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Sample records for cell rbc folate

  1. 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.

  2. Response of red blood cell folate to supplementation in non-pregnant women is predictable

    DEFF Research Database (Denmark)

    Obeid, Rima; Schön, Christiane; Wilhelm, Manfred

    2017-01-01

    SCOPE: We modelled red blood cell (RBC)-folate response to supplementation and developed personalized folate supplementation concepts. METHODS AND RESULTS: The changes of RBC-folate were modelled in a time- (4 or 8 weeks) and dose- (400 μg/d or 800 μg/d folate) dependent manner. Post-supplementat...... in women when baseline RBC-folate concentrations are measured and the time to pregnancy between 4-8 weeks. This article is protected by copyright. All rights reserved....

  3. Do serum and red blood cell folate levels indicate iron response in hemodialysis patients?

    Science.gov (United States)

    Mitsopoulos, Efstathios; Zanos, Stavros; Ginikopoulou, Eudoxia; Tsiatsiou, Maria; Giannakou, Anastasia; Pavlitou, Aikaterini; Sakellariou, Georgios

    2006-01-01

    The relationship among iron status, ferritin, and folate levels, and the possible contribution of folate measurement in the prediction of iron response in hemodialysis patients, have not been assessed. In addition to serum ferritin and transferrin saturation (TSAT), serum and red blood cell (RBC) folate levels were evaluated as indices for intravenous iron therapy responsiveness in 60 hemodialysis patients. Patients were classified as iron responders or nonresponders depending on whether they exhibited a rise in hemoglobin above 1 g/dl after administration of 1 g of iron sucrose. An inverse relation between serum ferritin concentration and RBC folate levels was found in iron responders (n=26, r=-0.62, p<0.001) but not in nonresponders (n=34, r=0.07, p=nonsignificant). Only serum and RBC folate levels could predict iron response in patients with ferritin levels above 150 microg/l (n=25), with a sensitivity of 83.3% and a specificity of 94.7%. Our findings suggest that RBC folate concentration is inversely related with ferritin levels in iron-responsive but not in non-responsive hemodialysis patients. Serum and RBC folate concentration seems to predict response to iron administration better than serum ferritin or TSAT in patients with ferritin levels above 150 microg/l; therefore, in these patients, it might be used to guide iron management.

  4. Extremely high concentration of folates in premature newborns.

    Science.gov (United States)

    Zikavska, T; Brucknerova, I

    2014-01-01

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

  5. The oldest old: red blood cell and plasma folate in African American and white octogenarians and centenarians in Georgia.

    Science.gov (United States)

    Hausman, D B; Johnson, M A; Davey, A; Woodard, J L; Poon, L W; Allen, R H; Stabler, S P

    2011-11-01

    To determine the overall folate status of a population-based multi-ethnic sample of octogenarians and centenarians and the specific dietary, demographic and physiological factors associated with observed abnormalities. Population-based multiethnic sample of adults aged 80 to 89 and 98 and above. Northern Georgia, USA. Men and women aged 80 to 89 (octogenarians, n = 77) and 98 and older (centenarians, n = 199). Wilcoxon rank sum tests, and Chi square and logistic regression analyses were used to examine associations of low and high folate status with hematological indicators and other variables of interest. The prevalence of low red blood cell (RBC) folate was low overall, but tended to be higher in centenarians than in octogenarians (6.5% vs. 1.3%, p = 0.058; defined as RBC folate 25th percentile for RBC folate for 60yr+ in NHANES 1999-2000) was greater in association with vitamin B12 deficiency (OR = 5.36; 95%CI: 2.87-10.01), African American race (OR = 4.29; 95%CI: 2.08-8.83), and residence in a skilled nursing facility (OR = 3.25; 95%CI: 1.56-6.78) but was not influenced by age, gender, B-vitamin supplement use, high/low food score or presence of atrophic gastritis. Combined high plasma folate and low vitamin B12 status was present in some individuals (n=11), but was not associated with increased prevalence of anemia or cognitive impairment in this study. Low RBC folate status (< 317 nmol/L) was rare in this post folic acid fortification sample of octogenarians and centenarians. RBC folate status (< 25th percentile) was strongly associated with 1) vitamin B12 deficiency, which has strong implications for vitamin treatment, and 2) with being African American, suggesting racial disparities exist even in the oldest old.

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

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

    2008-07-25

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

  7. Hubungan Antara Red Blood Cell Count (Rbc) Dan Retinopati Diabetik Pada Pasien Diabetes Melitus Tipe 2

    OpenAIRE

    Irmayani

    2016-01-01

    Background: Diabetic retinopathy is main complications of diabetes. Some studies suggest a relation between red blood cell count (RBC) and diabetic retinopathy. Diabetic retinopathy is diagnosed with funduscopic examination, while red blood cell count can be seen from the peripheral blood examination, with the result is a relation of a decreased red blood cell count with diabetic retinopathy. Objective: To determine the relation between RBC count and diabetic retinopathy in diabetic type...

  8. 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.

  9. Tc-99m Labeled Red Blood Cell by Ultra Tag RBC Kit in Patients Suspected of Gastrointestinal Bleeding

    International Nuclear Information System (INIS)

    Pusuwan, Pawana; Leaungwutiwong, Suraphong; Tocharoenchai, Chiraporn; Chaiwatanarat, Tawatchai; Sirisatipoch, Sasitorn; Rajadara, Samart; Naktong, Thanyada; Thanyarak, Sucheera

    2001-06-01

    Twenty patients suspected of gastrointestinal bleeding who underwent Tc-99m labeled red blood cell (RBC) by ultraTag RBC kit at Division of Nuclear Medicine, Bumrungrad Hospital between January 2000 and December 2002 were studied. The histories of patients together with either endoscopic results or angiographic findings or pathological reports were used as gold standards. Two by Two decision matrix was used for data analysis and the sensitivity together with specificity were calculated. The results show that the sensitivity and specificity of Tc-99m labeled RBC by ultraTag RBC kit are 87.5% and 91.7%, respectively. We conclude that Tc-99m labeled RBC by ultraTag RBC kit gives high percentages of sensitivity and specificity. Moreover, the image quality is improved because of the absence of free Tc-99m pertechnetate uptake in the stomach in all patients

  10. rBC2LCN, a new probe for live cell imaging of human pluripotent stem cells.

    Science.gov (United States)

    Onuma, Yasuko; Tateno, Hiroaki; Hirabayashi, Jun; Ito, Yuzuru; Asashima, Makoto

    2013-02-15

    Cell surface biomarkers have been applied to discriminate pluripotent human embryonic stem cells and induced pluripotent stem cells from differentiated cells. Here, we demonstrate that a recombinant lectin probe, rBC2LCN, a new tool for fluorescence-based imaging and flow cytometry analysis of pluripotent stem cells, is an alternative to conventional pluripotent maker antibodies. Live or fixed colonies of both human embryonic stem cells and induced pluripotent stem cells were visualized in culture medium containing fluorescent dye-labeled rBC2LCN. Fluorescent dye-labeled rBC2LCN was also successfully used to separate live pluripotent stem cells from a mixed cell population by flow cytometry. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Should pre-transfusion screening RBC panels contain Wr(a+) cells?

    Science.gov (United States)

    Coluzzi, S; De Nicolò, M C; Quattrocchi, L; Neri, A; Ferruzzi, I; Girelli, G

    2010-10-01

    Sometimes commercial RBC sets for the screening of irregular antibodies contain Wr(a+) cells. The aim of this study was to define the usefulness of employing RBC sets for the screening of irregular antibodies containing Wr(a+) cells in pre-transfusion tests. Anti-Wr(a) is a relatively common naturally occurring antibody in candidates to blood transfusion, although the risk of receiving a non-compatible unit is low. We have studied both the incidence of Wr(a) antibodies and the effects of having a Wr(a+) cell in the screening test on routine work in an unselected population of 787 patients requiring RBC transfusion and in 151 new blood donors. Irregular antibodies were found in 64 sera, 58 of which were specific for Wr(a) , 46 (5·8%) and 12 (7·9%) in patients and donors, respectively. The positive tested sera contained specific IgM in 16 cases, IgM + IgG in 13 cases and IgG in 27 cases. Anti-Wr(a) can usually be detected during cross-match procedures; therefore, the presence of Wr(a+) cells in pre-transfusion screening of blood recipients is not justified and it causes an undue increase in cost and time to unit release. Moreover, because of the rare association between anti-Wr(a) and haemolytic transfusion reaction, the use of Wr(a+) RBC-containing sets is also questionable in the countries that do not perform pre-transfusion cross-match tests. © 2010 The Authors. Transfusion Medicine © 2010 British Blood Transfusion Society.

  12. Folate supplementation in people with sickle cell disease.

    Science.gov (United States)

    Dixit, Ruchita; Nettem, Sowmya; Madan, Simerjit S; Soe, Htoo Htoo Kyaw; Abas, Adinegara Bl; Vance, Leah D; Stover, Patrick J

    2018-03-16

    Sickle cell disease (SCD) is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with SCD, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with SCD, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating SCD. To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with SCD. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 17 November 2017. Randomised, placebo-controlled trials of folate supplementation for SCD. Four review authors assessed We used the standard Cochrane-defined methodological procedures.Four review authors independently assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. The quality of the evidence was assessed using GRADE. One trial, undertaken in 1983, was eligible for inclusion in the review. This was

  13. Comparison of serum and red blood cell folate microbiologic assays for national population surveys.

    Science.gov (United States)

    Pfeiffer, Christine M; Zhang, Mindy; Lacher, David A; Molloy, Anne M; Tamura, Tsunenobu; Yetley, Elizabeth A; Picciano, Mary-Frances; Johnson, Clifford L

    2011-07-01

    Three laboratories participated with their laboratory-specific microbiologic growth assays (MA) in the NHANES 2007-2008 to assess whether the distributions of serum (n = 2645) and RBC folate (n = 2613) for the same one-third sample of participants were comparable among laboratories. Laboratory (L) 2 produced the highest and L1 the lowest serum and RBC folate geometric means (nmol/L) in the NHANES sample (serum: L1, 39.5; L2, 59.2; L3, 47.7; and RBC: L1, 1120; L2, 1380; L3, 1380). Each laboratory produced different reference intervals for the central 95% of the population. Pearson correlation coefficients were highest between L3 and L1 (serum, r = 0.95; RBC, r = 0.92) and lowest between L2 and L1 (serum, r = 0.81; RBC, r = 0.65). Notable procedural differences among the laboratories were the Lactobacillus rhamnosus microorganism (L1 and L3: chloramphenicol resistant, L2: wild type) and the calibrator [L1: [6S]5-methyltetrahydrofolate (5-methylTHF), L2: [6R,S] 5-formyltetrahydrofolate ([6R,S] 5-formylTHF), L3: folic acid (FA)]. Compared with 5-methylTHF as calibrator, the folate results were 22-32% higher with FA as calibrator and 8% higher with 5-formylTHF as calibrator, regardless of the matrix (n = 30 serum, n = 28 RBC). The use of different calibrators explained most of the differences in results between L3 and L1 but not between L2 and L1. The use of the wild-type L. rhamnosus by L2 appeared to be the main reason for the differences in results between L2 and the other 2 laboratories. These findings indicate how assay variations influence MA folate results and how those variations can affect population data. To ensure data comparability, better assay harmonization is needed.

  14. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells

    DEFF Research Database (Denmark)

    Baslund, B; Gregers, J; Nielsen, Claus Henrik

    2008-01-01

    To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.......To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells....

  15. Folate supplementation in people with sickle cell disease.

    Science.gov (United States)

    Dixit, Ruchita; Nettem, Sowmya; Madan, Simerjit S; Soe, Htoo Htoo Kyaw; Abas, Adinegara B L; Vance, Leah D; Stover, Patrick J

    2016-02-16

    Sickle cell disease is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with sickle cell disease, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with sickle cell disease, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating sickle cell disease. To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search: 07 December 2015. Randomised, placebo-controlled trials of folate supplementation for sickle cell disease. Four review authors assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. We used the standard Cochrane-defined methodological procedures. One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with sickle cell

  16. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2R, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults.

    Science.gov (United States)

    Using linear regression models, we studied the main and two-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma homocysteine normalized by red blood cell...

  17. Intake and blood concentrations of folate and their association with health-related behaviors in Korean college students

    OpenAIRE

    Jang, Han-Byul; Han, Young-Hee; Piyathilake, Chandrika J; Kim, Heon; Hyun, Taisun

    2013-01-01

    The purpose of this study is to assess folate intake, and serum and red blood cell (RBC) folate concentrations, and investigate the association between folate status and health-related behaviors among Korean college students. A total of 169 students, aged between 18 and 27 years, participated in this study. Dietary intake data were collected by trained interviewers using a 24-hour recall method for three non-consecutive days in 2009. Information on health-related behaviors was obtained by a s...

  18. Long-chain PUFA in Granulocytes, Mononuclear Cells, and RBC in Patients With Cystic Fibrosis: Relation to Liver Disease

    DEFF Research Database (Denmark)

    Jorgensen, Marianne H.; Ott, Peter; Michaelsen, Kim F.

    2012-01-01

    -related liver disease were matched with 20 CF patients without. Blood samples were analysed for liver biochemistry and haematology. Granulocytes, mononuclear cells, and RBC were separated by density gradient centrifugation, and fatty acid composition was measured by gas chromatography. Hepatic ultrasound......Background and Aim: Patients with cystic fibrosis (CF) have low levels of n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) in plasma or red blood cells (RBC), as also seen in other chronic and acute liver diseases. The differences may be more pronounced in CF transmembrane conductance...... of liver disease was negatively associated with LCPUFA n-3 levels in CFTR-expressing white blood cells but unrelated to those levels in CFTR-negative RBC....

  19. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging.

    Science.gov (United States)

    Ramos, Marisa I; Allen, Lindsay H; Mungas, Dan M; Jagust, William J; Haan, Mary N; Green, Ralph; Miller, Joshua W

    2005-12-01

    Low folate status is associated with poor cognitive function and dementia in the elderly. Since 1998, grain products in the United States have been fortified with folic acid, which has reduced the prevalence of folate deficiency and hyperhomocysteinemia. We investigated whether folate status is associated with cognitive function and dementia in a cohort of elderly Latinos (aged >or= 60 y; n = 1789) exposed to folic acid fortification. Global cognitive function was assessed by the Modified Mini-Mental State Examination (3MSE) and specific cognitive functions by cross-culturally validated neuropsychological tests. Dementia was diagnosed according to the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 3rd edition revised, and California Alzheimer Disease Diagnostic and Treatment criteria. Red blood cell (RBC) folate was measured by automated chemiluminescence and total plasma homocysteine by HPLC. The prevalence of folate deficiency (RBC folate cognitive impairment and dementia decreased with increasing RBC folate concentration. In contrast, adjusted odds ratios for low 3MSE score and dementia diagnosis per unit increase in homocysteine were not significant. RBC folate is directly associated with cognitive function scores and is inversely associated with dementia in elderly Latinos despite folic acid fortification.

  20. OpenRBC: Redefining the Frontier of Red Blood Cell Simulations at Protein Resolution

    Science.gov (United States)

    Tang, Yu-Hang; Lu, Lu; Li, He; Grinberg, Leopold; Sachdeva, Vipin; Evangelinos, Constantinos; Karniadakis, George

    We present a from-scratch development of OpenRBC, a coarse-grained molecular dynamics code, which is capable of performing an unprecedented in silico experiment - simulating an entire mammal red blood cell lipid bilayer and cytoskeleton modeled by 4 million mesoscopic particles - on a single shared memory node. To achieve this, we invented an adaptive spatial searching algorithm to accelerate the computation of short-range pairwise interactions in an extremely sparse 3D space. The algorithm is based on a Voronoi partitioning of the point cloud of coarse-grained particles, and is continuously updated over the course of the simulation. The algorithm enables the construction of a lattice-free cell list, i.e. the key spatial searching data structure in our code, in O (N) time and space space with cells whose position and shape adapts automatically to the local density and curvature. The code implements NUMA/NUCA-aware OpenMP parallelization and achieves perfect scaling with up to hundreds of hardware threads. The code outperforms a legacy solver by more than 8 times in time-to-solution and more than 20 times in problem size, thus providing a new venue for probing the cytomechanics of red blood cells. This work was supported by the Department of Energy (DOE) Collaboratory on Mathematics for Mesoscopic Model- ing of Materials (CM4). YHT acknowledges partial financial support from an IBM Ph.D. Scholarship Award.

  1. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients

    NARCIS (Netherlands)

    van der Dijs, FPL; Schnog, JJB; Brouwer, DAJ; Velvis, HJR; van den Berg, GA; Bakker, AJ; Duits, AJ; Muskiet, FD

    1998-01-01

    We investigated whether pediatric patients with sickle cell disease (SCD) (9 +/- 4 years; 27 homozygous SCD [HbSS]; 19 sickle-C disease [HbSC]) have different folate status compared with age-, sex-, and race-matched normal hemoglobin (HbAA) controls (n = 20), and whether their folate status can be

  2. Validity of the Food Frequency Questionnaire Assessing the Folate Intake in Women of Reproductive Age Living in a Country without Food Fortification: Application of the Method of Triads

    OpenAIRE

    Milica Zekovic; Marija Djekic-Ivankovic; Marina Nikolic; Mirjana Gurinovic; Dusanka Krajnovic; Marija Glibetic

    2017-01-01

    The study aimed to examine the external validity of the Folate Food Frequency Questionnaire (F-FFQ) designed for assessing the folate intake in Serbian women of reproductive age. The F-FFQ was tested against repeated 24 h dietary recalls and correspondent nutritional biomarkers (red blood cells (RBC) and serum folate concentrations) using the method of triads. In a cross sectional study, 503 women aged 18–49 years completed dietary questionnaires and representative validation subsample (n = 5...

  3. Targeting Gallium to Cancer Cells through the Folate Receptor

    Directory of Open Access Journals (Sweden)

    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.

  4. Targeting Gallium to Cancer Cells through the Folate Receptor

    Directory of Open Access Journals (Sweden)

    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.

  5. Folate and vitamin B12 status is associated with insulin resistance and metabolic syndrome in morbid obesity.

    Science.gov (United States)

    Li, Zhen; Gueant-Rodriguez, Rosa-Maria; Quilliot, Didier; Sirveaux, Marie-Aude; Meyre, David; Gueant, Jean-Louis; Brunaud, Laurent

    2017-07-24

    Low vitamin B12 and high folate during pregnancy are associated with visceral obesity and insulin resistance in offspring. In the general population, high folate exacerbates the increase of methylmalonic acid, a marker of vitamin B12 deficiency. However, the influence of vitamin B12 and folate and their related markers on insulin resistance and metabolic syndrome remains unknown in severe obesity. To evaluate the influence of vitamin B12 and folate on HOMA-IR and components of metabolic syndrome in severe obesity. 278 consecutive obese patients were assessed prospectively for HOMA-IR, red blood cell (RBC) folates, homocysteine and methylmalonic acid. We compared the associations with the components of metabolic syndrome during the preoperative multidisciplinary evaluation (period-1) and before bariatric surgery (period-2). The HOMA-IR was higher in patients with highest tertile of RBC and either lowest tertile of plasma B12 or highest tertile of MMA (p Nutrition and Metabolism. All rights reserved.

  6. Folate, homocysteine, and cobalamin status in patients with rheumatoid arthritis treated with methotrexate, and the effect of low dose folic acid supplement

    DEFF Research Database (Denmark)

    Hornung, Nete; Ellingsen, Torkell; Stengaard-Pedersen, Kristian

    2004-01-01

    -administered low dose folic acid; 38 patients were included prior to MTX therapy, 33 patients continued established MTX therapy, and 10 patients were excluded. Drug efficacy and side effects were monitored with biochemical and clinical indicators. RESULTS: MTX treatment resulted in decreased concentrations of red...... blood cell (RBC) folate and a rise in plasma homocysteine. Intracellular concentrations of MTX were inversely correlated to RBC folate levels after treatment for a longer period (mean 41 months). Supplement with low dose folic acid prevented or diminished the influence of MTX on folate status and had...

  7. 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...

  8. 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) ...

  9. Homologous RBC-derived vesicles as ultrasmall carriers of iron oxide for magnetic resonance imaging of stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Microsugar; Chien, Li-Ying; Yang, Chung-Shi; Huang, Dong-Ming [Center for Nanomedicine Research, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan (China); Hsiao, Jong-Kai; Liu, Hon-Man [Department of Medical Imaging, National Taiwan University, Taipei, Taiwan (China); Yao, Ming; Ko, Bor-Sheng; Chen, Yao-Chang [Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan (China); Hsu, Szu-Chun [Department of Laboratory Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan (China); Chen, Shin-Tai, E-mail: dmhuang@nhri.org.tw [Musculoskeletal Disease Center, J L Pettis VA Medical Center and Department of Biochemistry, Loma Linda University, Loma Linda, CA (United States)

    2010-06-11

    Ultrasmall superparamagnetic iron oxide (USPIO) particles are very useful for cellular magnetic resonance imaging (MRI), which plays a key role in developing successful stem cell therapies. However, their low intracellular labeling efficiency, and biosafety concerns associated with their use, have limited their potential usage. In this study we develop a novel system composed of RBC-derived vesicles (RDVs) for efficient delivery of USPIO particles into human bone marrow mesenchymal stem cells (MSCs) for cellular MRI in vitro and in vivo. RDVs are highly biosafe to their autologous MSCs as manifested by cell viability, differentiation, and gene microarray assays. The data demonstrate the potential of RDVs as intracellular delivery vehicles for biomedical applications.

  10. Homologous RBC-derived vesicles as ultrasmall carriers of iron oxide for magnetic resonance imaging of stem cells

    International Nuclear Information System (INIS)

    Chang, Microsugar; Chien, Li-Ying; Yang, Chung-Shi; Huang, Dong-Ming; Hsiao, Jong-Kai; Liu, Hon-Man; Yao, Ming; Ko, Bor-Sheng; Chen, Yao-Chang; Hsu, Szu-Chun; Chen, Shin-Tai

    2010-01-01

    Ultrasmall superparamagnetic iron oxide (USPIO) particles are very useful for cellular magnetic resonance imaging (MRI), which plays a key role in developing successful stem cell therapies. However, their low intracellular labeling efficiency, and biosafety concerns associated with their use, have limited their potential usage. In this study we develop a novel system composed of RBC-derived vesicles (RDVs) for efficient delivery of USPIO particles into human bone marrow mesenchymal stem cells (MSCs) for cellular MRI in vitro and in vivo. RDVs are highly biosafe to their autologous MSCs as manifested by cell viability, differentiation, and gene microarray assays. The data demonstrate the potential of RDVs as intracellular delivery vehicles for biomedical applications.

  11. Study Exploring the Effects of Daily Supplementation with 400 μg of Folic Acid on the Nutritional Status of Folate in Women of Reproductive Age.

    Science.gov (United States)

    Arias, Laidy D; Parra, Beatriz E; Muñoz, Angélica M; Cárdenas, Diana L; Duque, Tiffany G; Manjarrés, Luz M

    2017-05-01

    This investigation determines the nutritional state of serum and red blood cell (RBC) folate concentration and their relation with intake of folate, B 6 ,and B 12 , with serum vitamin B 12 , and with genetic variants after provision of 400 μg/day of folic acid for 3 months to a group of 34 Colombian women of reproductive age. We evaluated nutrient intake using 24-hr recall, assessing the levels of serum folate, RBC folate, serum B 12 , and homocysteine, as well as determining genetic variants of the enzyme MTHFR (C677T and A1298C) and CβS (844ins68pb). The results show that following intake of 400 μg/day of folic acid, the risk of folate deficiency as seen in regular dietary intake disappears and the nutritional status of this nutrient is increased (p supplementation also had decreased levels of serum homocysteine. Genetic factors did not influence the nutritional status of folate, although an association was found between the intake of nutrients and biochemical indicators. Given the results of our study, subsequent studies evaluating folic acid supplementation should also consider evaluating the status of B 12 and B 6 , and serum and RBC folate, as they participate interdependently in the cycle of folate and methionine and in homocysteine metabolism.Birth Defects Research 109:564-573, 2017.© 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  12. Folate, homocysteine and selected vitamins and minerals status in infertile women.

    Science.gov (United States)

    La Vecchia, Irene; Paffoni, Alessio; Castiglioni, Marta; Ferrari, Stefania; Bortolus, Renata; Ferraris Fusarini, Chiara; Bettinardi, Nora; Somigliana, Edgardo; Parazzini, Fabio

    2017-02-01

    Diet has been recognised as a crucial factor influencing fetal and maternal health. Adequate levels of substances such as homocysteine, folate and vitamin B 12 have been associated with a higher rate of success in infertility treatments. Few data, however, are available on the average levels of micronutrients in the blood of reproductive-aged women, and specific values for adequate levels are not available. The aim of this cross-sectional study was to measure levels of folate, homocysteine and selected vitamins and minerals in women attending the infertility unit of an academic hospital for in vitro fertilisation (IVF). Fasting venous blood samples were taken in the morning during routine screening before IVF in order to measure: serum folate, red blood cell (RBC) folate, total plasma homocysteine, vitamin B 12 , vitamin A, vitamin E, serum iron and serum ferritin. Among 269 women aged 37 ± 4 years, only 69% and 44% showed adequate levels of homocysteine and vitamin B 12 , respectively. Serum folate was appropriate in 78% of the study participants, but only a minority (12%) had a concentration of RBC folate regarded as optimal for the prevention of fetal neural tube defects. Serum levels of vitamin A, vitamin E, iron and ferritin were, however, appropriate in the vast majority of participants (>80%). Folate levels were largely inadequate among women attending an infertility clinic for IVF. Vitamin B 12 levels were also found to be inadequate.

  13. Folate: a functional food constituent.

    Science.gov (United States)

    Iyer, Ramya; Tomar, S K

    2009-01-01

    Folate, a water-soluble vitamin, includes naturally occurring food folate and synthetic folic acid in supplements and fortified foods. Mammalian cells cannot synthesize folate and its deficiency has been implicated in a wide variety of disorders. A number of reviews have dwelt up on the health benefits associated with increased folate intakes and many countries possess mandatory folate enrichment programs. Lately, a number of studies have shown that high intakes of folic acid, the chemically synthesized form, but not natural folates, can cause adverse effects in some individuals such as the masking of the hematological manifestations of vitamin B(12) deficiency, leukemia, arthritis, bowel cancer, and ectopic pregnancies. As fermented milk products are reported to contain even higher amounts of folate produced by the food-grade bacteria, primarily lactic acid bacteria (LAB), the focus has primarily shifted toward the natural folate, that is, folate produced by LAB and levels of folate present in foods fermented by/or containing these valuable microorganisms. The proper selection and use of folate-producing microorganisms is an interesting strategy to increase "natural" folate levels in foods. An attempt has been made through this review to share information available in the literature on wide ranging aspects of folate, namely, bioavailability, analysis, deficiency, dietary requirements, and health effects of synthetic and natural folate, dairy and nondairy products as a potential source of folate, microorganisms with special reference to Streptococcus thermophilus as prolific folate producer, and recent insight on modulation of folate production levels in LAB by metabolic engineering.

  14. A novel radioassay for the determination of folate in serum and red cells and new observations on the stability of serum folate

    International Nuclear Information System (INIS)

    Lynch, E.P.J.; Tovey, K.C.; Guilford, H.

    1977-01-01

    A Competitive Protein Binding assay for the determination of folate in serum and red cells has been developed. The assay has been fully validated in hospital trials and comparisons have been made with the microbiological assay. We have based the standardization of the radioassay on N 5 -methyltetrahydrofolate (N 5 -MTHF) as this is the predominant folate derivative in serum samples. At about pH 9.5 pteroylglutamic acid (PGA) and N 5 -MTHF demonstrate the same affinity for folate binding proteins. Therefore, many folate assays have adopted PGA largely because of the popular belief that N 5 -MTHF is highly unstable. However, we have demonstrated that N 5 -MTHF in serum standards is surprisingly stable at -20 0 C. All the reagents for the assay (including the N 5 -MTHF standards) have shown perfectly acceptable stability, permitting their storage for at least three weeks at -20 0 C and one week at 4 0 C. Evidence will be presented to support the use of N 5 -MTHF as being the more appropriate standard. Folate in human serum samples is stable even at room temperature in the presence of 0.1% sodium azide. (orig./AJ) [de

  15. Processing of equine bone marrow using the automated MarrowXpress System: RBC depletion, volume reduction, and mononuclear cell recovery.

    Science.gov (United States)

    Owens, Sean D; Burges, Julie; Johns, Jennifer L; Carrade, Danielle D; Galuppo, Larry D; Librach, Fred; Borjesson, Dori L

    2011-12-01

    The therapeutic use of bone marrow-derived mononuclear cells (MNCs) and mesenchymal stem cells for the treatment of soft tissue and orthopedic injuries in equine patients is expanding. After collection, bone marrow must be reduced in volume and depleted of RBCs for immediate therapeutic use or to prepare cells for culture or cryopreservation and storage. The MarrowXpress (MXP) System is an automated, closed, sterile system designed to process human bone marrow samples. The purpose of this study was to evaluate the capacity of the MXP System to process equine bone marrow to reduce volume, deplete RBCs, and enhance recovery of MNCs. Bone marrow was collected from 47 horses into 2 60-mL syringes containing heparin and processed using the MXP System. HCT, total nucleated cell (TNC) count, and MNC count were obtained for each sample before and after processing using an Advia 120 hematology analyzer. Volume reduction, RBC depletion, and recovery of TNCs and MNCs were calculated. For equine bone marrow samples, mean values were 73.2% for RBC depletion and 78.0% for volume reduction. TNC count before processing was 2.5 ± 1.2 × 10(7) and after processing was significantly higher at 7.8 ± 3.3 × 10(7) (P recovery of 68.5 ± 24.5% (mean ± SD). MNC count before processing was 1.1 ± 0.9 × 10(7) and after processing was significantly higher at 3.8 ± 1.9 × 10(7) (P recovery 73.0 ± 31.5%. The MXP System can reliably reduce volume and deplete RBCs from aspirates of equine bone marrow aspirates. MNCs can be recovered in a reproducible and sterile manner. Further studies evaluating the effects of the MXP System on cell viability, identification of mesenchymal stem cells (MSCs), and the efficacy of MSC expansion are warranted. © 2011 American Society for Veterinary Clinical Pathology.

  16. Nutritional role of folate.

    Science.gov (United States)

    Ebara, Shuhei

    2017-09-01

    Folate functions as a coenzyme to transfer one-carbon units that are necessary for deoxythymidylate synthesis, purine synthesis, and various methylation reactions. Ingested folate becomes a functional molecule through intestinal absorption, circulation, transport to cells, and various modifications to its structure. Associations between nutritional folate status and chronic diseases such as cardiovascular disease, cancer, and cognitive dysfunction have been reported. It has also been reported that maternal folate nutritional status is related to the risk of neural tube defects (NTDs) in the offspring. It has also been recommended that folate be consumed in the diet to promote the maintenance of good health. To reduce the risk of NTDs, supplementation with folic acid (a synthetic form of folate) during the periconceptional period has also been recommended. This paper describes the basic features and nutritional role of folate. © 2017 Japanese Teratology Society.

  17. RBC-NOS-Dependent S-Nitrosylation of Cytoskeletal Proteins Improves RBC Deformability

    Science.gov (United States)

    Grau, Marijke; Pauly, Sebastian; Ali, Jamal; Walpurgis, Katja; Thevis, Mario; Bloch, Wilhelm; Suhr, Frank

    2013-01-01

    Background Red blood cells (RBC) possess a nitric oxide synthase (RBC-NOS) whose activation depends on the PI3-kinase/Akt kinase pathway. RBC-NOS-produced NO exhibits important biological functions like maintaining RBC deformability. Until now, the cellular target structure for NO, to exert its influence on RBC deformability, remains unknown. In the present study we analyzed the modification of RBC-NOS activity by pharmacological treatments, the resulting influence on RBC deformability and provide first evidence for possible target proteins of RBC-NOS-produced NO in the RBC cytoskeletal scaffold. Methods/Findings Blood from fifteen male subjects was incubated with the NOS substrate L-arginine to directly stimulate enzyme activity. Direct inhibition of enzyme activity was induced by L-N5-(1-Iminoethyl)-ornithin (L-NIO). Indirect stimulation and inhibition of RBC-NOS were achieved by applying insulin and wortmannin, respectively, substances known to affect PI3-kinase/Akt kinase pathway. The NO donor sodium nitroprusside (SNP) and the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) were additionally applied as NO positive and negative controls, respectively. Immunohistochemical staining was used to determine phosphorylation and thus activation of RBC-NOS. As a marker for NO synthesis nitrite was measured in plasma and RBCs using chemiluminescence detection. S-nitrosylation of erythrocyte proteins was determined by biotin switch assay and modified proteins were identified using LC-MS. RBC deformability was determined by ektacytometry. The data reveal that activated RBC-NOS leads to increased NO production, S-nitrosylation of RBC proteins and RBC deformability, whereas RBC-NOS inhibition resulted in contrary effects. Conclusion/Significance This study first-time provides strong evidence that RBC-NOS-produced NO modifies RBC deformability through direct S-nitrosylation of cytoskeleton proteins, most likely α- and β-spectrins. Our

  18. Evaluation of red blood cell (RBC) labelling procedures in cardiovascular scintigraphy

    International Nuclear Information System (INIS)

    Hinkle, G.H.; Reid, R.D.; Shaffer, P.B.; Olsen, J.O.

    1984-01-01

    The clinical images obtained and the percentage of radioactivity associated with the red blood cells at the conclusion of this study provided a method of assessing four technique for preparing 99 mTc-labeled red blood cells for use in cardiovascular scintigraphy. The methods consisted of a totally in vivo preparation, and semi-in vitro and two different cell separation techniques. The semi-in vitro procedure provided the best clinical image with the highest ventricle to spleen and ventricle to lung ratios. Higher count rates in the left ventricle also led to shorter acquisition times and greater efficiency of ejection fraction calculations. A semi-in vitro method of labelling red-blood cells improves the nuclear medicine cardiovascular studies utilized for cardiac function determination

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

    Directory of Open Access Journals (Sweden)

    Michelle K Y Siu

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

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

    Science.gov (United States)

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

    2012-01-01

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

  1. Aleurone flour increases red-cell folate and lowers plasma homocyst(e)ine substantially in man.

    Science.gov (United States)

    Fenech, Michael; Noakes, Manny; Clifton, Peter; Topping, David

    2005-03-01

    Aleurone flour (ALF) is a rich source of natural folate (>500 microg/100 g wet weight). Our objective was to establish whether intake of ALF in man can significantly improve folate status and reduce plasma homocyst(e)ine. We performed a randomised, controlled intervention, of 16 weeks duration, in free-living healthy individuals (mean age 46-52 years). Participants were assigned to one of three groups: ALF, 175 g bread made with ALF and placebo tablet each day; PCS, 175 g bread made with pericarp seed coat (PCS) flour and placebo tablet each day (low-folate control); or FA, 175 g bread made with PCS flour and tablet containing 640 microg folic acid each day (high-folate control). The daily folate intake contributed by the bread and tablet was 233 microg in the PCS group, 615 microg in the ALF group and 819 microg in the FA group. The number of participants completing all phases of the PCS, ALF and FA interventions was twenty-five, twenty-five and eighteen, respectively. Plasma and red-cell folate increased significantly (Pine decreased significantly (Pine in the ALF group decreased from 9.1 (8.2, 10.0) micromol/l at baseline to 6.8 (6.2, 7.5) micromol/l after 16 weeks. In conclusion, moderate dietary intake of ALF can increase red-cell folate and decrease plasma homocyst(e)ine substantially.

  2. Folate-deficiency induced cell-specific changes in the distribution of lymphocytes and granulocytes in rats.

    Science.gov (United States)

    Abe, Ikumi; Shirato, Ken; Hashizume, Yoko; Mitsuhashi, Ryosuke; Kobayashi, Ayumu; Shiono, Chikako; Sato, Shogo; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko

    2013-01-01

    Folate (vitamin B(9)) plays key roles in cell growth and proliferation through regulating the synthesis and stabilization of DNA and RNA, and its deficiency leads to lymphocytopenia and granulocytopenia. However, precisely how folate deficiency affects the distribution of a variety of white blood cell subsets, including the minor population of basophils, and the cell specificity of the effects remain unclear. Therefore, we examined the effects of a folate-deficient diet on the circulating number of lymphocyte subsets [T-lymphocytes, B-lymphocytes, and natural killer (NK) cells] and granulocyte subsets (neutrophils, eosinophils, and basophils) in rats. Rats were divided into two groups, with one receiving the folate-deficient diet (FAD group) and the other a control diet (CON group). All rats were pair-fed for 8 weeks. Plasma folate level was dramatically lower in the FAD group than in the CON group, and the level of homocysteine in the plasma, a predictor of folate deficiency was significantly higher in the FAD group than in the CON group. The number of T-lymphocytes, B-lymphocytes, and NK cells was significantly lower in the FAD group than in the CON group by 0.73-, 0.49-, and 0.70-fold, respectively, indicating that B-lymphocytes are more sensitive to folate deficiency than the other lymphocyte subsets. As expected, the number of neutrophils and eosinophils was significantly lower in the FAD group than in the CON group. However, the number of basophils, the least common type of granulocyte, showed transiently an increasing tendency in the FAD group as compared with the CON group. These results suggest that folate deficiency induces lymphocytopenia and granulocytopenia in a cell-specific manner.

  3. Low maternal folate concentrations and maternal MTHFR C677T polymorphism are associated with an increased risk for neural tube defects in offspring: a case-control study among Pakistani case and control mothers.

    Science.gov (United States)

    Nauman, Nuzhat; Jalali, Samina; Shami, Sajjad; Rafiq, Shireen; Große, Greta; Hilger, Alina C; Zhang, Rhong; Mansoor, Saira; Ludwig, Michael; Reutter, Heiko

    2018-01-01

    There is considerable evidence that periconceptional maternal folate deficiency and coding variants in maternal genes coding for critical enzymes in the folate pathway are associated with neural tube defects (NTDs) in offspring. In a case-control study we investigated C677T polymorphism in the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene in case and control mothers of Pakistani origin, and compared these with the respective maternal folate concentrations measured at the time of delivery. A case-control study was conducted among 109 case and 100 control mothers identified through the Holy Family Hospital Rawalpindi, Quaid-i-Azam University, Islamabad, Pakistan. Red blood cell (RBC) and serum folate concentrations and MTHFRC677T polymorphism were compared between case and control mothers. Mean RBC folate and serum folate concentrations were significantly lower in cases compared with control mothers (pcases compared with control mothers (CC vs TT pcases compared with control mothers (C vs T pCase mothers with 677CT or 677TT genotypes had significantly lower serum (pstudy provides further evidence that maternal folate deficiency and MTHFRC677T polymorphism might be associated with an increased risk for NTDs in offspring. Our results are limited by the fact that maternal folate concentrations were not obtained during the periconceptional period, but at delivery. Further analyses, including maternal folate levels during the periconceptional period, are warranted.

  4. 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.

  5. 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...

  6. 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

  7. Atomic force microscopic study of folate receptors in live cells with functionalized tips

    Science.gov (United States)

    Girish, C. M.; Binulal, N. S.; Anitha, V. C.; Nair, Shantikumar; Mony, U.; Prasanth, R.

    2009-11-01

    Membrane associated folate receptors (FR) is gaining importance in cancer research. Understanding the FR density, distribution, and the strength of its interaction with ligands is crucial in cancer diagnostics and therapeutics. Here we reported the enhanced phase contrast image of FR by scanning with properly functionalized atomic force microscope (AFM) tips over live cell lines. The choice of the ligand was made for better interaction of tip with FR, expressed in the cell lines. The selectively enhanced force of interaction at the receptor molecule produced a considerable enhancement in the phase contrast between a receptor site and a nonreceptor site.

  8. Inhibition by methotrexate (MTX) polyglutamates (PGS) of folate-dependent biosyntheses in L1210 Leukemia cells

    International Nuclear Information System (INIS)

    Matherly, L.H.; Barlowe, C.K.; Goldman, I.D.

    1986-01-01

    The inhibition of folate-dependent pathways by MTX PGS was evaluated in folate-depleted L1210 cells incubated with (6S)5-formyl(CHO)tetrahydrofolate(FH 4 )(5μM). The accumulation of MTX PGS during exposure to MTX (10μM;3h) inhibited cell growth (>70%) under these conditions. In the presence of 5-CHO-FH 4 , carbon transfer from 14 C-formate or 3- 14 C-serine into purines, dTMP, and amino acids was suppressed following MTX-pretreatment, suggesting the formation of only low levels of FH 4 to drive these reactions. In cells treated with MTX (6S)5-CHO-[ 3 H]-FH 4 was metabolized predominantly to 10-CHO-[ 3 H]-FH 4 . While intracellular dihydrofolate (FH 2 ) increased 10-fold, indicating a block at FH 2 reductase by MTX PGS, FH 2 represented only 20% of the total metabolites of 5-CHO-FH 4 . The incorporation of 14 C from 5-[ 14 C]-CHO-FH 4 into serine and methionine was not affected by the presence of intracellular MTX PGS, however, carbon transfer into dTMP and purine nucleotides was reduced (50-60%). These findings demonstrate that MTX pretreatment inhibits de novo nucleotide and amino acid biosynthetic pathways even when high levels of reduced folates are present. The data suggest a suppression of dTMP synthase and the purine transformylase(s) by MTX and/or FH 2 PGS that accumulate in drug-treated cells. Inhibition of the purine biosynthetic steps appears to trap 10-CHO-FH 4 , limiting FH 4 for the synthesis of dTMP, serine, and methionine

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

    Science.gov (United States)

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

    2016-08-26

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

  10. Targeting of pegylated liposomal mitomycin-C prodrug to the folate receptor of cancer cells: Intracellular activation and enhanced cytotoxicity.

    Science.gov (United States)

    Patil, Yogita; Amitay, Yasmine; Ohana, Patricia; Shmeeda, Hilary; Gabizon, Alberto

    2016-03-10

    Mitomycin C (MMC) is a powerful anti-bacterial, anti-fungal and anti-tumor antibiotic, often active against multidrug resistant cells. Despite a broad spectrum of antitumor activity, MMC clinical use is relatively limited due to its fast clearance and dose-limiting toxicity. To exploit the potential antitumor activity of MMC and reduce its toxicity we have previously developed a formulation of pegylated liposomes with a lipophilic prodrug of MMC (PL-MLP), activated by endogenous reducing agents which are abundant in the tumor cell environment in the form of different thiols. PL-MLP has minimal in vitro cytotoxicity unless reducing agents are added to the cell culture to activate the prodrug. In the present study, we hypothesized that targeting PL-MLP via folate receptors will facilitate intracellular activation of prodrug and enhance cytotoxic activity without added reducing agents. We grafted a lipophilic folate conjugate (folate-PEG(5000)-DSPE) to formulate folate targeted liposomes (FT-PL-MLP) and examined in vitro cell uptake and cytotoxic activity in cancer cell lines with high folate receptors (HiFR). 3H-cholesterol-hexadecyl ether (3H-Chol)-radiolabeled liposomes were prepared to study liposome-cell binding in parallel to cellular uptake of prodrug MLP. 3H-Chol and MLP cell uptake levels were 4-fold and 9-fold greater in KB HiFR cells when FT-PL-MLP is compared to non-targeted PL-MLP liposomes. The cytotoxic activity of FT-PL-MLP liposomes was significantly increased up to ~5-fold compared with PL-MLP liposomes in all tested HiFR expressing cell lines. The enhanced uptake and intracytoplasmic liposome delivery was confirmed by confocal fluorescence studies with Rhodamine-labeled liposomes. In vivo, no significant differences in pharmacokinetics and biodistribution were observed when PL-MLP was compared to FT-PL-MLP by the intravenous route. However, when liposomes were directly injected into the peritoneal cavity of mice with malignant ascites of J6456 Hi

  11. Targeting Gallium to Cancer Cells through the Folate Receptor

    OpenAIRE

    Nerissa Viola-Villegas; Anthony Vortherms; Robert P. Doyle

    2008-01-01

    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’. Th...

  12. A study on the measurement of the nucleated red blood cell (nRBC count based on birth weight and its correlation with perinatal prognosis in infants with very low birth weights

    Directory of Open Access Journals (Sweden)

    Tae Hwan Kil

    2011-02-01

    Full Text Available Purpose : The aim of this study was conducted to investigate the mean nRBC count in very low births weight infants (VLBWIs and to determine the usefulness of the nRBC as an independent prognostic factors of perinatal complications in VLBWIs. Methods : This study was conducted on 112 VLBWIs who were hospitalized in the neonatal intensive care unit (NICU of the author's hospital within the period from March 2003 to and May 2008. Based on the infants’ nucleated red blood cells (nRBC counts at birth, on the third day after birth, on the seventh day after birth, in the second week after birth, and in the fourth week after birth in the medical records, the correlation between nRBC or absolute nRBC counts with birth weight, gestational age, and other perinatal outcomes were retrospectively investigated, Results : In VLBWIs, their mean nRBC and absolute nRBC counts were showing a gradual decrease after birth, and they were consisteantly kept at low values since one week after and inversely proportional to the birth weights. The mean nRBC counts based on the stage after birth showed a significant correlation with perinatal death, necrotizing enterocolitis, and severe intraventricular hemorrhage. Conclusion : The increase in the nRBC count showed a significant correlation with having a severe intraventricular hemorrhage, necrotizing enterocolitis, and perinatal death in VLBWIs. If an increase or no decrease in the nRBC count after birth is observed, newborninfant care precautions should be required.

  13. Non-covalent conjugates of single-walled carbon nanotubes and folic acid for interaction with cells overexpressing folate receptors

    DEFF Research Database (Denmark)

    Castillo, John J.; Rindzevicius, Tomas; Novoa, Leidy V.

    2013-01-01

    We here present amethod to form a noncovalent conjugate of single-walled carbon nanotubes and folic acid aimed to interact with cells over-expressing folate receptors. The bonding was obtained without covalent chemical functionalization using a simple, rapid “one pot” synthesis method. The zeta p...

  14. 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.

    Science.gov (United States)

    Houghton, Lisa A; Sherwood, Kelly L; O'Connor, Deborah L

    2007-10-25

    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. 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). 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 consuming 151-410 microg/d of synthetic folate (2nd quartile of intake) did not differ from that of women consuming >410 microg/d (3rd and 4th quartile). 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 microg/d in these women produced little additional benefit in terms of maximizing RBC

  15. Influence of iron deficiency in the radiopharmaceutical behavior of red blood cells labeled with 99mTc(99mTC-RBC)

    International Nuclear Information System (INIS)

    Calmanovici, G.; Salgueiro, M.J.; Pernas, L.; Collia, N.; Leonardi, N.; Zubillaga, M.

    2005-01-01

    Full text: Red blood cells (RBCs) labeled with 99m Tc are commonly used in the evaluation of cardiac function, gastrointestinal tract bleeding, red blood cell volume or splenic sequestration. Generally stannous ion is used as reducing agent. A proposed mechanism is that once the stannous ion (Sn) and the pertechnetate ( 99m Tc) reach the interior of the RBC, the radionuclide is mainly house in the β-chain of hemoglobin. The aim of this study was to determine if hemoglobin content reduction, an indicator of iron deficiency anemia, could affect the efficiency of RBC labeling and the biological distribution of this radiopharmaceutical. We studied 30 rats fed for 3 weeks after weaning with diets with iron contents of 6.5 ppm (group A), 18 ppm (group B) and 100 ppm (control). For all groups, the labeling yields were always higher than 97%; the percentage of radioactivity was mostly founded in blood with almost negligible radioactivity the rest of the studied organs. We can conclude that the decrease in hemoglobin content, an indicator of iron deficiency anemia, does not interfere neither in the labeling nor in the biodistribution of red blood cells labeled with 99m Tc. (author)

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

    Directory of Open Access Journals (Sweden)

    Bernadette N. Ng’eno

    2017-01-01

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

  17. 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

  18. 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, we...... examined RFC for mutations and promoter hypermethylation in (i) the inherently MTX-resistant lymphoma cell line (RL); (ii) 30 paired cases of acute lymphoblastic leukemia (ALL) obtained at diagnosis and at relapse after treatment with MTX; and (iii) 25 cases of diffuse large B-cell lymphoma (DLBCL......) at diagnosis, none of which had been previously exposed to MTX. Aberrant hypermethylation of the RFC promoter occurred in RL cells and two of the primary DLBCLs. In one additional DLBCL, a single-base substitution in RFC was identified, leading to the introduction of a premature termination codon (c.1396C>T; p...

  19. The Dihydrofolate Reductase 19 bp Polymorphism Is Not Associated with Biomarkers of Folate Status in Healthy Young Adults, Irrespective of Folic Acid Intake.

    Science.gov (United States)

    Ozaki, Mari; Molloy, Anne M; Mills, James L; Fan, Ruzong; Wang, Yifan; Gibney, Eileen R; Shane, Barry; Brody, Lawrence C; Parle-McDermott, Anne

    2015-10-01

    Dihydrofolate reductase (DHFR) is essential for the conversion of folic acid to active folate needed for one-carbon metabolism. Common genetic variation within DHFR is restricted to the noncoding regions, and previous studies have focused on a 19 bp deletion/insertion polymorphism (rs70991108) within intron 1. Reports of an association between this polymorphism and blood folate biomarker concentrations are conflicting. In this study, we evaluated whether the DHFR 19 bp deletion/insertion polymorphism affects circulating folate biomarkers in, to our knowledge, the largest cohort to address this question to date. Healthy young Irish individuals (n = 2507) between 19 and 36 y of age were recruited between February 2003 and February 2004. Folic acid intake from supplements and fortified foods was assessed with the use of a customized food intake questionnaire. Concentrations of serum folate and vitamin B-12, red blood cell (RBC) folate, and plasma total homocysteine (tHcy) were measured. Data were analyzed with the use of linear regression models. Folic acid intake was positively associated with serum (P folic acid intake (>326 μg folic acid/d; P = 0.96). A nonsignificant trend toward lower RBC folate by genotype (P = 0.09) was observed in the lowest folic acid intake quintile (0-51 μg/d). In this cohort of healthy young individuals, the DHFR 19 bp deletion allele did not significantly affect circulating folate status, irrespective of folic acid intake. Our data rule out a strong functional effect from this polymorphism on blood folate concentrations. © 2015 American Society for Nutrition.

  20. Predicting iron and folate deficiency anaemias from standard blood testing: the mechanism and implications for clinical medicine and public health in developing countries

    Directory of Open Access Journals (Sweden)

    Dugdale Alan E

    2006-10-01

    Full Text Available Abstract Background Developing countries have high prevalence of diseases, but facilities to diagnose and treat them are limited. We must use available resources in ways not needed where there are sophisticated equipment and trained staff. Anaemia is common; iron deficiency affects health and productivity; folate deficiency in pregnant women causes foetal abnormalities. Few developing countries can measure serum folate or ferritin, but standard automated blood analyses are widely available and can help predict folate and iron deficiency. The RDW-CV% (coefficient of variation of the red cell width measures the variability in the size of red blood cells (RBC in routine automated analysis of blood cells, but is seldom reported. Levels of RDW-CV% and haemoglobin (Hb can predict iron deficiency anaemia. Method and results I have written a computer model based on the standard mechanism for blood formation and destruction. This shows that before anaemia develops and during recovery, there are both normal and abnormal RBC (small in iron deficiency and large in folate deficiency in the circulation. The model calculates the abnormality in the RDW-CV% in standard automated blood analyses. In early iron deficiency and during recovery the full blood count shows the Hb near the lower limit of normal, a low MCV and a high RDW-CV%. A similar pattern, but with a higher MCV, develops in folate deficiency. Folate deficiency is often brief and may not cause anaemia. The high RDW-CV% may persist for three months. Conclusion This long footprint could be medically useful for detecting folate deficiency and so limiting foetal damage in individuals and communities. Few clinicians or public health workers know about RDW-CV%. Standard blood reports for clinical use should include the RDW-CV% and note the possible significance of abnormal values.

  1. Haematological implications of folate food fortification | Metz | South ...

    African Journals Online (AJOL)

    In assessing folate nutrition, the value of serum folate has been compromised by FFF, and both serum and red cell folate are necessary for optimal assessment of folate status. Although the limited data available suggest that large-scale masking of vitamin B12 deficiency by FFF has not occurred, it has been suggested that ...

  2. Fluoridated hydroxyapatite: Eu3+ nanorods-loaded folate-conjugated D-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS) micelles for targeted imaging of cancer cells

    Science.gov (United States)

    Wan, Dong; Liu, Weijiao; Wang, Lei; Wang, Hao; Pan, Jie

    2016-03-01

    In this study, fluoridated hydroxyapatite: Eu3+ nanorod-loaded folate-conjugated TPGS micelles were prepared by thin-film hydration. The findings in this study demonstrate that micelles show improved dispersion, high stability, and excellent fluorescent property in aqueous solutions, suitable for targeted imaging of cancer cells with over-expressing folate receptors on their surface. The micelles designed in this study will be a promising tool for early detection of cancer.

  3. Fractional order models of viscoelasticity as an alternative in the analysis of red blood cell (RBC) membrane mechanics.

    Science.gov (United States)

    Craiem, Damian; Magin, Richard L

    2010-01-20

    New lumped-element models of red blood cell mechanics can be constructed using fractional order generalizations of springs and dashpots. Such 'spring-pots' exhibit a fractional order viscoelastic behavior that captures a wide spectrum of experimental results through power-law expressions in both the time and frequency domains. The system dynamics is fully described by linear fractional order differential equations derived from first order stress-strain relationships using the tools of fractional calculus. Changes in the composition or structure of the membrane are conveniently expressed in the fractional order of the model system. This approach provides a concise way to describe and quantify the biomechanical behavior of membranes, cells and tissues.

  4. Fractional order models of viscoelasticity as an alternative in the analysis of red blood cell (RBC) membrane mechanics

    International Nuclear Information System (INIS)

    Craiem, Damian; Magin, Richard L

    2010-01-01

    New lumped-element models of red blood cell mechanics can be constructed using fractional order generalizations of springs and dashpots. Such 'spring-pots' exhibit a fractional order viscoelastic behavior that captures a wide spectrum of experimental results through power-law expressions in both the time and frequency domains. The system dynamics is fully described by linear fractional order differential equations derived from first order stress–strain relationships using the tools of fractional calculus. Changes in the composition or structure of the membrane are conveniently expressed in the fractional order of the model system. This approach provides a concise way to describe and quantify the biomechanical behavior of membranes, cells and tissues. (perspective)

  5. Increased cancer cell proliferation in prostate cancer patients with high levels of serum folate

    Science.gov (United States)

    Introduction: A recent clinical trial revealed that folic acid supplementation is associated with an increased incidence of prostate cancer (1). The present study evaluates serum and prostate tissue folate levels in men with prostate cancer, compared to histologically normal prostate glands from can...

