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  1. Including the Copenhagen Adduction Exercise in the FIFA 11+ Provides Missing Eccentric Hip Adduction Strength Effect in Male Soccer Players

    DEFF Research Database (Denmark)

    Harøy, Joar; Thorborg, Kristian; Serner, Andreas

    2017-01-01

    BACKGROUND: The FIFA 11+ was developed as a complete warm-up program to prevent injuries in soccer players. Although reduced hip adduction strength is associated with groin injuries, none of the exercises included in the FIFA 11+ seem to specifically target hip adduction strength. PURPOSE......: To investigate the effect on eccentric hip adduction strength of the FIFA 11+ warm-up program with or without the Copenhagen adduction exercise. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: We recruited 45 eligible players from 2 U19 elite male soccer teams. Players were randomized...... into 2 groups; 1 group carried out the standard FIFA 11+ program, while the other carried out the FIFA 11+ but replaced the Nordic hamstring exercise with the Copenhagen adduction exercise. Both groups performed the intervention 3 times weekly for 8 weeks. Players completed eccentric strength and sprint...

  2. Including the Copenhagen Adduction Exercise in the FIFA 11+ Provides Missing Eccentric Hip Adduction Strength Effect in Male Soccer Players: A Randomized Controlled Trial.

    Science.gov (United States)

    Harøy, Joar; Thorborg, Kristian; Serner, Andreas; Bjørkheim, André; Rolstad, Linn E; Hölmich, Per; Bahr, Roald; Andersen, Thor Einar

    2017-11-01

    The FIFA 11+ was developed as a complete warm-up program to prevent injuries in soccer players. Although reduced hip adduction strength is associated with groin injuries, none of the exercises included in the FIFA 11+ seem to specifically target hip adduction strength. To investigate the effect on eccentric hip adduction strength of the FIFA 11+ warm-up program with or without the Copenhagen adduction exercise. Randomized controlled trial; Level of evidence, 1. We recruited 45 eligible players from 2 U19 elite male soccer teams. Players were randomized into 2 groups; 1 group carried out the standard FIFA 11+ program, while the other carried out the FIFA 11+ but replaced the Nordic hamstring exercise with the Copenhagen adduction exercise. Both groups performed the intervention 3 times weekly for 8 weeks. Players completed eccentric strength and sprint testing before and after the intervention. Per-protocol analyses were performed, and 12 players were excluded due to low compliance (<67% of sessions completed). The main outcome was eccentric hip adduction strength (N·m/kg). Between-group analyses revealed a significantly greater increase in eccentric hip adduction strength of 0.29 Nm/kg (8.9%; P = .01) in favor of the group performing the Copenhagen adduction exercise, whereas no within-group change was noted in the group that used the standard FIFA 11+ program (-0.02 N·m/kg [-0.7%]; P = .69). Including the Copenhagen adduction exercise in the FIFA 11+ program increases eccentric hip adduction strength, while the standard FIFA 11+ program does not. Registration: Registration: ISRCTN13731446 (International Standard Randomised Controlled Trial Number registry).

  3. Comparison of EMG activity on abdominal muscles during plank exercise with unilateral and bilateral additional isometric hip adduction.

    Science.gov (United States)

    Kim, Soo-Yong; Kang, Min-Hyeok; Kim, Eui-Ryong; Jung, In-Gui; Seo, Eun-Young; Oh, Jae-Seop

    2016-10-01

    The aim of this study was to investigate the effects of additional isometric hip adduction during the plank exercise on the abdominal muscles. Twenty healthy young men participated in this study. Surface electromyography (EMG) was used to monitor the activity of the bilateral rectus abdominis (RA), the internal oblique (IO), and the external oblique (EO) muscles. The participants performed three types of plank exercise; the standard plank exercise, the plank exercise with bilateral isometric hip adduction, and the plank exercise with unilateral isometric hip adduction. All abdominal muscle activity was significantly increased during the plank exercise combined with the bilateral and unilateral isometric hip adduction compared with the standard plank exercise (pmuscle activity was significantly increased during the unilateral isometric hip adduction compared with the bilateral isometric hip adduction (pabdominal muscle activity. In particular, the unilateral isometric hip adduction is a more beneficial exercise than the bilateral isometric hip adduction. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Bracken (Pteridium aquilinum)-induced DNA adducts in mouse tissues are different from the adduct induced by the activated form of the Bracken carcinogen ptaquiloside.

    Science.gov (United States)

    Freitas, R N; O'Connor, P J; Prakash, A S; Shahin, M; Povey, A C

    2001-02-23

    Following treatment with bracken fern (Pteridium aquilinum) extract and bracken spores a number of DNA adducts were detected by (32)P-postlabeling. Three of these adducts have been described previously (Povey et al., Br. J. Cancer (1996) 74, 1342-1348) and in this study, using a slightly different protocol, four new adducts, with higher chromatographic mobility, were detected at levels ranging from 50 to 230% of those previously described. When DNA was treated in vitro with activated ptaquiloside (APT) and analysed by butanol extraction or nuclease P1 treatment, only one adduct was detected by (32)P-postlabeling. This adduct was not present in the DNA from mice treated with bracken fern or spores, suggesting either that bracken contains genotoxins other than ptaquiloside or that the metabolism of ptaquiloside produces genotoxins not reflected by activated ptaquiloside. However, as the ATP-derived adduct has been detected previously in ileal DNA of bracken-fed calves, species-specific differences in the metabolism of bracken genotoxins may exist, thereby leading to differences in their biological outcomes. Copyright 2001 Academic Press.

  5. Activation of dihaloalkanes by glutathione conjugation and formation of DNA adducts.

    Science.gov (United States)

    Guengerich, F P; Peterson, L A; Cmarik, J L; Koga, N; Inskeep, P B

    1987-01-01

    Ethylene dibromide (1,2-dibromoethane, EDB) can be activated to electrophilic species by either oxidative metabolism or conjugation with glutathione. Although conjugation is generally a route of detoxication, in this case it leads to genetic damage. The major DNA adduct has been identified as S-[2-(N7-guanyl)ethyl]glutathione, which is believed to arise via half-mustard and episulfonium ion intermediates. The adduct has a half-life of about 70 to 100 hr and does not appear to migrate to other DNA sites. Glutathione-dependent DNA damage by EDB was also demonstrated in human hepatocyte preparations. The possible relevance of this DNA adduct to genetic damage is discussed. Images FIGURE 3. PMID:3329096

  6. Activation of dihaloalkanes by glutathione conjugation and formation of DNA adducts

    International Nuclear Information System (INIS)

    Guengerich, F.P.; Peterson, L.A.; Cmarik, J.L.; Koga, N.; Inskeep, P.B.

    1987-01-01

    Ethylene dibromide (1,2-dibromoethane, EDB) can be activated to electrophilic species by either oxidative metabolism or conjugation with glutathione. Although conjugation is generally a route of detoxication, in this case it leads to genetic damage. The major DNA adduct has been identified as S-[2-(N 7 -guanyl)ethyl]glutathione, which is believed to arise via half-mustard and episulfonium ion intermediates. The adduct has a half-life of about 70 to 100 hr and does not appear to migrate to other DNA sites. Glutathione-dependent DNA damage by EDB was also demonstrated in human hepatocyte preparations. The possible relevance of this DNA adduct to genetic damage is discussed

  7. Activation of proinflammatory signaling by 4-hydroxynonenal-Src adducts in aged kidneys.

    Science.gov (United States)

    Jang, Eun Ji; Kim, Dae Hyun; Lee, Bonggi; Lee, Eun Kyeong; Chung, Ki Wung; Moon, Kyoung Mi; Kim, Min Jo; An, Hye Jin; Jeong, Ji Won; Kim, Ye Ra; Yu, Byung Pal; Chung, Hae Young

    2016-08-09

    In our previous study, reactive 4-hydroxy-2-nonenal (4-HNE) was shown to activate Src (a non-receptor tyrosine kinase) by forming an adduct on binding with a specific residue of Src, leading to the activation of proinflammatory signaling pathways in cultured cells. However, to date, the deleterious roles of 4-HNE in inflammatory signaling activation in kidneys during aging have not been explored. The purpose of the present study was to document the mechanisms by which 4-HNE induces inflammation in the kidney during aging. Initial experiments revealed that activated nuclear factor-κB (NF-κB) expression was caused by 4-HNE activation, which suppressed transcriptional activity in the aged kidney. Treatment of human umbilical vein endothelial cells with 4-HNE revealed that Src caused senescence via NF-κB activation. Furthermore, our immunohistochemistry data showed that 4-HNE-adducted Src significantly increased in aged kidney tissues. The data showed age-related upregulation of downstream signaling molecules such as mitogen activated protein kinases (MAPKs), activator protein-1 (AP-1), NF-κB, and COX-2 in a cell culture cell system.Taken together, the results of this study show that the formation of adducts between 4-HNE and Src activates inflammatory signaling pathways in the aged kidney, contributing to age-related nephropathy.

