 women between the ages of 18 and 45 years admitted for thalassemia screening. So...

  19. Selection of folate-producing lactic acid bacteria for improving fermented goat milk

    OpenAIRE

    Sanna, Maria Giovanna; Mangia, Nicoletta Pasqualina; Giovanni GARAU; Murgia, Marco Ambrogio; Massa, Tomasina G.; Franco, Mario Andrea; Deiana, Pietrino

    2005-01-01

    Goat milk is a complete food but its low level of folic acid diminisches its nutritional efficacy. In this study, Streptococcus thermophilus, Lactobacillus delbrueckii subsp. bulgaricus, Lb. delbrueckii subsp. lactis and Lb. helveticus strains were selected for folate production in goat milk to improve its quality. A suitable HPLC method was developed to directly determine both total folate and its biologically active derivatives such as 5-methyl-tetrahydrofolate (5- CH3-H4-PteGlu), tetrah...

  20. Serum Homocysteine and Folate Levels are Associated With Late-life Dementia in a Korean Population

    OpenAIRE

    Song, Ju Hee; Park, Moon Ho; Han, Changsu; Jo, Sangmee A.; Ahn, Kyungsook

    2010-01-01

    Objectives We aimed to determine whether serum levels of homocysteine (Hcy) and its biological determinants, folate and vitamin B12, are related to cognitive decline in elderly people. Methods The concentrations of total Hcy, folate, and vitamin B12 were measured in serum samples from 424 cognitively normal controls, 382 mild cognitive impairment patients, and 56 dementia patients from Ansan Geriatric cohort. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsycholo...

  1. Nutrition and Alzheimer's Disease: The Role of Folate and Vitamin B

    OpenAIRE

    Edmonds, Zachary V.

    1999-01-01

    Folate and vitamin B12 deficiency manifests in a number of known hematological and neurological disorders. Recently, an association has been discovered between these nutrients and Alzheimer's disease (AD). Although the initial evidence suggested that vitamin B12 levels may be reduced in AD patients, a number of studies failed to establish a consistent association between global deficiency in B12 and folate with this disease. However, more careful analysis of the biochemistry of these vitamins...

  2. Association of vitamin B12, folate, homocysteine and cognition in the elderly

    OpenAIRE

    Lökk, Johan

    2003-01-01

    Normal and subnormal serum levels of vitamin B12 and/or folate do not exclude functional deficiency, and elderly people are specifically exposed to deficiency owing to impaired nutrition, malabsorption, accompanying diseases and current medication. Several studies report that low levels of vitamin B12 are more common in people with Alzheimer’s disease (AD) than in non-demented people. Low levels of folate are also correlated with other types of dementia. Current studies suggest that low level...

  3. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery

    OpenAIRE

    Bourne, Christina R

    2014-01-01

    The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors for cellular function and contains a critical node, dihydrofolate reductase (DHFR), which is shared between prokaryotes and eukaryotes. The DHFR enz...

  4. Serum folate, vitamin B-12 and cognitive function in middle and older age: The HAPIEE study

    OpenAIRE

    Horvat, Pia; Gardiner, Julian; Kubinova, Ruzena; Pajak, Andrzej; Tamosiunas, Abdonas; Schöttker, Ben; Pikhart, Hynek; Peasey, Anne; Jansen, Eugene; Bobak, Martin

    2016-01-01

    Background Nutrient status of B vitamins, particularly folate and vitamin B-12, may be related to cognitive ageing but epidemiological evidence remains inconclusive. Objective The aim of this study was to estimate the association of serum folate and vitamin B-12 concentrations with cognitive function in middle-aged and older adults from three Central and Eastern European populations. Methods Men and women aged 45–69 at baseline participating in the Health, Alcohol and Psychosocial factors in ...

  5. Folate and fiber in the prevention of colorectal cancer:Between shadows and the light

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Colorectal cancer (CRC) is one of the most common malignancies and causes of cancer deaths throughout the world. Endoscopy has its functional and finan-cial limitations; therefore,chemoprevention might be crucial in reducing the incidence of CRC. Although a number of studies have demonstrated the potential chemopreventive effects of folate (or folic acid),many challenges still remain. The relationship between fo-late intake and CRC risk is a complex association that might depend on many factors including ge...

  6. Functional coating of liposomes using a folate–polymer conjugate to target folate receptors

    Directory of Open Access Journals (Sweden)

    Watanabe K

    2012-07-01

    Full Text Available Kazuo Watanabe, Makoto Kaneko, Yoshie MaitaniInstitute of Medical Chemistry, Hoshi University, Tokyo, JapanAbstract: Folate-polymer-coated liposomes were developed for targeted chemotherapy using doxorubicin (DXR as a model drug. Folate-poly(L-lysine (F–PLL conjugates with a folate modification degree of 16.7 mol% on epsilon amino groups of PLL were synthesized. DXR-loaded anionic liposomes were coated with F–PLL, and the cellular association of F–PLL-coated liposomes was evaluated by flow cytometry, and confocal microscopy in human nasopharyngeal carcinoma KB cells overexpressing folate receptors (FRs, and human lung adenocarcinoma A549 cells [FR (-]. The existence of a polymer layer on the surface of F–PLL-coated liposomes was confirmed by zeta potential analysis. The KB cellular association of F–PLL-coated liposomal DXR was increased compared with that of PLL-coated liposomes and was inhibited in the presence of free folic acid. Twofold higher cytotoxicity of F–PLL-coated liposomal DXR was observed compared with that of the PLL-coated liposomal DXR in KB cells, but not in A549 cells, suggesting the presence of FR-mediated endocytosis. These results indicated that folate-targeted liposomes were prepared successfully by coating the folate–polymer conjugate F–PLL. This novel preparation method of folate-targeted liposomes is expected to provide a powerful tool for the development of a folate-targeting drug nanodevice as coating with ligand–polymer conjugates can be applicable to many kinds of particles, as well as to lipid-based particles.Keywords: cellular association, folate-targeting, liposome, poly-L-lysine, polymer coating, tumor targeting

  7. Evaluation of radiogallium-labeled, folate-embedded superparamagnetic nanoparticles in fibrosarcoma-bearing mice

    Directory of Open Access Journals (Sweden)

    Seyyedeh Leila Hosseini-Salekdeh

    2012-01-01

    Full Text Available Context: Elevated expression of the folate receptor (FR occurs in many human malignancies. Thus, folate targeting is widely utilized in drug delivery purposes specially using nano-radioactive agents. Aims: In this work, we report production and biological evaluation of gallium-67 labeled superparamagnetic iron oxide nanoparticles, embedded by folic acid ( 67 Ga-SPION-folate complex especially in tumor-bearing mice for tumor imaging studies. Settings and Design: The structure of SPION-folate was confirmed by X-ray diffraction (XRD, transmission electron microscopy (TEM and foureir transform infrared spectroscopy (FT-IR analyses. The radiolabeled SPION-folate formation was confirmed by instant thin layer chromatography (ITLC. Tumor induction was performed by the use of poly-aromatic hydrocarbon injection in rodents as reported previously. Materials and Methods: [ 67 Ga]-SPION-folate was shown to possess a particle size of ≈5-10 nm using instrumental methods followed by ITLC test. Biocompatibility of the compound was investigated using an 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay followed by stability tests and tumor accumulation studies in fibrosarcoma-bearing mice after subcutaneous (s.c. application. Statistical Analysis Used: All values were expressed as mean ± standard deviation (mean ± SD and the data were compared using Student t-test. Statistical significance was defined as P95% radiochemical purity. Biodistribution studies demonstrated tumor:blood, tumor:bone and tumor:muscle ratios of 4.23, 4.98 and 11.54 respectively after 24 h. Conclusions: Due to the nano-scale size and high-penetrative property of the developed folate-containing nano-complex, this system can be an interesting drug delivery modality with therapeutic applications and folate receptor-targeting behavior, while possessing paramagnetic properties for thermotherapy.

  8. Prospective Evaluation of Procalcitonin, Soluble Triggering Receptor Expressed on Myeloid Cells-1 and C-Reactive Protein in Febrile Patients with Autoimmune Diseases

    OpenAIRE

    Lin, Chou-Han; Hsieh, Song-Chou; Keng, Li-Ta; Lee, Ho-Sheng; Chang, Hou-Tai; Liao, Wei-Yu; Ho, Chao-Chi; Yu, Chong-Jen

    2016-01-01

    Background Both procalcitonin (PCT) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) have been investigated separately as indicators of infection in patients with autoimmune diseases. Our study simultaneously evaluated both PCT and sTREM-1 along with C-reactive protein (CRP) in febrile patients with autoimmune diseases. Methods Fifty-nine patients were enrolled in the study. The patients were categorized into the infection group (n = 24) or the disease flare group (n = 3...

  9. Retinoid and thiazolidinedione therapies in melanoma: an analysis of differential response based on nuclear hormone receptor expression

    Directory of Open Access Journals (Sweden)

    Pugazhenthi Umarani

    2009-03-01

    Full Text Available Abstract Background Metastatic melanoma has a high mortality rate and suboptimal therapeutic options. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid × receptor selective agonist, and thiazolidinediones (TZD, PPARγ selective ligands, as novel treatments. Results Mouse xenograft models with human melanoma cell lines [A375(DRO or M14(5–16] were treated for 4 weeks with daily vehicle, RXR agonist (rexinoid, LGD1069, 30 mg/kg/d, PPARγ agonist (TZD, rosiglitazone, 10 mg/kg/d or combination. A375(DRO tumor growth was significantly inhibited by either ligand alone and the combination had an additive effect. M14(5–16 tumors only responded to LGD1069 100 mg/kg/day. A375(DRO sublines resistant to rexinoid, TZD and combination were generated and all three sublines had reduced PPARγ expression but preserved RXR expression. shRNA knockdown of PPARγ or RXRγ attenuated the rexinoid, TZD and combination ligand-mediated decreased proliferation in A375(DRO cells. Rexinoid (LGD1069 and retinoid (TTNPB treatment of M14(5–16 cells resulted in decreased proliferation that was additive with combination of both rexinoid and retinoid. shRNA knockdown of RXRγ resulted in a decreased response to either ligand. Conclusion A375 (DRO melanoma cell growth is inhibited by rexinoid and TZD treatment, and this response is dependent on RXR and PPARγ receptor expression. M14 (5–16 melanoma cell growth is inhibited by rexinoid and retinoid treatment, and this response is dependent on RXR expression. These findings may help guide molecular-based treatment strategies in melanoma and provide insight for mechanisms of resistance to nuclear receptor targeted therapies in certain cancers.

  10. Progesterone receptor expression declines in the guinea pig uterus during functional progesterone withdrawal and in response to prostaglandins.

    Directory of Open Access Journals (Sweden)

    Toni N Welsh

    Full Text Available Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone

  11. Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

    Directory of Open Access Journals (Sweden)

    Oihane Abiega

    2016-05-01

    Full Text Available Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets, microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed

  12. Association of Serum Soluble Triggering Receptor Expressed on Myeloid Cells Levels in Malignancy Febrile Neutropenic Patients with Bacteremia and Fungemia

    Directory of Open Access Journals (Sweden)

    Ahmad-Reza Shamshiri

    2011-09-01

    Full Text Available Objective:Infections are the major cause of morbidity and mortality in febrile neutropenic patients with malignancy. Rapid diagnostic tests are needed for prompt diagnosis and early treatment which is crucial for optimal management. We assessed the utility of soluble triggering receptor expressed on myeloid cells (sTREM-1 in the diagnosis of bacteremia and fungemia in febrile neutropenic patients. Methods:Sixty-five febrile neutropenic children with malignancy hospitalized in Mofid Children's Hospital during a period of one year from January 2007 were recruited for this cross sectional study (mean age 66.2± 37 months; 35 females and 30 males. Thirty patients (46.2% had acute lymphoblastic leukemia, 2 (3.1% acute myeloid leukemia, one (1.5% lymphoma and 32 (49.2% were under treatment for solid tumors. Simultaneous blood samples were collected for measurement of serum sTREM-1 levels and for blood cultures which were grown in BACTEC media. Gold standard for the presence of infection was a positive BACTEC culture as a more sensitive method compared to current blood culture techniques. Findings Blood cultures with BACTEC system were positive in 13(20% patients (12 bacterial and one fungal culture. The mean serum sTREM-1 level in BACTEC positive patients was 948.2±592.9 pg/ml but in BACTEC negative cases it was 76.3±118.8 pg/ml (P<0.001. The optimal cut-off point of sTREM-1 for detecting patients with positive result of BACTEC was 525 pg/ml with sensitivity and specificity of 84.6% and 100%, respectively. Conclusion:Our study revealed a significant association between serum sTREM-1 level and bacteremia and fungemia in febrile neutropenic patients suffering malignancy with acceptable sensitivity and specificity.

  13. Acetylcholine induces GABA release onto rod bipolar cells through heteromeric nicotinic receptors expressed in A17 amacrine cells

    Science.gov (United States)

    Elgueta, Claudio; Vielma, Alex H.; Palacios, Adrian G.; Schmachtenberg, Oliver

    2015-01-01

    Acetylcholine (ACh) is a major retinal neurotransmitter that modulates visual processing through a large repertoire of cholinergic receptors expressed on different retinal cell types. ACh is released from starburst amacrine cells (SACs) under scotopic conditions, but its effects on cells of the rod pathway have not been investigated. Using whole-cell patch clamp recordings in slices of rat retina, we found that ACh application triggers GABA release onto rod bipolar (RB) cells. GABA was released from A17 amacrine cells and activated postsynaptic GABAA and GABAC receptors in RB cells. The sensitivity of ACh-induced currents to nicotinic ACh receptor (nAChR) antagonists (TMPH ~ mecamylamine > erysodine > DhβE > MLA) together with the differential potency of specific agonists to mimic ACh responses (cytisine >> RJR2403 ~ choline), suggest that A17 cells express heteromeric nAChRs containing the β4 subunit. Activation of nAChRs induced GABA release after Ca2+ accumulation in A17 cell dendrites and varicosities mediated by L-type voltage-gated calcium channels (VGCCs) and intracellular Ca2+ stores. Inhibition of acetylcholinesterase depolarized A17 cells and increased spontaneous inhibitory postsynaptic currents in RB cells, indicating that endogenous ACh enhances GABAergic inhibition of RB cells. Moreover, injection of neostigmine or cytisine reduced the b-wave of the scotopic flash electroretinogram (ERG), suggesting that cholinergic modulation of GABA release controls RB cell activity in vivo. These results describe a novel regulatory mechanism of RB cell inhibition and complement our understanding of the neuromodulatory control of retinal signal processing. PMID:25709566

  14. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

    Directory of Open Access Journals (Sweden)

    Sofia Johansson

    Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

  15. A Review of Psoriasis, a Known Risk Factor for Cardiovascular Disease and Its Impact on Folate and Homocysteine Metabolism

    Directory of Open Access Journals (Sweden)

    Ian McDonald

    2012-01-01

    Full Text Available Psoriasis is a chronic inflammatory skin condition with an increased risk of cardiovascular disease. This risk has been attributed to an association with many independent risk factors including obesity, hypertension, smoking, and dyslipidemia. Psoriasis patients also have lower levels of folate and conversely higher levels of homocysteine, which in itself is a risk factor for cardiovascular disease. It has been postulated that low folate levels in this group may be a direct cause of hyperhomocysteinemia and therefore a treatable risk factor by folate supplementation. This paper looks at the literature published to date on the relationship between psoriasis, homocysteine, and folate levels.

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

    Science.gov (United States)

    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.

  17. High Dietary Folate in Mice Alters Immune Response and Reduces Survival after Malarial Infection.

    Directory of Open Access Journals (Sweden)

    Danielle N Meadows

    Full Text Available Malaria is a significant global health issue, with nearly 200 million cases in 2013 alone. Parasites obtain folate from the host or synthesize it de novo. Folate consumption has increased in many populations, prompting concerns regarding potential deleterious consequences of higher intake. The impact of high dietary folate on the host's immune function and response to malaria has not been examined. Our goal was to determine whether high dietary folate would affect response to malarial infection in a murine model of cerebral malaria. Mice were fed control diets (CD, recommended folate level for rodents or folic acid-supplemented diets (FASD, 10x recommended level for 5 weeks before infection with Plasmodium berghei ANKA. Survival, parasitemia, numbers of immune cells and other infection parameters were assessed. FASD mice had reduced survival (p<0.01, Cox proportional hazards and higher parasitemia (p< 0.01, joint model of parasitemia and survival compared with CD mice. FASD mice had lower numbers of splenocytes, total T cells, and lower numbers of specific T and NK cell sub-populations, compared with CD mice (p<0.05, linear mixed effects. Increased brain TNFα immunoreactive protein (p<0.01, t-test and increased liver Abca1 mRNA (p<0.01, t-test, a modulator of TNFα, were observed in FASD mice; these variables correlated positively (rs = 0.63, p = 0.01. Bcl-xl/Bak mRNA was increased in liver of FASD mice (p<0.01, t-test, suggesting reduced apoptotic potential. We conclude that high dietary folate increases parasite replication, disturbs the immune response and reduces resistance to malaria in mice. These findings have relevance for malaria-endemic regions, when considering anti-folate anti-malarials, food fortification or vitamin supplementation programs.

  18. Monoolein-based nanocarriers for enhanced folate receptor-mediated RNA delivery to cancer cells.

    Science.gov (United States)

    Lopes, Ivo; C N Oliveira, Ana; P Sárria, Marisa; P Neves Silva, João; Gonçalves, Odete; Gomes, Andreia C; Real Oliveira, Maria Elisabete C D

    2016-09-01

    We report the development and characterization of a novel nanometric system for specific delivery of therapeutic siRNA for cancer treatment. This vector is based on a binary mixture of the cationic surfactant dioctadecyldimethylammonium chloride (DODAC) and the helper lipid monoolein (MO). These liposomes were previously validated by our research group as promising non-viral vectors for nucleic acid delivery. In this work, the DODAC:MO vesicles were for the first time functionalized with polyethylene glycol and PEG-folate conjugates to achieve both maximal stability in biological fluids and increase selectivity toward folate receptor α expressing cells. The produced DODAC:MO:PEG liposomes were highly effective in RNA complexation (close to 100%), and the resulting lipoplexes also demonstrated high stability in conditions simulating their administration by intravenous injection (physiological pH, high NaCl, heparin and fetal bovine serum concentrations). In addition, cell uptake of the PEG-folate-coated lipoplexes was significantly greater in folate receptor α positive breast cancer cells (39% for 25 µg/mL of lipid and 31% for 40 µg/mL) when compared with folate receptor α negative cells (31% for 25 µg/mL of lipid and 23% for 40 µg/mL) and to systems without PEG-folate (≈13% to 16% for all tested conditions), supporting their selectivity towards the receptor. Overall, the results support these systems as appealing vectors for selective delivery of siRNA to cancer cells by folate receptor α-mediated internalization, aiming at future therapeutic applications of interest. PMID:26340109

  19. The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial

    Directory of Open Access Journals (Sweden)

    Brezina Paul R

    2012-02-01

    Full Text Available Abstract Background To assess the impact of luteal phase support on the expression of estrogen receptor (ER alpha and progesterone receptors B (PR-B on the endometrium of oocyte donors undergoing controlled ovarian hyperstimulation (COH. Methods A prospective, randomized study was conducted in women undergoing controlled ovarian hyperstimulation for oocyte donation. Participants were randomized to receive no luteal support, vaginal progesterone alone, or vaginal progesterone plus orally administered 17 Beta estradiol. Endometrial biopsies were obtained at 4 time points in the luteal phase and evaluated by tissue microarray for expression of ER alpha and PR-B. Results One-hundred and eight endometrial tissue samples were obtained from 12 patients. No differences were found in expression of ER alpha and PR-B among all the specimens with the exception of one sample value. Conclusions The administration of progesterone during the luteal phase of COH for oocyte donor cycles, either with or without estrogen, does not significantly affect the endometrial expression of ER alpha and PR.

  20. Comparative analysis of mineralocorticoid receptor expression among vocal learners (Bengalese finch and budgerigar) and non-vocal learners (quail and ring dove) has implications for the evolution of avian vocal learning.

    Science.gov (United States)

    Matsunaga, Eiji; Suzuki, Kenta; Kobayashi, Tetsuya; Okanoya, Kazuo

    2011-12-01

    Mineralocorticoid receptor is the receptor for corticosteroids such as corticosterone or aldosterone. Previously, we found that mineralocorticoid receptor was highly expressed in song nuclei of a songbird, Bengalese finch (Lonchura striata var. domestica). Here, to examine the relationship between mineralocorticoid receptor expression and avian vocal learning, we analyzed mineralocorticoid receptor expression in the developing brain of another vocal learner, budgerigar (Melopsittacus undulatus) and non-vocal learners, quail (Coturnix japonica) and ring dove (Streptopelia capicola). Mineralocorticoid receptor showed vocal control area-related expressions in budgerigars as Bengalese finches, whereas no such mineralocorticoid receptor expressions were seen in the telencephalon of non-vocal learners. Thus, these results suggest the possibility that mineralocorticoid receptor plays a role in vocal development of parrots as songbirds and that the acquisition of mineralocorticoid receptor expression is involved in the evolution of avian vocal learning.

  1. High serum folate is associated with reduced biochemical recurrence after radical prostatectomy: Results from the SEARCH Database

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    Daniel M. Moreira

    2013-06-01

    Full Text Available Introduction To analyze the association between serum levels of folate and risk of biochemical recurrence after radical prostatectomy among men from the Shared Equal Access Regional Cancer Hospital (SEARCH database. Materials and Methods Retrospective analysis of 135 subjects from the SEARCH database treated between 1991-2009 with available preoperative serum folate levels. Patients' characteristics at the time of the surgery were analyzed with ranksum and linear regression. Uni- and multivariable analyses of folate levels (log-transformed and time to biochemical recurrence were performed with Cox proportional hazards. Results The median preoperative folate level was 11.6ng/mL (reference = 1.5-20.0ng/mL. Folate levels were significantly lower among African-American men than Caucasians (P = 0.003. In univariable analysis, higher folate levels were associated with more recent year of surgery (P < 0.001 and lower preoperative PSA (P = 0.003. In univariable analysis, there was a trend towards lower risk of biochemical recurrence among men with high folate levels (HR = 0.61, 95%CI = 0.37-1.03, P = 0.064. After adjustments for patients characteristics' and pre- and post-operative clinical and pathological findings, higher serum levels of folate were independently associated with lower risk for biochemical recurrence (HR = 0.42, 95%CI = 0.20-0.89, P = 0.023. Conclusion In a cohort of men undergoing radical prostatectomy at several VAs across the country, higher serum folate levels were associated with lower PSA and lower risk for biochemical failure. While the source of the folate in the serum in this study is unknown (i.e. diet vs. supplement, these findings, if confirmed, suggest a potential role of folic acid supplementation or increased consumption of folate rich foods to reduce the risk of recurrence.

  2. Sex- and age-specific differences in relaxin family peptide receptor expression within the hippocampus and amygdala in rats.

    Science.gov (United States)

    Meadows, K L; Byrnes, E M

    2015-01-22

    Relaxin is an essential pregnancy-related hormone with broad peripheral effects mediated by activation of relaxin-like family peptide 1 receptors (RXFP1). More recent studies suggest an additional role for relaxin as a neuropeptide, with RXFP1 receptors expressed in numerous brain regions. Neurons in an area of the brainstem known as the nucleus incertus (NI) produce relaxin 3 (RLN3), the most recently identified neuropeptide in the relaxin family. RLN3 has been shown to activate both RXFP1 and relaxin-like family peptide receptor 3 (RXFP3) receptor subtypes. Studies suggest wide-ranging neuromodulatory effects of both RXFP1 and RXFP3 activation, although to date the majority of studies have been conducted in young males. In the current study, we examined potential sex- and age-related changes in RLN3 gene expression in the NI as well as RXFP1 and RXFP3 gene expression in the dorsal hippocampus (HI), ventral hippocampus (vHI) and amygdala (AMYG) using young adult (9-12weeks) and middle-aged (9-12months) male and female rats. In addition, regional changes in RXFP1 and RXFP3 protein expression were examined in the CA1, CA2/CA3 and dentate gyrus (DG) as well as within basolateral (BLA), central (CeA), and medial (MeA) amygdaloid nuclei. In the NI, RLN3 showed an age-related decrease in males. In the HI, only the RXFP3 receptor showed an age-related change in gene expression, however, both receptor subtypes showed age-related changes in protein expression that were region specific. Additionally, while gene and protein expression of both receptors increased with age in AMYG, these effects were both region- and sex-specific. Finally, overall males displayed a greater number of cells that express the RXFP3 protein in all of the amygdaloid nuclei examined. Cognitive and emotional processes regulated by activity within the HI and AMYG are modulated by both sex and age. The vast majority of studies exploring the influence of sex on age-related changes in the HI and AMYG have

  3. Synthesis and evaluation of a technetium-99m labeled cytotoxic bombesin peptide conjugate for targeting bombesin receptor-expressing tumors

    Energy Technology Data Exchange (ETDEWEB)

    Okarvi, Subhani M. [Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, MBC-03, PO Box 3354, Riyadh 11211 (Saudi Arabia)], E-mail: sokarvi@kfshrc.edu.sa; Al Jammaz, Ibrahim [Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, MBC-03, PO Box 3354, Riyadh 11211 (Saudi Arabia)

    2010-04-15

    Conjugation of the cytotoxic drugs to receptor-binding peptides is an attractive approach for the targeted delivery of cytotoxic peptide conjugates to tumor cells. In an attempt to develop an efficient peptide-based radiopharmaceutical for targeting bombesin (BN) receptor-expressing tumors (i.e., breast and prostate), we have prepared by solid-phase peptide synthesis, a novel BN analog derived from the universal sequence of BN and conjugated to a widely characterized antineoplastic agent, methotrexate (MTX). MTX-BN, after radiolabeling with {sup 99m}Tc via stannous-tartrate exchange, showed a good stability against cysteine and histidine transchelation as well as a high in vitro metabolic stability in human plasma. In vitro cell-binding and internalization on MDA-MB-231, MCF-7, T47-D breast cancer and PC-3 prostate cancer cell lines demonstrated high affinity and specificity of {sup 99m}Tc-MTX-BN towards both human breast and prostate cancer cells (binding affinities in nanomolar range). In addition, the radioconjugate displayed a significant internalization (values ranged between 19-35%) into the tumor cells. In vivo biodistribution and clearance kinetics in Balb/c mice are characterized by an efficient clearance from the blood and excretion mainly through the renal-urinary pathway with some elimination via the hepatobiliary system. In vivo tumor uptake in nude mice bearing MDA-MB-231 cells was 2.70{+-}0.44% ID/g at 1 h, whereas in nude mice with human epidermoid KB cells the accumulation in the tumor was found to be 1.48{+-}0.31% ID/g at 1 h post injection. The tumor uptake was always higher than in the blood and muscle, with good tumor retention and good tumor-to-blood and tumor-to-muscle ratios. The accumulation/retention in the major organs (i.e., lungs, stomach, liver, intestines, etc.) was low to moderate (<6% ID/g) in both healthy and tumor-bearing mice. However, the uptake/retention in the kidneys was rather high (up to 11.05{+-}1.80% ID/g), which is of a

  4. Sex-specific effects of prenatal chronic mild stress on adult spatial learning capacity and regional glutamate receptor expression profiles.