  6. Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations

    Science.gov (United States)

    Although obesity is prevalent worldwide, few studies have investigated whether obesity interacts with status of the B vitamin, folate. Based on data from the nationally representative NHANES survey, this study examined the association between a measure of obesity (body mass index [BMI],) factors ass...

  7. Size-dependent internalisation of folate-decorated nanoparticles via the pathways of clathrin and caveolae-mediated endocytosis in ARPE-19 cells.

    Science.gov (United States)

    Langston Suen, Wai-Leung; Chau, Ying

    2014-04-01

    We aim to quantify the effect of size and degree of folate loading of folate-decorated polymeric nanoparticles (NPs) on the kinetics of cellular uptake and the selection of endocytic pathways in retinal pigment epithelium (RPE) cells. In this study, methoxy-poly(ethylene glycol)-b-polycaprolactone (mPEG-b-PCL) and folate-functionalized PEG-b-PCL were synthesized for assembling into nanoparticles with sizes ranging from 50 nm to 250 nm. These nanoparticles were internalized into ARPE-19 (human RPE cell line) via receptor-mediated endocytosis. A two-step endocytosis process mathematical model was adopted to quantify binding affinity and uptake kinetics of nanoparticles in RPE cells in uptake and inhibition studies. Nanoparticles with 100% folate loading have highest binding affinity and uptake rate in RPE cells. Maximum uptake rate (Vmax) of nanoparticles increased as the size of particles decreased from 250 nm to 50 nm. Endocytic pathway study was studied by using chlorpromazine and methyl-β-cyclodextran (MβCD), which are clathrin- and caveolae-mediated endocytosis inhibitors, respectively. Both chlorpromazine and MβCD inhibited the uptake of folate-decorated nanoparticles. Inhibition constant (Ki) and maximum uptake rate (Vmax) revealed that 50 nm and 120 nm folate-decorated nanoparticles were found to be internalized via both clathrin- and caveolae-mediated endocytosis. The 250 nm folate-decorated nanoparticles, however, were only internalized via caveolae-mediated pathway. Increased uptake rate of folate-decorated NPs into RPE cells is observed with increasing degree of folate modification. These NPs utilize both clathrin- and caveolae-mediated receptor-mediated endocytosis pathways to enter RPE cells upon size variation. The 50 nm NPs are internalized the fastest, with clathrin-mediated endocytosis as the preferred route. Uptake of 250 nm particles is the slowest and is dominated by caveolae-mediated endocytosis. © 2013 Royal Pharmaceutical

  8. Validity of the Food Frequency Questionnaire Assessing the Folate Intake in Women of Reproductive Age Living in a Country without Food Fortification: Application of the Method of Triads.

    Science.gov (United States)

    Zekovic, Milica; Djekic-Ivankovic, Marija; Nikolic, Marina; Gurinovic, Mirjana; Krajnovic, Dusanka; Glibetic, Marija

    2017-02-13

    The study aimed to examine the external validity of the Folate Food Frequency Questionnaire (F-FFQ) designed for assessing the folate intake in Serbian women of reproductive age. The F-FFQ was tested against repeated 24 h dietary recalls and correspondent nutritional biomarkers (red blood cells (RBC) and serum folate concentrations) using the method of triads. In a cross sectional study, 503 women aged 18-49 years completed dietary questionnaires and representative validation subsample ( n = 50) provided fasting blood samples for biomarker analyses. Correlation coefficients were calculated between each of the dietary methods and three pair-wise correlations were applied for the calculation of validity coefficients. Correlation coefficients observed between F-FFQ and three 24 h recalls were r = 0.56 ( p food fortification.

  9. RBC nuclear scan

    Science.gov (United States)

    ... scan uses small amounts of radioactive material to mark (tag) red blood cells (RBCs). Your body is ... Goldman's Cecil Medicine . 25th ed. Philadelphia, PA: Elsevier Saunders; 2016:chap 135. Tavakkoli A, Ashley SW. Acute ...

  10. Use of Laser Assisted Optical Rotational Cell Analyzer (LoRRca MaxSis in the Diagnosis of RBC Membrane Disorders, Enzyme Defects, and Congenital Dyserythropoietic Anemias: A Monocentric Study on 202 Patients

    Directory of Open Access Journals (Sweden)

    Anna Zaninoni

    2018-04-01

    Full Text Available Chronic hemolytic anemias are a group of heterogeneous diseases mainly due to abnormalities of red cell (RBC membrane and metabolism. The more common RBC membrane disorders, classified on the basis of blood smear morphology, are hereditary spherocytosis (HS, elliptocytosis, and hereditary stomatocytoses (HSt. Among RBC enzymopathies, the most frequent is pyruvate kinase (PK deficiency, followed by glucose-6-phosphate isomerase, pyrimidine 5′ nucleotidase P5′N, and other rare enzymes defects. Because of the rarity and heterogeneity of these diseases, diagnosis may be often challenging despite the availability of a variety of laboratory tests. The ektacytometer laser-assisted optical rotational cell analyser (LoRRca MaxSis, able to assess the RBC deformability in osmotic gradient conditions (Osmoscan analysis, is a useful diagnostic tool for RBC membrane disorders and in particular for the identification of hereditary stomatocytosis. Few data are so far available in other hemolytic anemias. We evaluated the diagnostic power of LoRRca MaxSis in a large series of 140 patients affected by RBC membrane disorders, 37 by enzymopathies, and 16 by congenital diserythropoietic anemia type II. Moreover, nine patients with paroxysmal nocturnal hemoglobinuria (PNH were also investigated. All the hereditary spherocytoses, regardless the biochemical defect, showed altered Osmoscan curves, with a decreased Elongation Index (EI max and right shifted Omin; hereditary elliptocytosis (HE displayed a trapezoidal curve and decreased EImax. Dehydrated hereditary stomatocytosis (DHSt caused by PIEZO1 mutations was characterized by left-shifted curve, whereas KCNN4 mutations were associated with a normal curve. Congenital diserythropoietic anemia type II and RBC enzymopathies had Osmoscan curve within the normal range except for glucosephosphate isomerase (GPI deficient cases who displayed an enlarged curve associated with significantly increased Ohyper, offering a

  11. Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma

    International Nuclear Information System (INIS)

    Lu, Cheng; Xie, Hui; Wang, Fengliang; Shen, Hongbing; Wang, Jianming

    2011-01-01

    Folic acid may affect the development of human cancers. However, few studies have evaluated the consumption of diet folate in the prognosis of patients with esophageal squamous cell carcinoma (ESCC). One hundred and twenty five ESCC patients underwent esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed up. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms on the prognosis of ESCC were evaluated by using Cox proportional hazard regression models. Our analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 3.06 years for low or moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval) [HRs (95% CI)] were 0.72 (0.36-1.46) for moderate and 0.39 (0.20-0.78) for high folate intake, respectively (P for trend = 0.007). This preventive effect was more evident in patients carrying MTHFR 677CC genotype. No significant relation was observed between aberrant DNA methylation of P16, MGMT and hMLH1 gene, as well as MTHFR C677T genetic polymorphisms and the prognosis of ESCC. Our research indicated that diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. From a practical viewpoint, the findings of our study help to establish practical intervention and surveillance strategies for managements of ESCC patients and can finally decrease the disease burden

  12. Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in association with the prognosis of esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Shen Hongbing

    2011-03-01

    Full Text Available Abstract Background Folic acid may affect the development of human cancers. However, few studies have evaluated the consumption of diet folate in the prognosis of patients with esophageal squamous cell carcinoma (ESCC. Methods One hundred and twenty five ESCC patients underwent esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed up. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR C677T genetic polymorphisms on the prognosis of ESCC were evaluated by using Cox proportional hazard regression models. Results Our analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 3.06 years for low or moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval [HRs (95% CI] were 0.72 (0.36-1.46 for moderate and 0.39 (0.20-0.78 for high folate intake, respectively (P for trend = 0.007. This preventive effect was more evident in patients carrying MTHFR 677CC genotype. No significant relation was observed between aberrant DNA methylation of P16, MGMT and hMLH1 gene, as well as MTHFR C677T genetic polymorphisms and the prognosis of ESCC. Conclusions Our research indicated that diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. From a practical viewpoint, the findings of our study help to establish practical intervention and surveillance strategies for managements of ESCC patients and can finally decrease the disease burden.

  13. Folate absorption

    International Nuclear Information System (INIS)

    Baker, S.J.

    1976-01-01

    Folate is the generic term given to numerous compounds of pteroic acid with glutamic acid. Knowledge of absorption is limited because of the complexities introduced by the variety of compounds and because of the inadequacy of investigational methods. Two assay methods are in use, namely microbiological and radioactive. Techniques used to study absorption include measurement of urinary excretion, serum concentration, faecal excretion, intestinal perfusion, and haematological response. It is probably necessary to test absorption of both pteroylmonoglutamic acid and one or more polyglutamates, and such tests would be facilitated by availability of synthesized compounds labelled with radioactive tracers at specifically selected sites. (author)

  14. RBC micromotors carrying multiple cargos towards potential theranostic applications.

    Science.gov (United States)

    Wu, Zhiguang; Esteban-Fernández de Ávila, Berta; Martín, Aída; Christianson, Caleb; Gao, Weiwei; Thamphiwatana, Soracha Kun; Escarpa, Alberto; He, Qiang; Zhang, Liangfang; Wang, Joseph

    2015-08-28

    Red blood cell (RBC)-based micromotors containing both therapeutic and diagnostic modalities are described as a means for potential theranostic applications. In this natural RBC-based multicargo-loaded micromotor system, quantum dots (QDs), anti-cancer drug doxorubicin (DOX), and magnetic nanoparticles (MNPs), were co-encapsulated into RBC micromotors. The fluorescent emission of both QDs and DOX provides direct visualization of their loading inside the RBC motors at two distinct wavelengths. The presence of MNPs within the RBCs allows for efficient magnetic guidance under ultrasound propulsion along with providing the potential for magnetic resonance imaging. The simultaneous encapsulation of the imaging nanoparticles and therapeutic payloads within the same RBC micromotor has a minimal effect upon its propulsion behavior. The ability of the RBC micromotors to transport imaging and therapeutic agents at high speed and spatial precision through a complex microchannel network is also demonstrated. Such ability to load and transport diagnostic imaging agents and therapeutic drugs within a single cell-based motor, in addition to a lower toxicity observed once the drug is encapsulated within the multicargo RBC motor, opens the door to the development of theranostic micromotors that may simultaneously treat and monitor diseases.

  15. Functional characterization and expression of folate receptor-α in T47D human breast cancer cells

    Directory of Open Access Journals (Sweden)

    J Renukuntla

    2015-01-01

    Full Text Available Purpose: The objective of this study was to investigate the functional and molecular expression of a carrier mediated system responsible for folate uptake in breast cancer (BC (T47D cells and to delineate the mechanism of intracellular regulation of this transport system. Materials and Methods: [ 3 H]-folic acid uptake was studied in T47D cells with respect to time, pH, temperature, sodium and chloride ion dependency. Inhibition studies were conducted in the presence structural analogs, vitamins, metabolic and membrane transport inhibitors. [ 3 H]-folic acid uptake was also determined with varying concentrations of cold folic acid. Uptake kinetics was studied in the presence of various modulators of intracellular regulatory pathways; calcium-calmodulin, protein kinases A and C (PKA and PKC and protein tyrosine kinase (PTK. Molecular evidence was studied by qualitative and quantitative polymerase chain reaction (PCR and Western blot analysis. Results: Linear increase in [ 3 H]-folic acid uptake was observed over 30 min. The process followed saturation kinetics with an apparent K m of 11.05 nM, V max of 1.54 FNx01 10−8 μmoles/min/mg proteins and K d of 9.71 FNx01 10−6 /min for folic acid. Uptake process was found to be dependent on pH, sodium ions, chloride ions, temperature and energy. Uptake was inhibited in the presence of structural analogs (cold folic acid, methyltetrahydro folate and methotrexate, but structurally unrelated vitamins did not show any effect. Membrane transport inhibitors such as SITC, DIDS, probenecid and endocytic inhibitor colchicine significantly inhibited the [ 3 H]-folic acid uptake process. PKA, PTK and Ca 2+ /calmodulin pathways positively regulate the uptake process. Reverse transcriptase polymerase chain reaction (RT PCR analysis had shown mRNA expression of folate receptor (FR-α at 407 bp. Quantitative polymerase chain reaction analysis showed significantly higher FR-α mRNA levels in T47D cells compared to

  16. Genotoxicity and cytotoxicity of chromium, copper, manganese and lead, and their mixture in WIL2-NS human B lymphoblastoid cells is enhanced by folate depletion.

    Science.gov (United States)

    Alimba, Chibuisi G; Dhillon, Varinderpal; Bakare, Adekunle A; Fenech, Michael

    2016-03-01

    Heavy metal exposure or dietary deficiency is associated with increased genetic damage, cancer and age-related diseases. Folate (vitamin B9) required for DNA repair and synthesis may increase cellular susceptibility to metal induced genotoxicity. This study investigated the interactive effects of folic acid deficiency and sufficiency on genome instability and cytotoxicity induced by chromium (VI), copper (II), manganese (II), lead (IV), and their mixture (CCMP) in WIL2-NS human B lymphoblastoid cells. WIL2-NS cells were cultured in folic acid deficient (20 nM) and replete (2000 nM) RPMI 1640 medium treated with different concentrations (0.00-1000 μM) of the metals and CCMP for 48 h. Chromosomal damage and cytotoxicity were measured using the Cytokinesis-block Micronucleus Cytome assay. CCMP, Cr, Pb, Cu and Mn induced concentration dependent, increases in cells with chromosome damage (micronuclei, nucleoplasmic bridges, nuclear buds) and necrotic cells and decreased nuclear division index. The metals exhibited different cytotoxic and genotoxic potentials (CCMP>Cr>Pb>Cu>Mn) in both folate deficient and sufficient cells, with the cytogenotoxic effects being greater in folate deficient cells. Significant interaction between the metals and folic acid suggests that folic acid deficiency exacerbated cell proliferation inhibition and genome instability induced by metals. Folate deficiency, increasing metal concentration, and their interactions explained 3-11%, 74-92% and 4-12% of the variance of DNA damage biomarkers. In conclusion, exposure to the tested metals (0.01-1000 μM) increased chromosomal DNA damage in WIL2-NS cells and this was exacerbated by folate deficiency. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Chimeric bispecific OC/TR monoclonal antibody mediates lysis of tumor cells expressing the folate-binding protein (MOv18) and displays decreased immunogenicity in patients

    NARCIS (Netherlands)

    Luiten, R. M.; Warnaar, S. O.; Sanborn, D.; Lamers, C. H.; Bolhuis, R. L.; Litvinov, S. V.; Zurawski, V. R.; Coney, L. R.

    1997-01-01

    The bispecific OC/TR monoclonal antibody (mAb) cross-links the CD3 molecule on T cells with the human folate-binding protein (FBP), which is highly expressed on nonmucinous ovarian carcinomas. Clinical trials of patients with ovarian carcinoma with the OC/TR mAb have shown some complete and partial

  18. High folate production by naturally occurring Lactobacillus sp. with ...

    African Journals Online (AJOL)

    Rapidly proliferating cells require large amounts of folate to support efficient DNA replication, repair and methylation indicating the importance of folate in human metabolism. Milk products are good sources of such vitamins which are produced by probiotics. In order to find suitable strains capable of high folate production, ...

  19. Folate receptor-targeted nanoparticle delivery of HuR-RNAi suppresses lung cancer cell proliferation and migration.

    Science.gov (United States)

    Muralidharan, Ranganayaki; Babu, Anish; Amreddy, Narsireddy; Basalingappa, Kanthesh; Mehta, Meghna; Chen, Allshine; Zhao, Yan Daniel; Kompella, Uday B; Munshi, Anupama; Ramesh, Rajagopal

    2016-06-21

    Human antigen R (HuR) is an RNA binding protein that is overexpressed in many human cancers, including lung cancer, and has been shown to regulate the expression of several oncoproteins. Further, HuR overexpression in cancer cells has been associated with poor-prognosis and therapy resistance. Therefore, we hypothesized that targeted inhibition of HuR in cancer cells should suppress several HuR-regulated oncoproteins resulting in an effective anticancer efficacy. To test our hypothesis, in the present study we investigated the efficacy of folate receptor-α (FRA)-targeted DOTAP:Cholesterol lipid nanoparticles carrying HuR siRNA (HuR-FNP) against human lung cancer cells. The therapeutic efficacy of HuR-FNP was tested in FRA overexpressing human H1299 lung cancer cell line and compared to normal lung fibroblast (CCD16) cells that had low to no FRA expression. Physico-chemical characterization studies showed HuR-FNP particle size was 303.3 nm in diameter and had a positive surface charge (+4.3 mV). Gel retardation and serum stability assays showed that the FNPs were efficiently protected siRNA from rapid degradation. FNP uptake was significantly higher in H1299 cells compared to CCD16 cells indicating a receptor-dose effect. The results of competitive inhibition studies in H1299 cells demonstrated that HuR-FNPs were efficiently internalized via FRA-mediated endocytosis. Biologic studies demonstrated HuR-FNP but not C-FNP (control siRNA) induced G1 phase cell-cycle arrest and apoptosis in H1299 cells resulting in significant growth inhibition. Further, HuR-FNP exhibited significantly higher cytotoxicity against H1299 cells than it did against CCD16 cells. The reduction in H1299 cell viability was correlated with a marked decrease in HuR mRNA and protein expression. Further, reduced expression of HuR-regulated oncoproteins (cyclin D1, cyclin E, and Bcl-2) and increased p27 tumor suppressor protein were observed in HuR-FNP-treated H1299 cells but not in C

  20. Development and evaluation of a new modular nanotransporter for drug delivery into nuclei of pathological cells expressing folate receptors

    Directory of Open Access Journals (Sweden)

    Slastnikova TA

    2017-04-01

    Full Text Available Tatiana A Slastnikova,1 Andrey A Rosenkranz,1,2 Yuri V Khramtsov,1 Tatiana S Karyagina,1 Sergey A Ovechko,2 Alexander S Sobolev1,2 1Laboratory of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 2Department of Biophysics, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia Purpose: Modular nanotransporters (MNTs are artificial multifunctional systems designed to facilitate receptor-specific transport from the cell surface into the cell nucleus through inclusion of polypeptide domains for accomplishing receptor binding and internalization, as well as sequential endosomal escape and nuclear translocation. The objective of this study was to develop a new MNT targeted at folate receptors (FRs for precise delivery of therapeutic cargo to the nuclei of FR-positive cells and to evaluate its potential, particularly for delivery of therapeutic agents (eg, the Auger electron emitter 111In into the nuclei of target cancer cells.Methods: A FR-targeted MNT was developed by site-specific derivatization of ligand-free MNT with maleimide-polyethylene glycol-folic acid. The ability of FR-targeted MNT to accumulate in target FR-expressing cells was evaluated using flow cytometry, and intracellular localization of this MNT was assessed using confocal laser scanning microscopy of cells. The cytotoxicity of the 111In-labeled FR-targeted MNT was evaluated on HeLa and U87MG cancer cell lines expressing FR. In vivo micro-single-photon emission computed tomography/CT imaging and antitumor efficacy studies were performed with intratumoral injection of 111In-labeled FR-targeted MNT in HeLa xenograft-bearing mice.Results: The resulting FR-targeted MNT accumulated in FR-positive HeLa cancer cell lines specifically and demonstrated the ability to reach its target destination – the cell nuclei. 111In-labeled FR-targeted MNT demonstrated efficient and specific FR-positive cancer cell eradication. A He

  1. Polymersomes conjugated with des-octanoyl ghrelin and folate as a BBB-penetrating cancer cell-targeting delivery system.

    Science.gov (United States)

    Chen, Yung-Chu; Chiang, Chi-Feng; Chen, Li-Fang; Liang, Po-Chin; Hsieh, Wen-Yuan; Lin, Win-Li

    2014-04-01

    Chemotherapy for brain cancer tumors remains a big challenge for clinical medicine due to the inability to transport sufficient drug across the blood-brain barrier (BBB) and the poor penetration of drug into the tumors. To effectively treat brain tumors and reduce side effects on normal tissues, both des-octanoyl ghrelin and folate conjugated with polymersomal doxorubicin (GFP-D) was developed in this study to help transport across the BBB and target the tumor as well. The size measurements revealed that this BBB-penetrating cancer cell-targeting GFP-D was about 85 nm. In-vitro experiments with a BBB model and C6 glioma cells demonstrated that GFP-D owned a robust penetrating-targeting function for drug delivery. In C6 cell viability tests, GFP-D exhibited an inhibitory effect significantly different from the unmodified polymersomal doxorubicin (P-D). In-vivo antitumor experiments showed that GFP-D performed a much better anti-glioma effect and presented a significant improvement in the overall survival of the tumor-bearing mice as compared to the treatments with free doxorubicin (Dox), liposomal doxorubicin (L-D), P-D, or single ligand conjugated P-D. In addition, Cy 5.5 was used as a probe to investigate the delivery property of this penetrating-targeting delivery system. The overall experimental results indicate that this BBB-penetrating cancer cell-targeting GFP is a highly potential nanocarrier for the treatment of brain tumors. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. 99mTc-RBC subtraction scintigraphy

    International Nuclear Information System (INIS)

    Inagaki, Syoichi; Tonami, Syuichi; Yasui, Masakazu; Kuranishi, Makoto; Sugishita, Kouki; Nakamura, Mamoru

    1994-01-01

    Sequential abdominal scintigrams with 99m Tc-labelled red blood cells (RBC) were subtracted for observing a site of gastrointestinal bleeding and calculating the bleeding rate. This method is technically very easy and can detect the site of bleeding with the minimum rate, as low as 0.2 ml/min., in a phantom experiment. In 23 cases with final diagnosis of gastrointestinal bleeding, conventional non-subtraction scintigraphy detected only 30% (7/23), but subtraction scintigraphy detected 61% (14/23). It was concluded that subtraction scintigraphy had higher sensitivity than conventional scintigraphy for early diagnosing bleeding. A combination of non-subtraction and subtraction scintigraphy is recommended to detect a site of gastrointestinal bleeding in a clinical setting. (author)

  3. [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.

  4. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

    Science.gov (United States)

    Schreiner, Jens; Thommen, Daniela S.; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A.; Umana, Pablo; Pisa, Pavel; von Bergwelt-Baildon, M.; Lardinois, Didier; Müller, Philipp; Karanikas, Vaios; Zippelius, Alfred

    2016-01-01

    ABSTRACT T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction. PMID:27057429

  5. Elimination of Tumor Cells Using Folate Receptor Targeting by Antibody-Conjugated, Gold-Coated Magnetite Nanoparticles in a Murine Breast Cancer Model

    Directory of Open Access Journals (Sweden)

    Evan S. Krystofiak

    2012-01-01

    Full Text Available Background. The chemotherapeutic treatment of cancer suffers from poor specificity for targeting the tumor cells and often results in adverse effects such as systemic toxicity, damage to nontarget tissues, and development of drug-resistant tumors in patients. Increasingly, drug nanocarriers have been explored as a way of lessening or overcoming these problems. In this study, antibody-conjugated Au-coated magnetite nanoparticles, in conjunction with inductive heating produced by exposure to an oscillating magnetic field (OMF, were evaluated for their effects on the viability of tumor cells in a murine model of breast cancer. Treatment effects were evaluated by light microscopy and SEM. Results. 4T1 mammary epithelial carcinoma cells overexpressing the folate receptor were targeted with an anti-folate receptor primary antibody, followed by labeling with secondary antibody-conjugated Au-coated magnetite nanoparticles. In the absence of OMF exposure, nanoparticle labeling had no effect on 4T1 cell viability. However, following OMF treatment, many of the labeled 4T1 cells showed extensive membrane damage by SEM analysis, and dramatically reduced viability as assessed using a live/dead staining assay. Conclusions. These results demonstrate that Au-coated magnetite targeted to tumor cells through binding to an overexpressed surface receptor, in the presence of an OMF, can lead to tumor cell death.

  6. Clinical utility of folate-containing oral contraceptives

    Directory of Open Access Journals (Sweden)

    Lassi ZS

    2012-04-01

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

  7. [Folate and cancer].

    Science.gov (United States)

    Miao, Xiao-Ping; Lin, Dong-Xin

    2003-06-01

    Folate is one of the important constituents of vegetables and fruits that may provide protection against cancer. An important function of folate is to provide methyl groups required for intracellular methylation reactions and de novo deoxynucleoside synthesis. Therefore, folate deficiency has been thought to be carcinogenic through disruption of DNA methylation, synthesis, and repair. However, to serve as the active mediator, folate requires metabolism catalyzed by several enzymes including methylenetetrahydrofolate reductase (MTHFR), which plays a central role in biotransformation of folate. Thus, it is likely that two functional single nucleotide polymorphisms(677C-->T and 1298A-->C) in the MTHFR gene,both of which diminishes MTHFR activity,may contribute to risk of cancer.

  8. Reduced-folate carrier (RFC) is expressed in placenta and yolk sac, as well as in cells of the developing forebrain, hindbrain, neural tube, craniofacial region, eye, limb buds and heart.

    Science.gov (United States)

    Maddox, Dennis M; Manlapat, Anna; Roon, Penny; Prasad, Puttur; Ganapathy, Vadivel; Smith, Sylvia B

    2003-07-29

    Folate is essential for cellular proliferation and tissue regeneration. As mammalian cells cannot synthesize folates de novo, tightly regulated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support biosynthesis of purines, pyrimidines, and some amino acids (serine, methionine). Though reduced-folate carrier (RFC) is one of the major proteins mediating folate transport, knowledge of the developmental expression of RFC is lacking. We utilized in situ hybridization and immunolocalization to determine the developmental distribution of RFC message and protein, respectively. In the mouse, RFC transcripts and protein are expressed in the E10.0 placenta and yolk sac. In the E9.0 to E11.5 mouse embryo RFC is widely detectable, with intense signal localized to cell populations in the neural tube, craniofacial region, limb buds and heart. During early development, RFC is expressed throughout the eye, but by E12.5, RFC protein becomes localized to the retinal pigment epithelium (RPE). Clinical studies show a statistical decrease in the number of neural tube defects, craniofacial abnormalities, cardiovascular defects and limb abnormalities detected in offspring of female patients given supplementary folate during pregnancy. The mechanism, however, by which folate supplementation ameliorates the occurrence of developmental defects is unclear. The present work demonstrates that RFC is present in placenta and yolk sac and provides the first evidence that it is expressed in the neural tube, craniofacial region, limb buds and heart during organogenesis. These findings suggest that rapidly dividing cells in the developing neural tube, craniofacial region, limb buds and heart may be particularly susceptible to folate deficiency.

  9. Reduced-folate carrier (RFC is expressed in placenta and yolk sac, as well as in cells of the developing forebrain, hindbrain, neural tube, craniofacial region, eye, limb buds and heart

    Directory of Open Access Journals (Sweden)

    Prasad Puttur

    2003-07-01

    Full Text Available Abstract Background Folate is essential for cellular proliferation and tissue regeneration. As mammalian cells cannot synthesize folates de novo, tightly regulated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support biosynthesis of purines, pyrimidines, and some amino acids (serine, methionine. Though reduced-folate carrier (RFC is one of the major proteins mediating folate transport, knowledge of the developmental expression of RFC is lacking. We utilized in situ hybridization and immunolocalization to determine the developmental distribution of RFC message and protein, respectively. Results In the mouse, RFC transcripts and protein are expressed in the E10.0 placenta and yolk sac. In the E9.0 to E11.5 mouse embryo RFC is widely detectable, with intense signal localized to cell populations in the neural tube, craniofacial region, limb buds and heart. During early development, RFC is expressed throughout the eye, but by E12.5, RFC protein becomes localized to the retinal pigment epithelium (RPE. Conclusions Clinical studies show a statistical decrease in the number of neural tube defects, craniofacial abnormalities, cardiovascular defects and limb abnormalities detected in offspring of female patients given supplementary folate during pregnancy. The mechanism, however, by which folate supplementation ameliorates the occurrence of developmental defects is unclear. The present work demonstrates that RFC is present in placenta and yolk sac and provides the first evidence that it is expressed in the neural tube, craniofacial region, limb buds and heart during organogenesis. These findings suggest that rapidly dividing cells in the developing neural tube, craniofacial region, limb buds and heart may be particularly susceptible to folate deficiency.

  10. Synthesis and characterization of folate-poly(ethylene glycol ...

    African Journals Online (AJOL)

    Jane

    2011-07-04

    Jul 4, 2011 ... The use of chitosan and chitosan derivatives for gene delivery is limited due to the low transfection efficiency and difficulty in transfecting into a variety of cell types, including some cancer cells overexpressing folate receptor (FRs). In order to solve this problem, folate (FA) and poly(ethylene glycol) (PEG) ...

  11. RBC deformability and amino acid concentrations after hypo-osmotic challenge may reflect chronic cell hydration status in healthy young men

    OpenAIRE

    Stookey, Jodi D; Klein, Alexis; Hamer, Janice; Chi, Christine; Higa, Annie; Ng, Vivian; Arieff, Allen; Kuypers, Frans A; Larkin, Sandra; Perrier, Erica; Lang, Florian

    2013-01-01

    Biomarkers of chronic cell hydration status are needed to determine whether chronic hyperosmotic stress increases chronic disease risk in population-representative samples. In vitro, cells adapt to chronic hyperosmotic stress by upregulating protein breakdown to counter the osmotic gradient with higher intracellular amino acid concentrations. If cells are subsequently exposed to hypo-osmotic conditions, the adaptation results in excess cell swelling and/or efflux of free amino acids. This stu...

  12. [Colorectal cancer and folate].

    Science.gov (United States)

    Bott, C; Lembcke, B; Stein, J

    2003-03-01

    Nutritional factors are important contributors to colorectal cancer prevention. There is some evidence to suggest that a high dietary folate intake is associated with a reduced risk of colorectal cancer. Folate, which is found in green leafy vegetables, is involved in C1 group transfer and contributes to purin and thymi-dilate synthesis as well as to DNA methylation. Alterations in gene expression and DNA damage are discussed to result from low folate levels and might be associated with an elevated risk of colorectal malignancies. This hypothesis can be supported by the finding that a common polymorphism in the methylentetrahydrofolate reductase gene enhances the risk of colorectal cancer when folate status is low. Both retrospective and prospective epidemiologic studies confirm the observation that a high intake of folate correlates with a lower risk of colorectal cancer. There is also evidence from epidemiological studies that diets which are low in methyl donors, such as low contents of folate and/or methionine combined with relatively high alcohol consumption, even enhance the risk of colorectal cancer. A small number of intervention trials provide first evidence that folate intakes far above recommended dietary allowances might influence possible biomarkers of colorectal tumours.

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

    Science.gov (United States)

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

    2014-07-01

    Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder. Severe folate deficiency in HFM can result in immunodeficiency. We describe a female infant with HFM who acquired severe Pneumocystis pneumonia. The objective of the present study was to elucidate her immunological phenotype and to examine the time course of immune recovery following parenteral folate therapy. The patient demonstrated a combined immunodeficiency with an impaired T cell proliferation response, pan-hypogammaglobulinemia, and an imbalanced pro-inflammatory cytokine profile. She had normal white blood cell count, normal lymphocyte subsets, and normal complement levels. Two novel mutations were identified within the SLC46A1 gene to produce a compound heterozygote. We confirmed full recovery of her immunological and neurophysiological status with parenteral folate replacement. The time course of recovery of her immunological profile varied widely, however. HFM should be recognized as a unique form of immunodeficiency. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. CSF RBC count in successful first-attempt lumbar puncture: the interest of atraumatic needle use.

    Science.gov (United States)

    Renard, Dimitri; Thouvenot, Eric

    2017-12-01

    The objective of this study is to analyze CSF red blood cell (RBC) count from first-attempt lumbar punctures and to analyze parameters associated with first-attempt lumbar punctures and hemorrhagic lumbar puncture. This is a prospective analysis of consecutive patients who underwent lumbar puncture for any reason other than suspected acute subarachnoid hemorrhage. Analyzed parameters were the following: age, indication for lumbar puncture, aPTT ratio, PTT, platelet count, patient's position, needle type (atraumatic/standard), needle diameter, person performing lumbar puncture (medical student/resident/attending physician), number of lumbar levels punctured, necessity of needle repositioning, CSF RBC and white blood cell count, and protein level. Lumbar puncture resulting in RBC count > 5 RBC/mm 2 was classified as hemorrhagic lumbar puncture (different cut-offs were studied: > 5/> 10/> 100/> 500/> 1000 RBC). In total, 169 elective lumbar punctures in 165 different patients were included. First-attempt lumbar puncture occurred in 22% > 5 RBC, in 19.5% > 10 RBC, in 4.5% > 100 RBC, in 3% > 500 RBC, and 1.5% > 1000 RBC count. First-attempt lumbar puncture was associated with non-hemorrhagic lumbar puncture for each of the RBC count cut-offs (OR for non-hemorrhagic lumbar puncture in first-attempt lumbar puncture 2.8, 95% CI 1.4-5.7). The presence of a hemorrhagic disorder (concerning cerebral amyloid angiopathy in all patients) and higher aPTT ratio were associated with hemorrhagic lumbar puncture. Atraumatic needle use was associated with non-hemorrhagic lumbar puncture for RBC count cut-offs ≤ 5 and ≤ 10 RBC (OR for non-hemorrhagic lumbar puncture in atraumatic needle use 2.5 [95% CI 1.3-4.8] and 2.2 [95% CI 1.1-4.4], respectively). First-attempt lumbar puncture and hemorrhagic lumbar puncture were not associated with other parameters. Slightly elevated CSF RBC count after first-attempt lumbar puncture occurs relatively frequently, but is even more

  15. Maternal folate status and lactation.

    Science.gov (United States)

    O'Connor, D L; Green, T; Picciano, M F

    1997-07-01

    Folate plays an essential role in DNA, RNA, and protein biosynthesis. For this reason, the physiological need for this vitamin is increased during periods of rapid anabolic activity such as pregnancy and lactation. Although the importance of folate and the consequences of suboptimal folate status during pregnancy, especially during the periconceptional period, are well appreciated, little is known about the value of folate during lactation. The limited number of studies available on folate intake during lactation suggest that many women do not consume an adequate amount of folate and that recommended target intakes may be too low. Although inadequate maternal folate intake does not affect milk folate concentration unless maternal deficiency is severe, potential consequences of suboptimal folate nutrition to both the mother and her future offspring should also be considered.

  16. Physiological responses to folate overproduction in Lactobacillus plantarum WCFS1

    NARCIS (Netherlands)

    Wegkamp, A.; Mars, A.E.; Faijes, M.; Molenaar, D.; Vos, de R.C.H.; Klaus, M.J.; Hanson, A.D.; Vos, de W.M.; Smid, E.J.

    2010-01-01

    Background Using a functional genomics approach we addressed the impact of folate overproduction on metabolite formation and gene expression in Lactobacillus plantarum WCFS1. We focused specifically on the mechanism that reduces growth rates in folate-overproducing cells. Results Metabolite

  17. Pyridoxal, Vitamin B12 and Folate Metabolism Women Taking Oral ...

    African Journals Online (AJOL)

    1974-09-21

    Sep 21, 1974 ... contraceptive agents had significantly lower mean concen- trations of vitamin B I2 and serum and red cell folate. ... folate pool in women taking oral contraceptive agents is significantly lowered. There were fewer women with ..... Teratogenicity has been reported in vitamin B,-deficient pregnant rats," and the ...

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

    Science.gov (United States)

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

    2018-02-09

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

  19. Dietary folate deficiency blocks prostate cancer progression in the TRAMP model

    OpenAIRE

    Bistulfi, Gaia; Foster, Barbara A; Karasik, Ellen; Gillard, Bryan; Miecznikowski, Jeff; Dhiman, Vineet K; Smiraglia, Dominic J

    2011-01-01

    Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies found that dietary folate interventions can affect colon cancer biology in rodent models, impact on prostate is unknown. The purpose of this study was to determine if dietary folate manipulation, possibly bei...

  20. Clinical utility of folate-containing oral contraceptives.

    Science.gov (United States)

    Lassi, Zohra S; Bhutta, Zulfiqar A

    2012-01-01

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

  1. Physiological responses to folate overproduction in Lactobacillus plantarum WCFS1

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    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.

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

    International Nuclear Information System (INIS)

    Arjomand, A; Bucholz, B A; Clifford, A J; Duecker, S R; Johnson, H; Schneider, P D; Zulim, R A.

    1999-01-01

    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 Hodgkins 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

  3. Subcellular distribution of folate and folate binding protein in renal proximal tubules

    International Nuclear Information System (INIS)

    Sharkey, C.; Hjelle, J.T.; Selhub, J.

    1986-01-01

    High affinity folate binding protein (FBP) found in brush border membranes derived from renal cortices is thought to be involved in the renal conservation of folate. To examine the mechanisms of folate recovery, the subcellular distribution of FBP and 3 H-folate in rabbit renal proximal tubules (PT) was examined using analytical cell fractionation techniques. Tubules contain 3.41 +/- 0.32 picomoles FBP/mg protein (X +/- S.D.; n = 5). Postnuclear supernates (PNS) of PT were layered atop Percoll-sucrose gradients, centrifuged, fractions collected and assayed for various marker enzymes and FBP. Pooled fractions from such gradients were subsequently treated with digitonin and centrifuged in a stoichiometric manner with the activity of the microvillar enzyme, alanylaminopeptidase (AAP); excess FBP distributed with more buoyant particles. Infusion of 3 H-folate into rabbit kidneys followed by tubule isolation and fractionation revealed a time dependent shift in distribution of radiolabel from the AAP-rich gradient fractions to a region containing more buoyant particles; radiolevel was not associated with lysosomal markers. EM-radioautography revealed grains over intracellular vesicles. These results are consistent with the hypothesis that folate is recovered by a process involving receptor-mediated endocytosis or transcytosis

  4. Low folate metabolic stress reprograms DNA methylation-activated sonic hedgehog signaling to mediate cancer stem cell-like signatures and invasive tumour stage-specific malignancy of human colorectal cancers.

    Science.gov (United States)

    Feng, Hsin-Chun; Lin, Jhuan-Yu; Hsu, Shu-Han; Lan, Wen-Yu; Kuo, Chang-Sheng; Tian, Yu-Feng; Sun, Ding-Ping; Huang, Rwei-Fen Syu

    2017-12-15

    The mechanistic role of colonic low folate metabolic stress (LFMS) in colorectal cancer (CRC) malignancy development remains unknown. Folate analysis on the 99 paired human CRC tissues localized LFMS to the deep invasive T3/T4 staged tumours with hypo-methylated sonic hedgehog (Shh) promoter region and amplified expressions of Shh ligand and Gli1 effector, which coincided with deregulated expressions of the epithelial-mesenchymal transition (EMT) mediators. Colonic folate levels of CRC were inversely correlated with pluripotent expressions of the SOX2, NANOG and OCT4 markers (p cells to LFMS microenvironment significantly hypomethylated Shh promoter region, activated Shh signaling, induced transcript and protein expressions of the pluripotent markers, promoted trans-differentiation as EMT by deregulation of Snail mediator and epithelial marker E-cadherin, increased MMP2/MMP9 enzymatic digestion on matrix protein for invasion, and promoted self-renewal capability of anchorage-independent tumor-spheroid formation. LFMS-induced cancer stem cell (CSC) signature and CRC invasion is synergized with inhibition of DNA methylation by 5-Aza-2-deoxycytidine (5AZA) in rewiring EMT genotypes, which can be blockade by the Shh inhibitor (cyclopamine). The in vivo and in vitro data corroboratively identify CSC-like molecular targets specific to the LFMS-predisposed invasive CRC through reprogramming DNA methylation-activated Shh signaling. The study highlights CSC targets specific to LFMS-predisposed invasive CRC in optimizing folate co-chemotherapy to minimize tumour metastasis potential of CRC patients. © 2017 UICC.

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

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    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.

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

    Science.gov (United States)

    Kandalaft, Lana E; Powell, Daniel J; Coukos, George

    2012-08-03

    In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. 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. 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. 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.

  7. 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.

  8. Estimation of adult and neonatal RBC lifespans in anemic neonates using RBCs labeled at several discrete biotin densities.

    Science.gov (United States)

    Kuruvilla, Denison J; Widness, John A; Nalbant, Demet; Schmidt, Robert L; Mock, Donald M; An, Guohua; Veng-Pedersen, Peter

    2017-06-01

    Prior conclusions that autologous neonatal red blood cells (RBC) have substantially shorter lifespans than allogeneic adult RBCs were not based on direct comparison of autologous neonatal vs. allogeneic adult RBCs performed concurrently in the same infant. Biotin labeling of autologous neonatal RBCs and allogeneic adult donor RBCs permits concurrent direct comparison of autologous vs. allogeneic RBC lifespan. RBCs from 15 allogeneic adult donors and from 15 very-low-birth-weight (VLBW) neonates were labeled at separate biotin densities and transfused simultaneously into the 15 neonates. Two mathematical models that account for the RBC differences were employed to estimate lifespans for the two RBC populations. Mean ± SD lifespan for adult allogeneic RBC was 70.1 ± 19.1 d, which is substantially shorter than the 120 d lifespan of both autologous and adult allogeneic RBC in healthy adults. Mean ± SD lifespan for neonatal RBC was 54.2 ± 11.3 d, which is only about 30% shorter than that of the adult allogeneic RBCs. This study provides evidence that extrinsic environmental factors primarily determine RBC survival (e.g., small bore of the capillaries of neonates, rate of oxygenation/deoxygenation cycles) rather than factors intrinsic to RBC.

  9. Growth rate and medium composition strongly affect folate content in Saccharomyces cerevisiae.

    Science.gov (United States)

    Hjortmo, Sofia; Patring, Johan; Andlid, Thomas

    2008-03-31

    Folate content in a Saccharomyces cerevisiae strain was monitored during aerobic batch fermentation in synthetic growth medium, yeast peptone dextrose medium, and a molasses based medium. During growth in the synthetic medium large differences in intracellular folate content was observed at different phases. Specific folate levels, expressed per unit biomass, were highest during respiro-fermentative growth (120 microg/g) and decreased during the respiratory and stationary phases. Thus, the physiological state of the cells clearly affects the folate content. This was confirmed in chemostat cultures where total intracellular folate content increased linearly with increasing growth rate (r(2)=0.998), indicating high growth rate i.e. respiro-fermentative growth to be most favourable to obtain high specific folate content. In complex media however, much lower folate content (15-40 microg/g) was found throughout the batch growth. Only minor growth-phase related differences were detected. This shows the impact of cultivation medium on folate content in yeast. To further investigate which components that influence folate content, batch experiments in synthetic medium with addition of specific components were performed. Adding a raw mixture of peptides and amino acids (peptone) decreased folate levels extensively (90%) whereas adding amino acids one-by-one only had minor effects on the intracellular folate content. Furthermore, supplementing synthetic medium with pABA, folate or nucleotides did not change the intracellular folate content. This work constitutes the first steps towards an optimised process for production of natural folates for fortification purposes, as well as an effort to gain fundamental understanding of folate requirements in yeast in relation to environmental conditions.

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

    Science.gov (United States)

    Pascoe, Michaela C; Linden, Thomas

    2016-09-30

    Elderly stroke survivors are at risk of malnutrition and long-term cognitive impairment. Vitamin B-related metabolites, folate and methylmalonic acid, have been implicated in cognitive function. We conducted a study exploring the relationship between blood folate, methylmalonic acid and post-stroke cognitive impairment. This is a cross sectional study of elderly Swedish patients (n=149) 20 months post-stroke, assessed using the Mini Mental State Examination, serum blood levels of methylmalonic acid and red blood cell levels of folate. Linear modeling indicated that low levels of blood folate and elevated methylmalonic acid significantly contributed to cognitive impairment in stroke survivors. Half of the stroke survivors were shown to have folate deficiency at 20 months after stroke. Folate deficiency is common long term after stroke and both low folate and elevated methylmalonic acid appear to be associated with long term cognitive impairment, in elderly Swedish stroke survivors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  11. Production of folate by bacteria isolated from oat bran.

    Science.gov (United States)

    Kariluoto, Susanna; Edelmann, Minnamari; Herranen, Mirkka; Lampi, Anna-Maija; Shmelev, Anton; Salovaara, Hannu; Korhola, Matti; Piironen, Vieno

    2010-09-30

    Twenty bacteria isolated from three commercial oat bran products were tested for their folate production capability. The bacteria as well as some reference organisms were grown until early stationary phase on a rich medium (YPD), and the amount of total folate in the separated cell mass and the culture medium (supernatant) was determined by microbiological assay. Folate vitamer distribution was determined for eight bacteria including one isolated from rye flakes. For seven bacteria the effect of temperature and pH on folate production was studied in more detail. Relatively large amount of folate was both produced in the cell biomass (up to 20.8microg/g) and released to the culture medium (up to 0.38microg/g) by studied bacteria. The best producers were characterized as Bacillus subtilis ON4, Chryseobacterium sp. NR7, Janthinobacterium sp. RB4, Pantoea agglomerans ON2, and Pseudomonas sp ON8. The level of folate released in culture medium was the highest for B. subtilis ON5, Chryseobacterium sp. NR7, Curtobacterium sp. ON7, Enterococcus durans ON9, Janthinobacterium sp. RB4, Paenibacillus sp. ON10, Propionibacterium sp. RB9, and Staphylococcus kloosii RB7. Marked differences in the distribution of folate vitamers among the bacterial strains were revealed by the HPLC analysis. The main vitamers were tetrahydrofolate, 5,10-methenyltetrahydrofolate, 5-methyltetrahydrofolate, and 5-formyltetrahydrofolate. Increase in the folate content during bacterial growth was accompanied by proportional increase in the 5-methyltetrahydrofolate content and decrease of 5-formyltetrahydrofolate. 10-Formylfolic acid dominated in the culture media of four bacteria, and Janthinobacterium sp. RB4 was also found to excrete 5-methyltetrahydrofolate. Intracellular folate content was higher when the bacteria were grown at 28 degrees C than at 18 degrees C or 37 degrees C and also higher at pH 7 than at pH 5.5. Copyright 2010 Elsevier B.V. All rights reserved.

  12. RBC-choline: changes by lithium and relation to prophylactic response

    International Nuclear Information System (INIS)

    Haag, M.; Haag, H.; Eisenried, F.; Greil, W.

    1984-01-01

    Red blod cell (RBC)- and plasma-choline levels were measured in patients on lithium (n=96), antidepressants (n=32) and neuroleptics (n=51) and in 25 healthy drug-free controls. Lithium patients exhibited highly increased RBC- and slightly increased plasma-choline levels compared with controls (P<0.001 and P<0.05, respectively); the choline ratio (RBC-/plasma-choline) was elevated almost to the same extent as RBC-choline (P<0.001). With antidepressants RBC-choline and choline ratios were slightly reduced (P<0.05), whereas neuroleptics showed no effect on choline levels. 79% of lithium patients were responders (reduction in hospitalizations with lithium) 21% were non-responders (no reduction or increase in hospitalizations). Choline ratio exhibited a significant relation to prophylactic lithium response, but lithium ratio did not. The percentage of non-responders was significantly higher in patients with a choline ratio exceeding 100 than in patients with a choline ratio below this cut-off (P<0.01). Thus, the increase of RBC-choline and choline ratios appears to be an effect specific for lithium and might be related to the outcome of lithium prophylaxis. (author)

  13. Uso de índices hematimétricos no diagnóstico diferencial de anemias microcíticas: uma abordagem a ser adotada? Are Red Blood Cells (RBC indices valuable on differentiating microcytic anemias?: Differential diagnosis of microcytic anemia is a complex task, with considerable cost

    Directory of Open Access Journals (Sweden)

    MURILO REZENDE MELO

    2002-09-01

    Full Text Available O diagnóstico diferencial das anemias microcíticas é complexo e sua investigação laboratorial, de custo elevado. O uso de índices hematimétricos para racionalizar a abordagem diagnóstica tem sido proposto para contornar essa problemática. OBJETIVO: Avaliar a utilidade diagnóstica dos índices hematimétricos nas anemias microcíticas, de modo prospectivo, em hospital geral de alta complexidade. MÉTODOS: Foram analisados 2278 hemogramas realizados nos nossos serviços. Baseados em eletroforese de hemoglobina e ferritina, estratificamos 52 pacientes adultos com anemia microcítica em três grupos: Anemia ferropriva (AF; n=26 pacientes, Beta-Talassemia Menor (BTM; n=17 e Anemia não-ferropriva e não-beta-Talassemia (ANFNT; n=9. Avaliamos o uso dos seguintes índices hematimétricos na discriminação dos três grupos, por análise de variância e curvas ROC: RBC, VCM, HCM, RDW, índices de England e de Green. RESULTADOS: Nenhum dos índices permitiu a separação integral dos três grupos. Determinamos valores de corte para cada um dos índices e calculamos sensibilidade (S, especificidade(E, valores preditivos positivo e negativo e eficácia, em função de sua melhor discriminação. A discriminação de BTM foi melhor realizada pelo RBC acima de 5 milhões/mL, com S=82,3% e E=82,8%; enquanto a anemia ferropriva, pelo RDW acima de 16%, mas com S de apenas 69,2% e E=80,7%. CONCLUSÕES: A anemia ferropriva apresenta difícil diagnóstico presuntivo pelos índices, devendo ser realizada confirmação laboratorial. Valores elevados de RBC em anêmicos devem fazer suspeitar de traço talassêmico, sendo recomendável confirmação diagnóstica.OBJECTIVE: To evaluate prospectively RBC indices as a diagnostic tool at a high complexity general hospital. METHODS: We analyzed 2278 blood cell counts from the core laboratory of our service and we found 343(15% microcytic anemias. Concomitant serum samples were found from 52 patients above 14

  14. 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.

  15. Validity of the Food Frequency Questionnaire Assessing the Folate Intake in Women of Reproductive Age Living in a Country without Food Fortification: Application of the Method of Triads

    Directory of Open Access Journals (Sweden)

    Milica Zekovic

    2017-02-01

    Full Text Available The study aimed to examine the external validity of the Folate Food Frequency Questionnaire (F-FFQ designed for assessing the folate intake in Serbian women of reproductive age. The F-FFQ was tested against repeated 24 h dietary recalls and correspondent nutritional biomarkers (red blood cells (RBC and serum folate concentrations using the method of triads. In a cross sectional study, 503 women aged 18–49 years completed dietary questionnaires and representative validation subsample (n = 50 provided fasting blood samples for biomarker analyses. Correlation coefficients were calculated between each of the dietary methods and three pair-wise correlations were applied for the calculation of validity coefficients. Correlation coefficients observed between F-FFQ and three 24 h recalls were r = 0.56 (p < 0.001 and r = 0.57 (p < 0.001 for total sample and validation group, respectively. Bland–Altman plot and cross-classification analyses indicated good agreement between methods. High validity coefficients were determined between the true intake (I and dietary assessment methods, F-FFQ (Q and 24 h dietary recalls (R (ρQIrbc = 0.871 and ρQIser = 0.814; ρRIrbc = 0.652 and ρRIser = 0.698, and moderate ones for biomarkers (B (ρBIrbc = 0.428 and ρBIser = 0.421. The F-FFQ is valid instrument for the assessment of dietary folate intake in women living in Serbia, a country without mandatory folic acid food fortification.

  16. Validity of the Food Frequency Questionnaire Assessing the Folate Intake in Women of Reproductive Age Living in a Country without Food Fortification: Application of the Method of Triads

    Science.gov (United States)

    Zekovic, Milica; Djekic-Ivankovic, Marija; Nikolic, Marina; Gurinovic, Mirjana; Krajnovic, Dusanka; Glibetic, Marija

    2017-01-01

    The study aimed to examine the external validity of the Folate Food Frequency Questionnaire (F-FFQ) designed for assessing the folate intake in Serbian women of reproductive age. The F-FFQ was tested against repeated 24 h dietary recalls and correspondent nutritional biomarkers (red blood cells (RBC) and serum folate concentrations) using the method of triads. In a cross sectional study, 503 women aged 18–49 years completed dietary questionnaires and representative validation subsample (n = 50) provided fasting blood samples for biomarker analyses. Correlation coefficients were calculated between each of the dietary methods and three pair-wise correlations were applied for the calculation of validity coefficients. Correlation coefficients observed between F-FFQ and three 24 h recalls were r = 0.56 (p < 0.001) and r = 0.57 (p < 0.001) for total sample and validation group, respectively. Bland–Altman plot and cross-classification analyses indicated good agreement between methods. High validity coefficients were determined between the true intake (I) and dietary assessment methods, F-FFQ (Q) and 24 h dietary recalls (R) (ρQIrbc = 0.871 and ρQIser = 0.814; ρRIrbc = 0.652 and ρRIser = 0.698), and moderate ones for biomarkers (B) (ρBIrbc = 0.428 and ρBIser = 0.421). The F-FFQ is valid instrument for the assessment of dietary folate intake in women living in Serbia, a country without mandatory folic acid food fortification. PMID:28208817

  17. Haemostatic function and biomarkers of endothelial damage before and after RBC transfusion in patients with haematologic disease

    DEFF Research Database (Denmark)

    Larsen, A M; Leinøe, E B; Johansson, P I

    2015-01-01

    function and the endothelium) to RBC transfusion. MATERIALS AND METHODS: Blood was sampled from patients with various transfusion-dependent haematologic diseases before 1 and 24 h after RBC transfusion. Primary and secondary haemostasis was evaluated by whole-blood impedance aggregometry (Multiplate......BACKGROUND AND OBJECTIVES: Transfusion of red blood cells (RBC) is beneficial for the patient but can also be harmful, as randomized trials have demonstrated increased infection rates, bleeding and mortality. The study aim was to investigate the response of the vascular system (the haemostatic....... Compared to before transfusion, patients had slightly reduced coagulability 1 h after RBC transfusion, assessed by TEG. However, transfusion of older RBC products (>14 days) was associated with increased coagulability (all P transfusion (median...

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

    OpenAIRE

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

    2016-01-01

    Functional foods enriched with folate may be beneficial as a means of optimizing folate status in consumers. We recently developed novel eggs enriched with folate through folic acid supplementation of the hen’s feed, but their potential to influence consumer folate status is unknown because the natural folate forms incorporated into the eggs may not necessarily be retained during storage and cooking. This study aimed to determine the stability of natural folates in folate-enriched eggs under ...