  8. Activation of Reactive MALDI Adduct Ions Enables Differentiation of Dihydroxylated Vitamin D Isomers

    Science.gov (United States)

    Qi, Yulin; Müller, Miriam J.; Volmer, Dietrich A.

    2017-12-01

    Vitamin D compounds are secosteroids, which are best known for their role in bone health. More recent studies have shown that vitamin D metabolites and catabolites such as dihydroxylated species (e.g., 1,25- and 24,25-dihydroxyvitamin D3) play key roles in the pathologies of various diseases. Identification of these isomers by mass spectrometry is challenging and currently relies on liquid chromatography, as the isomers exhibit virtually identical product ion spectra under collision induced dissociation conditions. Here, we developed a simple MALDI-CID method that utilizes ion activation of reactive analyte/matrix adducts to distinguish isomeric dihydroxyvitamin D3 species, without the need for chromatography separation or chemical derivatization techniques. Specifically, reactive 1,5-diaminonaphthalene adducts of dihydroxyvitamin D3 compounds formed during MADI were activated and specific cleavages in the secosteroid's backbone structure were achieved that produced isomer-diagnostic fragment ions. [Figure not available: see fulltext.

  9. Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother-newborns

    DEFF Research Database (Denmark)

    Pedersen, Marie; Halldorsson, Thorhallur I; Autrup, Herman

    2012-01-01

    dietary variables and the biomarkers measured in maternal and fetal samples were identified. The present study suggests that maternal intake of meats with dark surface contributes to the bulky DNA adduct levels in maternal and umbilical cord blood. Relationship between food preparation and bulky DNA......Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei...... (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006-2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet...

  10. Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother-newborns

    Energy Technology Data Exchange (ETDEWEB)

    Pedersen, Marie, E-mail: mpedersen@creal.cat [Section of Environmental Health, Department of Public Health, University of Copenhagen, CSS, Oester Farimagsgade, Copenhagen K (Denmark); Halldorsson, Thorhallur I., E-mail: lur@ssi.dk [Faculty of Food Science and Nutrition, School of Health Sciences, University of Iceland Reykjavik (Iceland); Center for Fetal Programming, Department of Epidemiology, Statens Serum Institute, Copenhagen (Denmark); Autrup, Herman, E-mail: ha@mil.au.dk [School of Public Health, Department of Environmental and Occupational Medicine, Aarhus University, Aarhus (Denmark); Brouwer, Abraham, E-mail: Bram.Brouwer@bds.nl [BioDetection Systems B.V., Amsterdam (Netherlands); Besselink, Harrie, E-mail: Harrie.Besselink@bds.nl [BioDetection Systems B.V., Amsterdam (Netherlands); Loft, Steffen, E-mail: stl@sund.ku.dk [Section of Environmental Health, Department of Public Health, University of Copenhagen, CSS, Oester Farimagsgade, Copenhagen K (Denmark); Knudsen, Lisbeth E., E-mail: liek@sund.ku.dk [Section of Environmental Health, Department of Public Health, University of Copenhagen, CSS, Oester Farimagsgade, Copenhagen K (Denmark)

    2012-06-01

    Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006-2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet was estimated on the basis of maternal food frequency questionnaire (FFQ) completed by the end of pregnancy. Biomarkers were detected in paired blood samples through the dioxin-responsive chemical-activated luciferase expression (CALUX){sup Registered-Sign} bioassay, {sup 32}P-postlabelling technique and cytokinesis-block MN assay. Maternal preference for meats with dark surface were significantly associated with higher bulky DNA adducts in both maternal ({beta} 95%CI; 0.46 (0.08, 0.84)) and cord blood ({beta} 95%CI; 0.46 (0.05, 0.86)) before and after adjustment for potential confounders. No other significant associations between the 18 dietary variables and the biomarkers measured in maternal and fetal samples were identified. The present study suggests that maternal intake of meats with dark surface contributes to the bulky DNA adduct levels in maternal and umbilical cord blood. Relationship between food preparation and bulky DNA adducts appear to be captured by a FFQ while potential associations for other biomarkers might be more complex or need larger sample size.

  11. Maternal diet and dioxin-like activity, bulky DNA adducts and micronuclei in mother–newborns

    International Nuclear Information System (INIS)

    Pedersen, Marie; Halldorsson, Thorhallur I.; Autrup, Herman; Brouwer, Abraham; Besselink, Harrie; Loft, Steffen; Knudsen, Lisbeth E.

    2012-01-01

    Maternal diet can contribute to carcinogenic exposures and also modify effects of environmental exposures on maternal and fetal genetic stability. In this study, associations between maternal diet and the levels of dioxin-like plasma activity, bulky DNA adducts in white blood cells and micronuclei (MN) in lymphocytes from mother to newborns were examined. From 98 pregnant women living in the greater area of Copenhagen, Denmark in 2006–2007, maternal peripheral blood and umbilical cord blood were collected, together with information on health, environmental exposure and lifestyle. Maternal diet was estimated on the basis of maternal food frequency questionnaire (FFQ) completed by the end of pregnancy. Biomarkers were detected in paired blood samples through the dioxin-responsive chemical-activated luciferase expression (CALUX) ® bioassay, 32 P-postlabelling technique and cytokinesis-block MN assay. Maternal preference for meats with dark surface were significantly associated with higher bulky DNA adducts in both maternal (β 95%CI; 0.46 (0.08, 0.84)) and cord blood (β 95%CI; 0.46 (0.05, 0.86)) before and after adjustment for potential confounders. No other significant associations between the 18 dietary variables and the biomarkers measured in maternal and fetal samples were identified. The present study suggests that maternal intake of meats with dark surface contributes to the bulky DNA adduct levels in maternal and umbilical cord blood. Relationship between food preparation and bulky DNA adducts appear to be captured by a FFQ while potential associations for other biomarkers might be more complex or need larger sample size.

  12. Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo

    Directory of Open Access Journals (Sweden)

    Ming W. Chou

    2005-04-01

    Full Text Available Pyrrolizidine alkaloids are naturally occurring genotoxic chemicals produced by a large number of plants. The high toxicity of many pyrrolizidine alkaloids has caused considerable loss of free-ranging livestock due to liver and pulmonary lesions. Chronic exposure of toxic pyrrolizidine alkaloids to laboratory animals induces cancer. This investigation studies the metabolic activation of retrorsine, a representative naturally occurring tumorigenic pyrrolizidine alkaloid, and shows that a genotoxic mechanism is correlated to the tumorigenicity of retrorsine. Metabolism of retrorsine by liver microsomes of F344 female rats produced two metabolites, 6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP, at a rate of 4.8 ± 0.1 nmol/mg/min, and retrorsine-N-oxide, at a rate of 17.6±0.5 nmol/mg/min. Metabolism was enhanced 1.7-fold by using liver microsomes prepared from dexamethasone-treated rats. DHP formation was inhibited 77% and retrorsine N-oxide formation was inhibited 29% by troleandomycin, a P450 3A enzyme inhibitor. Metabolism of retrorsine with lung, kidney, and spleen microsomes from dexamethasone-treated rats also generated DHP and the N-oxide derivative. When rat liver microsomal metabolism of retrorsine occurred in the presence of calf thymus DNA, a set of DHP-derived DNA adducts was formed; these adducts were detected and quantified by using a previously developed 32P-postlabeling/HPLC method. These same DNA adducts were also found in liver DNA of rats gavaged with retrorsine. Since DHP-derived DNA adducts are suggested to be potential biomarkers of riddelliine-induced tumorigenicity, our results indicate that (i similar to the metabolic activation of riddelliine, the mechanism of retrorsine-induced carcinogenicity in rats is also through a genotoxic mechanism involving DHP; and (ii the set of DHP-derived DNA adducts found in liver DNA of rats gavaged with retrorsine or riddelliine can serve as biomarkers for the

  13. Metabolic Activation of the Tumorigenic Pyrrolizidine Alkaloid, Retrorsine, Leading to DNA Adduct Formation In Vivo

    Science.gov (United States)

    Wang, Yu-Ping; Fu, Peter P.; Chou, Ming W.