    Science.gov (United States)

    Wang, Yan; Ma, Yuchao; Hu, Jingmin; Zhang, Xinxin; Cheng, Wenwen; Jiang, Han; Li, Min; Ren, Jintao; Zhang, Xiaosong; Liu, Mengxi; Sun, Anji; Wang, Qi; Li, Xiaobai

    2016-07-01

    Both animal experiments and clinical studies have demonstrated that prenatal stress can cause cognitive disorders in offspring. To explore the scope of these deficits and identify potential underlying mechanisms, we examined the spatial learning and memory performance and glutamate receptor (GluR) expression patterns of adult rats exposed to prenatal chronic mild stress (PCMS). Principal component analysis (PCA) was employed to reveal the interrelationships among spatial learning indices and GluR expression changes. Female PCMS-exposed offspring exhibited markedly impaired spatial learning and memory in the Morris water maze (MWM) task compared to control females, while PCMS-exposed males showed better initial spatial learning in the MWM compared to control males. PCMS also altered basal and post-MWM glutamate receptor expression patterns, but these effects differed markedly between sexes. Male PCMS-exposed offspring exhibited elevated basal expression of NR1, mGluR5, and mGluR2/3 in the prefrontal cortex (PFC), whereas females showed no basal expression changes. Following MWM training, PCMS-exposed males expressed higher NR1 in the PFC and mammillary body (MB), higher mGluR2/3 in PFC, and lower NR2B in the hippocampus (HIP), PFC, and MB compared to unstressed MWM-trained males. Female PCMS-exposed offspring showed strongly reduced NR1 in MB and NR2B in the HIP, PFC, and MB, and increased mGluR2/3 in PFC compared to unstressed MWM-trained females. This is the first report suggesting that NMDA subunits in the MB are involved in spatial learning. Additionally, PCA further suggests that the NR1-NR2B form is the most important for spatial memory formation. These results reveal long-term sex-specific effects of PCMS on spatial learning and memory performance in adulthood and implicate GluR expression changes within HIP, PFC, and MB as possible molecular mechanisms underlying cognitive dysfunction in offspring exposed to prenatal stress. PMID:27094122

  5. Mechanisms of dysregulation of low-density lipoprotein receptor expression in HepG2 cells induced by inflammatory cytokines

    Institute of Scientific and Technical Information of China (English)

    CHEN Ya-xi; RUAN Xiong-zhong; HUANG Ai-long; LI Qiu; John F. Moorhead; Zac Varghese

    2007-01-01

    feedback regulation by enhancing SCAP-SREBP complex translocation from the ER to the Golgi,thereby increasing SREBP-2 mediated LDL receptor expression even in the presence of high concentration of LDL.This results in LDL cholesterol accumulation in hepatic cells via LDL receptor pathway under inflammatory stress.

  6. Bioaccessibility of folic acid and (6S)-5-methyltetrahydrofolate decreases after the addition of folate-binding protein to yogurt as studied in a dynamic in vitro gastrointestinal model.

    Science.gov (United States)

    Arkbåge, Karin; Verwei, Miriam; Havenaar, Robert; Witthöft, Cornelia

    2003-11-01

    Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of this study was to investigate the bioaccessibility of folic acid and (6S)-5-methyltetrahydrofolate (5-CH3-H4folate) from fortified yogurt using a dynamic in vitro gastrointestinal model (TIM). In addition, the effect of FBP on folate bioaccessibility and the stability of FBP added to yogurt during gastrointestinal passage were investigated. Folate bioaccessibility was 82% from yogurt fortified with folic acid and 5-CH3-H4folate. The addition of FBP to yogurt decreased (P folic acid (34% folate bioaccessibility) than from yogurt fortified with 5-CH3-H4folate (57% folate bioaccessibility). After gastrointestinal passage, 17% of the FBP in yogurt fortified with 5-CH3-H4folate and 34% of the FBP in yogurt fortified with folic acid were recovered. No difference in folate bioaccessibility was found between folate-fortified yogurt and folate-fortified pasteurized milk (P = 0.10), whereas the lowering effect of FBP was (P folic acid and 5-CH3-H4folate, yogurt without active FBP can be considered to be an appropriate food matrix for folate fortification.

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

    OpenAIRE

    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 reduct...

  8. Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.

    Directory of Open Access Journals (Sweden)

    Radek Bukowski

    2009-05-01

    Full Text Available BACKGROUND: Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. METHODS AND FINDINGS: In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08-0.61, p = 0.004 and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24-0.83, p = 0.010. Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11-0.90, p = 0.031 and 0.53, 0.28-0.99, p = 0.046, respectively. Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth

  9. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Lian-Hua Cui

    2016-06-01

    Full Text Available Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients’ clinical characteristics including tumor-node-metastasis (TNM stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR (95% confidence intervals (CI of HCC from the highest to lowest quartile of folate were 0.30 (0.15–0.60, 0.33 (0.17–0.65, and 0.19 (0.09–0.38. Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02–3.98. HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels, whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results.

  10. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma.

    Science.gov (United States)

    Cui, Lian-Hua; Quan, Zhen-Yu; Piao, Jin-Mei; Zhang, Ting-Ting; Jiang, Meng-Hui; Shin, Min-Ho; Choi, Jin-Su

    2016-01-01

    Folate and vitamin B12 involved in the one-carbon metabolism may play a key role in carcinogenesis and progression of hepatocellular carcinoma (HCC) through influencing DNA integrity. The purpose of this study is to evaluate the association of plasma folate and vitamin B12 levels with HCC in a case-control study on 312 HCC patients and 325 cancer-free controls. Plasma concentrations of folate and vitamin B12 in all the subjects were measured by electrochemiluminescence immunoassay. Meanwhile, the information of HCC patients' clinical characteristics including tumor-node-metastasis (TNM) stage, tumor size and tumor markers were collected. The patients of HCC had significantly lower folate levels than those of controls; there was no significant difference in the mean of plasma vitamin B12 levels. We also observed an inverse association between the levels of plasma folate and HCC: the adjusted odds ratios (OR) (95% confidence intervals (CI)) of HCC from the highest to lowest quartile of folate were 0.30 (0.15-0.60), 0.33 (0.17-0.65), and 0.19 (0.09-0.38). Compared to the subjects in the lowest quartile of plasma vitamin B12, only the subjects in the highest quartile of vitamin B12 exhibited a significant positive relationship with HCC, the adjusted OR was 2.01 (95% CI, 1.02-3.98). HCC patients with Stage III and IV or bigger tumor size had lower folate and higher vitamin B12 levels. There was no significant difference in the mean plasma folate levels of the HCC cases in tumor markers status (AFP, CEA and CA19-9 levels), whereas patients with higher CEA or CA19-9 levels retained significantly more plasma vitamin B12 than those with normal-CEA or CA19-9 level. In conclusion, plasma folate and vitamin B12 levels could be associated with HCC, and might be used as predictors of clinical characteristics of HCC patients. However, further prospective studies are essential to confirm the observed results. PMID:27376276

  11. Association between betel nut consumption and folate deficiency among pregnant women in rural Bangladesh

    Directory of Open Access Journals (Sweden)

    Manzur Kader

    2013-04-01

    Full Text Available Background: Betel nut (BN or areca nut (AN chewing habits on its own or with other ingredients including chewing tobacco are highly prevalent in many South East Asian countries as well as among the migrants from these countries residing around the world. The major alkaloid arecoline in the BN has been found to carcinogenic and to be associated with a range of health risks, including negative effects on pregnancy outcomes. Pregnancy imposes stress on folate stores because of increased requirements for growth of maternal tissues, fetus, and placenta. Folate defi ciency during pregnancy is a major public health concern as is associated with many adverse health outcomes including neural tube defects, low birth weight, preterm birth, and delayed maturation of the nervous system, growth retardation, and megaloblastic anemia. Objective: To investigate any association between BN consumption and folate status among pregn ant women in rural Bangladesh. Materials and Methods: Data of 730 pregnant women aged 14-50 years from the Maternal and Infant Nutrition Intervention in Matlab (MINIMat trial in Bangladesh were included in this study. Logistic regression analysis and analyses of covariance (ANCOVA were used. Results were adjusted for potential confounders. Results and Interpretation: Two-third (63% of the women consumed BN and 17% had folate defi ciency. The women who consumed BN combined with chewing tobacco were 2.57 times more likely to have folate defi ciency (OR2.57; 95% CI1.23-5.36; P0.012; and the women who consumed BN 2-3 times/day were 2.51 times more likely to develop folate defi ciency among users (OR 2.51; 95% CI1.07-5.92; P0.035. Mean serum folate levels were signifi cantly lower among BN users as compared to nonusers. Conclusion: The results suggest that betel nut consumption combined with chewing tobacco is associated with lower serum folate level and folate defi ciency among pregnant

  12. Integrin alphaVbeta6 is a high-affinity receptor for coxsackievirus A9.

    Science.gov (United States)

    Heikkilä, Outi; Susi, Petri; Stanway, Glyn; Hyypiä, Timo

    2009-01-01

    Coxsackievirus A9 (CAV9), a member of the genus Enterovirus in the family Picornaviridae, possesses an integrin-binding arginine-glycine-aspartic acid (RGD) motif in the C terminus of VP1 capsid protein. CAV9 has been shown to utilize integrins alphaVbeta3 and alphaVbeta6 as primary receptors for cell attachment. While CAV9 RGD-mutants (RGE and RGDdel) are capable of infecting rhabdomyosarcoma (RD) cell line, they grow very poorly in an epithelial lung carcinoma cell line (A549). In this study, the relationships between CAV9 infectivity in A549 and RD cells, receptor expression and integrin binding were analysed. A549 cells were shown to express both integrins alphaVbeta3 and alphaVbeta6, whereas alphaVbeta6 expression was not detected on the RD cells. Native CAV9 but not RGE and RGDdel mutants bound efficiently to immobilized alphaVbeta3 and alphaVbeta6. Adhesion of CAV9 but not RGE/RGDdel to A549 cells was also significantly higher than to RD cells. In contrast, no affinity or adhesion of bacterially produced VP1 proteins to the integrins or to the cells was detected. Function-blocking antibodies against alphaV-integrins blocked CAV9 but not CAV9-RGDdel infectivity, indicating that the viruses use different internalization routes; this may explain the differential infection kinetics of CAV9 and RGDdel. In an affinity assay, soluble alphaVbeta6, but not alphaVbeta3, bound to immobilized CAV9. Similarly, only soluble alphaVbeta6 blocked virus infectivity. These data suggest that CAV9 binding to alphaVbeta6 is a high-affinity interaction, which may indicate its importance in clinical infections; this remains to be determined.

  13. Antioxidative effect of folate-modified chitosan nanoparticles

    Institute of Scientific and Technical Information of China (English)

    Subhankari; Prasad; Chakraborty; Santanu; Kar; Mahapatra; Sumanta; Kumar; Sahu; Panchanan; Pramanik; Somenath; Roy

    2011-01-01

    Objective:To evaluate the potency of carboxymethyl chitosan-2,2’ ethylenedioxy bisethylamine-folate(CMC-EDBE-FA) on tissue injury,antioxidant status and glutathione system in tissue mitochondria and serum against nicotine-induced oxidative stress in mice.Methods: CMC-EDBE-FA was prepared on basis of carboxymethyl chitosan tagged with folic acid by covalently linkage through 2,2’ ethylenedioxy bis-ethylamine.Animals were divided into four groups,i.e.,control,nicotine(1 mg/kg bw/day),CMC-EDBE-FA(1 mg/kg bw/day) and nicotine(1 mg/kg bw/day) and CMC-EDBE-FA(1 mg/kg bw/day) for 7 days.Levels of lipid peroxidation, oxidized glutathione level,antioxidant enzyme status and DNA damage were observed and compared.Results:The significantly increase of lipid peroxidation,oxidized glutathione levels and DNA damage was observed in nicotine treated group as compared with control group;those were significantly reduced in CMC-EDBE-FA supplemented group.Moreover,significantly reduced antioxidant status in nicotine treated group was effectively ameliorated by the supplementation of CMC-EDBE-FA.Only CMC-EDBE-FA treated groups showed no significant change as compared with control group;rather than it repairs the tissue damage of nicotine treated group.Conclusions:These findings suggest that CMC-EDBE-FA is non-toxic and ameliorates nicotine-induced toxicity.

  14. Antioxidative effect of folate-modified chitosan nanoparticles

    Institute of Scientific and Technical Information of China (English)

    Subhankari Prasad Chakraborty; Santanu Kar Mahapatra; Sumanta Kumar Sahu; Panchanan Pramanik; Somenath Roy

    2011-01-01

    Objective: To evaluate the potency of carboxymethyl chitosan-2, 2’ ethylenedioxy bis-ethylamine-folate (CMC-EDBE-FA) on tissue injury, antioxidant status and glutathione system in tissue mitochondria and serum against nicotine-induced oxidative stress in mice. Methods:CMC-EDBE-FA was prepared on basis of carboxymethyl chitosan tagged with folic acid by covalently linkage through 2, 2’ ethylenedioxy bis-ethylamine. Animals were divided into four groups, i.e., control, nicotine (1 mg/kg bw/day), CMC-EDBE-FA (1 mg/kg bw/day) and nicotine (1 mg/kg bw/day) and CMC-EDBE-FA (1 mg/kg bw/day) for 7 days. Levels of lipid peroxidation, oxidized glutathione level, antioxidant enzyme status and DNA damage were observed and compared. Results: The significantly increase of lipid peroxidation, oxidized glutathione levels and DNA damage was observed in nicotine treated group as compared with control group; those were significantly reduced in CMC-EDBE-FA supplemented group. Moreover, significantly reduced antioxidant status in nicotine treated group was effectively ameliorated by the supplementation of CMC-EDBE-FA. Only CMC-EDBE-FA treated groups showed no significant change as compared with control group; rather than it repairs the tissue damage of nicotine treated group. Conclusions: These findings suggest that CMC-EDBE-FA is non-toxic and ameliorates nicotine-induced toxicity.

  15. Targeting Gallium to Cancer Cells through the Folate Receptor

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    Nerissa Viola-Villegas

    2008-01-01

    Full Text Available The development of gallium(III compounds as anti-cancer agents for both treatment and diagnosis is a rapidly developing field of research. Problems remain in exploring the full potential of gallium(III as a safe and successful therapeutic agent or as an imaging agent. One of the major issues is that gallium(III compounds have little tropism for cancer cells. We have combined the targeting properties of folic acid (FA with long chain liquid polymer poly(ethylene glycol (PEG ‘spacers’. This FA-PEG unit has been coupled to the gallium coordination complex of 1,4,7,10-tetraazacyclo-dodecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA through amide linkages for delivery into target cells overexpressing the folate receptor (FR. In vitro cytotoxicity assays were conducted against a multi-drug resistant ovarian cell line (A2780/AD that overexpresses the FR and contrasted against a FR free Chinese hamster ovary (CHO cell line. Results are rationalized taking into account stability studies conducted in RPMI 1640 media and HEPES buffer at pH 7.4.

  16. Folate Intake and Methylenetetrahydrofolate Reductase Gene Polymorphisms as Predictive and Prognostic Biomarkers for Ovarian Cancer Risk

    Directory of Open Access Journals (Sweden)

    Ke Wang

    2012-03-01

    Full Text Available Folic acid and methylenetetrahydrofolate reductase (MTHFR may affect the development of human cancer. However, few studies have evaluated folate intake and MTHFR in susceptibility to and prognosis of patients with ovarian cancer. We conducted a prospective case-control study in 215 ovarian cancer patients and 218 controls (all Chinese between Jan. 2004 and Jan. 2007. MTHFR C677T genotyping was done by PCR-RFLP. All patients were followed up until Dec. 2010. We found a 2.43-fold increased risk of ovarian cancer among MTHFR 677TT carriers, and a decreased risk of ovarian cancer in individuals with high folate intake (OR = 0.54, 95% CI = 0.32–0.94. Cox regression survival analysis showed that among the ovarian cancer patients, those carrying the 677TT genotype had a higher risk of death (HR = 2.17, 95% CI = 1.20–4.79, while high folate intake was associated with a lower risk of death (HR = 0.43, 95% CI = 0.33–0.88. Moreover, MTHFR 677CC carriers with higher folate intake showed a lower risk of death from ovarian cancer (HR = 0.32, 95% CI = 0.27–0.82. In summary, high folate intake may lessen susceptibility and improve the prognosis of ovarian cancer patients, while the MTHFR 677TT genotype appears to increase ovarian cancer risk and worsen its prognosis in a Chinese population.

  17. Folate-conjugated beta-cyclodextrin-based polymeric micelles with enhanced doxorubicin antitumor efficacy.

    Science.gov (United States)

    Zhang, Lu; Lu, Jiafei; Jin, Yangmin; Qiu, Liyan

    2014-10-01

    In order to enhance the antitumor effects of doxorubicin (DOX), a novel micellar vector with high DOX loading and tumor targeting function based on folate-conjugated amphiphilic copolymer folate-poly(ethylene glycol)-poly(d,l-lactide)-β-cyclodextrin (FA-PEL-CD) was constructed. Cytotoxicity and cellular uptake experiments were performed in HeLa, KB, and A549 cell lines expressing different amounts of folate receptors in order to evaluate the targeting effect of the folate modification. The antitumor experiments performed in a KB cell-xenografted nude mouse model showed that the treatment with 10mg/kg DOX loaded FA-PEL-CD micelles achieved approximately 86% of tumor growth inhibition compared to the control. Ex vivo fluorescence imaging experiments and histological examination confirmed that folate modification can enhance the antitumorigenesis efficacy and reduce the cardiotoxicity of DOX. These results suggest that FA-PEL-CD copolymer-based micelles are promising nanocarriers for targeted doxorubicin delivery, with improved antitumor efficacy and reduced toxicity in normal tissues. PMID:25058857

  18. Developmental consequences of in utero sodium arsenate exposure in mice with folate transport deficiencies

    International Nuclear Information System (INIS)

    Previous studies have demonstrated that mice lacking a functional folate binding protein 2 gene (Folbp2-/-) were significantly more sensitive to in utero arsenic exposure than were the wild-type mice similarly exposed. When these mice were fed a folate-deficient diet, the embryotoxic effect of arsenate was further exacerbated. Contrary to expectations, studies on 24-h urinary speciation of sodium arsenate did not demonstrate any significant difference in arsenic biotransformation between Folbp2-/- and Folbp2+/+ mice. To better understand the influence of folate pathway genes on arsenic embryotoxicity, the present investigation utilized transgenic mice with disrupted folate binding protein 1 (Folbp1) and reduced folate carrier (RFC) genes. Because complete inactivation of Folbp1 and RFC genes results in embryonic lethality, we used heterozygous animals. Overall, no RFC genotype-related differences in embryonic susceptibility to arsenic exposure were observed. Embryonic lethality and neural tube defect (NTD) frequency in Folbp1 mice was dose-dependent and differed from the RFC mice; however, no genotype-related differences were observed. The RFC heterozygotes tended to have higher plasma levels of S-adenosylhomocysteine (SAH) than did the wild-type controls, although this effect was not robust. It is concluded that genetic modifications at the Folbp1 and RFC loci confers no particular sensitivity to arsenic toxicity compared to wild-type controls, thus disproving the working hypothesis that decreased methylating capacity of the genetically modified mice would put them at increased risk for arsenic-induced reproductive toxicity

  19. Maternal Risk for Down Syndrome Is Modulated by Genes Involved in Folate Metabolism

    Directory of Open Access Journals (Sweden)

    Bruna Lancia Zampieri

    2012-01-01

    Full Text Available Studies have shown that the maternal risk for Down syndrome (DS may be modulated by alterations in folate metabolism. The aim of this study was to evaluate the influence of 12 genetic polymorphisms involved in folate metabolism on maternal risk for DS. In addition, we evaluated the impact of these polymorphisms on serum folate and plasma methylmalonic acid (MMA, an indicator of vitamin B12 status concentrations. The polymorphisms transcobalamin II (TCN2 c.776C>G, betaine-homocysteine S-methyltransferase (BHMT c.742A>G, methylenetetrahydrofolate reductase (NAD(PH (MTHFR c.677 C>T and the MTHFR 677C-1298A-1317T haplotype modulate DS risk. The polymorphisms MTHFR c.677C>T and solute carrier family 19 (folate transporter, member 1 (SLC19A1 c.80 A>G modulate folate concentrations, whereas the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR c.66A>G polymorphism affects the MMA concentration. These results are consistent with the modulation of the maternal risk for DS by these polymorphisms.

  20. Cyclodextrin-assisted assembly of PEGylated polyester nanoparticles decorated with folate.

    Science.gov (United States)

    Conte, Claudia; Fotticchia, Iolanda; Tirino, Pasquale; Moret, Francesca; Pagano, Bruno; Gref, Ruxandra; Ungaro, Francesca; Reddi, Elena; Giancola, Concetta; Quaglia, Fabiana

    2016-05-01

    In the last decades, nano-oncologicals bearing a polyethylene glycol (PEG) coating are being emerging as biomimetic devices able to drive their drug cargo to solid tumors through passive mechanisms. To improve selectivity toward cancer cells, nanocarriers decorated with the small ligand folate have been widely investigated. Nevertheless, a great challenge remains the effective exposition of folate on nanoparticles (NPs), which is a key prerequisite to ensure the correct binding to receptor and the following endocytic uptake. On these premises, in this study we propose a novel strategy to produce core-shell folate-targeted NPs based on diblock copolymers of poly(ε-caprolactone) (PCL) and PEG through the aid of (2-hydroxypropyl)-β-cyclodextrin (HPβCD). PCL4300-PEG2000 and PCL4300-PEG2000-Fol copolymers were synthesized, characterized and employed to produce NPs without and with HPβCD by a melting/sonication procedure. Colloidal properties of targeted NPs produced with HPβCD demonstrated a highly extended conformation of PEG chains in the shell, an enhanced interaction with a specific antibody against folate and a higher uptake in cells overexpressing folate receptor. Overall, these results suggest that proper manipulation of PEG shell conformation through HPβCD can represent a novel non-covalent strategy to modify shell features. PMID:26852098

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

    Science.gov (United States)

    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.

  2. Ab initio alpha-alpha scattering

    CERN Document Server

    Elhatisari, Serdar; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A; Luu, Thomas; Meißner, Ulf-G

    2015-01-01

    Processes involving alpha particles and alpha-like nuclei comprise a major part of stellar nucleosynthesis and hypothesized mechanisms for thermonuclear supernovae. In an effort towards understanding alpha processes from first principles, we describe in this letter the first ab initio calculation of alpha-alpha scattering. We use lattice effective field theory to describe the low-energy interactions of nucleons and apply a technique called the adiabatic projection method to reduce the eight-body system to an effective two-cluster system. We find good agreement between lattice results and experimental phase shifts for S-wave and D-wave scattering. The computational scaling with particle number suggests that alpha processes involving heavier nuclei are also within reach in the near future.

  3. Effect of soybean processing on content and bioaccessibility of folate, vitamin B12 and isoflavones in tofu and tempe

    NARCIS (Netherlands)

    Mo, H.; Kariluoto, S.; Piironen, V.; Zhu, Y.; Sanders, M.G.; Vincken, J.P.; Wolkers-Rooijackers, J.C.M.; Nout, M.J.R.

    2013-01-01

    Purpose - To compare the content of bioaccessible folate, vitamin B12, and isoflavones in tofu and tempe, as influenced by soybean variety and food processing, particularly fermentation. Principal results - Raw soybeans contained 2207–2671 µg/kg (dry matter) folate, cooked tempe 1493–4143, and cooke

  4. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon

    Science.gov (United States)

    Elder age and inadequate folate intake are strongly implicated as important risk factors for colon cancer, and each is associated with altered DNA methylation. This study was designed to determine the effect of aging and dietary folate on select features of DNA methylation in the colon that are rele...

  5. Dietary folate and choline status differentially affect lipid metabolism and behavior-mediated neurotransmitters in young rats

    Science.gov (United States)

    The relationship between choline and folate metabolisms is an important issue due to the essential role of these nutrients in brain plasticity and cognitive functions. Present study was designed to investigate whether modification of the dietary folate-choline status in young rats would affect brain...

  6. Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia.

    NARCIS (Netherlands)

    Muntjewerff, J.W.; Put, N.M.J. van der; Eskes, T.K.A.B.; Ellenbroek, B.A.; Steegers, E.A.P.; Blom, H.J.; Zitman, F.G.