  19. Evaluation of mechanical and electrical properties of RBC suspensions. Role of RBC deformability and aggregating agent

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Říha, Pavel; Ivanov, I.

    2009-01-01

    Roč. 42, č. 3 (2009), s. 211-212 ISSN 1386-0291. [Conference of the European Society for Clinical Hemorheology and Microcirculation /15./. 28.06.2009-01.07.2009, Pontresina] R&D Projects: GA AV ČR IAA200600803 Institutional research plan: CEZ:AV0Z20600510 Keywords : RBC electrical properties Subject RIV: BK - Fluid Dynamics

  20. Experimental evaluation of mechanical and electrical properties of RBC suspensions under flow. Role of RBC deformability

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Říha, Pavel; Ivanov, I.

    2010-01-01

    Roč. 25, 3-4 (2010), s. 45-52 ISSN 1313-2458 Institutional research plan: CEZ:AV0Z20600510 Keywords : apparent viscosity * conductivity * RBC suspensions * dextran 70 * PEG 35 000 * glutaraldehyde Subject RIV: BK - Fluid Dynamics

  1. Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC).

    Science.gov (United States)

    Alvarez-Fernandez, Carlos; Perez-Arnillas, Quionia; Ruiz-Echeverria, Lucrecia; Rodriguez-Rubi, David; Sanchez-Lorenzo, Luisa; Li-Torres, Walter; Izquierdo-Manuel, Marta; Berros, Jose P; Luque-Cabal, Maria; Jimenez-Fonseca, Paula; Villanueva-Palicio, Noemi; Esteban-Gonzalez, Emilio

    2014-04-01

    RFC is the major transport system in mammalian cells for folate cofactors and antifolate therapeutics. The aim of this study was to assess the predictive value of RFC expression in patients receiving pemetrexed for advanced NSCLC. The study was carried out in a population of 48 patients with advanced NSCLC which have received pemetrexed monotherapy in second and third line. RFC expression was assessed using a two-step model of immunohistochemical staining in paraffin-embedded tissue samples. RFC expression was detected in 16 (33 %) patients. In the global population, the median progression free survival (PFS) and the median overall survival (OS) were 3.3 and 6.5 months respectively. The subgroup of patients with expression of RFC had a tendency to better median PFS (4.5 vs 2.8 months; p = 0.926) and median OS (11.7 vs 4.8; p = 0.150). In patients with adenocarcinoma histology and RFC expression median OS after treatment with pemetrexed was 14.4 months versus 5.0 in those with adenocarcinoma but without RFC expression (p = 0.039). These results suggest the possible relation between RFC expression and response to treatment with antifolates (pemetrexed) independently of the tumor histology. Further studies are required to confirm these results.

  2. Expression of folate receptor alpha in the mammalian retinol pigmented epithelium and retina.

    Science.gov (United States)

    Smith, S B; Kekuda, R; Gu, X; Chancy, C; Conway, S J; Ganapathy, V

    1999-04-01

    Folic acid is essential for DNA, RNA, and protein synthesis, and deficiencies in folate can lead to nutritional amblyopia and optic neuropathy. The transport of folate from the choroidal blood supply to the retina is only now beginning to be understood. The reduced-folate transporter was reported recently to be present in cultured human retinal pigment epithelial (RPE) cells and is thought to be localized to the apical region of these cells. The authors hypothesize that the RPE plays a role in the vectorial transport of folate from the choroidal blood to the neural retina and uses not only the reduced-folate transporter but also the folate receptor alpha in mediating this transport. The purpose of the present study was to determine whether the folate receptor alpha was present in the RPE and, if so, whether it was distributed along the basolateral membrane of the RPE, supporting a role for the protein in the initial steps of folate transport into the RPE. The expression of the folate receptor alpha in mouse RPE was analyzed by reverse transcription-polymerase chain reaction (RT-PCR), functional assays, in situ hybridization, immunohistochemistry, and laser scanning confocal microscopy. RT-PCR analysis, cloning of the RT-PCR product, and subsequent sequencing established that folate receptor alpha mRNA transcripts are expressed in the mouse RPE/choroid and are expressed also in the neural retina. A heterologous functional expression assay using MTX(R)-ZR-75-1 cells showed that the folate receptor alpha cDNA obtained by RT-PCR from the RPE/choroid complex and the neural retina was functional as assessed by the binding of folic acid and by the uptake of N5-methyltetrahydrofolate. In situ hybridization localized the folate receptor alpha mRNA to the mouse RPE cells and to cells of the neural retina. The folate receptor alpha was detected immunohistochemically in the mouse and rat RPE and in several layers of the neural retina. Laser scanning confocal microscopy

  3. In vivo crossmatching with Tc-99m-RBC's and In-111-oxine-RBC's

    International Nuclear Information System (INIS)

    Marcus, C.S.; Myhre, B.A.; Angulo, M.C.; Salk, R.D.; Essex, C.E.

    1984-01-01

    In vitro crossmatching techniques are often inadequate for patients who have received multiple prior transfusions. These patients usually have multiple antibodies to minor blood groups, not all of which are necessarily important to vivo. It becomes increasingly difficult to obtain appropriate units for transfusion, and often units are used with hopes that a minor group antibody will not be significantly active in vivo. If a transfusion reaction occurs, the unit is stopped. The authors have developed and successfully tested a method whereby 1.5 to 3c of potential donor RBC's are labeled with 25-50 μCi of Tc-99m using the BNL kits. After injection, samples are drawn at 10, 20, 60, and 120 minutes and the RBC survival is measured. If it is desirable to test 2 units simultaneously, the authors use 400 μCi Tc-99m to label an RBC aliquot of one unit and 25 μCi In-111-oxine to label the other; both labeled aliquots are injected together. The method is simple and reliable. In addition to assessing compatibility, the authors may also estimate the % viability of transfused, compatible RBC's by starting with 400 μCi of Tc-99m and multiplying % survival at 24 hours by 1.2. For 24 hr. survival measurements of IN-111-oxine-RBC's, 25 μCi is adequate and no multiplication factor is necessary. The authors have performed 13 in vivo crossmatches, 4 of which were double, in 6 patients. One documented mild transfusion reaction occurred. There were no false positive or false negative results

  4. 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. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Experimental prestorage filtration removes antibodies and decreases lipids in RBC supernatants mitigating TRALI in vivo

    Science.gov (United States)

    Kelher, Marguerite R.; Khan, Samina Y.; LaSarre, Monica; West, F. Bernadette; Land, Kevin J.; Mish, Barbara; Ceriano, Linda; Sowemimo-Coker, Samuel

    2014-01-01

    Transfusion-related acute lung injury (TRALI) remains a significant cause of transfusion-related mortality with red cell transfusion. We hypothesize that prestorage filtration may reduce proinflammatory activity in the red blood cell (RBC) supernatant and prevent TRALI. Filters were manufactured for both small volumes and RBC units. Plasma containing antibodies to human lymphocyte antigen (HLA)-A2 or human neutrophil antigen (HNA)-3a was filtered, and immunoglobulins and specific HNA-3a and HLA-2a neutrophil (PMN) priming activity were measured. Antibodies to OX27 were added to plasma, and filtration was evaluated in a 2-event animal model of TRALI. RBC units from 31 donors known to have antibodies against HLA antigens and from 16 antibody-negative controls were filtered. Furthermore, 4 RBC units were drawn and underwent standard leukoreduction. Immunoglobulins, HLA antibodies, PMN priming activity, and the ability to induce TRALI in an animal model were measured. Small-volume filtration of plasma removed >96% of IgG, antibodies to HLA-A2 and HNA-3a, and their respective priming activity, as well as mitigating antibody-mediated in vivo TRALI. In RBC units, experimental filtration removed antibodies to HLA antigens and inhibited the accumulation of lipid priming activity and lipid-mediated TRALI. We conclude that filtration removes proinflammatory activity and the ability to induce TRALI from RBCs and may represent a TRALI mitigation step. PMID:24747436

  6. Less is more: removing membrane attachments stiffens the RBC cytoskeleton

    International Nuclear Information System (INIS)

    Gov, Nir S

    2007-01-01

    The polymerized network of the cytoskeleton of the red-blood cell (RBC) contains different protein components that maintain its overall integrity and attachment to the lipid bilayer. One of these key components is the band 3-ankyrin complex that attaches the spectrin filaments to the fluid bilayer. Defects in this particular component result in the shape transformation called spherocytosis, through the shedding of membrane nano-vesicles. We show here that this transition and membrane shedding can be explained through the increased stiffness of the network when the band 3-ankyrin complexes are removed. ATP-induced transient dissociations lead to network softening, which offsets the stiffening to some extent, and causes increased fragility of these mutant cells, as is observed

  7. In situ enrichment of folate by microorganisms in beta-glucan rich oat and barley matrices.

    Science.gov (United States)

    Kariluoto, Susanna; Edelmann, Minnamari; Nyström, Laura; Sontag-Strohm, Tuula; Salovaara, Hannu; Kivelä, Reetta; Herranen, Mirkka; Korhola, Matti; Piironen, Vieno

    2014-04-17

    The objective was to study folate production of yeast strains, bacteria isolated from oat bran, and selected lactic acid bacteria as well as one propionibacterium in oat and barley based models. Simultaneously, we aimed at sustaining the stability of viscosity, representing the physicochemical state of beta-glucan. Total folate contents were determined microbiologically and vitamers for selected samples by UHPLC. Folate in yeast cells comprised mainly 5-methyltetrahydrofolate and tetrahydrofolate. Folate production by microbes in YPD medium was different to that in cereal fermentations where vitamers included 5-methyltetrahydrofolate, 5,10-methenyltetrahydrofolate and formylated derivatives. Microbes producing significant amounts of folate without affecting viscosity were Saccharomyces cerevisiae ALKO743 and Candida milleri ABM4949 among yeasts and Pseudomonas sp. ON8 and Janthinobacterium sp. RB4 among bacteria. Net folate production was up to 120 ng/g after 24 h fermentation and could increase during 2-week storage. Glucose addition increased the proportion of 5-methyltetrahydrofolate. Streptococcus thermophilus ABM5097, Lactobacillus reuteri, and Propionibacterium sp. ABM5378 produced folate but in lower concentrations. Both endogenous and added microbes contribute to folate enhancement. Selection of microbes with folate producing capability and limited hydrolytic activity will enable the development of products rich in folate and beta-glucan. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. RBC Models and the Hours-Wages Puzzle: Puzzle Solved!

    OpenAIRE

    Vasilev, Aleksandar

    2015-01-01

    This paper shows that a modified real business cycle (RBC) model, one that includes home production and fiscal spending shocks, can solve one of the RBC puzzles and generates zero correlation between wages and hours. In addition, the micro-founded model presented here provides a sound theoretical model to analyze fiscal policy in a neoclassical framework and is able to capture many aspects of the data that the benchmark RBC model was missing.

  9. Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood-Brain Barrier.

    Science.gov (United States)

    Alam, Camille; Hoque, Md Tozammel; Finnell, Richard H; Goldman, I David; Bendayan, Reina

    2017-11-06

    Folates are essential for brain development and function. Folate transport in mammalian tissues is mediated by three major folate transport systems, i.e., reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα), known to be regulated by ligand-activated nuclear receptors, such as vitamin D receptor (VDR). Folate uptake at the choroid plexus, which requires the actions of both FRα and PCFT, is critical to cerebral folate delivery. Inactivating FRα or PCFT mutations cause severe cerebral folate deficiency resulting in early childhood neurodegeneration. The objective of this study was to investigate the role of RFC in folate uptake at the level of the blood-brain barrier (BBB) and its potential regulation by VDR. We detected robust expression of RFC in different in vitro BBB model systems, particularly in immortalized cultures of human cerebral microvascular endothelial cells (hCMEC/D3) and isolated mouse brain capillaries. [ 3 H]-methotrexate uptake by hCMEC/D3 cells at pH 7.4 was inhibited by PT523 and pemetrexed, antifolates with high affinity for RFC. We also showed that activation of VDR through calcitriol (1,25-dihydroxyvitamin D 3 ) exposure up-regulates RFC mRNA and protein expression as well as function in hCMEC/D3 cells and isolated mouse brain capillaries. We further demonstrated that RFC expression could be down-regulated by VDR-targeting siRNA, further confirming the role of VDR in the direct regulation of this folate transporter. Together, these data suggest that augmenting RFC functional expression could constitute a novel strategy for enhancing brain folate delivery for the treatment of neurometabolic disorders caused by loss of FRα or PCFT function.

  10. Folate mediated self-assembled phytosterol-alginate nanoparticles for targeted intracellular anticancer drug delivery.

    Science.gov (United States)

    Wang, Jianting; Wang, Ming; Zheng, Mingming; Guo, Qiong; Wang, Yafan; Wang, Heqing; Xie, Xiangrong; Huang, Fenghong; Gong, Renmin

    2015-05-01

    Self-assembled core/shell nanoparticles (NPs) were synthesized from water-soluble alginate substituted by hydrophobic phytosterols. Folate, a cancer-cell-specific ligand, was conjugated to the phytosterol-alginate (PA) NPs for targeting folate-receptor-overexpressing cancer cells. The physicochemical properties of folate-phytosterol-alginate (FPA) NPs were characterized by nuclear magnetic resonance, transmission electron microscopy, dynamic light scattering, electrophoretic light scattering, and fluorescence spectroscopy. Doxorubicin (DOX), an anticancer drug, was entrapped inside prepared NPs by dialysis method. The identification of prepared FPA NPs to folate-receptor-overexpressing cancer cells (KB cells) was confirmed by cytotoxicity and folate competition assays. Compared to the pure DOX and DOX/PA NPs, the DOX/FPA NPs had lower IC50 value to KB cells because of folate-receptor-mediated endocytosis process and the cytotoxicity of DOX/FPA NPs to KB cells could be competitively inhibited by free folate. The cellular uptake and internalization of pure DOX and DOX/FPA NPs was confirmed by confocal laser scanning microscopy image and the higher intracellular uptake of drug for DOX/FPA NPs over pure DOX was observed. The FPA NPs had the potential as a promising carrier to target drugs to cancer cells overexpressing folate receptors and avoid cytotoxicity to normal tissues. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2012-12-01

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

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

    Science.gov (United States)

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

    2016-11-01

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

  13. Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury

    Science.gov (United States)

    Knight, Sarah F.; Kundu, Kousik; Joseph, Giji; Dikalov, Sergey; Weiss, Daiana; Murthy, Niren

    2012-01-01

    Antioxidant therapy can protect against ischemic injury, but the inability to selectively target the kidney would require extremely high doses to achieve effective local concentrations of drug. Here, we developed a directed therapeutic that specifically targets an antioxidant to renal proximal tubule cells via the folate receptor. Because a local increase in superoxide contributes to renal ischemic injury, we created the folate-antioxidant conjugate 4-hydroxy-Tempo (tempol)-folate to target folate receptors, which are highly expressed in the proximal tubule. Dihydroethidium high-performance liquid chromatography demonstrated that conjugated tempol retained its efficacy to scavenge superoxide in proximal tubule cells. In a mouse model of renal ischemia-reperfusion injury, tempol-folate reduced renal superoxide levels more effectively than tempol alone. Furthermore, electron spin resonance revealed the successful targeting of the tempol-folate conjugate to the kidney and other tissues expressing folate receptors. Administration of tempol-folate protected the renal function of mice after ischemia-reperfusion injury and inhibited infiltration of macrophages. In conclusion, kidney-specific targeting of an antioxidant has therapeutic potential to prevent renal ischemic injury. Conjugation of other pharmaceuticals to folate may also facilitate the development of treatments for other kidney diseases. PMID:22282594

  14. Development of new folate-based PET radiotracers: preclinical evaluation of 68Ga-DOTA-folate conjugates

    International Nuclear Information System (INIS)

    Fani, Melpomeni; Maecke, Helmut R.; Wang, Xuejuan; Nicolas, Guillaume; Medina, Christelle; Raynal, Isabelle; Port, Marc

    2011-01-01

    A number of 111 In- and 99m Tc-folate-based tracers have been evaluated as diagnostic agents for imaging folate receptor (FR)-positive tumours. A 68 Ga-folate-based radiopharmaceutical would be of great interest, combining the advantages of PET technology and the availability of 68 Ga from a generator. The aim of the study was to develop a new 68 Ga-folate-based PET radiotracer. Two new DOTA-folate conjugates, named P3026 and P1254, were synthesized using the 1,2-diaminoethane and 3-{2-[2-(3-amino-propoxy)-ethoxy]-ethoxy}-propylamine as a spacer, respectively. Both conjugates were labelled with 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 111 In-DTPA-folate ( 111 In-P3139). The K d values of 67/68 Ga-P3026 (4.65 ± 0.82 nM) and 67/68 Ga-P1254 (4.27 ± 0.42 nM) showed high affinity for the FR. The internalization rate followed the order 67/68 Ga-P3026 > 67/68 Ga-P1254 > 111 In-P3139, while almost double cellular retention was found for 67/68 Ga-P3026 and 67/68 Ga-P1254, compared to 111 In-P3139. The biodistribution data of 67/68 Ga-DOTA-folates showed high and receptor-mediated uptake on the FR-positive tumours and kidneys, with no significant differences compared to 111 In-P3139. PET/CT images, performed with 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 68 Ga in labelling yields and specific activities which allow clinical application. The characteristics of the 67/68 Ga-DOTA-folates are comparable to 111 In-DTPA-folate, which has already been used in clinical trials, showing that the new conjugates are promising candidates as PET radiotracers

  15. Single Nucleotide Polymorphisms in Key One-Carbon Metabolism Genes and Their Association with Blood Folate and Homocysteine Levels in a Chinese Population in Yunnan.

    Science.gov (United States)

    Ni, Juan; Liu, Yaoxian; Zhou, Tao; Wu, Xiayu; Wang, Xu

    2018-02-16

    One-carbon metabolism (OCM) is essential for DNA synthesis and methylation. Single nucleotide polymorphisms (SNPs) within OCM genes may affect folic acid (FA) metabolism, disrupt homocysteine (Hcy) homeostasis, and increase the risk of disease. This study investigated the relationship between SNPs in key OCM genes and their association with blood FA and Hcy levels in a healthy population in Yunnan, China. Six SNPs within five key OCM genes (MTHFR C677T, MTHFR A1298C, MS A2756G, MTRR A66G, CBS T833C, and SHMT C1420T) were genotyped in 300 healthy volunteers (148 males and 152 females) using polymerase chain reaction/restriction fragment length polymorphism. Blood folate [serum FA (SFA) and red blood cell folate (RBC FA)] and Hcy levels were determined by chemiluminescence immunoassays and enzymatic assays. Subjects with the MTHFR 677TT genotype had significantly higher Hcy levels and RBC FA concentrations compared with those harboring the MTHFR 677CC/CT genotypes (p < 0.01). Both Hcy and blood FA concentrations were also increased in subjects with MS 2756AA, as well as those within CBS 833TT, when compared with those with MS 2756AG/GG (p < 0.05) and CBS 833TC/CC (p < 0.05) genotypes, respectively. Subjects harboring the combined genotype of MTHFR 677TT and MS 2756AA had a higher Hcy concentration than those carrying other MTHFR and MS combinations (p = 0.002). Similarly, subjects harboring the combination of CBS 833TT with MTHFR 677TT had higher Hcy concentrations than those harboring other CBS and MTHFR combinations (p = 0.011). The genotypes involving the MTHFR C677T, MS A2756G, and CBS T833C polymorphisms, including combinations of these genotypes, were the most important factors associated with blood FA and Hcy levels of the investigated SNPs in the OCM genes.

  16. Methionine synthase A2756G and reduced folate carrier1 A80G ...

    African Journals Online (AJOL)

    Maha Moustafa

    2015-10-09

    Oct 9, 2015 ... the RFC1 80G>A polymorphism has been associated with reduced red cell folate concentrations among healthy women. [21], and with reduced serum folate concentrations in mothers of down syndrome children (MDS) [22]. However, less than. 1.000 MDS were available for those meta-analyses, and sub-.

  17. Red blood cell distribution width predicts homocysteine levels in adult population without vitamin B12and folate deficiencies.

    Science.gov (United States)

    Peng, You-Fan; Pan, Guo-Gang

    2017-01-15

    Our aim in this study was to explore the relationship between red blood cell distribution width (RDW) and homocysteine levels in an adult population. The study included 344 subjects who underwent health check-up in our hospital. The demographic characteristics and laboratory parameters of participants were grouped in accordance with tertiles of RDW. An increase of homocysteine levels was found from the first to third tertiles of RDW in all participants. There was a positive correlation between RDW and homocysteine (r=0.227, Phomocysteine independently of age, NC, MCV and Hb values in multivariable logistic regression analysis (OR=1.501; 95% CI, 1.290-1.746; Phomocysteine levels among the study population, the results may support that elevated RDW should be considered to be a marker of cardiovascular events. However, the results need to be affirmed in future studies with larger samples. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Xenopus reduced folate carrier regulates neural crest development epigenetically.

    Directory of Open Access Journals (Sweden)

    Jiejing Li

    Full Text Available Folic acid deficiency during pregnancy causes birth neurocristopathic malformations resulting from aberrant development of neural crest cells. The Reduced folate carrier (RFC is a membrane-bound receptor for facilitating transfer of reduced folate into the cells. RFC knockout mice are embryonic lethal and develop multiple malformations, including neurocristopathies. Here we show that XRFC is specifically expressed in neural crest tissues in Xenopus embryos and knockdown of XRFC by specific morpholino results in severe neurocristopathies. Inhibition of RFC blocked the expression of a series of neural crest marker genes while overexpression of RFC or injection of 5-methyltetrahydrofolate expanded the neural crest territories. In animal cap assays, knockdown of RFC dramatically reduced the mono- and trimethyl-Histone3-K4 levels and co-injection of the lysine methyltransferase hMLL1 largely rescued the XRFC morpholino phenotype. Our data revealed that the RFC mediated folate metabolic pathway likely potentiates neural crest gene expression through epigenetic modifications.

  19. 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

  20. Dietary folate deficiency blocks prostate cancer progression in the TRAMP model.

    Science.gov (United States)

    Bistulfi, Gaia; Foster, Barbara A; Karasik, Ellen; Gillard, Bryan; Miecznikowski, Jeff; Dhiman, Vineet K; Smiraglia, Dominic J

    2011-11-01

    Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies have found that dietary folate interventions can affect colon cancer biology in rodent models, its impact on prostate is unknown. The purpose of this study was to determine whether dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer progression. Strikingly, mild dietary folate depletion arrested prostate cancer progression in 25 of 26 transgenic adenoma of the mouse prostate (TRAMP) mice, in which tumorigenesis is prostate-specific and characteristically aggressive. The significant effect on prostate cancer growth was characterized by size, grade, proliferation, and apoptosis analyses. Folate supplementation had a mild, nonsignificant, beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines and nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that prostate cancer is highly sensitive to folate manipulation and suggest that antifolates, paired with current therapeutic strategies, might significantly improve treatment of prostate cancer, the most commonly diagnosed cancer in American men.

  1. A gene phylogeny of the red algae (Rhodophyta) based on plastid rbcL.

    Science.gov (United States)

    Freshwater, D W; Fredericq, S; Butler, B S; Hommersand, M H; Chase, M W

    1994-01-01

    A phylogeny for the Rhodophyta has been inferred by parsimony analysis of plastid rbcL sequences representing 81 species, 68 genera, 38 families, and 17 orders of red algae; rbcL encodes the large subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase. Levels of sequence divergence among species, genera, and families are high in red algae, typically much greater than those reported for flowering plants. The Rhodophyta traditionally consists of one class, Rhodophyceae, and two subclasses, Bangiophycidae and Florideophycidae. The Bangiophycidae with three orders (Porphyridiales, Compsopogonales, and Bangiales) appears to be polyphyletic, and the Florideophycidae with 17 orders is monophyletic in this study. The current classification of the Florideophycidae based on ultrastructure of pit connections is supported. With the exception of the Rhodogorgonales, which appears to be misplaced, orders with one or two pit-plug cap layers (Hildenbrandiales, Corallinales, Acrochaetiales, Palmanales, Batrachospermales, and Nemaliales) terminate long branches of basal position within Florideophycidae in the most parsimonious rbcL tree. Orders that lack typical cap layers but possess a cap membrane are resolved as a monophyletic clade sister to the Ahnfeltiales. The large order Gigartinales, which is distributed among five rbcL clades, is polyphyletic. Families that possess typical carrageenan in their cell walls are resolved as a terminal clade containing two family complexes centered around the Solieriaceae and Gigartinaceae. PMID:8041781

  2. Development of a kit for RBC labelling with 99mTc and its clinic evaluation

    International Nuclear Information System (INIS)

    Marafuschi, A.M.; Nowotny, G.A.; Palcos, M.C.; Rotta, M. del C.

    1980-01-01

    A kit for labelling red blood cells (RBC) with 99m Tc based on a Tin Pyrophosphate mixture freeze-dried and a saline solution saturated with nitrogen has been prepared for spleen and placenta scanning, circulatory studies and blood volume determinations. The stannous tin is intended to reduce the 99m Tc pertechnetate, obtained either from generators or from solvent extraction, to the appropriate valence state suitable for labelling. The technique is as follows: Add to the heparinized blood sample the Tin-Pyrophosphate mixture dissolved in the saline solution. After five minutes incubation time at room temperature the plasma is discarded by centrifugation. Following the addition of the tracer activity to the separated RBC, the supernatant is discarded after a second centrifugation. Depending on the test to be performed, the RBC are either resuspended in saline solution for blood pool or circulation studies or denaturalized at 49.5 deg C for spleen scanning. The labelling yield (95-88%) and its stability has been checked by in vitro measurements, up to four hours after labelling. The biological distribution and spleen uptake have been determined in rats and rabbits. The developed method proved to be adequate for labelling RBC with good labelling retention. An interesting application is shown in babies with congenital cardiac defects and suspected absence of the spleen, where the scan gave a good image of the existing spleen. (author) [es

  3. Antioxidant activity of citrullus colocynthis pulp extract in the RBC's of alloxan-induced diabetic rats

    International Nuclear Information System (INIS)

    Dallak, M.; Jaliah, B.I.

    2010-01-01

    Previous studies in our laboratory showed that Citrullus colocynthis pulp seedless extract have antihyperglycemic and insulinotropic effects in alloxan induced diabetes. Reactive oxygen species have been implicated in the mechanism of damage of red blood cells and anaemia in diabetic patients. So the current study was carried out to investigate the protective role of citrullus colocynthis against oxidative stress in the RBC's of alloxan induced diabetic rats. Methods: Rats were divided into four groups each of ten rats, the first group was normal non diabetic rats given normal saline orally and was named control group, the second group was diabetic rats given normal saline orally and were named normal saline treated-diabetic rats, the third and fourth group were diabetic rats treated with the pulp extract or glibenclamide (a positive control) orally. Evaluations were made for haematological parameters in the blood and for lipid peroxidation and oxidative stress enzymes activities in the RBC's of all experimental rats. Results: The diabetic rats had a significant decrease (p<0.05) in total erythrocytes count and Packed Cell Volume (PCV) and a normal Haemoglobin (Hb) value in the blood. They also showed decreased levels of Thiobarbituric Acid Reactive Substances (TBARS) and decreased activities of Superoxide Dismutase (SOD) and Catalase (CAT) in the RBC's hemolysate. On other hand, oral administration of citrullus colocynthis or glibenclamide alleviated these altered parameters in the treated rats, they resulted in a significant increase (p<0.05) in the in total erythrocytes count and PCV (Haematocrit) values in the blood and caused a significant decreased levels of TBARS and increased activities of SOD and CAT in the RBC's of those diabetic treated rats when compared to diabetic rats given normal saline. The effect was more profound in citrullus colocynthis treated diabetic rats. Conclusion: Citrullus colocynthis pulp extract possesses a potent antioxidant property

  4. A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence.

    Science.gov (United States)

    Tefferi, A; Al-Ali, H K; Barosi, G; Devos, T; Gisslinger, H; Jiang, Q; Kiladjian, J-J; Mesa, R; Passamonti, F; Ribrag, V; Schiller, G; Vannucchi, A M; Zhou, D; Reiser, D; Zhong, J; Gale, R P

    2017-04-01

    RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 10 9 /l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.

  5. Mutation at the folate receptor 4 locus modulates gene expression profiles in the mouse uterus in response to preconceptual folate supplementation

    Science.gov (United States)

    Salbaum, J. michael; Kruger, Claudia; Kappen, Claudia

    2013-01-01

    Periconceptional supplementation of folic acid to the diet of women is considered a great success for a public health intervention. Higher folate status, either by supplementation, or via the mandatory fortification of grain products in the United States, has lead to significant reduction in the incidence of neural tube defects. Besides birth defects, folate deficiency has been linked to a variety of morbidities, most notably to increased risk for cancer. However, recent evidence suggests that excess folate may be detrimental - for birth defect incidence or in the progression of cancer. How folate mediates beneficial or detrimental effects is not well understood. It is also unknown what molecular responses are elicited in women taking folate supplements, and thus experience a bolus of folate on top of the status achieved by fortification. To characterize the response to a preconceptional regimen of supplementation with folinic acid, we performed gene expression profiling experiments on uterus tissue of pregnant mice with either wildtype alleles or targeted disruption at the folate receptor 4 locus. We observed that, depending on the genetic background, folinic acid supplementation affects expression of genes that contribute to lipid metabolism, protein synthesis, mitochondrial function, cell cycle, and cell activation. The extent of the response is strongly modulated by the genetic background. Finally, we provide evidence that folinic acid supplementation in the mutant paradigm affects histone methylation status, a potential mechanisms of gene regulation in this model. PMID:23651732

  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. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Folate biofortification in food plants

    NARCIS (Netherlands)

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

    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

  9. Association of vitamin b/sub 12/, serum ferritin and folate levels with recurrent oral ulceration

    International Nuclear Information System (INIS)

    Ghafoor, F.; Khan, A.

    2012-01-01

    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)

  10. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

    OpenAIRE

    Schreiner, Jens; Thommen, Daniela S.; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A.; Umana, Pablo; Pisa, Pavel; Lardinois, Didier

    2015-01-01

    T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting fola...

  11. Adaptive evolution of rbcL in Conocephalum (Hepaticae, bryophytes).

    Science.gov (United States)

    Miwa, Hidetsugu; Odrzykoski, Ireneusz J; Matsui, Atsushi; Hasegawa, Masami; Akiyama, Hiroyuki; Jia, Yu; Sabirov, Renat; Takahashi, Hideki; Boufford, David E; Murakami, Noriaki

    2009-07-15

    An excess of nonsynonymous substitutions over synonymous ones has been regarded as an important indicator of adaptive evolution or positive selection at the molecular level. We now report such a case for rbcL sequences among cryptic species in Conocephalum (Hepaticae, Bryophytes). This finding can be regarded as evidence of adaptive evolution in several cryptic species (especially in F and JN types) within the genus. Bryophytes are small land plants with simple morphology. We can therefore expect the existence of several biologically distinct units or cryptic species within each morphological species. In our previous study, we found three rbcL types in Asian Conocephalum japonicum (Thunb.) Grolle and also found evidence strongly suggesting that the three types are reproductively isolated cryptic species. Additionally, we examined rbcL sequence variation in six cryptic species of C. conicum (L.) Dumort. previously recognized by allozyme analyses. As a result, we were able to discriminate the six cryptic species based only on their rbcL sequences. We were able to show that rbcL sequence variation is also useful in finding cryptic species of C. conicum.

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

    Science.gov (United States)

    Deep, S; Ojha, S; Kundu, S

    2017-07-31

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

  13. Folate promotes S-adenosyl methionine reactions and the microbial methylation cycle and boosts ruminants production and reproduction.

    Science.gov (United States)

    Abbasi, Imtiaz Hussain Raja; Abbasi, Farzana; Wang, Lamei; Abd El Hack, Mohamed E; Swelum, Ayman A; Hao, Ren; Yao, Junhu; Cao, Yangchun

    2018-04-23

    Folate has gained significant attention due to its vital role in biological methylation and epigenetic machinery. Folate, or vitamin (B 9 ), is only produced through a de novo mechanism by plants and micro-organisms in the rumen of mature animals. Although limited research has been conducted on folate in ruminants, it has been noted that ruminal synthesis could not maintain folate levels in high yielding dairy animals. Folate has an essential role in one-carbon metabolism and is a strong antiproliferative agent. Folate increases DNA stability, being crucial for DNA synthesis and repair, the methylation cycle, and preventing oxidation of DNA by free radicals. Folate is also critical for cell division, metabolism of proteins, synthesis of purine and pyrimidine, and increasing the de novo delivery of methyl groups and S-adenosylmethionine. However, in ruminants, metabolism of B 12 and B 9 vitamins are closely connected and utilization of folate by cells is significantly affected by B 12 vitamin concentration. Supplementation of folate through diet, particularly in early lactation, enhanced metabolic efficiency, lactational performance, and nutritional quality of milk. Impaired absorption, oxidative degradation, or deficient supply of folate in ruminants affects DNA stability, cell division, homocysteine remethylation to methionine, de novo synthesis of S-adenosylmethionine, and increases DNA hypomethylation, uracil misincorporation into DNA, chromosomal damage, abnormal cell growth, oxidative species, premature birth, low calf weight, placental tube defects, and decreases production and reproduction of ruminant animals. However, more studies are needed to overcome these problems and reduce enormous dietary supplement waste and impaired absorption of folate in ruminants. This review was aimed to highlight the vital role of folic acid in ruminants performance.

  14. Strategi Perancangan Mutu Ripe Banana Chip (RBC Berbasis Harapan Konsumen

    Directory of Open Access Journals (Sweden)

    Bambang Herry P

    2016-11-01

    Full Text Available Ripe Banana Chip (RBC, merupakan salah satu jenis kripik yang dibuat dari pisang masak. RBC dapat dilakukan dengan menggunakan teknologi penggorengan vakum (vacum frying ataupun pembekuan (freezing. RBC pisang mas cukup banyak memiliki keunggulan dari nilai gizinya. Produk ini masih belum diketahui tingkat kesesuain mutunya dengan keinginan konsumen dilihat dari aspek fisik ataupun organoleptik. Tujuan penelitian ini agar dapat mengetahui rancangan mutu yang tepat untuk produk RBC pisang mas. Penelitian ini menggunakan tiga metode, diantaranya metode skoring, Customer Satisfaction Index (CSI, dan metode diagram tulang ikan. Hasil dari penelitian, yaitu : warna RBC dengan intensitas 5,56 (kuning dan skor 3,862 (suka ; informasi kemasan dengan intensitas 4,5 (setuju dan skor 3,534 (suka ; kenyamanan kemasan dengan intensitas 8,58 (nyaman dan skor 4,155 (suka ; keamanan kemasan dengan intensitas 8,15 (sangat aman dan skor 4,086 (suka ; ketebalan dengan intensitas 8,31(sangat tebal dan skor 1,604 (sangat tidak suka ; Oil dengan intensitas 4,86 (banyak dan skor 2,483 (tidak suka ; kerenyahan dengan intensitas 7,32 (keras dan skor 2,843 (cukup suka ; Easy of breaking dengan intensitas 5,17 (mudah dipatahkan dan skor 3,158 (cukup suka ; rasa manis dengan intensitas 7,89 (manis dan skor 3,208 (cukup suka ; rasa asam dengan intensitas 4,84 (agak asam dan skor 3,309 (cukup suka. Nilai CSI yang dihasilkan, yaitu sebesar 64% (puas. Strategi untuk meningkatkan mutu RBC diantaranya: mengurangi ukuran ketebalan bahan baku sebelum diproses; lebih dipertimbangkan lagi tingkat kematangan pisang; memberi pengarahan dan motivasi kepada pekerja; melakukan pengawasan saat produksi berlangsung; lebih memperhatikan keseragaman ukuran pisang, dan menggunakan alternatif lain dalam penirisan minyak, misalnya sentrifuse agar keberadaan minyak berkurang.

  15. 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.

  16. Evaluation of in vivo mutagenicity of isopropyl methanesulfonate by RBC Pig-a and PIGRET assays.

    Science.gov (United States)

    Itoh, Satoru; Hattori, Chiharu; Nakayama, Shiho; Hanamoto, Akiharu

    2016-11-15

    A comparison between the original red blood cell (RBC) Pig-a assay, which measures Pig-a mutant cells in RBCs, and the PIGRET assay, which uses reticulocytes, was conducted using the in vivo mutagenesis assay with isopropyl methanesulfonate (iPMS) as a part of a collaborative study by the Mammalian Mutagenicity Study Group in the Japanese Environmental Mutagen Society. Three dose levels of iPMS (50, 100, and 200mg/kg) were administered once intraperitoneally to 8-week-old male Crl:CD(SD) rats, and peripheral blood was sampled at 0 (1 day before dosing), and 1, 2, and 4 weeks after dosing with iPMS. As a result, a time-dependent increase in the mutant frequency of Pig-a mutant RBCs was observed in the RBC Pig-a assay, and a statistically significant increase was observed from 2 weeks after dosing. In the PIGRET assay, on the other hand, a statistically significant increase in Pig-a mutant frequency was obtained from 1 week after dosing at all dose levels, and the Pig-a mutant frequency at the highest dose level had already reached a plateau on week 1. The maximum Pig-a mutant frequency induced by a single treatment with iPMS at 200mg/kg in the PIGRET assay was approximately two times higher than that in the RBC Pig-a assay. These results indicate that the PIGRET assay can detect Pig-a mutants much earlier and with a higher value in Pig-a mutant frequency compared with the original RBC Pig-a assay, and it can enable judgement of mutagenicity of iPMS within 1 week after a single dose. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in vivo.

    Science.gov (United States)

    Narayanan, Sabrina; McConnell, Josie; Little, Julian; Sharp, Linda; Piyathilake, Chandrika J; Powers, Hilary; Basten, Graham; Duthie, Susan J

    2004-09-01

    Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.

  18. Folate metabolism abnormalities in autism: potential biomarkers.

    Science.gov (United States)

    Frye, Richard E; Slattery, John C; Quadros, Edward V

    2017-08-03

    Autism spectrum disorder (ASD) has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD.

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

    Science.gov (United States)

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

    2016-11-30

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

  20. Endocytosis of GPI-linked membrane folate receptor-alpha.

    Science.gov (United States)

    Rijnboutt, S; Jansen, G; Posthuma, G; Hynes, J B; Schornagel, J H; Strous, G J

    1996-01-01

    GPI-linked membrane folate receptors (MFRs) have been implicated in the receptor-mediated uptake of reduced folate cofactors and folate-based chemotherapeutic drugs. We have studied the biosynthetic transport to and internalization of MFR isoform alpha in KB-cells. MFR-alpha was synthesized as a 32-kD protein and converted in a maturely glycosylated 36-38-kD protein 1 h after synthesis. 32-kD MFR-alpha was completely soluble in Triton X-100 at 0 degree C. In contrast, only 33% of the 36-38-kD species could be solubilized at these conditions whereas complete solubilization was obtained in Triton X-100 at 37 degrees C or in the presence of saponin at 0 degree C. Similar solubilization characteristics were found when MFR-alpha at the plasma membrane was labeled with a crosslinkable 125I-labeled photoaffinity-analog of folic acid as a ligand. Triton X-100-insoluble membrane domains containing MFR-alpha could be separated from soluble MFR-alpha on sucrose flotation gradients. Only Triton X-100 soluble MFR-alpha was internalized from the plasma membrane. The reduced-folate-carrier, an integral membrane protein capable of translocating (anti-)folates across membranes, was completely excluded from the Triton X-100-resistant membrane domains. Internalized MFR-alpha recycled slowly to the cell surface during which it remained soluble in Triton X-100 at 0 degree C. Using immunoelectron microscopy, we found MFR-alpha along the entire endocytic pathway: in clathrin-coated buds and vesicles, and in small and large endosomal vacuoles. In conclusion, our data indicate that a large fraction, if not all, of internalizing MFR-alpha bypasses caveolae.

  1. 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

  2. Chitosan-folate decorated carbon nanotubes for site specific lung cancer delivery.

    Science.gov (United States)

    Singh, Rahul Pratap; Sharma, Gunjan; Sonali; Singh, Sanjay; Bharti, Shreekant; Pandey, Bajarangprasad L; Koch, Biplob; Muthu, Madaswamy S

    2017-08-01

    The aim of this work was to formulate chitosan-folate conjugated multi-walled carbon nanotubes for the lung cancer targeted delivery of docetaxel. The chitosan-folate conjugate was synthesized and the conjugation was confirmed by Fourier transform infrared spectroscopy. The multi-walled carbon nanotubes were characterized for their particle size, polydispersity, zeta potential, surface morphology, drug encapsulation efficiency and in vitro release study. The in vitro cellular uptake, cytotoxicity, and cell cycle analysis of the docetaxel/coumarin-6 loaded multi-walled carbon nanotubes were carried out to compare the effectiveness of the formulations. The biocompatibility and safety of chitosan-folate conjugated multi-walled carbon nanotubes was analyzed by lung histopathology in comparison with marketed docetaxel formulation (Docel™) and acylated multi-walled carbon nanotubes. The cellular internalization study shown that the chitosan-folate conjugated multi-walled carbon nanotubes could be easily internalized into the lung cancer cells through a folate receptor-mediated endocytic pathway. The IC 50 values exhibited that chitosan-folate conjugated multi-walled carbon nanotubes could be 89-fold more effective than Docel™ in human lung cancer cells (A549 cells). Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Near-elimination of folate-deficiency anemia by mandatory folic acid fortification in older US adults: Reasons for Geographic and Racial Differences in Stroke study 2003-2007.

    Science.gov (United States)

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

    2013-10-01

    The United States implemented mandatory folic acid fortification of enriched cereal grains in 1998. Although several studies have documented the resulting decrease in anemia and folate deficiency, to our knowledge, no one has determined the prevalence of folate-deficiency anemia after fortification. We determined the prevalence of folate deficiency and folate-deficiency anemia within a sample of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The REGARDS cohort is a prospective cohort of 30,239 black and white participants living in the contiguous United States. We measured serum folate concentrations in a random sample of 1546 REGARDS participants aged ≥50 y with baseline hemoglobin and red blood cell mean corpuscular volume measurements. Folate deficiency was defined as a serum folate concentration folic acid fortification, the prevalence of folate-deficiency anemia is nearly nonexistent in a community-dwelling population in the United States.

  4. Experimental evaluation of mechanical and electrical properties of RBC suspensions under flow. Role of RBC aggregating agent

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Říha, Pavel; Ivanov, I.

    2010-01-01

    Roč. 45, 2-4 (2010), s. 253-261 ISSN 1386-0291 R&D Projects: GA AV ČR IAA200600803 Institutional research plan: CEZ:AV0Z20600510 Keywords : apparent viscosity * conductivity * unsteady flow * RBC suspensions * dextrans * PEG Subject RIV: BK - Fluid Dynamics Impact factor: 2.838, year: 2010

  5. Imaging Atherosclerotic Plaque Inflammation via Folate Receptor Targeting Using a Novel 18F-Folate Radiotracer

    Directory of Open Access Journals (Sweden)

    Adrienne Müller

    2014-03-01

    Full Text Available Folate receptor β (FR-β is overexpressed on activated, but not resting, macrophages involved in a variety of inflammatory and autoimmune diseases. A pivotal step in atherogenesis is the subendothelial accumulation of macrophages. In nascent lesions, they coordinate the scavenging of lipids and cellular debris to define the likelihood of plaque inflammation and eventually rupture. In this study, we determined the presence of FR-β-expressing macrophages in atherosclerotic lesions by the use of a fluorine-18-labeled folate-based radiotracer. Human endarterectomized specimens were used to measure gene expression levels of FR-β and CD68. Increased FR-β and CD68 levels were found in atherosclerotic plaques compared to normal artery walls by quantitative real-time polymerase chain reaction. Western blotting and immunohistochemistry demonstrated prominent FR-β protein levels in plaques. FR- β-positive cells colocalized with activated macrophages (CD68 in plaque tissue. Carotid sections incubated with 3′-aza-2′- [18F]fluorofolic acid displayed increased accumulation in atherosclerotic plaques through in vitro autoradiography. Specific binding of the radiotracer correlated with FR-β-expressing macrophages. These results demonstrate high FR-β expression in atherosclerotic lesions of human carotid tissue correlating with CD68-positive macrophages. Areas of high 3′-aza-2′-[18F]fluorofolic acid binding within the lesions represented FR-β-expressing macrophages. Selectively targeting FR-β-positive macrophages through folate-based radiopharmaceuticals may be useful for noninvasive imaging of plaque inflammation.

  6. Arabidopsis Pol II-Dependent in Vitro Transcription System Reveals Role of Chromatin for Light-Inducible rbcS Gene Transcription1

    Science.gov (United States)

    Ido, Ayaka; Iwata, Shinya; Iwata, Yuka; Igarashi, Hisako; Hamada, Takahiro; Sonobe, Seiji; Sugiura, Masahiro; Yukawa, Yasushi

    2016-01-01

    In vitro transcription is an essential tool to study the molecular mechanisms of transcription. For over a decade, we have developed an in vitro transcription system from tobacco (Nicotiana tabacum)-cultured cells (BY-2), and this system supported the basic activities of the three RNA polymerases (Pol I, Pol II, and Pol III). However, it was not suitable to study photosynthetic genes, because BY-2 cells have lost their photosynthetic activity. Therefore, Arabidopsis (Arabidopsis thaliana) in vitro transcription systems were developed from green and etiolated suspension cells. Sufficient in vitro Pol II activity was detected after the minor modification of the nuclear soluble extracts preparation method; removal of vacuoles from protoplasts and L-ascorbic acid supplementation in the extraction buffer were particularly effective. Surprisingly, all four Arabidopsis Rubisco small subunit (rbcS-1A, rbcS-1B, rbcS-2B, and rbcS-3B) gene members were in vitro transcribed from the naked DNA templates without any light-dependent manner. However, clear light-inducible transcriptions were observed using chromatin template of rbcS-1A gene, which was prepared with a human nucleosome assembly protein 1 (hNAP1) and HeLa histones. This suggested that a key determinant of light-dependency through the rbcS gene transcription was a higher order of DNA structure (i.e. chromatin). PMID:26662274

  7. 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

  8. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cellsTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Baslund, B.; Gregers, J.; Nielsen, Claus Henrik

    2008-01-01

    OBJECTIVE: To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells. METHODS: Mononuclear cells were isolated from peripheral blood of healthy persons. Real-time PCR was used to detect the RFC80 variants. FITC-labelled MTX was added...... to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression. RESULTS: Antigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n...... = 9) exhibited lower uptake of MTX than individuals expressing the AA variant (n = 8), or the GA variant (n = 8). No difference could be demonstrated between the three groups with respect to the expression of RFC by CD4+ T cells and B cells, and CD4+ T cells from individuals homozygous for the G...

  9. Folates: Key Nutrients to Remember

    OpenAIRE

    Gourchala Freha; Mihoub Fatma; Henchiri Cherifa

    2017-01-01

    Folic acid or vitamin B9 or pteroylglutamic acid, is a relatively simple molecule with two characteristics; firstly, it must be reduced by 2 or 4 hydrogen atoms to be metabolically active which makes it sensitive to oxidation and must be protected by ascorbic acid, secondly it may include in addition to the constituent residues of the molecule, 1-7 glutamate residue at one of its ends. These polyglutamate forms that make up the largest share of food folate, must be deconjugated by a specific ...

  10. Molecular phylogeny of cycads inferred from rbcL sequences

    Science.gov (United States)

    Treutlein, Jens; Wink, Michael

    2002-03-01

    The chloroplast gene rbcL was sequenced to elucidate the evolution of the gymnosperm plant order Cycadales. In accordance with traditional systematics, the order Cycadales and the corresponding genera cluster as monophyletic clades. Among them, the genus Cycas forms a basal group. The genetic distances within the genus Encephalartos and between the sister groups Encephalartos, Lepidozamia and Macrozamia, are unexpectedly small, suggesting that the extant species are the result of Miocene and Pliocene speciation. Their distribution in Africa or Australia, respectively, may therefore rather be due to long-distance dispersal than to Cretaceous continental drift, as had previously been assumed. The rbcL sequences also indicate that the colonisation of Madagascar by Cycas thouarsii occurred only recently as the sequences of C. thouarsii and Cycas rumphii from Indonesia are identical. In contrast, the divergence of the Cycadaceae and Zamiaceae apparently occurred in the Mesozoic.

  11. Quantification of endocytosis using a folate functionalized silica hollow nanoshell platform.

    Science.gov (United States)

    Sandoval, Sergio; Mendez, Natalie; Alfaro, Jesus G; Yang, Jian; Aschemeyer, Sharraya; Liberman, Alex; Trogler, William C; Kummel, Andrew C

    2015-08-01

    A quantification method to measure endocytosis was designed to assess cellular uptake and specificity of a targeting nanoparticle platform. A simple N -hydroxysuccinimide ester conjugation technique to functionalize 100-nm hollow silica nanoshell particles with fluorescent reporter fluorescein isothiocyanate and folate or polyethylene glycol (PEG) was developed. Functionalized nanoshells were characterized using scanning electron microscopy and transmission electron microscopy and the maximum amount of folate functionalized on nanoshell surfaces was quantified with UV-Vis spectroscopy. The extent of endocytosis by HeLa cervical cancer cells and human foreskin fibroblast (HFF-1) cells was investigated in vitro using fluorescence and confocal microscopy. A simple fluorescence ratio analysis was developed to quantify endocytosis versus surface adhesion. Nanoshells functionalized with folate showed enhanced endocytosis by cancer cells when compared to PEG functionalized nanoshells. Fluorescence ratio analyses showed that 95% of folate functionalized silica nanoshells which adhered to cancer cells were endocytosed, while only 27% of PEG functionalized nanoshells adhered to the cell surface and underwent endocytosis when functionalized with 200 and 900  μg , respectively. Additionally, the endocytosis of folate functionalized nanoshells proved to be cancer cell selective while sparing normal cells. The developed fluorescence ratio analysis is a simple and rapid verification/validation method to quantify cellular uptake between datasets by using an internal control for normalization.

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

    Directory of Open Access Journals (Sweden)

    Leslie Altic

    2016-11-01

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

  13. 77 FR 50487 - Application To Export Electric Energy; RBC Energy Services LP

    Science.gov (United States)

    2012-08-21

    ... a power marketer for a five-year term. The current export authority in Order No EA-328 will expire... to RBC Energy. The application also indicates that RBC Energy is a power marketer authorized by the...

  14. The study of serum folate in patients with colon cancer

    International Nuclear Information System (INIS)

    Xu Sumei; Li Long

    2002-01-01

    Serum folate concentration was measured by radioimmunoassay in 36 patients with colon cancer. Folate concentration in the patients was lower than that in controls (P<0.05). Serum folate concentration was closely related to colon cancer. Regulating food and drink structure to improve lower folate condition could play a active part in preventing colon cancer

  15. Folate recommendations for pregnancy, lactation, and infancy.

    Science.gov (United States)

    Lamers, Yvonne

    2011-01-01

    An adequate intake of folate during pregnancy, lactation, and infancy is essential for maternal and child health and normal growth. Higher folate requirements during pregnancy and lactation are difficult to meet by increased intake of folate-rich food products only. Supplementation with folic acid is recommended not only to meet the higher requirements but also to prevent adverse pregnancy outcomes such as neural tube defects (NTDs). In countries that have implemented food fortification with folic acid, the folate intake has raised but does not yet meet the recommended amount for NTD risk reduction. Women's awareness of the need to supplement with folic acid prior to conception shall be raised in all countries. It is under debate whether a high folic acid intake might have metabolic and functional effects in utero and for the infant. Research is needed to investigate potential alternative folate forms for food fortification programs and to test their efficacy in risk reduction of adverse pregnancy outcomes. Breast-fed infants most likely receive sufficient folate. While the folate level of human milk is simulated in infant formula, data are lacking on the bioavailability and effect of folic acid in infants and on whether a tolerable upper intake level should be defined. Copyright © 2011 S. Karger AG, Basel.

  16. 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.

  17. An ATPase dependent, radiosensitive acidic microclimate essential for intestinal folate absorption

    International Nuclear Information System (INIS)

    Kesavan, V.; Noronha, J.M.

    1978-01-01

    Methyltetrahydrofolic acid transport was studied across everted sacs of rat jejunal segments from control and whole-body X-irradiated (700 rad) rats at 10 -5 M concentrations (at which optimum transport occurs) at various pHs. The folate transport from mucosal to serosal compartment was inhibited by about 55% in irradiated rats at the pH of the intestinal chyme (6.5). Extraneous ATP in the incubation system could restore the defective transport of the irradiated intestine. The maximum folate transport which occurred at pH 4.0 was not adversely affected by whole body irradiation. An acidic, pH dependent, passive uptake of 5-methyltetrahydrofolic acid was observed. The normal absorption barrier of the small bowel was not disrupted by the acidification process as practically no uptake was observed with irradiated segments pretreated at pH 4.0 except in the presence of ATP. Leucine and serine transport at a zero concentration gradient indicated active transport mechanisms which were not affected by acidification. Their uptake was additively increased in the presence of glucose and ATP, further indicating that the normal physiology of the intestines was not affected by the acidification process. An intestinal mucosal cell surface ATPase was observed which was Mg 2+ dependent. It could hydrolyse solution phase ATP and thus generate the protons necessary for the acidification of a microenvironment where passive uptake of the neutral folate species could occur. The ATPase activity was inhibited about 90% by 50 mM-Na azide at pH 6.5. Below this concentration folate transport was also inhibited. Na azide did not inhibit folate transport at pH 4.0, suggesting that its inhibition of folate uptake at pH 6.5 is related to its inhibitory effect on ATPase, rather than on folate transport per se. ATPase activity was therefore essential for folate transport at the pH of the intestinal chyme. (author)

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

    Science.gov (United States)

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

    2012-01-01

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

  19. 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.

  20. Folate

    Science.gov (United States)

    ... peas, and kidney beans). Grains (including whole grains ; fortified cold cereals; enriched flour products such as bread, bagels, cornmeal, and pasta; ... 400 mcg of folic acid daily from supplements, fortified foods, or both in ... bread, cereal, flour, cornmeal, pasta, rice, and other grain products sold ...

  1. Folate receptor targeting silica nanoparticle probe for two-photon fluorescence bioimaging

    Science.gov (United States)

    Wang, Xuhua; Yao, Sheng; Ahn, Hyo-Yang; Zhang, Yuanwei; Bondar, Mykhailo V.; Torres, Joseph A.; Belfield, Kevin D.