    2005-01-01

    Pyrrolizidine alkaloids are naturally occurring genotoxic chemicals produced by a large number of plants. The high toxicity of many pyrrolizidine alkaloids has caused considerable loss of free-ranging livestock due to liver and pulmonary lesions. Chronic exposure of toxic pyrrolizidine alkaloids to laboratory animals induces cancer. This investigation studies the metabolic activation of retrorsine, a representative naturally occurring tumorigenic pyrrolizidine alkaloid, and shows that a genotoxic mechanism is correlated to the tumorigenicity of retrorsine. Metabolism of retrorsine by liver microsomes of F344 female rats produced two metabolites, 6, 7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), at a rate of 4.8 ± 0.1 nmol/mg/min, and retrorsine-N-oxide, at a rate of 17.6±0.5 nmol/mg/min. Metabolism was enhanced 1.7-fold by using liver microsomes prepared from dexamethasone-treated rats. DHP formation was inhibited 77% and retrorsine N-oxide formation was inhibited 29% by troleandomycin, a P450 3A enzyme inhibitor. Metabolism of retrorsine with lung, kidney, and spleen microsomes from dexamethasone-treated rats also generated DHP and the N-oxide derivative. When rat liver microsomal metabolism of retrorsine occurred in the presence of calf thymus DNA, a set of DHP-derived DNA adducts was formed; these adducts were detected and quantified by using a previously developed 32P-postlabeling/HPLC method. These same DNA adducts were also found in liver DNA of rats gavaged with retrorsine. Since DHP-derived DNA adducts are suggested to be potential biomarkers of riddelliine-induced tumorigenicity, our results indicate that (i) similar to the metabolic activation of riddelliine, the mechanism of retrorsine-induced carcinogenicity in rats is also through a genotoxic mechanism involving DHP; and (ii) the set of DHP-derived DNA adducts found in liver DNA of rats gavaged with retrorsine or riddelliine can serve as biomarkers for the tumorigenicity induced by

  14. Synthesis, structure characterization, and anticancer activity of a novel oxygen-bridged tricyclic Biginelli adduct

    Science.gov (United States)

    Ibrahim, Mohamed M.; El-Sheshtawy, Hamdy S.; El-Kemary, Maged; Al-Juaid, Salih; Youssef, Mohamed; El-Azab, Islam H.

    2017-06-01

    Herein, we report the one-pot cyclization of Biginelli Adduct, ethyl 4-(2-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (I) to the oxygen-bridged adduct, ethyl 2-methyl-4-thioxo-3,4,5,6-tetrahydro-2H-2,6-methanobenzo[g] [1,3,5]oxadiazocine-11-carboxylate (II) in a high yield and purity under mild reaction condition using zinc(II) perchlorate hexahydrate as a highly efficient catalyst. The cyclic product (II) was characterized both in the solid state and in solution using FT-IR, 1H NMR, and UV-visible spectroscopy. Theoretical calculations using density functional theory with B3LYP/6-311++G(d,p) level were used to further investigate the structure properties. DFT calculations (gas phase) revealed the stability of cyclic compound II (3.45 kcal/mol) than compound I. In addition, the anticancer activity of II was investigated using MCF-7 human breast cell line. The results revealed a moderate activity with 223.55 μg/ml IC50 value.

  15. Myeloperoxidase (MPO) -463G->A reduces MPO activity and DNA adduct levels in bronchoalveolar lavages of smokers.

    Science.gov (United States)

    Van Schooten, Frederik J; Boots, Agnes W; Knaapen, Ad M; Godschalk, Roger W L; Maas, Lou M; Borm, Paul J A; Drent, Marjolein; Jacobs, Jan A

    2004-05-01

    The myeloperoxidase (MPO) -463G-->A genetic polymorphism is associated with a reduced risk for lung cancer, but the underlying mechanism is not yet elucidated. Therefore, the impact of this polymorphism on MPO activity and lipophilic DNA adducts was studied in respectively bronchoalveolar lavage (BAL) fluid and cells, from 106 smoking Caucasian lung patients. MPO activity was determined spectrophotometrically, aromatic DNA adducts by (32)P-postlabeling and MPO genotypes by RFLP analysis. Frequencies of MPO -463AA (13%), MPO -463AG (36%), and MPO -463GG (51%) were in line with earlier observations. MPO activity/neutrophil was lower in MPO -463AA (median 0.04 pU/cell) than in MPO -463AG (median 0.07 pU/cell) and MPO -463GG (median 0.14 pU/cell; P = 0.059) individuals. DNA adducts in BAL cells were measured in 11 MPO -463AA subjects and equal numbers of MPO -463AG and MPO -463GG subjects matched for smoking, age, gender, and clinical diagnosis. DNA adduct levels in MPO -463AA individuals (median 0.62 adducts/10(8) nucleotides) were lower than in MPO -463AG (median 1.51 adducts/10(8) nucleotides) and MPO -463GG (median 3.26 adducts/10(8) nucleotides; P = 0.003) subjects. Overall, no significant correlation was observed between amount of inhaled tar/day and DNA adduct levels. However, correlations improved considerably on grouping according to the MPO genotype; MPO -463AA subjects were the least responsive (R(2) = 0.73, slope = 0.4, P = 0.01) followed by MPO -463AG subjects (R(2) = 0.70, slope = 1.3, P = 0.01) and MPO -463GG patients (R(2) = 0.67, slope = 2.8, P = 0.02). These data demonstrate that MPO -463AA/AG genotypes are associated with (a) reduced MPO activity in BAL fluid and (b) reduced smoking-related DNA adduct levels in BAL cells in a gene-dose manner. These data provide a plausible biological explanation for the reduced risk for lung cancer as observed in MPO -463AA/AG compared with MPO -463GG subjects.

  16. Myeloperoxidase (MPO) -463G->A reduces MPO activity and DNA adduct levels in bronchoalveolar lavages of smokers

    NARCIS (Netherlands)

    van Schooten, F.J.; Boots, A.W.; Knaapen, A.M.; Godschalk, R.W.; Maas, L.M.; Borm, P.J.A.; Drent, M.; Jacobs, J.A.

    2004-01-01

    The myeloperoxidase (MPO) -463G-->A genetic polymorphism is associated with a reduced risk for lung cancer, but the underlying mechanism is not yet elucidated. Therefore, the impact of this polymorphism on MPO activity and lipophilic DNA adducts was studied in respectively bronchoalveolar lavage

  17. DNA adducts as molecular dosimeters

    International Nuclear Information System (INIS)

    Lucier, G.W.

    1990-01-01

    There is compelling evidence that DNA adducts play an important role in the actions of many pulmonary carcinogens. During the last ten years sensitive methods (antibodies and 32 P-postlabeling) have been developed that permit detection of DNA adducts in tissues of animals or humans exposed to low levels of some genotoxic carcinogens. This capability has led to approaches designed to more reliably estimate the shape of the dose-response curve in the low dose region for a few carcinogens. Moreover, dosimetry comparisions can, in some cases, be made between animals and humans which help in judging the adequacy of animal models for human risk assessments. There are several points that need to be considered in the evaluation of DNA adducts as a molecular dosimeter. For example, DNA adduct formation is only one of many events that are needed for tumor development and some potent carcinogens do not form DNA adducts; i.e., TCDD. Other issues that need to be considered are DNA adduct heterogeneity, DNA repair, relationship of DNA adducts to somatic mutation and cell specificity in DNA adduct formation and persistence. Molecular epidemiology studies often require quantitation of adducts in cells such as lymphocytes which may or may not be reliable surrogates for adduct concentrations in target issues. In summary, accurate quantitation of low levels of DNA adducts may provide data useful in species to species extrapolation of risk including the development of more meaningful human monitoring programs

  18. Oxidative DNA Adducts Following Cu2+-Mediated Activation of Dihydroxy PCBs: Role of Reactive Oxygen Species1

    Science.gov (United States)

    Spencer, Wendy A.; Lehmler, Hans-Joachim; Robertson, Larry W.; Gupta, Ramesh C.