    2003-01-01

    Two apparently unrelated disorders, neural tube defects (NTD) and schizophrenia showed increased risks in birth cohorts exposed to famine during early gestation. NTD is associated with impaired folate metabolism. We investigated whether schizophrenia is also linked with a dysfunctional folate metabo

  7. Elevation of the Folate Content of Arabidopsis Plants by Heterologous Expression of the Bacterial Gene Encoding Dihydropteroate Synthase

    NARCIS (Netherlands)

    Liang, Y.; Bovy, A.G.; Fan, Yun-Liu

    2006-01-01

    Folate cannot be synthesized de novo in human's body. Plants are the main source of dietary folates for human, but many fruits, tubers and seeds are poor in this vitamin. Inadequate intake is accociated with the increased risk of anemia, neural tube defect of new births, cardiovascular disease and e

  8. Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    NARCIS (Netherlands)

    Kelemen, L.E.; Terry, K.L.; Goodman, M.T.; Webb, P.M.; Bandera, E.V.; McGuire, V.; Rossing, M.A.; Wang, Q.; Dicks, E.; Tyrer, J.P.; Song, H.; Kupryjanczyk, J.; Dansonka-Mieszkowska, A.; Plisiecka-Halasa, J.; Timorek, A.; Menon, U.; Gentry-Maharaj, A.; Gayther, S.A.; Ramus, S.J.; Narod, S.A.; Risch, H.A.; McLaughlin, J.R.; Siddiqui, N.; Glasspool, R.; Paul, J.; Carty, K.; Gronwald, J.; Lubinski, J.; Jakubowska, A.; Cybulski, C.; Kiemeney, L.A.L.M.; Massuger, L.F.A.G.; Altena, A.M. van; Aben, K.K.H.; Olson, S.H.; Orlow, I.; Cramer, D.W; Levine, D.A.; Bisogna, M.; Giles, G.G.; Southey, M.C.; Bruinsma, F.; Kjaer, S.K.; Hogdall, E.; Jensen, A.; Hogdall, C.K.; Lundvall, L.; Engelholm, S.A.; Heitz, F.; Bois, A. du; Harter, P.; Schwaab, I.; Butzow, R.; Nevanlinna, H.; Pelttari, L.M.; Leminen, A.; Thompson, P.J.; Lurie, G.; Wilkens, L.R.; Lambrechts, D.; Nieuwenhuysen, E. Van; Lambrechts, S.; Vergote, I.; Beesley, J.; Investigators, A.S.G.A.; Fasching, P.A.; Beckmann, M.W.; Hein, A.; Ekici, A.B.; Doherty, J.A.; Wu, A.H.; Pearce, C.L.; Pike, M.C.; Stram, D.; Chang-Claude, J.; Rudolph, A.; Dork, T.; Durst, M.; Hillemanns, P.; Runnebaum, I.B.; Bogdanova, N.; Antonenkova, N.; Odunsi, K.; Edwards, R.P.; Kelley, J.L.; Modugno, F.; Ness, R.B.; Karlan, B.Y.; Walsh, C.; Lester, J.; Orsulic, S.; Fridley, B.L.; Vierkant, R.A.; Cunningham, J.M.; Wu, X.; Lu, K.; Liang, D.; Hildebrandt, M.A.T.; Weber, R.P.; Iversen, E.S.

    2014-01-01

    SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios

  9. High-level folate production in fermented foods by the B12 producer Lactobacillus reuteri JCM1112

    NARCIS (Netherlands)

    F. Santos; A. Wegkamp; W.M. de Vos; E.J. Smid; J. Hugenholtz

    2008-01-01

    We observed that Lactobacillus reuteri JCM1112 produces B12 and folate. However, the folate/B12 mass ratio found was far below that desired for human consumption (~170:1). We used metabolic engineering applying genetic and physiological approaches to improve this ratio and developed a generic and na

  10. Synthesis and evaluation of {sup 99m}Tc-labeled folate-tripeptide conjugate as a folate receptor-targeeted imaging agent in a tumor-bearing mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Myoung Hyoun; Kim, Chang Guhn; Kim, Dae Weung [Dept. of Nuclear Medicine, Wonkwang University School of Medicine, Iksan (Korea, Republic of); Kim, Woo Hyoung [Dept. of Nuclear Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2015-09-15

    The folate receptor (FR) is an attractive molecular target since it is overexpressed in a variety of human tumors. The purpose of the present study was to synthesize and evaluate the feasibility of a novel {sup 99m}Tc-ECG-EDA (Glu-Cys-Gly-ethylenediamine)-folate as an FR-positive tumor imaging agent in a mouse tumor model. ECG-EDA-folate was synthesized using solid phase peptide synthesis (SPPS) and radiolabeled with {sup 99m}Tc using tripeptide ECG as a chelator. FR-positive KB cells were inoculated in athymic nude mice. Following injection of {sup 99m}Tc-ECG-EDA-folate, serial scintigraphy and micro-SPECT/CT imaging were performed at various time points with and without pre-administration of excess free folate. Mean count densities (MCD) for regions of interest drawn on KB tumors and major normal organs at each time point were measured, and uptake ratios of tumor to normal organs were calculated. ECG-EDA-folate was labeled with {sup 99m}Tc with high radiolabeling efficiency and stability (>96 %). FR-positive tumors were clearly visualized on both scintigraphy and micro-SPECT/CT images and the tumor uptake of {sup 99m}Tc-ECG-EDA-folate was markedly suppressed with faint visualization of tumors by pre-administration of excess free folate on serial planar scintigraphy, indicating FR-specific binding of the agent. Furthermore, semiquantitative analysis of MCD data showed again that both tumor MCD and tumor-to-normal organ ratios decreased considerably by pre-administration of excess free folate, supporting FR-specific tumor uptake. Tumor-to-normal organ ratios approximately increased with time after injection until 4 h. The present study demonstrated that 9{sup 99m}Tc-ECG-EDA-folate can bind specifically to FR with clear visualization of FR-positive tumors in a mouse tumor model.

  11. Estimation of folate binding capacity (unsaturated and total) in normal human serum and in β-thalassaemia

    International Nuclear Information System (INIS)

    A method is described for measuring the total serum folate binding capacity (TBC) after treating the serum with urea at pH5.5, the unsaturated serum folate binding capacity (UBC) being determined without treatment with urea. The method was applied to 50 normal controls and 20 patients with homozygous β-thalassaemia. The results show an increase in folate binding capacity after treating the serum with urea in all cases studied. There is no correlation between serum folic acid level and total or unsaturated folate binding capacity or per cent saturation. The method described is a simple and rapid one for screening the different groups studied for saturated and unsaturated specific folate-binding proteins. (author)

  12. Estimation of folate binding capacity (unsaturated and total) in normal human serum and in β-thalassaemia

    International Nuclear Information System (INIS)

    A method is described for measuring the Total serum folate binding capacity (TBC) after treating the serum with urea at pH 5.5. Unsaturated serum folate binding capacity (UBC) being determined without treatment with urea. The method was applied to 50 normal controls and 20 patients with homozygous β-thalassaemia. The results show an increase in folate binding capacity after treating the serum with urea in all cases studied. There is not any correlation between serum folic acid level and Total or Unsaturated folate bindung capacity or per cent Saturation. The method described is a simple and rapid method for screening the different groups studied for Saturated and Unsaturated specific folate binding proteins. (orig.)

  13. The relationship between cerebrovascular disease and homocysteine, folate and vitamin B12 in serum

    International Nuclear Information System (INIS)

    To investigate the relationship between cerebrovascular disease and the serum levels of homocysteine(Hcy), folate and vitamin B12, the serum levels of Hcy, folate and vitamin B12 in 148 patients with cerebrovascular disease were measured by fluorescence polarization immuno- assay and chemiluminescence and were compared with those in healthy controls. The result showed that the serum Hcy levels in patients with cerebral infarction, cerebral hemorrhage and vertebrobasilar ischemiay were significantly higher than those in healthy controls (P12 levels were signifieantly lower (P0.05). No significantly higher ratio of increased Hcy levels was observed in patient with complications (P> 0.05). Our conclusion is that hyperhomocysteinemia may be a new and an independent risk factor for cerebrovascular disease. The serum Hcy level is correlated with decreased levels of folate and vitamin B12 but not obviously correlated with hypertension, diabetes and coronary heart disease. (authors)

  14. A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice.

    Science.gov (United States)

    Couch, Yvonne; Xie, Qin; Lundberg, Louise; Sharp, Trevor; Anthony, Daniel C

    2015-01-01

    It is well documented that serotonin (5-HT) plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS), which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5 mg/kg i.p.), at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS. PMID:26147001

  15. A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice.

    Directory of Open Access Journals (Sweden)

    Yvonne Couch

    Full Text Available It is well documented that serotonin (5-HT plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS, which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5 mg/kg i.p., at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS.

  16. Ab initio alpha-alpha scattering

    Science.gov (United States)

    Elhatisari, Serdar; Lee, Dean; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A.; Luu, Thomas; Meißner, Ulf-G.

    2015-12-01

    Processes such as the scattering of alpha particles (4He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars. In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei—nuclei with even and equal numbers of protons and neutrons—is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the ‘adiabatic projection method’ to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of

  17. Ab initio alpha-alpha scattering.

    Science.gov (United States)

    Elhatisari, Serdar; Lee, Dean; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A; Luu, Thomas; Meißner, Ulf-G

    2015-12-01

    Processes such as the scattering of alpha particles ((4)He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars. In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei--nuclei with even and equal numbers of protons and neutrons--is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the 'adiabatic projection method' to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of

  18. Folate intake and the risk of breast cancer: a dose-response meta-analysis of prospective studies.

    Directory of Open Access Journals (Sweden)

    Yu-Fei Zhang

    Full Text Available BACKGROUND: Previous observational studies regarding the existence of an association between folate intake and the risk of breast cancer have been inconsistent. This study aimed to summarize the evidence regarding this relationship using a dose-response meta-analytic approach. METHODOLOGY AND PRINCIPAL FINDINGS: We performed electronic searches of the PubMed, EmBase, and Cochrane Library databases to identify studies published through June 2013. Only prospective observational studies that reported breast cancer effect estimates with 95% confidence intervals (CIs for more than 2 folate intake categories were included. We excluded traditional case-control studies because of possible bias from various confounding factors. Overall, we included 14 prospective studies that reported data on 677,858 individuals. Folate intake had little effect on the breast cancer risk (relative risk (RR for highest versus lowest category = 0.97; 95% CI, 0.90-1.05; P = 0.451. Dose-response meta-analysis also suggested that a 100 µg/day increase in folate intake had no significant effect on the risk of breast cancer (RR = 0.99; 95% CI, 0.98-1.01; P = 0.361. Furthermore, we used restricted cubic splines to evaluate the nonlinear relationship between folate intake and the risk of breast cancer, and discovered a potential J-shaped correlation between folate intake and breast cancer risk (P = 0.007 and revealed that a daily folate intake of 200-320 µg was associated with a lower breast cancer risk; however, the breast cancer risk increased significantly with a daily folate intake >400 µg. CONCLUSION/SIGNIFICANCE: Our study revealed that folate intake had little or no effect on the risk of breast cancer; moreover, a dose-response meta-analysis suggested a J-shaped association between folate intake and breast cancer.

  19. Folate deficiency during early-mid pregnancy affects the skeletal muscle transcriptome of piglets from a reciprocal cross.

    Directory of Open Access Journals (Sweden)

    Yi Li

    Full Text Available Folate deficiency (FD during pregnancy can cause fetal intrauterine growth restriction in pigs, of which the skeletal dysplasia is a major manifestation. Factors influencing muscle development are very important in the formation of porcine meat quality trait. However, the effect of folate deficiency on skeletal muscle development and its molecular mechanisms are unknown. The objective of this study is to determine the effect of maternal folate deficiency on the skeletal muscle transcriptome of piglets from a reciprocal cross, in which full-sibling Landrace (LR and full-sibling Chinese local breed Laiwu (LW pigs were used for reciprocal cross matings, and sows were fed either a folate deficient or a normal diet during early-mid gestation. In addition, the difference in the responsiveness of the piglets to folate deficiency during early-mid pregnancy between reciprocal cross groups was investigated. Longissimus dorsi (LD muscle samples were collected from newborn piglets and a 4 × 44K Agilent porcine oligo microarray was used for transcriptome analysis of porcine LD muscle. The results showed that folate deficiency during early-mid pregnancy affected piglet body weight, LD muscle fiber number and content of intramuscular triglyceride. The microarray results indicated that 3154 genes were differentially expressed between folate deficient and normal piglets from the LR♂ × LW♀ cross, and 3885 differentially expressed genes (DEGs in the ones from the LW♂ × LR♀ cross. From functional analyses, sow folate deficiency affected almost all biological processes in the progeny. Lipid metabolism-related genes and associated metabolic pathways were regulated extensively by folate deficiency, especially in LR♂ × LW♀ cross piglets. Most of the genes that are regulated by folate deficiency in the LD muscle of piglets were different between LR♂ × LW♀ and LW♂ × LR♀ crosses, suggesting some epigenetic effects of FD exist in genes underlying

  20. The Rickettsia Endosymbiont of Ixodes pacificus Contains All the Genes of De Novo Folate Biosynthesis.

    Directory of Open Access Journals (Sweden)

    Daniel J Hunter

    Full Text Available Ticks and other arthropods often are hosts to nutrient providing bacterial endosymbionts, which contribute to their host's fitness by supplying nutrients such as vitamins and amino acids. It has been detected, in our lab, that Ixodes pacificus is host to Rickettsia species phylotype G021. This endosymbiont is predominantly present, and 100% maternally transmitted in I. pacificus. To study roles of phylotype G021 in I. pacificus, bioinformatic and molecular approaches were carried out. MUMmer genome alignments of whole genome sequence of I. scapularis, a close relative to I. pacificus, against completely sequenced genomes of R. bellii OSU85-389, R. conorii, and R. felis, identified 8,190 unique sequences that are homologous to Rickettsia sequences in the NCBI Trace Archive. MetaCyc metabolic reconstructions revealed that all folate gene orthologues (folA, folC, folE, folKP, ptpS required for de novo folate biosynthesis are present in the genome of Rickettsia buchneri in I. scapularis. To examine the metabolic capability of phylotype G021 in I. pacificus, genes of the folate biosynthesis pathway of the bacterium were PCR amplified using degenerate primers. BLAST searches identified that nucleotide sequences of the folA, folC, folE, folKP, and ptpS genes possess 98.6%, 98.8%, 98.9%, 98.5% and 99.0% identity respectively to the corresponding genes of Rickettsia buchneri. Phylogenetic tree constructions show that the folate genes of phylotype G021 and homologous genes from various Rickettsia species are monophyletic. This study has shown that all folate genes exist in the genome of Rickettsia species phylotype G021 and that this bacterium has the genetic capability for de novo folate synthesis.

  1. Folate deficiency and DNA-methyltransferase inhibition modulate G-quadruplex frequency.

    Science.gov (United States)

    François, Maxime; Leifert, Wayne Richard; Tellam, Ross; Fenech, Michael Felix

    2016-07-01

    G-quadruplexes (G4) are highly stable tetra-stranded DNA secondary structures known to mediate gene regulation and to trigger genomic instability events during replication. G4 structural stability can be affected by DNA methylation and oxidation modifications; thus nutrients such as folate that have the ability to alter these processes could potentially modify the genomic occurrence of G4 elements. Hela cells were cultured in a range of folate concentrations or in the presence or absence of 5-aza-2'-deoxycytidine, a DNA-methyltransferase inhibitor. G4 structures were then quantified by immunofluorescence using an automated quantitative imaging system. G4 frequency in Hela cells and nuclei area mean were increased in 20nM folate medium compared with 2000nM folate, as well as in the presence of 5-aza-2'-deoxycytidine when compared to cells non-exposed to 5-aza-2'-deoxycytidine. These changes were exacerbated when pyridostatin, a G4 stabilising ligand, was added to the culture medium. G4 intensity in Hela cells cultured in deficient folate condition with pyridostatin was highly correlated with DNA damage as measured by γH2AX immunofluorescence (r = 0.71). This study showed for the first time that cellular G4 balance is modifiable by low folate concentrations and that these changes may occur as a consequence of DNA hypomethylation. Although the exact mechanism by which these changes occur is unclear, these findings establish the possibility that nutrients could be utilised as a tool for sustaining genome integrity by modifying G4 frequency at a cellular level. PMID:26758645

  2. Effects of antiepileptic drugs on the serum folate and vitamin B12 in various epileptic patients

    Science.gov (United States)

    Huang, Hong-Li; Zhou, Hao; Wang, Nuan; Yu, Chun-Yu

    2016-01-01

    Epilepsy is a common neurodegenerative disease with an increasing morbidity. Clinical treatment of epilepsy includes symptomatic treatment, etiological treatment, surgery and prevention. The aim of the present study was to determine the effects of antiepileptic drugs (AEDs) on serum folate and vitamin B12 in various epileptic patients, and to examine the correlation between these effects and secondary cerebrovascular events. A total of 68 epileptic patients, diagnosed between May 2012 and May 2014, were included in the present study. The study included 8 cases of autonomic seizures, 10 cases of absence seizures, 13 cases of complex partial seizures, 28 cases of generalized tonic-clonic seizures, and 9 cases of simple partial seizures. The patients received appropriate AED treatment according to the characteristics of epileptic seizure and the treatment guidance. The differences in the serum levels of folate and vitamin B12 in these patients, and the differences in the secondary cerebrovascular events in these patients after 1 year follow-up were analyzed. The difference in the AEDs used by various epileptic patients was statistically significant (P0.05). The difference in the incidence of cerebrovascular events in these groups at follow up was not statistically significant (P>0.05). The multifactorial logistic regression analysis revealed that the serum levels of folate and vitamin B12 were the independent risk factors for epilepsy with secondary cerebrovascular events [folate: odds ratio (OR)=0.536, P=0.039; vitamin: OR=0.382, P=0.041]. In conclusion, various AEDs may decrease the serum levels of folate and vitamin B12 and affect the secondary cerebrovascular events in various epileptic patients. Thus, regular supplementation of folate and vitamin B12 may be an option.

  3. Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia

    Directory of Open Access Journals (Sweden)

    Lorenza Mistura

    2013-05-01

    Full Text Available To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with “moderate” hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR gene. Subjects/Methods: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF, 200 μg folic acid or placebo. Participants were stratified according to their MTHFR genotype. Results: Homocysteine (Hcy levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002, 19.4% (p < 0.001 and 21.9% (p < 0.001, as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid. After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. Conclusions: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations.

  4. Homocysteine Lowering by Folate-Rich Diet or Pharmacological Supplementations in Subjects with Moderate Hyperhomocysteinemia

    Science.gov (United States)

    Zappacosta, Bruno; Mastroiacovo, Pierpaolo; Persichilli, Silvia; Pounis, George; Ruggeri, Stefania; Minucci, Angelo; Carnovale, Emilia; Andria, Generoso; Ricci, Roberta; Scala, Iris; Genovese, Orazio; Turrini, Aida; Mistura, Lorenza; Giardina, Bruno; Iacoviello, Licia

    2013-01-01

    Background/Objectives: To compare the efficacy of a diet rich in natural folate and of two different folic acid supplementation protocols in subjects with “moderate” hyperhomocysteinemia, also taking into account C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. Subjects/Methods: We performed a 13 week open, randomized, double blind clinical trial on 149 free living persons with mild hyperhomocyteinemia, with daily 200 μg from a natural folate-rich diet, 200 μg [6S]5-methyltetrahydrofolate (5-MTHF), 200 μg folic acid or placebo. Participants were stratified according to their MTHFR genotype. Results: Homocysteine (Hcy) levels were reduced after folate enriched diet, 5-MTHF or folic acid supplementation respectively by 20.1% (p < 0.002), 19.4% (p < 0.001) and 21.9% (p < 0.001), as compared to baseline levels and significantly as compared to placebo (p < 0.001, p < 0.002 and p < 0.001, respectively for enriched diet, 5-MTHF and folic acid). After this enriched diet and the folic acid supplementation, Hcy in both genotype groups decreased approximately to the same level, with higher percentage decreases observed for the TT group because of their higher pre-treatment value. Similar results were not seen by genotype for 5-MTHF. A significant increase in RBC folate concentration was observed after folic acid and natural folate-rich food supplementations, as compared to placebo. Conclusions: Supplementation with natural folate-rich foods, folic acid and 5-MTHF reached a similar reduction in Hcy concentrations. PMID:23698160

  5. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery

    Directory of Open Access Journals (Sweden)

    Christina R. Bourne

    2014-01-01

    Full Text Available The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors for cellular function and contains a critical node, dihydrofolate reductase (DHFR, which is shared between prokaryotes and eukaryotes. The DHFR enzyme is currently targeted by methotrexate in anti-cancer therapies, by trimethoprim for antibacterial uses, and by pyrimethamine for anti-protozoal applications. An additional anti-folate target is dihyropteroate synthase (DHPS, which is unique to prokaryotes as they cannot acquire folate through dietary means. It has been demonstrated as a primary target for the longest standing antibiotic class, the sulfonamides, which act synergistically with DHFR inhibitors. Investigations have revealed most DHPS enzymes possess the ability to utilize sulfa drugs metabolically, producing alternate products that presumably inhibit downstream enzymes requiring the produced dihydropteroate. Recent work has established an off-target effect of sulfonamide antibiotics on a eukaryotic enzyme, sepiapterin reductase, causing alterations in neurotransmitter synthesis. Given that inhibitors of both DHFR and DHPS are designed to mimic their cognate substrate, which contain shared substructures, it is reasonable to expect such “off-target” effects. These inhibitors are also likely to interact with the enzymatic neighbors in the folate pathway that bind products of the DHFR or DHPS enzymes and/or substrates of similar substructure. Computational studies designed to assess polypharmacology reiterate these conclusions. This leads to hypotheses exploring the vast utility of multiple members of the folate pathway for modulating cellular metabolism, and includes an appealing capacity for

  6. Utility of the Biosynthetic Folate Pathway for Targets in Antimicrobial Discovery.

    Science.gov (United States)

    Bourne, Christina R

    2014-01-01

    The need for new antimicrobials is great in face of a growing pool of resistant pathogenic organisms. This review will address the potential for antimicrobial therapy based on polypharmacological activities within the currently utilized bacterial biosynthetic folate pathway. The folate metabolic pathway leads to synthesis of required precursors for cellular function and contains a critical node, dihydrofolate reductase (DHFR), which is shared between prokaryotes and eukaryotes. The DHFR enzyme is currently targeted by methotrexate in anti-cancer therapies, by trimethoprim for antibacterial uses, and by pyrimethamine for anti-protozoal applications. An additional anti-folate target is dihyropteroate synthase (DHPS), which is unique to prokaryotes as they cannot acquire folate through dietary means. It has been demonstrated as a primary target for the longest standing antibiotic class, the sulfonamides, which act synergistically with DHFR inhibitors. Investigations have revealed most DHPS enzymes possess the ability to utilize sulfa drugs metabolically, producing alternate products that presumably inhibit downstream enzymes requiring the produced dihydropteroate. Recent work has established an off-target effect of sulfonamide antibiotics on a eukaryotic enzyme, sepiapterin reductase, causing alterations in neurotransmitter synthesis. Given that inhibitors of both DHFR and DHPS are designed to mimic their cognate substrate, which contain shared substructures, it is reasonable to expect such "off-target" effects. These inhibitors are also likely to interact with the enzymatic neighbors in the folate pathway that bind products of the DHFR or DHPS enzymes and/or substrates of similar substructure. Computational studies designed to assess polypharmacology reiterate these conclusions. This leads to hypotheses exploring the vast utility of multiple members of the folate pathway for modulating cellular metabolism, and includes an appealing capacity for prokaryotic

  7. Androgen Receptor Expression and Cellular Proliferation During Transition from Androgen-Dependent to Recurrent Growth after Castration in the CWR22 Prostate Cancer Xenograft

    OpenAIRE

    Kim, Desok; Gregory, Christopher W.; French, Frank S.; Smith, Gary J.; Mohler, James L.

    2002-01-01

    Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 ± 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 ± 0.08). Cellular proliferation measured using Ki-67 revealed

  8. Transcriptional Down-Regulation of Thromboxane A(2) Receptor Expression via Activation of MAPK ERK1/2, p38/NF-kappaB Pathways

    DEFF Research Database (Denmark)

    Zhang, Wei; Zhang, Yaping; Edvinsson, Lars;

    2008-01-01

    . Phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and nuclear factor-kappaB (NF-kappaB) was seen by Western blot within 1-3 h after organ culture. Inhibition of ERK1/2, p38 or NF-kappaB reversed depressed contraction as well as decreased receptor mRNA expression. Actinomycin D...... arteries down-regulates VSMC TP receptor expression through activation of ERK1/2 and p38/NF-kappaB signal pathways....

  9. Transcriptional down-regulation of thromboxane A(2) receptor expression via activation of MAPK ERK1/2, p38/NF-kappaB pathways

    DEFF Research Database (Denmark)

    Zhang, Wei; Zhang, Yaping; Edvinsson, Lars;

    2009-01-01

    . Phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 and nuclear factor-kappaB (NF-kappaB) was seen by Western blot within 1-3 h after organ culture. Inhibition of ERK1/2, p38 or NF-kappaB reversed depressed contraction as well as decreased receptor mRNA expression. Actinomycin D...... arteries down-regulates VSMC TP receptor expression through activation of ERK1/2 and p38/NF-kappaB signal pathways....

  10. Bioaccessibility of Folic Acid and (6S)-5-Methyltetrahydrofolate Decreases after the Addition of Folate-Binding Protein to Yogurt as Studied in a Dynamic in Vitro Gastrointestinal Model

    NARCIS (Netherlands)

    Arkbåge, K.; Verwei, M.; Havenaar, R.; Witthöft, C.

    2003-01-01

    Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of

  11. Bioaccessibility of Folic Acid and (6S)-5-Methyltetrahydrofolate Decreases after the Addiction of Folate-Binding Protein to Yogurt as Studied in a Dynamic In Vitro Gastrointestinal Model

    NARCIS (Netherlands)

    Arkbåge, K.; Verwei, M.; Havenaar, R.; Witthöft, C.