    2010-01-01

    Narrow dispersity organically modified silica nanoparticles (SiNPs), diameter ~30 nm, entrapping a hydrophobic two-photon absorbing fluorenyl dye, were synthesized by hydrolysis of triethoxyvinylsilane and (3-aminopropyl)triethoxysilane in the nonpolar core of Aerosol-OT micelles. The surface of the SiNPs were functionalized with folic acid, to specifically deliver the probe to folate receptor (FR) over-expressing Hela cells, making these folate two-photon dye-doped SiNPs potential candidates as probes for two-photon fluorescence microscopy (2PFM) bioimaging. In vitro studies using FR over-expressing Hela cells and low FR expressing MG63 cells demonstrated specific cellular uptake of the functionalized nanoparticles. One-photon fluorescence microscopy (1PFM) imaging, 2PFM imaging, and two-photon fluorescence lifetime microscopy (2P-FLIM) imaging of Hela cells incubated with folate-modified two-photon dye-doped SiNPs were demonstrated. PMID:21258480

  2. Increase in Red Blood Cell-Nitric Oxide Synthase Dependent Nitric Oxide Production during Red Blood Cell Aging in Health and Disease: A Study on Age Dependent Changes of Rheologic and Enzymatic Properties in Red Blood Cells

    Science.gov (United States)

    Bizjak, Daniel Alexander; Brinkmann, Christian; Bloch, Wilhelm; Grau, Marijke

    2015-01-01

    Aim To investigate RBC-NOS dependent NO signaling during in vivo RBC aging in health and disease. Method RBC from fifteen healthy volunteers (HC) and four patients with type 2 diabetes mellitus (DM) were separated in seven subpopulations by Percoll density gradient centrifugation. Results The proportion of old RBC was significantly higher in DM compared to HC. In both groups, in vivo aging was marked by changes in RBC shape and decreased cell volume. RBC nitrite, as marker for NO, was higher in DM and increased in both HC and DM during aging. RBC deformability was lower in DM and significantly decreased in old compared to young RBC in both HC and DM. RBC-NOS Serine1177 phosphorylation, indicating enzyme activation, increased during aging in both HC and DM. Arginase I activity remained unchanged during aging in HC. In DM, arginase I activity was significantly higher in young RBC compared to HC but decreased during aging. In HC, concentration of L-arginine, the substrate of RBC-NOS and arginase I, significantly dropped from young to old RBC. In DM, L-arginine concentration was significantly higher in young RBC compared to HC and significantly decreased during aging. In blood from healthy subjects, RBC-NOS activation was additionally inhibited by N5-(1-iminoethyl)-L-Ornithine dihydrochloride which decreased RBC nitrite, and impaired RBC deformability of all but the oldest RBC subpopulation. Conclusion This study first-time showed highest RBC-NOS activation and NO production in old RBC, possibly to counteract the negative impact of cell shrinkage on RBC deformability. This was even more pronounced in DM. It is further suggested that highly produced NO only insufficiently affects cell function of old RBC maybe because of isolated RBC-NOS in old RBC thus decreasing NO bioavailability. Thus, increasing NO availability may improve RBC function and may extend cell life span in old RBC. PMID:25902315

  3. Folate status in Aboriginal people before and after mandatory fortification of flour for bread-making in Australia.

    Science.gov (United States)

    Bower, Carol; Maxwell, Susannah; Hickling, Siobhan; D'Antoine, Heather; O'Leary, Peter

    2016-06-01

    Mandatory fortification of wheat flour for bread-making was introduced in Australia in September 2009, to assist in the prevention of neural tube defects (NTD). NTD are twice as common in Aboriginal compared with non-Aboriginal infants, and folate levels are lower in the Aboriginal population. This study was undertaken to compare folate status and NTD in the Aboriginal population before and after fortification. Postfortification, 95 Aboriginal men and nonpregnant women aged 16-44 years in metropolitan and regional Western Australia (WA) completed a rapid dietary assessment tool and had blood taken to measure red cell folate. Measures were compared with prefortification values obtained in an earlier study using the same methods. Data on NTD in Aboriginal infants were obtained from the WA Register of Developmental Anomalies. No participant was folate deficient. The mean red cell folate increased after fortification to 443 ng/mL for males and 567 ng/mL for females. The mean difference between red cell folate after fortification compared with before was 129 ng/mL for males (95% CI 81-177); t = 5.4; P fortified shop-bought bread at least weekly, resulting in an estimated additional folate intake per day of 178 (males) and 145 (females) dietary folate equivalents. NTD prevalence fell by 68% following fortification (prevalence ratio 0.32 (CI 0.15-0.69)). The population health intervention of mandatory fortification of wheat flour for bread-making has had the desired effect of increasing folate status and reducing NTD in the Australian Aboriginal population. © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  4. Autologus or allogenic uses of umbilical cord blood whole or RBC transfusion - a review.

    Science.gov (United States)

    Chakrabarty, P; Rudra, S

    2013-01-01

    Once Umbilical Cord with Placenta considered a biological waste product and generally discarded after delivery but now cord blood has emerged as a viable source of hematopoietic stem cell transplantation. High-risk premature infants require red cell transfusions for anemia. A unique property of cord blood (CB) for its high content of immature hematopoietic progenitor cells (HPCs). Placental blood for autologous transfusions can be collected with aseptic precaution/sterilely into citrate-phosphate-dextrose and stored at 4°C. During storage for 8 days, the placental red cell content of adenosine triphosphate remained normal. The 2,3,-diphosphoglycerate concentration of cells stored beyond 8 days declined sharply. So we have to store umbilical cord blood (UCB) within 7 days for its best result. During storage, placental blood underwent an exchange of extra-cellular Na+ and K+, but no change in glutathione content. Hemolysis was less than 1 percent. Bacteriologic and fungal cultures remained sterile. These suggest that human placental blood can be collected safely and preserved effectively for autologous/allogenic transfusion therapy. In neonatal transfusion practice, efforts have been made to provide premature infants with autologous red blood cell (RBC), especially those born before 32 gestational weeks. In India no adverse transfusion effects were seen in a wide variety of patients that received (pooled) allogeneic fresh whole blood / UCB transfusions. The use of UCB for small volume allogeneic transfusions in anaemic children in Africa or in malaria endemic areas has also been proposed. A preclinical study showed that donation and transfusion of UCB would be acceptable to women living in Mombasa, Kenya. In view of the small volumes RBC per unit that can be collected, it is most likely that anaemic children need of a small volume of transfusions. In resource-restricted countries would benefit most from this easily available transfusion product.

  5. Super-Resolution Localization Microscopy of γ-H2AX and Heterochromatin after Folate Deficiency.

    Science.gov (United States)

    Bach, Margund; Savini, Claudia; Krufczik, Matthias; Cremer, Christoph; Rösl, Frank; Hausmann, Michael

    2017-08-08

    Folate is an essential water-soluble vitamin in food and nutrition supplements. As a one-carbon source, it is involved in many central regulatory processes, such as DNA, RNA, and protein methylation as well as DNA synthesis and repair. Deficiency in folate is considered to be associated with an increased incidence of several malignancies, including cervical cancer that is etiologically linked to an infection with "high-risk" human papilloma viruses (HPV). However, it is still not known how a recommended increase in dietary folate after its deprivation affects the physiological status of cells. To study the impact of folate depletion and its subsequent reconstitution in single cells, we used quantitative chromatin conformation measurements obtained by super-resolution fluorescence microscopy, i.e., single molecule localization microscopy (SMLM). As a read-out, we examined the levels and the (re)positioning of γ-H2AX tags and histone H3K9me3 heterochromatin tags after immunostaining in three-dimensional (3D)-conserved cell nuclei. As model, we used HPV16 positive immortalized human keratinocytes that were cultivated under normal, folate deficient, and reconstituted conditions for different periods of time. The results were compared to cells continuously cultivated in standard folate medium. After 13 weeks in low folate, an increase in the phosphorylation of the histone H2AX was noted, indicative of an accumulation of DNA double strand breaks. DNA repair activity represented by the formation of those γ-H2AX clusters was maintained during the following 15 weeks of examination. However, the clustered arrangements of tags appeared to relax in a time-dependent manner. Parallel to the repair activity, the chromatin methylation activity increased as detected by H3K9me3 tags. The progress of DNA double strand repair was accompanied by a reduction of the detected nucleosome density around the γ-H2AX clusters, suggesting a shift from hetero- to euchromatin to allow access

  6. 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

  7. Impact of MTHFR polymorphisms on methylation of MGMT in glioma patients from Northeast China with different folate levels.

    Science.gov (United States)

    Liu, N; Jiang, J; Song, Y J; Zhao, S G; Tong, Z G; Song, H S; Wu, H; Zhu, J Y; Gu, Y H; Sun, Y; Hua, W; Qi, J P

    2013-10-29

    Hypomethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter in glioma cells has been associated with temozolomide resistance. S-adenosylmethionine (SAM), which is produced during folate metabolism, is the main source of methyl groups during DNA methylation. As a key enzyme during folate metabolism, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) may regulate folate end-products. We investigated the effect of typical polymorphisms of MTHFR (C677T and A1298C) on MGMT methylation based on different serum folate levels in patients with glioma from Northeast China. A total of 275 patients with glioma and 329 without malignant tumors were tested. Serum folate concentration was assayed by using the electrochemiluminescence immunoassay. MTHFR polymorphisms were detected by Taqman-Fluorescence quantitative polymerase chain reaction (PCR). Methylation-specific PCR was used to assess MGMT methylation. The constituent ratio of glioma patients below the serum folate biological reference value was significantly higher than that of the control population (P A1298C mutation were found in higher frequency than homozygotes or wild types (oligodendroglioma, P methylation of MGMT (median, P < 0.001; biological reference value, P = 0.036). These data suggest that, in combination with a negative folate balance in glioma patients, T/T genotypes in MTHFR C677T may be associated with MGMT demethylation.

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

    International Nuclear Information System (INIS)

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

    1987-01-01

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

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

    International Nuclear Information System (INIS)

    Guo Congying; Zhu Jianhua; Qian Jun; Yang Yang; Shen Haixing; Zhang Zhengwei

    2009-01-01

    This work is aimed at synthesizing an 18 F-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, 18 F labeling of folic acid was achieved in three steps of 18 F 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. 18 F-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: 18 F-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, 18 F-flurophenethyl folate accumulated in the tumor tissue, exhibiting its potential as a tumor PET imaging agent. (authors)

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

    DEFF Research Database (Denmark)

    Birn, Henrik; Zhai, Xiaoyue; Holm, Jan

    2005-01-01

    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...... 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...

  11. 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.

  12. In vitro particulate analogue fluids for experimental studies of rheological and hemorheological behavior of glucose-rich RBC suspensions.

    Science.gov (United States)

    Pinho, Diana; Campo-Deaño, Laura; Lima, Rui; Pinho, Fernando T

    2017-09-01

    Suspensions of healthy and pathological red blood cells (RBC) flowing in microfluidic devices are frequently used to perform in vitro blood experiments for a better understanding of human microcirculation hemodynamic phenomena. This work reports the development of particulate viscoelastic analogue fluids able to mimic the rheological and hemorheological behavior of pathological RBC suspensions flowing in microfluidic systems. The pathological RBCs were obtained by an incubation of healthy RBCs at a high concentration of glucose, representing the pathological stage of hyperglycaemia in diabetic complications, and analyses of their deformability and aggregation were carried out. Overall, the developed in vitro analogue fluids were composed of a suspension of semi-rigid microbeads in a carrier viscoelastic fluid made of dextran 40 and xanthan gum. All suspensions of healthy and pathological RBCs, as well as their particulate analogue fluids, were extensively characterized in steady shear flow, as well as in small and large amplitude oscillatory shear flow. In addition, the well-known cell-free layer (CFL) phenomenon occurring in microchannels was investigated in detail to provide comparisons between healthy and pathological in vitro RBC suspensions and their corresponding analogue fluids at different volume concentrations (5% and 20%). The experimental results have shown a similar rheological behavior between the samples containing a suspension of pathological RBCs and the proposed analogue fluids. Moreover, this work shows that the particulate in vitro analogue fluids used have the ability to mimic well the CFL phenomenon occurring downstream of a microchannel contraction for pathological RBC suspensions. The proposed particulate fluids provide a more realistic behavior of the flow properties of suspended RBCs when compared with existing non-particulate blood analogues, and consequently, they are advantageous for detailed investigations of microcirculation.

  13. Simultaneous radioassay of folate and vitamin B12

    International Nuclear Information System (INIS)

    1981-01-01

    An improved simultaneous radioassay for folate and vitamin B 12 in biological specimens is described. A sample containing folate and vitamin B 12 is contacted with 125 I-folate and 57 Co-vitamin B 12 and their respective specific binders. After separation of the bound and free portions, the radioactivity in the portions is counted and the amounts of folate and vitamin B 12 then determined from standard curves. (U.K.)

  14. Folates in plants: research advances and progress in crop biofortification

    Science.gov (United States)

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

    2017-03-01

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

  15. Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.

    Science.gov (United States)

    Golding, Paul Henry

    2014-01-01

    The currently accepted theory, that the human liver store of folate is limited to about four months, is based on the findings of Victor Herbert and others of the era before folate fortification of food. A recent model, developed by Lin et al., predicts far greater liver folate storage capacity than reported by Herbert. The conflict between Herbert's and Lin's models needs to be resolved experimentally, however current research is restricted because ethical considerations prevent such risky experimentation on patients or healthy human volunteers. The objective was to provide a detailed record of the biochemical and haematological responses to the development of severe experimental folate deficiency in an initially replete human subject. This 58 year old male severely depleted himself of folate, using a folate-deficient diet, until overt megaloblastic anaemia developed. The biochemical and haematological responses were monitored by routine blood tests. Daily intake of dietary supplements prevented deficiencies of other relevant nutrients. The rate of change of all analytes was significantly slower, and the delay before any change for several analytes was significantly longer, than reported for previous experiments. The time before reporting of abnormal biochemical and haematological results was therefore very significantly longer than reported by Herbert, but was consistent with the recent model of Lin et al. Serum folate and red-cell folate became abnormally low after 219 and 413 days respectively. Macrocytic anaemia was produced after 469 days, and megaloblastic anaemia was confirmed by bone marrow biopsy on day 575. Folate starvation ceased on day 586, and recovery was complete on day 772. The currently accepted four month time scale for development of megaloblastic anaemia from folate deficiency, based on the early work of Herbert and others, is not consistent with the results from this study. The > 300 day liver folate storage time, predicted by the

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

    Science.gov (United States)

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

    2013-12-01

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

  17. Screening of polymorphisms in the folate pathway in Turkish ...

    African Journals Online (AJOL)

    Background and aim: Folate metabolic pathway plays a significant role in leukemogenesis because of its necessity for nucleotide synthesis and DNA methylation. Folate deficiency causes DNA damage. Thus polymorphisms of folate-related genes may affect the susceptibility to childhood Acute Lymphoblastic Leukemia ...

  18. Evaluation of iron and folate deficiencies as possible causes of ...

    African Journals Online (AJOL)

    Since experience shows that iron and folate deficiencies are common causes of anaemia in the population, it is desirable to investigate the iron and folate status of prospective donors who fail the blood donor fitness test to confirm whether or not, iron and folate deficiencies are part of the reasons for failure. AIM AND ...

  19. [sup 99m]Tc-RBC subtraction scintigraphy; Assessmet of bleeding site and rate

    Energy Technology Data Exchange (ETDEWEB)

    Inagaki, Syoichi; Tonami, Syuichi; Yasui, Masakazu; Kuranishi, Makoto; Sugishita, Kouki; Nakamura, Mamoru (Toyama Medical and Pharmaceutical Univ. (Japan). Hospital)

    1994-03-01

    Sequential abdominal scintigrams with [sup 99m]Tc-labelled red blood cells (RBC) were subtracted for observing a site of gastrointestinal bleeding and calculating the bleeding rate. This method is technically very easy and can detect the site of bleeding with the minimum rate, as low as 0.2 ml/min., in a phantom experiment. In 23 cases with final diagnosis of gastrointestinal bleeding, conventional non-subtraction scintigraphy detected only 30% (7/23), but subtraction scintigraphy detected 61% (14/23). It was concluded that subtraction scintigraphy had higher sensitivity than conventional scintigraphy for early diagnosing bleeding. A combination of non-subtraction and subtraction scintigraphy is recommended to detect a site of gastrointestinal bleeding in a clinical setting. (author).

  20. RBC electrophoresis with discontinuous power supply - a newly established hemoglobin release test.

    Science.gov (United States)

    Su, Yan; Shao, Guo; Gao, Lijun; Zhou, Lishe; Qin, Liangyi; Qin, Wenbin

    2009-09-01

    In this paper, we aimed to introduce a newly established red blood cells (RBCs) electrophoresis method hemoglobin release test (HRT) and tried to determine its significance. Human blood samples from beta-thalassemia patients and healthy controls were analyzed with HRT, which was carried out on starch-agarose mixed gel. First, the whole blood samples were electrophoresed for 2 h, then paused for 15 min and ran for 15 min by turns. This "pause-run-pause" experiment was performed for several turns and the total electrophoresis time lasted for about 6 h. The results showed that some other hemoglobin (Hb) components were released from the origin of each sample during the HRT, and the samples from beta-thalassemia patients released more Hb than the healthy controls. This finding demonstrates that Hb may exist differently associated in RBCs, and it may have an important theoretical and clinical significance in Hb and RBC research.

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

    International Nuclear Information System (INIS)

    Piyasena, R.D.; Weerasekera, D.A.; Hettiaratchi, N.; Wikramanayake, T.W.; Sri Lanka Univ., Peradeniya Campus. Nuclear Medicine Unit)

    1977-01-01

    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.) [de

  2. Initiation of protein synthesis by folate-sufficient and folate-deficient Streptococcus faecalis R: partial purification and properties of methionyl-transfer ribonucleic acid synthetase and methionyl-transfer ribonucleic acid formyltransferase.

    Science.gov (United States)

    Samuel, C E; Rabinowitz, J C

    1974-04-01

    The initiation of protein synthesis by Streptococcus faecalis R grown in folate-free culture occurs without N-formylation or N-acylation of methionyl-tRNA(f) (Met). Methionyl-tRNA synthetase and methionyl-tRNA formyltransferase were partially purified from S. faecalis grown under normal culture conditions in the presence of folate (plus-folate); the general properties of the enzymes were determined and compared with the properties of the enzymes purified from wild-type cells grown in the absence of folate (minus-folate). S. faecalis methionyl-tRNA synthetase displays optimal activity at pH values between 7.2 and 7.8, requires Mg(2+), and has an apparent molecular weight of 106,000, as determined by gel filtration, and 127,000, as determined by sucrose density gradient centrifugation. The K(m) values of plus-folate methionyl-tRNA synthetase for each of the three substrates in the aminoacylation reaction (l-methionine, adenosine triphosphate, and tRNA) are nearly identical to the respective substrate Michaelis constants of minus-folate methionyl-tRNA synthetase. Furthermore, both plus- and minus-folate S. faecalis methionyl-tRNA synthetases catalyze, at equal rates, the aminoacylation of tRNA(f) (Met) and tRNA(m) (Met) isolated from either plus-folate or minus-folate cells. S. faecalis methionyl-tRNA formyltransferase displays optimal activity at pH values near 7.0, is stimulated by Mg(2+), and has an apparent molecular weight of approximately 29,900 when estimated by sucrose density gradient centrifugation. The K(m) value of plus-folate formyltransferase for plus-folate Met-tRNA(f) (Met) does not differ significantly from that of minus-folate formyltransferase for minus-folate Met-tRNA(f) (Met). Both enzymes can utilize either 10-formyltetrahydrofolate or 10-formyltetrahydropteroyltriglutamate as the formyl donor; the Michaelis constant for the monoglutamyl pteroyl coenzyme is slightly less than that of the triglutamyl pteroyl coenzyme for both transformylases

  3. Folate, vitamin B12, and vitamin B6 status of a group of high socioeconomic status women in the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort.

    Science.gov (United States)

    Fayyaz, Faiqa; Wang, Flora; Jacobs, René L; O'Connor, Deborah L; Bell, Rhonda C; Field, Catherine J

    2014-12-01

    Folic acid supplementation and food fortification policies have improved folate status in North American women of child bearing age. Recent studies have reported the possible inadequacy of vitamin B12 and B6 in the etiology of neural tube defects in folate-fortified populations. The aims of this study were to describe folate status and its relationship to supplementation and to assess vitamin B12 and B6 status in a cohort of pregnant women. Supplement intake data were collected in each trimester from the first cohort (n = 599) of the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Red blood cell folate (RBCF) and plasma folate, holotranscobalamin, and pyridoxal 5-phosphate were measured. Overt folate deficiency was rare (3%) but 24% of women in their first trimester had suboptimal RBCF concentration (1360 nmol·L(-1)) was observed in approximately half of the women during each pregnancy trimester. Vitamin B12 and B6 deficiencies were rare (supplements above the upper level had significantly higher RBCF and plasma folate concentrations. In conclusion, the prevalence of vitamin B12 and B6 deficiency was very low. A quarter of the women had suboptimal folate status in the first trimester of pregnancy and over half the women had abnormally high RBCF, suggesting that supplementation during pregnancy is not appropriate in a cohort of women considered to be healthy and a low risk for nutritional deficiencies.

  4. RBC acetyl cholinesterase: A poor man′s early diagnostic biomarker for familial alzheimer′s and Parkinson′s disease dementia

    Directory of Open Access Journals (Sweden)

    Himmatrao Saluba Bawaskar

    2015-01-01

    Full Text Available Objective: Analysis of red blood cell acetyl cholinesterase (AChE in a familial Alzheimer′s diseases (AD Parkinson′s disease dementia (PDD and their first generation. Setting: General hospital, Mahad district, Raigad. Patients and Methods: Clinically diagnosed patients of AD and PDD and their asymptomatic relatives. Their blood was collected in EDTA tube and transferred to laboratory at Mumbai. Result: Median red blood cell (RBC cholinesterase levels amongst PDD, their first generation asymptomatic relatives, familial AD, asymptomatic relatives of AD, healthy controls, farmers exposed to pesticides (positive control and other neurological condition without dementia (hypertension with TIA 1, sub-dural hematoma 2, hypothyroid 1, non-familial unilateral parkinsonism without dementia 3, writers cramps 2, hyponitremia 1 and cerebral palsy with non-fluent aphasia 1. Median values of RBC AChE were 19086.78 U/L, 15666.05 U/L, 9013.11 U/L, 7806.19 U/L, 14334.57 U/L, 9785.05 U/L and 13162.60 U/L, respectively. As compared to controls, RBC AChE levels were statistically significant among PDD (P = 0.004 and significantly lowered among familial AD patients (P = 0.010, relatives of patients (P = 0.010. Interpretations: Below the normal RBC AChE level is a potential biomarker in asymptomatic relatives of familial AD patients. RBC AChE is raised than normal level in patients suffering from PDD, where AChE inhibitors are helpful. However, RBC AChE level below the normal where AChE inhibitor may not be effective.

  5. 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 of ...

  6. Folate Functionalized Boron Nitride Nanotubes and their Selective Uptake by Glioblastoma Multiforme Cells: Implications for their Use as Boron Carriers in Clinical Boron Neutron Capture Therapy.

    Science.gov (United States)

    Ciofani, Gianni; Raffa, Vittoria; Menciassi, Arianna; Cuschieri, Alfred

    2008-11-25

    Boron neutron capture therapy (BNCT) is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of (10)B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots) to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors.

  7. Folate Functionalized Boron Nitride Nanotubes and their Selective Uptake by Glioblastoma Multiforme Cells: Implications for their Use as Boron Carriers in Clinical Boron Neutron Capture Therapy

    Directory of Open Access Journals (Sweden)

    Ciofani Gianni

    2008-01-01

    Full Text Available Abstract Boron neutron capture therapy (BNCT is increasingly being used in the treatment of several aggressive cancers, including cerebral glioblastoma multiforme. The main requirement for this therapy is selective targeting of tumor cells by sufficient quantities of10B atoms required for their capture/irradiation with low-energy thermal neutrons. The low content of boron targeting species in glioblastoma multiforme accounts for the difficulty in selective targeting of this very malignant cerebral tumor by this radiation modality. In the present study, we have used for the first time boron nitride nanotubes as carriers of boron atoms to overcome this problem and enhance the selective targeting and ablative efficacy of BNCT for these tumors. Following their dispersion in aqueous solution by noncovalent coating with biocompatible poly-l-lysine solutions, boron nitride nanotubes were functionalized with a fluorescent probe (quantum dots to enable their tracking and with folic acid as selective tumor targeting ligand. Initial in vitro studies have confirmed substantive and selective uptake of these nanovectors by glioblastoma multiforme cells, an observation which confirms their potential clinical application for BNCT therapy for these malignant cerebral tumors.

  8. Dosagem de folatos maternos e fetais, séricos e eritrocitários em malformações por defeito de fechamento do tubo neural no feto Maternal and fetal serum and red blood cell folate levels in pregnancies complicated by neural tube defects

    Directory of Open Access Journals (Sweden)

    Victor Bunduki

    1998-07-01

    Full Text Available Objetivos: avaliar os níveis de folatos maternos e fetais gestações com malformações por defeitos de fechamento do tubo neural (DFTN. Métodos: o estudo foi do tipo caso-controle, no qual 14 casos de fetos com DFTN (grupo estudo e 14 casos de fetos com outras malformações (grupo controle foram estudados em gestantes de baixo risco para DFTN. Propusemo-nos a dosar o ácido fólico, na sua forma total e metilada, nos compartimentos fetal e materno, utilizando dosagens séricas e tissulares (eritrocitárias, assim como o volume corpuscular médio, o hematócrito e a hemoglobina. As coletas foram realizadas imediatamente antes da interrupção da gestação. Os resultados nos dois grupos foram comparados pelo teste t de Student, método de amostras pareados pela idade gestacional. Resultados: não se encontrou diferença nas taxas de folatos fetais e nos parâmetros hematológicos dos fetos, entre os dois grupos. Por outro lado, taxas anormalmente baixas de folatos foram encontradas nos eritrócitos das mães portadoras de fetos com DFTN, tanto para as formas totais(293,9 ng/mL contra 399,1 ng/mL no grupo controle, p=0,01 quanto para as formas metiladas (201,9 ng/mL contra 314,0 ng/mL para o grupo controle, p=0,02. Os folatos séricos maternos não se mostraram diferentes nos grupos estudo e controle. Conclusão: este estudo demonstrou que há uma menor taxa de folatos intratissulares, nas mães de fetos acometidos por DFTN, porém com taxas de folatos séricos semelhantes em relação ao grupo controle.Objective: to analyze maternal and fetal folate status in cases of neural tube defects (NTD. Methods: a case-control study was designed with 14 cases of fetuses with neural tube defects (study group and 14 cases of fetuses with other unrelated malformations (control group gestational age matched, in low-risk pregnant women. Both total and methylated folic acid levels in fetal and maternal compartments using serum and tissular (red blood cells

  9. Enhancement of the folate content in Egyptian pita bread

    Directory of Open Access Journals (Sweden)

    Cornelia M. Witthöft

    2012-04-01

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

  10. 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...

  11. 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.

  12. 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...

  13. Dietary folate: Bioavailability studies in humans

    NARCIS (Netherlands)

    Melse, A.

    2003-01-01

    Keywords:Folate; Folic acid; Dietaryfolateintake;Folatebioavailability;Polyglutamylfolic acid;Homocysteine; GCPII 1561C>T polymorphism; Stable

  14. Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores).

    Science.gov (United States)

    Shah, Khushbu; Raghavan, Sudhir; Hou, Zhanjun; Matherly, Larry H; Gangjee, Aleem

    2018-05-01

    All clinically used antifolates lack transport selectivity for tumors over normal cells resulting in dose-limiting toxicities. There is growing interest in developing novel tumor-targeted cytotoxic antifolates with selective transport into tumors over normal cells via the proton-coupled folate transporter (PCFT) over the ubiquitously expressed reduced folate carrier (RFC). A lack of X-ray crystal structures or predictive models for PCFT or RFC has hindered structure-aided drug design for PCFT-selective therapeutics. Four-point validated models (pharmacophores) were generated for PCFT/Activity (HBA, NI, RA, RA) and RFC/Activity (HBD, NI, HBA, HBA) based on inhibition (IC 50 ) of proliferation of isogenic Chinese hamster ovary (CHO) cells engineered to express only human PCFT or only RFC. Our results revealed substantial differences in structural features required for transport of novel molecules by these transporters which can be utilized for developing transporter-selective antifolates. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Production of folate in oat bran fermentation by yeasts isolated from barley and diverse foods.

    Science.gov (United States)

    Korhola, M; Hakonen, R; Juuti, K; Edelmann, M; Kariluoto, S; Nyström, L; Sontag-Strohm, T; Piironen, V

    2014-09-01

    The focus of the research was to identify yeasts from barley kernels in order to study their folate production capability while maintaining high viscosity caused by soluble fibres in oat bran fermentation. The 65 isolated yeasts were characterized by API carbohydrate utilization tests, and assays for extracellular enzyme activities were the following: amylase, beta-glucanase, cellulase or CMCase, lipase, protease and xylanase. Yeasts were identified by partial DNA sequencing of the 25S D1/D2 and ITS1-5.8S-ITS2 regions. They belonged to the genera Aureobasidium, Cryptococcus, Pseudozyma and Rhodotorula. Folate production was determined from supernatant and cells grown in a rich laboratory medium or directly from oat bran solution inoculated with the appropriate yeast. Food yeasts, Saccharomyces cerevisiae, Candida milleri, Kluyveromyces marxianus and Galactomyces geotrichum, were used for comparison. Most of the yeasts isolated from barley destroyed the solid, viscous structure of the oat bran solution, indicating that they degraded the viscosity-generating soluble fibres, considered to be nutritionally advantageous. The best folate producers were S. cerevisiae, followed by Pseudozyma sp., Rhodotorula glutinis and K. marxianus. The yeasts maintaining high viscosity were used together with lactic acid bacteria (LAB) Streptococcus thermophilus or Lactobacillus rhamnosus to ferment oat bran solution. None of the yeasts isolated from barley, contrary to S. cerevisiae and C. milleri, produced together with LAB significant amounts of folate. Fermentative yeasts together with LAB are potential for use in developing novel high folate content healthy foods and snacks from oat bran. High soluble fibre content and high natural folate content but low energy content food and snack products with pleasant fermentation aroma provide possibilities for new developments in the food industry. © 2014 The Society for Applied Microbiology.

  16. 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

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  18. Folate deficiency and over-supplementation causes impaired folate metabolism: Regulation and adaptation mechanisms in Caenorhabditis elegans.

    Science.gov (United States)

    Ortbauer, Martina; Ripper, Doris; Fuhrmann, Thomas; Lassi, Maximilian; Auernigg-Haselmaier, Sandra; Stiegler, Christina; König, Jürgen

    2016-04-01

    Impaired folate metabolism increases the risk of birth defects, neurodegenerative and cardiovascular disease, osteoporosis and cancer. We used Caenorhabditis elegans to investigate impaired folate metabolism by RNA interference of key enzymes in the methionine synthase (MS) and thymidylate synthase (TS) cycle and by folate deficiency and over-supplementation feeding studies. Folate status is influenced by genetic variations (polymorphisms), folate deficiency and supplementation. Single RNAi of dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR) and MS revealed that gene regulation is largely affected in both folate cycles. Adaptation requires a close transcriptional connection between TS and MS cycle. Coupled DHFR and MS expression is required to balance both cycles, but seems to reduce the overall rate of folate conversion. Feeding studies showed that folate over-supplementation to functioning metabolism inactivates MS and MTHFR expression and enhances TS activity, which favors DNA synthesis over methylation reactions. Folate deficiency disrupted homeostasis by favoring TS cycle and led to malformation in C. elegans offspring. Embryos show aneuploidy and are nonviable lacking DNA repair during meiotic stage of diakinesis. Single gene silencing alters gene expression in both cycles and disrupts folate homeostasis. Folate over-supplementation and deficiency favors TS over MS cycle and causes prophase DNA damage. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. Endogenous folates and single-carbon metabolism in the ovarian follicle, oocyte and pre-implantation embryo.

    Science.gov (United States)

    Kwong, W Y; Adamiak, S J; Gwynn, A; Singh, R; Sinclair, K D

    2010-04-01

    Maternal B-vitamin status at conception can affect fertility and the health of offspring. This study details transcript expression for genes encoding key enzymes in the linked methionine/folate cycles in the bovine oocyte, somatic cells of the ovarian follicle and pre-implantation embryo. Transcripts for all 12 enzymes that were studied and for the two folate receptors (FOLR1 and FOLR2) and reduced folate carrier (SLC19A1) were expressed in liver cells, but transcripts for betaine-homocysteine methyltransferase and methionine adenosyl transferase 1A were absent in all ovarian cells, and transcripts for FOLR2 were absent in embryonic cells. Transcripts for glycine methyltransferase were also absent/weak in cumulus and granulosa cells. The absence of these enzymes could have a profound effect on single-carbon metabolism within the ovary and pre-implantation embryo. Immunocytochemical analysis revealed SLC19A1 protein expression on the plasma and basal-lateral membranes of the pre-implantation embryo. The folate antagonist methotrexate (MTX) enters the cell via SLC19A1, and in the current study, MTX inclusion in bovine/ovine culture media at either 1 or 10 microM from the 1-cell stage inhibited embryo development beyond the 8-cell stage. Hypoxanthine and thymidine (100 microM) increased the proportion of embryos that developed to blastocysts, but the cell number was reduced by 20%. The reduced uptake of [(35)S] methionine into intra-cellular S-adenosylmethionine and S-adenosylhomocysteine pools, together with reduced uptake of glutamate and tryptophan, was consistent with depleted intra-cellular pools of reduced folates. These data provide an insight into the importance of maternal dietary folate/B-vitamin status during the peri-conceptional period.

  20. 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.

  1. Molecular cloning of RBCS genes in Selaginella and the evolution of the rbcS gene family

    Directory of Open Access Journals (Sweden)

    Wang Bo

    2015-01-01

    Full Text Available Rubisco small subunits (RBCS are encoded by a nuclear rbcS multigene family in higher plants and green algae. However, owing to the lack of rbcS sequences in lycophytes, the characteristics of rbcS genes in lycophytes is unclear. Recently, the complete genome sequence of the lycophyte Selaginella moellendorffii provided the first insight into the rbcS gene family in lycophytes. To understand further the characteristics of rbcS genes in other Selaginella, the full length of rbcS genes (rbcS1 and rbcS2 from two other Selaginella species were isolated. Both rbcS1 and rbcS2 genes shared more than 97% identity among three Selaginella species. RBCS proteins from Selaginella contained the Pfam RBCS domain F00101, which was a major domain of other plant RBCS proteins. To explore the evolution of the rbcS gene family across Selaginella and other plants, we identified and performed comparative analysis of the rbcS gene family among 16 model plants based on a genome-wide analysis. The results showed that (i two rbcS genes were obtained in Selaginella, which is the second fewest number of rbcS genes among the 16 representative plants; (ii an expansion of rbcS genes occurred in the moss Physcomitrella patens; (iii only RBCS proteins from angiosperms contained the Pfam PF12338 domains, and (iv a pattern of concerted evolution existed in the rbcS gene family. Our study provides new insights into the evolution of the rbcS gene family in Selaginella and other plants.

  2. Folate-Hapten-Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer.

    Science.gov (United States)

    Bandara, N Achini; Bates, Cody D; Lu, Yingjuan; Hoylman, Emily K; Low, Philip S

    2017-03-01

    The overexpression of folate receptors (FR) on many human cancers has led to the development of folate-linked drugs for the imaging and therapy of FR-expressing cancers. In a recent phase I clinical trial of late-stage renal cell carcinoma patients, folate was exploited to deliver an immunogenic hapten, fluorescein, to FR + tumor cells in an effort to render the cancer cells more immunogenic. Although >50% of the patients showed prolonged stable disease, all patients eventually progressed, suggesting that the folate-hapten immunotherapy was insufficient by itself to treat the cancer. In an effort to identify a companion therapy that might augment the folate-hapten immunotherapy, we explored coadministration of two approved cancer drugs that had been previously shown to also stimulate the immune system. We report that sunitinib and axitinib (VEGF receptor inhibitors that simultaneously mitigate immune suppression) synergize with the folate-hapten-targeted immunotherapy to reduce tumor growth in three different syngeneic murine tumor models. We further demonstrate that the combination therapy not only enhances tumor infiltration of CD4 + and CD8 + effector cells, but surprisingly reduces tumor neovasculogenesis more than predicted. Subsequent investigation of the mechanism for this unexpected suppression of neovasculogenesis revealed that it is independent of elimination of any tumor cells, but instead likely derives from a reduction in the numbers of FR + tumor-associated macrophages and myeloid-derived suppressor cells, that is, immunosuppressive cells that release significant quantities of VEGF. These data suggest that a reduction in stromal cells of myeloid origin can inhibit tumor growth by suppressing neovasculogenesis. Mol Cancer Ther; 16(3); 461-8. ©2016 AACR . ©2016 American Association for Cancer Research.

  3. 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.

  4. Hydrophobic erythrocyte folate binding proteins are converted to hydrophilic forms by trypsin in vitro.

    Science.gov (United States)

    Antony, A C; Verma, R S

    1989-02-13

    Human erythrocyte membranes contain high-affinity folate-binding proteins (FBPs) which on solubilization with detergents resolve into apparent 160,000 Mr moieties on Sephacryl S-200 gel filtration in Triton X-100. These FBPs share antigenic and ligand binding characteristics with particulate FBPs from other human tissues. During studies to define the vectorial orientation of these FBPs on the erythrocytes, we trypsinized intact cells with 250 micrograms trypsin per ml packed cells and quantitatively analysed the remaining cell-associated FBPs as well as the products of proteolysed FBPs in the supernatant. Incubation of intact cells with trypsin resulted in a dose-dependent decrease in their capacity to bind 125I-labelled pteroylglutamate (histamine derivative); at 250 micrograms/ml trypsin, folate binding was decreased by 77% compared to nontrypsin-treated control cells. While trypsinized cells contained proportionately lower quantities of apparent 160,000 Mr FBPs than untreated control cells, the supernatant of trypsinized cells (soluble phase) contained a single species of Mr = 40,000 which retained folate binding capacity. The sum of FBPs in trypsin supernatant and trypsin-treated cells was 87% of that found in untreated cells. Analysis of solubilized particulate erythrocyte FBPs and soluble (trypsin product) FBPs by sucrose density gradient ultracentrifugation in H2O and 2H2O above the critical micellar concentration of Triton X-100 revealed that apparent 160,000 Mr FBPs were detergent-binding (hydrophobic) species (which sedimented at Mr = 40,000 in H2O) while soluble FBPs (also sedimenting at Mr = 40,000) were hydrophilic and did not bind Triton X-100. These are the first data which show that hydrophobic FBPs can be directly converted to hydrophilic FBPs by a trypsin-mediated proteolytic event. The trypsin-sensitive site is likely to be at the junction between the detergent-binding site and the major body of the protein (Mr = 40,000) containing the folate

  5. Association of folate intake, dietary habits, smoking and COX-2 promotor-765G > C polymorphism with K-ras mutation in patients with colorectal cancer

    International Nuclear Information System (INIS)

    Kamal, M.M.; Youssef, O.Z.; Lotfy, A.N.; Elsaed, E.T.; Fawzy, M.M.T.

    2012-01-01

    Background: Understanding the role of environmental and molecular influences on the nature and rate of K-ras mutations in colorectal neoplasms is crucial. COX-2 polymorphisms -765G > C may play a role in carcinogenic processes in combination with specific life-style conditions or dependent on the racial composition of a particular population. If mutational events play an important role in colorectal carcinogenesis sequence, one can hypothesize that modification of these events by life-style or other factors would be a useful prevention strategy. Aim of work: To explore the association between K-ras mutation and potential variables known or suspected to be related to the risk of colorectal cancer (CRC) as well as determining the possible modulating effect of the COX-2 polymorphism, —765G > C. Subjects and methods: The study was conducted on 80 patients with colorectal cancer from Tropical Medicine and Gastrointestinal Tract endoscopy Departments and those attending clinic of the National Cancer Institute, Cairo University during the period extending from April 2009 to March 2010. Full history taking with emphasis on the risk factors of interest, namely age, sex, family history, smoking and dietary history. Serum CEA and CA19-9, RBCs folic acid and occult blood in stool were done to all samples. K-ras protooncogene mutation at codon 12 (exon 1) and cyclooxygenase 2 (COX-2) —765G > C polymorphism were determined by PCR-RFLP. Results: The K-ras mutation was positive in 23 (28.7%) patients. COX-2 polymorphism revealed GG in 62.5%, GC in 26.2 % and CC genotype was found in 11.3 % of cases. The mean red blood cell folic acid level was lower in the K-ras positive group (100.96 ± 51.3 ng/ml) than the negative group (216.6 ± 166.4 ng/ml), (P < 0.01). Higher folate levels were found in males than females (median = 173 ng/ml and 85 ng/ml; respectively, P = 0.002) with adjusted odds ratio (OR) of 0.984. Only, the RBCs folate (P = 0.0018) followed by gender (P = 0

  6. Primary evaluation of 99mTc-RBC imaging for the diagnosis of lower gastrointestinal bleeding

    International Nuclear Information System (INIS)

    Zhang Songhai

    1995-01-01

    99m Tc-RBC gastrointestinal (GI) scintigraphy was performed in 10 patients with lower GI bleeding which was confirmed by operation later. The results suggested that 99m Tc-RBC imaging was an effective method for the diagnosis of intestinal hemorrhage, especially the small intestine. However, there was some difficulty in accurately localizing the bleeding site due to the movement of the blood containing labelled RBC from original bleeding site to lower portion during intestinal peristalsis and also displacement of the moving colon. Therefore it is necessary to completely explore the intestine carefully and awareness of the possibility of biliary hemorrhage

  7. The Effect of Trimethoprim on Serum Folate Levels in Humans

    DEFF Research Database (Denmark)

    Petersen, Kasper Meidahl; Eplov, Kasper; Nielsen, Torben Kjær

    2016-01-01

    allocations within sealed opaque envelopes. Participants and all staff were kept blinded to treatment allocations during the trial. Serum folate was measured at baseline and at end of trial. In the 58 participants analyzed (30 in the trimethoprim group and 28 in the placebo group), 8 had folate deficiency......Trimethoprim antagonize the actions of folate by inhibition of dihydrofolate reductase. This could diminish serum folate levels in humans and causes folate deficiency in some patients. We conducted a randomized, double-blind, placebo-controlled trial, to investigate the effect of trimethoprim...... on serum folate levels in healthy participants after a 7-day trial period. Thirty young, healthy males were randomly allocated to receive trimethoprim, 200 mg twice daily, and 30 were randomly allocated to placebo. Before trial initiation, participant numbers were given randomly generated treatment...

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

    Science.gov (United States)

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

    2012-11-01

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

  9. Folate intake, lifestyle factors, and homocysteine concentrations in younger and older women

    DEFF Research Database (Denmark)

    Rasmussen, Lone Banke; Ovesen, L.; Bulow, I.

    2000-01-01

    status, and the association between folate intake. other dietary and lifestyle factors, and tHcy concentrations in young and older women. Design: tHcy concentrations were measured in 290 young women aged 25-30 y and in 288 older women aged 60-65 y. All participants completed questionnaires about factors...... including lifestyle, health, and use of vitamin supplements. Red blood cell folate was measured in 204 of the participants. A subgroup of 258 participants completed dietary records. Results: Median tHcy was 7.6 mu mol/L (range: 6.5-8.9) in the younger women and 9.4 mu mol/L (7.7-11.1) in the older women....... Folate intake from diet was 283 (224-348) and 268(210-326) mug/d, respectively, in the 2 age groups. Folic acid intake from supplements (P women and P = 0.026 for the older women) and total folate intake (P = 0.024 and P = 0.079) were inversely associated with log tHcy in multiple...

  10. Association of reduced folate carrier-1 (RFC-1) polymorphisms with ischemic stroke and silent brain infarction.

    Science.gov (United States)

    Cho, Yunkyung; Kim, Jung O; Lee, Jeong Han; Park, Hye Mi; Jeon, Young Joo; Oh, Seung Hun; Bae, Jinkun; Park, Young Seok; Kim, Ok Joon; Kim, Nam Keun

    2015-01-01

    Stroke is the second leading cause of death in the world and in South Korea. Ischemic stroke and silent brain infarction (SBI) are complex, multifactorial diseases influenced by multiple genetic and environmental factors. Moderately elevated plasma homocysteine levels are a major risk factor for vascular diseases, including stroke and SBI. Folate and vitamin B12 are important regulators of homocysteine metabolism. Reduced folate carrier (RFC), a bidirectional anion exchanger, mediates folate delivery to a variety of cells. We selected three known RFC-1 polymorphisms (-43C>T, 80A>G, 696T>C) and investigated their relationship to cerebral infarction in the Korean population. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze associations between the three RFC-1 polymorphisms, disease status, and folate and homocysteine levels in 584 ischemic stroke patients, 353 SBI patients, and 505 control subjects. The frequencies of the RFC-1 -43TT, 80GG, and 696CC genotypes differed significantly between the stroke and control groups. The RFC-1 80A>G substitution was also associated with small artery occlusion and SBI. In a gene-environment analysis, the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms in the ischemic stroke group had combined effects with all environmental factors. In summary, we found that the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms may be risk factors for ischemic stroke.

  11. Effects of Oral Supplementation of Vitamin E on Fragility of RBC in Hemolytic Anemic Patients with G6PD Deficiency

    Directory of Open Access Journals (Sweden)

    Nayma Sultana

    2009-11-01

    Full Text Available Background: Vitamin E has role in maintaining the integrity of red cell membrane by preventing oxidation of polyunsaturated fatty acids and thereby protects cells from oxidative stress- induced lysis in G6PD deficiency, which can be reflected by changes in osmotic fragility of RBC and some absolute values like MCV, MCH & MCHC. Objective: To observe the effects of vitamin E supplementation on fragility of RBC in order to evaluate role of this antioxidant vitamin in reducing chronic hemolysis in G6PD deficient patients. Methods: For this, a total number of 102 subjects with age ranged from 5 to 40 years of both sexes were included in the study. Among them 68 were G6PD enzyme deficient patients, of whom 34 were in supplemented group (study group and 34 were in non-supplemented group (control group. The supplemented group received vitamin E supplementation for 60 consecutive days at a dose of 800 IU/day for adult and 400 IU/day for children < 12 years (in a divided dose i,e. 4 times daily. Age and sex matched 34 apparently healthy subjects with normal blood G6PD level were taken to observe the base line data (healthy control and also for comparison. All the G6PD deficient patients were selected from Out Patient Department (OPD of Hematology, Bangabandhu Sheikh Mujib Medical University (BSMMU, Dhaka, Bangladesh during the period of July 2005 to June 2006 and all the healthy subjects were selected from personal contact. Blood G6PD level, osmotic fragility of RBC were measured by standard techniques and MCV, MCH, and MCHC were obtained by calculation. All the parameters were measured on day 1 (one of their first visit and also were on day 60 in deficient group. Data were compared among the deficient groups, also in supplemented group just before and after supplementation. Analysis of data was done by appropriate statistical method. Results: Mean starting and completing points of osmotic fragility of RBC were significantly higher but MCV, MCH, MCHC were

  12. Genetic Determinants of Folate Status in Central Bohemia

    Czech Academy of Sciences Publication Activity Database

    Veselá, K.; Pavlíková, Markéta; Janošíková, B.; Anděl, M.; Zvárová, Jana; Hyánek, J.; Kožich, V.

    2005-01-01

    Roč. 54, č. 3 (2005), s. 295-303 ISSN 0862-8408 R&D Projects: GA MZd(CZ) NM6548 Institutional research plan: CEZ:MSM 11110003 Keywords : folates * folate hydrolase * reduced folate carrier * 5, 10-methylenetetrahydrofolate reductase * polymorphism Subject RIV: BA - General Mathematics Impact factor: 1.806, year: 2005 http://www.biomed.cas.cz/physiolres/pdf/54/54_295.pdf

  13. Simultaneous radioassay of folate and vitamin B12

    International Nuclear Information System (INIS)

    Gutcho, S.; Mansbach, L.

    1979-01-01

    A serum sample is heated at an alkaline pH to release folate and vitamin B 12 from endogenous binders. A simultaneous radioassay for folate and vitamin B 12 is effected by contacting the sample with binder for folate, binder for vitamin B 12 , folote labeled with one radioactive isotope and vitamin B 12 labeled with another radioacitve isotope, followed by separation of bound and free portions, and determination of the radioactivity of at least one of the portions. The amounts of folate and vitamin B 12 present in the sample may be determined from standard curves

  14. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    Directory of Open Access Journals (Sweden)

    Yanli Li

    2015-08-01

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

  15. 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.

  16. The Effects of Permanent Technology Shocks on Labour Productivity and Hours in the RBC Model

    OpenAIRE

    Lindé, Jesper

    2005-01-01

    Recent work on the effects of permanent technology shocks argue that the basic RBC model cannot account for a negative correlation between hours worked and labour productivity. In this Paper, I show that this conjecture is not necessarily correct. In the basic RBC model, I find that hours worked fall and labour productivity rises after a positive permanent technology shock once one allows for the possibility that the process for the permanent technology shock is persistent in growth rates. A ...

  17. Isolation, expression and characterization of rbcL gene from Ulva prolifera J. Agardh (Ulvophyceae, Chlorophyta)

    Science.gov (United States)

    Shao, Zhanru; Li, Wei; Guo, Hui; Duan, Delin

    2015-12-01

    Ulva prolifera is a typical green alga in subtidal areas and can grow tremendously fast. A highly efficient Rubisco enzyme which is encoded by UpRbcL gene may contribute to the rapid growth. In this study, the full-length UpRbcL open reading frame (ORF) was identified, which encoded a protein of 474 amino acids. Phylogenetic analysis of UpRbcL sequences revealed that Chlorophyta had a closer genetic relationship with higher plants than with Rhodophyta and Phaeophyta. The two distinct residues (aa11 and aa91) were presumed to be unique for Rubisco catalytic activity. The predicted three-dimensional structure showed that one α/β-barrel existed in the C-terminal region, and the sites for Mg2+ coordination and CO2 fixation were also located in this region. Gene expression profile indicated that UpRbcL was expressed at a higher level under light exposure than in darkness. When the culture temperature reached 35°C, the expression level of UpRbcL was 2.5-fold lower than at 15°C, and the carboxylase activity exhibited 13.8-fold decrease. UpRbcL was heterologously expressed in E. coli and was purified by Ni2+ affinity chromatography. The physiological and biochemical characterization of recombinant Rubisco will be explored in the future.

  18. Stability and dosimetry of 99mTc-RBC prepared by kit method in health volunteers

    International Nuclear Information System (INIS)

    Du Yanrong; Chen Fang; Li Fang; Chen Libo; Long Mingqing

    2005-01-01

    Objective: To study the in vivo stability of and absorbed radiation dose from 99m Tc-RBC, prepared using RBC kit made in our laboratory. Methods: Four healthy volunteers were studied with 99m Tc-RBC prepared by kit method. Whole body images were acquired at 5 min, 1, 2.5, 4, 8 and 24 hours after intravenous injection of 481-555 MBq 99m Tc-RBC. Biodistribution analysis was performed in regions of interest (ROI). The absorbed radiation doses were calculated using the MIRDOSE3.0 analysis program and the time-related activity curves for different organs were used for the residence time calculations. Results: 99m Tc-RBC prepared by kit method was stable in vivo. The quality of blood pool imaging from 5 min to 8 h in healthy volunteers was satisfactory. The absorbed radiation dose was lower than the permissible value. Conclusion: 99m Tc-RBC prepared by kit method is very suitable for clinical application. (authors)

  19. Experimental evaluation of mechanical and electrical properties of RBC suspensions in Dextran and PEG under flow II. Role of RBC deformability and morphology

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Říha, Pavel; Ivanov, I.; Gluhcheva, Y.

    2011-01-01

    Roč. 49, 1-4 (2011), s. 441-450 ISSN 1386-0291 Institutional research plan: CEZ:AV0Z20600510 Keywords : RBC suspensions * conductivity * Dextran 70 * Polyethylene glycol 35 000 (PEG) Subject RIV: BK - Fluid Dynamics Impact factor: 3.398, year: 2011

  20. Rapid synthesis and in vitro and in vivo evaluation of folic acid derivatives labeled with fluorine-18 for PET imaging of folate receptor-positive tumors

    Energy Technology Data Exchange (ETDEWEB)

    Jammaz, I. Al, E-mail: jammaz@kfshrc.edu.sa; Al-Otaibi, B.; Amer, S.; Okarvi, S.M.

    2011-10-15

    In an attempt to visualize folate receptors that overexpress on many cancers, [{sup 18}F]-fluorobenzene and pyridinecarbohydrazide-folate/methotrexate conjugates ([{sup 18}F]-1, [{sup 18}F]-2-folates and [{sup 18}F]-8, [{sup 18}F]-9-MTXs) were synthesized by the nucleophilic displacement reactions using ethyl-trimethylammonium-benzoate and pyridinecarboxylate precursors. The intermediates ethyl [{sup 18}F]-fluorinated benzene and pyridine esters were reacted with hydrazine to produce the [{sup 18}F]-fluorobenzene and pyridinecarbohydrazides, followed by coupling with N-hydroxysuccinimide-folate/MTX. Radiochemical yields were greater than 80% (decay corrected), with total synthesis time of less than 45 min. Radiochemical purities were always greater than 97% without high-performance liquid chromatography purification. These synthetic approaches hold considerable promise as rapid and simple method for the radiofluorination of folate derivatives with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that significant amount of the radioconjugates were associated with cell fractions, and in vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and partially by the hepatobiliary systems. Biodistribution studies in nude mice bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable biodistribution profile for [{sup 18}F]-2-folate over the other conjugates. The uptake in the tumors was blocked by excess coinjection of folic acid, suggesting a receptor-mediated process. Micro-positron emission tomography images of nude mice bearing human KB cell line xenografts confirmed these observations. These results demonstrate that [{sup 18}F]-2-folate may be useful as molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response

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

    International Nuclear Information System (INIS)

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

    2014-01-01

    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

  2. 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

  3. Impact of HIV Infection and Zidovudine Therapy on RBC Parameters and Urine Methylmalonic Acid Levels

    Directory of Open Access Journals (Sweden)

    Adewumi Adediran

    2016-01-01

    Full Text Available Background. Anaemia is a common complication of human immunodeficiency virus (HIV infection. The aim of this study was to investigate the impact of HIV infection and zidovudine on red blood cells (RBC parameters and urine methylmalonic acid (UMMA levels in patients with HIV infection. Material and Methods. A cross-sectional study involving 114 subjects, 94 of which are HIV-infected nonanaemic and 20 HIV negative subjects (Cg as control. Full blood count parameters and urine methylmalonic acid (UMMA level of each subject were determined. Associations were determined by Chi-square test and logistic regression statistics where appropriate. Results. Subjects on zidovudine-based ART had mean MCV (93 fL higher than that of control group (82.9 fL and ART-naïve (85.9 fL subjects and the highest mean RDW. Mean UMMA level, which reflects vitamin B12 level status, was high in all HIV-infected groups but was significantly higher in ART-naïve subjects than in ART-experienced subjects. Conclusion. Although non-zidovudine therapy may be associated with macrocytosis (MCV > 95 fL, zidovudine therapy and ART naivety may not. Suboptimal level of vitamin B12 as measured by high UMMA though highest in ART-naïve subjects was common in all HIV-infected subjects.