    2009-01-01

    Polychlorinated biphenyls (PCBs) are toxic industrial chemicals, complete carcinogens and efficacious tumor promoters. However, the mechanism(s) of PCB-mediated carcinogenicity remains largely undefined. One likely pathway by which these agents may play a role in carcinogenesis is the generation of oxidative DNA damage by redox cycling of dihydroxylated PCB metabolites. We have now employed a new 32P-postlabeling system to examine novel oxidative DNA lesions induced by Cu2+-mediated activation of PCB metabolites. 32P-Postlabeling of DNA incubated with various PCB metabolites resulted in over a dozen novel polar oxidative DNA adducts that were chromatographically similar for all active agents. The most potent metabolites tested were the hydroquinones (hydroxyl groups arranged para to each other) yielding polar oxidative adduct levels ranging from 55 to 142 adducts/106 nucleotides. PCB catechols, or ortho-dihydroxy metabolites, were up to 40% less active than their corresponding hydroquinone congeners while mono hydroxylated and quinone metabolites did not produce detectable oxidative damage over that of vehicle. With the exception of 2,4,5-Cl-2′,5′-dihydroxybiphenyl, this oxidative DNA damage appeared to be inversely related to chlorine content: no chlorine ≈ mono- > di- > tri-chlorinated metabolites. Importantly, copper, but not iron, was essential for activation of the PCB metabolites to these polar oxidative DNA adducts since in its absence or in the presence of the Cu+-specific scavenger, bathocuproine, no adducts were detected. Intervention studies with known reactive oxygen species (ROS) modifiers suggested that H2O2, singlet oxygen, hydroxyl radical and superoxide may also be involved in this PCB-mediated oxidative DNA damage. These data indicate a mechanistic role of several ROS, in addition to copper, in PCB-induced DNA damage and provide further support for oxidative DNA damage in PCB-mediated carcinogenesis. PMID:19233261

  19. Correlation between electrochemical and theoretical studies on the leishmanicidal activity of twelve Morita-Baylis-Hillman adducts

    OpenAIRE

    Paiva, Yen G. de; Souza, Antônio A. de; Lima-Junior, Claudio G.; Silva, Fábio P. L.; A. Filho, Edilson B.; Vasconcelos, Camila C. de; Abreu, Fabiane C. de; Goulart, Marília O. F.; Vasconcellos, Mário L. A. A.

    2012-01-01

    Enzymatic bioreduction of nitro groups plays an important role on the activity of biologically active nitroaromatic compounds. Electrochemical methods are useful tools to simulate in vivo metabolic processes. This work presents electrochemical studies in aprotic media (N, N-dimethylformamide (DMF) plus tetrabutylammonium perchlorate (TBAP) 0.1 mol L-1) using cyclic voltammetry (CV), differential pulse voltammetry (DPV) and square wave voltammetry (SWV) of twelve Morita-Baylis-Hillman adducts ...

  20. Synthesis and activity of novel homodimers of Morita-Baylis-Hillman adducts against Leishmania donovani: A twin drug approach.

    Science.gov (United States)

    da Silva, Wagner A V; Rodrigues, Daniele C; de Oliveira, Ramon G; Mendes, Rhuan K S; Olegário, Tayná R; Rocha, Juliana C; Keesen, Tatjana S L; Lima-Junior, Claudio G; Vasconcellos, Mário L A A

    2016-09-15

    It is reported here the synthesis of novel Homodimers 12-19 of Morita-Baylis-Hillman adducts (MBHA) from one-pot Morita-Baylis-Hillman Reaction (MBHR) between aromatic aldehydes as eletrophiles and ethylene glycol diacrylate as Michael acceptor (35-94% yields) using cheap and green conditions. The bioactivities were evaluated against promastigote form of Leishmania donovani. All homodimers showed to be more potent than corresponding monomers. It is worth highlighting that the halogenated homodimers 17 and 18 (0.50μM) is almost 400 times more active than the corresponding monomer 10 and 1.24 times more potent than the second-line drug amphotericin B (0.62μM). Moreover, the selectivity index to 18 is very high (SIrb>400) far better than amphotericin B (SIrb=18.73). This is the first report of twin drugs strategy applied on Morita-Baylis-Hillman adducts. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. DNA adducts induced by in vitro activation of extracts of diesel and biodiesel exhaust particles

    Science.gov (United States)

    AbstractContext: Biodiesel and biodiesel-blend fuels offer a renewable alternative to petroleum diesel, but few data are available concerning the carcinogenic potential of biodiesel exhausts. Objectives: We compared the formation of covalent DNA adducts by the in vitro metabol...

  2. Sterically Bulky NHC Adducts of GaMe3 and InMe3 for H2 Activation and Lactide Polymerization

    Directory of Open Access Journals (Sweden)

    Anaëlle Bolley

    2018-01-01

    Full Text Available The sterically bulky Ga(III and In(III (IPr*MMe3 adducts (1 and 2 and (SItBuMMe3 adducts (3 and 4 (M = Ga, In; IPr* = 1,3-bis{2,6-bis(diphenylmethyl-4-methylphenyl}-1,3-dihydro- imidazol-2-ylidene; SItBu = 1,3-bis(1,1-dimethylethyl-imidazolidin-2-ylidene were prepared and structurally characterized, allowing an estimation of the steric hindrance of such Lewis pairs (yields in 1–4: 92%, 90%, 73%, and 42%, respectively. While the IPr* adducts 1 and 2 are robust species, the more severely congested SItBu adducts 3 and 4 are more reactive and exhibit a limited stability in solution. Adduct (SItBuGaMe3 (3 reacts quickly with H2 at room temperature to afford the corresponding aminal product, 1,3-di-tert-butylimidazolidine (5, along with free GaMe3. Such Frustrated Lewis Pair (FLP reactivity constitutes the first instance of a H2 activation involving a simple trialkyl GaR3 species. Adduct 3 also mediates the ring-opening polymerization (ROP of rac-lactide at room temperature to afford cyclic polylactide (PLA.

  3. Metabolic Activation of the Antibacterial Agent Triclocarban by Cytochrome P450 1A1 Yielding Glutathione Adducts

    Science.gov (United States)

    Muvvala, Jaya B.; Morin, Dexter; Buckpitt, Alan R.; Hammock, Bruce D.; Rice, Robert H.

    2014-01-01

    Triclocarban (3,4,4′-trichlorocarbanilide; TCC) is an antibacterial agent used in personal care products such as bar soaps. Small amounts of chemical are absorbed through the epidermis. Recent studies show that residues of reactive TCC metabolites are bound covalently to proteins in incubations with keratinocytes, raising concerns about the potential toxicity of this antimicrobial agent. To obtain additional information on metabolic activation of TCC, this study characterized the reactive metabolites trapped as glutathione conjugates. Incubations were carried out with 14C-labeled TCC, recombinant CYP1A1 or CYP1B1, coexpressed with cytochrome P450 reductase, glutathione-S-transferases (GSH), and an NADPH-generating system. Incubations containing CYP1A1, but not 1B1, led to formation of a single TCC-GSH adduct with a conversion rate of 1% of parent compound in 2 hours. Using high-resolution mass spectrometry and diagnostic fragmentation, the adduct was tentatively identified as 3,4-dichloro-3′-glutathionyl-4′-hydroxycarbanilide. These findings support the hypothesis that TCC is activated by oxidative dehalogenation and oxidation to a quinone imine. Incubations of TCDD-induced keratinocytes with 14C-TCC yielded a minor radioactive peak coeluting with TCC-GSH. Thus, we conclude that covalent protein modification by TCC in TCDD-induced human keratinocyte incubations is mainly caused by activation of TCC by CYP1A1 via a dehalogenated TCC derivative as reactive species. PMID:24733789

  4. Isolevuglandin adducts in disease.

    Science.gov (United States)

    Salomon, Robert G; Bi, Wenzhao

    2015-06-20

    A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences. IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo. The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Aβ1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells. Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.

  5. Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A.