    2003-01-01

    Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of

  12. New insights into carrier binding and epithelial uptake of the erythropoietic nutrients cobalamin and folate

    DEFF Research Database (Denmark)

    Moestrup, Søren K

    2006-01-01

    PURPOSE OF REVIEW: In addition to malnutrition several genetic and acquired conditions may affect the homeostasis of cobalamin (vitamin B12) and folate, leading to megaloblastic anemia and other diseases. The present review describes new insight into protein handling of cobalamin and folate. RECENT...... FINDINGS: The recent solution of the three-dimensional structure of the cobalamin binder transcobalamin shows two separate domains enclosing the vitamin. This structure apparently also applies for the other homologous cobalamin binders, intrinsic factor and haptocorrin. Genetic studies of inherited....... Genetic abnormalities in three different genes encoding proteins in the epithelial uptake of cobalamin are now known to cause malabsorption of cobalamin and megaloblastic anemia....

  13. Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women

    OpenAIRE

    Zhang, Shumin M.; Moore, Steven C.; Lin, Jennifer; Cook, Nancy R.; Manson, JoAnn E.; Lee, I-Min; Buring, Julie E

    2005-01-01

    The authors evaluated associations between intakes of folate and vitamin B6 and colorectal cancer risk in women enrolled in a randomized trial of aspirin and vitamin E. During an average of 10.1 years of follow-up, 220 colorectal adenocarcinoma cases were documented among 37,916 women, aged 45 years or older, free of cancer and cardiovascular disease, who provided dietary information at baseline. Intakes of total folate and vitamin B6 were not significantly associated with the risk of colorec...

  14. Faddeev calculation of 3 alpha and alpha alpha Lambda systems using alpha alpha resonating-group method kernel

    CERN Document Server

    Fujiwara, Y; Kohno, M; Suzuki, Y; Baye, D; Sparenberg, J M

    2004-01-01

    We carry out Faddeev calculations of three-alpha (3 alpha) and two-alpha plus Lambda (alpha alpha Lambda) systems, using two-cluster resonating-group method kernels. The input includes an effective two-nucleon force for the alpha alpha resonating-group method and a new effective Lambda N force for the Lambda alpha interaction. The latter force is a simple two-range Gaussian potential for each spin-singlet and triplet state, generated from the phase-shift behavior of the quark-model hyperon-nucleon interaction, fss2, by using an inversion method based on supersymmetric quantum mechanics. Owing to the exact treatment of the Pauli-forbidden states between the clusters, the present three-cluster Faddeev formalism can describe the mutually related, alpha alpha, 3 alpha and alpha alpha Lambda systems, in terms of a unique set of the baryon-baryon interactions. For the three-range Minnesota force which describes the alpha alpha phase shifts quite accurately, the ground-state and excitation energies of 9Be Lambda are...

  15. Agonist actions of clothianidin on synaptic and extrasynaptic nicotinic acetylcholine receptors expressed on cockroach sixth abdominal ganglion.

    Science.gov (United States)

    Thany, Steeve H

    2009-11-01

    Clothianidin is new neonicotinoid insecticide acting selectively on insect nicotinic acetylcholine receptors (nAChRs). Its effects on nAChRs expressed on cercal afferent/giant interneuron synapses and DUM neurons have been studied using mannitol-gap and whole-cell patch-clamp techniques, respectively. Bath-application of clothianidin-induced dose-dependent depolarizations of cockroach cercal afferent/giant interneuron synapses which were not reversed after wash-out suggesting a strong desensitization of postsynaptic interneurons at the 6th abdominal ganglion (A6). Clothinidin activity on the nerve preparation was characterized by an increased firing rate of action potentials which then ceased when the depolarization reached a peak. Clothianidin responses were insensitive to all muscarinic antagonists tested but were blocked by co-application of specific nicotinic antagonists methyllicaconitine, alpha-bungarotoxin and d-tubocurarine. In a second round of experiment, clothianidin actions were tested on DUM neurons isolated from the A6. There was a strong desensitization of nAChRs which was not affected by muscarinic antagonists, pirenzepine and atropine, but was reduced with nicotinic antagonist alpha-bungarotoxin. In addition, clothianidin-induced currents were completely blocked by methyllicaconitine suggesting that (1) clothianidin acted as a specific agonist of nAChR subtypes and (2) a small proportion of receptors blocked by MLA was insensitive to alpha-bungarotoxin. Moreover, because clothianidin currents were blocked by d-tubocurarine and mecamylamine, we provided that clothianidin was an agonist of both nAChRs: imidacloprid-sensitive nAChR1 and -insensitive nAChR2 subtypes. PMID:19583978

  16. Preparation and biodistribution of 188Re-labeled folate conjugated human serum albumin magnetic cisplatin nanoparticles (188Re-folate-CDDP/HSA MNPs in vivo

    Directory of Open Access Journals (Sweden)

    Tang QS

    2011-11-01

    Full Text Available Qiu-Sha Tang1,*, Dao-Zhen Chen2,*, Wen-Qun Xue2, Jing-Ying Xiang2, Yong-Chi Gong1, Li Zhang2, Cai-Qin Guo21Department of Pathology and Pathophysiology, Medical College, Southeast University, Nanjing, Jiangsu; 2Central Laboratory, Wuxi Hospital for Maternal and Child Health Care, Affiliated Medical School of Nanjin, Wuxi, Jiangsu, China *Authors contributed equally to this workBackground: The purpose of this study was to develop intraperitoneal hyperthermic therapy based on magnetic fluid hyperthermia, nanoparticle-wrapped cisplatin chemotherapy, and magnetic particles of albumin. In addition, to combine the multiple-killing effects of hyperthermal targeting therapy, chemotherapy, and radiotherapy, the albumin-nanoparticle surfaces were linked with radionuclide 188Re-labeled folic acid ligand (188Re-folate-CDDP/HSA.Methods: Human serum albumin was labeled with 188Re using the pre-tin method. Reaction time and optimal conditions of labeling were investigated. The particles were intravenously injected into mice, which were sacrificed at different time points. Radioactivity per gram of tissue of percent injected dose (% ID/g was measured in vital organs. The biodistribution of 188Re-folate-CDDP/HAS magnetic nanoparticles was assessed.Results: Optimal conditions for 188Re-labeled folate-conjugated albumin combined with cisplatin magnetic nanoparticles were: 0.1 mL of sodium gluconate solution (0.3 mol/L, 0.1 mL of concentrated hydrochloric acid with dissolved stannous chloride (10 mg/mL, 0.04 mL of acetic acid buffer solution (pH 5, 0.2 mol/L, 30 mg of folate-conjugated albumin combined with cisplatin magnetic nanoparticles, and 188ReO4 eluent (0.1 mL. The rate of 188Re-folate-CDDP-HSA magnetic nanoparticle formation exceeded 90%, and radiochemical purity exceeded 95%. The overall labeling rate was 83% in calf serum at 37°C. The major uptake tissues were the liver, kidney, intestine, and tumor after the 188Re-folate-CDDP/HSA magnetic nanoparticles

  17. Clinical application of serum folate and red blood cell folate determinations%血清叶酸和红细胞叶酸检测的临床应用

    Institute of Scientific and Technical Information of China (English)

    陈朴; 潘柏申

    2016-01-01

    Folate deficiency is closely related to neural tube defect in newborns and megaloblastic anemia. The determinations of serum folate and red blood cell folate could be primary evidence for folate deficiency. However, the determination methods have not yet been standardized. This article will describe the biological characteristics of folate,the causes of folate deficiency,its epidemiological study,clinical manifestation,diagnostic cut-off values and the clinical application of folate determinations.%叶酸缺乏与新生儿神经管缺陷症及巨幼细胞性贫血密切相关。血清叶酸和红细胞叶酸检测是临床诊断叶酸缺乏的主要依据,但二者的检测方法目前均尚未标准化。文章对叶酸的生物特性、叶酸缺乏的病因、流行病学研究、临床表现、诊断临界值和实验室检测进行了介绍。

  18. Effect of folate status and methylenetetrahydrofolate reductase genotypes on the complications and outcome of high dose methotrexate chemotherapy in north Indian children with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Nirmalya Roy Moulik

    2016-01-01

    Full Text Available Purpose: The genes of the folate metabolic pathway have been associated with toxicities during high dose methotrexate therapy for childhood ALL, however, the importance of intrinsic folate status in this regard is unclear. Methods: In the present study the effect of precourse folate levels and MTHFR genotypes on the complications during high dose methotrexate chemotherapy in children with ALL were examined. Results: Twenty-one children were studied. Folate deficiency was associated with higher incidence of neutropenia (P = 0.03 and longer duration of chemotherapy interruption (P = 0.009. Children with MTHFR1298 mutations needed more red cell transfusion (P = 0.03. All 3 deaths encountered were seen in folate deficient children. Conclusions: Folate deficiency was associated with higher complications during high dose methotrexate therapy, the implications of which are important especially in resource poor settings with high prevalence of folate deficiency.

  19. N-methyl-D-aspartate receptor expression in the spinal dorsal horn of a rat model of formalin-induced inflammatory pain following intrathecal injection of butorphanol

    Institute of Scientific and Technical Information of China (English)

    Yichun Wang; Yuan Zhang; Qulian Guo; Xiaohong Liu; Mingde Wang; Hui Luo

    2010-01-01

    Clinical and animal experiments have proved that intrathecal injection of butorphanol has an analgesic effect. However, whether the analgesic effect is associated with activation of the N-methyl-D-aspartate (NMDA) receptor remains unclear. This study presumed that intrathecal injection of butorphanol has an analgesic effect on formalin-induced inflammatory pain in rats, and its analgesic effect is associated with inhibition of NMDA receptors. Concurrently, ketamine was injected into the intrathecal space, which is a non-competitive NMDA receptor antagonist, to determine the analgesic mechanism of butorphanol. The total reflection time in phase 1 and phase 2 of rat hind paws carding action was reduced when the butorphanol dose was increased to 25 μg,or a low dose of butorphanol was combined with ketamine. Intrathecal injection of a high dose of butorphanol alone or a Iow dose of butorphanol combined with ketamine can remarkably reduce NMDA receptor expression in the L5 spinal dorsal horn of formalin-induced pain rats. The results suggest that intrathecal injection of butorphanol has analgesic effects on formalin-induced inflammatory pain, and remarkably reduces NMDA receptor expression in the rat spinal dorsal horn.Ketamine strengthens this analgesic effect. The analgesic mechanism of intrathecal injection of butorphanol is associated with inhibition of NMDA receptor activation.

  20. Influence of type-I Interferon receptor expression level on the response to type-I Interferons in human pancreatic cancer cells.

    Science.gov (United States)

    Booy, Stephanie; van Eijck, Casper H J; Dogan, Fadime; van Koetsveld, Peter M; Hofland, Leo J

    2014-03-01

    Pancreatic cancer is a highly aggressive malignancy with limited treatment options. Type-I interferons (e.g. IFN-α/-β) have several anti-tumour activities. Over the past few years, clinical studies evaluating the effect of adjuvant IFN-α therapy in pancreatic cancer yielded equivocal results. Although IFN-α and -β act via the type-I IFN receptor, the role of the number of receptors present on tumour cells is still unknown. Therefore, this study associated, for the first time, in a large panel of pancreatic cancer cell lines the effects of IFN-α/-β with the expression of type-I IFN receptors. The anti-tumour effects of IFN-α or IFN-β on cell proliferation and apoptosis were evaluated in 11 human pancreatic cell lines. Type-I IFN receptor expression was determined on both the mRNA and protein level. After 7 days of incubation, IFN-α significantly reduced cell growth in eight cell lines by 5-67%. IFN-β inhibited cell growth statistically significant in all cell lines by 43-100%. After 3 days of treatment, IFN-β induced significantly more apoptosis than IFN-α. The cell lines variably expressed the type-I IFN receptor. The maximal inhibitory effect of IFN-α was positively correlated with the IFNAR-1 mRNA (P interferon receptor expression and seems, therefore, more promising than IFN-α.

  1. Applicability of a Lactobacillus amylovorus strain as co-culture for natural folate bio-enrichment of fermented milk.

    Science.gov (United States)

    Laiño, Jonathan Emiliano; Juarez del Valle, Marianela; Savoy de Giori, Graciela; LeBlanc, Jean Guy Joseph

    2014-11-17

    The ability of 55 strains from different Lactobacillus species to produce folate was investigated. In order to evaluate folic acid productivity, lactobacilli were cultivated in the folate-free culture medium (FACM). Most of the tested strains needed folate for growth. The production and the extent of vitamin accumulation were distinctive features of individual strains. Lactobacillus amylovorus CRL887 was selected for further studies because of its ability to produce significantly higher concentrations of vitamin (81.2 ± 5.4 μg/L). The safety of this newly identified folate producing strain was evaluated through healthy experimental mice. No bacterial translocation was detected in liver and spleen after consumption of CRL887 during 7 days and no undesirable side effects were observed in the animals that received this strain. This strain in co-culture with previously selected folate producing starter cultures (Lactobacillus bulgaricus CRL871, and Streptococcus thermophilus CRL803 and CRL415) yielded a yogurt containing high folate concentrations (263.1 ± 2.4 μg/L); a single portion of which would provide 15% of the recommended dietary allowance. This is the first report where a Lactobacillus amylovorus strain was successfully used as co-culture for natural folate bio-enrichment of fermented milk.

  2. Review of alpha_s determinations

    CERN Document Server

    Pich, Antonio

    2013-01-01

    The present knowledge on the strong coupling is briefly summarized. The most precise determinations of alpha_s, at different energies, are reviewed and compared at the Z mass scale, using the predicted QCD running. The impressive agreement achieved between experimental measurements and theoretical predictions constitutes a beautiful and very significant test of Asymptotic Freedom, establishing QCD as the fundamental theory of the strong interaction. The world average value of the strong coupling is found to be alpha_s(M_Z^2)= 0.1186 \\pm 0.0007.

  3. Periconceptional folate consumption is associated with neonatal DNA methylation modifications in neural crest regulatory and cancer development genes.

    Science.gov (United States)

    Gonseth, Semira; Roy, Ritu; Houseman, E Andres; de Smith, Adam J; Zhou, Mi; Lee, Seung-Tae; Nusslé, Sébastien; Singer, Amanda W; Wrensch, Margaret R; Metayer, Catherine; Wiemels, Joseph L

    2015-01-01

    Folate deficiency during early embryonic development constitutes a risk factor for neural tube defects and potentially for childhood leukemia via unknown mechanisms. We tested whether folate consumption during the 12 months prior to conception induced DNA methylation modifications at birth in healthy neonates with a genome-wide and agnostic approach. We hypothesized that DNA methylation in genes involved in neural tube development and/or cancer susceptibility would be affected by folate exposure. We retrospectively assessed folate exposure at the time of conception by food-frequency questionnaires administered to the mothers of 343 healthy newborns. We measured genome-wide DNA methylation from neonatal blood spots. We implemented a method based on bootstrap resampling to decrease false-positive findings. Folate was inversely associated with DNA methylation throughout the genome. Among the top folate-associated genes that were replicated in an independent Gambian study were TFAP2A, a gene critical for neural crest development, STX11, a gene implicated in acute myeloid leukemia, and CYS1, a candidate gene for cystic kidney disease. Reduced periconceptional folate intake was associated with increased methylation and, in turn, decreased gene expression at these 3 loci. The top folate-sensitive genes defined by their associated CpG sites were enriched for numerous transcription factors by Gene Set Enrichment Analysis, including those implicated in cancer development (e.g., MYC-associated zinc finger protein). The influence of estimated periconceptional folate intake on neonatal DNA methylation levels provides potential mechanistic insights into the role of this vitamin in the development of neural tube defects and childhood cancers. PMID:26646725

  4. Association of folate deficiency and selected tumor marker concentrations in long-term hexavalent chromium exposed population.

    Science.gov (United States)

    Wang, Tian-Cheng; Song, Yan-Shuang; Yu, Shan-Fa; Zhang, Ji; Wang, Hui; Gu, Yong-En; Chen, Tian; Jia, Guang

    2014-01-01

    Both hexavalent chromium [Cr (VI)] exposure and folate deficiency have been associated with increased cancer risks. Our previous studies have found folate deficiency in Cr (VI) exposed population. Here the relationship between some tumor markers and folate status in long-term Cr (VI) exposure was investigated carefully to show the multiple aspects of Cr (VI) carcinogenesis. A group of 115 workers occupationally exposed to chromate and 60 matched, unexposed controls in Shandong province of China were recruited. Environmental and biological exposure assessments including personal exposure to airborne Cr and Cr contents in erythrocytes were performed. Serum folate, plasma total homocysteine (tHcy) and plasma carcinoembryonic antigen (CEA), neuron specific enolase (NSE), squamous cell carcinoma antigen (SCC), cytokeratin fragment antigen 21-1 (CYFRA 21-1), cancer antigen 72-4 (CA72-4), as well as α-fetoprotein (AFP) were measured. Smoking index (SI) was also calculated to discriminate possible confounding effects of smoking status. Serum folate level decreased significantly, while plasma tHcy, CEA, NSE, SCC, CYFRA21-1, CA72-4 and AFP concentrations increased significantly after Cr (VI) exposure. Meanwhile, plasma CEA, NSE and SCC were negatively correlated with serum folate. SI was negatively correlated with serum folate but positively correlated with plasma tHcy, CEA and NSE levels. Present study suggests that folate deficiency was associated with increased cancer risks and might be affected by smoking in Cr (VI) exposed population. Folate might play a key role in Cr (VI) carcinogenesis although further detailed investigations are needed to clarify the mechanism of this process. PMID:23623598

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

    Science.gov (United States)

    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…

  6. Folate intake, alcohol and risk of breast cancer among postmenopausal women in Denmark

    DEFF Research Database (Denmark)

    Tjønneland, A; Christensen, J; Olsen, A;

    2006-01-01

    There is consistent evidence that alcohol increases the risk of breast cancer. It has been suggested that the increased risk associated with alcohol intake may be reduced by adequate intake of folate. Since many women consume alcohol, detection of a risk-reducing mechanism would have major public...

  7. Clinical Significances of Serum Vitamin B12, Folate and Ferritin Levels in Patients with Malignant Tumors

    International Nuclear Information System (INIS)

    In order to evaluate the clinical significances of the serum vitamin B12, folate and ferritin levels in patients with malignant tumors, the levels were measured in 10 normal control subjects, 70 patients with malignant tumors, 7 patients with liver cirrhosis and 25 patients with other benign diseases. The results are as follows: 1) In normal control subjects, mean serum values for vitamin B12, folate and ferritin level were 588.80±131.58 pg/ml, 5.59±1.52 ng/ml and 89.22±42.78 ng/ml retrospectively. 2) There was no significant difference in serum levels between patients with benign diseases and normal control subjects. 3) The serum vitamin B12 and ferritin levels in patients with liver cirrhosis were significantly higher than in normal control, and the serum folate levels in these patients were lower than in normal control subjects. 4) The serum vitamin B12 and ferritin levels in patients with malignant tumors were significantly higher than in normal control subjects, and the serum folate levels in these patients were significantly lower than in normal control subjects. The above results suggest that the serum vitamin B12 and ferritin may be useful as tumor markers in patients with malignant tumors.

  8. Periconceptional intake of folic acid and food folate and risks of preterm delivery.

    Science.gov (United States)

    Shaw, Gary M; Carmichael, Suzan L; Yang, Wei; Siega-Riz, Anna Maria

    2011-12-01

    We investigated multiple sources of folate and folic acid to determine whether their periconceptional intakes were associated with preterm delivery. Studied were controls from the National Birth Defects Prevention Study delivered September 1998 to December 2005. Telephone interviews were conducted with 5952 (68% of eligible) mothers. Women were queried about intake of vitamin supplements in the 12 weeks before conception through delivery. A version of the Nurse's Health Study food frequency questionnaire was used to assess food sources. Eight percent of infants ( N = 487) were preterm (folic acid before pregnancy, those who began any time during pregnancy had an ~20% lowered risk of preterm delivery. Lower dietary intakes showed a modest increased risk of preterm delivery: odds ratios were 1.44 (1.01 to 2.04) for lowest quartile intake of folate and 1.27 (0.95 to 1.69) for lowest quartile intake of folic acid compared with the highest. Findings suggest some evidence that folates influenced risks; however, an interpretation of results was also consistent with no association between intake of folates and preterm delivery.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  11. Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults

    NARCIS (Netherlands)

    Schiepers, Olga; Van Boxtel, Martin; De Groot, Renate; Jolles, Jelle; Bekers, Otto; Kok, Frans; Verhoef, Petra; Durga, Jane

    2012-01-01

    Schiepers, O. J. G., Van Boxtel, M. J. P., De Groot, R. H. M., Jolles, J., Bekers, O., Kok, F. J., Verhoef, P., & Durga, J. (2011). Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults. Progress in Neuropsychopharmacology and Biological Psychi

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

    Science.gov (United States)

    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...

  13. Folate, cancer risk, and the greek god, Proteus: a tale of two chameleons

    Science.gov (United States)

    Evidence indicates that an abundant intake of foodstuffs rich in folate conveys protection against the development of colorectal cancer, and perhaps some other common cancers as well. The issue is a complex one however, since some observations in animal and human studies demonstrate that an overly ...

  14. Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories : The Rotterdam Predict Study

    NARCIS (Netherlands)

    Koning, Irene V; Groenenberg, Irene A L; Gotink, Anniek W; Willemsen, Sten P; Gijtenbeek, Manon; Dudink, Jeroen; Go, Attie T J I; Reiss, Irwin K M; Steegers, Eric A P; Steegers-Theunissen, Régine P M

    2015-01-01

    We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestatio

  15. Prospective study on dietary intakes of folate, betaine, and choline and cardiovascular disease risk in women

    NARCIS (Netherlands)

    Dalmeijer, G.W.; Olthof, M.R.; Verhoef, P.; Bots, M.L.; Schouw, van der Y.T.

    2008-01-01

    Objective: To investigate the association between dietary intakes of folate, betaine and choline and the risk of cardiovascular disease (CVD). Design: Prospective cohort study. Subjects: A total of 16 165 women aged 49¿70 years without prior CVD. Subjects were breast cancer screening participants in

  16. Long-Term Dietary Folate Deficiency Accelerates Progressive Hearing Loss On CBA/Ca Mice.

    Directory of Open Access Journals (Sweden)

    Raquel Martinez-Vega

    2016-08-01

    Full Text Available Dietary folic acid deficiency induced early hearing loss in C57BL/6J mice after two-months, corroborating 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 the folate-deficient 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.

  17. The importance of (early) folate status to primary and secondary coronary artery disease prevention

    NARCIS (Netherlands)

    Muskiet, FAJ

    2005-01-01

    Folate, methionine, betaine, choline, zinc and Vitamins B-12, B-6 and B-2 are involved in one-carbon metabolism, which includes S-adenosylmethionine (SAM) substrated methylation. Inadequate enzyme activities and imbalances of substrates and cofactors in one-carbon metabolism, together referred to as

  18. A prospective cohort study on antioxidant and folate intake and male lung cancer risk

    NARCIS (Netherlands)

    Voorrips, L.E.; Goldbohm, R.A.; Brants, H.A.M.; Poppel, G.A.F.C. van; Sturmans, F.; Hermus, R.J.J.; Brandt, P.A. van den

    2000-01-01

    Many studies have reported inverse associations between vegetable and fruit consumption and lung cancer risk. The aim of the present study was to elucidate the role of several antioxidants and folate in this relationship. In the Netherlands Cohort Study on Diet and Cancer, 58,279 men of ages 55-69 y

  19. The interrelationship between ligand binding and self-association of the folate binding protein

    DEFF Research Database (Denmark)

    Holm, Jan; Schou, Christian; Babol, Linnea N.;

    2011-01-01

    The folate binding protein (FBP) regulates homeostasis and intracellular trafficking of folic acid, a vitamin of decisive importance in cell division and growth. We analyzed whether interrelationship between ligand binding and self-association of FBP plays a significant role in the physiology...

  20. Vitamin B12, folate, and homocysteine levels in patients with obsessive–compulsive disorder

    Directory of Open Access Journals (Sweden)

    Türksoy N

    2014-09-01

    Full Text Available Nuray Türksoy,1 Rabia Bilici,2 Altan Yalçiner,3 Y Özay Özdemir,2 Ibrahim Örnek,4 Ali Evren Tufan,5 Ayşe Kara6 1Simurg Psychiatry and Psychotherapy Center, Istanbul, 2Erenköy State Hospital for Psychiatric and Neurological Diseases, Istanbul, 3Düzen Laboratories, Istanbul, 4Florence Nightingale Hospital, Istanbul, 5Department of Child and Adolescent Psychiatry, Abant Izzet Baysal University, Bolu, 6Bakırköy State Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey Abstract: It is known that elevated serum homocysteine, decreased folate, and low vitamin B12 serum levels are associated with poor cognitive function, cognitive decline, and dementia. Current literature shows that some psychiatric disorders, mainly affective and psychotic ones, can be related to the levels of vitamin B12, folate, and homocysteine. These results can be explained by the importance of vitamin B12, folate, and homocysteine in carbon transfer metabolism (methylation, which is required for the production of serotonin as well as for other monoamine neurotransmitters and catecholamines. Earlier studies focused on the relationship between folate deficiency, hyperhomocysteinemia, and depressive disorders. Although depressive and anxiety disorders show a common comorbidity pattern, there are few studies addressing the effect of impaired one-carbon metabolism in anxiety disorders – especially in obsessive–compulsive disorder (OCD. This study aimed to measure the levels of vitamin B12, folate, and homocysteine specifically in order to see if eventual alterations have an etiopathogenetic significance on patients with OCD. Serum vitamin B12, folate, and homocysteine concentrations were measured in 35 patients with OCD and 22 controls. In addition, the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision, Yale–Brown Obsessive Compulsive Scale, Hamilton Rating Scale for Depression

  1. Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk

    DEFF Research Database (Denmark)

    Kelemen, Linda E; Terry, Kathryn L; Goodman, Marc T;

    2014-01-01

    ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs...... was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were...