  4. Synthesis and characterization of folate decorated albumin bio-conjugate nanoparticles loaded with a synthetic curcumin difluorinated analogue.

    Science.gov (United States)

    Gawde, Kaustubh A; Kesharwani, Prashant; Sau, Samaresh; Sarkar, Fazlul H; Padhye, Subhash; Kashaw, Sushil K; Iyer, Arun K

    2017-06-15

    Albumin-bound paclitaxel colloidal nanoparticle (Abraxane®) is an FDA approved anticancer formulation available in the market. It is a suspension which is currently used therapeutically for treating cancers of the breast, lung, and pancreas among others. CDF is a novel new and potent synthetic curcumin analogue that is widely used for breast and ovarian cancer. The aim of this study was to use biocompatible albumin as well as folate decorated albumin to formulate colloidal nanoparticles encapsulating curcumin difluorinated (CDF). CDF has demonstrated a 16-fold improvement in stability and remarkable anticancer potency compared to its natural derivative, curcumin. CDF showed marked inhibition of cancer cell growth through down-regulation of multiple miRNAs, up-regulation of phosphatase and tensin homolog (PTEN), and attenuation of histone methyl transferase EZH2. However, CDF is highly hydrophobic and photodegradable with sparing aqueous solubility. In this study, we have formulated albumin nanoparticle using a modified desolvation method, which yielded high CDF loading in a nanoformulation. The physicochemical properties of CDF loaded albumin and folate-decorated albumin nanosuspensions were assessed for particle size, morphology, zeta potential, drug encapsulation efficiency/loading, solubility and drug release. Importantly, the folate ligand decorated albumin nanoparticles were formulated in principle to passively and actively target folate-overexpressing-cancers. In this study, the synthesis and optimization of BSA and folate decorated BSA conjugated CDF nanoparticles are assessed in detail that will be useful for its future clinical translation. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Potential probiotic Pichia kudriavzevii strains and their ability to enhance folate content of traditional cereal-based African fermented food.

    Science.gov (United States)

    Greppi, Anna; Saubade, Fabien; Botta, Cristian; Humblot, Christèle; Guyot, Jean-Pierre; Cocolin, Luca

    2017-04-01

    With the aim of selecting starter cultures with interesting probiotic potential and with the ability to produce folate in a food matrix, yeast strains isolated from fermented cereal-based African foods were investigated. A total of 93 yeast strains were screened for their tolerance to pH 2 and 0.3% of bile salts. Pichia kudriavzevii isolates gave the best results. Selected P. kudriavzevii strains were tested for survival to the simulated human digestion and for adhesion to Caco-2 cells. Moreover, presence of folate biosynthesis genes was verified and production of extra and intra-cellular folate determined during growth in culture medium. 31% of yeast strains could tolerate pH 2, while 99% bile salts. Survival rate after simulated digestion ranged between 11 and 45%, while adhesion rate between 12 and 40%. Folate production was mainly intracellular, maximum after 24 h of growth. To be closer to traditional cereal-based fermentations, a P. kudriavzevii strain with good probiotic potential was co-inoculated with Lactobacillus fermentum strains in a pearl millet gruel. This resulted in in situ folate production that peaked after 4 h. The use of strains with both probiotic and nutritional enrichment properties may have a greater impact for the consumers. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

    International Nuclear Information System (INIS)

    Mason, J.B.; Selhub, J.

    1986-01-01

    The folate in milk is bound to high affinity FBPs but it is unknown whether this binding affects intestinal transport of milk folate in the suckling rat. The authors examined the FBP activity of segments of the GI tract in fed and fasting states. Under fed conditions, the FBP activity in the mucosa of the stomach and proximal small intestine were similar (0.28 and 0.32 pMole folic acid binding/mg protein, N.S.). Both demonstrated less activity than the mucosa of the distal small intestine (1.31 pMole/mg protein, P 3 pteryolmonoglutamate (H 3 PGA) was examined in suckling rats by the intestinal loop model. Unbound H 3 PGA demonstrated greater lumenal disappearance in the proximal segment of the small intestine compared to the distal segment (79% vs. 56%, P 3 PGA demonstrated greater lumenal disappearance in the distal segment (36% vs. 21%, p < .005). That porton of FBP activity in the distal small intestine that disappears with fasting may represent FBP absorbed from the lumen of the intestine. The FBP-bound folate in milk appears to be absorbed in the suckling rat by a mechanism that favors the distal small intestine and is different from the mechanism responsible for absorption of the unbound folate

  7. Pregnancy- and lactation related folate deficiency in South Africa - a ...

    African Journals Online (AJOL)

    Pregnancy- and lactation-related folate deficiency up to 2 years after delivery remains a common cause of megaloblastic anaemia in South Africa. Certain communities in rural South Africa have recently been shown to have high incidences of both neural tube defects and folate deficiency. The fortification of a staple food ...

  8. Acute folate deficiency in a critically ill patient

    NARCIS (Netherlands)

    Geerlings, S. E.; Rommes, J. H.; van Toorn, D. W.; Bakker, J.

    1997-01-01

    A 19-year-old male patient developed thrombocytopenia and leukopenia due to acute folate deficiency while recovering from a multiple organ failure syndrome. Risk factors for acute folate deficiency are extensive tissue damage due to sepsis, trauma or surgery and acute renal failure requiring renal

  9. 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

  10. 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

  11. Simultaneous radiodetermination of folate and vitamin B12

    International Nuclear Information System (INIS)

    Gutcho, S.; Mansbach, L.

    1978-01-01

    The invention concerns a method to simultaneously investigate or determine folate and vitamin B12. The differentiation between both compounds is based on the use of radioactive tracers; a radio-iodized folic acid is used as folate tracer; vitamin B12 can be labelled with 57 Co. (VJ) [de

  12. Association of polymorphisms in folate metabolic genes and ...

    Indian Academy of Sciences (India)

    Epidemiological studies have shown an association between low folate intake and an increased cancer risk. Folate defi- ciency is thought to increase the risk of cancer through im- paired DNA repair synthesis and disruption of DNA methy- lation (Duthie 1999; Choi and Mason 2000; Wei et al. 2003;. Shen et al. 2005).

  13. Analysis of diversity of chromophytic phytoplankton in a mangrove ecosystem using rbcL gene sequencing.

    Science.gov (United States)

    Samanta, Brajogopal; Bhadury, Punyasloke

    2014-04-01

    Phytoplankton forms the basis of primary production in mangrove environments. The phylogeny and diversity based on the amplification and sequencing of rbcL, the large subunit encoding the key enzyme ribulose-1, 5-bisphosphate carboxylase/oxygenase was investigated for improved understanding of the community structure and temporal trends of chromophytic eukaryotic phytoplankton assemblages in Sundarbans, the world's largest continuous mangrove. Diatoms (Bacillariophyceae) were by far the most frequently detected group in clone libraries (485 out of 525 clones), consistent with their importance as a major bloom-forming group. Other major chromophytic algal groups including Cryptophyceae, Haptophyceae, Pelagophyceae, Eustigmatophyceae, and Raphidophyceae which are important component of the assemblages were detected for the first time from Sundarbans based on rbcL approach. Many of the sequences from Sundarbans rbcL clone libraries showed identity with key bloom forming diatom genera namely Thalassiosira, Skeletonema and Nitzschia. Similarly, several rbcL sequences which were diatom-like were also detected highlighting the need to explore diatom communities from the study area. Some of the rbcL sequences detected from Sundarbans were ubiquitous in distribution showing 100% identities with uncultured rbcL sequences targeted previously from the Gulf of Mexico and California upwelling system that are geographically separated from study area. Novel rbcL lineages were also detected highlighting the need to culture and sequence phytoplankton from the ecoregion. Principal component analysis revealed that nitrate is an important variable that is associated with observed variation in phytoplankton assemblages (operational taxonomic units). This study applied molecular tools to highlight the ecological significance of diatoms, in addition to other chromophytic algal groups in Sundarbans. © 2014 Phycological Society of America.

  14. The sweet potato RbcS gene (IbRbcS1) promoter confers high-level and green tissue-specific expression of the GUS reporter gene in transgenic Arabidopsis.

    Science.gov (United States)

    Tanabe, Noriaki; Tamoi, Masahiro; Shigeoka, Shigeru

    2015-08-10

    Sweet potato is an important crop because of its high yield and biomass production. We herein investigated the potential of the promoter activity of a small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (RbcS) from sweet potato (Ipomoea batatas) in order to develop the high expression system of exogenous DNA in Arabidopsis. We isolated two different cDNAs (IbRbcS1 and IbRbcS2) encoding RbcS from sweet potato. Their predicted amino acid sequences were well conserved with the mature RbcS protein of other plants. The tissue-specific expression patterns of these two genes revealed that expression of IbRbcS1 was specific to green tissue, whereas that of IbRbcS2 was non-photosynthetic tissues such as roots and tubers. These results suggested that IbRbcS1 was predominantly expressed in the green tissue-specific of sweet potato over IbRbcS2. Therefore, the IbRbcS1 promoter was transformed into Arabidopsis along with β-glucuronidase (GUS) as a reporter gene. GUS staining and semi-quantitative RT-PCR showed that the IbRbcS1 promoter conferred the expression of the GUS reporter gene in green tissue-specific and light-inducible manners. Furthermore, qPCR showed that the expression levels of GUS reporter gene in IbRbcS1 pro:GUS were same as those in CaMV 35S pro:GUS plants. These results suggest that the IbRbcS1 promoter is a potentially strong foreign gene expression system for genetic transformation in plants. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. 177Lu-EC0800 combined with the antifolate pemetrexed: preclinical pilot study of folate receptor targeted radionuclide tumor therapy.

    Science.gov (United States)

    Reber, Josefine; Haller, Stephanie; Leamon, Christopher P; Müller, Cristina

    2013-11-01

    Targeted radionuclide therapy has shown impressive results for the palliative treatment of several types of cancer diseases. The folate receptor has been identified as specifically associated with a variety of frequent tumor types. Therefore, it is an attractive target for the development of new radionuclide therapies using folate-based radioconjugates. Previously, we found that pemetrexed (PMX) has a favorable effect in reducing undesired renal uptake of radiofolates. Moreover, PMX also acts as a chemotherapeutic and radiosensitizing agent on tumors. Thus, the aim of our study was to investigate the combined application of PMX and the therapeutic radiofolate (177)Lu-EC0800. Determination of the combination index (CI) revealed a synergistic inhibitory effect of (177)Lu-EC0800 and PMX on the viability of folate receptor-positive cervical (KB) and ovarian (IGROV-1) cancer cells in vitro (CI radionuclide therapy and prevented undesired radio-nephrotoxicity. ©2013 AACR.

  16. BGMUT: NCBI dbRBC database of allelic variations of genes encoding antigens of blood group systems.

    Science.gov (United States)

    Patnaik, Santosh Kumar; Helmberg, Wolfgang; Blumenfeld, Olga O

    2012-01-01

    Analogous to human leukocyte antigens, blood group antigens are surface markers on the erythrocyte cell membrane whose structures differ among individuals and which can be serologically identified. The Blood Group Antigen Gene Mutation Database (BGMUT) is an online repository of allelic variations in genes that determine the antigens of various human blood group systems. The database is manually curated with allelic information collated from scientific literature and from direct submissions from research laboratories. Currently, the database documents sequence variations of a total of 1251 alleles of all 40 gene loci that together are known to affect antigens of 30 human blood group systems. When available, information on the geographic or ethnic prevalence of an allele is also provided. The BGMUT website also has general information on the human blood group systems and the genes responsible for them. BGMUT is a part of the dbRBC resource of the National Center for Biotechnology Information, USA, and is available online at http://www.ncbi.nlm.nih.gov/projects/gv/rbc/xslcgi.fcgi?cmd=bgmut. The database should be of use to members of the transfusion medicine community, those interested in studies of genetic variation and related topics such as human migrations, and students as well as members of the general public.

  17. Oral supplementation of vitamin E reduces osmotic fragility of RBC in hemolytic anemic patients with G6PD deficiency

    International Nuclear Information System (INIS)

    Sultana, N.; Begum, S.; Begum, N.; Ali, T.

    2009-01-01

    Vitamin E has role in maintaining the integrity of red cell member by preventing oxidation of polyunsaturated fatty acids, thus protects cells from oxidative stress-induced lysis in G6PD deficiency. Changes in osmotic fragility of RBC and some absolute values like MCV, MCH and MCHC may occur in haemolytic anaemic patients with G6PD deficiency. To observe the effects of vitamin E supplementation on these changes in order to evaluate the role of this anti-oxidant vitamin in reducing chronic haemolysis in G6PD deficient patients. A total number of 102 subjects with age ranged of 5 to 40 years of both sexes were included in the study. Among them 68 were G6PD enzyme deficient patients, of whom 34 were in supplemented group (experimental group) and 34 were in non-supplemented group (control group). The supplemented group received vitamin E supplementation for 60 consecutive days at a dose of 800 IU/day for adult and 400 IU/day for children ?12 years (in a divided dose, i.e., 4 times daily). Age and sex matched 34 apparently healthy subjects with normal blood G6PD level were taken to observe the base line data (healthy control) and also for comparison. All the G6PD deficient patients were selected from Out Patient Department (OPD) of Haematology, Banglabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from July 2005 to June 2006 and all healthy subjects were selected from personal contact. Blood G6PD level, osmotic fragility of RBC were measured by standard techniques and MCV, MCH, and MCHC were obtained by calculation. All the parameters were measured on day 1 of their first visit and also were on day 60 in deficient group. Data were compared among the deficient groups, also in supplemented group just before and after supplementation. Analysis of data was done by appropriate statistical method. Mean starting and completing points of osmotic fragility of RBC were significantly higher but MCV. MCH, MCHC were significantly lower in patients suffering from

  18. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics

    Science.gov (United States)

    Kager, Leo; Cheok, Meyling; Yang, Wenjian; Zaza, Gianluigi; Cheng, Qing; Panetta, John C.; Pui, Ching-Hon; Downing, James R.; Relling, Mary V.; Evans, William E.

    2005-01-01

    The ability of leukemia cells to accumulate methotrexate polyglutamate (MTXPG) is an important determinant of the antileukemic effects of methotrexate (MTX). We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (fewer than 50 chromosomes) ALL. To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays to analyze expression of 32 folate pathway genes in diagnostic leukemia cells from 197 children. This revealed ALL subtype–specific patterns of folate pathway gene expression that were significantly related to MTXPG accumulation. We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL. PMID:15630450

  19. Synthesis and evaluation of Lys1(α,γ-Folate)Lys3(177Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer

    International Nuclear Information System (INIS)

    Aranda-Lara, Liliana; Ferro-Flores, Guillermina; Azorín-Vega, Erika; Ramírez, Flor de María; Jiménez-Mancilla, Nallely; Ocampo-García, Blanca; Santos-Cuevas, Clara; Isaac-Olivé, Keila

    2016-01-01

    The aim of this work was to synthesize Lys 1 (α,γ-Folate)-Lys 3 ( 177 Lu-DOTA)-Bombesin (1-14) ( 177 Lu-Folate-BN), as well as to assess its potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (FR) and gastrin-releasing peptide receptors (GRPR). Radiation absorbed doses of 177 Lu-Folate-BN (74 MBq, i.v.) estimated in athymic mice with T47D-induced breast tumors (positive to FR and GRPR), showed tumor doses of 23.9±2.1 Gy. T47D-tumors were clearly visible (Micro-SPECT/CT images). 177 Lu-Folate-BN demonstrated properties suitable as a theranostic radiopharmaceutical. - Highlights: • 177 Lu-Folate-BN improves recognition of breast cancer cells positive to FR and GRPR. • 177 Lu-Folate-BN shows theranostic (imaging and radiation therapy) properties. • The heterobivalent 177 Lu-Folate-BN tracer interacts with different targets on tumors.

  20. Targeted folate receptor β fluorescence imaging as a measure of inflammation to estimate vulnerability within human atherosclerotic carotid plaque

    NARCIS (Netherlands)

    Jager, Nynke A.; Westra, Johanna; van Dam, Gooitzen M.; Teteloshvili, Nato; Tio, Rene A.; Breek, Jan-Cees; Slart, Riemer H. J. A.; Boersma, Hendrikus H.; Low, Phillip S.; Bijl, Marc; Zeebregts, Clark J.

    UNLABELLED: The probability of atherosclerotic plaque rupture and its thrombotic sequelae are thought to be increased at sites of macrophage accumulation. Folate receptor β (FR-β) is present on activated macrophages but not on quiescent macrophages or other immune cells. By conjugating the ligand

  1. Influence of processing on total, monoglutamate and polyglutamate folate contents of leeks, cauliflower, and green beans

    NARCIS (Netherlands)

    Melse-Boonstra, A.; Verhoef, P.; Konings, E.J.; Dusseldorp, van M.; Matser, A.; Hollman, P.C.H.; Meyboom, S.; Kok, F.J.; West, C.E.

    2002-01-01

    Bioavailability of dietary folate might be impaired by the polyglutamate chain to which ~70␘f dietary folates are bound. This chain must be removed enzymatically in the intestine before folate is absorbed as a monoglutamate. To increase formation of monoglutamate folate in vegetables, the vegetables

  2. alpha isoforms of soluble and membrane-linked folate-binding protein in human blood

    DEFF Research Database (Denmark)

    Hoier-Madsen, M.; Holm, J.; Hansen, S.I.

    2008-01-01

    supported the hypothesis that serum FBP (29 kDa) mainly originates from neutrophils. The presence of FBP/FR alpha isoforms were established for the first time in human blood using antibodies specifically directed against human milk FBP alpha. The alpha isoforms identified on erythrocyte membranes......, and in granulocytes and serum, only constituted an almost undetectable fraction of the functional FBP The FBP alpha in neutrophil granulocytes was identified as a cytoplasmic component by indirect immunofluorescence. Gel filtration of serum revealed a peak of FBP alpha (>120 kDa), which could represent receptor...... fragments from decomposed erythrocytes and granulocytes. The soluble FBPs may exert bacteriostatic effects and protect folates in plasma from biological degradation, whereas FRs on the surface of blood cells could be involved in intracellular folate uptake or serve as signal proteins. The latter receptors...

  3. Folic acid derivatives for PET imaging and therapy addressing folate receptor positive tumors

    International Nuclear Information System (INIS)

    Schieferstein, Hanno

    2013-01-01

    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 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 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 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 18 F-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

  4. 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

  5. Importance of methodological standardization for the ektacytometric measures of red blood cell deformability in sickle cell anemia

    NARCIS (Netherlands)

    Renoux, Céline; Parrow, Nermi; Faes, Camille; Joly, Philippe; Hardeman, Max; Tisdale, John; Levine, Mark; Garnier, Nathalie; Bertrand, Yves; Kebaili, Kamila; Cuzzubbo, Daniela; Cannas, Giovanna; Martin, Cyril; Connes, Philippe

    2016-01-01

    Red blood cell (RBC) deformability is severely decreased in patients with sickle cell anemia (SCA), which plays a role in the pathophysiology of the disease. However, investigation of RBC deformability from SCA patients demands careful methodological considerations. We assessed RBC deformability by

  6. Role of folate in nonalcoholic fatty liver disease.

    Science.gov (United States)

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

    2017-10-01

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

  7. Association of low dietary folate intake with lower CAMKK2 gene methylation, adiposity, and insulin resistance in obese subjects.

    Science.gov (United States)

    Ramos-Lopez, Omar; Samblas, Mirian; Milagro, Fermin I; Zulet, M Angeles; Mansego, Maria L; Riezu-Boj, Jose I; Martinez, J Alfredo

    2018-02-01

    Folate deficiency has been putatively implicated in the onset of diverse metabolic abnormalities, including insulin resistance, by altering epigenetic processes on key regulatory genes. The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is involved in the regulation of critical metabolic processes such as adiposity and glucose homeostasis. This study hypothesized associations between low folate intakes and lower methylation levels of the CAMKK2 gene, with the presence of metabolic alterations in subjects with obesity. A cross-sectional ancillary study was conducted in obese subjects (n=47) from the RESMENA study (Spain). Fat mass was measured by dual-energy x-ray absorptiometry. Dietary intake and metabolic profile were assessed by validated methods. DNA methylation and gene expression in peripheral white blood cells were analyzed by microarray approaches. A total of 51 cytosine-phosphate-guanine sites were associated with folate intake (false discovery rate values < 0.0001), including one located in the 5' untranslated region of the CAMKK2 gene (Illumina ID, cg16942632), which was selected and separately analyzed. Subjects with total folate intake lower than 300μg/d showed more fat mass (especially trunk fat), as well as statistically higher levels of glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR) index, cortisol, and plasminogen activator inhibitor-1 than those consuming at least or more than 300μg/d. Of note, folate deficiency was related to lower CAMKK2 methylation. Interestingly, CAMKK2 methylation negatively correlated with the HOMA-IR index. Furthermore, CAMKK2 expression directly correlated with HOMA-IR values. In summary, this study suggests associations between low folate intakes, lower CAMKK2 gene methylation, and insulin resistance in obese individuals. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    Wani, Nissar Ahmad; Kaur, Jyotdeep

    2011-03-01

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

  9. [High plasma folate in patients with phenylketonuria].

    Science.gov (United States)

    Zielińska, Magdalena; Żółkowska, Joanna; Przybylska-Kruszewska, Amanda; Gładysz, Dominika; Korycińska-Chaaban, Dorota; Nowacka, Maria; Hozyasz, Kamil K

    2016-04-01

    Phenylketonuria is an inborn error of metabolism treated with a closely monitored low phenylalanine diet. Protein substitutes used for treatment are supplemented with vitamins and micronutrients. The aim of this study was to investigate plasma folic acid concentrations in children with phenylketonuria. Retrospective analysis of medical records of 73 patients with phenylketonuria and 28 with mild hyperphenylalaninemia (on normal diet) was carried out. Intake of folic acid was calculated on the basis of protein substitute intake. Folate concentrations were analyzed according to their intake, and concentration of homocysteine and phenylalanine. In 76.7% patients with phenylketonuria intake of folic acid exceeded recommended dietary allowance. Serum folic acid concentrations above upper reference level were detected in 75.3% patients with phenylketonuria and only in 25% patients with hyperphenylalaninemia (pphenylketonuria requires further detailed research. © 2016 MEDPRESS.

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

    Science.gov (United States)

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

    2012-01-01

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

  11. 40 CFR 35.2035 - Rotating biological contractor (RBC) replacement grants.

    Science.gov (United States)

    2010-07-01

    ... treatment works owner, the applicant, its engineers, contractors, equipment manufacturers or suppliers; (b) The RBC failure has significantly increased the project's capital or operation and maintenance costs; (c) The modification/replacement project meets all requirements of EPA's construction grant and other...

  12. Rheological and electrical properties of polymeric nanoparticle solutions and their influence on RBC suspensions

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Koseva, N.; Kowalczyk, A.; Říha, Pavel; Ivanov, I.

    2014-01-01

    Roč. 24, č. 3 (2014), s. 35190 ISSN 1430-6395 Institutional support: RVO:67985874 Keywords : nanoparticles and RBC suspensions * poly(acrylic acid) * rheology * electrical conductivity Subject RIV: BK - Fluid Dynamics Impact factor: 1.078, year: 2014 http://www.ar.ethz.ch/TMPPDF/24308140293.696/ApplRheol_24_35190.pdf

  13. Treatment of domestic sewage in a combined UASB/RBC system. Process optimization for irrigation purposes

    NARCIS (Netherlands)

    Tawfik Ibrahim, A.; Zeeman, G.; Klapwijk, A.; Sanders, W.T.M.; El-Gohary, F.; Lettinga, G.

    2003-01-01

    A Rotating Biological Contactor (RBC) was fed with raw domestic wastewater or anaerobic effluents. The experiments were conducted at increasing operational temperatures viz. 11, 20 and 30degreesC to assess the potential increase in removal efficiencies for the different COD fractions (CODtotal,

  14. A comprehensive framework for functional diversity patterns of marine chromophytic phytoplankton using rbcL phylogeny

    Science.gov (United States)

    Samanta, Brajogopal; Bhadury, Punyasloke

    2016-01-01

    Marine chromophytes are taxonomically diverse group of algae and contribute approximately half of the total oceanic primary production. To understand the global patterns of functional diversity of chromophytic phytoplankton, robust bioinformatics and statistical analyses including deep phylogeny based on 2476 form ID rbcL gene sequences representing seven ecologically significant oceanographic ecoregions were undertaken. In addition, 12 form ID rbcL clone libraries were generated and analyzed (148 sequences) from Sundarbans Biosphere Reserve representing the world’s largest mangrove ecosystem as part of this study. Global phylogenetic analyses recovered 11 major clades of chromophytic phytoplankton in varying proportions with several novel rbcL sequences in each of the seven targeted ecoregions. Majority of OTUs was found to be exclusive to each ecoregion, whereas some were shared by two or more ecoregions based on beta-diversity analysis. Present phylogenetic and bioinformatics analyses provide a strong statistical support for the hypothesis that different oceanographic regimes harbor distinct and coherent groups of chromophytic phytoplankton. It has been also shown as part of this study that varying natural selection pressure on form ID rbcL gene under different environmental conditions could lead to functional differences and overall fitness of chromophytic phytoplankton populations. PMID:26861415

  15. Functional analysis of a Lemna gibba rbcS promoter regulated by ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 92; Issue 1. Functional analysis of a Lemna gibba rbcS ... Photosynthesis-associated nuclear genes (PhANGs) are able to respond to multiple environmental and developmental signals, including light, sugar and abscisic acid (ABA). PhANGs have been extensively studied at the ...

  16. Time dependent variation of human blood conductivity as a method for an estimation of RBC aggregation

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Říha, Pavel; Ivanov, I.

    2008-01-01

    Roč. 39, č. 1 (2008), s. 69-78 ISSN 1386-0291 Institutional research plan: CEZ:AV0Z20600510 Keywords : RBC aggregation * blood conductivity * low shear rate viscometry Subject RIV: BO - Biophysics Impact factor: 1.814, year: 2008

  17. Folate receptor targeted 17-allylamino-17-demethoxygeldanamycin (17-AAG) loaded polymeric nanoparticles for breast cancer.

    Science.gov (United States)

    Saxena, Vipin; Naguib, Youssef; Hussain, M Delwar

    2012-06-01

    Low water solubility and hepatotoxicity limited the clinical use of 17-allylamino-17-demethoxy geldanamycin (17-AAG), an inhibitor of heat shock protein 90 (HSP90). Folate targeted polylactide-co-glycolide-polyethylene glycol-folic acid (PLGA-PEG-FA) nanoparticles containing 17-AAG were prepared and characterized. Cellular uptake and in vitro cytotoxicity of the prepared nanoparticles were determined in MCF-7 human breast cancer cells. The particle size of 17-AAG loaded folate targeted nanoparticles was 238.67±3.52 nm, drug loading was 8.25±2.49% and about 80% of drug was released from the nanoparticles over 10 days. Cellular uptake studies showed much higher intracellular uptake of folate targeted nanoparticle as compared to nontargeted nanoparticles. Cytotoxicity study showed 2 fold increase (PAAG loaded PLGA-PEG-FA nanoparticles might be developed as a targeted delivery system for breast and other cancer treatment. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Reduction of Folate by Dihydrofolate Reductase from Thermotoga maritima

    NARCIS (Netherlands)

    Loveridge, E Joel; Hroch, Lukas; Hughes, Robert L; Williams, Thomas; Davies, Rhidian L; Angelastro, Antonio; Luk, Louis Y P; Maglia, Giovanni; Allemann, Rudolf K

    2017-01-01

    Mammalian dihydrofolate reductases (DHFR) catalyse the reduction of folate more efficiently than the equivalent bacterial enzymes, despite typically having similar efficiencies for the reduction of their natural substrate dihydrofolate. In contrast, we show here that DHFR from the hyperthermophilic

  19. Dietary folate and reproductive success among women undergoing assisted reproduction.

    Science.gov (United States)

    Gaskins, Audrey J; Afeiche, Myriam C; Wright, Diane L; Toth, Thomas L; Williams, Paige L; Gillman, Matthew W; Hauser, Russ; Chavarro, Jorge E

    2014-10-01

    To prospectively evaluate the associations of folate with assisted reproductive technology outcomes within a population in the United States. This analysis included women (n=232) in a prospective cohort study at the Massachusetts General Hospital Fertility Center. Diet was assessed before assisted reproductive technology treatment using a validated food frequency questionnaire. Intermediate and clinical endpoints of assisted reproductive technology were abstracted from medical records. Generalized linear mixed models with random intercepts to account for multiple cycles per woman were used to evaluate the association of folate intake with assisted reproductive technology outcomes adjusting for calorie intake, age, body mass index, race, smoking status, infertility diagnosis, and protocol type. Among the 232 women (median age 35.2 years, median folate intake 1,778 micrograms/day), higher folate intake was associated with higher rates of implantation, clinical pregnancy, and live birth. The adjusted percentage (95% confidence interval [CI]) of initiated assisted reproductive technology cycles resulting in a live birth for women in increasing quartiles of folate intake were 30% (95% CI 21-42%), 47% (95% CI 35-59%), 42% (95% CI 30-35%) and 56% (95% CI 43-67%) (P for trend=0.01). Live birth rates were 20% (95% CI 8-31%) higher among women in the highest quartile of supplemental folate intake (more than 800 micrograms/day) than among women in the lowest quartile (less than 400 micrograms/day). Higher supplemental folate intake was associated with higher fertilization rates and lower cycle failure rates before embryo transfer (P for trend=0.03 and 0.02). Higher intake of supplemental folate was associated with higher live birth rates after assisted reproductive technology treatment. : II.

  20. Simulator for training operators of electric substation: an approach via RBC-Paraconsistent; Simulador para treinamento de operadores de subestacao eletrica: um enfoque via RBC-paraconsistente

    Energy Technology Data Exchange (ETDEWEB)

    Lambert-Torres, G.; Martins, H.G.; Coutinho, M.P.; Goulart, J.D.C.; Soares, F.M.A. [Universidade Federal de Itajuba (UNIFEI), MG (Brazil). Dept. de Engenharia Eletrica], Emails: germanoltorres@gmail.com, helgagonzaga@gmail.com, maurilio.coutinho@gmail.com, janaina157@yahoo.com.br, francis.azevedo@gmail.com

    2009-07-01

    This article presents a combination of two techniques applied artificial intelligence to solve problems to Restoration of an Electric Substation: Casebased Reasoning - CBR and the Four Values Annotated Paraconsistent Logic - 4vAPL. The process occurs in the connection functions of belief, disbelief, specialty and temporality to LPA4v in the retrieval of cases to determine process diagnostic of an RBC. The field of CBR is applied in a recovery of an electric substation. The LPA4v is the support applied in problems that have inconsistent information, partials and undefined. Thus this study is closer of the real situations.

  1. Folates in foods: reactivity, stability during processing, and nutritional implications.

    Science.gov (United States)

    Hawkes, J G; Villota, R

    1989-01-01

    Nutritional deficiencies are eminent at all socioeconomic levels of the world population and have created a critical need for a reevaluation of the nutritional quality of the food supply. A particular group of vitamers, collectively referred to as folates, has received a great deal of attention due to their significance in human metabolism, their prevalent deficiency worldwide, as well as their complexity of analysis. Severe folate deficiency may result in megaloblastic anemia and is generally attributed to low dietary intake, although it may also result from malabsorption. Such concerns have instigated increased interest in food-fortification programs. In order to ensure appropriate levels of nutrient fortification and optimization of food processes for maximum folate retention, it is of great importance to have a basic understanding of the kinetic behavior of individual vitamers with respect to processing parameters and various environmental conditions. This article reviews kinetic stability of folates as affected by processing conditions, discusses problems associated with current methodology for folate analyses, and integrates this information with the nutritional aspects of folates.

  2. 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.......2% postpartum (P homocysteine demonstrated a significant increase: median value was 6.4, 7.0, 7.7 and 10.8 micromol/L, respectively (P homocysteine >13 micromol/L increased during pregnancy from 0.7% to 20.8% postpartum (P

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

    Directory of Open Access Journals (Sweden)

    Erika Castaño

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

  4. A novel system for heterologous expression of flavocytochrome c in phototrophic bacteria using the Allochromatium vinosum rbcA promoter.

    Science.gov (United States)

    De Smet, L; Kostanjevecki, V; Guisez, Y; Van Beeumen, J

    2001-07-01

    Flavocytochrome c-sulfide dehydrogenase (FCSD), an enzyme that catalyzes the reversible conversion of sulfide to elemental sulfur in vitro, is common to bacteria that utilize reduced sulfur compounds as electron donors in the process of carbon dioxide fixation. FCSD is a heterodimer containing two different cofactors, a flavin (FAD) and one or two heme c groups, located on the separate protein subunits. Efforts to produce the holoproteins of the soluble Allochromatium vinosum FCSD and the membrane-bound Ectothiorhodospira vacuolata protein in Escherichia coli using several expression systems were unsuccessful. Although all systems used were able to export the recombinant FCSDs to the periplasm, the proteins did not incorporate heme. In order to develop a new expression system involving photosynthetic hosts (Rhodobacter capsulatus, Rhodobacter sphaeroides and Ect. vacuolata), plasmid mobilisation from E. coli donors was studied. In the search for efficient promoters for such hosts, a system was developed combining the broad-host-range plasmid pGV910 and the promoter of the A. vinosum RuBisCo gene, rbcA. Conjugation was used to enable transfer from the expression plasmid of E. coli into Rba. capsulatus, Rba. sphaeroides strains and into Ect. vacuolata. Both Rhodobacter hosts were able to transcribe the genes coding for FCSD from the rbcA promoter and to produce detectable amounts of recombinant FCSD holoprotein. Western blots showed that the best production was obtained from cells grown photosynthetically on malate or acetate with sulfide. This system may prove to be of general use for the production of recombinant c-type cytochromes in homologous or related host systems.

  5. Use of hydroxyethyl starch for inducing red blood cell aggregation

    NARCIS (Netherlands)

    Henkelman, Sandra; Rakhorst, Gerhard; van der Mei, Henny C.; Busscher, Henk J.

    2012-01-01

    Aggregation of human red blood cells (RBC) remains of biological and clinical interest. Replacement of plasma proteins by polymers to induce RBC aggregation may help to unravel the fundamentals of the aggregation process. Two theories exist to explain RBC aggregation mechanisms: a depletion and a

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

    International Nuclear Information System (INIS)

    Tani, M.; Iwai, K.

    1984-01-01

    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 [ 3 H]PteGlu (i.e., bound to the FBP from milk), was delivered to rats intragastrically via oral intubation, the amounts of [ 3 H]PteGlu excreted into the feces did not change. On the other hand, the urinary excretion of 3 H-labeled folate compounds, especially [ 3 H]5-methyltetrahydrofolic acid (5-CH 3 -H 4 PteGlu), after the administration of bound [ 3 H]PteGlu was significantly lower (P less than 0.01) than that after the administration of free [ 3 H]PteGlu. The urinary excretion of [ 3 H]5-CH 3 -H 4 PteGlu was directly proportional to the initial amount of free [ 3 H]PteGlu administered. The similar effect of FBP was also observed when the biliary excretion of 3 H-labeled folate compounds was investigated in situ. Furthermore, the incorporation of [ 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

  7. Prevention of pathologies associated with oxidative stress and dietary intake deficiencies: folate deficiency and requirements.

    Science.gov (United States)

    Tapiero, H; Tew, K D; Gaté, L; Machover, D

    2001-09-01

    Folate (folic acid, folacin) is an essential vitamin that is found in nature. Folates contain the core chemical structure of pteroylglutamic acid, but vary in their state of reduction, the single carbon moiety they bear and/or the length of the glutamate chain. At least 50% of whole body folate is stored in the liver. The influence of intracellular folate concentration depends largely on dietary intake. The supply of folate depends primarily on the quantity and bioavailability of ingested folate and the rate of loss by urinary and fecal routes and through catabolism.

  8. 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......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 different phenotypes of asthma and atopy....

  9. RBC indices

    Science.gov (United States)

    ... below normal. Hypochromic anemia (often due to low iron levels). MCH normal. Normochromic anemia (may be due to sudden blood loss, long-term diseases, kidney failure, aplastic anemia, or man-made heart valves). MCH above normal. Hyperchromic anemia ( ...

  10. Multifunctional pH-Responsive Folate Receptor Mediated Polymer Nanoparticles for Drug Delivery.

    Science.gov (United States)

    Cai, Xiaoqing; Yang, Xiaoye; Wang, Fang; Zhang, Chen; Sun, Deqing; Zhai, Guangxi

    2016-07-01

    Multifunctional pH-responsive folate receptor mediated targeted polymer nanoparticles (TPNps) were developed for docetaxel (DTX) delivery based on poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)poly (β-amino ester) (P123-PAE) and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)-folate (P123-FA) copolymers. The DTX was loaded into the TPNps with a decent drug loading content of 15.02 ± 0.14 wt%. In vitro drug release results showed that the DTX was released from the TPNps at a pH-dependent manner. Tetrazolium dye (MTT) assay revealed that the bland polymer nanoparticles displayed almost nontoxicity at 200 μg/mL concentration. However, the DTX-loaded TPNps showed high anti-tumor activity at low IC50 (0.72 μg/mL) for MCF-7 cells following 48 h incubation. Cellular uptake experiments revealed that the TPNps had higher degree of cellular uptake than nontargeted polymer nanoparticles, indicating that the nanoparticles were internalized into the cells via FA receptor-mediated endocytosis. Moreover, the cellular uptake pathways for the FA grafted polymer were involved in energy-dependent, clathrin-mediated and caveolae-mediated endocytosis. The cell killing effect and cellular uptake of the DTX-TPNps by the MCF-7 cells were all enhanced by about two folds at pH 5.5 when compared with pH 7.4. The TPNps also significantly prolonged the in vivo retention time for the DTX. These results suggest that the biocompatible pH responsive folate-modified polymer nanoparticles present a promising safe nanosystem for intracellular targeted delivery of DTX.

  11. [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.

  12. Comparison of blood levels of riboflavin and folate with dietary correlates estimated from a semi-quantitative food-frequency questionnaire in older persons in Portugal.

    Science.gov (United States)

    Tavares, Nelson R; Moreira, Pedro S; Amaral, Teresa F

    2012-01-01

    Since information regarding biochemical parameters of riboflavin and folate status is limited in some populations of older adults, a food-frequency questionnaire is often used to estimate riboflavin and folate status. However, the performance of this type of questionnaire among this age group has not been comprehensively evaluated. Thus, we sought to assess riboflavin and folate status in older adults living in Portugal and to validate findings from a semiquantitative food-frequency questionnaire (FFQ), by comparison to these blood measures. We used a cross-sectional study to investigate riboflavin in red blood cells (as Glutathione Reductase Activity Coefficient; EGRAC) and folate in the serum of 88 older persons (66.7% female), aged between 60 and 94 years, recruited from seven adult day care community centers in Porto, Portugal. Forty-six subjects had low EGRAC levels (riboflavin dietary intakes from FFQ, the mean was 3.34 mg, the median 3.37 mg, and range 0.66-4.81 mg. The Spearman correlation between these two measures was r = 0.073, (P = 0.497) and Pearson correlation, after adjustment for energy, was r = 0.263, P = 0.013. All participants were above the 7 nmol/L serum folate cut-off for adequacy. Spearman correlation coefficient between serum and FFQ measures was r = -0.10, (P = 0.359), and the Pearson correlation, after adjustment for energy and following log(e) transformation, was r = -0.58, (P = 0.593). Thus riboflavin and folate intakes estimated by FFQ correlated poorly with EGRAC and folate serum values.

  13. Folate-modified lipid–polymer hybrid nanoparticles for targeted paclitaxel delivery

    Directory of Open Access Journals (Sweden)

    Zhang L

    2015-03-01

    Full Text Available Linhua Zhang,1 Dunwan Zhu,1 Xia Dong,1 Hongfan Sun,1 Cunxian Song,1 Chun Wang,2 Deling Kong1 1Tianjin Key Laboratory of Biomaterials, Institute of Biomedical Engineering, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, People’s Republic of China; 2Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA Abstract: The purpose of this study was to develop a novel lipid–polymer hybrid drug carrier comprised of folate (FA modified lipid-shell and polymer-core nanoparticles (FLPNPs for sustained, controlled, and targeted delivery of paclitaxel (PTX. The core-shell NPs consist of 1 a poly(ε-caprolactone hydrophobic core based on self-assembly of poly(ε-caprolactone–poly(ethylene glycol–poly(ε-caprolactone (PCL-PEG-PCL amphiphilic copolymers, 2 a lipid monolayer formed with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol-2000] (DSPE-PEG2000, 3 a targeting ligand (FA on the surface, and were prepared using a thin-film hydration and ultrasonic dispersion method. Transmission electron microscopy and dynamic light scattering analysis confirmed the coating of the lipid monolayer on the hydrophobic polymer core. Physicochemical characterizations of PTX-loaded FLPNPs, such as particle size and size distribution, zeta potential, morphology, drug loading content, encapsulation efficiency, and in vitro drug release, were also evaluated. Fluorescent microscopy proved the internalization efficiency and targeting ability of the folate conjugated on the lipid monolayer for the EMT6 cancer cells which overexpress folate receptor. In vitro cytotoxicity assay demonstrated that the cytotoxic effect of PTX-loaded FLPNPs was lower than that of Taxol®, but higher than that of PTX-loaded LPNPs (without folate conjugation. In EMT6 breast tumor model, intratumoral administration of PTX-loaded FLPNPs showed similar antitumor efficacy but low toxicity compared to Taxol®. More

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

    Directory of Open Access Journals (Sweden)

    Whitaker Rhiannon

    2007-11-01

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

  15. Studies on RBC lipid and protein phosphorylation during blood bank storage

    International Nuclear Information System (INIS)

    Dumaswala, U.J.; Bryan, D.J.; Greenwalt, T.J.

    1986-01-01

    Recent evidence has suggested that phosphoinositides play a significant role in maintaining membrane structure and function. Their importance during blood bank storage is not understood. They have performed preliminary studies of the phosphoinositide synthetic pathway enzymes of RBC during blood bank storage. At 0 and 35 days of storage leaky ghosts were prepared and incubated with [γ- 32 P]ATP for 5 minutes at 30 C. One aliquot was subjected to acidified solvent extraction and thin layer chromatography. The labeled phosphoinositide -4,5 biphosphate (PIP 2 ), phosphoinositide-4 phosphate (PIP) and phosphatidic acid (PA) spots were scraped and counted by liquid scintillation spectrometry. Another aliquot was used for SDS-PAGE and the radioactivity associated with the β-spectrin was measured. These experiments suggest a decrease in RBC phosphoinositol and PIP-Kinases and β-spectrin kinase activities during blood bank storage. Further studies are being done to evaluate significance of these observations

  16. Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery

    Directory of Open Access Journals (Sweden)

    Pamela T. Wong

    2015-01-01

    Full Text Available The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+ KB cancer cells.

  17. Phylogeny and intraspecific variability of holoparasitic Orobanche (Orobanchaceae) inferred from plastid rbcL sequences.

    Science.gov (United States)

    Manen, Jean-François; Habashi, Christine; Jeanmonod, Daniel; Park, Jeong-Mi; Schneeweiss, Gerald M

    2004-11-01

    The rbcL sequences of 106 specimens representing 28 species of the four recognized sections of Orobanche were analyzed and compared. Most sequences represent pseudogenes with premature stop codons. This study confirms that the American lineage (sects. Gymnocaulis and Myzorrhiza) contains potentially functional rbcL-copies with intact open reading frames and low rates of non-synonymous substitutions. For the first time, this is also shown for a member of the Eurasian lineage, O. coerulescens of sect. Orobanche, while all other investigated species of sects. Orobanche and Trionychon contain pseudogenes with distorted reading frames and significantly higher rates of non-synonymous substitutions. Phylogenetic analyses of the rbcL sequences give equivocal results concerning the monophyly of Orobanche, and the American lineage might be more closely related to Boschniakia and Cistanche than to the other sections of Orobanche. Additionally, species of sect. Trionychon phylogenetically nest in sect. Orobanche. This is in concordance with results from other plastid markers (rps2 and matK), but in disagreement with other molecular (nuclear ITS), morphological, and karyological data. This might indicate that the ancestor of sect. Trionychon has captured the plastid genome, or parts of it, of a member of sect. Orobanche. Apart from the phylogenetically problematic position of sect. Trionychon, the phylogenetic relationships within sect. Orobanche are similar to those inferred from nuclear ITS data and are close to the traditional groupings traditionally recognized based on morphology. The intraspecific variation of rbcL is low and is neither correlated with intraspecific morphological variability nor with host range. Ancestral character reconstruction using parsimony suggests that the ancestor of O. sect. Orobanche had a narrow host range.

  18. Experimental method for the study of blood and RBC suspension conductivity under flow

    Czech Academy of Sciences Publication Activity Database

    Antonova, N.; Říha, Pavel; Ivanov, I.

    2014-01-01

    Roč. 67, č. 7 (2014), s. 995-1004 ISSN 1310-1331 Grant - others:The Ministry of Education and Science of Bulgaria(BG) BG051PO001-3.3-05/0001; The Ministry of Education, Youth and Science of Bulgaria(BG) DO-805/2012 Institutional support: RVO:67985874 Keywords : viscometric flow * conductivity * blood/RBC suspension microstructural changes Subject RIV: BK - Fluid Dynamics Impact factor: 0.284, year: 2014

  19. /sup 99m/Tc RBC scintigraphy: correlation of gastrointestinal bleeding rates with scintigraphic findings

    International Nuclear Information System (INIS)

    Smith, R.; Copely, D.J.; Bolen, F.H.

    1987-01-01

    In 62 consecutive patients, /sup 99m/Tc RBC studies were reviewed and the scintigraphic findings were characterized to determine the ability of /sup 99m/Tc RBC scintigraphy to estimate bleeding rates in patients with active gastrointestinal hemorrhage. Of the 62 scans, 10 showed early positivity (less than 1 hr) with a strongly intense bleeding focus relative to hepatic activity (group 1), four showed delayed positivity (greater than 1 hr) with a strong focus (group 2), five showed early positivity with a weak focus (group 3), 12 showed delayed positivity with a weak focus (group 4), and 31 studies were negative (group 5). The mean bleeding rates were then calculated by dividing the blood transfusion volume requirements by the duration of active bleeding for each patient, as recorded in the patients' charts. The mean bleeding rates for these groups were 0.4, 0.3, 0.2, 0.15, and 0.1 ml/min, respectively. Group 1 patients had the greatest mean blood-volume loss, longest duration of active bleeding, and highest mean bleeding rate, and they required more aggressive therapy than the other groups. The minimum mean bleeding rate detectable by scintigraphy was 0.1 ml/min. Our results suggest that /sup 99m/Tc RBC scintigraphy can estimate bleeding rates and identify those patients who are at higher risk for developing massive gastrointestinal hemorrhage requiring more aggressive therapy

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

    International Nuclear Information System (INIS)

    Piyasena, R.D.; Weerasekera, D.A.; Hettiaratchi, N.; Wikramanayake, T.W.

    1978-01-01

    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 them to be used as binding agents in a radioassay for serum and whole-blood folate. The binding of folate by cow milk preparations in particular was found to be very poor. Goat milk was preferred to pig plasma as a binder for folate radioassay for reasons of convenience, economy and greater stability, and because pteroylglutamic acid (PGA) can be used both as tracer and standard. Where pig plasma is used with the inclusion of folate-free serum in the standard tubes, differences were observed between the standard and serum blanks which themselves varied from sample to sample. By contrast, with goat milk, all blank readings were normally 3% or less. Five out of eight samples of goat milk were seen to contain 'releasing factor' necessary to liberate folate from endogenous binder (FABP). Where present, the factor was found to be stable for at least three months when the partially purified milk was stored freeze dried at 4 0 C. Goat milk binder was found unable to distinguish between PGA and methyltetrahydrofolic acid (MTFA) at pH9.3. This enabled PGA rather than the more unstable MTFA to be used as tracer and standard. The assay employs a one-step incubation procedure at room temperature. It is sensitive to about 0.1 ng of PGA and is reproducible to less than 5% variation. The mean % recovery of inactive added folate was 101+-4%. (author)

  1. Head and neck cancer: genetic polymorphisms and folate metabolism.

    Science.gov (United States)

    Galbiatti, Ana Lívia Silva; Ruiz, Mariangela Torreglosa; Maniglia, José Victor; Raposo, Luis Sérgio; Pavarino-Bertelli, Erika Cristina; Goloni-Bertollo, Eny Maria

    2012-02-01

    Epidemiological evidence suggests that genetic variants encoding enzymes involved in folate metabolism may modulate HNSCC risk by altering DNA methylation synthesis and genomic estability. A review of the literature on genetic polymorphisms involved in folate metabolism and risk of head and neck cancer was carried out. An electronic search was made on the Medline database to select papers on head and neck cancer and polymorphisms involved in folate metabolism. The association between MTHFR C677T polymorphism and the risk of this tumor type was evaluated in nine studies; there was an association with this disease in three papers. The MTR A2756G and MTRR A66G and RFC1 A80G polymorphisms were also associated with increased risk for HNSCC. MTHFD1 G1958A polymorphism was not associated with increased risk of this disease; the evaluation results of the MTHFR A1298C polymorphism in this neoplasm were contradictory. Other polymorphisms involved in folate metabolism were not studied for this neoplasm. We conclude that polymorphisms involved in folate metabolism may modulate the risk of head and neck cancer, however, these results need to be demonstrated in different populations.

  2. Targeted tumor theranostics using folate-conjugated and camptothecin-loaded acoustic nanodroplets in a mouse xenograft model.

    Science.gov (United States)

    Chen, Wei-Tsung; Kang, Shih-Tsung; Lin, Jian-Liang; Wang, Chung-Hsin; Chen, Ran-Chou; Yeh, Chih-Kuang

    2015-01-01

    In this study, we aimed to validate the feasibility of receptor-targeted tumor theranostics with folate-conjugated (FA) and camptothecin-loaded (CPT) acoustic nanodroplets (NDs) (collectively termed FA-CPT-NDs). The ND formulation was based on lipid-stabilized low-boiling perfluorocarbon that can undergo acoustic droplet vaporization (ADV) under ultrasound (US) exposure. Conjugation of folate enhanced the selective delivery to tumors expressing high levels of folate receptor (FR) under mediation by the enhanced permeability and retention effect. In vitro and in vivo studies were performed using FR-positive KB and FR-negative HT-1080 cell lines and mouse xenograft tumor models. Simultaneous therapy and imaging were conducted with a clinical US imaging system at mechanical indices of up to 1.4 at a center frequency of 10 MHz. The results demonstrated that FA-CPT-NDs selectively attached to KB cells, but not HT-1080 cells. The targeted ADV caused instant and delayed damage via mechanical disruption and chemical toxicity to decrease the viability of KB cells by up to 45%, a much higher decrease than that achieved by the NDs without folate conjugation. The in vivo experiments showed that FR-mediated targeting successfully enhanced the EPR of FA-CPT-NDs in KB tumors mainly on the tumor periphery as indicated by immunofluorescence microscopy and US B-mode imaging. Treatments with FA-CPT-NDs at a CPT dose of 50 μg/kg inhibited the growth of KB tumors for up to six weeks, whereas treatment with NDs lacking folate produced a 4.6-fold increase in tumor volume. For HT-1080 tumors, neither the treatments with FA-CPT-NDs nor those with the NDs lacking folate presented tumor growth inhibition. In summary, FR-targeted tumor theranostics has been successfully implemented with FA-CPT-NDs and a clinical US unit. The ligand-directed and EPR-mediated accumulation provides active and passive targeting capabilities, permitting the antitumor effects of FA-CPT-NDs to be exerted

  3. Red Blood Cell Membrane-Cloaked Nanoparticles For Drug Delivery

    Science.gov (United States)

    Carpenter, Cody Westcott

    Herein we describe the development of the Red Blood Cell coated nanoparticle, RBC-NP. Purified natural erythrocyte membrane is used to coat drug-loaded poly(lacticco-glycolic acid) (PLGA). Synthetic PLGA co-polymer is biocompatible and biodegradable and has already received US FDA approval for drug-delivery and diagnostics. This work looks specifically at the retention of immunosuppressive proteins on RBC-NPs, right-sidedness of natural RBC membranes interfacing with synthetic polymer nanoparticles, sustained and retarded drug release of RBC-NPs as well as further surface modification of RBC-NPs for increased targeting of model cancer cell lines.

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

    International Nuclear Information System (INIS)

    Hansen, S.I.; Holm, J.; Lyngbye, J.

    1982-01-01

    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

  5. 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

  6. "Transfusion indication RBC (PBM-02)": gap analysis of a Joint Commission Patient Blood Management Performance Measure at a community hospital.

    Science.gov (United States)

    De Leon, Essel Marie Bagang; Szallasi, Arpad

    2014-01-01

    The Joint Commission accredits health care organisations in the USA as a prerequisite for licensure. In 2011, TJC published seven Patient Blood Management Performance Measures to improve the safety and quality of care. These Measures will provide hospital-specific information about clinical performance. Of the seven TJC PBM Performance Measures, we decided to evaluate PBM-02, "Transfusion indication RBC", at our hospital. Blood transfusion orders were collected from May 2 to August 2, 2011 and the data analysed. Of the 724 consecutive red blood cell transfusion orders, 694 (96%) documented both clinical indication and pre-transfusion haemoglobin/haematocrit results. The leading transfusion indication (47% of total) was "high risk patients with pre-transfusion Hb of change by introducing the single-unit transfusion policy. The majority (96%) of the transfusion orders met The Joint Commission criteria by providing both transfusion indication and pre-transfusion Hb and/or Hct values. Our transfusion guidelines recommend single-unit red blood cell transfusions with reassessment of the patient after each transfusion for need to receive more blood. Although most (72%) initial orders followed our transfusion guidelines, 70% of patients who received a single unit initially went on to receive more blood (some in excess of 10 units). Our objective data may be helpful in evaluating blood ordering practices at our hospital and in identifying specific clinical services for review.