    Science.gov (United States)

    Stornetta, Alessia; Deng, Kai-Cheng Kieren; Danielli, Sara; Liyanage, H D Sarath; Sturla, Shana J; Wilson, William R; Gu, Yongchuan

    2018-04-07

    PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R 2  = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Synthesis, characterization and DNA cleavage activity of nickel(II adducts with aromatic heterocyclic bases

    Directory of Open Access Journals (Sweden)

    G. H. PHILIP

    2010-01-01

    Full Text Available Mixed ligand complexes of nickel(II with 2,4-dihydroxyaceto-phenone oxime (DAPO and 2,4-dihydroxybenzophenone oxime (DBPO as primary ligands, and pyridine (Py and imidazole (Im as secondary ligands were synthesized and characterized by molar conductivity, magnetic moments measurements, as well as by electronic, IR, and 1H-NMR spectroscopy. Electrochemical studies were performed by cyclic voltammetry. The active signals are assignable to the NiIII/II and NiII/I redox couples. The binding interactions between the metal complexes and calf thymus DNA were investigated by absorption and thermal denaturation. The cleavage activity of the complexes was determined using double-stranded pBR322 circular plasmid DNA by gel electrophoresis. All complexes showed increased nuclease activity in the presence of the oxidant H2O2. The nuclease activities of mixed ligand complexes were compared with those of the parent copper(II complexes.

  7. Pulmonary heat shock protein expression after exposure to a metabolically activated Clara cell toxicant: relationship to protein adduct formation

    International Nuclear Information System (INIS)

    Williams, Kurt J.; Cruikshank, Michael K.; Plopper, Charles G.

    2003-01-01

    Heat shock proteins/stress proteins (Hsps) participate in regulation of protein synthesis and degradation and serve as general cytoprotectants, yet their role in lethal Clara cell injury is not clear. To define the pattern of Hsp expression in acute lethal Clara cell injury, mice were treated with the Clara cell-specific toxicant naphthalene (NA), and patterns of expression compared to electrophilic protein adduction and previously established organellar degradation and gluathione (GSH) depletion. In sites of lethal injury (distal bronchiole), prior to organellar degradation (1 h post-NA), protein adduction is detectable and ubiquitin, Hsp 25, Hsp 72, and heme-oxygenase 1 (HO-1) are increased. Maximal Hsp expression, protein adduction, and GSH depletion occur simultaneous (by 2-3 h) with early organelle disruption. Hsp expression is higher later (6-24 h), only in exfoliating cells. In airway sites (proximal bronchiole) with nonlethal Clara cell injury elevation of Hsp 25, 72, and HO-1 expression follows significant GSH depletion (greater than 50% 2 h post-NA). This data build upon our previous studies and we conclude that (1) in lethal (terminal bronchiole) and nonlethal (proximal bronchiole) Clara cell injury, Hsp induction is associated with the loss of GSH and increased protein adduction, and (2) in these same sites, organelle disruption is not a prerequisite for Hsp induction

  8. Formation of DHP-derived DNA adducts from metabolic activation of the prototype heliotridine-type pyrrolizidine alkaloid, heliotrine.

    Science.gov (United States)

    Xia, Qingsu; Yan, Jian; Chou, Ming W; Fu, Peter P

    2008-05-05

    Pyrrolizidine alkaloid-containing plants are widespread in the world and may be the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolism to exert their genotoxicity and tumorigenicity. Our mechanistic studies have determined that metabolism of the retronecine-type (riddelliine, retrorsine, and monocrotaline), heliotridine-type (lasiocarpine), and otonecine-type (clivorine) tumorigenic pyrrolizidine alkaloids in vivo and/or in vitro all generates a common set of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts responsible for tumor induction. All the pyrrolizidine alkaloids studied previously are diesters with an ester linkage at the C7 and C9 positions of the necine base. In this study, we report that F344 rat liver microsomal metabolism of heliotrine, a tumorigenic monoester bearing a hydroxyl group at the C7 of the necine base, resulted in the formation of the dehydroheliotridine (DHH) metabolite. When incubations of heliotrine were carried out in the presence of calf thymus DNA, the same set of DHP-derived DNA adducts was formed. These results support that DHP-derived DNA adducts are potential common biomarkers of pyrrolizidine alkaloid exposure and tumorigenicity. For comparison, the dehydroretronecine (DHR)-derived DNA adducts formed from metabolism of riddleiine, retrorsine, monocrotaline, riddelleiine N-oxide, and retrorsine N-oxide were measured in parallel; the levels of DHP-derived DNA adduct formation were in the order: riddelliine approximately retrorsine>monocrotaline>retrorsine N-oxide>or=riddelliine N-oxide>heliotrine.

  9. Tetraphenylphosphonium allyldithiocarbimates derived from Morita-Baylis-Hillman adducts: Synthesis, characterization, crystal structure and antifungal activity

    Science.gov (United States)

    Tavares, Eder C.; Rubinger, Mayura M. M.; Filho, Eclair V.; Oliveira, Marcelo R. L.; Piló-Veloso, Dorila; Ellena, Javier; Guilardi, Silvana; Souza, Rafael A. C.; Zambolim, Laércio

    2016-02-01

    Botrytis blight is a very destructive disease caused by Botrytis spp., infecting flowers, trees, vegetables and fruits. Twelve new compounds were prepared by the reaction of potassium N-aryl-sulfonyldithiocarbimates with Morita-Baylis-Hillman derivatives bearing phenyl and furyl groups. These are the first examples of allyldithiocarbimate anions and were isolated as tetraphenylphosphonium salts. The new compounds were characterized by HRMS, NMR and Infrared spectroscopy. Further, the structures of three allyldithiocarbimates were determined by single crystal X-ray diffraction. The compounds are isostructural and crystallize in the space group P21/c of the monoclinic system, and the allyldithiocarbimate anions present Z configuration. All the compounds were active against Botrytis cinerea. The best results were achieved with the tetraphenylphosphonium (Z)-3-(furan-2-yl)-2-(methoxycarbonyl)allyl-(4-chlorophenylsulfonyl)dithiocarbimate (IC50 38 μM).

  10. Synthesis, Cytotoxic Activity on Leukemia Cell Lines and Quantitative Structure-Activity Relationships (QSAR) Studies of Morita-Baylis-Hillman Adducts.

    Science.gov (United States)

    Lima-, Claudio G; Faheina-Martins, Gláucia V; Bomfim, Caio C B; Dantas, Bruna B; Silva, Everton P; Araújo, Demetrius A M de; Filho, Edilson B A; Vasconcellos, Mário L A A

    2016-01-01

    The Morita-Baylis-Hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. The Morita-Baylis-Hillman adducts (MBHA) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g. as anti-Leishmania chagasi and Leishmania amazonensis, anti- Trypanosoma cruzi, anti-Plasmodium falciparum and Plasmodium berghei, lethal against Biomphalaria glabrata, antibacterial, antifungal, herbicide and others. The goal of this work is to describe the primary cytotoxic activities against strains of human leukemia HL-60 cell line for thirty-four Morita-Baylis- Hillman adducts (MBHA), followed by a Quantitative Structure-Activity Relationships study (QSAR). The conventional or microwave-assisted syntheses of MBHA, derived from substituted aromatics or Isatin, were performed in good to excellent yields (70-100%) in short reaction times, using protocols recently developed by us. Isatin derivatives, MBHA 31 and 32, were the most active in this congener series of compounds, with IC50 values of 10.8 μM and 7.8 μM, respectively. The primary cytotoxic activities against chronic leukemia cells (K562) were also evaluated to these two most active compounds (MBHA 31 and 32), presenting IC50 values of 53 μM and 43 μM respectively. QSAR study was performed considering 3D, 2D and constitutional molecular descriptors. These were selected from Ordered Predictor Selection algorithm and submitted to Partial Least Squares Modeling. We present an interesting investigation about cytotoxic activities on human leukemia cell line (HL-60) for 34 synthetic MBHA. In a good way we discovered that the most cytotoxic compounds (31-32, 10.8 μM and 7.8 μM respectively) were also prepared quantitatively (100% yields) in a short reaction time using microwave irradiation. We demonstrate that 31 and 32 induced

  11. Chemistry and Biology of Aflatoxin-DNA Adducts

    Energy Technology Data Exchange (ETDEWEB)

    Stone, Michael P.; Banerjee, Surajit; Brown, Kyle L.; Egli, Martin (Vanderbilt)