  2. Review of alpha_s determinations

    OpenAIRE

    Pich, Antonio

    2013-01-01

    The present knowledge on the strong coupling is briefly summarized. The most precise determinations of alpha_s, at different energies, are reviewed and compared at the Z mass scale, using the predicted QCD running. The impressive agreement achieved between experimental measurements and theoretical predictions constitutes a beautiful and very significant test of Asymptotic Freedom, establishing QCD as the fundamental theory of the strong interaction. The world average value of the strong coupl...

  3. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets.

    Science.gov (United States)

    Grarup, Niels; Sulem, Patrick; Sandholt, Camilla H; Thorleifsson, Gudmar; Ahluwalia, Tarunveer S; Steinthorsdottir, Valgerdur; Bjarnason, Helgi; Gudbjartsson, Daniel F; Magnusson, Olafur T; Sparsø, Thomas; Albrechtsen, Anders; Kong, Augustine; Masson, Gisli; Tian, Geng; Cao, Hongzhi; Nie, Chao; Kristiansen, Karsten; Husemoen, Lise Lotte; Thuesen, Betina; Li, Yingrui; Nielsen, Rasmus; Linneberg, Allan; Olafsson, Isleifur; Eyjolfsson, Gudmundur I; Jørgensen, Torben; Wang, Jun; Hansen, Torben; Thorsteinsdottir, Unnur; Stefánsson, Kari; Pedersen, Oluf

    2013-06-01

    Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations. PMID:23754956

  4. Plasma folate studies in HIV-positive patients at the Lagos university teaching hospital, Nigeria

    Directory of Open Access Journals (Sweden)

    Alani Akanmu

    2010-01-01

    Full Text Available Introduction: In various studies globally, the prevalence of anemia in persons with HIV infection range from 10 to 20% at initial presentation, and anemia is diagnosed in 70 to 80% of these patients over the course of HIV disease. The etiology of anemia in this group of patients has not been fully established, thus a need to evaluate the role of plasma folate as a possible etiological factor. Objective: This study was set to determine plasma folate levels in newly diagnosed, treatment naïve, HIV-positive patients, and relate this to other hematological changes. Materials and Methods: A total of 200 participants were recruited for this study, of which 100 were HIV positive, treatment naive patients who were recruited at the point of registration and 100 were HIV-negative subjects (controls. 5 ml of venous blood was collected and plasma extracted for folic acid estimation by HPLC. A full blood count, CD4 and Viral load were estimated. Results: Mean ages for control and study group were 38 ± 2.3 and 32 ± 1.7 years, respectively. Mean plasma folate concentration among the study group (5.04 μg/l was significantly lower than that for the control group (15.89 μg/l; P = 0.0002. Prevalence of anemia among the study group was 72% (144 of 200, with a mean hemoglobin (Hb concentration of 9.5 g/dl compared with mean Hb of 13.0 g/dl among the control group (P = 0.002. Plasma folate correlated positively with CD4 cell count (r = 0.304, P<0.05 and inversely with the viral load (r = -0.566; P<0.05. Conclusion: Plasma folate level is a predictor of anemia in early HIV infections.

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

    International Nuclear Information System (INIS)

    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 μM concentration of either activated [3H]folate or activated [3H]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

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

    International Nuclear Information System (INIS)

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

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

    Directory of Open Access Journals (Sweden)

    Malaguarnera G

    2015-08-01

    Full Text Available Giulia Malaguarnera,1 Caterina Gagliano,2,3 Salvatore Salomone,1 Maria Giordano,4 Claudio Bucolo,1 Antonino Pappalardo,5 Filippo Drago,1 Filippo Caraci,6,7 Teresio Avitabile,2 Massimo Motta51Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; 2Department of Ophthalmology, University of Catania, Catania, Italy; 3Neurovisual Science Technology (NEST, Catania, Catania, Italy; 4Gerontology and Bone Metabolic Disease Section, Department of Medical Sciences, University of Turin, Turin; 5Department of Medical and Paediatric Sciences, University of Catania, Italy; 6Department of Drug Sciences, University of Catania, Catania, Italy; 7IRCCS Association Oasi Maria S.S.-Institute for Research on Mental Retardation and Brain Aging, Troina, Enna, ItalyBackground: 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. Keywords: homocysteine, proliferative diabetic retinopathy, nonproliferative diabetic retinopathy, diabetes mellitus

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

    Energy Technology Data Exchange (ETDEWEB)

    Guérard, Melanie, E-mail: melanie.guerard@roche.com; Zeller, Andreas; Festag, Matthias; Schubert, Christine; Singer, Thomas; Müller, Lutz

    2014-09-15

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

  9. (64)Cu- and (68)Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-Folate.

    Science.gov (United States)

    Farkas, Renáta; Siwowska, Klaudia; Ametamey, Simon M; Schibli, Roger; van der Meulen, Nicholas P; Müller, Cristina

    2016-06-01

    A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with (64)Cu and (68)Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with (64)Cu and (68)Ga was carried out at room temperature within 10 min resulting in (64)Cu-rf42 and (68)Ga-rf42 with >95% radiochemical purity. (64)Cu-rf42 and (68)Ga-rf42 were stable (>95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of (64)Cu-rf42 and (68)Ga-rf42 was determined to be >96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to <1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of (64)Cu-rf42 and (68)Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43-0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of (64)Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of (64)Cu-rf42 and (68)Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with (64)Cu-rf42 and a (64)Cu-labeled DOTA-folate conjugate (cm10) clearly proved the superiority of NODAGA

  10. Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: an experimental study in mice

    Directory of Open Access Journals (Sweden)

    Baskin Laurence S

    2006-02-01

    estradiol. Conclusion The results suggest that vinclozolin virilizes females and directly or indirectly affects progesterone receptor expression. It also affects estrogen receptor expression in a sex-based manner. We found no in vivo effect of vinclozolin on androgen receptor expression. We propose that vinclozolin, which has been designated an anti-androgen, may also exert its effects by involving additional steroid-signaling pathways.

  11. Activated human mast cells induce LOX-1-specific scavenger receptor expression in human monocyte-derived macrophages.

    Directory of Open Access Journals (Sweden)

    Mervi Alanne-Kinnunen

    Full Text Available Activated mast cells in atherosclerotic lesions degranulate and release bioactive compounds capable of regulating atherogenesis. Here we examined the ability of activated human primary mast cells to regulate the expression of the major scavenger receptors in cultured human primary monocyte-derived macrophages (HMDMs.Components released by immunologically activated human primary mast cells induced a transient expression of lectin-like oxidized LDL receptor (LOX-1 mRNA in HMDMs, while the expression of two other scavenger receptors, MSR1 and CD36, remained unaffected. The LOX-1-inducing secretory components were identified as histamine, tumor necrosis factor alpha (TNF-α, and transforming growth factor beta (TGF-β1, which exhibited a synergistic effect on LOX-1 mRNA expression. Histamine induced a transient expression of LOX-1 protein. Mast cell -induced increase in LOX-1 expression was not associated with increased uptake of oxidized LDL by the macrophages.Mast cell-derived histamine, TNF-α, and TGF-β1 act in concert to induce a transient increase in LOX-1 expression in human primary monocyte-derived macrophages. The LOX-1-inducing activity potentially endows mast cells a hitherto unrecognized role in the regulation of innate immune reactions in atherogenesis.

  12. New ALPHA-2 magnet

    CERN Multimedia

    Anaïs Schaeffer

    2012-01-01

    On 21 June, members of the ALPHA collaboration celebrated the handover of the first solenoid designed for the ALPHA-2 experiment. The magnet has since been successfully installed and is working well.   Khalid Mansoor, Sumera Yamin and Jeffrey Hangst in front of the new ALPHA-2 solenoid. “This was the first of three identical solenoids that will be installed between now and September, as the rest of the ALPHA-2 device is installed and commissioned,” explains ALPHA spokesperson Jeffrey Hangst. “These magnets are designed to allow us to transfer particles - antiprotons, electrons and positrons - between various parts of the new ALPHA-2 device by controlling the transverse size of the particle bunch that is being transferred.” Sumera Yamin and Khalid Mansoor, two Pakistani scientists from the National Centre for Physics in Islamabad, came to CERN in February specifically to design and manufacture these magnets. “We had the chance to work on act...

  13. A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations

    Directory of Open Access Journals (Sweden)

    2005-04-01

    Full Text Available Background & Aims: At least 500 μg of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 μg of folate or with one 500 μg capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (p

  14. Vitamin B12 and folate status in acute geropsychiatric inpatients: affective and cognitive characteristics of a vitamin nondeficient population.

    Science.gov (United States)

    Bell, I R; Edman, J S; Marby, D W; Satlin, A; Dreier, T; Liptzin, B; Cole, J O

    1990-01-15

    This chart review study examined the serum vitamin B12 and folate status of 102 geriatric patients newly admitted to a private psychiatric hospital. Only 3.7% were B12 deficient and 1.3% were folate deficient; 4% were anemic. Nevertheless, those with below-median values of both vitamins had significantly lower Mini-Mental State scores than patients higher in one or both vitamins. Patients with "organic psychosis" with a negative family history for psychiatric disorder had significantly lower B12 levels than those with a positive family history. In major depression, folate levels correlated negatively with age at onset of psychiatric illness and length of hospitalization. These data suggest that (1) biochemically interrelated vitamins such as B12 and folate may exert both a separate and a concomitant influence on affect and cognition; (2) poorer vitamin status may contribute to certain geropsychiatric disorders that begin at a later age and lack a familial predisposition.

  15. Triggering receptor expressed on myeloid cells-1 and respiratory disease%髓样细胞触发受体-1与呼吸系统疾病

    Institute of Scientific and Technical Information of China (English)

    李新胜; 陈绍平

    2013-01-01

    髓样细胞触发受体-1(triggering receptor expressed on myeloid cells-1,TREM-1)是表达于中性粒细胞和单核细胞表面的膜受体,属于免疫蛋白超家族,与未知配体结合有放大炎症反应的作用.近来研究发现可溶性髓样细胞触发受体-1作为生物标记物与呼吸系统多种疾病有密切的联系.本文就TREM-1的结构、表达及其与呼吸系统疾病的关系进行综述.

  16. GABA agonist induced changes in ultrastructure and GABA receptor expression in cerebellar granule cells is linked to hyperpolarization of the neurons

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, G H; Schousboe, A

    1990-01-01

    GABA has been shown to exert a neurotrophic like activity by enhancing the morphological and functional maturation of neurons. Mechanisms involved in this effect of GABA are largely unknown but since GABA has been shown to mediate a hyperpolarizing action on neurons it can be assumed...... that this action might be important. In order to investigate this possibility, the ability to mimic the trophic actions of GABA of different agents known to influence the membrane potential or the GABA gated chloride channels was studied. Hence, GABA receptor expression as well as the ultrastructure of cerebellar...... granule cells were monitored after exposure of the cells in culture to either bromide, valinomycin or picrotoxin. It was found that cells which at early developmental stages (4 days in culture) were exposed to bromide or valinomycin expressed low affinity GABA receptors similar to cells treated...

  17. GABA agonist induced changes in ultrastructure and GABA receptor expression in cerebellar granule cells is linked to hyperpolarization of the neurons

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, Gert Helge; Schousboe, A

    1990-01-01

    GABA has been shown to exert a neurotrophic like activity by enhancing the morphological and functional maturation of neurons. Mechanisms involved in this effect of GABA are largely unknown but since GABA has been shown to mediate a hyperpolarizing action on neurons it can be assumed that this...... action might be important. In order to investigate this possibility, the ability to mimic the trophic actions of GABA of different agents known to influence the membrane potential or the GABA gated chloride channels was studied. Hence, GABA receptor expression as well as the ultrastructure of cerebellar...... granule cells were monitored after exposure of the cells in culture to either bromide, valinomycin or picrotoxin. It was found that cells which at early developmental stages (4 days in culture) were exposed to bromide or valinomycin expressed low affinity GABA receptors similar to cells treated with the...

  18. Multiple micronutrient supplementation improves vitamin B12 and folate concentrations of HIV infected children in Uganda: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Bolann Bjørn J

    2011-05-01

    Full Text Available Abstract Background The effect of multiple micronutrient supplementation on vitamin B12 and folate has hither to not been reported in African HIV infected children. This paper describes vitamin B12 and folate status of Ugandan HIV infected children aged 1-5 years and reports the effect of multiple micronutrient supplementation on serum vitamin B12 and folate concentrations. Methods Of 847 children who participated in a multiple micronutrient supplementation trial, 214 were assessed for vitamin B12 and folate concentrations pre and post supplementation. One hundred and four children were randomised to two times the recommended dietary allowance (RDA of a 14 multiple micronutrient supplement (MMS and 114 to a 'standard of care' supplement of 6 multivitamins (MV. Serum vitamin B12 was measured by an electrochemiluminescence immunoassay and folate by a competitive protein-binding assay using Modular E (Roche automatic analyzer. Vitamin B12 concentrations were considered low if less than 221picomoles per litre (pmol/L and folate if Results Vitamin B12 was low in 60/214 (28% and folate in 62/214 (29.0% children. In the MMS group, the median concentration (IQR of vitamin B12 at 6 months was 401.5 (264.3 - 518.8 pmol/L compared to the baseline of 285.5 (216.5 - 371.8 pmol/L, p 12 at 6 months was 288.5 (198.8 - 391.0 pmol/L compared to the baseline of 280.0 (211.5 - 386.3 pmol/L while the median (IQR folate concentrations at 6 months were 16.5 (11.7 - 22.1 nmol/L compared to 15.7 (11.9 - 22.1 nmol/L at baseline. There was a significant difference in the MMS group in both vitamin B12 and folate concentrations but no difference in the MV group. Conclusions Almost a third of the HIV infected Ugandan children aged 1-5 years had low serum concentrations of vitamin B12 and folate. Multiple micronutrient supplementation compared to the 'standard of care' supplement of 6 multivitamins improved the vitamin B12 and folate status of HIV infected children in Uganda

  19. A comparison of folate status in women of child-bearing age in Korea and in the United States

    Directory of Open Access Journals (Sweden)

    Hyun T

    2012-07-01

    Full Text Available Taisun Hyun,1 Suguna Badiga,2 Han Byul Jang,1 Young-Hee Han,1 Chandrika J Piyathilake21Department of Food and Nutrition, Chungbuk National University, Cheongju, Korea; 2Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USABackground: Even though several studies have demonstrated that periconceptional supplementation with folic acid (FA reduces the occurrence of neural tube defects, FA fortification has been a topic of intense debate due to the possible adverse effects of higher folate status on several health conditions. Several countries, including Korea, have been indecisive as to whether fortification is warranted or not. It is therefore helpful for these countries to compare folate concentrations in their populations with populations exposed to mandatory FA fortification.Purpose: To evaluate the differences in the distribution of circulating concentrations of folate in Korea and the United States (US at different time points.Methods: The Korean study populations consisted of women of child-bearing age recruited in 1999 and in 2009. The US study populations consisted of women of child-bearing age recruited in the post FA fortification era (2005 and 2009. Plasma and red blood cell (RBC folate concentrations were measured using the Lactobacillus casei microbiological assay.Results: The percentage of US women with neural tube defect-protective levels of RBC folate was significantly higher compared to Korean women in 1999 and 2009. However, in 2009, when FA supplements became readily available for Koreans, 50% of Korean women in the study achieved the neural tube defect-protective level of RBC folate; 11% of them demonstrating supraphysiologic concentrations of plasma folate. Even though FA fortification in the US resulted in more than 80of women achieving >400 ng/mL of RBC folate by 2009, nearly 50% also demonstrated having supraphysiologic concentrations of plasma folate, which prompted some researchers to

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

    Energy Technology Data Exchange (ETDEWEB)

    Tsang, Verne [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Fry, Rebecca C. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Niculescu, Mihai D. [UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Rager, Julia E. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Saunders, Jesse; Paul, David S. [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Zeisel, Steven H. [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); UNC Nutrition Research Institute, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Waalkes, Michael P. [NIEHS, Research Triangle Park, NC 27709 (United States); Stýblo, Miroslav [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Drobná, Zuzana, E-mail: drobnazu@med.unc.edu [Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States)

    2012-11-01

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

  1. Alpha Shapes and Proteins

    DEFF Research Database (Denmark)

    Winter, Pawel; Sterner, Henrik; Sterner, Peter

    2009-01-01

    We provide a unified description of (weighted) alpha shapes, beta shapes and the corresponding simplicialcomplexes. We discuss their applicability to various protein-related problems. We also discuss filtrations of alpha shapes and touch upon related persistence issues.We claim that the full...... potential of alpha-shapes and related geometrical constructs in protein-related problems yet remains to be realized and verified. We suggest parallel algorithms for (weighted) alpha shapes, and we argue that future use of filtrations and kinetic variants for larger proteins will need such implementation....

  2. Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Kastrup, Ingelise Bjerring; Worm, Jesper; Ralfkiaer, Elisabeth;

    2007-01-01

    The reduced folate carrier (RFC) is a transmembrane protein that mediates cellular uptake of reduced folates and antifolate drugs, including methotrexate (MTX). Acquired alterations of the RFC gene have been associated with resistance to MTX in cancer cell lines and primary osteosarcomas. Here, w...... with adverse outcome. In DLBCL, genetic and epigenetic alterations of RFC were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma. Udgivelsesdato: 2008-Jan...

  3. Genetic and epigenetic alterations of the reduced folate carrier in untreated diffuse large B-cell lymphoma

    DEFF Research Database (Denmark)

    Kastrup, I.B.; Worm, J.; Ralfkiaer, E.;

    2008-01-01

    The reduced folate carrier (RFC) is a transmembrane protein that mediates cellular uptake of reduced folates and antifolate drugs, including methotrexate (MTX). Acquired alterations of the RFC gene have been associated with resistance to MTX in cancer cell lines and primary osteosarcomas. Here, w...... with adverse outcome. In DLBCL, genetic and epigenetic alterations of RFC were detected at diagnosis in the absence of a selective MTX pressure, suggesting that these alterations may possibly contribute to the development of lymphoma Udgivelsesdato: 2008/1...

  4. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity

    Energy Technology Data Exchange (ETDEWEB)

    Fenech, Michael, E-mail: michael.fenech@csiro.au [CSIRO Food and Nutritional Sciences, PO Box 10041 Adelaide BC, SA 5000 (Australia)

    2012-05-01

    Folate plays a critical role in the prevention of uracil incorporation into DNA and hypomethylation of DNA. This activity is compromised when vitamin B12 concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation, DNA hypomethylation and mitochondrial DNA deletions. In vivo studies show that folate and/or vitamin B12 deficiency and elevated plasma homocysteine (a metabolic indicator of folate deficiency) are significantly correlated with increased micronucleus formation and reduced telomere length respectively. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is greater than 100 nmol/L. Intervention studies in humans show (a) that DNA hypomethylation, chromosome breaks, uracil incorporation and micronucleus formation are minimised when red cell folate concentration is greater than 700 nmol/L and (b) micronucleus formation is minimised when plasma concentration of vitamin B12 is greater than 300 pmol/L and plasma homocysteine is less than 7.5 {mu}mol/L. These concentrations are achievable at intake levels at or above current recommended dietary intakes of folate (i.e. >400 {mu}g/day) and vitamin B12 (i.e. >2 {mu}g/day) depending on an individual's capacity to absorb and metabolise these vitamins which may vary due to genetic and epigenetic differences.

  5. Intake and Biomarkers of Folate and Risk of Cancer Morbidity in Older Adults, NHANES 1999-2002 with Medicare Linkage.

    Directory of Open Access Journals (Sweden)

    Jing Hu

    Full Text Available After the 1998 mandatory folic acid fortification of enriched cereal-grain products in the U.S., safety concerns were raised that excess consumption of folic acid and high blood folate biomarkers detected in adults may increase the risk of certain types of cancer.Baseline data from about 1400 participants in the National Health and Nutrition Examination Survey (NHANES 1999-2002, aged ≥ 57 years were linked to Medicare and mortality files through December 31, 2007. Using cox proportional hazards regression models, we assessed associations between dietary folate equivalents, folate biomarkers, the presence of unmetabolized folic acid and, overall cancer incidence.With 8,114 person-years of follow-up (median follow-up, 6.3 years, about 125 cancer cases were identified. After adjusting for confounders, the hazard ratios of the highest quartile versus the second quartile of RBC folate and dietary folate equivalents were 0.54 (95% CI: 0.31-0.93 and 0.54 (95% CI: 0.30-0.95, respectively. Additionally, serum and RBC folate as continuous variables were inversely and significantly associated with cancer incidence (p<0.01. No significant associations were observed between the presence of unmetabolized folic acid, intake of naturally-occurring food folate or folic acid separately, and cancer incidence.High total folate intake and biomarkers in older adults appear to be protective against cancer in post-folic acid fortification years. This study does not show a negative impact of current level of folic acid fortification on cancer risk. As this is one of the few studies to examine the association between unmetabolized folic acid and cancer outcome, a study including a larger nationwide representative sample of the U.S. population is needed.

  6. High performance liquid chromatography coupled to mass spectrometry for profiling and quantitative analysis of folate monoglutamates in tomato.

    Science.gov (United States)

    Tyagi, Kamal; Upadhyaya, Pallawi; Sarma, Supriya; Tamboli, Vajir; Sreelakshmi, Yellamaraju; Sharma, Rameshwar

    2015-07-15

    Folates are essential micronutrients for animals as they play a major role in one carbon metabolism. Animals are unable to synthesize folates and obtain them from plant derived food. In the present study, a high performance liquid chromatography coupled to mass spectrometric (HPLC-MS/MS) method was developed for the high throughput screening and quantitative analysis of folate monoglutamates in tomato fruits. For folate extraction, several parameters were optimized including extraction conditions, pH range, amount of tri-enzyme and boiling time. After processing the extract was purified using ultra-filtration with 10 kDa membrane filter. The ultra-filtered extract was chromatographed on a RP Luna C18 column using gradient elution program. The method was validated by determining linearity, sensitivity and recovery. This method was successfully applied to folate estimation in spinach, capsicum, and garden pea and demonstrated that this method offers a versatile approach for accurate and fast determination of different folate monoglutamates in vegetables. PMID:25722141

  7. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns

    Science.gov (United States)

    Joubert, Bonnie R.; den Dekker, Herman T.; Felix, Janine F.; Bohlin, Jon; Ligthart, Symen; Beckett, Emma; Tiemeier, Henning; van Meurs, Joyce B.; Uitterlinden, Andre G.; Hofman, Albert; Håberg, Siri E.; Reese, Sarah E.; Peters, Marjolein J.; Kulle Andreassen, Bettina; Steegers, Eric A. P.; Nilsen, Roy M.; Vollset, Stein E.; Midttun, Øivind; Ueland, Per M.; Franco, Oscar H.; Dehghan, Abbas; de Jongste, Johan C.; Wu, Michael C.; Wang, Tianyuan; Peddada, Shyamal D.; Jaddoe, Vincent W. V.; Nystad, Wenche; Duijts, Liesbeth; London, Stephanie J.

    2016-01-01

    Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring. PMID:26861414

  8. Targeted Alpha Therapy: From Alpha to Omega

    International Nuclear Information System (INIS)

    This review covers the broad spectrum of Targeted Alpha Therapy (TAT) research in Australia; from in vitro and in vivo studies to clinical trials. The principle of tumour anti-vascular alpha therapy (TAVAT) is discussed in terms of its validation by Monte Carlo calculations of vascular models and the potential role of biological dosimetry is examined. Summmary of this review is as follows: 1. The essence of TAT 2. Therapeutic objectives 3. TAVAT and Monte Carlo microdosimetry 4. Biological dosimetry 5. Preclinical studies 6. Clinical trials 7. What next? 8. Obstacles. (author)

  9. Cytosolic phospholipase A2-alpha expression in breast cancer is associated with EGFR expression and correlates with an adverse prognosis in luminal tumours.

    LENUS (Irish Health Repository)

    Caiazza, F

    2012-02-01

    BACKGROUND: The eicosanoid signalling pathway promotes the progression of malignancies through the production of proliferative prostaglandins (PGs). Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) activity provides the substrate for cyclooxygenase-dependent PG release, and we have previously found that cPLA(2)alpha expression correlated with EGFR\\/HER2 over-expression in a small number of breast cancer cell lines. METHODS: The importance of differential cPLA(2)alpha activity in clinical breast cancer was established by relating the expression of cPLA(2)alpha in tissue samples from breast cancer patients, and two microarray-based gene expression datasets to different clinicopathological and therapeutic parameters. RESULTS: High cPLA(2)alpha mRNA expression correlated with clinical parameters of poor prognosis, which are characteristic of highly invasive tumours of the HER2-positive and basal-like subtype, including low oestrogen receptor expression and high EGFR expression. High cPLA(2)alpha expression decreased overall survival in patients with luminal cancers, and correlated with a reduced effect of tamoxifen treatment. The cPLA(2)alpha expression was an independent predictive parameter of poor response to endocrine therapy in the first 5 years of follow-up. CONCLUSION: This study shows a role of cPLA(2)alpha in luminal breast cancer progression, in which the enzyme could represent a novel therapeutic target and a predictive marker.

  10. Rho GTPases RhoA and Rac1 mediate effects of dietary folate on metastatic potential of A549 cancer cells through the control of cofilin phosphorylation.