  7. Periconception Maternal Folate Status and Human Embryonic Cerebellum Growth Trajectories: The Rotterdam Predict Study.

    Directory of Open Access Journals (Sweden)

    Irene V Koning

    Full Text Available 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 gestational age (GA. Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD, left and right cerebellar diameters (LCD, RCD. Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: β = 0.260mm, 95%CI = 0.023-0.491, p<0.05; LCD: β = 0.171mm, 95%CI = 0.038-0.305, p<0.05; RCD: β = 0.156mm, 95%CI = 0.032-0.280, p<0.05 and with proportional cerebellar growth (TCD/CRL:β = 0.015mm/mm, 95%CI = 0.005-0.024, p<0.01; LCD/CRL:β = 0.012mm/mm, 95%CI = 0.005-0.018, p<0.01; RCD/CRL:β = 0.011mm/mm, 95%CI = 0.005-0.017, p<0.01. Cerebellar growth was significantly highest in the third quartile of maternal red blood cell folate levels (1538-1813 nmol/L. These first findings show that periconceptional maternal folate status is associated with human embryonic cerebellar development. Implications of these small but significant variations for fetal cerebellar growth trajectories and the child's neurodevelopmental outcome are yet unknown and warrant further investigation.

  8. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    Directory of Open Access Journals (Sweden)

    Gao Lei

    2011-06-01

    Full Text Available Abstract Background The chloroplast-localized ribulose-1, 5-biphosphate carboxylase/oxygenase (Rubisco, the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. Results We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. Conclusions The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional

  9. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns.

    Science.gov (United States)

    Sen, Lin; Fares, Mario A; Liang, Bo; Gao, Lei; Wang, Bo; Wang, Ting; Su, Ying-Juan

    2011-06-03

    The chloroplast-localized ribulose-1, 5-biphosphate carboxylase/oxygenase (Rubisco), the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU) of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional implications of such mutations put forward the conclusion that

  10. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    LENUS (Irish Health Repository)

    Sen, Lin

    2011-06-03

    Abstract Background The chloroplast-localized ribulose-1, 5-biphosphate carboxylase\\/oxygenase (Rubisco), the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU) of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield clues on the biological meaning of such adaptive processes. The role of such coevolutionary dynamics in the continual fine-tuning of RbcL remains obscure. Results We used the timescale and phylogenetic analyses to investigate and search for processes of adaptive evolution in rbcL gene in three gymnosperm families, namely Podocarpaceae, Taxaceae and Cephalotaxaceae. To understand the relationships between regions identified as having evolved under adaptive evolution, we performed coevolutionary analyses using the software CAPS. Importantly, adaptive processes were identified at amino acid sites located on the contact regions among the Rubisco subunits and on the interface between Rubisco and its activase. Adaptive amino acid replacements at these regions may have optimized the holoenzyme activity. This hypothesis was pinpointed by evidence originated from our analysis of coevolution that supported the correlated evolution between Rubisco and its activase. Interestingly, the correlated adaptive processes between both these proteins have paralleled the geological variation history of the concentration of atmospheric CO2. Conclusions The gene rbcL has experienced bursts of adaptations in response to the changing concentration of CO2 in the atmosphere. These adaptations have emerged as a result of a continuous dynamic of mutations, many of which may have involved innovation of functional Rubisco features. Analysis of the protein structure and the functional implications of such

  11. Folate-modified Annonaceous acetogenins nanosuspensions and their improved antitumor efficacy.

    Science.gov (United States)

    Hong, Jingyi; Sun, Zhonghao; Li, Yijing; Guo, Yifei; Liao, Yonghong; Liu, Meifeng; Wang, Xiangtao

    2017-01-01

    Annonaceous acetogenins (ACGs) are a large family of fatty acid derived natural products that are exclusively isolated from the Annonaceae species. Many members of this diverse family have a broad spectrum of biological activities, the most impressive of which is anticancer activity. However, their poor solubility and severe toxicity restrict their clinical application, and their complicated composition hinders their formulation and drug delivery. In this study, β-cyclodextrin was modified with folic acid (FA) and then combined with soybean lecithin to prepare FA-modified ACGs nanosuspensions (FA-ACGs-NSps). The obtained FA-ACGs-NSps had a high drug payload of 57.59% and average particle size of 199.5 nm, and they exhibited sustained drug release within 142 hours. In comparison with ACGs-NSps, FA-ACGs-NSps showed significantly enhanced cytotoxicity and higher cell uptake toward folate receptor-positive 4T1 cell lines. An in vivo study demonstrated that FA-ACGs-NSps more effectively accumulated in tumors and enhanced the antitumor therapeutic efficacy with less toxicity in 4T1 tumor bearing mice. Therefore, FA-ACGs-NSps may be a promising drug delivery system for ACGs to improve their therapeutic window and may be suitable for clinical application to treat folate-positive tumors.

  12. 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...

  13. Oxidative-stress-mediated teratogenesis and the role of folate

    NARCIS (Netherlands)

    Tran, Y.H.; Bergman, J.; Bakker, M.; Groen, H.; Wilffert, B.

    2016-01-01

    Background: Oxidative stress (OS) is one of the underlying teratogenic mechanisms of medical drugs. Folate is indirectly involved in OS because of its role in the methylation steps in the detoxification of xenobiotics and in the repair of OS-induced DNA damage. Our study was to explore the

  14. A patient with bulimia nervosa and profound folate deficiency.

    Science.gov (United States)

    Eedy, D. J.; Curran, J. G.; Andrews, W. J.

    1986-01-01

    A case is reported of a young woman with bulimia nervosa who presented with profound folate deficiency. This association has not been reported before despite the increased theoretical possibility. Initially she has responded well to folic acid therapy and social support. PMID:3809077

  15. Prevalence of Vitamin B12 and Folate Deficiencies and ...

    African Journals Online (AJOL)

    Purpose: To investigate the prevalence of cobalamin and folate deficiencies among the elderly in the general population of Shiraz in southern Iran. Methods: This is a descriptive cross-sectional study including 340 individuals who are over 50 years old and were selected randomly from all the regions of Shiraz. Results: The ...

  16. Prevalence of Vitamin B12 and Folate Deficiencies and ...

    African Journals Online (AJOL)

    folate deficiency (≤ 2 - 3 ng/mL). Correlation analysis showed that serum cobalamin and homocysteine in the study samples were not significant (p > 0.05). Conclusion: The prevalence of severe cobalamin deficiency with clinical significance is high in the elderly population of Shiraz, Iran. Keywords: Vitamin B12 deficiency, ...

  17. Bioavailability and bioefficacy of folate and folic acid in man

    NARCIS (Netherlands)

    Brouwer, I.A.; Dusseldorp, van M.; West, C.E.; Steegers-Theunissen, R.P.M.

    2001-01-01

    Folic acid is important because supplementation around the time of conception has been proven to lower the risk of having offspring with a neural-tube defect. Furthermore, both dietary folate and folic acid decrease plasma total homocysteine concentrations. Elevated plasma homocysteine

  18. 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,

  19. Synthesis and characterization of folate-poly(ethylene glycol ...

    African Journals Online (AJOL)

    polyethylenimine as a non-viral carrier for tumor-targeted gene delivery. ... It was concluded that FA-PEG-CHI-g-PEI, which has improved transfection efficiency and FRs specificity in vitro and in vivo, may be useful in gene therapy. Key words: Folate ...

  20. High folate production by naturally occurring Lactobacillus sp. with ...

    African Journals Online (AJOL)

    USER

    2010-08-16

    Aug 16, 2010 ... properties showed that both strains were similar to Lactobacillus crustorum. Therefore .... was similar to L. plantarum except fermentation of rhamnose. L. plantarum cannot ferment rhamnose but this strain can. The results of biochemical analyses are ... folate is produced by Lactobacilli reuteri (Santos et al., ...

  1. Folate deficiency in women of reproductive age in nine ...

    African Journals Online (AJOL)

    2009-10-13

    Oct 13, 2009 ... Original Research: Folate deficiency in women of reproductive age in nine administrative regions of Ethiopia. 2010;23(3) ... a School of Public Health, Addis Ababa University, Ethiopia b Department of Biochemistry, Addis Ababa University Medical Faculty and Ethiopian ... Information on the prevalence.

  2. Association of polymorphisms in folate metabolic genes and ...

    Indian Academy of Sciences (India)

    1996 Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG com- plementation group of folate/cobalamin disorders. Hum. Mol. Genet. 5, 1867–1874. Marchal C., Redondo M., Reyes-Engel A., Perea-Milla E., Gaitan. M., Machuca J. et al. 2008 Association between polymorphisms.

  3. Association of anaemia with micronutrient (iron, folate and Vitamin ...

    African Journals Online (AJOL)

    After informed verbal consent from the guardian or parent was obtained, information on demographic and clinical characteristics was collected from the parent or guardian. The following laboratory tests on blood were done on all subjects: full blood count; serum iron; serum transferrin; serum folate; and active serum vitamin ...

  4. INVITRO ACTIVITY OF NOVEL ANTIFOLATES AGAINST HUMAN SQUAMOUS CARCINOMA CELL-LINES OF THE HEAD AND NECK WITH INHERENT RESISTANCE TO METHOTREXATE

    NARCIS (Netherlands)

    van der Laan, B.F.A.M.; JANSEN, G; KATHMANN, GAM; WESTERHOF, GR; SCHORNAGEL, JH; HORDIJK, GJ

    1992-01-01

    A series of 7 human squamous carcinoma cell lines of the head and neck (HNSCC), grown in standard medium containing high folate concentrations and in "folate-conditioned" medium containing nanomolar concentrations of folates, were all found to be sensitive (IC50: less-than-or-equal-to 50 nM) in

  5. Tumor targeting using {sup 67}Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

    Energy Technology Data Exchange (ETDEWEB)

    Mueller, Cristina, E-mail: cristina.mueller@psi.ch [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Vlahov, Iontcho R.; Santhapuram, Hari Krishna R.; Leamon, Christopher P. [Endocyte Inc., West Lafayette, IN 47906 (United States); Schibli, Roger [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

    2011-07-15

    Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [{sup 67}Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-({gamma})-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with {sup 67}GaCl{sub 3} according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: {sup 67}Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%{+-}0.75% ID/g, 1 h pi and 6.08%{+-}0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of {sup 67}Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel {sup 67}Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR

  6. METHYLMALONIC ACID AND HOMOCYSTEIN SERUM IN DIAGNOSING MEGALOBLASTIC ANEMIA DUE TO COBALAMIN AND FOLATE DEFICIENCY IN TRAVEL MEDICINE

    Directory of Open Access Journals (Sweden)

    Made Gian Indra Rahayuda

    2014-01-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE Anemia is a major global health problem, especially in developing countries. Anemia is a condition where the red blood cell mass and / or hemoglobin mass that circulating in the body was decreased to below normal level so it can not function well in providing oxygen to the body tissues. One of the most common type is megaloblastic anemia. Megaloblastic anemia is mostly caused by vitamin B12 (cobalamin and folate deficiency. One of the causes of cobalamin and folate deficiency anemia is tropical sprue. Cobalamin deficiency anemia and folate deficiency anemia gives a similar symptom, but in cobalamin deficiency there is neuropathy symptoms. Normal serum folate is between 3-15 ng/mL. Normal folate erythrocyte is 150-600 ng/mL. In cobalamin deficiency, serum cobalamin decreased below the cut off point 100pg/mL (normally 100 - 400pg/mL. Other examination such as elevated homocysteine??, methylmalonic acid, or formioglutamic acid (FIGLU in the urine can confirm the diagnosis of cobalamin and folic acid deficiency. There is no consensus on the cut-off point of homocysteine ??and MMA. Homocysteine ??has been considered to increase when the levels are above 12-14 ?mol /L in women and in the 14-15 ?mol/L. According to research by Robert et al in the case of cobalamin deficiency, serum tHcy> 15.0 ?mol/L. Most research considers the increase of MMA in cobalamin deficiency is> 0:28 ?mol / L, but the cut off point in circulation varies between 0:21 to 0:48 ?mol/L. MMA level is increased in serum and urine in cobalamin deficiency, whereas MMA normal in folate deficiency. /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font

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

    Directory of Open Access Journals (Sweden)

    Susanne Westenbrink

    2012-04-01

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

  8. A functional polymorphism in the reduced folate carrier gene and DNA hypomethylation in mothers of children with autism.

    Science.gov (United States)

    James, S Jill; Melnyk, Stepan; Jernigan, Stefanie; Pavliv, Oleksandra; Trusty, Timothy; Lehman, Sara; Seidel, Lisa; Gaylor, David W; Cleves, Mario A

    2010-09-01

    The biologic basis of autism is complex and is thought to involve multiple and variable gene-environment interactions. While the logical focus has been on the affected child, the impact of maternal genetics on intrauterine microenvironment during pivotal developmental windows could be substantial. Folate-dependent one carbon metabolism is a highly polymorphic pathway that regulates the distribution of one-carbon derivatives between DNA synthesis (proliferation) and DNA methylation (cell-specific gene expression and differentiation). These pathways are essential to support the programmed shifts between proliferation and differentiation during embryogenesis and organogenesis. Maternal genetic variants that compromise intrauterine availability of folate derivatives could alter fetal cell trajectories and disrupt normal neurodevelopment. In this investigation, the frequency of common functional polymorphisms in the folate pathway was investigated in a large population-based sample of autism case-parent triads. In case-control analysis, a significant increase in the reduced folate carrier (RFC1) G allele frequency was found among case mothers, but not among fathers or affected children. Subsequent log linear analysis of the RFC1 A80G genotype within family trios revealed that the maternal G allele was associated with a significant increase in risk of autism whereas the inherited genotype of the child was not. Further, maternal DNA from the autism mothers was found to be significantly hypomethylated relative to reference control DNA. Metabolic profiling indicated that plasma homocysteine, adenosine, and S-adenosylhomocyteine were significantly elevated among autism mothers consistent with reduced methylation capacity and DNA hypomethylation. Together, these results suggest that the maternal genetics/epigenetics may influence fetal predisposition to autism. (c) 2010 Wiley-Liss, Inc.

  9. Folate Decorated Nanomicelles Loaded with a Potent Curcumin Analogue for Targeting Retinoblastoma

    Directory of Open Access Journals (Sweden)

    Hashem Alsaab

    2017-04-01

    Full Text Available The aim of this study was to develop a novel folate receptor-targeted drug delivery system for retinoblastoma cells using a promising anticancer agent, curcumin-difluorinated (CDF, loaded in polymeric micelles. Folic acid was used as a targeting moiety to enhance the targeting and bioavailability of CDF. For this purpose, amphiphilic poly(styrene-co-maleic acid-conjugated-folic acid (SMA-FA was synthesized and utilized to improve the aqueous solubility of a highly hydrophobic, but very potent anticancer compound, CDF, and its targeted delivery to folate overexpressing cancers. The SMA-FA conjugate was first synthesized and characterized by 1H NMR, FTIR and DSC. Furthermore, the chromatographic condition (HPLC for estimating CDF was determined and validated. The formulation was optimized to achieve maximum entrapment of CDF. The particle size of the micelles was measured and confirmed by dynamic light scattering (DLS and transmission electron microscopy (TEM. Cytotoxicity studies were conducted on (Y-79 and WERI-RB retinoblastoma cells. Results showed that the solubility of CDF could be increased with the newly-synthesized polymer, and the entrapment efficiency was >85%. The drug-loaded nanomicelles exhibited an appropriate size of <200 nm and a narrow size distribution. The formulation did not show any adverse cytotoxicity on a human retinal pigment epithelial cell (ARPE-19, indicating its safety. However, it showed significant cell killing activity in both Y-79 and WERI-RB retinoblastoma cell lines, indicating its potency in killing cancer cells. In conclusion, the folic acid-conjugated SMA loaded with CDF showed promising potential with high safety and pronounced anticancer activity on the tested retinoblastoma cell lines. The newly-formulated targeted nanomicelles thus could be a viable option as an alternative approach to current retinoblastoma therapies.

  10. Novel Water-Borne Polyurethane Nanomicelles for Cancer Chemotherapy: Higher Efficiency of Folate Receptors Than TRAIL Receptors in a Cancerous Balb/C Mouse Model.

    Science.gov (United States)

    Ajorlou, Elham; Khosroushahi, Ahmad Yari; Yeganeh, Hamid

    2016-06-01

    Since the introduction of nanocarriers, the delivery of chemotherapeutic agents for treatment of patients with cancer has been possible with better effectiveness. The latest findings are also support that further enhancement in therapeutic effectiveness of these nanocarriers can be attained, if surface decoration with proper targeting agents is considered. This study aimed at treating a variety of 4T1 murine breast cancer cell line, mainly demonstrating high folate and TRAIL receptor expression of cancerous cells. The therapeutic efficacy of paclitaxel loaded Cremophore EL (Taxol®), paclitaxel loaded waterborne polyurethane nanomicelles (PTX-PU) and paclitaxel loaded waterborne polyurethane nanomicelles conjugated with folate (PTX-PU-FA) and TRAIL (PTX-PU-TRAIL) on treating 4T1 cell was also compared. The findings that worth noting are: PTX-PU outperformed Taxol® in a Balb/C mouse model, furthermore, tumor growth was adequately curbed by folate and TRAIL-decorated nanomicelles rather than the unconjugated formulation. Tumors of mice treated with PTX-PU-FA and PTX-PU-TRAIL shrank substantially compared to those treated with Taxol®, PTX-PU and PTX-PU-TRAIL (average 573 mm(3) versus 2640, 846, 717 mm(3) respectively), 45 days subsequent to tumor inoculation. The microscopic study of hematoxylin-eosin stained tumors tissue and apoptotic cell fraction substantiated that the most successful therapeutic effects have been observed for the mice treated with PTX-PU-FA (about 90% in PTX-PU-FA versus 75%, 60%, 15% in PTX-PU-TRAIL, PTX-PU, and Taxol® group respectively). Using folate-targeted nanocarriers to treat cancers characterized by a high level of folate ligand expression is well substantiated by the findings of this study.

  11. Folate-receptor-targeted NIR-sensitive polydopamine nanoparticles for chemo-photothermal cancer therapy

    Science.gov (United States)

    Li, Hao; Jin, Zhen; Cho, Sunghoon; Jeon, Mi Jeong; Du Nguyen, Van; Park, Jong-Oh; Park, Sukho

    2017-10-01

    We propose the use of folate-receptor-targeted, near-infrared-sensitive polydopamine nanoparticles (NPs) for chemo-photothermal cancer therapy as an enhanced type of drug-delivery system which can be synthesized by in situ polymerization and conjugation with folic acid. The NPs consist of a Fe3O4/Au core, coated polydopamine, conjugated folic acid, and loaded anti-cancer drug (doxorubicin). The proposed multifunctional NPs show many advantages for therapeutic applications such as good biocompatibility and easy bioconjugation. The polydopamine coating of the NPs show a higher photothermal effect and thus more effective cancer killing compared to Fe3O4/Au nanoparticles at the same intensity as near-infrared laser irradiation. In addition, the conjugation of folic acid was shown to enhance cancer cellular uptake efficiency via the folate receptor and thus improve chemotherapeutic efficiency. Through in vitro cancer cell treatment testing, the proposed multifunctional NPs showed advanced photothermal and chemotherapeutic performance. Based on these enhanced anti-cancer properties, we expect that the proposed multifunctional NPs can be used as a drug-delivery system in cancer therapy.

  12. Discriminatory power of rbcL barcode locus for authentication of some of United Arab Emirates (UAE) native plants.

    Science.gov (United States)

    Maloukh, Lina; Kumarappan, Alagappan; Jarrar, Mohammad; Salehi, Jawad; El-Wakil, Houssam; Rajya Lakshmi, T V

    2017-06-01

    DNA barcoding of United Arab Emirates (UAE) native plants is of high practical and scientific value as the plants adapt to very harsh environmental conditions that challenge their identification. Fifty-one plant species belonged to 22 families, 2 monocots, and 20 eudicots; a maximum number of species being legumes and grasses were collected. To authenticate the morphological identification of the wild plant taxa, rbcL and matK regions were used in the study. The primer universality and discriminatory power of rbcL is 100%, while it is 35% for matK locus for these plant species. The sequences were submitted to GenBank; accession numbers were obtained for all the rbcL sequences and for 6 of matK sequences. We suggest rbcL as a promising barcode locus for the tested group of 51 plants. In the present study, an inexpensive, simple method of identification of rare desert plant taxa through rbcL barcode is being reported.

  13. 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

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

    Science.gov (United States)

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

    2017-04-13

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

  15. 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

    2015-12-08

    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.

  16. Folate-targeted docetaxel-lipid-based-nanosuspensions for active-targeted cancer therapy.

    Science.gov (United States)

    Wang, Lili; Li, Min; Zhang, Na

    2012-01-01

    The purpose of this study was to develop two novel drug delivery systems based on biodegradable docetaxel-lipid-based-nanosuspensions. The first one was poly(ethylene glycol)- modified docetaxel-lipid-based-nanosuspensions (pLNS). It was developed to increase the cycle time of the drug within the body and enhance the accumulation of the drug at the tumor site. The second one was targeted docetaxel-lipid-based-nanosuspensions (tLNS) using folate as the target ligand. The tLNS could target the tumor cells that overexpressed folate receptor (FR). The morphology, particle size, and zeta potential of pLNS and tLNS were characterized, respectively. The in vitro cytotoxicity evaluation of Duopafei(®), pLNS, and tLNS were performed in human hepatocellular liver carcinoma HepG2 (FR-) and B16 (FR+) cells, respectively. The in vivo antitumor efficacy and pharmacokinetics, as well as the drug tissue distribution, were evaluated in Kunming mice bearing B16 cells. The particle size of pLNS was 204.2 ± 6.18 nm and tLNS had a mean particle size of 220.6 ± 9.54 nm. Cytotoxicity of tLNS against B16 (FR+) cell lines was superior to pLNS (P < 0.05), while there was no significant difference in the half maximum inhibitory concentration values for HepG2 (FR-) cells between pLNS and tLNS. The results of the in vivo antitumor efficacy evaluation showed that tLNS exhibited higher antitumor efficacy by reducing tumor volume (P < 0.01) compared with Duopafei and pLNS, respectively. The results of the in vivo biodistribution study indicate that the better antitumor efficacy of tLNS was attributed to the increased accumulation of the drug in the tumor.

  17. Development and optimization of targeted radionuclide tumor therapy using folate based radiopharmaceuticals

    CERN Document Server

    Reber, Josefine Astrid

    The folate receptor (FR) has been used for a quarter of a century as a tumor-associated target for selective delivery of drugs and imaging agents to cancer cells. While several folic acid radioconjugates have been successfully employed for imaging purposes in (pre)clinical studies, a therapeutic application of folic acid radioconjugates has not yet reached the critical stage which would allow a clinical translation. Due to a substantial expression of the FR in the proximal tubule cells, radiofolates accumulate in the kidneys which are at risk of damage by particle-radiation. To improve this situation, we aimed to develop and evaluate strategies for the performance of FR-targeted radionuclide therapy by decreasing the renal uptake of radiofolates and thereby reducing potential nephrotoxic effects. Two different strategies were investigated. First, the combination of radiofolates with chemotherapeutic agents such as pemetrexed (PMX) and 5-fluorouracil (5-FU) and secondly, an approach based on radioiodinated fol...

  18. A comparative analysis on ranking insurance firms using RBC and CAMELS

    Directory of Open Access Journals (Sweden)

    Zahra Houshmand Neghabi

    2012-10-01

    Full Text Available Ranking insurance firms plays an important role on choosing the most appropriate company for receiving appropriate services especially long term insurances such as life insurances. The proposed model of this paper uses two well-known methods of CAMELS and RBC to rank 18 active private and governmental insurance firms in Iran over the period of 2009-2011. The results of Spearman test imply that there is no meaningful difference between these two methods for year 2010 and year 2011 and according to Freedman test, there is not meaningful difference between these two methods in any three years of 2009, 2010 and 2011. In summary, we can conclude that the results of both methods could be used in practice.

  19. Quantitative Trait Loci Analysis of Folate Content in Dry Beans, Phaseolus vulgaris L.

    Directory of Open Access Journals (Sweden)

    S. Khanal

    2013-01-01

    Full Text Available Dry beans (Phaseolus vulgaris L. contain high levels of folates, yet the level of folate may vary among different genotypes. Folates are essential vitamins and folate deficiencies may lead to a number of health problems. Among the different forms of folates, 5-methyltetrahydrofolate (5MTHF comprises more than 80% of the total folate in dry beans. The objectives of this paper were to compare selected genotypes of dry beans for the folate content of the dry seeds and to identify quantitative trait loci (QTL associated with the folate content in a population derived from an inter-gene-pool cross of dry beans. The folate content was examined in three large-seeded (AC Elk, Redhawk, and Taylor and one medium-seeded (Othello dry bean genotypes, their six F1 (i.e., one-way diallel crosses, and the F2 of Othello/Redhawk that were evaluated in the field in 2009. Total folate and 5MTHF contents were measured twice with one-hour time interval. The significant variation (P<0.05 in the folate content was observed among the parental genotypes, their F1 progeny, and members of the F2 population, ranging from 147 to 345 μg/100 g. There was a reduction in the 5MTHF and total folate contents in the second compared to the first measurement. Dark red kidney variety Redhawk consistently had the highest and pinto Othello had the lowest total folate and 5MTHF contents in both measurements. A single marker QTL analysis identified three QTL for total folate and 5MTHF contents in the first measurement and one marker for the total folate in the second measurement in the F2. These QTL had significant dominance effects and individually accounted for 7.7% to 10.5% of the total phenotypic variance. The total phenotypic variance explained by the four QTL was 18% for 5MTHF and 19% for total folate in the first measurement, but only 8% for total folate in the second measurement.

  20. Red blood cell alloimmunization in sickle cell disease patients in ...

    African Journals Online (AJOL)

    Objective: Alloimmunization is a recognized complication of red blood cell (RBC) transfusion and causes delayed hemolytic transfusion reactions and provides problems sourcing compatible blood for future transfusions. The objective of this study was to determine the frequency of RBC alloimmunization in SCD patients in ...

  1. Rational ‘correction’ of the amino-acid sequence of RbcX protein from the thermophilic cyanobacterium Thermosynechococcus elongatus dramatically improves crystallization

    International Nuclear Information System (INIS)

    Tarnawski, Miroslaw; Krzywda, Szymon; Szczepaniak, Andrzej; Jaskolski, Mariusz

    2008-01-01

    Recombinant RuBisCO chaperone from T. elongatus, TeRbcX, was aggregated and could not be crystallized. Mutations of an unusual Cys residue in the TeRbcX sequence yielded much better behaved proteins that could rapidly be crystallized. RbcX is a dimeric protein found in cyanobacteria that assists in the assembly of the oligomeric RuBisCO complex. RbcX from the thermophile Thermosynechococcus elongatus (TeRbcX) contains an unusual Cys103 residue in its sequence and when expressed recombinantly the protein aggregates and cannot be crystallized. Site-directed mutagenesis of Cys103 to either Arg or Ala produced non-aggregating proteins that could be readily crystallized in several crystal forms. Synchrotron-radiation X-ray diffraction data were collected to 1.96 Å resolution and formed the basis of crystal structure analysis of TeRbcX

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

    Science.gov (United States)

    Hoffbrand, A Victor

    2014-02-01

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

  3. 21 CFR 101.79 - Health claims: Folate and neural tube defects.

    Science.gov (United States)

    2010-04-01

    ... the nutrient, the claim shall use the terms “folate,” “folic acid,” “folacin,” “folate, a B vitamin,” “folic acid, a B vitamin,” or “folacin, a B vitamin.” (C) Specifying the condition. In specifying the... parentheses. (G) The claim shall state that folate needs to be consumed as part of a healthful diet. (ii...

  4. 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....../CT individuals [odds ratio 1.76, 95% confidence interval (95% CI) 1.19-2.60]. Additionally, gene-diet interaction effects were identified. Dietary markers were negatively associated with risk of atopy in persons with the TT genotype. Total homocysteine was not related to atopy (odds ratio per 5 mumol/l = 1...

  5. Importance of methodological standardization for the ektacytometric measures of red blood cell deformability in sickle cell anemia.

    Science.gov (United States)

    Renoux, Céline; Parrow, Nermi; Faes, Camille; Joly, Philippe; Hardeman, Max; Tisdale, John; Levine, Mark; Garnier, Nathalie; Bertrand, Yves; Kebaili, Kamila; Cuzzubbo, Daniela; Cannas, Giovanna; Martin, Cyril; Connes, Philippe

    2016-01-01

    Red blood cell (RBC) deformability is severely decreased in patients with sickle cell anemia (SCA), which plays a role in the pathophysiology of the disease. However, investigation of RBC deformability from SCA patients demands careful methodological considerations. We assessed RBC deformability by ektacytometry (LORRCA MaxSis, Mechatronics, The Netherlands) in 6 healthy individuals and 49 SCA patients and tested the effects of different heights of the RBC diffraction patterns, obtained by altering the camera gain of the LORRCA, on the result of RBC deformability measurements, expressed as Elongation Index (EI). Results indicate that the pattern of RBCs from control subjects adopts an elliptical shape under shear stress, whereas the pattern of RBCs from individuals with SCA adopts a diamond shape arising from the superposition of elliptical and circular patterns. The latter represent rigid RBCs. While the EI measures did not change with the variations of the RBC diffraction pattern heights in the control subjects, we observed a decrease of EI when the RBC diffraction pattern height is increased in the SCA group. The differences in SCA EI values measured at 5 Pa between the different diffraction pattern heights correlated with the percent of hemoglobin S and the percent of sickled RBC observed by microscopy. Our study confirms that the camera gain or aperture of the ektacytometer should be used to standardize the size of the RBC diffraction pattern height when measuring RBC deformability in sickle cell patients and underscores the potential clinical utility of this technique.

  6. Folate status in women of childbearing age with obesity: a review.

    Science.gov (United States)

    Maffoni, Silvia; De Giuseppe, Rachele; Stanford, Fatima Cody; Cena, Hellas

    2017-12-01

    Several studies have described a positive association between elevated BMI and birth defects risk. Data on plasma concentration of folate in pregnant women with obesity have shown values far below those recommended, regardless of diet, while folate levels should increase before pregnancy to reduce neural tube defects. We report a descriptive review of the most recent studies (from 2005 to 2015) to evaluate folate status through a population of women of childbearing age affected by obesity. The literature contains few studies, which present conflicting results regarding folate status in non-pregnant women of childbearing age affected by obesity, and it appears that there is a modification in folate metabolism, with a reduction in plasma folate levels and an increase in erythrocyte folate uptake. In conclusion, the folate status in women of childbearing age should be assessed by both plasma and erythrocyte levels to start a personalised and more adequate supplementation before conception. Further studies need to be conducted in a larger population, which take into account variables that can affect folate metabolism, such as dietary intake, lifestyle and genetic factors, oral contraceptives or other drug use, previous weight-loss programmes, or a history of bariatric surgery.

  7. Utility, charge, and cost of inpatient and emergency department serum folate testing.

    Science.gov (United States)

    Theisen-Toupal, Jesse; Horowitz, Gary L; Breu, Anthony C

    2013-02-01

    Serum folate levels are commonly ordered for multiple indications in the inpatient and emergency department settings. Since mandatory folic acid fortification in 1998, there has been a decreasing prevalence of folate deficiency in the United States. Our objective was to determine the indications, rate of deficiency, charge and cost per deficient result, and change in management per deficient result in serum folate testing in inpatients and emergency department patients. Retrospective analysis of all inpatient and emergency department serum folate tests. We analyzed all inpatient and emergency department serum folate tests performed over a 12-month period. We reviewed the charts of 250 patients and all low-normal or deficient serum folate levels to determine indications, comorbidities, and change in management based on result. Charge and cost analyses were performed. All inpatient and emergency department patients with a serum folate test performed at a major medical center in Boston, Massachusetts. A total of 2093 serum folate tests were performed in 1944 patients with 2 deficient levels. The most common indications were anemia without macrocytosis and anemia with macrocytosis. The amount charged per deficient result was $158,022. The cost to the hospital per deficient result was less than $2093. In folic acid fortified countries, serum folate testing has low utility and poor cost effectiveness for all indications in inpatients and emergency department patients. Copyright © 2012 Society of Hospital Medicine.

  8. 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.

  9. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis.

    Science.gov (United States)

    Duthie, Susan J

    2011-02-01

    Inappropriate diet may contribute to one third of cancer deaths. Folates, a group of water-soluble B vitamins present in high concentrations in green, leafy vegetables, maintain DNA stability through their ability to donate one-carbon units for cellular metabolism. Folate deficiency has been implicated in the development of several cancers, including cancer of the colorectum, breast, ovary, pancreas, brain, lung and cervix. Generally, data from the majority of human studies suggest that people who habitually consume the highest level of folate, or with the highest blood folate concentrations, have a significantly reduced risk of developing colon polyps or cancer. However, an entirely protective role for folate against carcinogenesis has been questioned, and recent data indicate that an excessive intake of synthetic folic acid (from high-dose supplements or fortified foods) may increase human cancers by accelerating growth of precancerous lesions. Nonetheless, on balance, evidence from the majority of human studies indicates that dietary folate is genoprotective against colon cancer. Suboptimal folate status in humans is widespread. Folate maintains genomic stability by regulating DNA biosynthesis, repair and methylation. Folate deficiency induces and accelerates carcinogenesis by perturbing each of these processes. This review presents recent evidence describing how these mechanisms act, and interact, to modify colon cancer risk.

  10. Relationship of folate to colorectal and cervical cancer: review and recommendations for practitioners.

    Science.gov (United States)

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

    2002-09-01

    Evidence suggests that folate may play a role in cancer prevention. A plausible mechanism for prevention lies in the integral role that folate plays in deoxyribonucleic acid (DNA) synthesis and methylation. DNA methylation most likely regulates gene expression. Abnormal methylation, specifically hypomethylation, has been associated with tumorigenesis. The availability of methyl groups needed for adequate DNA methylation may be negatively influenced by low folate status, alcohol intake, or genetic polymorphisms that affect folate metabolism. Observational studies evaluating the association between folate and risk for colorectal and cervical cancers or precancerous conditions have produced conflicting results, and clinical trial data are needed to confirm a cause-and-effect relationship. However, several studies show interesting associations between cancer risk and factors that influence methyl group availability. Although data relating folate to cancer risk remain equivocal, when coupled with the other potential health benefits associated with folate, evidence supports recommending that people consume folate-rich foods such as fruits and vegetables. People consuming alcohol on a daily basis may especially benefit from additional folate in their diets.

  11. Plasma homocyst(e)ine concentrations in pregnant and nonpregnant women with controlled folate intake.

    Science.gov (United States)

    Bonnette, R E; Caudill, M A; Boddie, A M; Hutson, A D; Kauwell, G P; Bailey, L B

    1998-08-01

    To assess the effects of folate intake and pregnancy on plasma total homocyst(e)ine concentrations in women during the second trimester of pregnancy compared with young, healthy nonpregnant women. The diet provided either 450 or 850 microg of folate per day. These levels are approximately the current (400 microg/day) and previous (800 microg/day) Recommended Dietary Allowances for folate in pregnant women. Folate was provided as both food folate (120 microg/day) and supplemental folic acid (either 330 or 730 microg/day) for a period of 12 weeks. Plasma homocyst(e)ine (sum of free and protein-bound homocysteine), serum folate, and erythrocyte folate concentrations were determined weekly. Homocyst(e)ine concentrations were lower in pregnant women during the second trimester of normal pregnancy than in nonpregnant controls, independent of dietary folate intake. The overall mean (+/- standard deviation) homocyst(e)ine concentration of the pregnant subjects (5.4 +/- 1.4 micromol/L) was significantly lower than that observed in the nonpregnant control group (8.7 +/- 1.7 micromol/L) (P ine concentrations remained constant throughout the 12 weeks of the investigation. The folate intakes in this investigation were adequate to maintain constant homocyst(e)ine concentrations in pregnant and nonpregnant women. The lower homocyst(e)ine concentrations observed in pregnant subjects compared with nonpregnant controls may be a physiologic response to pregnancy.

  12. Avidity Modulation of Folate-Targeted Multivalent Dendrimers for Evaluating Biophysical Models of Cancer Targeting Nanoparticles

    Science.gov (United States)

    Silpe, Justin E.; Sumit, Madhuresh; Thomas, Thommey P.; Huang, Baohua; Kotlyar, Alina; van Dongen, Mallory A.; Banaszak Holl, Mark M.; Orr, Bradford G.; Choi, Seok Ki

    2013-01-01

    We investigated two types of generation 5 polyamidoamine (PAMAM) dendrimers, each conjugated stochastically with a mean number of five or ten methotrexate (MTX) ligands per dendrimer (G5-MTX5, G5-MTX10), for their binding to surface-immobilized folate binding protein (FBP) as a function of receptor density. The binding study was performed under flow by surface plasmon resonance spectroscopy. Two multivalent models were examined to simulate binding of the dendrimer to the receptor surface, showing that at relatively high receptor density, both dendrimer conjugates exhibit high avidity. However, upon reducing the receptor density by a factor of three and thirteen relative to the high density level, the avidity of the lower-valent G5-MTX5 decreases by up to several orders of magnitude (KD = nM to μM), whereas the avidity of G5-MTX10 remains largely unaffected regardless of the density variation. Notably, on the 13-fold reduced FBP surface, G5-MTX5 displays binding kinetics similar to that of monovalent methotrexate, which is patently different from the still tight binding of the higher-valent G5-MTX10. Thus, the binding analysis demonstrates that avidity displayed by multivalent MTX conjugates varies in response to the receptor density, and it can be modulated for achieving tighter, more specific binding to the higher receptor density by modulation of ligand valency. We believe this study provides experimental evidence supportive of the mechanistic hypothesis of multivalent NP uptake to a cancer cell over a healthy cell where the diseased cell expresses the folate receptor at higher density. PMID:23855478

  13. Anemias excluding cobalamin and folate deficiencies.

    Science.gov (United States)

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

    2014-01-01

    Anemias are one of the commonest maladies affecting humans. They result from either a failure of production by the bone marrow (hypoproliferative), or from premature destruction or loss (hyperproliferative) of red cells. Hypoproliferative anemias typically result from deficiencies of essential nutrients, stem cell abnormalities or deficiency, and infiltrative processes of the bone marrow. In the hyperproliferative forms, the bone marrow function is normal and anemia results from bleeding or shortened erythrocyte lifespan due to hemoglobinopathies, red cell enzyme disorders, membrane defects, or external factors such as antibodies, trauma, or heat injury. The etiology of anemia is frequently obvious, but when obscure, a systematic diagnostic approach frequently yields the answer. It is important to realize that anemias are usually a consequence of another disease process, which must be identified. Without correction of the underlying disease process, the treatment is likely to fail. © 2014 Elsevier B.V. All rights reserved.

  14. Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man

    International Nuclear Information System (INIS)

    Gregory, J.F. III; Toth, J.P.

    1988-01-01

    The synthesis and in vivo application of stable-isotopically labeled folic acid was investigated to devise methods suitable for studies of folate metabolism in human subjects. Glutamate-labeled tetradeutero-pteroylglutamic acid (d4-folic acid) was prepared by mixed anhydride coupling of N10-trifluoroacetylpteroic acid and dimethyl L-[3,3,4,4-2H4]glutamic acid, saponification in sodium deuteroxide, and chromatographic purification. Retention of the isotopic label was verified by proton NMR and mass spectrometry of the para-aminobenzoylglutamic acid product of C9-N10 bond cleavage. A method was devised for determination of of isotopic enrichment of urinary d4-folates derived from orally administered d4-folic acid using affinity chromatographic purification, chemical cleavage of the C9-N10 bond, HPLC isolation of the p-[2H4]aminobenzoylglutamate product, followed by negative-ion chemical-ionization gas chromatography/mass spectrometry. Data concerning the urinary excretion of d4-folates derived from an oral dose of d4-folic acid in an adult human are presented

  15. Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man

    Energy Technology Data Exchange (ETDEWEB)

    Gregory, J.F. III; Toth, J.P.

    1988-04-01

    The synthesis and in vivo application of stable-isotopically labeled folic acid was investigated to devise methods suitable for studies of folate metabolism in human subjects. Glutamate-labeled tetradeutero-pteroylglutamic acid (d4-folic acid) was prepared by mixed anhydride coupling of N10-trifluoroacetylpteroic acid and dimethyl L-(3,3,4,4-2H4)glutamic acid, saponification in sodium deuteroxide, and chromatographic purification. Retention of the isotopic label was verified by proton NMR and mass spectrometry of the para-aminobenzoylglutamic acid product of C9-N10 bond cleavage. A method was devised for determination of of isotopic enrichment of urinary d4-folates derived from orally administered d4-folic acid using affinity chromatographic purification, chemical cleavage of the C9-N10 bond, HPLC isolation of the p-(2H4)aminobenzoylglutamate product, followed by negative-ion chemical-ionization gas chromatography/mass spectrometry. Data concerning the urinary excretion of d4-folates derived from an oral dose of d4-folic acid in an adult human are presented.

  16. Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man.

    Science.gov (United States)

    Gregory, J F; Toth, J P

    1988-04-01

    the synthesis and in vivo application of stable-isotopically labeled folic acid was investigated to devise methods suitable for studies of folate metabolism in human subjects. Glutamate-labeled tetradeutero-pteroylglutamic acid (d4-folic acid) was prepared by mixed anhydride coupling of N10-trifluoroacetylpteroic acid and dimethyl L-[3,3,4,4-2H4]glutamic acid, saponification in sodium deuteroxide, and chromatographic purification. Retention of the isotopic label was verified by proton NMR and mass spectrometry of the para-aminobenzoylglutamic acid product of C9-N10 bond cleavage. A method was devised for determination of of isotopic enrichment of urinary d4-folates derived from orally administered d4-folic acid using affinity chromatographic purification, chemical cleavage of the C9-N10 bond, HPLC isolation of the p-[2H4]aminobenzoylglutamate product, followed by negative-ion chemical-ionization gas chromatography/mass spectrometry. Data concerning the urinary excretion of d4-folates derived from an oral dose of d4-folic acid in an adult human are presented.

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

    Science.gov (United States)

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

    2017-08-29

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

  18. DETERMINANTS OF RED-BLOOD-CELL DEFORMABILITY IN RELATION TO CELL AGE

    NARCIS (Netherlands)

    BOSCH, FH; WERRE, JM; ROERDINKHOLDERSTOELWINDER, B; HULS, T; WILLEKENS, FLA; WICHERS, G; HALIE, MR

    Red blood cell (RBC) deformability was determined with an ektacytometer in fractions separated on the basis of differences in cell volume or density. Deformability was measured with ektacytometry (rpm-scan and osmo-scan). We studied three groups of RBC fractions:l. By counterflow centrifugation we

  19. A lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR in the presence of lower concentrations of plasma folate.

    Science.gov (United States)

    Piyathilake, Chandrika J; Badiga, Suguna; Alvarez, Ronald D; Partridge, Edward E; Johanning, Gary L

    2013-01-01

    Identification of associations between global DNA methylation and excess body weight (EBW) and related diseases and their modifying factors are an unmet research need that may lead to decreasing DNA methylation-associated disease risks in humans. The purpose of the current study was to evaluate the following; 1) Association between the degree of peripheral blood mononuclear cell (PBMC) L1 methylation and folate, and indicators of EBW, 2) Association between the degree of PBMC L1 methylation and folate, and insulin resistance (IR) as indicated by a higher homeostasis model assessment (HOMA-IR). The study population consisted of 470 child-bearing age women diagnosed with abnormal pap. The degree of PBMC L1 methylation was assessed by pyrosequencing. Logistic regression models specified indicators of EBW (body mass index-BMI, body fat-BF and waist circumference-WC) or HOMA-IR as dependent variables and the degree of PBMC L1 methylation and circulating concentrations of folate as the independent predictor of primary interest. Women with a lower degree of PBMC L1 methylation and lower plasma folate concentrations were significantly more likely to have higher BMI, % BF or WC (OR = 2.49, 95% CI:1.41-4.47, P = 0.002; OR = 2.49, 95% CI:1.40-4.51, P = 0.002 and OR = 1.98, 95% = 1.14-3.48 P = 0.0145, respectively) and higher HOMA-IR (OR = 1.78, 95% CI:1.02-3.13, P = 0.041). Our results demonstrated that a lower degree of PBMC L1 methylation is associated with excess body weight and higher HOMA-IR, especially in the presence of lower concentrations of plasma folate.

  20. Concentrations of blood folate in Brazilian studies prior to and after fortification of wheat and cornmeal (maize flour with folic acid: a review

    Directory of Open Access Journals (Sweden)

    Jéssica Carrilho Britto

    2014-07-01

    Full Text Available BACKGROUND: In July 2004, the Brazilian Ministry of Health through the National Health Surveillance Agency made the fortification of wheat flour and cornmeal (maize flour with iron and folic acid mandatory, with the intention of reducing the rate of diseases such as neural tube defects. OBJECTIVE: The aim of the study was to investigate the impact of the folic acid fortified wheat flour and cornmeal on serum and red blood cell folate levels and on the reduction of neural tube defects in different Brazilian studies. METHODS: In order to compare folate concentrations in the Brazilian population prior to and following the implementation of mandatory fortification of wheat and cornmeal, studies that involved blood draws between January 1997 and May 2004 (pre-fortification period, and from June 2004 to the present (post-fortification period were chosen. The data search included PubMed and Scopus databases as well as the Brazilian Digital Library of Theses and Dissertations. The following keywords were employed for the query: folate, folic acid, fortification, Brazil, healthy population, the elderly, children and pregnant women. RESULTS: A total of 47 Brazilian studies were selected; 26 from the pre-fortification period and 22 after the fortification implementation. The studies were classified according to the cohort investigated (pregnant women, children, adolescents, adults and the elderly. After the implementation of flour fortification with folic acid in Brazil, serum folate concentrations increased in healthy populations (57% in children and adolescents and 174% in adults, and the incidence of neural tube defects dropped. CONCLUSION: Folic acid fortification of wheat flour and cornmeal increased the blood folate concentrations and reduced the incidence of neural tube defects.

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

    Science.gov (United States)

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

    2013-01-01

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

  2. In vivo therapeutic efficacy of TNFα silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice.

    Science.gov (United States)

    Shi, Qin; Rondon-Cavanzo, Elsa-Patricia; Dalla Picola, Isadora Pfeifer; Tiera, Marcio José; Zhang, Xiaoling; Dai, Kerong; Benabdoune, Houda Abir; Benderdour, Mohamed; Fernandes, Julio Cesar

    2018-01-01

    Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, has been shown to play a role in the pathophysiology of rheumatoid arthritis. Silencing TNFα expression with small interfering RNA (siRNA) is a promising approach to treatment of the condition. Towards this end, our team has developed a modified chitosan (CH) nanocarrier, deploying folic acid, diethylethylamine (DEAE) and polyethylene glycol (PEG) (folate-PEG-CH-DEAE 15 ). The gene carrier protects siRNA against nuclease destruction, its ligands facilitate siRNA uptake via cell surface receptors, and it provides improved solubility at neutral pH with transport of its load into target cells. In the present study, nanoparticles were prepared with siRNA-TNFα, DEAE, and folic acid-CH derivative. Nanoparticle size and zeta potential were verified by dynamic light scattering. Their TNFα-knockdown effects were tested in a murine collagen antibody-induced arthritis model. TNFα expression was examined along with measurements of various cartilage and bone turnover markers by performing histology and microcomputed tomography analysis. We demonstrated that folate-PEG-CH-DEAE 15 /siRNA nanoparticles did not alter cell viability, and significantly decreased inflammation, as demonstrated by improved clinical scores and lower TNFα protein concentrations in target tissues. This siRNA nanocarrier also decreased articular cartilage destruction and bone loss. The results indicate that folate-PEG-CH-DEAE 15 nanoparticles are a safe and effective platform for nonviral gene delivery of siRNA, and their potential clinical applications warrant further investigation.

  3. 177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

    Directory of Open Access Journals (Sweden)

    Héctor Mendoza-Nava

    2016-01-01

    Full Text Available 177Lu-labeled nanoparticles conjugated to biomolecules have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this research was to synthesize 177Lu-dendrimer(PAMAM-G4-folate-bombesin with gold nanoparticles (AuNPs in the dendritic cavity and to evaluate the radiopharmaceutical potential for targeted radiotherapy and the simultaneous detection of folate receptors (FRs and gastrin-releasing peptide receptors (GRPRs overexpressed in breast cancer cells. p-SCN-Benzyl-DOTA was conjugated in aqueous-basic medium to the dendrimer. The carboxylate groups of Lys1Lys3(DOTA-bombesin and folic acid were activated with HATU and also conjugated to the dendrimer. The conjugate was mixed with 1% HAuCl4 followed by the addition of NaBH4 and purified by ultrafiltration. Elemental analysis (EDS, particle size distribution (DLS, TEM analysis, UV-Vis, and infrared and fluorescence spectroscopies were performed. The conjugate was radiolabeled using 177LuCl3 or 68GaCl3 and analyzed by radio-HPLC. Studies confirmed the dendrimer functionalization with high radiochemical purity (>95%. Fluorescence results demonstrated that the presence of AuNPs in the dendritic cavity confers useful photophysical properties to the radiopharmaceutical for optical imaging. Preliminary binding studies in T47D breast cancer cells showed a specific cell uptake (41.15±2.72%. 177Lu-dendrimer(AuNP-folate-bombesin may be useful as an optical and nuclear imaging agent for breast tumors overexpressing GRPR and FRs, as well as for targeted radiotherapy.

  4. Red blood cell in simple shear flow

    Science.gov (United States)

    Chien, Wei; Hew, Yayu; Chen, Yeng-Long

    2013-03-01

    The dynamics of red blood cells (RBC) in blood flow is critical for oxygen transport, and it also influences inflammation (white blood cells), thrombosis (platelets), and circulatory tumor migration. The physical properties of a RBC can be captured by modeling RBC as lipid membrane linked to a cytoskeletal spectrin network that encapsulates cytoplasm rich in hemoglobin, with bi-concave equilibrium shape. Depending on the shear force, RBC elasticity, membrane viscosity, and cytoplasm viscosity, RBC can undergo tumbling, tank-treading, or oscillatory motion. We investigate the dynamic state diagram of RBC in shear and pressure-driven flow using a combined immersed boundary-lattice Boltzmann method with a multi-scale RBC model that accurately captures the experimentally established RBC force-deformation relation. It is found that the tumbling (TU) to tank-treading (TT) transition occurs as shear rate increases for cytoplasm/outer fluid viscosity ratio smaller than 0.67. The TU frequency is found to be half of the TT frequency, in agreement with experiment observations. Larger viscosity ratios lead to the disappearance of stable TT phase and unstable complex dynamics, including the oscillation of the symmetry axis of the bi-concave shape perpendicular to the flow direction. The dependence on RBC bending rigidity, shear modulus, the order of membrane spectrin network and fluid field in the unstable region will also be discussed.

  5. How is the process of setting micronutrients recommendations reflected in nutrition policies in Poland? The case study of folate

    Directory of Open Access Journals (Sweden)

    Ewa Sicińska

    2018-03-01

    The current Polish nutrition recommendations for folate are consistent with the levels set by most other countries. The constant improvement of nutritional knowledge on folate among consumers, especially young women, is necessary.

  6. Clinical utility of serum folate measurement in tertiary care patients: Argument for revising reference range for serum folate from 3.0 ng/mL to 13.0 ng/mL

    Directory of Open Access Journals (Sweden)

    Gurmukh Singh

    2015-04-01

    Full Text Available Objective: Assess the need for folate testing, frequency of corrective action, and determine reference level for serum folate. Methods: Serum folate levels in 5313 samples from 4448 patients, and clinical data were reviewed for patient characteristics and for (a evidence of corrective action in patients with serum folate values 25.7 ng/mL. Results: The prevalence of serum folate levels, in patients, 25.7 ng/mL the sample was collected after supplementation with folic acid. Of the 128 patients with serum folate 60% of the patients. Since serum folate levels ≥13.0 ng/mL are needed for optimal prevention of neural tube defects in the embryo/fetus, we propose that normal serum folate level should be designated to be ≥13.0 ng/mL. Keywords: Serum folate, Prevalence of folate deficiency, Neural tube defects, Optimum serum folate level, Utility of folate testing

  7. 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...

  8. Folate Biofortification in Hydroponically Cultivated Spinach by the Addition of Phenylalanine.

    Science.gov (United States)

    Watanabe, Sho; Ohtani, Yuta; Tatsukami, Yohei; Aoki, Wataru; Amemiya, Takashi; Sukekiyo, Yasunori; Kubokawa, Seiichi; Ueda, Mitsuyoshi

    2017-06-14

    Folate is an important vitamin mainly ingested from vegetables, and folate deficiency causes various health problems. Recently, several studies demonstrated folate biofortification in plants or food crops by metabolic engineering through genetic modifications. However, the production and sales of genetically modified foods are under strict regulation. Here, we developed a new approach to achieve folate biofortification in spinach (Spinacia oleracea) without genetic modification. We hydroponically cultivated spinach with the addition of three candidate compounds expected to fortify folate. As a result of liquid chromatography tandem mass spectrometry analysis, we found that the addition of phenylalanine increased the folate content up to 2.0-fold (306 μg in 100 g of fresh spinach), representing 76.5% of the recommended daily allowance for adults. By measuring the intermediates of folate biosynthesis, we revealed that phenylalanine activated folate biosynthesis in spinach by increasing the levels of pteridine and p-aminobenzoic acid. Our approach is a promising and practical approach to cultivate nutrient-enriched vegetables.

  9. 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.

  10. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. 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...

  12. 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 ...

  13. Methionine synthase A2756G and reduced folate carrier1 A80G ...

    African Journals Online (AJOL)

    Background: Polymorphisms of genes encoding enzymes involved in folate metabolism have long been hypothesized to be maternal risk factors for Down syndrome, however, results are conflicting and inconclusive. Aim of the study: To analyze the effect of methionine synthase (MTR) A2756G, and reduced folate carrier ...

  14. Genetic Architecture of Vitamin B-12 and Folate Levels Uncovered Applying Deeply Sequenced Large Datasets

    DEFF Research Database (Denmark)

    Grarup, N.; Sulem, P.; Sandholt, C. H.

    2013-01-01

    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...