    2012-03-27

    Aspergillus flavus is a fungal contaminant of stored rice, wheat, corn, and other grainstuffs, and peanuts. This is of concern to human health because it produces the mycotoxin aflatoxin B{sub 1} (AFB{sub 1}), which is genotoxic and is implicated in the etiology of liver cancer. AFB{sub 1} is oxidized in vivo by cytochrome P450 to form aflatoxin B{sub 1} epoxide, which forms an N7-dG adduct (AFB{sub 1}-N7-dG) in DNA. The latter rearranges to a formamidopyrimidine (AFB{sub 1}-FAPY) derivative that equilibrates between {alpha} and {beta} anomers of the deoxyribose. In DNA, both the AFB{sub 1}-N7-dG and AFB{sub 1}-{beta}-FAPY adducts intercalate above the 5'-face of the damaged guanine. Each produces G {yields} T transversions in Escherichia coli, but the AFB{sub 1}-{beta}-FAPY adduct is more mutagenic. The Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) provides a model for understanding error-prone bypass of the AFB{sub 1}-N7-dG and AFB{sub 1}-{beta}-FAPY adducts. It bypasses the AFB{sub 1}-N7-dG adduct, but it conducts error-prone replication past the AFB{sub 1}-FAPY adduct, including mis-insertion of dATP, consistent with the G {yields} T mutations characteristic of AFB{sub 1} mutagenesis in E. coli. Crystallographic analyses of a series of binary and ternary complexes with the Dpo4 polymerase revealed differing orientations of the N7-C8 bond of the AFB{sub 1}-N7-dG adduct as compared to the N{sup 5}-C8 bond in the AFB{sub 1}-{beta}-FAPY adduct, and differential accommodation of the intercalated AFB{sub 1} moieties within the active site. These may modulate AFB{sub 1} lesion bypass by this polymerase.

  12. Comparison of hip extensor muscle activity including the adductor magnus during three prone hip extension exercises.

    Science.gov (United States)

    Ko, Han-I; Jeon, Seung-Yeon; Kim, Si-Hyun; Park, Kyue-Nam

    2018-03-30

    This study compared the role of the adductor magnus muscle (Amag) as a hip extensor while performing active prone hip extension (PHE), PHE with hip adduction (PHE-ADD), and PHE with hip abduction (PHE-ABD) with the gluteus maximus (Gmax) and hamstrings. The study recruited 22 healthy participants. Electromyography data were recorded from the Amag, Gmax, and medial and lateral hamstrings during PHE, PHE-ADD, and PHE-ABD. Normalized electromyographic data were examined using one-way, repeated-measures analyses of variance. The magnitude of the Amag, Gmax, and hamstring activations did not differ significantly while performing PHE (p = 0.41). Furthermore, the Amag and hamstring activations were significantly greater than the Gmax activation when performing PHE-ADD (p < 0.05). The Gmax showed significantly greater activation during PHE-ABD than the Amag and medial and lateral hamstrings (p < 0.05). Based on these results, we advocate including the Amag as a hip extensor during the PHE test or exercise. Our preliminary results have the potential to be applied directly to the PHE test, for investigating the muscle-activation pattern of the Amag with the Gmax and hamstrings in patients with hip or lower back pain.

  13. Facile Synthesis of N-Tosyl Aza-Baylis-Hillman Adducts of Acrylamide via a Pd-Catalyzed Hydration of Nitrile to Amide

    International Nuclear Information System (INIS)

    Kim, Eun Sun; Kim, Yu Mi; Kim, Jae Nyoung

    2010-01-01

    We developed an efficient palladium-catalyzed two-step protocol for the synthesis of N-tosyl aza-Baylis-Hillman adducts of acrylamide. The method involved the preparation of the corresponding Baylis-Hillman adducts of acrylonitrile and the following Pd-catalyzed hydration of nitrile with acetaldoxime. The Baylis-Hillman reaction, which involves the coupling of activated vinyl compounds with electrophiles under the catalytic influence of a tertiary amine, gives rise to adducts, so called Baylis-Hillman adducts, with a new stereocenter and has proven to be a very useful carbon-carbon bond-forming method in the synthesis of highly functionalized molecules. As the activated vinyl compounds, various compounds have been used in the Baylis-Hillman reaction including acrylates, acrylonitrile, vinyl ketones, vinyl sulfones and acrylamides. However, among the activated vinyl compounds acrylamide has not been used much for the synthesis of the corresponding Baylis-Hillman adducts due to its sluggish reactivity

  14. Facile Synthesis of N-Tosyl Aza-Baylis-Hillman Adducts of Acrylamide via a Pd-Catalyzed Hydration of Nitrile to Amide

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Sun; Kim, Yu Mi; Kim, Jae Nyoung [Chonnam National Univ., Gwangju (Korea, Republic of)

    2010-03-15

    We developed an efficient palladium-catalyzed two-step protocol for the synthesis of N-tosyl aza-Baylis-Hillman adducts of acrylamide. The method involved the preparation of the corresponding Baylis-Hillman adducts of acrylonitrile and the following Pd-catalyzed hydration of nitrile with acetaldoxime. The Baylis-Hillman reaction, which involves the coupling of activated vinyl compounds with electrophiles under the catalytic influence of a tertiary amine, gives rise to adducts, so called Baylis-Hillman adducts, with a new stereocenter and has proven to be a very useful carbon-carbon bond-forming method in the synthesis of highly functionalized molecules. As the activated vinyl compounds, various compounds have been used in the Baylis-Hillman reaction including acrylates, acrylonitrile, vinyl ketones, vinyl sulfones and acrylamides. However, among the activated vinyl compounds acrylamide has not been used much for the synthesis of the corresponding Baylis-Hillman adducts due to its sluggish reactivity.

  15. Theoretical investigations on the formation of nitrobenzanthrone-DNA adducts.

    Science.gov (United States)

    Arlt, Volker M; Phillips, David H; Reynisson, Jóhannes

    2011-09-07

    3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. The thermochemical formation cascades were calculated for six 3-NBA-derived DNA adducts employing its arylnitrenium ion as precursor using density functional theory (DFT). Clear exothermic pathways were found for four adducts, i.e., 2-(2'-deoxyadenosin-N(6)-yl)-3-aminobenzanthrone, 2-(2'-deoxyguanosin-N(2)-yl)-3-aminobenzanthrone, N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone and 2-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone. All four have been observed to be formed in cell-free experimental systems. The formation of N-(2'-deoxyadenosin-8-yl)-3-aminobenzanthrone is predicted to be not thermochemically viable explaining its absence in either in vitro or in vivo model systems. However, 2-(2'-deoxyadenosin-8-yl)-3-aminobenzanthrone, can be formed, albeit not as a major product, and is a viable candidate for an unknown adenine adduct observed experimentally. 2-nitrobenzanthrone (2-NBA), an isomer of 3-NBA, was also included in the calculations; it has a higher abundance in ambient air than 3-NBA, but a much lower genotoxic potency. Similar thermochemical profiles were obtained for the calculated 2-NBA-derived DNA adducts. This leads to the conclusion that enzymatic activation as well as the stability of its arylnitrenium ion are important determinants of 2-NBA genotoxicity.