    Science.gov (United States)

    Oleinik, Natalia V; Helke, Kristi L; Kistner-Griffin, Emily; Krupenko, Natalia I; Krupenko, Sergey A

    2014-09-19

    Folate, an important nutrient in the human diet, has been implicated in cancer, but its role in metastasis is not established. We have shown previously that the withdrawal of medium folate leads to the inhibition of migration and invasion of A549 lung carcinoma cells. Here we have demonstrated that medium folate regulates the function of Rho GTPases by enabling their carboxyl methylation and translocation to plasma membrane. Conversely, the lack of folate leads to the retention of these proteins in endoplasmic reticulum. Folate also promoted the switch from inactive (GDP-bound) to active (GTP-bound) GTPases, resulting in the activation of downstream kinases p21-activated kinase and LIM kinase and phosphorylation of the actin-depolymerizing factor cofilin. We have further demonstrated that in A549 cells two GTPases, RhoA and Rac1, but not Cdc42, are immediate sensors of folate status: the siRNA silencing of RhoA or Rac1 blocked effects of folate on cofilin phosphorylation and cellular migration and invasion. The finding that folate modulates metastatic potential of cancer cells was confirmed in an animal model of lung cancer using tail vein injection of A549 cells in SCID mice. A folate-rich diet enhanced lung colonization and distant metastasis to lymph nodes and decreased overall survival (35 versus 63 days for mice on a folate-restricted diet). High folate also promoted epithelial-mesenchymal transition in cancer cells and experimental mouse tumors. Our study provides experimental evidence for a mechanism of metastasis promotion by dietary folate and highlights the interaction between nutrients and metastasis-related signaling.

  11. Buffett’s Alpha

    DEFF Research Database (Denmark)

    Frazzini, Andrea; Kabiller, David; Heje Pedersen, Lasse

    Berkshire Hathaway has realized a Sharpe ratio of 0.76, higher than any other stock or mutual fund with a history of more than 30 years, and Berkshire has a significant alpha to traditional risk factors. However, we find that the alpha becomes insignificant when controlling for exposures to Betting...

  12. Inflammatory reaction versus endogenous peroxisome proliferator-activated receptors expression,re-exploring secondary organ complications of spontaneously hypertensive rats

    Institute of Scientific and Technical Information of China (English)

    SUN Li; KE Yan; ZHU Chun-yun; TANG Ning; TIAN Deng-ke; GAO Yue-hong; ZHENG Jian-pu; BIAN Ka

    2008-01-01

    Background The chronic pathological changes in vascular walls of hypertension may exert destructive effects on multiple organ systems.Accumulating evidence indicates that inflammatory reactions are involved in the pathological changes of hypertension.Three peroxisome proliferator-activated receptors (PPARs) have been identified:PPARα,PPARβ/δ,and PPARγ,all of which have multiple biological effects,especially the inhibition of inflammation.The aim of this study was to evaluate PPAR isoforms expression profile in important organs of spontaneously hypertensive rats (SHR) and to understand the modulation of endogenous PPAR isoforms under inflammatory condition.Methods Tissues (kidney,liver,heart,and brain) were dissected from SHR and age-matched control Wistar-Kyoto rats (WKY) to investigate the abundance of PPAR isoforms and PPAR-responsive genes (acyl-CoA oxidase and CD36).The expression of CCAAT/enhancer-binding protein δ (C/EBPδ),which can trans-activate PPARγ expression,was also observed.The inflammatory response was analyzed by the expression of inflammatory mediators inducible nitric oxide synthase (iNOS),intercellular adhesion molecule-1 (ICAM-1),vascular cell adhesion molecule-1 (VCAM-1),E-selectin,interleukin-1 beta (IL-1β),and tumor necrosis factor alpha (TNFα),and formation of carbonyl and nitrated proteins.Results The expressions of 3 PPAR isoforms and PPAR-responsive genes were markedly upregulated in SHR compared with those of WKY.Specifically,the expression of PPARa protein in the kidney,liver,heart and brain increased by 130.76 %,91.48%,306.24%,and 90.70%;PPARβ/δ upregulated by 109.34%,161.98%,137.04%,and 131.66%;PPARγ increased by 393.76%,193.17%,559.29%,and 591.18%.In consistent with the changes in PPARγ,the expression of C/EBPδ was also dramatically elevated in SHR.Inflammatory mediators expressions were significantly increased in the most organs of SHR than WKY.As a consequence,increased formation of carbonyl and nitrated proteins were

  13. Alpha-particle diagnostics

    Energy Technology Data Exchange (ETDEWEB)

    Young, K.M.

    1991-01-01

    This paper will focus on the state of development of diagnostics which are expected to provide the information needed for {alpha}- physics studies in the future. Conventional measurement of detailed temporal and spatial profiles of background plasma properties in DT will be essential for such aspects as determining heating effectiveness, shaping of the plasma profiles and effects of MHD, but will not be addressed here. This paper will address (1) the measurement of the neutron source, and hence {alpha}-particle birth profile, (2) measurement of the escaping {alpha}-particles and (3) measurement of the confined {alpha}-particles over their full energy range. There will also be a brief discussion of (4) the concerns about instabilities being generated by {alpha}-particles and the methods necessary for measuring these effects. 51 refs., 10 figs.

  14. Imaging alpha particle detector

    Science.gov (United States)

    Anderson, D.F.

    1980-10-29

    A method and apparatus for detecting and imaging alpha particles sources is described. A dielectric coated high voltage electrode and a tungsten wire grid constitute a diode configuration discharge generator for electrons dislodged from atoms or molecules located in between these electrodes when struck by alpha particles from a source to be quantitatively or qualitatively analyzed. A thin polyester film window allows the alpha particles to pass into the gas enclosure and the combination of the glass electrode, grid and window is light transparent such that the details of the source which is imaged with high resolution and sensitivity by the sparks produced can be observed visually as well. The source can be viewed directly, electronically counted or integrated over time using photographic methods. A significant increase in sensitivity over other alpha particle detectors is observed, and the device has very low sensitivity to gamma or beta emissions which might otherwise appear as noise on the alpha particle signal.

  15. Cellular uptake of folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Woo, Kyoungja [Nano-Materials Research Center, Korea Institute of Science and Technology, P. O. Box 131, Cheongryang, Seoul 130-650 (Korea, Republic of)], E-mail: kjwoo@kist.re.kr; Moon, Jihyung [Nano-Materials Research Center, Korea Institute of Science and Technology, P. O. Box 131, Cheongryang, Seoul 130-650 (Korea, Republic of); Department of Materials Science and Engineering, Korea University, 5-1, Anam-Dong, Sungbook-Ku, Seoul, 136-713 (Korea, Republic of); Choi, Kyu-Sil [Division of Molecular Imaging, Samsung Biomedical Research Institute, Samsung Medical Center, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Seong, Tae-Yeon [Department of Materials Science and Engineering, Korea University, 5-1, Anam-Dong, Sungbook-Ku, Seoul, 136-713 (Korea, Republic of); Yoon, Kwon-Ha [Institute for Radiological Imaging Science, Wonkwang University School of Medicine, 344-2, Shinyong, Iksan, Jeonbuk 570-749 (Korea, Republic of)

    2009-05-15

    We prepared five folate-conjugated lipophilic superparamagnetic iron oxide nanoparticles (F{sub 5}-Liposuperparamagnetic iron oxide nanoparticles(SPIONs), 5.5 and 11 nm) and investigated their cellular uptake with KB cells, which is one of the representative folate-receptor over-expressing human epidermoid carcinoma cells, using MRI. The cellular uptake tests with the respective 5.5 and 11 nm F{sub 5}-LipoSPIONs at a fixed particle concentration showed appreciable amount of receptor-mediated uptakes and the specificity was higher in 5.5 nm SPIONs, due to its higher folic acid (FA) density, without inhibition. However, the numbers of the particles taken up under FA inhibition were similar, irrespective of their sizes.

  16. Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

    International Nuclear Information System (INIS)

    Folic acid, also known as vitamin B9, is the oxidized form of 5,6,7,8-tetrahydrofolate, which serves as methyl- or methylene donor (C1-building blocks) during DNA synthesis. Under physiological conditions the required amount of 5,6,7,8-tetrahydrofolate for survival of the cell is accomplished through the reduced folate carrier (RFC). In contrast, the supply of 5,6,7,8-tetrahydrofolate is insufficient under pathophysiological conditions of tumors due to an increased proliferation rate. Consequently, many tumor cells exhibit an (over)expression of the folate receptor. This phenomenon has been applied to diagnostics (PET, SPECT, MR) to image FR-positive tumors and on the other hand to treat malignancies related to a FR (over)expression. Based on this concept, a new 18F-labeled folate for PET imaging has been developed and was evaluated in vivo using tumor-bearing mice. The incorporation of oligoethylene spacers into the molecular structure led to a significant enhancement of the pharmacokinetics in comparison to previously developed 18F-folates. The liver uptake could be reduced by one sixth by remaining a tumor uptake of 3%ID/g leading to better contrast ratios. Encouraged by these results, a clickable 18F-labeled serine-based prosthetic group has been synthesized, again with the idea to improve the metabolic and pharmacokinetic profile of hydrophilic radiotracers. Therefore, an alkyne-carrying azido-functionalized serine derivative for coupling to biomolecules was synthesized and a chlorine leaving group for 18F-labeling, which could be accomplished using a microwave-assisted synthesis, a [K is contained in 2.2.2]+/carbonate system in DMSO. Radiochemical yields of 77±6% could be achieved. The promising results obtained from the FR-targeting concept in the diagnostic field have been transferred to the boron neutron capture therapy. Therefore, a folate derivative was coupled to different boron clusters and cell uptake studies were conducted. The synthesis of the

  17. Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Schieferstein, Hanno

    2013-07-01

    Folic acid, also known as vitamin B9, is the oxidized form of 5,6,7,8-tetrahydrofolate, which serves as methyl- or methylene donor (C1-building blocks) during DNA synthesis. Under physiological conditions the required amount of 5,6,7,8-tetrahydrofolate for survival of the cell is accomplished through the reduced folate carrier (RFC). In contrast, the supply of 5,6,7,8-tetrahydrofolate is insufficient under pathophysiological conditions of tumors due to an increased proliferation rate. Consequently, many tumor cells exhibit an (over)expression of the folate receptor. This phenomenon has been applied to diagnostics (PET, SPECT, MR) to image FR-positive tumors and on the other hand to treat malignancies related to a FR (over)expression. Based on this concept, a new {sup 18}F-labeled folate for PET imaging has been developed and was evaluated in vivo using tumor-bearing mice. The incorporation of oligoethylene spacers into the molecular structure led to a significant enhancement of the pharmacokinetics in comparison to previously developed {sup 18}F-folates. The liver uptake could be reduced by one sixth by remaining a tumor uptake of 3%ID/g leading to better contrast ratios. Encouraged by these results, a clickable {sup 18}F-labeled serine-based prosthetic group has been synthesized, again with the idea to improve the metabolic and pharmacokinetic profile of hydrophilic radiotracers. Therefore, an alkyne-carrying azido-functionalized serine derivative for coupling to biomolecules was synthesized and a chlorine leaving group for {sup 18}F-labeling, which could be accomplished using a microwave-assisted synthesis, a [K is contained in 2.2.2]{sup +}/carbonate system in DMSO. Radiochemical yields of 77±6% could be achieved. The promising results obtained from the FR-targeting concept in the diagnostic field have been transferred to the boron neutron capture therapy. Therefore, a folate derivative was coupled to different boron clusters and cell uptake studies were

  18. In vitro and in vivo targeting effect of folate decorated paclitaxel loaded PLA-TPGS nanoparticles.

    Science.gov (United States)

    Thu, Ha Phuong; Nam, Nguyen Hoai; Quang, Bui Thuc; Son, Ho Anh; Toan, Nguyen Linh; Quang, Duong Tuan

    2015-11-01

    Paclitaxel is one of the most effective chemotherapeutic agents for treating various types of cancer. However, the clinical application of paclitaxel in cancer treatment is considerably limited due to its poor water solubility and low therapeutic index. Thus, it requires an urgent solution to improve therapeutic efficacy of paclitaxel. In this study, folate decorated paclitaxel loaded PLA-TPGS nanoparticles were prepared by a modified emulsification/solvent evaporation method. The obtained nanoparticles were characterized by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared (FTIR) and Dynamic Light Scattering (DLS) method. The spherical nanoparticles were around 50 nm in size with a narrow size distribution. Targeting effect of nanoparticles was investigated in vitro on cancer cell line and in vivo on tumor bearing nude mouse. The results indicated the effective targeting of folate decorated paclitaxel loaded copolymer nanoparticles on cancer cells both in vitro and in vivo. PMID:26702264

  19. Genetic effects on variation in red-blood-cell folate in adults: Implications for the familial aggregation of neural tube defects

    Energy Technology Data Exchange (ETDEWEB)

    Mitchell, L.E. [Children`s Hospital of Philadelphia, PA (United States); Duffy, P.; Bellingham, G. [Prince Charles Hospital, Brisbane (Australia)] [and others

    1997-02-01

    Recent studies have implicated folic acid as an important determinant of normal human growth, development, and function. Insufficient folate levels appear to be a risk factor for neural tube defects (NTD), as well as for several chronic diseases of adulthood. However, relatively little is known about the factors that influence folate status in the general population. To estimate the relative contribution of genetic and nongenetic factors to variation in folate, we have evaluated red blood cell (RBC) folate levels in 440 pairs of MZ twins and in 331 pairs of DZ twins. The data were best described by a model in which 46% of the variance in RBC folate was attributable to additive genetic effects, 16% of the variance was due to measured phenotypic covariates, and 38% of the variance was due to random environmental effects. Moreover, the correlations for RBC folate in MZ co-twins (r = .46) and in repeat measures from the same individual (r = .51) were very similar, indicating that virtually all repeatable variation in RBC folate is attributable to genetic factors. On the basis of these results, it would seem reasonable to initiate a search for the specific genes that influence RBC folate levels in the general population. Such genes ultimately may be used to identify individuals at increased risk for NTD and other folate-related diseases. 23 refs., 1 tab.

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

    Directory of Open Access Journals (Sweden)

    Abinet Arega Sadore

    2015-01-01

    Full Text Available 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.

  1. Serum folate levels among healthy infants aged 6–8 months: relation to infants’ nutritional status indicators and maternal knowledge-attitude-practice

    Directory of Open Access Journals (Sweden)

    Tutik Ernawati

    2011-05-01

    Full Text Available Background: Vitamin B12 and folate deficiency can cause anemia which may lead growth and development impairments. This study was aimed to determine serum folate levels among infants aged 6–8 months and the relation to infants’ nutritional indicators and maternal knowledge-attitude-practice about infant feeding.Methods: A cross–sectional design was implemented in infants aged 6–8 months and their mothers as respondents who met the study criteria. Data collected among the infants included sex, age, length, weight, intake of energy, protein and folate (based on a one–month semi–quantitative FFQ and a 24–hour food recall, serum folate and hemoglobin levels. Data collected among the mothers included age, education level, income based on average minimum monthly wage, knowledge, attitude and behavior concerning infant’s feeding, i.e. breast milk and complementary feeding practices.Results: This study found that the median of serum folate levels was 43.05 nmol/L with values ranging from 19.92 nmol/L to 104.24 nmol/L. Serum folate level had a strong positive correlation with its related factors, protein and folate intake.Conclusions: Protein-folate–rich complementay food should be provided to infants aged 6 months and over to maintain serum folate level. (Med J Indones 2011; 20:138-42Keywords: Folate, infants, nutrient intake, nutritional status

  2. Elevated maternal serum folate in the third trimester and reduced fetal growth: a longitudinal study.

    Science.gov (United States)

    Takimoto, Hidemi; Hayashi, Fumi; Kusama, Kaoru; Kato, Noriko; Yoshiike, Nobuo; Toba, Mikayo; Ishibashi, Tomoko; Miyasaka, Naoyuki; Kubota, Toshiro

    2011-01-01

    This study aimed to examine the association of fetal growth and elevated third trimester maternal serum folate due to folic acid (FA) supplement intake. Dietary intake, use of FA supplements, weight, and blood biomarkers of B-vitamins (serum folate, pyridoxal, vitamin B(12), and plasma total homocysteine) were observed in 33 healthy pregnant women at the third trimester (average gestational age 35 wk). Birth outcomes were assessed through hospital birth records. Infant anthropometry and maternal blood biomarkers were followed up at 1 mo postpartum. Fourteen women were taking FA supplements at the third trimester. Dietary intake was similar among FA users and non-users, but serum folate and pyridoxal were significantly higher in users (11.6±6.7 vs. 6.1±3.2 ng/mL, and 13.8±21.7 vs. 3.2±1.4 ng/mL, respectively). Plasma total homocystein (tHcy) was higher in non-users compared to users, but not significantly. Nine FA users and eight non-users had low serum vitamin B(12) values (<203 pg/mL). Nine FA users and all non-users had low serum pyridoxal values (<7.0 ng/mL). Infant birthweight was significantly lower in users compared to non-users (2,894±318 vs. 3,154±230 g). At 1 mo postpartum, infant weight and length were similar between FA users and non-users, but infant weight gain was larger in users. Higher serum folate values due to FA use in the third trimester was related to reduced fetal size. Excess FA under low vitamin B(6) and B(12) status may affect fetal growth. PMID:21697631

  3. The nutritional status of iron, folate, and vitamin B-12 of Buddhist vegetarians.

    Science.gov (United States)

    Lee, Yujin; Krawinkel, Michael

    2011-01-01

    Nutritional status of iron, folate, and vitamin B-12 in vegetarians were assessed and compared with those of non- vegetarians in Korea. The vegetarian subjects were 54 Buddhist nuns who ate no animal source food except for dairy products. The non-vegetarians were divided into two groups: 31 Catholic nuns and 31 female college students. Three-day dietary records were completed, and the blood samples were collected for analyzing a complete blood count, and serum levels of ferritin, folate, and vitamin B-12. There was no difference in hemoglobin among the diet groups. The serum ferritin and hematocrit levels of vegetarians did not differ from that of non- vegetarian students with a high intake of animal source food but low intake of vitamin C, and the levels were lower than that of non-vegetarian Catholic nuns with a modest consumption of animal source food and a high intake of vitamin C. The serum vitamin B-12 levels of all subjects except one vegetarian and the serum folate levels of all subjects except one non-vegetarian student fell within a normal range. In vegetarians, there was a positive correlation between the vitamin C intake and serum ferritin levels as well as between the laver intake and serum vitamin B-12 levels. In order to achieve an optimal iron status, both an adequate amount of iron intake and its bioavailability should be considered. Sufficient intake of vegetables and fruits was reflected in adequate serum folate status. Korean laver can be a good source of vitamin B-12 for vegetarians. PMID:21393109

  4. Association of vitamin b/sub 12/, serum ferritin and folate levels with recurrent oral ulceration

    International Nuclear Information System (INIS)

    Background: The pathophysiology of recurrent aphthous stomatitis or aphthous ulcers remains obscure but malnutrition is one of its contributory factors. There is some role of vitamin B/sub 12/, ferritin and folate in the development of these lesions. Objectives: To determine the relationship between recurrent aphthous stomatitis and levels of ferritin, folate and vitamin B/sub 12/. Studytype settings: This case control study was conducted at Immunoassay lab, NHRC and Department of Dentistry, ShaikhZayed Hospital, Lahore. Patients and Methods: Sixty patients of all ages and both genders having history of recurrent ulcers over the past period of 3-6 months. Similar number of healthy controls were chosen who were either attendants of the patients or staff of the hospital and did not have any history of aphthous ulcers. Proforma was filled for each participant and 5ml blood was drawn and tested for complete picture blood by Sismex, serum ferritin by ELISA (Biocheck), vitamin B/sub 12/ and RBC folate by IBL kits from USA. Results: Fifty seven (57) age and gender matched patients with recurrent aphthous ulcers and 57 normal healthy controls were studied.Anemia was present in 24(42.1%) patients and 18(31.6%) controls. Hematocrit levels were normal in 45(79%) patients and 40(70.2%) controls. Low levels of RBC folate was seen in 26(45.6%) patients and 26(45.6%) controls. Vitamin B/sub 12/ deficiency was present in 29(50.1%) patients and none of the controls. The low levels of ferritin was seen in 6(10.5%) patients and 18(31.5%) controls. Conclusions: Patients with recurrent aphthous ulcers had more hematinic deficiencies, particularly of vitamin B/sub 12/ as compared to controls. (author)

  5. Emerging roles for folate and related B-vitamins in brain health across the lifecycle.

    Science.gov (United States)

    McGarel, C; Pentieva, K; Strain, J J; McNulty, H

    2015-02-01

    Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy and extending into later life. A growing body of evidence suggests that folate and the metabolically related B-vitamins are essential for brain health across all age groups, owing to their specific roles in C1 metabolism and particularly in the production of S-adenosylmethionine, a universal methyl donor essential for the production of neurotransmitters. Emerging, though not entirely consistent, evidence suggests that maternal folate status throughout pregnancy may influence neurodevelopment and behaviour of the offspring. Furthermore optimal B-vitamin status is associated with better cognitive health in ageing. Of note, a recent clinical trial provided evidence that supplementation with folic acid and related B-vitamins over a 2-year-period reduced global and regional brain atrophy, as measured by MRI scan in older adults. In terms of potential mechanisms, the effects of these B-vitamins on cognitive health may be independent or may be mediated by nutrient-nutrient and/or relevant gene-nutrient interactions. Furthermore, a new area of research suggests that the in utero environment influences health in later life. Folate, an important cofactor in C1 metabolism, is indirectly involved in DNA methylation, which in turn is considered to be one of the epigenetic mechanisms that may underlie fetal programming and brain development. The present review will explore the evidence that supports a role for folate and the related B-vitamins in brain health across the lifecycle, and potential mechanisms to explain such effects. PMID:25371067

  6. Folate-related gene variants in Irish families affected by neural tube defects

    Directory of Open Access Journals (Sweden)

    Ridgely eFisk Green

    2013-11-01

    Full Text Available Periconceptional folic acid use can often prevent neural tube defects (NTDs. Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative (risk genotypes and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p=0.017. We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential

  7. Bioprospecting of strains of Streptococcus thermophilus from Indian fermented milk products for folate production

    OpenAIRE

    Iyer, Ramya; Tomar, Sudhir Kumar; Mohanty, Ashok Kumar; Singh, Prashant; Singh, Rameshwar

    2011-01-01

    International audience This study deals with the bio-prospecting of folate producing strains of Streptococcus thermophilus isolated from milk and different fermented milk products of Indian origin. From a total of 500 randomly selected colonies isolated from 209 different samples, 117 isolates were identified as S. thermophilus by classical biochemical and molecular characterization. Frequency of incidence of S. thermophilus in the different samples of milk and milk products was variable w...

  8. Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis.

    Science.gov (United States)

    Qi, Rong; Majoros, Istvan; Misra, Asish C; Koch, Alisa E; Campbell, Phil; Marotte, Hubert; Bergin, Ingrid L; Cao, Zhengyi; Goonewardena, Sascha; Morry, Jingga; Zhang, Shuai; Beer, Michael; Makidon, Paul; Kotlyar, Alina; Thomas, Thommey P; Baker, James R

    2015-08-01

    Generation 5 (G5) poly(amidoamide) (PAMAM) dendrimers are synthetic polymers that have been broadly applied as drug delivery carriers. Methotrexate (MTX), an anti-folate metabolite, has been successfully used as an anti-inflammatory drug to treat rheumatoid arthritis (RA) in the clinic. In this study, we examine the therapeutic efficacy of G5 PAMAM dendrimer methotrexate conjugates (G5-MTX) that also have folic acid (FA) conjugated to the G5-MTX (G5-FA-MTX) to target inflammation-activated folate receptors overexpressing macrophages. These cells are thought to play an important role in the development of RA. With G5 serving as a control, the in vitro binding affinities of G5-FA-MTX and G5-MTX to activated macrophages were assessed in RAW264.7, NR8383 and primary rat peritoneal macrophages. The results indicated that the binding of either conjugate to macrophages was concentration- and temperature-dependent and could be blocked by the presence of 6.25 mM free FA (p < 0.005). The preventive effects of G5-MTX and G5-FA-MTX conjugates on the development of arthritis were explored on an adjuvant-induced inflammatory arthritis model and had similar preventive effects in inflammatory arthritis at a MTX equivalent dose of 4.95 μmol/kg. These studies indicated that when multiples of MTX are conjugated on dendritic polymers, they specifically bind to folate receptor overexpressing macrophages and have comparable anti-inflammatory effects to folate targeted MTX conjugated polymers.

  9. Lack of association between folate-receptor autoantibodies and neural-tube defects.

    LENUS (Irish Health Repository)

    Molloy, Anne M

    2009-07-09

    BACKGROUND: A previous report described the presence of autoantibodies against folate receptors in 75% of serum samples from women with a history of pregnancy complicated by a neural-tube defect, as compared with 10% of controls. We sought to confirm this finding in an Irish population, which traditionally has had a high prevalence of neural-tube defects. METHODS: We performed two studies. Study 1 consisted of analysis of stored frozen blood samples collected from 1993 through 1994 from 103 mothers with a history of pregnancy complicated by a neural-tube defect (case mothers), 103 mothers with a history of pregnancy but no complication by a neural-tube defect (matched with regard to number of pregnancies and sampling dates), 58 women who had never been pregnant, and 36 men. Study 2, conducted to confirm that the storage of samples did not influence the folate-receptor autoantibodies, included fresh samples from 37 case mothers, 22 control mothers, 10 women who had never been pregnant, and 9 men. All samples were assayed for blocking and binding autoantibodies against folate receptors. RESULTS: In Study 1, blocking autoantibodies were found in 17% of case mothers, as compared with 13% of control mothers (odds ratio, 1.54; 95% confidence interval [CI], 0.70 to 3.39), and binding autoantibodies in 29%, as compared with 32%, respectively (odds ratio, 0.82; 95% CI, 0.44 to 1.50). Study 2 showed similar results, indicating that sample degradation was unlikely. CONCLUSIONS: The presence and titer of maternal folate-receptor autoantibodies were not significantly associated with a neural-tube defect-affected pregnancy in this Irish population.