  15. Vitamin B12 and folate deficiency in chronic heart failure.

    Science.gov (United States)

    van der Wal, Haye H; Comin-Colet, Josep; Klip, Ijsbrand T; Enjuanes, Cristina; Grote Beverborg, Niels; Voors, Adriaan A; Banasiak, Waldemar; van Veldhuisen, Dirk J; Bruguera, Jordi; Ponikowski, Piotr; Jankowska, Ewa A; van der Meer, Peter

    2015-02-01

    To determine the prevalence, clinical correlates and the effects on outcome of vitamin B12 and folic acid levels in patients with chronic heart failure (HF). We studied an international pooled cohort comprising 610 patients with chronic HF. The main outcome measure was all-cause mortality. Mean age of the patients was 68±12 years and median serum N-terminal prohormone brain natriuretic peptide level was 1801 pg/mL (IQR 705-4335). Thirteen per cent of the patients had an LVEF >45%. Vitamin B12 deficiency (serum level <200 pg/mL), folate deficiency (serum level <4.0 ng/mL) and iron deficiency (serum ferritin level <100 µg/L, or 100-299 µg/L with a transferrin saturation <20%) were present in 5%, 4% and 58% of the patients, respectively. No significant correlation between mean corpuscular volume and vitamin B12, folic acid or ferritin levels was observed. Lower folate levels were associated with an impaired health-related quality of life (p=0.029). During a median follow-up of 2.10 years (1.31-3.60 years), 254 subjects died. In multivariable proportional hazard models, vitamin B12 and folic acid levels were not associated with prognosis. Vitamin B12 and folate deficiency are relatively rare in patients with chronic HF. Since no significant association was observed between mean corpuscular volume and neither vitamin B12 nor folic acid levels, this cellular index should be used with caution in the differential diagnosis of anaemia in patients with chronic HF. In contrast to iron deficiency, vitamin B12 and folic acid levels were not related to prognosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  16. 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.

  17. 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

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

    Science.gov (United States)

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

  19. Case-control analysis of dietary folate and risk of bladder cancer.

    Science.gov (United States)

    Schabath, Matthew B; Spitz, Margaret R; Lerner, Seth P; Pillow, Patricia C; Hernandez, Ladia M; Delclos, George L; Grossman, H Barton; Wu, Xifeng

    2005-01-01

    Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (microg/kcal/day), dietary folate equivalents (DFE) from food sources (microg DFE/kcal/day), and DFE from all sources (microg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns

  20. Targeted delivery of mutant tolerant anti-coxsackievirus artificial microRNAs using folate conjugated bacteriophage Phi29 pRNA.

    Directory of Open Access Journals (Sweden)

    Xin Ye

    Full Text Available Myocarditis is the major heart disease in infants and young adults. It is very commonly caused by coxsackievirus B3 (CVB3 infection; however, no specific treatment or vaccine is available at present. RNA interference (RNAi-based anti-viral therapy has shown potential to inhibit viral replication, but this strategy faces two major challenges; viral mutational escape from drug suppression and targeted delivery of the reagents to specific cell populations.In this study, we designed artificial microRNAs (AmiRs targeting the 3'untranslated region (3'UTR of CVB3 genome with mismatches to the central region of their targeting sites. Antiviral evaluation showed that AmiR-1 and AmiR-2 reduced CVB3 (Kandolf and CG strains replication approximately 100-fold in both HeLa cells and HL-1 cardiomyocytes. To achieve specific delivery, we linked AmiRs to the folate-conjugated bacterial phage packaging RNA (pRNA and delivered the complexes into HeLa cells, a folate receptor positive cancer cells widely used as an in vitro model for CVB3 infection, via folate-mediated specific internalization. We found that our designed pRNA-AmiRs conjugates were tolerable to target mutations and have great potential to suppress viral mutational escape with little effect on triggering interferon induction.This study provides important clues for designing AmiRs targeting the 3'UTR of viral genome. It also proves the feasibility of specific deliver of AmiRs using conjugated pRNA vehicles. These small AmiRs combined with pRNA-folate conjugates could form a promising system for antiviral drug development.

  1. 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

    Danish legislation regarding food fortification has been very restrictive resulting in few fortified food items on the Danish market. Folate and vitamin B12 deficiency is thought to be common due to inadequate intakes but little is known about the actual prevalence of low serum folate and vitamin B...... and the prevalence was lower with increasing age. Low serum folate was associated with smoking, low alcohol intake, high coffee intake, unhealthy diet, and the TT genotype of the methylenetetrahydrofolate reductase (MTHFR)-C677T polymorphism. The overall prevalence of low serum vitamin B12 ( ....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...

  2. Frequent epigenetic silencing of the folate-metabolising gene cystathionine-beta-synthase in gastrointestinal cancer.

    Directory of Open Access Journals (Sweden)

    Hong Zhao

    Full Text Available Both gastric and colorectal cancers (CRC are the most frequently occurring malignancies worldwide with the overall survival of these patients remains unsatisfied. Identification of tumor suppressor genes (TSG silenced by promoter CpG methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic biomarkers for early cancer detection and prognosis assessment. Cystathionine-beta-synthase (CBS functions in the folate metabolism pathway, which is intricately linked to methylation of genomic DNA. Dysregulation of DNA methylation contributes substantially to cancer development.To identify potential TSGs silenced by aberrant promoter methylation in CRC, we analyzed tumor and adjacent tissues from CRC cases using the Illumina Human Methylation45 BeadChip. We identified hypermethylation of the CBS gene in CRC samples, compared to adjacent tissues. Methylation and decreased mRNA expression of CBS were detected in most CRC cell lines by methylation-specific PCR and semiquantitative RT-PCR, as well as in gastric cancer. Treatment with 5-aza-2'-deoxycytidine and/or trichostatin A reversed methylation and restored CBS mRNA expression indicating a direct effect. Aberrant methylation was further detected in 31% of primary CRCs (29 of 96 and 55% of gastric tumors (11 of 20. In contrast, methylation was seldom found in normal tissues adjacent to the tumor. CBS methylation was associated with KRAS mutations in primary CRCs (P = 0.04, by χ(2-test. However, no association was found between CBS methylation or KRAS mutations with cancer relapse/metastasis in Stage II CRC patients.A novel finding from this study is that the folate metabolism enzyme CBS mRNA levels are frequently downregulated through CpG methylation of the CBS gene in gastric cancer and CRC, suggesting that CBS functions as a tumor suppressor gene. These findings warrant further study of CBS as an epigenetic biomarker for molecular diagnosis of gastrointestinal cancers.

  3. Folate/NIR 797-conjugated albumin magnetic nanospheres: synthesis, characterisation, and in vitro and in vivo targeting evaluation.

    Science.gov (United States)

    Tang, Qiusha; An, Yanli; Liu, Dongfang; Liu, Peidang; Zhang, Dongsheng

    2014-01-01

    A practical and effective strategy for synthesis of Folate-NIR 797-conjugated Magnetic Albumin Nanospheres (FA-NIR 797-MAN) was developed. For this strategy, Magnetic Albumin Nanospheres (MAN), composed of superparamagnetic iron oxide nanoparticles (SPIONs) and bovine serum albumin (BSA), were covalently conjugated with folic acid (FA) ligands to enhance the targeting capability of the particles to folate receptor (FR) over-expressing tumours. Subsequently, a near-infrared (NIR) fluorescent dye NIR 797 was conjugated with FA-conjugated MAN for in vivo fluorescence imaging. The FA-NIR 797-MAN exhibited low toxicity to a human nasopharyngeal epidermal carcinoma cell line (KB cells). Additionally, in vitro and in vivo evaluation of the dynamic behaviour and targeting ability of FA-NIR 797-MAN to KB tumours validated the highly selective affinity of FA-NIR 797-MAN for FR-positive tumours. In summary, the FA-NIR 797-MAN prepared here exhibited great potential for tumour imaging, since the near-infrared fluorescence contrast agents target cells via FR-mediated endocytosis. The high fluorescence intensity together with the targeting effect makes FA-NIR 797-MAN a promising candidate for imaging, monitoring, and early diagnosis of cancer at the molecular and cellular levels.

  4. Folate/NIR 797-conjugated albumin magnetic nanospheres: synthesis, characterisation, and in vitro and in vivo targeting evaluation.

    Directory of Open Access Journals (Sweden)

    Qiusha Tang

    Full Text Available A practical and effective strategy for synthesis of Folate-NIR 797-conjugated Magnetic Albumin Nanospheres (FA-NIR 797-MAN was developed. For this strategy, Magnetic Albumin Nanospheres (MAN, composed of superparamagnetic iron oxide nanoparticles (SPIONs and bovine serum albumin (BSA, were covalently conjugated with folic acid (FA ligands to enhance the targeting capability of the particles to folate receptor (FR over-expressing tumours. Subsequently, a near-infrared (NIR fluorescent dye NIR 797 was conjugated with FA-conjugated MAN for in vivo fluorescence imaging. The FA-NIR 797-MAN exhibited low toxicity to a human nasopharyngeal epidermal carcinoma cell line (KB cells. Additionally, in vitro and in vivo evaluation of the dynamic behaviour and targeting ability of FA-NIR 797-MAN to KB tumours validated the highly selective affinity of FA-NIR 797-MAN for FR-positive tumours. In summary, the FA-NIR 797-MAN prepared here exhibited great potential for tumour imaging, since the near-infrared fluorescence contrast agents target cells via FR-mediated endocytosis. The high fluorescence intensity together with the targeting effect makes FA-NIR 797-MAN a promising candidate for imaging, monitoring, and early diagnosis of cancer at the molecular and cellular levels.

  5. Folate-modified, indocyanine green-loaded lipid-polymer hybrid nanoparticles for targeted delivery of cisplatin.

    Science.gov (United States)

    Gu, Lianshuai; Shi, Tianyi; Sun, Yu; You, Chaoqun; Wang, Senlin; Wen, Gaoju; Chen, Lan; Zhang, Xiangyang; Zhu, Jin; Sun, Baiwang

    2017-05-01

    Cisplatin is a potent antitumor drug, which is widely applied in clinical cancer treatment. However, cisplatin can hardly distinguish between healthy tissue and tumor tissue, resulting in serious toxic side effects. Indocyanine green (ICG) is a FDA-approved near-infrared (NIR) fluorescence dye which has been used in photothermal therapy and optically mediated diagnostic, but the application of ICG is limited by its concentration-dependent aggregation, poor aqueous stability in vitro, lack of target specificity and rapid elimination from the body. Herein, to overcome these limitations of cisplatin and ICG, we fabricated folate-modified, cisplatin, ICG-loaded lipid-polymer hybrid nanoparticles (FCINPs) using a single-step sonication method. The FCINPs exhibited well-defined monodispersity, significant stability and excellent NIR penetration ability. The intracellular uptake experiment showed that the targeting efficacy of the FCINPs was more effective in folate receptors (FRs) over-expressing MCF-7 cells than FRs negative A549 cells. In addition, compared with chemo or photothermal treatment alone, the treatment of FCINPs in combination with 808 nm NIR laser irradiation can significantly induce the apoptosis and necrosis of MCF-7 cells. These findings indicated that the FCINPs would be a promising nanosized drug formulation for tumor-targeted therapy in the future.

  6. 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.

  7. Synthesis and evaluation of Lys1(α, γ-Folate)Lys3(177Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer

    International Nuclear Information System (INIS)

    Aranda L, L.; Ferro F, G.; Azorin V, E.; Ramirez, F. M.; Ocampo G, B.; Santos C, C.; Jimenez M, N.; Issac O, K.

    2015-10-01

    Full text: Lutetium-177 labeled hetero bivalent molecules that interact with different targets on tumor cells have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this work was to synthesize Lys 1 (α,γ-Folate)-Lys 3 ( 177 Lu-DOTA)-Bombesin (1-14) ( 177 LuFolate-Bn), as well as to assess its in vitro and in vivo potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (Fr) and gastrin releasing peptide receptors (GRPR). Lys 1 Lys 3 (DOTA)-Bombesin (1-14) was conjugated to the terminal carboxylic group of the folic acid and the product purified by size-exclusion HPLC. Chemical characterization was carried out by UV-vis, Ft-IR spectroscopies and MALDI-TOF mass spectrometry. 177 Lu labeling was performed by reaction of 177 LuCl 3 with the Lys 1 (α,γ-Folate)-Lys 3 (DOTA)-Bombesin (Folate-Bn) conjugate. In vitro binding studies were carried out in T47D breast cancer cells (positive to Fr and GRPR). Biokinetic studies and micro-SPECT/CT images were obtained using athymic mice with T47D induced tumors. Spectroscopic studies and HPLC analyses indicated that the conjugate was obtained with high chemical and radiochemical purity (98 ± 1.3%). T47D-tumors were clearly visible with high contrast at 2 h after radiopharmaceutical administration. The 177 Lu-absorbed dose delivered to tumors was 23.9 ± 2.1 Gy (74 MBq, intravenously administered) 177 Lu-Folate-Bn demonstrated properties suitable as a theranostic radiopharmaceutical for breast tumors expressing Fr s and GRPR s. (Author)

  8. Synthesis and evaluation of Lys{sup 1}(α, γ-Folate)Lys{sup 3}({sup 177}Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Aranda L, L.; Ferro F, G.; Azorin V, E.; Ramirez, F. M.; Ocampo G, B.; Santos C, C.; Jimenez M, N. [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico); Issac O, K. [Universidad Autonoma del Estado de Mexico, Facultad de Medicina, 50180 Toluca, Estado de Mexico (Mexico)

    2015-10-15

    Full text: Lutetium-177 labeled hetero bivalent molecules that interact with different targets on tumor cells have been proposed as a new class of theranostic radiopharmaceuticals. The aim of this work was to synthesize Lys{sup 1} (α,γ-Folate)-Lys{sup 3}({sup 177}Lu-DOTA)-Bombesin (1-14) ({sup 177}LuFolate-Bn), as well as to assess its in vitro and in vivo potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (Fr) and gastrin releasing peptide receptors (GRPR). Lys{sup 1} Lys{sup 3} (DOTA)-Bombesin (1-14) was conjugated to the terminal carboxylic group of the folic acid and the product purified by size-exclusion HPLC. Chemical characterization was carried out by UV-vis, Ft-IR spectroscopies and MALDI-TOF mass spectrometry. {sup 177}Lu labeling was performed by reaction of {sup 177}LuCl{sub 3} with the Lys{sup 1} (α,γ-Folate)-Lys{sup 3} (DOTA)-Bombesin (Folate-Bn) conjugate. In vitro binding studies were carried out in T47D breast cancer cells (positive to Fr and GRPR). Biokinetic studies and micro-SPECT/CT images were obtained using athymic mice with T47D induced tumors. Spectroscopic studies and HPLC analyses indicated that the conjugate was obtained with high chemical and radiochemical purity (98 ± 1.3%). T47D-tumors were clearly visible with high contrast at 2 h after radiopharmaceutical administration. The {sup 177}Lu-absorbed dose delivered to tumors was 23.9 ± 2.1 Gy (74 MBq, intravenously administered) {sup 177}Lu-Folate-Bn demonstrated properties suitable as a theranostic radiopharmaceutical for breast tumors expressing Fr s and GRPR s. (Author)

  9. Mechanisms of red blood cell transfusion-related immunomodulation

    NARCIS (Netherlands)

    Remy, Kenneth E.; Hall, Mark W.; Cholette, Jill; Juffermans, Nicole P.; Nicol, Kathleen; Doctor, Allan; Blumberg, Neil; Spinella, Philip C.; Norris, Philip J.; Dahmer, Mary K.; Muszynski, Jennifer A.

    2018-01-01

    Red blood cell (RBC) transfusion is common in critically ill, postsurgical, and posttrauma patients in whom both systemic inflammation and immune suppression are associated with adverse outcomes. RBC products contain a multitude of immunomodulatory mediators that interact with and alter immune cell

  10. Major clades of Australasian Rutoideae (Rutaceae) based on rbcL and atpB sequences.

    Science.gov (United States)

    Bayly, Michael J; Holmes, Gareth D; Forster, Paul I; Cantrill, David J; Ladiges, Pauline Y

    2013-01-01

    Rutaceae subfamily Rutoideae (46 genera, c. 660 species) is diverse in both rainforests and sclerophyll vegetation of Australasia. Australia and New Caledonia are centres of endemism with a number of genera and species distributed disjunctly between the two regions. Our aim was to generate a high-level molecular phylogeny for the Australasian Rutoideae and identify major clades as a framework for assessing morphological and biogeographic patterns and taxonomy. Phylogenetic analyses were based on chloroplast genes, rbcL and atpB, for 108 samples (78 new here), including 38 of 46 Australasian genera. Results were integrated with those from other molecular studies to produce a supertree for Rutaceae worldwide, including 115 of 154 genera. Australasian clades are poorly matched with existing tribal classifications, and genera Philotheca and Boronia are not monophyletic. Major sclerophyll lineages in Australia belong to two separate clades, each with an early divergence between rainforest and sclerophyll taxa. Dehiscent fruits with seeds ejected at maturity (often associated with myrmecochory) are inferred as ancestral; derived states include woody capsules with winged seeds, samaras, fleshy drupes, and retention and display of seeds in dehisced fruits (the last two states adaptations to bird dispersal, with multiple origins among rainforest genera). Patterns of relationship and levels of sequence divergence in some taxa, mostly species, with bird-dispersed (Acronychia, Sarcomelicope, Halfordia and Melicope) or winged (Flindersia) seeds are consistent with recent long-distance dispersal between Australia and New Caledonia. Other deeper Australian/New Caledonian divergences, some involving ant-dispersed taxa (e.g., Neoschmidia), suggest older vicariance. This comprehensive molecular phylogeny of the Australasian Rutoideae gives a broad overview of the group's evolutionary and biogeographic history. Deficiencies of infrafamilial classifications of Rutoideae have long been

  11. Grateloupia ramosa Wang & Luan sp. nov. (Halymeniaceae, Rhodophyta), a new species from China based on morphological evidence and comparative rbcL sequences

    Science.gov (United States)

    Cao, Cuicui; Liu, Miao; Guo, Shaoru; Zhao, Dan; Luan, Rixiao; Wang, Hongwei

    2016-03-01

    Grateloupia ramosa Wang & Luan sp. nov. (Halymeniaceae, Rhodophyta) is newly described from Hainan Province, southern China. The organism has the following morphological features: (1) purplish red, cartilaginous and lubricous thalli 5-10 cm in height; (2) compressed percurrent axes bearing abundant branches with opposite arrangement; (3) claw-like apices on top, constricted to 2-4 cm at the base; (4) cortex consisting of 3-6 layers of elliptical or anomalous cells and a medulla covered by compact medullary filaments; (5) reproductive structures distributed throughout the thallus, especially centralized at the bottom of the end portion of the branches; and (6) 4-celled Carpogonial branches and 3-celled auxiliary-cell branches, both of the Grateloupia-type. The morphological diff erences were supported by molecular phylogenetics based on ribulose-1, 5-bisphosphate carboxylase/oxygenase ( rbcL) gene sequence analysis. There was only a 1 bp divergence between specimens collected from Wenchang and Lingshui of Hainan province. The new species was embedded in the large Grateloupia clade of the Halymeniaceae. The pairwise distances between G. ramosa and other species within Grateloupia ranged from 26 to 105 bp, within pairwise distances of 13-111 bp between species of the large genus Grateloupia in Halymeniaceae. Thus, we propose this new species as G. ramosa Wang & Luan sp. nov.

  12. Monocyte-mediated activation of endothelial cells occurs only after binding to extracellular vesicles from red blood cell products, a process mediated by β-integrin

    NARCIS (Netherlands)

    Straat, Marleen; van Hezel, Maike E.; Böing, Anita; Tuip-de Boer, Anita; Weber, Nina; Nieuwland, Rienk; van Bruggen, Robin; Juffermans, Nicole P.

    2016-01-01

    Red blood cell (RBC) transfusion is associated with organ failure. The mechanism remains unknown, but may include adherence of blood cells to the microvasculature. We hypothesized that RBC-derived extracellular vesicles (EVs) interact with monocytes to activate endothelial cells. Human umbilical

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

    Science.gov (United States)

    Achebe, Maureen M; Gafter-Gvili, Anat

    2017-02-23

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

  14. Delimiting the species Neosiphonia yendoi (Rhodomelaceae, Rhodophyta) based on COI and rbcL genetic variation in Korea and Japan

    Science.gov (United States)

    Kim, Byeongseok; Yang, Mi Yeon; Kim, Myung Sook

    2016-09-01

    Although the marine red algal genus Neosiphonia is well characterized, many species of Neosiphonia are poorly understood. To correctly define the species delimitation of Neosiphonia yendoi using genetic variation, owing to the confusion over identification with " N. sphaerocarpa" from Korea, we investigated intensively the haplotype network of the mitochondrial COI and the plastid rbcL genes of specimens collected from Korea and Japan. The molecular analyses indicated that specimens collected in different sites of Korea and Japan belong to the same species, Neosiphonia yendoi and " Neosiphonia sphaerocarpa" from Korea, which is distinguished from N. sphaerocarpa from Florida and is allied with N. yendoi collected from the type locality, Muroran of Japan. A total of 29 COI and 13 rbcL haplotypes were found and the COI haplotype network shows evidence of a clear break between specimens from Jeju Island and all other locations of Korea, suggesting the possibility of cryptic diversity within N. yendoi.

  15. J-Integral Estimate for Circumferential Cracked Pipes Under Primary and Secondary Stress in R, RBC-MR A

    Energy Technology Data Exchange (ETDEWEB)

    Nam, Hyun Suk; Oh, Chang Young; Kim, Yun Jae [Korea Univ., Seoul (Korea, Republic of)

    2013-05-15

    This paper provides a comparison of the J-integral estimation method under combined primary and secondary stress in the R, RBC-MR A code. The comparisons of each code are based on finite element analysis using Abacus with regard to the crack shape, crack depth, and magnitude of secondary load. The estimate of the R code is conservative near L{sub r} = 1, and that of the RBC-MR A code is conservative near L{sub r} = 0. As a result, this paper proposes a modified method of J-integral estimation in the R, RCC{sub M}R A code. The J-integral using the modified method corresponds to the finite element analysis result.

  16. Folate-targeted polymeric micelles loaded with ultrasmall superparamagnetic iron oxide: combined small size and high MRI sensitivity

    Directory of Open Access Journals (Sweden)

    Hong GB

    2012-06-01

    Full Text Available Guo-bin Hong,1,2 Jing-xing Zhou,2 Ren-xu Yuan31Department of Radiology, Fifth Affiliated Hospital, Zhuhai, 2Department of Radiology, Sun Yat-sen Memorial Hospital, Guangzhou, 3School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, ChinaAbstract: Targeted delivery of contrast agents is a highly desirable strategy for enhancing diagnostic efficiency and reducing side effects and toxicity. Water-soluble and tumor-targeting superparamagnetic iron oxide nanoparticles (SPIONs were synthesized by loading hydrophobic SPIONs into micelles assembled from an amphiphilic block copolymer poly(ethylene glycol-poly(ε-caprolactone (PEG-PCL bearing folate in the distal ends of PEG chains. Compared to the water-soluble SPIONs obtained by small molecular surfactant coating, ultrasmall SPION encapsulation with PEG-PCL micelles (PEG-PCL-SPIONs simultaneously increases transverse (r2 and decreases longitudinal (r1 magnetic resonance (MR relaxivities of water proton in micelle solution, leading to a notably high r2/r1 ratio up to 78, which makes the PEG-PCL-SPIONs a highly sensitive MR imaging (MRI T2 contrast agent. The mean size of folate-attached SPION micelles (Fa-PEG-PCL-SPIONs is 44 ± 3 nm on average, ideal for in vivo MRI applications in which long circulation is greatly determined by small particle size and is highly desirable. Prussian blue staining of BEL-7402 cells over-expressing folate receptors, after incubation with micelle-containing medium, demonstrated that folate functionalization of the magnetic particles significantly enhanced their cell uptake. The potential of Fa-PEG-PCL-SPIONs as a potent MRI probe for in vivo tumor detection was assessed. At 3 hours after intravenous injection of the Fa-PEG-PCL-SPION solution into mice bearing subcutaneous xenografts of human BEL-7402 hepatoma, a 41.2% signal intensity decrease was detected in the T2-weighted MR images of the tumor, indicating the efficient accumulation of Fa

  17. Molecular evolution of rbcL in three gymnosperm families: identifying adaptive and coevolutionary patterns

    OpenAIRE

    Gao Lei; Liang Bo; Fares Mario A; Sen Lin; Wang Bo; Wang Ting; Su Ying-Juan

    2011-01-01

    Abstract Background The chloroplast-localized ribulose-1, 5-biphosphate carboxylase/oxygenase (Rubisco), the primary enzyme responsible for autotrophy, is instrumental in the continual adaptation of plants to variations in the concentrations of CO2. The large subunit (LSU) of Rubisco is encoded by the chloroplast rbcL gene. Although adaptive processes have been previously identified at this gene, characterizing the relationships between the mutational dynamics at the protein level may yield c...

  18. Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity

    International Nuclear Information System (INIS)

    Esfandyari-Manesh, Mehdi; Darvishi, Behrad; Ishkuh, Fatemeh Azizi; Shahmoradi, Elnaz; Mohammadi, Ali; Javanbakht, Mehran; Dinarvand, Rassoul; Atyabi, Fatemeh

    2016-01-01

    The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 ± 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC 50 ) of 4.9 ± 0.9, 7.4 ± 0.5 and 32.8 ± 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells. - Highlights: • MIP-PEG-FA was synthesized as a controlled release carrier for targeting delivery to cancerous cells. • Nanoparticles

  19. Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Esfandyari-Manesh, Mehdi [Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Department of Chemistry, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Darvishi, Behrad [Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Ishkuh, Fatemeh Azizi [Department of Chemistry, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Shahmoradi, Elnaz [Department of Chemical Engineering, Sharif University of Technology, Tehran (Iran, Islamic Republic of); Mohammadi, Ali [Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Javanbakht, Mehran [Department of Chemistry, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of); Dinarvand, Rassoul [Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of); Atyabi, Fatemeh, E-mail: atyabifa@tums.ac.ir [Nanotechnology Research Center,Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of)

    2016-05-01

    The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 ± 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC{sub 50}) of 4.9 ± 0.9, 7.4 ± 0.5 and 32.8 ± 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells. - Highlights: • MIP-PEG-FA was synthesized as a controlled release carrier for targeting delivery to cancerous cells. • Nanoparticles

  20. Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier

    Directory of Open Access Journals (Sweden)

    Kheradpour Albert

    2008-05-01

    Full Text Available Abstract Background Methotrexate (MTX uptake is mediated by the reduced folate carrier (RFC. Defective drug uptake in association with decreased RFC expression is a common mechanism of MTX resistance in many tumor types. Heavy promoter methylation was previously identified as a basis for the complete silencing of RFC in MDA-MB-231 breast cancer cells, its role and prevalence in RFC transcription regulation are, however, not widely studied. Methods In the current study, RFC promoter methylation was assessed using methylation specific PCR in a panel of malignant cell lines (n = 8, including MDA-MB-231, and M805, a MTX resistant cell line directly established from the specimen of a patient with malignant fibrohistocytoma, whom received multiple doses of MTX. A quantitative approach of real-time PCR for measuring the extent of RFC promoter methylation was developed, and was validated by direct bisulfite genomic sequencing. RFC mRNA levels were determined by quantitative real-time RT-PCR and were related to the extent of promoter methylation in these cell lines. Results A partial promoter methylation and RFC mRNA down-regulation were observed in M805. Using the quantitative approach, a reverse correlation (correlation coefficient = -0.59, p Conclusion This study further suggests that promoter methylation is a potential basis for MTX resistance. The quantitative correlation identified in this study implies that promoter methylation is possibly a mechanism involved in the fine regulation of RFC transcription.

  1. RBC-/Cr-51/ half-life and albumin turnover in growing Beagle dogs during chronic radial acceleration

    Science.gov (United States)

    Beckman, D. A.; Evans, J. W.; Oyama, J.

    1979-01-01

    The effects of chronic centrifugation on growing Beagle dogs exposed to -2 or -2.6 Gx on albumin and RBC turnover rates, albumin concentration and space, and total blood volume were determined and compared with caged and run control of animals. Albumin-(I-125) and autologous RBC-(Cr-51) preparations were injected into all dogs at day 82 of the centrifugation periods, and the disappearance curves were determined by successive bleedings of the animals over the next 35 d, during which the centrifugation was continued. There were no differences in albumin turnover rates or space. Two populations of RBCs were found in both centrifugated groups, one with a normal half-life of 27 + or - 1 S.E.M. d, and one with a significantly (p less than 0.01) shorter half-life of 15 + or - 2 S.E.M. d. An absolute polycythemia was also observed in both centrifuged groups. The results suggest that chronic centrifugation acts through some as-yet unknown mechanism to affect RBC population kinetics.

  2. Contínua evolução da RBC: um obrigado a todos os colaboradores!

    Directory of Open Access Journals (Sweden)

    Bruno Telles

    2017-07-01

    Full Text Available Desde de seu nascimento, a RBC prima pela divulgação do conhecimento pericial tecnicamente validado e pela discussão de novos métodos e de casos. É o caminho que há de ser constantemente trilhado pelos profissionais da perícia para que não eivem seus laudos periciais e pareceres técnicos de vícios insanáveis cujas consequências seriam nefastas para a justiça. Não é à toa que o Corpo Editorial da RBC, com o imprescindível auxílio dos editores de sessão e dos avaliadores, não envida esforços na contínua evolução da revista em direção à qualidade. Prova disso é a permanente busca por indexação em vários meios e pela elevação dos índices de qualidade por qualificação externa. A RBC aparece no Latindex, no CrossRef, no Google Scholar, no Research Gate, no Directory of Open Access Journals (DOAJ, no Electronic Journal Library (EZ3, no Scilit, no Diadorim, na ABEC Brasil, na Universitäts Bibliothek UBL Leipzig e na Qualis/CAPES.

  3. Improved stable isotope dilution assay for dietary folates using LC-MS/MS and its application to strawberries

    Science.gov (United States)

    Striegel, Lisa; Chebib, Soraya; Netzel, Michael E.; Rychlik, Michael

    2018-02-01

    Folates play an important role in the human body and a deficiency of this vitamin can cause several diseases. Therefore, a reliable analytical method is crucial for the determination of folate vitamers in strawberries and other dietary folate sources. A stable isotope dilution LC-MS/MS method for analyzing folates in food was developed and validated. The folate vitamers Pteroylmonoglutamic acid, tetrahydrofolate, 5-methyltetrahydrofolate and 5-formyltetrahydrofolate were quantified using 13C-labelled internal standards. Validation of the assay was accomplished by determining linearity, precision, recovery, limit of detection and limit of quantification and revealed to be a precise, sensitive and accurate method to determine folate vitamers. Strawberries are worldwide consumed and known to be a good dietary source of nutritive compounds. Using this method, folate concentrations in selected commercial strawberry cultivars and experimental breeding lines grown in Germany were investigated. Total folates varied from 59 to 153 µg/100 g on fresh weight basis. Furthermore, folate content after lyophilizing or freezing did not show any significant differences compared to fresh strawberries. However, significant losses of total folates in pureed strawberries could be observed after 5 days of storage with only 16 % of the original concentration retained. In summary, some of the investigated strawberry cultivars/breeding lines can be considered as rich dietary sources of natural folates.

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

    Science.gov (United States)

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

    2009-06-10

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

  5. Disruption of redox homeostasis in liver function and activation of apoptosis on consumption of aspartame in folate deficient rat model

    Directory of Open Access Journals (Sweden)

    Ashok Iyaswamy

    2017-06-01

    Full Text Available This study assesses the effect of long-term intake of aspartame on liver function and apoptosis signaling pathway in the Wistar albino rats. Several reports have suggested that methanol is one of the major metabolites of Aspartame. Non-primate animals are usually resistant to methanol-induced metabolic acidosis due to high levels of hepatic folate content; hence a folate deficiency model was induced by treating animals with methotrexate (MTX prior to aspartame exposure. The aspartame treated MTX animals exhibited a marked significant increase in hepatic alanine transaminase (ALT, aspartate transaminase (AST, alkaline phosphatase (ALP and lactic acid dehydrogenase (LDH activity compared to controls. Aspartame treated MTX animals additionally exhibited down-regulation of genes namely B-cell lymphoma 2 (Bcl2 expression and up-regulation of Bcl-2-associated X protein (Bax, Fas-associated protein with death domain (FADD and Caspase 3, 9 genes and apoptotic protein expression, indicating the augmentation of hepatic apoptosis. Nuclear condensation, micro vacuole formation in the cytoplasm and necrosis were observed in the liver of the aspartame treated animals on histopathology evaluation. Additionally, Immunohistochemical analysis revealed a significant increase in positive cells expressing Fas, FADD, Bax and Caspase 9 protein, indicating an increase in apoptotic protein expression in the liver. Thus, Aspartame may act as a chemical stressor which alters the functional status of liver, leading to hepatotoxicity.

  6. Deep coverage mouse red blood cell proteome: a first comparison with the human red blood cell

    DEFF Research Database (Denmark)

    Pasini, Erica M; Kirkegaard, Morten; Salerno, Doris

    2008-01-01

    Mice have close genetic/physiological relationships to humans, breed rapidly, and can be genetically modified, making them the most used mammal in biomedical research. Because the red blood cell (RBC) is the sole gas transporter in vertebrates, diseases of the RBC are frequently severe; much...

  7. Divalent folate modification on PEG: an effective strategy for improving the cellular uptake and targetability of PEGylated polyamidoamine-polyethylenimine copolymer.

    Science.gov (United States)

    Cao, Duanwen; Tian, Shouqin; Huang, Huan; Chen, Jianhai; Pan, Shirong

    2015-01-05

    The stability and targeting ability of nanocarrier gene delivery systems are necessary conditions to ensure the good therapeutic effect and low nonspecific toxicity of cancer treatment. Poly(ethylene glycol) (PEG) has been widely applied for improving stability and as a spacer for linking ligands and nanocarriers to improve targetability. However, the cellular uptake and endosomal escape capacity of nanocarriers has been seriously harmed due to the introduction of PEG. In the present study, we synthesized a new gene delivery vector by coupling divalent folate-PEG (PEG3.4k-FA2) onto polyamidoamine-polyethylenimine (PME) copolymer (PME-(PEG3.4k-FA2)1.72). Both PEG and monovalent folate-PEG (PEG3.4k-FA1) modified PME were prepared as control polymers, which were named as PME-(PEG3.5k)1.69 and PME-(PEG3.4k-FA1)1.66, respectively. PME-(PEG3.4k-FA2)1.72 exhibited strong DNA condensation capacity like parent polymer PME which was not significantly influenced by PEG. PME-(PEG3.4k-FA2)1.72/DNA complexes at N/P = 10 had a diameter ∼143 nm and zeta potential ∼13 mV and showed the lowest cytotoxicity and hemolysis and the highest transfection efficiency among all tested polymers. In folate receptor positive (FR-positive) cells, the cellular uptake and transfection efficiency were increased with the increase in the number of folates coupled on PEG; the order was PME-(PEG3.4k-FA2)1.72 > PME-(PEG3.4k-FA1)1.66 > PME-(PEG3.5k)1.69. Folate competition assays showed that PME-(PEG3.4k-FA2)1.72 complexes had stronger targeting ability than PME-(PEG3.5k)1.69 and PME-(PEG3.4k-FA1)1.66 complexes due to their higher folate density per PEG molecule. Cellular uptake mechanism study showed that the folate density on PEG could change the endocytosis pathway of PME-(PEG3.5k)1.69 from clathrin-mediated endocytosis to caveolae-mediated endocytosis, leading to less lysosomal degradation. Distribution and uptake in 3D multicellular spheroid assays showed that divalent folate could offer PME

  8. Antibodies to biotinylated red blood cells in adults and infants: improved detection, partial characterization, and dependence on red blood cell-biotin dose.

    Science.gov (United States)

    Schmidt, Robert L; Mock, Donald M; Franco, Robert S; Cohen, Robert M; North, Anne K; Cancelas, José A; Geisen, Christof; Strauss, Ronald G; Vlaar, Alexander P; Nalbant, Demet; Widness, John A

    2017-06-01

    Biotin-labeled red blood cells (BioRBCs) are used for in vivo kinetic studies. Because BioRBC dosing occasionally induces antibodies, a sensitive and specific anti-BioRBC detection assay is needed. Aims were to 1) develop a gel card assay to evaluate existing, naturally occurring and BioRBC-induced plasma antibodies, 2) compare gel card and tube agglutination detection results, and 3) test for a relationship of antibody induction and BioRBC dose. Reagent BioRBCs were prepared using sulfo-NHS biotin ranging from densities 18 (BioRBC-18) to 1458 (BioRBC-1458) µg/mL RBCs. Among BioRBC-exposed subjects, gel card and tube agglutination results were concordant in 21 of 22 adults and all 19 infant plasma samples. Gel card antibody detection sensitivity was more than 10-fold greater than tube agglutination. Twelve to 16 weeks after BioRBC exposure, induced anti-antibodies were detected by gel card in three of 26 adults (12%) at reagent densities BioRBC-256 or less, but in none of 41 infants. Importantly, induced anti-BioRBC antibodies were associated with higher BioRBC dose (p = 0.008); no antibodies were detected in 18 subjects who received BioRBC doses less than or equal to BioRBC-18. For noninduced BioRBC antibodies, six of 1125 naïve adults (0.3%) and none of 46 naïve infants demonstrated existing anti-BioRBC antibodies using reagent BioRBC-140 or -162. Existing anti-BioRBCs were all neutralized by biotin compounds, while induced antibodies were not. The gel card assay is more sensitive than the tube agglutination assay. We recommend reagent BioRBC-256 for identifying anti-BioRBCs. Use of a low total RBC biotin label dose (≤ BioRBC-18) may minimize antibody induction. © 2017 AABB.

  9. Epidemiology of RBC Transfusions in Patients With Severe Acute Kidney Injury: Analysis From the Randomized Evaluation of Normal Versus Augmented Level Study.

    Science.gov (United States)

    Bellomo, Rinaldo; Mårtensson, Johan; Kaukonen, Kirsi-Maija; Lo, Serigne; Gallagher, Martin; Cass, Alan; Myburgh, John; Finfer, Simon

    2016-05-01

    To assess the epidemiology and outcomes associated with RBC transfusion in patients with severe acute kidney injury requiring continuous renal replacement therapy. Post hoc analysis of data from a multicenter, randomized, controlled trial. Thirty-five ICUs in Australia and New Zealand. Cohort of 1,465 patients enrolled in the Randomized Evaluation of Normal versus Augmented Level replacement therapy study. Daily information on morning hemoglobin level and amount of RBC transfused were prospectively collected in the Randomized Evaluation of Normal versus Augmented Level study. We analyzed the epidemiology of such transfusions and their association with clinical outcomes. Overall, 977 patients(66.7%) received a total of 1,192 RBC units. By day 5, 785 of 977 transfused patients (80.4%) had received at least one RBC transfusion. Hemoglobin at randomization was lower in transfused than in nontransfused patients (94 vs 111 g/L; p regression analysis, RBC transfusion was independently associated with lower 90-day mortality (hazard ratio, 0.55; 95% CI, 0.38-0.79). However, we found no independent association between RBC transfusions and mortality when the analyses were restricted to patients surviving at least 5 days (hazard ratio, 1.29; 95% CI, 0.90-1.85). We found no independent association between RBC transfusion and renal replacement therapy-free days, mechanical ventilator-free days, or length of stay in ICU or hospital. In patients with severe acute kidney injury treated with continuous renal replacement therapy, we found no association of RBC transfusion with 90-day mortality or other patient-centered outcomes. The optimal hemoglobin threshold for RBC transfusion in such patients needs to be determined in future randomized controlled trials.

  10. Association of serum vitamin B12 and folate with mortality in incident hemodialysis patients.

    Science.gov (United States)

    Soohoo, Melissa; Ahmadi, Seyed-Foad; Qader, Hemn; Streja, Elani; Obi, Yoshitsugu; Moradi, Hamid; Rhee, Connie M; Kim, Tae Hee; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

    2017-06-01

    Vitamin B12 (B12) and folate are essential vitamins that play important roles in physiological processes. In the general population, many studies have evaluated the association of these vitamins with clinical outcomes, yet this association in hemodialysis (HD) patients remains unclear. We examined the association of serum folate and B12 with mortality in a 5-year cohort of 9517 (folate) and 12 968 (B12) HD patients using Cox models with hierarchical adjustment for sociodemographics, comorbidities, and laboratory variables associated with the malnutrition and inflammation complex syndrome. The associations of baseline B12 and folate (separately) with all-cause mortality were evaluated across five categories of B12 [B12 measurements had a mean ± standard deviation age of 63 ± 15 years, among whom 43% were female, 33% were African-American, and 57% were diabetic. Higher B12 concentrations ≥550 pg/mL were associated with a higher risk of mortality after adjusting for sociodemographic and laboratory variables. However, only lower serum folate concentrations B12 concentrations are associated with higher all-cause mortality in HD patients independent of sociodemographics and laboratory variables, whereas lower folate concentrations were associated with higher all-cause mortality after accounting for sociodemographic variables. Further studies are warranted to determine the optimal B12 and folate level targets in this population. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

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

    Science.gov (United States)

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

    2012-06-01

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

  12. Red Blood Cell Storage Lesion

    Directory of Open Access Journals (Sweden)

    Daryl J. Kor

    2009-10-01

    Full Text Available The past two decades have witnessed increased scrutiny regarding efficacy and risk of the once unquestioned therapy of red blood cell (RBC transfusion. Simultaneously, a variety of changes have been identified within the RBC and storage media during RBC preservation that are correlated with reduced tissue oxygenation and transfusion-associated adverse effects. These alterations are collectively termed the storage lesion and include extensive biochemical, biomechanical, and immunologic changes involving cells of diverse origin. Time-dependent falls is 2,3-diphosphoglycerate, intracellular RBC adenosine triphosphate, and nitric oxide have been shown to impact RBC deformability and delivery of oxygen to the end-organ. The accumulation of biologic response modifiers such as soluble CD40 ligand (sCD40L, lysophosphatidylcholine (lyso-PC, and Regulated on Activation, Normal T-cell Expressed and Secreted (RANTES have been associated with altered recipient immune function as well. This review will address the alterations occurring within the RBC and storage media during RBC preservation and will address the potential clinical consequence thereof.

  13. Clustering of red blood cells using digital holographic microscopy

    Science.gov (United States)

    Jaferzadeh, K.; Ahmadzadeh, E.; Moon, I.; Gholami, S.

    2017-05-01

    Digital holographic microscopy can provide quantitative phase images (QPIs) of 3D profile of red blood cell (RBC) with nanometer accuracy. In this paper we propose applying k-means clustering method to cluster RBCs into two groups of young and old RBCs by using a four-dimensional feature vector. The features are RBC thickness average, surface area-volume ratio, sphericity coefficient and RBC perimeter that can be obtained from QPIs. The proposed features are related to the morphology of RBC. The experimental result shows that by utilizing the proposed method two groups of sphero-echinocytes (old RBCs) and non-spheroechinocytes RBCs can be perfectly clustered.

  14. Assessment of the specificity of a new folate-targeted photosensitizer for peritoneal metastasis of epithelial ovarian cancer to enable intraperitoneal photodynamic therapy. A preclinical study.

    Science.gov (United States)

    Azaïs, Henri; Schmitt, Caroline; Tardivel, Meryem; Kerdraon, Olivier; Stallivieri, Aurélie; Frochot, Céline; Betrouni, Nacim; Collinet, Pierre; Mordon, Serge

    2016-03-01

    Ovarian cancer's prognosis remains dire after primary therapy. Recurrence rate is disappointingly high as 60% of women with epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis during surgery is necessary as they are the main predictive factors of recurrences. Folate Receptor α (FRα) shows promising prospects in targeting ovarian cancerous cells and intraperitoneal photodynamic therapy (PDT) could be a solution in addition to macroscopic cytoreductive surgery to treat peritoneal micrometastasis. The aim of this preclinical study is to assess the specificity of a folate-targeted photosensitizer for ovarian peritoneal micrometastasis. We used the NuTu-19 epithelial ovarian cancer cell line to induce peritoneal carcinomatosis in female Fischer 344 rats. Three groups of 6 rats were studied (Control (no photosensitizer)/Non-conjugated photosensitizer (Porph)/Folate-conjugated photosensitizer (Porph-s-FA)). Four hours after the administration of the photosensitizer, animals were sacrificed and intraperitoneal organs tissues were sampled. FRα tissue expression was evaluated by immunohistochemistry. Tissue incorporation of photosensitizers was assessed by confocal microscopy and tissue quantification. FRα is overexpressed in tumor, ovary, and liver whereas, peritoneum, colon, small intestine, and kidney do not express it. Cytoplasmic red endocytosis vesicles observed by confocal microscopy are well correlated to FRα tissue expression. Photosensitizer tissue quantification shows a mean tumor-to-normal tissue ratio of 9.6. We demonstrated that this new generation folate-targeted photosensitizer is specific of epithelial ovarian peritoneal metastasis and may allow the development of efficient and safe intraperitoneal PDT procedure. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Reconstructing a herbivore's diet using a novel rbcL DNA mini-barcode for plants.

    Science.gov (United States)

    Erickson, David L; Reed, Elizabeth; Ramachandran, Padmini; Bourg, Norman A; McShea, William J; Ottesen, Andrea

    2017-05-01

    Next Generation Sequencing and the application of metagenomic analyses can be used to answer questions about animal diet choice and study the consequences of selective foraging by herbivores. The quantification of herbivore diet choice with respect to native versus exotic plant species is particularly relevant given concerns of invasive species establishment and their effects on ecosystems. While increased abundance of white-tailed deer ( Odocoileus virginianus ) appears to correlate with increased incidence of invasive plant species, data supporting a causal link is scarce. We used a metabarcoding approach (PCR amplicons of the plant rbc L gene) to survey the diet of white-tailed deer (fecal samples), from a forested site in Warren County, Virginia with a comprehensive plant species inventory and corresponding reference collection of plant barcode and chloroplast sequences. We sampled fecal pellet piles and extracted DNA from 12 individual deer in October 2014. These samples were compared to a reference DNA library of plant species collected within the study area. For 72 % of the amplicons, we were able to assign taxonomy at the species level, which provides for the first time-sufficient taxonomic resolution to quantify the relative frequency at which native and exotic plant species are being consumed by white-tailed deer. For each of the 12 individual deer we collected three subsamples from the same fecal sample, resulting in sequencing 36 total samples. Using Qiime, we quantified the plant DNA found in all 36 samples, and found that variance within samples was less than variance between samples ( F  = 1.73, P  = 0.004), indicating additional subsamples may not be necessary. Species level diversity ranged from 60 to 93 OTUs per individual and nearly 70 % of all plant sequences recovered were from native plant species. The number of species detected did reduce significantly (range 4-12) when we excluded species whose OTU composed plants inventoried

  16. 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...... was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether...

  17. Mitochondrial-targeted photosensitizer-loaded folate-albumin nanoparticle for photodynamic therapy of cancer.

    Science.gov (United States)

    Battogtokh, Gantumur; Ko, Young Tag

    2017-02-01

    The objective of this study was to develop a mitochondria-targeted photosensitizer (PS) for photodynamic therapy (PDT). Herein, a porphyrin-derivative photosensitizer, pheophorbide-a (PheoA), was conjugated to carboxybutyltriphenylphosphonium (TPP) via a carbodiimide linkage to enhance mitochondrial targeting and TPP-PheoA conjugate was further loaded into folate-cholesteryl albumin (FA-chol-BSA) nanoparticles (NPs) to improve its biocompatibility. Cellular uptake results showed that TPP-PheoA and TPP-PheoA@FA-chol-BSA NPs were readily taken up by B16F10 and HeLa cells. Further in vitro studies exhibited that TPP-PheoA and its nanoparticle primarily accumulate in the mitochondria, greatly generate ROS, lead mitochondrial disruption and cell apoptosis, and have higher phototoxicity against cancer cells. In vivo bioimaging and the in vivo antitumor studies indicated that TPP-PheoA@FA-chol-BSA NP greatly accumulated in the tumor area and significantly suppress the tumor growth as compared to PheoA@FA-chol-BSA NP in tumor-bearing mice. Taken together, TPP-PheoA@FA-chol-BSA NP could be a promising mitochondria-targeted PS for image-guided PDT. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Pediatric cancer epigenome and the influence of folate

    Science.gov (United States)

    Yiu, Teresa T; Li, Wei

    2015-01-01

    Despite improvement in clinical treatment of childhood cancer, it remains the leading cause of disease-related mortality in children with survivors often suffering from treatment-related toxicity and premature death. Because childhood cancer is vastly different from cancer in adults, a thorough understanding of the underlying molecular mechanisms specific to childhood cancer is essential. Although childhood cancer contains much fewer mutations, a subset of cancer subtypes has a higher frequency of mutations in gene encoding epigenetic regulators. Thus, in this review, we will focus on epigenetic deregulations in childhood cancers, the use of genome-wide analysis for cancer subtype classification, prediction of clinical outcomes and the influence of folate on epigenetic mechanisms. PMID:25950259

  19. Low folate and vitamin B12 nourishment is common in Omani children with newly diagnosed autism.

    Science.gov (United States)

    Al-Farsi, Yahya M; Waly, Mostafa I; Deth, Richard C; Al-Sharbati, Marwan M; Al-Shafaee, Mohamed; Al-Farsi, Omar; Al-Khaduri, Maha M; Gupta, Ishita; Ali, Amanat; Al-Khalili, Maha; Al-Adawi, Samir; Hodgson, Nathaniel W; Ouhtit, Allal

    2013-03-01

    Arab populations lack data related to nutritional assessment in children with autism spectrum disorders (ASDs), especially micronutrient deficiencies such as folate and vitamin B12. To assess the dietary and serum folate and vitamin B12 statuses, a hospital-based case-control study was conducted in 80 Omani children (40 children with ASDs versus 40 controls). The ASD cases showed significantly lower levels of folate, vitamin B12, and related parameters in dietary intake and serum levels. These data showed that Omani children with ASDs exhibit significant deficiencies in folate and vitamin B12 and call for increasing efforts to ensure sufficient intakes of essential nutrients by children with ASDs to minimize or reverse any ongoing impact of nutrient deficiencies. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Reduced folate carrier mutations are not the mechanism underlying methotrexate resistance in childhood acute lymphoblastic leukemia.

    NARCIS (Netherlands)

    Kaufman, Y; Drori, S.; Cole, PD; Kamen, BA; Sirota, J; Ifergan, I; Arush, MW; Elhasid, R; Sahar, D; Kaspers, G.J.L.; Jansen, G.; Matherly, LH; Rechavi, G; Toren, A; Assaraf, Y.G.

    2004-01-01

    BACKGROUND: Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with combination chemotherapy containing methotrexate (MTX), drug resistance contributes to treatment failure for a substantial fraction of patients. The primary transporter for folates and MTX is the

  1. Serum folate levels after UVA exposure: a two-group parallel randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Altmeyer Peter

    2001-11-01

    Full Text Available Abstract Background Photodegradation of certain vitamins such as riboflavins, carotinoids, tocopherol, and folate has been well-documented. Previous observations suggest that ultraviolet (UV radiation may cause folate deficiency. This is of great importance since folate deficiency is also known to be linked with the development of neural tube defects. To investigate the influence of UVA radiation on serum folate levels in vivo, we conducted a two-group randomised controlled trial on healthy subjects. Material and methods Twenty-four healthy volunteers with skin type II were enrolled into the study. Eight volunteers of the study population were randomly assigned to the control group. UVA irradiation was administered with an air-conditioned sunbed. Blood samples were taken from all volunteers at baseline (T1, 30 min after the first UVA exposure (T2, and at the end of the study 24 h after the sixth UV exposure (T3. The volunteers had two UVA exposures weekly within three weeks (cumulative UVA dose: 96 J/cm2. Volunteers of the control group had no UVA exposures. Serum folate was analysed with an automated immunoassay system. Results At all times of blood collection the differences between serum folate levels were insignificant (P > 0.05, except of the non-exposed controls at T2 (P 0.05. Conclusions Our data suggest that both single and serial UVA exposures do not significantly influence serum folate levels of healthy subjects. Therefore, neural tube defects claimed to occur after periconceptual UVA exposure are probably not due to UVA induced folate deficiency.

  2. Association between serum folate and vitamin B-12 and outcomes of assisted reproductive technologies.

    Science.gov (United States)

    Gaskins, Audrey J; Chiu, Yu-Han; Williams, Paige L; Ford, Jennifer B; Toth, Thomas L; Hauser, Russ; Chavarro, Jorge E

    2015-10-01

    Preconceptional folate and vitamin B-12 have been linked to beneficial reproductive outcomes in both natural pregnancies and those after assisted reproductive technology (ART) treatment. The objective of the study was to evaluate the associations of serum folate and vitamin B-12 with ART outcomes. This analysis included a random sample of 100 women (154 ART cycles) participating in a prospective cohort study [Environment and Reproductive Health (EARTH)] at the Massachusetts General Hospital Fertility Center (2007-2013). Serum folate and vitamin B-12 were measured in blood samples collected between days 3 and 9 of treatment. Generalized estimating equations with adjustment for age, BMI, and race were used to evaluate the association of serum folate and vitamin B-12 with ART outcomes. Women in the highest quartile of serum folate (>26.3 ng/mL) had 1.62 (95% CI: 0.99, 2.65) times the probability of live birth compared with women in the lowest quartile (Women in the highest quartile of serum vitamin B-12 (>701 pg/mL) had 2.04 (95% CI: 1.14, 3.62) times the probability of live birth compared with women in the lowest quartile (women with serum folate and vitamin B-12 concentrations greater than the median had 1.92 (95% CI: 1.12, 3.29) times the probability of live birth compared with women with folate and vitamin B-12 concentrations less than or equal to the median. This translated into an adjusted difference in live birth rates of 26% (95% CI: 10%, 48%; P = 0.02). Higher serum concentrations of folate and vitamin B-12 before ART treatment were associated with higher live birth rates among a population exposed to folic acid fortification. This trial was registered at clinicaltrials.gov as NCT00011713. © 2015 American Society for Nutrition.

  3. 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.

  4. Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use.