  16. Hyphenating the curtius rearrangement with Morita-Baylis-Hillman adducts: synthesis of biologically active acyloins and vicinal aminoalcohols

    Energy Technology Data Exchange (ETDEWEB)

    Amarante, Giovanni W.; Cavallaro, Mayra; Coelho, Fernando, E-mail: coelho@iqm.unicamp.b [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Inst. de Quimica. Lab. de Sintese de Produtos Naturais e Farmacos

    2011-07-01

    Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (+-)-bupropion, a drug used to treat the abstinence syndrome of smoker and (+-)-spisulosine, a potent anti-tumoral compound originally isolated from a marine source. (author)

  17. 2'-Deoxythymidine Adducts from the Anti-HIV Drug Nevirapine

    Directory of Open Access Journals (Sweden)

    M. Matilde Marques

    2013-04-01

    Full Text Available Nevirapine (NVP is a non-nucleoside reverse transcriptase inhibitor (NNRTI used against HIV-1. Currently, NVP is the most widely used anti-HIV drug in developing countries, both in combination therapy and to prevent mother-to-child transmission of HIV. Despite its efficacy against HIV, NVP produces a variety of toxic responses, including hepatotoxicity and skin rash. It is also associated with increased incidences of hepatoneoplasias in rodents. In addition, epidemiological data suggest that NNRTI use is a risk factor for non-AIDS-defining cancers in HIV-positive patients. Current evidence supports the involvement of metabolic activation to reactive electrophiles in NVP toxicity. NVP metabolism includes oxidation to 12-hydroxy-NVP; subsequent Phase II sulfonation produces an electrophilic metabolite, 12-sulfoxy-NVP, capable of reacting with DNA to yield covalent adducts. Since 2’-deoxythymidine (dT adducts from several alkylating agents are regarded as having significant mutagenic/carcinogenic potential, we investigated the formation of NVP-dT adducts under biomimetic conditions. Toward this goal, we initially prepared and characterized synthetic NVP-dT adduct standards using a palladium-mediated Buchwald-Hartwig coupling strategy. The synthetic standards enabled the identification, by LC-ESI-MS, of 12-(2'-deoxythymidin-N3-yl-nevirapine (N3-NVP-dT in the enzymatic hydrolysate of salmon testis DNA reacted with 12-mesyloxy-NVP, a synthetic surrogate for 12-sulfoxy-NVP. N3-NVP-dT, a potentially cytotoxic and mutagenic DNA lesion, was also the only dT-specific adduct detected upon reaction of dT with 12-mesyloxy-NVP. Our data suggest that N3-NVP-dT may be formed in vivo and play a role in the hepatotoxicity and/or putative hepatocarcinogenicity of NVP.

  18. Molar ratios of therapeutic water-soluble phenothiazine⋅water-insoluble phospholipid adducts reveal a Fibonacci correlation and a putative link for structure–activity relationships

    DEFF Research Database (Denmark)

    Keyzer, Hendrik; Fey, S. J.; Thornton, Barry

    2015-01-01

    larger than that of the self-associated pure PTH. In summary, the reproducibility and similarity of the measurements using different PTH derivatives and PL suggests that similar adducts are formed in all the cases. We propose that the PTH$PL adduct has a “helical shape” showing Fibonacci properties...

  19. Effect of turmeric and curcumin on BP-DNA adducts.

    Science.gov (United States)

    Mukundan, M A; Chacko, M C; Annapurna, V V; Krishnaswamy, K

    1993-03-01

    Many human cancers that are widely prevalent today can be prevented through modifications in life-styles, of which diet appears to be an important agent. Several dietary constituents modulate the process of carcinogenesis and prevent genotoxicity. Many plant constituents including turmeric appear to be potent antimutagens and antioxidants. Therefore the modulatory effects of turmeric and curcumin on the levels of benzo[a]pyrene induced DNA adducts in the livers of rats were studied by the newly developed 32P-postlabelling assay method. Turmeric when fed at 0.1, 0.5 and 3% and the active principle of turmeric (curcumin) when fed at a level of 0.03% in the diet for 4 weeks significantly reduced the level of BP-DNA adducts including the major adduct dG-N2-BP, formed within 24 h in response to a single i.p. injection of benzo[a]pyrene. The significance of these effects in terms of the potential anticarcinogenic effects of turmeric is discussed. Further, these results strengthen the various other biological effects of turmeric which have direct relevance to anticarcinogenesis and chemoprevention.

  20. Large eccentric strength increase using the Copenhagen Adduction exercise in football

    DEFF Research Database (Denmark)

    Ishøi, L; Sørensen, C N; Kaae, N M

    2016-01-01

    Hip adductor injuries are frequent in football, and players with low adductor strength appear to be at increased risk of injury. High adductor muscle activity has been shown in the Copenhagen Adduction exercise (CA); however, an associated strength gain has not been investigated. This study aims...... to examine the eccentric hip adduction strength (EHAD) gain using the CA in-season. Two U-19 sub-elite football teams, including 24 football players, were randomized to either an 8-week supervised progressive training program in addition to the usual training (intervention) or to continue training as usual...

  1. Inhibition of nicotine-DNA adduct formation by polyphenolic compounds in vitro

    International Nuclear Information System (INIS)

    Cheng Yan; Wang Haifang; Sun Hongfang; Li Hongli

    2004-01-01

    Nicotine[3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco products, has proven to be a potential genotoxic compound. Some polyphenolic compounds can suppress the DNA adduction, and hence act as the potential inhibitors of carcinogenesis. In this study, the inhibitory effects of three polyphenolic compounds, curcumin (diferuloylmethane), resveratrol (trans-3, 5, 4-trihydroxystilbene) and tea polyphenols, on the nicotine-DNA adduction have been investigated in vitro using radiolabelled nicotine and liquid scintillation counting (LSC) technique. Also, the inhibition mechanism of these chemopreventive agents in regard to the activity of the biotransformation enzymes, including cytochrome P450 (CYP450), cytochrome b 5 (CYb 5 ) and glutathione S-transferase (GST), has been studied. The results demonstrated that these three polyphenols induced marked dose-dependent decrease in nicotine-DNA adducts as compared with the controls. The elimination rate of adducts reached above 46% at the highest dose for all the three agents with 51.6% for resveratrol. Correspondingly, three polyphenols all suppressed CYP450 and CYb 5 , whereas curcumin and resveratrol induced GST. The authors may arrive at a point that the three polyphenols are beneficial to prevent the nicotine adduct formation, and thus may be used to block the potential carcinogenesis induced by nicotine. (authors)

  2. Everglades National Park Including Biscayne National Park. Activity Book.

    Science.gov (United States)

    Ruehrwein, Dick

    Intended to help elementary school children learn about the resources of the Everglades and Biscayne National Parks, this activity book includes information, puzzles, games, and quizzes. The booklet deals with concepts related to: (1) the seasons; (2) fire ecology; (3) water; (4) fish; (5) mammals; (6) mosquitos; (7) birds; (8) venomous snakes;…

  3. Identification of human and murine sulfotransferases able to activate hydroxylated metabolites of methyleugenol to mutagens in Salmonella typhimurium and detection of associated DNA adducts using UPLC-MS/MS methods.

    Science.gov (United States)

    Herrmann, Kristin; Engst, Wolfram; Appel, Klaus E; Monien, Bernhard H; Glatt, Hansruedi

    2012-07-01

    Methyleugenol, a secondary metabolite present in many herbal spices, is carcinogenic in various tissues of mice and rats but negative in standard in vitro mutagenicity tests. Several observations indicate that hydroxylation followed by sulfation is an important activation pathway in the carcinogenicity and DNA adduct formation by methyleugenol and other alkenylbenzenes in animal models. However, sulfation is not taken into account in standard in vitro tests. Therefore, we have studied whether expression of murine or human sulfotransferases (SULTs) in the target strain, Salmonella typhimurium TA100, leads to the activation of hydroxylated metabolites of methyleugenol [(+)-1'-hydroxymethyleugenol, (-)-1'-hydroxymethyleugenol and (E)-3'-hydroxymethylisoeugenol]. Human SULT1A1 (a form expressed at high levels in many tissues) and SULT1C2 (expressed primarily in foetal tissues) activated all three compounds even at very low substrate concentrations. At higher concentrations, activation was also observed with human SULT1A2 and SULT1E1. Murine Sult1a1 required higher substrate concentrations than its human orthologue. Other SULT forms (human 1A3, 1C1, 1C3, 2A1 and 2B1b as well as murine 1d1) did not activate any methyleugenol metabolites studied. Furthermore, we developed isotope-dilution mass-spectrometric methods for the sensitive and specific detection of DNA adducts formed by methyleugenol metabolites. All three hydroxylated metabolites formed the same DNA adducts in S. typhimurium TA100-hSULT1A1: high levels of N (2)-(trans-methylisoeugenol-3'-yl)-2'-deoxyguanosine and modest levels of N (6)-(trans-methylisoeugenol-3'-yl)-2'-deoxyadenosine. Adduct levels correlated with the mutagenic effects induced. No adducts were formed by the test compounds in the SULT-deficient standard strain TA100. In conclusion, several methyleugenol metabolites are activated to DNA-reactive mutagens in S. typhimurium upon incorporation of appropriate sulfation capacity. We have identified

  4. New adducts of Lapachol with primary amines

    Energy Technology Data Exchange (ETDEWEB)