  10. Folate, Vitamin B12, and Homocysteine as Risk Factors for Cognitive Decline in the Elderly

    OpenAIRE

    Kim, Jae-Min; Kim, Sung-Wan; Shin, Il-Seon; Yang, Su-Jin; Park, Woo-Young; Kim, Sung-Jin; Shin, Hee-Young; Yoon, Jin-Sang

    2008-01-01

    Objective Cross-sectional studies have shown that the dysregulation of one-carbon metabolism is associated with cognitive impairment. However, the findings of longitudinal studies investigating this association have been inconsistent. This study investigated the prospective associations between cognitive decline and the levels of folate, vitamin B12 and homocysteine both at baseline and over course of the study period. Methods A total of 607 (83%) elderly individuals were selected from a grou...

  11. Intergenotypic variation of Vitamin B12 and Folate in AD: In north Indian population

    OpenAIRE

    Neelam Chhillar; Neeraj Kumar Singh; Basu Dev Banerjee; Kiran Bala; Mitra Basu; Deepika Sharma

    2014-01-01

    Objectives: Changes in lifestyle habits such as diet modification or supplementation have been indicated as probable protective factors for a number of chronic conditions including Alzheimer's disease (AD). With this background, we aim to hypothesize that whether C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene contributes towards the risk of developing AD and its association with vitamin B12 and folate levels. Materials and Methods: A case-control study comprising of to...

  12. Modeling and optimization of degree of folate grafted on chitosan and carboxymethyl-chitosan

    OpenAIRE

    Esfandiarpour-Boroujeni, S.; Bagheri-Khoulenjani, S.; Mirzadeh, H.

    2015-01-01

    Chitosan is a cationic polysaccharide with great properties and so is considered as an attractive biopolymer. However, chitosan shows its antibacterial activity only in acidic environment and this restricts its uses. So water-soluble chitosan derivatives such as carboxymethyl chitosan could be good candidates for such biomedical applications. Modified chitosan with hydrophobic functional groups such as folate (FA) is able to make self-assembled nanoparticles in aqueous media. One of the most ...

  13. Polymorphisms in folate pathway genes are not associated with somatic nondisjunction in turner syndrome.

    Science.gov (United States)

    Bispo, Adriana Valéria Sales; dos Santos, Luana Oliveira; de Barros, Juliana Vieira; Duarte, Andrea Rezende; Araújo, Jacqueline; Muniz, Maria Tereza Cartaxo; Santos, Neide

    2015-07-01

    Folate metabolism dysfunction can lead to DNA hypomethylation and abnormal chromosomal segregation. Previous investigations of this association have produced controversial results. Here we performed a case-control study in patients with Turner syndrome (TS) to determine the effects of genetic polymorphisms of folate pathway genes as potential risk factors for somatic chromosomal nondisjunction. TS is a useful model for this investigation because patients with TS show a high frequency of chromosome mosaicism. Here we investigated the possible association of polymorphisms of the MTHFR gene with TS risk, which has been previously investigated with controversial results. We also examined the effects of MTR, RFC1, and TYMS gene polymorphisms in TS for the first time. The risk was evaluated according to allelic and genotype (independent and combined) frequencies among 70 patients with TS and 144 age-matched healthy control subjects. Polymorphism genotyping was performed by PCR, PCR-RFLP, and PCR-ASA. The polymorphisms MTHFR 677C>T and 1298A>C, MTR 2756A>G, RFC1 80G>A, and TYMS 2R/3R-alone or in combinations-were not associated with the risk of chromosomal aneuploidy in TS. In conclusion, our present findings did not support a link between impaired folate metabolism and abnormal chromosome segregation leading to somatic nondisjunction in TS patients. PMID:25858821

  14. Synthesis and evaluation of boron folates for Boron-Neutron-Capture-Therapy (BNCT)

    Energy Technology Data Exchange (ETDEWEB)

    Kettenbach, Kathrin; Schieferstein, Hanno; Grunewald, Catrin; Hampel, Gabriele; Schuetz, Christian L. [Mainz Univ. (Germany). Inst. of Nuclear Chemistry; Iffland, Dorothee; Bings, Nicolas H. [Mainz Univ. (Germany). Inst. of Inorganic Chemistry and Analytical Chemistry; Reffert, Laura M. [Hannover Medical School (Germany). Radiopharmaceutical Chemistry; Ross, Tobias L. [Mainz Univ. (Germany). Inst. of Nuclear Chemistry; Hannover Medical School (Germany). Radiopharmaceutical Chemistry

    2015-07-01

    Boron neutron capture therapy (BNCT) employs {sup 10}B-pharmaceuticals administered for the treatment of malignancies, and subsequently irradiated with thermal neutrons. So far, clinical established pharmaceuticals like boron phenylalanine (BPA) or sodium boron mercaptate (BSH) use imperfect (BPA) or passive (BSH) targeting for accumulation at target sites. Due to the need of a selective transportation of boron drugs into cancer cells and sparing healthy tissues, we combined the BNCT approach with the specific and effective folate receptor (FR) targeting concept. The FR is overexpressed on many human carcinomas and provides a selective and specific target for molecular imaging as well as for tumor therapy. We synthesized and characterized a carborane-folate as well as a BSH-folate to study their in vitro characteristics and their potential as new boron-carriers for BNCT. Uptake studies were carried out using human KB cells showing a significant increase of the boron content in cells and demonstrating the successful combination of active FR-targeting and BNCT.

  15. The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation.

    Science.gov (United States)

    Gustafsson Sheppard, Nina; Jarl, Lisa; Mahadessian, Diana; Strittmatter, Laura; Schmidt, Angelika; Madhusudan, Nikhil; Tegnér, Jesper; Lundberg, Emma K; Asplund, Anna; Jain, Mohit; Nilsson, Roland

    2015-01-01

    Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism.

  16. Folate-Based Radiotracers for PET Imaging—Update and Perspectives

    Directory of Open Access Journals (Sweden)

    Cristina Müller

    2013-04-01

    Full Text Available The folate receptor (FR is expressed in many tumor types, among those ovarian and lung cancer. Due to the high FR affinity of folic acid, it has been used for targeting of FR-positive tumors, allowing specific delivery of attached probes to the malignant tissue. Therefore, nuclear imaging of FR-positive cancer is of clinical interest for selecting patients who could benefit from innovative therapy concepts based on FR-targeting. Positron emission computed tomography (PET has become an established technique in clinical routine because it provides an increased spatial resolution and higher sensitivity compared to single photon emission computed tomography (SPECT. Therefore, it is of critical importance to develop folate radiotracers suitable for PET imaging. This review article updates on the design, preparation and pre-clinical investigation of folate derivatives for radiolabeling with radioisotopes for PET. Among those the most relevant radionuclides so far are fluorine-18 (t1/2: 110 min, Eavβ+: 250 keV and gallium-68 (t1/2: 68 min, Eav β+: 830 keV. Recent results obtained with new PET isotopes such as terbium-152 (t1/2: 17.5 h, Eβ+: 470 keV or scandium-44 (t1/2: 3.97 h, Eav β+: 632 keV are also presented and discussed. Current endeavors for clinical implementation of PET agents open new perspectives for identification of FR-positive malignancies in patients.

  17. Properties of Folate Binding Protein Purified from Cow’s Milk

    Directory of Open Access Journals (Sweden)

    SUBANDRATE

    2012-09-01

    Full Text Available Folic acid played an important role in the metabolism of the body. To measure the serum folic acid levels could use the folate binding protein (FBP from cow’s milk with a technique analogous to ELISA. The aims of this study were to identify characteristics of FBP from cow’s milk and binding capacity of FBP to folic acid and to purify FBP from other whey protein passed through DEAE-cellulose chromatography column. Each of DEAE-cellulose peaks was passed in affinity chromatography column. FBP was released from affinity column with sodium acetate buffer pH 3.5. The purity of obtained FBP was demonstrated by a single spot in SDS-PAGE analysis and the estimated molecular weight of FBP was around 31 kDa. Our study indicated that 1 mol FBP bound 1 mol folic acid. Alkylation with iodoacetic acid decreased the binding capacity of FBP which suggested the presence of a–SH or imidazol group in its active site. The importance of disulfide bridge was proven by decreasing of folate binding capacity of FBP after -mercaptoethanol treatment. In contrary, the folate binding didn need Ca2+ ion, as indicated by EDTA test which gave the same result as control.

  18. PENYULUHAN DAN PEMBERIAN TABLET ASAM FOLAT BAGI IBU-IBU USIA REPRODUKTIF DI DESA ABIANSEMAL, BADUNG

    Directory of Open Access Journals (Sweden)

    DESAK MADE WIHANDANI

    2012-09-01

    Full Text Available ABSTRACT Folat deficiency that happened during early period of pregnancy, has known as one of the factor that cause fetal abnormalities. That why it is important for pregnant women to get information about the rule of folic acid in preventing fetal abnormalities. From 93 women within reproductive age, 6 of them were pregnant. Pregnant women were given 30 tablets of 0,4 mg folic acid taken once a day, and the less 87 women who were not in pregnant state received 10 tablets of folic acid to be taken once a day. PENYULUHAN DAN PEMBERIAN TABLET ASAM FOLAT BAGI IBU-IBU USIA REPRODUKTIF DI DESA ABIANSEMAL, BADUNG DESAK MADE WIHANDANI, NYOMAN AGUS BAGIADA DAN WAYAN SURUDARMA Bagian Biokimia Fakultas Kedokteran Universitas Udayana ABSTRACT Folat deficiency that happened during early period of pregnancy, has known as one of the factor that cause fetal abnormalities. That why it is important for pregnant women to get information about the rule of folic acid in preventing fetal abnormalities. From 93 women within reproductive age, 6 of them were pregnant. Pregnant women were given 30 tablets of 0,4 mg folic acid taken once a day, and the less 87 women who were not in pregnant state received 10 tablets of folic acid to be taken once a day.

  19. [Synthesis and bioactivity of the folate receptor targeted gamma-cyclodextrin-folate inclusion-coated CdSe/ZnS quantum dots].

    Science.gov (United States)

    Zhao, Mei-Xia; Li, Yang; Wang, Chao-Jie

    2013-04-01

    The gamma-cyclodextrin-folate (gamma-CD/FA) inclusion-coated CdSe/ZnS quantum dots (QDs) with folate-receptor (FR) targeted were synthesized by simple and convenient sonochemical method. The products were studied using Fourier transform infrared (FTIR), proton nuclear magnetic resonance (1H NMR), utraviolet-visible spectrometry (UV-vis), fluorescence spectrum and transmission electron micrographs (TEM). The results showed that the gamma-CD/FA-coated CdSe/ZnS QDs not only have good monodispersity and smaller size, but also have good optical performance, such as higher quantum yield (QY) and a long fluorescence lifetime. The cytotoxicity experiments showed that the gamma-CD/FA-coated CdSe/ZnS QDs have lower cytotoxicity and could more effectively enter cancer cells with FR over-expression. The QDs with 4-5 nm in diameter were relatively easy to enter the cell and to be removed through kidneys, so it is more suitable for biomedical applications for bioprobes and bioimaging. PMID:23833947

  20. The alpha channeling effect

    Energy Technology Data Exchange (ETDEWEB)

    Fisch, N. J.

    2015-12-10

    Alpha particles born through fusion reactions in a tokamak reactor tend to slow down on electrons, but that could take up to hundreds of milliseconds. Before that happens, the energy in these alpha particles can destabilize on collisionless timescales toroidal Alfven modes and other waves, in a way deleterious to energy confinement. However, it has been speculated that this energy might be instead be channeled into useful energy, so as to heat fuel ions or to drive current. Such a channeling needs to be catalyzed by waves Waves can produce diffusion in energy of the alpha particles in a way that is strictly coupled to diffusion in space. If these diffusion paths in energy-position space point from high energy in the center to low energy on the periphery, then alpha particles will be cooled while forced to the periphery. The energy from the alpha particles is absorbed by the wave. The amplified wave can then heat ions or drive current. This process or paradigm for extracting alpha particle energy collisionlessly has been called alpha channeling. While the effect is speculative, the upside potential for economical fusion is immense. The paradigm also operates more generally in other contexts of magnetically confined plasma.

  1. Iron, zinc, folate and vitamin B12 nutritional status and milk composition of low-income Brazilian mothers.

    Science.gov (United States)

    Donangelo, C M; Trugo, N M; Koury, J C; Barreto Silva, M I; Freitas, L A; Feldheim, W; Barth, C

    1989-04-01

    The purpose of this study was to assess the nutritional status of low-income Brazilian mothers, who were supplemented with iron and vitamin B12 during pregnancy, in terms of iron, zinc, folate and vitamin B12, in different stages of lactation and to determine the influence of the maternal nutritional status on milk composition. The effect of folate supplementation during pregnancy on folate status of the nursing mothers and milk composition was investigated. The effect of partial weaning on maternal status and milk composition was also studied. In general, the nutritional status of iron, zinc, folate and vitamin B12 of the mothers appears adequate. However, some of the mothers had indices of status lower than normal limits for non-pregnant women. These values, particularly after 30 d post-partum, indicate that these mothers might be at nutritional risk and that the nutrient supplementation received during pregnancy was insufficient to meet demands. There was an increase with the stage of lactation for haematocrit, serum vitamin B12, serum zinc, serum albumin, milk folate and saturation of its binding protein, but there was a decrease for milk protein, total and whey-bound iron and zinc, and lactoferrin. Mothers who took folate supplements during pregnancy had higher serum folate levels immediately after birth than those not taking the supplements but no differences were found at later stages of lactation. Milk composition was not affected. Partial weaning did not affect the maternal nutritional status or the milk composition except for iron which was higher in milk from mothers who were partially breastfeeding.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2661218

  2. SERUM METHYLMALONIC ACID DAN HOMOCYSTEIN DALAM MENDIAGNOSIS ANEMIA MEGALOBLASTIK AKIBAT DEFISIENSI KOBALAMIN DAN FOLAT PADA TRAVEL MEDICINE

    Directory of Open Access Journals (Sweden)

    Made Gian Indra Rahayuda

    2014-09-01

    Full Text Available Anemia adalah salah satu masalah kesehatan global yang utama, terutama pada negara-negara berkembang.Anemia adalah kondisi dimana massa sel darah merah dan/atau massa hemoglobin yang beredar dalam tubuh menurun hingga dibawah kadar normal sehingga tidak dapat berfungsi dengan baik dalam menyediakan oksigen untuk jaringan tubuh. Salah satu jenis yang banyak ditemukan adalah anemia megaloblastik.Anemia megaloblastik paling banyak disebabkan oleh kekurangan vitamin B12(kobalamin dan folat.Salah satu penyebab anemia defisiensi kobalamin dan folat adalah tropical sprue.Anemia defisiensi kobalamin dan asam folat memberikan gambaran yang serupa namun pada defisiensi kobalamin terdapat gejala neuropati.Batas normal serum folat antara 3-15 ng/mL.Folat eritrosit batas normalnya dari 150 – 600 ng/mL.Pada defisiensi kobalamin, serum kobalamin menurun di bawah cut off point100pg/mL (normalnya 100- 400pg/mL.Pemeriksaan lain seperti homocystein, methylmalonic acid, atau formioglutamic acid(FIGLU yang meningkat pada urin dapat memastikan diagnosis defisiensi kobalamindan asam folat. Belum ada konsensus mengenai cut off point Homocystein dan MMA. Homocysteine telah dianggap meningkat bila kadarnya di atas 12-14 µmol/L pada wanita dan di atas 14-15 µmol/L. Menurut penelitian yang dilakukan Robert et al pada kasus defisiensi kobalamin, kadar serum tHcy> 15.0 µmol/L.Kebanyakan penelitian menganggap peningkatan MMA pada defisiensi kobalamin adalah >0.28 µmol/L, tapi cut off point yang beredar bervariasi antara 0.21-0.48 µmol/L.Kadar MMA meningkat dalam serumdan urin pada defisiensi kobalamin, sedangkan pada defisiensi folat MMA normal.

  3. IRON, VITAMIN B12 AND FOLATE DEFICIENCY IN ADOLESCENTS HAVING NUTRITIONAL ANAEMIA

    Directory of Open Access Journals (Sweden)

    Rajendra

    2014-09-01

    Full Text Available BACKGROUND: Adolescence is the formative period of life when the maximum amount of physical, psychological and behavioral changes takes place and this is a vulnerable period in the human life cycle for the development of nutritional anaemia, which has been constantly neglected by public health programs. The prevalence of anaemia is disproportionately high in developing countries than developed countries. It has mainly been ascribed to poverty, inadequate diet, certain diseases, pregnancy and lactation, and poor access to health services in developing countries Prevalence of anaemia in adolescents in India have been reported in limited studies available from 16.25% to 96.5%. Nutritional anaemia constitutes the most important cause of anaemia in adolescents. It is mainly due to deficiency of Iron, Vitamin B12 and Folate. Megaloblastic Anaemia resulting from deficiency of folate and B12 appears to be increasing over the last two decades. AIMS AND OBJECTIVES: 1.To study the types of nutritional anemia in adolescents (10-18 yrs. attending the hospital and correlate severity of nutritional anemia with serum levels of ferritin, Vit B12 & folate. 2. And also to determine demographic, socio-economic & nutritional factors for nutritional anemia in adolescents. STUDY DESIGN: A cross sectional study was conducted in selected sample of 200 subjects. SETTINGS: The study was conducted in the Department of General Medicine, Azeezia Medical College; during November 2011 to April 2013, as a cross-sectional observational study. MATERIALS AND METHODS: Subjects were selected based on the inclusion criteria set and evaluated with aid of laboratory investigation of blood samples collected from subjects. RESULTS AND CONCLUSION: Present study was undertaken to find out etiology and socio-demographic correlates of nutritional anaemia in adolescents. And it was found out that Folate deficiency was the most common followed by Vitamin B12 deficiency & then irons deficiency

  4. Investigation of 177Lu-folate based radionuclide tumor therapy in combination with pemetrexed

    International Nuclear Information System (INIS)

    Full text of publication follows. Aim: The antifolate pemetrexed (PMX) was shown to improve the tissue distribution profile of radio-folates by reducing undesired renal accumulation without affecting uptake in the tumor. We hypothesized that PMX would have a dual role in combination with therapeutic radio-folates as it may protect kidneys from radio-nephrotoxicity and contribute to the anticancer effect as a chemotherapeutic and/or radiosensitizing agent. Therefore, the aim of the study was to investigate the combined application of 177Lu-folate and PMX in vitro an in vivo. Material and Methods: The DOTA-folate conjugate (EC0800, Endocyte Inc.) was labeled with 177Lu at high specific activity. In vitro the effects of 177Lu-EC0800 alone and in combination with PMX was tested with FR-positive KB tumor cells using MTT and clonogenic assays. In vivo, undesired effects of 177Lu-EC0800 (20 MBq/mouse) with/without co-application of PMX were investigated in non-tumor bearing mice over six months. Kidney function was monitored by the determination of renal accumulation of 99mTc-DMSA using SPECT. Therapy studies in KB tumor-bearing mice were performed with 177Lu-EC0800 (20 MBq) combined with subtherapeutic (0.4 mg) and therapeutic amounts (1.6 mg) of PMX. Results: Determination of the combination index revealed a synergistic inhibitory effect of 177Lu-EC0800 and PMX on the viability of both FR-positive cancer cell lines in vitro (CI < 0.8). In vivo application of 20 MBq 177Lu-EC0800 impaired kidney function 6 months as demonstrated by a significantly reduced renal uptake of 99mTc-DMSA and elevated plasma levels of blood urea nitrogen. Pre-injection of subtherapeutic amounts of PMX (0.4 mg) protected kidneys effectively as demonstrated by parameters which were in the same range as those of untreated control animals. Therapy studies revealed a 3-fold more pronounced anticancer effect and 25% increased survival if 177Lu-EC0800 was combined with therapeutic amounts of PMX

  5. Effects of coriaria lactone-activated, astrocyte-conditioned medium on estrogen receptor and progesterone receptor expression in rat cortical and hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Jie Rong; Shuhua Zhang

    2009-01-01

    ; seizures reached grade Ⅲ at 45 minutes; rat behavior was nearly normal at 2 hours.CONCLUSION: Activated astrocytes can induce seizures in the rat by enhancing estrogen receptor expression and decreasing progesterone receptor expression in cerebral cortical and hippocampal neurons.

  6. Local versus nonlocal $\\alpha\\alpha$ interactions in $3\\alpha$ description of $^{12}$C

    CERN Document Server

    Suzuki, Y; Descouvemont, P; Fujiwara, Y; Matsumura, H; Orabi, M; Theeten, M

    2008-01-01

    Local $\\alpha \\alpha$ potentials fail to describe $^{12}$C as a $3\\alpha$ system. Nonlocal $\\alpha \\alpha$ potentials that renormalize the energy-dependent kernel of the resonating group method allow interpreting simultaneously the ground state and $0^+_2$ resonance of $^{12}$C as $3\\alpha$ states. A comparison with fully microscopic calculations provides a measure of the importance of three-cluster exchanges in those states.

  7. 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

    Energy Technology Data Exchange (ETDEWEB)

    Lasry, Inbal; Berman, Bluma [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel); Glaser, Fabian [Bioinformatics Knowledge Unit, The Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion, Haifa 32000 (Israel); Jansen, Gerrit [Department of Rheumatology, VU University Medical Center, Amsterdam (Netherlands); Assaraf, Yehuda G., E-mail: assaraf@tx.technion.ac.il [The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa 32000 (Israel)

    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.

  8. Bremsstrahlung in $\\alpha$ Decay

    CERN Document Server

    Takigawa, N; Hagino, K; Ono, A; Brink, D M

    1999-01-01

    A quantum mechanical analysis of the bremsstrahlung in $\\alpha$ decay of $^{210}$Po is performed in close reference to a semiclassical theory. We clarify the contribution from the tunneling, mixed, outside barrier regions and from the wall of the inner potential well to the final spectral distribution, and discuss their interplay. We also comment on the validity of semiclassical calculations, and the possibility to eliminate the ambiguity in the nuclear potential between the alpha particle and daughter nucleus using the bremsstrahlung spectrum.

  9. ALPHA-2: the sequel

    CERN Multimedia

    Katarina Anthony

    2012-01-01

    While many experiments are methodically planning for intense works over the long shutdown, there is one experiment that is already working at full steam: ALPHA-2. Its final components arrived last month and will completely replace the previous ALPHA set-up. Unlike its predecessor, this next generation experiment has been specifically designed to measure the properties of antimatter.   The ALPHA team lower the new superconducting solenoid magnet into place. The ALPHA collaboration is working at full speed to complete the ALPHA-2 set-up for mid-November – this will give them a few weeks of running before the AD shutdown on 17 December. “We really want to get some experience with this device this year so that, if we need to make any changes, we will have time during the long shutdown in which to make them,” says Jeffrey Hangst, ALPHA spokesperson. “Rather than starting the 2014 run in the commissioning stage, we will be up and running from the get go.&...

  10. Folate-decorated chitosan/doxorubicin poly(butyl)cyanoacrylate nanoparticles for tumor-targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Duan Jinghua [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Liu Mujun [Central South University, School of Biological Science and Technology (China); Zhang Yangde; Zhao Jinfeng; Pan Yifeng [Xiangya Hospital, Central South University, Hepatobiliary and Enteric Surgery Research Center (China); Yang Xiyun, E-mail: bax_2007@126.com [Central South University, School of Metallurgical Science and Engineering (China)

    2012-03-15

    A novel chitosan coated poly(butyl cyanoacrylate) (PBCA) nanoparticles loaded doxorubicin (DOX) were synthesized and then conjugated with folic acid to produce a folate-targeted drug carrier for tumor-specific drug delivery. Prepared nanoparticles were surface modified by folate for targeting cancer cells, which is confirmed by FTIR spectroscopy and characterized for shape, size, and zeta potential measurements. The size and zeta potential of prepared DOX-PBCA nanoparticles (DOX-PBCA NPs) were almost 174 {+-} 8.23 nm and +23.14 {+-} 4.25 mV, respectively with 46.8 {+-} 3.32% encapsulation capacity. The transmission electron microscopy study revealed that preparation allowed the formation of spherical nanometric and homogeneous. Fluorescent microscopy imaging and flow cytometry analysis revealed that DOX-PBCA NPs were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells. The results demonstrate that folate-conjugated DOX-PBCA NPs drug delivery system could provide increased therapeutic benefit by delivering the encapsulated drug to the folate receptor positive cancer cells.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  13. A folate-rich diet is as effective as folic acid from supplements in decreasing plasma homocysteine concentrations.

    Science.gov (United States)

    Pintó, Xavier; Vilaseca, M Antonia; Balcells, Susana; Artuch, Rafael; Corbella, Emili; Meco, José F; Vila, Ramon; Pujol, Ramon; Grinberg, Daniel

    2005-01-01

    Background & Aims: At least 500 mug of folic acid are required daily to treat hyperhomocysteinemia. To reach this amount by dietary changes alone may be difficult because food has a low folic acid content and bioavailability. No studies have compared the effects of similar amounts of additional folate derived from a combination of folate-rich and fortified foods or folic acid from supplements on plasma total homocysteine (tHcy) concentrations, which was the aim of this study. Methods: Twenty male patients with hyperhomocysteinemia and coronary artery disease were included in a randomized, crossover intervention trial. Patients were treated daily with a combination of foods containing approximately 500 mug of folate or with one 500 mug capsule of synthetic folic acid over two five-week periods separated by a five-week wash-out period. Results: Plasma folate increased markedly (pfoods decreased tHcy by 8.6% (95% CI: -15.9 to -1.2) and synthetic folic acid capsules by 8% (95% CI: -13.3 to -2.7). Conclusions: This study shows, for the first time in the literature, that a folate-rich diet is as effective as folic acid capsules in decreasing plasma tHcy concentrations and adds further support to the recommendation of those diets to prevent cardiovascular disease.