    Science.gov (United States)

    Lewis, C J; Crane, N T; Wilson, D B; Yetley, E A

    1999-08-01

    There is a critical need to estimate dietary folate intakes for nutrition monitoring and food safety evaluations, but available intake data are seriously limited by several factors. Our objective was to update 2 national food consumption surveys to reflect folate intakes as a result of the recently initiated food fortification program and to correct folate intakes for the apparently higher bioavailability of synthetic folic acid (SFA; ie, folate added to foods or from dietary supplements) than of naturally occurring folate so as to express intakes as dietary folate equivalents. It was not possible to chemically analyze foods, so adjustments were made to food-composition data by using information about food ingredients and characteristics. Total folate intakes were estimated for several sex and age groups by using the modified data coupled with dietary supplement use. Within the limitations of the data, our findings suggested that 67-95% of the population met or surpassed the new estimated average requirement, depending on the sex and age group and survey. Nonetheless, some subgroups had estimated intakes below these standards. Estimated SFA intakes suggested that approximately 15-25% of children aged 1-8 y, depending on the survey, had intakes above the newly established tolerable upper intake level. We estimated that 68-87% of females of childbearing age had SFA intakes below the recommended intake of 400 microgram/d, depending on the age group and survey. There is a need to explore ways to improve folate intakes in targeted subgroups, including females of childbearing age, while not putting other population groups at risk of excessive intakes.

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

    Science.gov (United States)

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

    2014-06-01

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

  6. Efficient and Specific Analysis of Red Blood Cell Glycerophospholipid Fatty Acid Composition

    OpenAIRE

    Klem, Sabrina; Klingler, Mario; Demmelmair, Hans; Koletzko, Berthold

    2012-01-01

    BACKGROUND: Red blood cell (RBC) n-3 fatty acid status is related to various health outcomes. Accepted biological markers for the fatty acid status determination are RBC phospholipids, phosphatidylcholine, and phosphatidyletholamine. The analysis of these lipid fractions is demanding and time consuming and total phospholipid n-3 fatty acid levels might be affected by changes of sphingomyelin contents in the RBC membrane during n-3 supplementation. AIM: We developed a method for the specific a...

  7. The Heritability of Glutathione and Related Metabolites in Stored Red Blood Cells

    OpenAIRE

    van ‘t Erve, Thomas J.; Doskey, Claire M.; Wagner, Brett A.; Hess, John R.; Darbro, Benjamin W.; Ryckman, Kelli K.; Murray, Jeffrey C.; Raife, Thomas J.; Buettner, Garry R.

    2014-01-01

    Red blood cells (RBCs) collected for transfusion deteriorate during storage. This deterioration is termed the “RBC storage lesion”. There is increasing concern over the safety, therapeutic efficacy, and toxicity of transfusing longer-stored units of blood. The severity of the RBC storage lesion is dependent on storage-time and varies markedly between individuals. Oxidative damage is considered a significant factor in development of the RBC storage lesion. In this study, the variability during...

  8. Blood volume measurements in gopher snakes, using autologous 51Cr-labeled red blood cells.

    Science.gov (United States)

    Smeller, J M; Bush, M; Seal, U S

    1978-02-01

    Blood volume determinations were performed in 5 anesthetized gopher snakes (Pituophis melanoleucus catenifer) by means of a 51Cr-labeled red blood cell (RBC) method. The mean blood volume was 52.8 ml/kg of body weight (+/- 6.21 SE). Previous blood volume measurements have not been reported for this species. The RBC survival rate was estimated to be greater than 660 days. The RBC survival rate is long, but it cannot be determined accurately by this method.

  9. Red blood cell transfusion during septic shock in the ICU

    DEFF Research Database (Denmark)

    Perner, A; Smith, S H; Carlsen, S

    2012-01-01

    Transfusion of red blood cells (RBCs) remains controversial in patients with septic shock, but current practice is unknown. Our aim was to evaluate RBC transfusion practice in septic shock in the intensive care unit (ICU), and patient characteristics and outcome associated with RBC transfusion....

  10. The Rh complex exports ammonium from human red blood cells

    NARCIS (Netherlands)

    Hemker, Mirte B.; Cheroutre, Goedele; van Zwieten, Rob; Maaskant-van Wijk, Petra A.; Roos, Dirk; Loos, Johannes A.; van der Schoot, C. Ellen; von dem Borne, Albert E. G. Kr

    2003-01-01

    The Rh blood group system represents a major immunodominant protein complex on red blood cells (RBC). Recently, the Rh homologues RhAG and RhCG were shown to promote ammonium ion transport in yeast. In this study, we showed that also in RBC the human Rh complex functions as an exporter of ammonium

  11. Phylogeny of the Juncaceae based on rbcL sequences, with special emphasis on Luzula DC. and Juncus L

    DEFF Research Database (Denmark)

    Drábková, L.; Kirschner, J.; Seberg, Ole

    2003-01-01

    Cladistic analysis of rbcL nucleotide sequences was applied to 58 taxa representing most subgenera and sections of Luzula and Juncus, chosen to reflect morphological and geographical diversity of both genera. Additionally, representatives of all other genera of the Juncaceae and two taxa from...... the Cyperaceae were included. Phylogenetic trees were constructed using parsimony with Prionium serratum as outgroup. The dataset has 190 parsimony informative sites. The analysis yielded more than 332,400 equally parsimonious trees (length 620, CI=0.47, RI=0.82). A jackknife analysis revealed several well...

  12. Improvement of Folate Biosynthesis by Lactic Acid Bacteria Using Response Surface Methodology

    Directory of Open Access Journals (Sweden)

    Norfarina Muhamad Nor

    2010-01-01

    Full Text Available Lactic acid bacteria (Lactococcus lactis NZ9000, Lactococcus lactis MG1363, Lactobacillus plantarum I-UL4 and Lactobacillus johnsonii DSM 20553 have been screened for their ability to produce folate intracellularly and/or extracellularly. L. plantarum I-UL4 was shown to be superior producer of folate compared to other strains. Statistically based experimental designs were used to optimize the medium formulation for the growth of L. plantarum I-UL4 and folate biosynthesis. The optimal values of important factors were determined by response surface methodology (RSM. The effects of carbon sources, nitrogen sources and para-aminobenzoic acid (PABA concentrations on folate biosynthesis were determined prior to RSM study. The biosynthesis of folate by L. plantarum I-UL4 increased from 36.36 to 60.39 µg/L using the optimized medium formulation compared to the selective Man de Rogosa Sharpe (MRS medium. Conditions for the optimal growth of L. plantarum I-UL4 and folate biosynthesis as suggested by RSM were as follows: lactose 20 g/L, meat extract 16.57 g/L and PABA 10 µM.

  13. Gene-diet-interactions in folate-mediated one-carbon metabolism modify colon cancer risk.

    Science.gov (United States)

    Liu, Amy Y; Scherer, Dominique; Poole, Elizabeth; Potter, John D; Curtin, Karen; Makar, Karen; Slattery, Martha L; Caan, Bette J; Ulrich, Cornelia M

    2013-04-01

    The importance of folate-mediated one-carbon metabolism (FOCM) in colorectal carcinogenesis is emphasized by observations that high dietary folate intake is associated with decreased risk of colon cancer (CC) and its precursors. Additionally, polymorphisms in FOCM-related genes have been repeatedly associated with risk, supporting a causal relationship between folate and colorectal carcinogenesis. We investigated ten candidate polymorphisms with defined or probable functional impact in eight FOCM-related genes (SHMT1, DHFR, DNMT1, MTHFD1, MTHFR, MTRR, TCN2, and TDG) in 1609 CC cases and 1974 controls for association with CC risk and for interaction with dietary factors. No polymorphism was statistically significantly associated with overall risk of CC. However, statistically significant interactions modifying CC risk were observed for DNMT1 I311V with dietary folate, methionine, vitamin B2 , and vitamin B12 intake and for MTRR I22M with dietary folate, a predefined one-carbon dietary pattern, and vitamin B6 intake. We observed statistically significant gene-diet interactions with five additional polymorphisms. Our results provide evidence that FOCM-related dietary intakes modify the association between CC risk and FOCM allelic variants. These findings add to observations showing that folate-related gene-nutrient interactions play an important role in modifying the risk of CC. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Comparison of radioassay and microbiological assay for serum folate, with clinical assessment of discrepant results

    International Nuclear Information System (INIS)

    Baril, L.; Carmel, R.

    1978-01-01

    Folate assays by use of radiolabeled folate provide obvious practical advantages over the standard microbiological assay, but remain incompletely tested. We therefore compared results for 415 sera with a kit involving 3 H-labeled folate and the Lactobacillus casei microbiological method. We examined the patients' data when there were discrepancies between the two methods. Although the correlation overall was satisfactory, results were discrepant in 25% of cases. In 74% of the latter, the radioassay result appeared to be the correct one, primarily because L. casei results were suppressed by antibiotics being taken by the patient. The radioassay occasionally gave falsely high values for patients with liver disease and falsely low ones for patients who had received isotopes for scanning purposes. Several assay kits that make use of 125 I- or 75 Se-labeled folate were also tested. Although these results correlated with the results of 3 H-labeled folate assay, various problems appeared, including the possible need for serum-supernate control tubes in one kit. Answers to these and other questions and careful clinical correlation of results are needed for any folate radioassays before their adoption for routine clinical use

  15. Is red blood cell rheology preserved during routine blood bank storage?

    NARCIS (Netherlands)

    Henkelman, Sandra; Dijkstra-Tiekstra, Margriet J.; de Wildt-Eggen, Janny; Graaff, Reindert; Rakhorst, Gerhard; van Oeveren, Willem

    BACKGROUND: Red blood cell (RBC) units stored for more than 2 weeks at 4 degrees C are currently considered of impaired quality. This opinion has primarily been based on altered RBC rheologic properties (i.e., enhanced aggregability, reduced deformability, and elevated endothelial cell interaction),

  16. Grateloupia tenuis Wang et Luan sp. nov. (Halymeniaceae, Rhodophyta): a new species from South China Sea based on morphological observation and rbcL gene sequences analysis.

    Science.gov (United States)

    Yu, Ling; Wang, Hongwei; Luan, Rixiao

    2013-01-01

    Grateloupia tenuis Wang et Luan sp. nov. is a new species described from Lingshui, Hainan Province, South China Sea. Based on the external form and internal structure, combined with rbcL gene sequence analysis, Grateloupia tenuis is distinct from other Grateloupia species as follows: (1) thalli is slippery and cartilaginous in texture; possess fewer branches, relatively slight main axes, and two or three dichotomous branches; (2) cortex is 5-6 layers; medulla is solid when young, but hollow in old branches; reproductive structures are dispersed in main axes of thalli and lower portions of branchlets; exhibits Grateloupia-type auxiliary cell ampullae; (3) the four studied G. tenuis sequences were positioned in a large Grateloupia clade of Halymeniaceae, which included sister group generitype G. filicina with 68 bp differences; G. tenuis was determined to be a sister taxon to the G. catenata, G. ramosissima, G. orientalis, and G. filiformis subclade. The pairwise distances between G. tenuis and these species were 39 to 50 bp. The sequences of G. tenuis differed by 81-108 bp from the sequences of other samples in Grateloupia; there are 114-133 bp changes between G. tenuis and other genera of Halymeniaceae. In final analysis, we considered Grateloupia tenuis Wang et Luan sp. nov. to be a new species of genus Grateloupia.

  17. Grateloupia tenuis Wang et Luan sp. nov. (Halymeniaceae, Rhodophyta): A New Species from South China Sea Based on Morphological Observation and rbcL Gene Sequences Analysis

    Science.gov (United States)

    Wang, Hongwei; Luan, Rixiao

    2013-01-01

    Grateloupia tenuis Wang et Luan sp. nov. is a new species described from Lingshui, Hainan Province, South China Sea. Based on the external form and internal structure, combined with rbcL gene sequence analysis, Grateloupia tenuis is distinct from other Grateloupia species as follows: (1) thalli is slippery and cartilaginous in texture; possess fewer branches, relatively slight main axes, and two or three dichotomous branches; (2) cortex is 5-6 layers; medulla is solid when young, but hollow in old branches; reproductive structures are dispersed in main axes of thalli and lower portions of branchlets; exhibits Grateloupia-type auxiliary cell ampullae; (3) the four studied G. tenuis sequences were positioned in a large Grateloupia clade of Halymeniaceae, which included sister group generitype G. filicina with 68 bp differences; G. tenuis was determined to be a sister taxon to the G. catenata, G. ramosissima, G. orientalis, and G. filiformis subclade. The pairwise distances between G. tenuis and these species were 39 to 50 bp. The sequences of G. tenuis differed by 81–108 bp from the sequences of other samples in Grateloupia; there are 114–133 bp changes between G. tenuis and other genera of Halymeniaceae. In final analysis, we considered Grateloupia tenuis Wang et Luan sp. nov. to be a new species of genus Grateloupia. PMID:24455703

  18. Grateloupia tenuis Wang et Luan sp. nov. (Halymeniaceae, Rhodophyta: A New Species from South China Sea Based on Morphological Observation and rbcL Gene Sequences Analysis

    Directory of Open Access Journals (Sweden)

    Ling Yu

    2013-01-01

    Full Text Available Grateloupia tenuis Wang et Luan sp. nov. is a new species described from Lingshui, Hainan Province, South China Sea. Based on the external form and internal structure, combined with rbcL gene sequence analysis, Grateloupia tenuis is distinct from other Grateloupia species as follows: (1 thalli is slippery and cartilaginous in texture; possess fewer branches, relatively slight main axes, and two or three dichotomous branches; (2 cortex is 5-6 layers; medulla is solid when young, but hollow in old branches; reproductive structures are dispersed in main axes of thalli and lower portions of branchlets; exhibits Grateloupia-type auxiliary cell ampullae; (3 the four studied G. tenuis sequences were positioned in a large Grateloupia clade of Halymeniaceae, which included sister group generitype G. filicina with 68 bp differences; G. tenuis was determined to be a sister taxon to the G. catenata, G. ramosissima, G. orientalis, and G. filiformis subclade. The pairwise distances between G. tenuis and these species were 39 to 50 bp. The sequences of G. tenuis differed by 81–108 bp from the sequences of other samples in Grateloupia; there are 114–133 bp changes between G. tenuis and other genera of Halymeniaceae. In final analysis, we considered Grateloupia tenuis Wang et Luan sp. nov. to be a new species of genus Grateloupia.

  19. Design, Synthesis, and Characterization of Folate-Targeted Platinum-Loaded Theranostic Nanoemulsions for Therapy and Imaging of Ovarian Cancer.

    Science.gov (United States)

    Patel, Niravkumar R; Piroyan, Aleksandr; Nack, Abbegial H; Galati, Corin A; McHugh, Mackenzi; Orosz, Samantha; Keeler, Amanda W; O'Neal, Sara; Zamboni, William C; Davis, Barbara; Coleman, Timothy P

    2016-06-06

    Platinum (Pt) based chemotherapy is widely used to treat many types of cancer. Pt therapy faces challenges such as dose limiting toxicities, cumulative side effects, and multidrug resistance. Nanoemulsions (NEs) have tremendous potential in overcoming these challenges as they can be designed to improve circulation time, limit non-disease tissue uptake, and enhance tumor uptake by surface modification. We designed novel synthesis of three difattyacid platins, dimyrisplatin, dipalmiplatin, and distearyplatin, suitable for encapsulation in the oil core of an NE. The dimyrisplatin, dipalmiplatin, and distearyplatin were synthesized, characterized, and loaded into the oil core of our NEs, NMI-350, NMI-351, and NMI-352 respectively. Sequestration of the difattyacid platins was accomplished through high energy microfluidization. To target the NE, FA-PEG3400-DSPE was incorporated into the surface during microfluidization. The FA-NEs selectively bind the folate receptor α (FR-α) and utilize receptor mediated endocytosis to deliver Pt past cell surface resistance mechanisms. FR-α is overexpressed in a number of oncological conditions including ovarian cancer. The difattyacid platins, lipidated Gd-DTPA, and lipidated folate were characterized by nuclear magnetic resonance (NMR), mass spectrometry (MS), and elemental analysis. NEs were synthesized using high shear microfluidization process and characterized for size, zeta-potential, and loading efficiency. In vitro cytotoxicity was determined using KB-WT (Pt-sensitive) and KBCR-1000 (Pt-resistant) cancer cells and measured by MTT assay. Pharmacokinetic profiles were studied in CD-1 mice. NEs loaded with difattyacid platins are highly stable and had size distribution in the range of ∼120 to 150 nm with low PDI. Cytotoxicity data indicates the longer the fatty acid chains, the less potent the NEs. The inclusion of C6-ceramide, an apoptosis enhancer, and surface functionalization with folate molecules significantly increased

  20. Effect of 2 pieces of nutritional advice on folate status in Swedish women: a randomized controlled trial.

    Science.gov (United States)

    Ohrvik, Veronica E; Olsson, Johan C; Sundberg, Birgitta E; Witthöft, Cornelia M

    2009-04-01

    Ten years after the introduction of mandatory folic acid fortification in the United States, Canada, and Costa Rica, the issue is still under debate in several countries, and Sweden recently decided against mandatory fortification. The objective was to determine the folate status of women after an intervention involving 2 Swedish dietary recommendations: a food recommendation (bread) and a complete meal recommendation (breakfast). Fifty-one free-living women with normal folate status participated in a 12-wk controlled intervention trial. Subjects were randomly assigned to one of the following interventions: apple juice (control group; n = 17), a breakfast providing 125 microg folate (breakfast group; n = 17), or 5 slices of whole-meal bread to be eaten over the course of the day, which provided 70 microg folate (bread group; n = 17). Folate status was assessed on the basis of concentrations of erythrocyte folate, serum folate, and plasma total homocysteine (tHcy) at baseline and at weeks 8 and 12 of the trial. In the breakfast group, initial median concentrations of erythrocyte folate (805 nmol/L) increased by 172 nmol/L (95% CI: 24, 293; P = 0.02) relative to the control. The relative increase in initial serum folate (2 nmol/L, 95% CI: 0, 5; P = 0.06) was nonsignificant. The initial tHcy concentration (8.7 micromol/L) decreased by 2.3 micromol/L (95% CI: -1, -3.4; P < 0.01). In the bread group, the initial tHcy concentration (9.1 micromol/L) decreased nonsignificantly by 1.4 micromol/L (95% CI: 0, -2.8; P = 0.08) relative to the control group, whereas other outcomes were stable. The folate status of the subjects improved after regular consumption of the breakfast meal. The additional folate intake from the bread maintained the folate status but was not sufficient to improve it.

  1. Selection of GP. Mur antigen-negative RBC for blood recipients with anti-'Mia' records decreases transfusion reaction rates in Taiwan.

    Science.gov (United States)

    Yang, C-A; Lin, J-A; Chang, C-W; Wu, K-H; Yeh, S-P; Ho, C-M; Chang, J-G

    2016-10-01

    To evaluate the clinical significance of GP. Mur antigen-negative blood selection for transfusion in patients with anti-'Mi a ' records. The GP. Mur RBC phenotype is prevalent (7·3%) in Taiwan. Antibodies against GP. Mur (anti-'Mi a ') are identified in 1·24% of our population, and anti-'Mi a ' screening using GP. Mur RBC has been routine for Taiwan's blood banks. However, due to the lack of commercial antibodies, only cross-matching was used to prevent transfusion of GP. Mur-positive blood to patients with anti-'Mi a ' in most hospitals. There is still a risk of GP. Mur-positive RBC exposure and subsequent anti-'Mi a '-related transfusion reactions. Since February 2014, GP. Mur antigen-negative RBCs identified by reaction with anti-'Mi a '-positive serum were selected for blood recipients with anti-'Mi a ' records. The transfusion reactions between January 2013 and January 2014 were compared with those that occurred between February 2014 and July 2015. The transfusion reaction rate was significantly higher in anti-'Mi a '-positive blood recipients compared to total subjects receiving an RBC transfusion before GP. Mur-negative donor RBC selection. After antigen-negative RBC selection, the transfusion reaction frequency in subjects with anti-'Mi a ' became similar to total blood recipients. IgG form anti-'Mi a ' antibodies were present in all cases of probable anti-'Mi a '-related transfusion reactions. The time required for anti-'Mi a ' boosting after transfusion was around 4-21 days. Selection of GP. Mur-negative RBC for transfusion to patients with anti-'Mi a ' records could decrease the rate of transfusion reaction and antibody boosting. This procedure should be incorporated into blood bank routines in areas where anti-'Mi a ' is prevalent. © 2016 British Blood Transfusion Society.

  2. Dietary folate levels alter the kinetics and molecular mechanism of prostate cancer recurrence in the CWR22 model.

    Science.gov (United States)

    Affronti, Hayley C; Long, Mark D; Rosario, Spencer R; Gillard, Bryan M; Karasik, Ellen; Boerlin, Christoph S; Pellerite, Anthony J; Foster, Barbara A; Attwood, Kristopher; Pili, Roberto; Wilton, John H; Campbell, Moray J; Smiraglia, Dominic J

    2017-11-28

    Folate impacts the genome and epigenome by feeding into one-carbon metabolism to produce critical metabolites, deoxythymidine monophosphate and s-adenosylmethionine. The impact of folate exposure and intervention timing on cancer progression remains controversial. Due to polyamine metabolism's extraordinary biosynthetic flux in prostate cancer (CaP) we demonstrated androgen stimulated CaP is susceptible to dietary folate deficiency. We hypothesized dietary folate levels may also affect castration recurrent CaP. We used the CWR22 human xenograft model which recurs following androgen withdrawal. Engrafted mice were fed a folate depleted or supplemented diet beginning at androgen withdrawal, or prior to xenograft implantation. Both folate depletion and supplementation at the time of withdrawal significantly decreased recurrence incidence. Folate supplementation prior to xenograft implantation increased time to recurrence, suggesting a protective role. By contrast, folate depleted recurrent tumors exhibited transcriptional adaptive responses that maintained high polyamine levels at the expense of increased DNA damage and DNA methylation alterations. Mining of publically available data demonstrated folate related pathways are exceptionally dysregulated in human CaP, which correlated with decreased time to biochemical recurrence. These findings highlight the potential for novel therapeutic interventions that target these metabolic pathways in CaP and provide a rationale to apply such strategies alongside androgen withdrawal.

  3. 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

    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...... 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...

  4. Evidence that the low-affinity folate-binding protein in erythrocyte hemolysate is identical to hemoglobin

    International Nuclear Information System (INIS)

    Hansen, S.I.; Holm, J.; Lyngbye, J.

    1981-01-01

    Gel filtration studies on erythrocyte hemolysate demonstrated the presence of a folate binding protein, apparently of the low-affinity type, that co-elutes with hemoglobin. Further, the folate binder eluted with a low salt concentration after DEAE-Sepharose CL-6B anion-exchange chromatography of erythrocyte hemolysate at pH 6.3. The chromatographic behavior of hemoglobin labeled with [3H]folate was so similar to that of the present binder as to suggest that the folate binder in erythrocytes is in fact hemoglobin

  5. Folated Synperonic-Cholesteryl Hemisuccinate Polymeric Micelles for the Targeted Delivery of Docetaxel in Melanoma

    Directory of Open Access Journals (Sweden)

    Jaleh Varshosaz

    2015-01-01

    Full Text Available The objective of this study was the synthesis of folic acid- (FA- targeted polymeric micelles of Synperonic PE/F 127-cholesteryl hemisuccinate (PF127-Chol for specific delivery of docetaxel (DTX. Targeted or nontargeted micelles loaded with DTX were prepared via dialysis method. The effects of processing variables on the physicochemical properties of targeted micelles were evaluated using a full factorial design. After the optimization of the polymer/drug ratio, the organic solvent type used for the preparation of the micelles, and the temperature of dialyzing medium, the in vitro cytotoxicity and cellular uptake of the optimized micelles were studied on B16F10 melanoma cells by flow cytometry and fluorescent microscopy. The anticancer efficacy of DTX-loaded FA-PF127-Chol was evaluated in mice bearing melanoma tumor. Optimized targeted micelles had the particle size of 171.3 nm, zeta potential of −7.8 mV, PDI of 0.325, and a high encapsulation efficiency that released the drug within 144 h. The MTT assay indicated that targeted micelles carrying DTX were significantly more cytotoxic, had higher cellular uptake, and reduced the tumor volume significantly more than the nontargeted micelles and the free drug. FA-PF127-Chol could be, therefore, a promising biomaterial for tumors overexpressing folate receptors.

  6. Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression.

    Science.gov (United States)

    Wang, Eunice S; O'Connor, Owen; She, Yuhong; Zelenetz, Andrew D; Sirotnak, F M; Moore, Malcolm A S

    2003-06-01

    PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM, IC50MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.

  7. Reflexiones sobre la estrategia de rehabilitación basada en la comunidad (RBC: la experiencia de un programa de RBC en Bolivia Reflections on community-based rehabilitation strategy (CBR: the experience of a CBR program in Bolivia

    Directory of Open Access Journals (Sweden)

    Urko Díaz-Aristizabal

    2012-01-01

    Full Text Available La Rehabilitación Basada en la Comunidad (RBC es una estrategia de desarrollo comunitario avalada por la Organización Mundial de la Salud (OMS, la Organización Internacional del Trabajo (OIT y la Organización de las Naciones Unidas para la Educación, la Ciencia y la Cultura (UNESCO, que persigue la rehabilitación, la igualdad de oportunidades y la integración social de las Personas con Discapacidad (PD en sus entornos. Con este objetivo promueve la colaboración entre las PD, sus familias y los diferentes actores de la comunidad involucrados, así como el liderazgo comunitario y la participación de las PD mediante el impulso de la colaboración multisectorial. Este artículo expone los antecedentes históricos y las características fundamentales de la estrategia de RBC a partir de un programa llevado a cabo por una fundación del departamento de Cochabamba (Bolivia, para después incidir en algunos aspectos referentes al contexto sociocultural, que especialmente en situaciones de interculturalidad, pueden determinar que un programa de RBC tenga éxito o esté abocado al fracaso.Community-Based Rehabilitation (CBR is a strategy for community development endorsed by the World Health Organization (WHO, the International Labor Office (ILO and the United Nations Educational, Scientific and Cultural Organization (UNESCO. It is designed to promote rehabilitation, equal opportunity and social inclusion of Disabled Persons (DP in their home communities by fostering cooperation among disabled individuals, their families, and other concerned social actors, it encourages community leadership and full social participation by DP through multi-sector cooperation. This article explores the historical antecedents and basic features of CBR strategy through an analysis of a directed culture change initiative developed by a foundation in the Cochabamba administrative region of Bolivia. Especially in intercultural environments, certain aspects of the socio

  8. Red blood cell storage duration and long-term mortality in patients undergoing cardiac intervention

    DEFF Research Database (Denmark)

    Dencker, D; Pedersen, F; Engstrøm, T

    2017-01-01

    OBJECTIVES: To study the effect of red blood cell (RBC) storage duration on long-term mortality in patients undergoing cardiac intervention. BACKGROUND: RBCs undergo numerous structural and functional changes during storage. Observational studies have assessed the association between RBC storage...... duration and patient outcomes with conflicting results. METHODS: Between January 2006 and December 2014, 82 408 patients underwent coronary angiography. Of these, 1856 patients received one to four RBC units within 30 days after this procedure. Patients were allocated according to length of RBC storage...

  9. Folate intake and risk of colorectal cancer and adenoma: modification by time1234

    Science.gov (United States)

    Lee, Jung Eun; Willett, Walter C; Fuchs, Charles S; Smith-Warner, Stephanie A; Wu, Kana; Ma, Jing; Giovannucci, Edward

    2011-01-01

    Background: Experimental and observational studies have suggested that folate may play dual roles in colorectal cancer risk depending on the timing and dose. Objective: We examined the latency between folate intake and the incidence of colorectal cancer. Design: We prospectively examined associations between folate intake assessed every 2 to 4 y by using validated food-frequency questionnaires and risk of colorectal cancer and adenoma in the Nurses' Health Study and Health Professionals Follow-Up Study, which included 2299 incident colorectal cancers and 5655 colorectal adenomas from 1980 to 2004. Results: There was an association between total folate intake 12–16 y before diagnosis and lower risk of colorectal cancer (relative risk: 0.69; 95% CI: 0.51, 0.94; ≥800 compared with intake in the recent past and colorectal cancer risk. Long- and short-term intakes of total folate were associated with a lower risk of colorectal adenoma, with a strong association with intake 4–8 y before diagnosis (odds ratio: 0.68; 95% CI: 0.60, 0.78; ≥800 compared with 15 y, but not a shorter duration of use, was associated with lower risk of colorectal cancer; and a shorter duration of use was related to lower risk of adenoma. We did not observe an adverse effect of total folate or synthetic folic acid on risk of colorectal cancer or adenoma even during the folic acid fortification era. Conclusion: Folate intake is inversely associated with risk of colorectal cancer only during early preadenoma stages. PMID:21270374

  10. 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

    2014-07-01

    To evaluate prospectively the relationship between prepregnancy folate intake and risk of spontaneous abortion and stillbirth. Women in the Nurses' Health Study II who self-reported a pregnancy between 1992 and 2009 were included in this analysis. Dietary folate and supplement use was assessed every 4 years, starting in 1991, by a food frequency questionnaire. Pregnancies were self-reported with case pregnancies lost spontaneously (spontaneous abortion less than 20 weeks of gestation and stillbirth 20+ weeks of gestation) and comparison pregnancies ending in ectopic pregnancy, induced abortion, or live birth. Among the 11,072 women, 15,950 pregnancies were reported of which 2,756 (17.3%) ended in spontaneous abortion and 120 (0.8%) ended in stillbirth. Compared with women in the lowest quintile of prepregnancy folate intake (less than 285 micrograms/d), those in the highest quintile (greater than 851 micrograms/d) had a relative risk of spontaneous abortion of 0.91 (95% confidence interval [CI] 0.82-1.02) after multivariable adjustment (P trend=.04). This association was primarily attributable to intake of folate from supplements. Compared with women without supplemental folate intake (0 micrograms/d), those in the highest category (greater than 730 micrograms/d) had a relative risk of spontaneous abortion of 0.80 (95% CI 0.71-0.90) after multivariable adjustment (P trend spontaneous abortion was consistent across gestational period of loss. A similar inverse trend was observed with the risk of stillbirth, which fell short of conventional significance (P trend=.06). Higher intake of folate from supplements was associated with reduced risk of spontaneous abortion. Women at risk of pregnancy should use supplemental folate for neural tube defect prevention and because it may decrease the risk of spontaneous abortion. : II.

  11. Associations between serum folate and vitamin D levels and incident mouse sensitization in adults.

    Science.gov (United States)

    Keet, Corinne A; Shreffler, Wayne G; Peng, Roger D; Matsui, William; Matsui, Elizabeth C

    2014-02-01

    Although both folic acid intake and vitamin D levels are hypothesized to be contributors to the increased incidence of allergic diseases, prospective studies of these relationships have not been done in adults. We sought to determine whether serum folate or vitamin D levels are associated with incident mouse sensitization among new workers at a mouse facility. Subjects started employment at the Jackson Laboratory between June 2004 and July 2007. Skin testing to mouse and other allergens and collection of questionnaire data were performed at baseline and every 6 months. Serum folate and vitamin D levels were assessed on baseline samples stored at -80°C. Folate was categorized into tertiles (2.5-10.5, 10.5-16.2, and 16.2-78.4 ng/mL, respectively). Vitamin D was categorized as less than 20 ng/mL, 20 to 29 ng/mL, or 30 ng/mL or greater. This was a nested case-control study in which 5 control subjects were matched to each case on baseline atopy and type of employment. Multivariate analyses controlled for age, sex, education, smoking, season, personal mouse exposure, and serum folate and vitamin D levels. Thirty-five cases and 47 control subjects were included. The odds of incident mouse sensitization were higher in the intermediate and highest tertiles of serum folate compared with the lowest tertile of serum folate (odds ratio of 10.5 [95% CI, 1.8-61.5; P = .009] and odds ratio of 5.6 [95% CI, 1.8-31.3; P = .049], respectively, in the multivariate model). Serum vitamin D levels were not associated with incident mouse sensitization. These findings support a role for higher serum folate levels in increased risk of incident allergic disease, even during adulthood. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  12. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cellsTumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease

    DEFF Research Database (Denmark)

    Baslund, B.; Gregers, J.; Nielsen, Claus Henrik

    2008-01-01

    to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression. RESULTS: Antigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n...

  13. A reassessment of the in vitro RBC haemolysis assay with defibrinated sheep blood for the determination of the ocular irritation potential of cosmetic products: comparison with the in vivo Draize rabbit test.

    Science.gov (United States)

    Alves, Eloísa Nunes; Presgrave, Rosaura de Farias; Presgrave, Octávio Augusto França; Sabagh, Fernanda Peres; de Freitas, João Carlos Borges Rolim; Corrado, Alexandre P

    2008-07-01

    We examined the correlation between results obtained from the in vivo Draize test for ocular irritation and in vitro results obtained from the sheep red blood cell (RBC) haemolytic assay, which assesses haemolysis and protein denaturation in erythrocytes, induced by cosmetic products. We sought to validate the haemolytic assay as a preliminary test for identifying highly-irritative products, and also to evaluate the in vitro test as alternative assay for replacement of the in vivo test. In vitro and in vivo analyses were carried out on 19 cosmetic products, in order to correlate the lesions in the ocular structures with three in vitro parameters: (i) the extent of haemolysis (H50); (ii) the protein denaturation index (DI); and (iii) the H50/DI ratio, which reflects the irritation potential (IP). There was significant correlation between maximum average scores (MAS) and the parameters determined in vitro (r = 0.752-0.764). These results indicate that the RBC assay is a useful and rapid test for use as a screening method to assess the IP of cosmetic products, and for predicting the IP value with a high level of concordance (94.7%). The assay showed high sensitivity and specificity rates of 91.6% and 100%, respectively.

  14. Targeting folate metabolism for therapeutic option: A bioinformatics approach.

    Science.gov (United States)

    Hande, Sneha; Goswami, Kalyan; Sharma, Richa; Bhoj, Priyanka; Jena, Lingaraj; Reddy, Maryada Venkata Rami

    2015-11-01

    Lymphatic filariasis, commonly called elephantiasis, poses a burden of estimated level of 5.09 million disability adjusted life year. Limitations of its sole drug, diethylcarbamazine (DEC) drive exploration of effective filarial target. A few plant extracts having polyphenolic ingredients and some synthetic compounds possess potential dihydrofolate reductase (DHFR) inhibitory effect. Here, we postulated a plausible link between folates and polyphenolics based on their common precursor in shikimate metabolism. Considering its implication in structural resemblance based antagonism, we have attempted to validate parasitic DHFR protein as a target. The bioinformatics approach, in the absence of crystal structure of the proposed target, used to authenticate and for virtual docking with suitable tested compounds, showed remarkably lower thermodynamic parameters as opposed to the positive control. A comparative docking analysis between human and Brugia malayi DHFR also showed effective binding parameters with lower inhibition constants of these ligands with parasitic target, but not with human counterpart highlighting safety and efficacy. This study suggests that DHFR could be a valid drug target for lymphatic filariasis, and further reveal that bioinformatics may be an effective tool in reverse pharmacological approach for drug design.

  15. Cylindrotheca closterium is a species complex as was evidenced by the variations of rbcL gene and SSU rDNA

    Science.gov (United States)

    Li, Haitao; Yang, Guanpin; Sun, Ying; Wu, Suihan; Zhang, Xiufang

    2007-04-01

    The genus Cylindrotheca consists of a small group of marine diatoms with a few species described. Eleven isolates of diatoms identified as Cylindrotheca closterium morphologically were obtained from Jiaozhou Bay with their nuclear-encoded small-subunit ribosomal RNA (SSU rDNA) and chloroplast-encoded rbcL gene sequences determined in this study. Interestingly, very high sequence divergences of SSU rDNA and rbcL gene were found among these isolates, and numerous nucleotide variation of rbcL gene caused relatively few variation of deduced amino acid sequence. Phylogenetic analyses based on SSU rDNA and rbcL gene, respectively, grouped the isolates into 6 clades. Phylogenetic tree of SSU rDNA placed all the Cylindrotheca isolates together, separating them into two lineages clearly. Lineage I was composed of the eleven C. closterium isolates obtained in this study together with another C. closterium isolate, but some clades were not well supported. Lineage II contained two C. closterium isolates and one C. fusiformis isolate. Phylogenetic analysis of rbcL gene also separated the Cylindrotheca isolates into two well-defined lineages. The eleven C. closterium isolates formed a lineage and all clades were supported strongly. Statistical comparisons of SSU rDNA indicated that the average distance within lineage I was significantly higher than that of other microalgae species ( P < 0.01). These results suggested the existence of cryptic species within C. closterium.

  16. Tissue distribution and tumor uptake of folate receptor–targeted epothilone folate conjugate, BMS-753493, in CD2F1 mice after systemic administration

    Directory of Open Access Journals (Sweden)

    Hong Shen

    2016-09-01

    Full Text Available To assess targeting of an epothilone folate conjugate (BMS-753493 to the folate receptor (FR-overexpressed tumor in mice bearing both FR+ and FR– tumors, a series of experiments were conducted by quantitative whole-body autoradiography (QWBA and LC–MS/MS following i.v. administration of BMS-753493 or its active moiety, BMS-748285 in mice bearing FR+ (98M109 and FR– (M109 tumors. QWBA showed [3H]BMS-753493–derived radioactivity was extensively distributed to various tissues. The FR over-expressing 98M109 tumors showed consistently higher level of radioactivity than FR-negative tumors (i.e., M109 tumors up to 48 h post dose of [3H]BMS-753493, despite the magnitude of difference between the tumors is relatively small (generally 3~5-fold. The radioactivity level in 98M109 tumors was 2~12-fold of normal tissues except intestine/content at 48 h post dose. No selective radioactivity uptake into 98M109 tumors over M109 or normal tissues was observed after i.v. administration of the active epothilone, [3H]BMS-748285. LC–MS/MS measurements demonstrated that the concentrations of BMS-748285, presumably from hydrolysis of the folate conjugate, in 98M109 tumors were greater than those in M109 tumors after i.v. administration of BMS-753493 (2–3-fold whereas no differential uptake in the tumors following BMS-748285 administration. Those data were consistent with radioactivity determinations. Those results demonstrated that the folate conjugation in BMS-753493 enabled moderately preferential distribution of the active epothilone to FR over-expressing 98M109 tumors, thereby supporting targeted delivery of cytotoxics through the folate receptor.

  17. Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drug

    Directory of Open Access Journals (Sweden)

    Feng S

    2016-09-01

    Full Text Available Shini Feng,1 Huijie Zhang,1 Ting Yan,1 Dandi Huang,1 Chunyi Zhi,2 Hideki Nakanishi,1 Xiao-Dong Gao1 1Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, People’s Republic of China; 2Department of Physics and Materials Science, City University of Hong Kong, Hong Kong SAR, People’s Republic of China Abstract: With its unique physical and chemical properties and structural similarity to carbon, boron nitride (BN has attracted considerable attention and found many applications. Biomedical applications of BN have recently started to emerge, raising great hopes in drug and gene delivery. Here, we developed a targeted anticancer drug delivery system based on folate-conjugated BN nanospheres (BNNS with receptor-mediated targeting. Folic acid (FA was successfully grafted onto BNNS via esterification reaction. In vitro cytotoxicity assay showed that BNNS-FA complexes were non-toxic to HeLa cells up to a concentration of 100 µg/mL. Then, doxorubicin hydrochloride (DOX, a commonly used anticancer drug, was loaded onto BNNS-FA complexes. BNNS-FA/DOX complexes were stable at pH 7.4 but effectively released DOX at pH 5.0, which exhibited a pH sensitive and sustained release pattern. BNNS-FA/DOX complexes could be recognized and specifically internalized by HeLa cells via FA receptor-mediated endocytosis. BNNS-FA/DOX complexes exhibited greater cytotoxicity to HeLa cells than free DOX and BNNS/DOX complexes due to the increased cellular uptake of DOX mediated by the FA receptor. Therefore, BNNS-FA complexes had strong potential for targeted cancer therapy. Keywords: boron nitride nanospheres, folic acid, doxorubicin, targeted delivery, cancer therapy

  18. 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 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.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 beyond 32 wk. The association between

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Mursleen, M Tahir; Riaz, Samreen

    2017-11-01

    Diabetes mellitus is an acutely debilitating ailment affecting a large population of the world. At present, over 415 million people around the world including 7 million people in Pakistan suffering from diabetes. Homocysteine is an amino acid that is inversely related to vitamin B12 and folate, and raised level of homocysteine is implicated in many adverse health conditions. In this study, the potential role of homocysteine in diabetes and the epidemiology of hyperhomocysteinaemia, and vitamin B12 and folate deficiency is reviewed along with the impact of folate and vitamin B12 in regulation of homocysteine level. Deficiency of vitamin B12 and folate is rare in developed countries and the countries which adopted fortification programs, but deficiency of these vitamins is found to be highly prevalent in developing world, particularly in Pakistan. Several studies have found an association of high homocysteine levels and diabetes, but a few studies found contrary results. Hence, further epidemiological studies are recommended for homocysteine involvement in diabetes and vitamin B12 and folate deficiency, so that an urgent action can be taken to control the hyperhomocysteinaemia and consequently the ever increasing burden of disease and specifically diabetes. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  2. IMPACT OF FOOD AND FOLATE SUPPLEMENTATION DURING Salmonella TYPHI INFECTION IN Caenorhabditis elegans

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    Bhagavathi Sundaram Sivamaruthi

    2012-06-01

    Full Text Available Caenorhabditis elegans is an instructive and suitable model for studying pathogenesis of almost all human pathogens. Salmonella Typhi is gram-negative facultative intracellular anaerobe that causes several pathetic infections. Necessary enriched nutrient ingestion during pathological conditions may reduce the harshness of the infection. We investigated the impact of folate and food supplementation during S. Typhi infection on the model system, C. elegans. Our data indicated that folate supplementation (10 µg increases the lifespan of S. Typhi infected C. elegans up to 20%. In combination with laboratory food source E. coli OP50, folate increases the infected the worm’s lifespan to 40%. The wild type C. elegans infected by S. Typhi died with the LT50 of 60 ± 12 h. The LT50 of S. Typhi infected folt-1 mutant strain VC959 was 96 ± 6 h. However, the folate supplemented mutant worms exhibited an extended life with LT50 of 120 ± 6 h. The short time exposure and pharyngeal pumping studies confirmed that folt-1 mutant worm exhibited increased survival rate during pathogenic course at significant level when compared to wild-type. Our data revealed that folt-1 plays a significant role in host defense system against S. Typhi infection and the folate supplementation in combination with food increases the host survival during S. Typhi infection.

  3. Optimization of the trienzyme extraction for the microbiological assay of folate in vegetables.

    Science.gov (United States)

    Chen, Liwen; Eitenmiller, Ronald R

    2007-05-16

    Response surface methodology was applied to optimize the trienzyme digestion for the extraction of folate from vegetables. Trienzyme extraction is a combined enzymatic digestion by protease, alpha-amylase, and conjugase (gamma-glutamyl hydrolase) to liberate the carbohydrate and protein-bound folates from food matrices for total folate analysis. It is the extraction method used in AOAC Official Method 2004.05 for assay of total folate in cereal grain products. Certified reference material (CRM) 485 mixed vegetables was used to represent the matrix of vegetables. Regression and ridge analysis were performed by statistical analysis software. The predicted second-order polynomial model was adequate (R2 = 0.947), without significant lack of fit (p > 0.1). Both protease and alpha-amylase have significant effects on the extraction. Ridge analysis gave an optimum trienzyme digestion time: Pronase, 1.5 h; alpha-amylase, 1.5 h; and conjugase, 3 h. The experimental value for CRM 485 under this optimum digestion was close to the predicted value from the model, confirming the validity and adequacy of the model. The optimized trienzyme digestion condition was applied to five vegetables and yielded higher folate levels than the trienzyme digestion parameters employed in AOAC Official Method 2004.05.

  4. Functional analysis of a Lemna gibba rbcS promoter regulated by ...

    Indian Academy of Sciences (India)

    2013-04-12

    Apr 12, 2013 ... controlled expression of a foreign gene using the chalcone syn- thase promoter in tobacco BY-2 cells. J. Ferment. Bioeng. 86,. 317–323. Laby R. J., Kincaid M. S., Kim D. and Gibson S. I. 2000. The Arabidopsis sugar-insensitive mutants sis4 and sis5 are defective in abscisic acid synthesis and response.

  5. A molecular phylogeny of the heterokont algae based on analyses of choroplast-encoded rbcL sequence data

    DEFF Research Database (Denmark)

    Daugbjerg, Niels; Andersen, Robert A.

    1997-01-01

    and second codon positions only and for third positions only. In light of this observation, third codon positions were excluded from phylogenetic analyses. Both weighted-parsimony and maximum-likelihood analyses supported with high bootstrap values the monophyly of the nine currently recognized classes....... The branch lengths in the maximum-likelihood reconstruction suggest that these two classes have evolved at an accelerated rate. Six major carotenoids were analyzed cladistically to study the usefulness of carotenoid pigmentation as a class-level character in the heterokont algae. In addition, each carotenoid...... was mapped onto both the rbcL tree and a consensus tree derived from nuclear-encoded small-subunit ribosomal DNA (SSU rDNA) sequences. Carotenoid pigmentation does not provide unambiguous phylogenetic information, whether analyzed cladistically by itself or when mapped onto phylogenetic trees based upon...

  6. The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number

    DEFF Research Database (Denmark)

    Gregers, Jannie; Christensen, Ib Jarle; Dalhoff, Kim

    2010-01-01

    The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G>A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact...... variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants...

  7. Exercise, training and red blood cell turnover.

    Science.gov (United States)

    Smith, J A

    1995-01-01

    Endurance training can lead to what has been termed 'sports anaemia'. Although under normal conditions, red blood cells (RBCs) have a lifespan of about 120 days, the rate of aging may increase during intensive training. However, RBC deficiency is rare in athletes, and sports anaemia is probably due to an expanded plasma volume. Cycling, running and swimming have been shown to cause RBC damage. While most investigators measure indices of haemolysis (for example, plasma haemoglobin or haptoglobin), RBC removal is normally an extravascular process that does not involve haemolysis. Attention is now turning to cellular indices (such as antioxidant depletion, or protein or lipid damage) that may be more indicative of exercise-induced damage. RBCs are vulnerable to oxidative damage because of their continuous exposure to oxygen and their high concentrations of polyunsaturated fatty acids and haem iron. As oxidative stress may be proportional to oxygen uptake, it is not surprising that antioxidants in muscle, liver and RBCs can be depleted during exercise. Oxidative damage to RBCs can also perturb ionic homeostasis and facilitate cellular dehydration. These changes impair RBC deformability which can, in turn, impede the passage of RBCs through the microcirculation. This may lead to hypoxia in working muscle during single episodes of exercise and possibly an increased rate of RBC destruction with long term exercise. Providing RBC destruction does not exceed the rate of RBC production, no detrimental effect to athletic performance should occur. An increased rate of RBC turnover may be advantageous because young cells are more efficient in transporting oxygen. Because most techniques examine the RBC population as a whole, more sophisticated methods which analyse cells individually are required to determine the mechanisms involved in exercise-induced damage of RBCs.

  8. A multivariate shape quantification approach for sickle red blood cell in patient-specific microscopy image data

    Science.gov (United States)

    Xu, Mengjia; Yang, Jinzhu; Zhao, Hong

    2017-07-01

    The morphological change of red blood cells(RBCs) plays an important role in revealing the biomechanical and biorheological characteristics of RBCs. Aiming to extract the shape indices for the sickle RBCs, an automated ex-vivo RBC shape quantification method is proposed. First, single RBC regions (ROIs) are extracted from raw microscopy image via an automatic hierarchical ROI extraction method. Second, an improved random walk method is used to detect the RBC outline. Finally, three types of RBC shape factors are calculated based on the elliptical fitting RBC contour. Experiments indicate that the proposed method can accurately segment the RBCs from the microscopy images with low contrast and prevent the disturbance of artifacts. Moreover, it can provide an efficient shape quantification means for diverse RBC shapes in a batch manner.

  9. Effects of CO2 and iron availability on rbcL gene expression in Bering Sea diatoms

    Science.gov (United States)

    Endo, H.; Sugie, K.; Yoshimura, T.; Suzuki, K.

    2014-12-01

    Iron (Fe) can limit phytoplankton productivity in approximately 40% of the global ocean, including high-nutrient, low-chlorophyll (HNLC) waters. However, there is little information available on the impact of CO2-induced seawater acidification on natural phytoplankton assemblages in HNLC regions. We therefore conducted an on-deck experiment manipulating CO2 and Fe using Fe-deficient Bering Sea waters during the summer of 2009. The concentrations of CO2 in the incubation bottles were set at 380 and 600 ppm in the non-Fe-added (control) bottles and 180, 380, 600, and 1000 ppm in the Fe-added bottles. The phytoplankton assemblages were primarily composed of diatoms followed by haptophytes in all incubation bottles as estimated by pigment signatures throughout the 7 day incubation period. At the end of incubation, the relative contributions of diatoms to chlorophyll a biomass decreased significantly with increased CO2 levels in the controls, whereas minimal changes were found in the Fe-added treatments. These results indicate that, under Fe-deficient conditions, the growth of diatoms was negatively affected by the increase in CO2 availability. To confirm this, we estimated the expression and phylogeny of rbcL (which encodes the large subunit of RubisCO) mRNA in diatoms by quantitative reverse transcription PCR and clone library techniques, respectively. Interestingly, regardless of Fe availability, the expression and diversity of rbcL cDNA decreased in the high CO2 treatments (600 and 1000 ppm). The present study suggests that the projected future increase in seawater pCO2 could reduce the RubisCO activity of diatoms, resulting in a decrease in primary productivity and a shift in the food web structure of the Bering Sea.

  10. Pengaruh suplementasi besi-folat, vitamin A dan seng terhadap durasi dan frekuensi sakit ISPA pada anak sekolah dasar dengan status gizi kurang di Kabupaten Bantul

    Directory of Open Access Journals (Sweden)

    Sri Mulyati

    2007-07-01

    Conclusion: There were influence differences between iron-folate supplementation with Vitamin A and/or zinc and iron-folate supplementation to ISPA duration, but it did not give smaller influence statistically among frequency of ARI. Students with iron-folate, zinc and vitamin A supplementation had the shortest duration of ARI while students with iron-folate supplementation had the longest duration of ARI.

  11. 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

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2015-01-01

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

  14. 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

  15. Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure

    Directory of Open Access Journals (Sweden)

    Kit-Yi Leung

    2017-11-01

    Full Text Available Summary: Abnormal folate one-carbon metabolism (FOCM is implicated in neural tube defects (NTDs, severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary. : Leung at al. find that embryonic neural tube closure depends both on the supply of one-carbon units to the folate cycle from glycine cleavage and on the methionine cycle. In contrast, transfer of one-carbon units from the folate cycle to the methionine cycle by MTHFR is dispensable. Keywords: one-carbon metabolism, folic acid, neural tube defects, spina bifida, glycine cleavage system, non-ketotic hyperglycinemia, eye, Mthfr, Gldc

  16. 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...

  17. A Giant Hepatic Hemangioma Complicated by Kasabach-Merritt Syndrome: Findings of Tc-99m RBC Scintigraphy and SPECT Including a Total Body Blood Pool Imaging Study

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Myung Hee; Jeong, Hwan Jeong; Lim, Seok Tae; Kim, Dong Wook; Yim, Chang Yeol [Chonbuk National University Medical School, Jeonju (Korea, Republic of)

    2009-02-15

    Kasabach-Merritt syndrome (KMS) consists of thrombocytopenia, microangiopathic hemolytic anemia, and localized consumption coagulopathy that develops within vascular hemangioma. This syndrome may also be associated with occult hemangiomas located at various sites. Tc-99m RBC scintigraphy and SPECT have proven to be reliable for confirming or excluding hemangioma. Total body blood pool imaging study during the scintigraphy also provides a means of screening for occult lesions. The authors report the case of a 29-year-old man who presented with a giant hepatic hemangioma complicated by KMS, and underwent Tc-99m RBC scintigraphy and SPECT including a total body blood pool imaging study.

  18. Effects of red blood cell storage time on transfused patients in the ICU-protocol for a systematic review

    DEFF Research Database (Denmark)

    Rygård, S L; Jonsson, A B; Madsen, M B

    2017-01-01

    BACKGROUND: Patients in the intensive care unit (ICU) are often anaemic due to blood loss, impaired red blood cell (RBC) production and increased RBC destruction. In some studies, more than half of the patients were treated with RBC transfusion. During storage, the RBC and the storage medium...... evidence to assess the effects of shorter vs. longer storage time of transfused RBCs for ICU patients. METHODS: We will conduct a systematic review with meta-analyses and trial sequential analyses of randomised clinical trials, and also include results of severe adverse events from large observational...

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

    Science.gov (United States)

    Bukowski, Radek; Malone, Fergal D; Porter, Flint T; Nyberg, David A; Comstock, Christine H; Hankins, Gary D V; Eddleman, Keith; Gross, Susan J; Dugoff, Lorraine; Craigo, Sabrina D; Timor-Tritsch, Ilan E; Carr, Stephen R; Wolfe, Honor M; D'Alton, Mary E

    2009-05-05

    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. 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 beyond 32 wk. The association between shorter duration

  20. Vitamin B12 and folate levels in normal population of northern Pakistan

    International Nuclear Information System (INIS)

    Madood-ul-mannan; Anwar, M.; Saleem, M.; Waqar, A.; Ahmad, M.

    1990-01-01

    Diagnosis of vitamin B12 or folate deficiency can not be made unless reference ranges of these vitamins in a given population are known. These serum levels depend upon the dietary intake of these vitamins which in turn depends upon the availability of foods containing these vitamins and the methods of cooking/processing. The latter vary in different populations. Therefore serum level of these vitamins would vary in different populations. Serum levels of vitamin B12 and folate were estimated by radioimmunoassay technique in 30 normal subjects of different age groups. The levels of vitamin B12 were found to be 215.2 pg/ml and that of folate 3.9 ng/ml. These values are much lower than those described for European population. It is therefore concluded that the cut off point of the levels of these vitamins should be different than the European figures. (author)

  1. Autoantibodies to folate receptor alpha during early pregnancy and risk of oral clefts in Denmark

    DEFF Research Database (Denmark)

    Bille, Camilla; Pedersen, Dorthe Almind; Andersen, Anne-Marie Nybo

    2010-01-01

    The objective of this study was to determine whether IgG and IgM autoantibodies to folate receptor alpha (FRalpha) in pregnant women are associated with an increased risk of oral cleft-affected offspring. A case-control study nested in the prospective Danish National Birth Cohort (100......,418 pregnancies, enrolled during 1997-2003) was done. Hundred eighty-five children were born with an oral cleft. Maternal serum from their mothers (cases) was compared with maternal serum from 77