  14. Endocytosis Pathways of the Folate Tethered Star-Shaped PEG-PCL Micelles in Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Yu-Lun Li

    2014-03-01

    Full Text Available This study reports on the cellular uptake of folate tethered micelles using a branched skeleton of poly(ethylene glycol and poly(ε-caprolactone. The chemical structures of the copolymers were characterized by proton nuclear magnetic resonance spectroscopy, and Fourier transform infrared spectroscopy. Doxorubicin (DOX was utilized as an anticancer drug. The highest drug loading efficiencies of DOX in the folate decorated micelle (DMCF and folate-free micelle (DMC were found to be 88.5% and 88.2%, respectively, depending on the segment length of the poly(ε-caprolactone in the copolymers. A comparison of fluorescent microscopic images of the endocytosis pathway in two cell lines, human breast cancer cells (MCF-7 and human oral cavity carcinoma cells (KB, revealed that the micelles were engulfed by KB and MCF-7 cells following in vitro incubation for one hour. Flow cytometric analysis revealed that free folic acid can inhibit the uptake of DOX by 48%–57% and 26%–39% in KB cells and MCF-7 cells, respectively. These results prove that KB cells are relatively sensitive to folate-tethered micelles. Upon administering methyl-β-cyclodextrin, an inhibitor of the caveolae-mediated endocytosis pathway, the uptake of DOX by KB cells was reduced by 69% and that by MCF-7 cells was reduced by 56%. This finding suggests that DMCF enters cells via multiple pathways, thus implying that the folate receptor is not the only target of tumor therapeutics.

  15. Predictors of folate status among pregnant Japanese women: the Hokkaido Study on Environment and Children's Health, 2002-2012.

    Science.gov (United States)

    Yila, Thamar A; Araki, Atsuko; Sasaki, Seiko; Miyashita, Chihiro; Itoh, Kumiko; Ikeno, Tamiko; Yoshioka, Eiji; Kobayashi, Sumitaka; Goudarzi, Houman; Baba, Toshiaki; Braimoh, Titilola; Minakami, Hisanori; Endo, Toshiaki; Sengoku, Kazuo; Kishi, Reiko

    2016-06-01

    The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1·48; 95 % CI 1·32, 1·66), lower educational level (AOR 1·27; 95 % CI 1·17, 1·39) and lower annual income (AOR 1·11; 95 % CI 1·01, 1·22). Plasma cotinine concentrations of 1·19-65·21 nmol/l increased the risk of low folate status (AOR 1·20; 95 % CI 1·10, 1·31) and concentrations >65·21 nmol/l further increased the risk (AOR 1·91; 95 % CI 1·70, 2·14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0·19; 95 % CI 0·17, 0·22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women. PMID:27121118

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

    Directory of Open Access Journals (Sweden)

    Matthew P.G. Barnett

    2015-05-01

    Full Text Available 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.

  17. Plasma Homocysteine, Vitamin B12 and Folate Levels in Multiple System Atrophy: A Case-Control Study.

    Directory of Open Access Journals (Sweden)

    Shuyu Zhang

    Full Text Available Multiple system atrophy (MSA is a neurodegenerative disease, and its pathological hallmark is the accumulation of α-synuclein proteins. Homocysteine (Hcy is an intermediate amino acid generated during the metabolism of methionine. Hcy may contribute to the pathogenesis of neurodegenerative disorders. Vitamin B12 and folate are cofactors necessary for the methylation of homocysteine.This study compared the levels of serum Hcy, vitamin B12 and folate in patients with MSA with those in healthy people to reveal the possible association between MSA and plasma levels of Hcy, vitamin B12 and folate. We enrolled 161 patients with MSA and 161 healthy people in this study. The association between MSA and the levels of Hcy, vitamin B12 and folate were analyzed using binary logistic regression.The mean level of Hcy in patients with MSA was significantly higher than that in healthy controls (16.23 ± 8.09 umol/l vs 14.04 ± 4.25 umol/l, p < 0.05. After adjusting for age, sex and medical history, the odds ratio for Hcy was 1.07 (95% CI = 1.01-1.13, p < 0.05 for patients with MSA. Vitamin B12 and folate levels were not significantly different between patients with MSA and controls.Our data suggest that higher levels of Hcy may be associated with an increased risk for MSA.

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

    Science.gov (United States)

    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. PMID:27406144

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

    Science.gov (United States)

    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 (Hbvitamin 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 vitamin B12 deficiency defined as 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. PMID:26481660

  20. Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport.

    Science.gov (United States)

    Zhang, Gui-Bin; Wang, Hua; Hu, Jun; Guo, Min-Yin; Wang, Ying; Zhou, Yan; Yu, Zhen; Fu, Lin; Chen, Yuan-Hua; Xu, De-Xiang

    2016-09-01

    Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl2 (2.5 or 5.0mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl2 on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl2. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl2 on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl2 on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. PMID:27417525

  1. Organ-Specific Gene Expression Changes in the Fetal Liver and Placenta in Response to Maternal Folate Depletion

    Science.gov (United States)

    McKay, Jill A.; Xie, Long; Adriaens, Michiel; Evelo, Chris T.; Ford, Dianne; Mathers, John C.

    2016-01-01

    Growing evidence supports the hypothesis that the in utero environment can have profound implications for fetal development and later life offspring health. Current theory suggests conditions experienced in utero prepare, or “programme”, the fetus for its anticipated post-natal environment. The mechanisms responsible for these programming events are poorly understood but are likely to involve gene expression changes. Folate is essential for normal fetal development and inadequate maternal folate supply during pregnancy has long term adverse effects for offspring. We tested the hypothesis that folate depletion during pregnancy alters offspring programming through altered gene expression. Female C57BL/6J mice were fed diets containing 2 mg or 0.4 mg folic acid/kg for 4 weeks before mating and throughout pregnancy. At 17.5 day gestation, genome-wide gene expression was measured in male fetal livers and placentas. In the fetal liver, 989 genes were expressed differentially (555 up-regulated, 434 down-regulated) in response to maternal folate depletion, with 460 genes expressed differentially (250 up-regulated, 255 down-regulated) in the placenta. Only 25 differentially expressed genes were common between organs. Maternal folate intake during pregnancy influences fetal gene expression in a highly organ specific manner which may reflect organ-specific functions. PMID:27782079

  2. “Warming yang and invigorating qi” acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Science.gov (United States)

    Huang, Hai-peng; Pan, Hong; Wang, Hong-feng

    2016-01-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. “Warming yang and invigorating qi” acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following “warming yang and invigorating qi” acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that “warming yang and invigorating qi” acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis. PMID:27127487

  3. "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis.

    Science.gov (United States)

    Huang, Hai-Peng; Pan, Hong; Wang, Hong-Feng

    2016-03-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10), Zusanli (ST36), Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis. PMID:27127487

  4. TiO2 nanoparticle-induced neurotoxicity may be involved in dysfunction of glutamate metabolism and its receptor expression in mice.

    Science.gov (United States)

    Ze, Xiao; Su, Mingyu; Zhao, Xiaoyang; Jiang, Hao; Hong, Jie; Yu, Xiaohong; Liu, Dong; Xu, Bingqing; Sheng, Lei; Zhou, Qiuping; Zhou, Junling; Cui, Jingwen; Li, Kai; Wang, Ling; Ze, Yuguan; Hong, Fashui

    2016-06-01

    Titanium dioxide nanoparticles (TiO2 NPs) have been used in environmental management, food, medicine, and industry. But TiO2 NPs have been demonstrated to cross the blood-brain barrier and store up in the brain organization, leading to glutamate-mediated neurotoxicity. However, the neurotoxicity in the brain is not well understood. In this study, mice were exposed to 1.25, 2.5, or 5 mg/kg body weight TiO2 NPs for 9 months, and the glutamate-glutamine cyclic pathway and expressions of glutamate receptors associated with the hippocampal neurotoxicity were investigated. Our findings showed elevations of glutamate release and phosphate-activated glutaminase activity, and reductions in glutamine and glutamine synthetase in the hippocampus following exposure to TiO2 NPs. Furthermore, TiO2 NPs significantly inhibited the expression of N-methyl-d-aspartate receptor subunits (including NR1, NR2A, and NR2B) and metabotropic glutamate receptor 2 in mouse hippocampus. These findings suggest that the imbalance of glutamate metabolism triggered inhibitions of glutamate receptor expression in the TiO2 NP-exposed hippocampus. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 655-662, 2016. PMID:25411160

  5. Effect of Increased Cyclic AMP Concentration on Muscle Protein Synthesis and Beta-Adrenergic Receptor Expression in Chicken Skeletal Muscle Cells in Culture

    Science.gov (United States)

    Young, R. B.; Vaughn, J. R.; Bridge, K. Y.; Smith, C. K.

    1998-01-01

    Analogies of epinephrine are known to cause hypertrophy of skeletal muscle when fed to animals. These compounds presumably exert their physiological action through interaction with the P-adrenergic receptor. Since the intracellular signal generated by the Beta-adrenergic receptor is cyclic AMP (cAMP), experiments were initiated in cell culture to determine if artificial elevation of cAMP by treatment with forskolin would alter muscle protein metabolism and P-adrenergic receptor expression. Chicken skeletal muscle cells after 7 days in culture were treated with 0.2-30 micrometers forskolin for a total of three days. At the end of the treatment period, both the concentration of cAMP and the quantity of myosin heavy chain (MHC) were measured. Concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. In contrast, the quantity of MHC was increased approximately 50% above control cells at 0.2 micrometers forskolin, but exhibited a gradual decline at higher levels of forskolin so that the quantity of MHC in cells treated with 30 micrometers forskolin was not significantly different from controls. Curiously, the intracellular concentration of cAMP which elicited the maximum increase in the quantity of MHC was only 40% higher than cAMP concentration in control cells.

  6. Cinnamomum camphora Seed Kernel Oil Improves Lipid Metabolism and Enhances β3-Adrenergic Receptor Expression in Diet-Induced Obese Rats.

    Science.gov (United States)

    Fu, Jing; Zeng, Cheng; Zeng, Zheling; Wang, Baogui; Wen, Xuefang; Yu, Ping; Gong, Deming

    2016-06-01

    The effects of dietary Cinnamomum camphora seed kernel oil (CCSKO) containing medium-chain triacylglycerols on lipid metabolism and mRNA and protein expression of β-3 adrenergic receptor in adipose tissue were studied in diet-induced obese rats. High fat food-induced obese rats were randomly divided into CCSKO group, Lard group, Soybean oil (SOY) group and naturally restoring group (n = 10). Rats fed with low fat food were used as a normal control group. Significant decreases in body mass and abdominal fat mass/body mass after 12 weeks were found in CCSKO group as compared with Lard and SOY groups (p triglyceride, free fatty acid, fasting insulin and insulin resistance in the CCSKO group were decreased significantly, and noradrenaline level and insulin sensitivity index in the CCSKO group were significantly higher than other groups. Meanwhile liver TC and triglyceride levels in the CCSKO group were also decreased markedly. Expression levels of β3-adrenergic receptor mRNA and protein were higher in CCSKO group than in Lard and SOY groups. These results suggest that CCSKO may contribute to reduction of the body fat mass, promote lipid metabolism and up-regulate β3-adrenergic receptor expression in high fat diet-induced obese rats. PMID:27068065

  7. “Warmingyang and invigoratingqi” acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Institute of Scientific and Technical Information of China (English)

    Hai-peng Huang; Hong Pan; Hong-feng Wang

    2016-01-01

    Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. “Warmingyang and invigoratingqi” acupuncture treatment has been shown to reduce serum inlfammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental au-toimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following “warmingyang and invigoratingqi” acupuncture therapy. Needles were inserted at acupressure pointsShou-sanli (LI10),Zusanli(ST36),Pishu (BL20), and Shenshu (BL23) once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was signiifcantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These ifndings suggest that “warmingyangand invigoratingqi” acu-puncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.

  8. "Warming yang and invigorating qi" acupuncture alters acetylcholine receptor expression in the neuromuscular junction of rats with experimental autoimmune myasthenia gravis

    Directory of Open Access Journals (Sweden)

    Hai-peng Huang

    2016-01-01

    Full Text Available Myasthenia gravis is an autoimmune disorder in which antibodies have been shown to form against the nicotinic acetylcholine nicotinic postsynaptic receptors located at the neuromuscular junction. "Warming yang and invigorating qi" acupuncture treatment has been shown to reduce serum inflammatory cytokine expression and increase transforming growth factor beta expression in rats with experimental autoimmune myasthenia gravis. However, few studies have addressed the effects of this type of acupuncture on the acetylcholine receptors at the neuromuscular junction. Here, we used confocal laser scanning microscopy to examine the area and density of immunoreactivity for an antibody to the nicotinic acetylcholine receptor at the neuromuscular junction in the phrenic nerve of rats with experimental autoimmune myasthenia gravis following "warming yang and invigorating qi" acupuncture therapy. Needles were inserted at acupressure points Shousanli (LI10, Zusanli (ST36, Pishu (BL20, and Shenshu (BL23 once daily for 7 consecutive days. The treatment was repeated after 1 day of rest. We found that area and the integrated optical density of the immunoreactivity for the acetylcholine receptor at the neuromuscular junction of the phrenic nerve was significantly increased following acupuncture treatment. This outcome of the acupuncture therapy was similar to that of the cholinesterase inhibitor pyridostigmine bromide. These findings suggest that "warming yang and invigorating qi" acupuncture treatment increases acetylcholine receptor expression at the neuromuscular junction in a rat model of autoimmune myasthenia gravis.

  9. Application of Near-Infrared and Fourier Transform Infrared Spectroscopy in the Characterization of Ligand-Induced Conformation Changes in Folate Binding Protein Purified from Bovine Milk

    DEFF Research Database (Denmark)

    Bruun, Susanne Wrang; Holm, Jan; Hansen, Steen Ingemann;

    2006-01-01

    Fourier transform infrared (FT-IR) and near-infrared (NIR) spectroscopy have been applied to detect structural alterations in folate binding protein (FBP) induced by ligation in different buffer types. The amide I region pointed to a beta-sheet to alpha-helix transition upon ligation in acetate...... and phosphate buffers, and the formation of intermolecular beta-sheet was indicated at pH 5.0, in agreement with a dimerization of FBP taking place at this pH. The ligand-induced changes in the 2100-2300 nm NIR region were significant for FBP in acetate and phosphate buffers of pH 5.0, and the variations were...... indicated similar changes at the two pH values. Therefore, we suggest that FT-IR and NIR spectroscopy may complement each other, such that the two techniques in combination may give information on all three types of protein conformational changes. While the secondary structure changes are revealed by FT-IR...

  10. Isostructural folate conjugates radiolabeled with the matched pair 99mTc/188Re: a potential strategy for diagnosis and therapy of folate receptor-positive tumors

    International Nuclear Information System (INIS)

    99mTc-technetium (99mTc) and 188Re-rhenium (188Re) represent an interesting pair of radionuclides for diagnosis and therapy. The aim of this study was to synthesize and characterize in vitro/in vivo the first 188Re-folate derivative [188Re(CO)3-picolylamine monoacetic acid 188Re-PAMA-folate (2)] for potential targeted radionuclide therapy of FR-positive tumors. The data were compared with those of the isostructural 99mTc-analog [99mTc-PAMA folate (1)] reported previously. Methods: In vitro stability of compound was tested in phosphate-buffered saline and human plasma. Cell binding experiments were performed with FR-positive human KB cells. Biodistribution was assessed in female nude mice, bearing KB tumor xenografts. Results: Cell binding experiments showed high and FR-specific uptake. In vivo, compound accumulated specifically in the FR-positive tumors with maximal values 4 h post injection (p.i.) [: 1.87±0.04 percent injected dose per gram of weight tissue (% ID/g) vs. : 2.33±0.36% ID/g]. Unfavorably high retention of radioactivity was found in FR-positive kidneys (12.04±0.62% ID/g; 4 h p.i.). Tumor-to-blood ratio of radioactivity (: 14.5±1.32, 4 h p.i.) was lower than for compound (58.0±12.2, 4 h p.i.), whereas tumor-to-kidney ratios were in the same range (: 0.15±0.01 vs. : 0.13±0.02, 4 h p.i.). Preadministration of the antifolate pemetrexed significantly improved the tumor-to-kidney ratio (: 1.59±0.30, 4 h p.i.). Conclusions: The isostructural radiofolates and displayed almost identical pharmacokinetic profiles and accumulated both specifically in FR-positive tumors. However, only the coapplication of the antifolate pemetrexed improved the biodistribution of the radiotracers in such ways that a potential therapeutic application of compound can be envisaged in the future

  11. Resting alpha activity predicts learning ability in alpha neurofeedback

    OpenAIRE

    Wenya eNan; Feng eWan; Mang I eVai; Agostinho eRosa

    2014-01-01

    Individuals differ in their ability to learn how to regulate the alpha activity by neurofeedback. This study aimed to investigate whether the resting alpha activity is related to the learning ability of alpha enhancement in neurofeedback and could be used as a predictor. A total of 25 subjects performed 20 sessions of individualized alpha neurofeedback in order to learn how to enhance activity in the alpha frequency band. The learning ability was assessed by three indices respectively: the tr...

  12. Alpha particles in fusion research

    International Nuclear Information System (INIS)

    This collection of 39 (mostly view graph) presentations addresses various aspects of alpha particle physics in thermonuclear fusion research, including energy balance and alpha particle losses, transport, the influence of alpha particles on plasma stability, helium ash, the transition to and sustainment of a burning fusion plasma, as well as alpha particle diagnostics. Refs, figs and tabs

  13. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk : a meta-analysis of genetic studies and randomised trials

    NARCIS (Netherlands)

    Holmes, Michael V.; Newcombe, Paul; Hubacek, Jaroslav A.; Sofat, Reecha; Ricketts, Sally L.; Cooper, Jackie; Breteler, Monique M. B.; Bautista, Leonelo E.; Sharma, Pankaj; Whittaker, John C.; Smeeth, Liam; Fowkes, F. Gerald R.; Algra, Ale; Shmeleva, Veronika; Szolnoki, Zoltan; Roest, Mark; Linnebank, Michael; Zacho, Jeppe; Nalls, Michael A.; Singleton, Andrew B.; Ferrucci, Luigi; Hardy, John; Worrall, Bradford B.; Rich, Stephen S.; Matarin, Mar; Norman, Paul E.; Flicker, Leon; Almeida, Osvaldo P.; van Bockxmeer, Frank M.; Shimokata, Hiroshi; Khaw, Kay-Tee; Wareham, Nicholas J.; Bobak, Martin; Sterne, Jonathan A. C.; Smith, George Davey; Talmud, Philippa J.; van Duijn, Cornelia; Humphries, Steve E.; Price, Jackie F.; Ebrahim, Shah; Lawlor, Debbie A.; Hankey, Graeme J.; Meschia, James F.; Sandhu, Manjinder S.; Hingorani, Aroon D.; Casas, Juan P.

    2011-01-01

    Background The MTHFR 677C -> T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-st

  14. Folate/Folic Acid Knowledge, Intake, and Self-Efficacy of College-Aged Women: Impact of Text Messaging and Availability of a Folic Acid-Containing Supplement

    Science.gov (United States)

    Rampersaud, Gail C.; Sokolow, Andrew; Gruspe, Abigail; Colee, James C.; Kauwell, Gail P. A.

    2016-01-01

    Objective: To evaluate the impact of educational text messages (TMs) on folate/folic acid knowledge and consumption among college-aged women, and to evaluate the impact of providing folic acid supplements on folate/folic acid intake among college-aged women. Participants: A total of 162 women (18-24 years) recruited from a university. Methods: The…

  15. Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition study.

    NARCIS (Netherlands)

    Johansson, M.; Appleby, P.N.; Allen, N.E.; Travis, R.C.; Roddam, A.W.; Egevad, L.; Jenab, M.; Rinaldi, S.; Kiemeney, L.A.L.M.; Bueno-De-Mesquita, H.B.; Vollset, S.E.; Ueland, P.M.; Sanchez, M.J.; Quiros, J.R.; Gonzalez, C.A.; Larranaga, N.; Chirlaque, M.D.; Ardanaz, E.; Sieri, S.; Palli, D.; Vineis, P.; Tumino, R.; Linseisen, J.; Kaaks, R.; Boeing, H.; Pischon, T.; Psaltopoulou, T.; Trichopoulou, A.; Trichopoulos, D.; Khaw, K.T.; Bingham, S.; Hallmans, G.; Riboli, E.; Stattin, P.; Key, T.J.

    2008-01-01

    BACKGROUND: Determinants of one-carbon metabolism, such as folate and vitamin B(12), have been implicated in cancer development. Previous studies have not provided conclusive evidence for the importance of circulating concentrations of folate and vitamin B(12) in prostate cancer etiology. The aim of

  16. Folate depletion in human lymphocytes up-regulates p53 expression despite marked induction of strand breaks in exons 5 – 8 of the gene

    Science.gov (United States)

    Low dietary folate intake is associated with an elevated risk for carcinogenesis. One putative mechanism by which folate depletion promotes carcinogenesis is by inducing gene-specific strand breakage and impaired expression of affected genes. Primary human lymphocytes were cultured in media containi...

  17. The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma

    Directory of Open Access Journals (Sweden)

    Erculj Nina

    2014-09-01

    Full Text Available Background. We evaluated the influence of folate pathway polymorphisms on high-dose methotrexate (HD-MTX related toxicity in paediatric patients with T-cell non-Hodgkin lymphoma (NHL. Patients and methods. In total, 30 NHL patients were genotyped for selected folate pathway polymorphisms.

  18. Synthesis and preliminary evaluation of novel 99mTc-labeled folate derivative via click reaction for SPECT imaging

    International Nuclear Information System (INIS)

    The folate receptor is over expressed in a wide variety of human tumors. In this study, a novel 99mTc-labeled folate derivative (99mTc-HYNIC-T-FA) was synthesized as a potential FR-targeting imaging probe and its efficiency was evaluated. This 99mTc-complex could be obtained through practical manner and showed improved in vivo characteristics compared with other radiofolates. Thus, this novel 99mTc-HYNIC-T-FA compound could serve as a potential imaging agent for folate receptor positive tumors. - Highlights: • An efficient synthetic strategy (click chemistry) was used to improve the overall efficiency. • 99mTc-HYNIC-T-FA showed a high tumor uptake but low no-target tissues uptakes. • Excellent tumor-to-kidney ratio was achieved by injecting PMX. • A kit formulation was developed to obtain the desired product without any purification

  19. Homocysteine, Cobalamin and Folate Status and their Relations to Neurocognitive and Psychological Markers in Elderly in Northeastern of Iran

    Directory of Open Access Journals (Sweden)

    Lida Manavifar

    2013-06-01

    Full Text Available       Objective(s: Incidence of neurocognitive and psychological disorders may be related to serum homocystein (Hcy, cobalamin (vitamin B12 and folate levels in old people. The aim of this study was to assess the relation between Hcy, cobalamin, folate and neurocognitive and/or psychological disorders in the elderly.   Materials and Methods: In this cross-sectional study, 280 subjects with ≥ 65 years old, were evaluated. The subjects were selected from 12 regions of Mashhad, Iran, over March to October 2009. After blood sampling, data were collected by questionnaire, face to face interview and performing neurocognitive and psychological tests. The sera of 250 persons were analyzed for cobalamin and folate by RIA method. Amongst the aforementioned samples, 78 cases with cobalamin Results: Amongst the people, 126 (45% were male and 154 (55% were female. The prevalence of hyperhomocysteinemia (HHcy was 59.5% and 37.1% in male and female respectively (P -value =0.049. Hcy inversely correlated to cobalamin (r=-0.282, P=0.014 and to folate (r=-0.203, P=0.014. Hcy, cobalamin and folate correlations to neurocognitive and psychological impairments were not statically significant. Conclusion: Hyper Hcy or low cobalamin and folate in the elderly, are prevalent but their relationships with neurocognitive and psychological impairments is controversial. If these relationships had been confirmed, performing a single serum Hcy or cobalamin test would have been enough to diagnose and prevent neurocognitive impairments and inversely, neurocognitive-psychological sign and symptoms could have meant probable tissue vitamin deficiencies. However methods of assessing neurocognitive and psychological markers with validity and reliability of clinical and laboratory tests for finding aforementioned relationships should be revised.  

  20. Conjugating folate on superparamagnetic Fe{sub 3}O{sub 4}@Au nanoparticles using click chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Xiaofang, E-mail: xfshen@jiangnan.edu.cn; Ge, Zhaoqiang; Pang, Yuehong

    2015-02-15

    Gold-coated magnetic core@shell nanoparticles, which exhibit magneto-optical properties, not only enhance the chemical stability of core and biocompatibility of surface, but also provide a combination of multimodal imaging and therapeutics. The conjugation of these tiny nanoparticles with specific biomolecules allows researchers to target the desired location. In this paper, superparamagnetic Fe{sub 3}O{sub 4}@Au nanoparticles were synthesized and functionalized with the azide group on the surface by formation of self-assembled monolayers. Folate (FA) molecules, non-immunogenic target ligands for cancer cells, are conjugated with alkyne and then immobilized on the azide-terminated Fe{sub 3}O{sub 4}@Au nanoparticles through copper(I)-catalyzed azide-alkyne cycloaddition (click reaction). Myelogenous leukemia K562 cells were used as a folate receptor (FR) model, which can be targeted and extracted by magnetic field after interaction with the Fe{sub 3}O{sub 4}@Au–FA nanoparticles. - Graphical abstract: Self-assembled azide-terminated group on superparamagnetic Fe{sub 3}O{sub 4}@Au nanoparticles followed by click reaction with alkyne-functionalized folate, allowing the nanoparticles target folate receptor of cancer cells. - Highlights: • Azidoundecanethiol was coated on the superparamagnetic Fe{sub 3}O{sub 4}@Au nanoparticles by forming self-assembled monolayers. • Alkyne-terminated folate was synthesized from a reaction between the amine and the carboxylic acid. • Conjugation of Fe{sub 3}O{sub 4}@Au nanoparticles with folate was made by copper-catalyzed azide-alkyne cycloaddition click chemistry.