    Santos, Mirelly D.F.; Litivack-Junior, Jose T.; Antunes, Roberto V.; Silva, Tania M.S.; Camara, Celso A., E-mail: ccelso@dq.ufrpe.b [Universidade Federal Rural de Pernambuco (UFRPE), Recife, PE (Brazil). Dept. de Quimica

    2011-07-01

    New adducts of lapachol with neat primary aliphatic amines were obtained in a solvent-free reaction in good to reasonable yields (52 to 88%), at room temperature. The new compounds containing a phenazine moiety were obtained from suitable functionalized aminoalkyl compounds, including ethanolamine, 3-propanolamine, 2-methoxy-ethylamine, 3-methoxy-propylamine, n-butylamine and 2-phenetylamine. (author)

  5. Alcohol, Aldehydes, Adducts and Airways

    Directory of Open Access Journals (Sweden)

    Muna Sapkota

    2015-11-01

    Full Text Available Drinking alcohol and smoking cigarettes results in the formation of reactive aldehydes in the lung, which are capable of forming adducts with several proteins and DNA. Acetaldehyde and malondialdehyde are the major aldehydes generated in high levels in the lung of subjects with alcohol use disorder who smoke cigarettes. In addition to the above aldehydes, several other aldehydes like 4-hydroxynonenal, formaldehyde and acrolein are also detected in the lung due to exposure to toxic gases, vapors and chemicals. These aldehydes react with nucleophilic targets in cells such as DNA, lipids and proteins to form both stable and unstable adducts. This adduction may disturb cellular functions as well as damage proteins, nucleic acids and lipids. Among several adducts formed in the lung, malondialdehyde DNA (MDA-DNA adduct and hybrid malondialdehyde-acetaldehyde (MAA protein adducts have been shown to initiate several pathological conditions in the lung. MDA-DNA adducts are pre-mutagenic in mammalian cells and induce frame shift and base-pair substitution mutations, whereas MAA protein adducts have been shown to induce inflammation and inhibit wound healing. This review provides an insight into different reactive aldehyde adducts and their role in the pathogenesis of lung disease.

  6. Photochemical Reaction of 7,12-Dimethylbenz[a]anthracene (DMBA and Formation of DNA Covalent Adducts

    Directory of Open Access Journals (Sweden)

    Peter P. Fu

    2005-04-01

    Full Text Available DMBA, 7,12-dimethylbenz[a]anthracene, is a widely studied polycyclic aromatic hydrocarbon that has long been recognized as a probable human carcinogen. It has been found that DMBA is phototoxic in bacteria as well as in animal or human cells and photomutagenic in Salmonella typhimurium strain TA102. This article tempts to explain the photochemistry and photomutagenicity mechanism. Light irradiation converts DMBA into several photoproducts including benz[a]anthracene-7,12-dione, 7-hydroxy-12-keto-7-methylbenz[a]anthracene, 7,12-epidioxy-7,12-dihydro-DMBA, 7-hydroxymethyl-12-methylbenz[a]anthracene and 12-hydroxymethyl-7-methylbenz[a]anthracene. Structures of these photoproducts have been identified by either comparison with authentic samples or by NMR/MS. At least four other photoproducts need to be assigned. Photo-irradiation of DMBA in the presence of calf thymus DNA was similarly conducted and light-induced DMBA-DNA adducts were analyzed by 32P-postlabeling/TLC, which indicates that multiple DNA adducts were formed. This indicates that formation of DNA adducts might be the source of photomutagenicity of DMBA. Metabolites obtained from the metabolism of DMBA by rat liver microsomes were reacted with calf thymus DNA and the resulting DNA adducts were analyzed by 32P-postlabeling/TLC under identical conditions. Comparison of the DNA adduct profiles indicates that the DNA adducts formed from photo-irradiation are different from the DNA adducts formed due to the reaction of DMBA metabolites with DNA. These results suggest that photo-irradiation of DMBA can lead to genotoxicity through activation pathways different from those by microsomal metabolism of DMBA.

  7. DNA adduct measurements in zebra mussels, Dreissena polymorpha, Pallas

    International Nuclear Information System (INIS)

    Le Goff, J.; Gallois, J.; Pelhuet, L.; Devier, M.H.; Budzinski, H.; Pottier, D.; Andre, V.; Cachot, J.

    2006-01-01

    The purpose of this study was to examine PAH accumulation and bulky DNA adduct formation in the digestive gland of zebra mussels exposed in their habitat or in controlled laboratory conditions to complex mixture of PAH. DNA adducts were measured using a 32 P-postlabelling protocol with nuclease P1 enrichment adapted from Reddy and Randerath [Reddy, M.V., Randerath, K., 1986. Nuclease P1-mediated enhancement of sensitivity of 32 P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551]. Specimens collected in the upper part of the Seine estuary were shown to accumulate higher levels of PAH (up to 1.6 μg g -1 dry weight) in comparison to individuals from the reference site (0.053 μg g -1 dry weight). The former exhibited elevated levels of DNA adducts (up to 4.0/10 8 nucleotides) and higher diversity of individual adducts with five distinct spots being specifically detected in individuals originating from the Seine estuary. Zebra mussels exposed for 5 days to 0.01% (v/v) of organic extract of sediment from the Seine estuary were shown to accumulate high amounts of PAH (up to 138 μg g -1 dry weight) but exhibited relatively low levels of DNA adducts. Exposure to benzo[a]pyrene led to a dose-dependent accumulation of B[a]P (up to 7063 μg g -1 dry weight) and a clear induction of DNA adduct formation in the digestive gland of mussels (up to 1.13/10 8 nucleotides). Comparisons with other bivalves exposed to the same model PAH, revealed similar levels of adducts and comparable adduct profiles with a main adduct spot and a second faint one. This study clearly demonstrated that zebra mussels are able to biotransform B[a]P and probably other PAH into reactive metabolites with DNA-binding activity. This work also demonstrated the applicability of the nuclease P1 enhanced 32 P-postlabelling method for bulky adduct detection in the digestive gland of zebra mussels. DNA adduct measurement in zebra mussels could be a suitable biomarker to monitor

  8. DNA adduct measurements in zebra mussels, Dreissena polymorpha, Pallas

    Energy Technology Data Exchange (ETDEWEB)

    Le Goff, J. [GRECAN, UPRES EA-1772, University of Caen, Caen (France); Gallois, J. [Laboratory F. Duncombe, Conseil General du Calvados, Caen (France); Pelhuet, L. [LPTC, UMR-5472 CNRS, University Bordeaux I, Bordeaux (France); Devier, M.H. [LPTC, UMR-5472 CNRS, University Bordeaux I, Bordeaux (France); Budzinski, H. [LPTC, UMR-5472 CNRS, University Bordeaux I, Bordeaux (France); Pottier, D. [GRECAN, UPRES EA-1772, University of Caen, Caen (France); Andre, V. [GRECAN, UPRES EA-1772, University of Caen, Caen (France); Cachot, J. [LEMA, UPRES EA-3222, IFRMP 23, University of Le Havre, 25 rue Philippe Lebon, B.P. 540, 76058 Le Havre Cedex (France)]. E-mail: jerome.cachot@univ-lehavre.fr

    2006-08-12

    The purpose of this study was to examine PAH accumulation and bulky DNA adduct formation in the digestive gland of zebra mussels exposed in their habitat or in controlled laboratory conditions to complex mixture of PAH. DNA adducts were measured using a {sup 32}P-postlabelling protocol with nuclease P1 enrichment adapted from Reddy and Randerath [Reddy, M.V., Randerath, K., 1986. Nuclease P1-mediated enhancement of sensitivity of {sup 32}P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551]. Specimens collected in the upper part of the Seine estuary were shown to accumulate higher levels of PAH (up to 1.6 {mu}g g{sup -1} dry weight) in comparison to individuals from the reference site (0.053 {mu}g g{sup -1} dry weight). The former exhibited elevated levels of DNA adducts (up to 4.0/10{sup 8} nucleotides) and higher diversity of individual adducts with five distinct spots being specifically detected in individuals originating from the Seine estuary. Zebra mussels exposed for 5 days to 0.01% (v/v) of organic extract of sediment from the Seine estuary were shown to accumulate high amounts of PAH (up to 138 {mu}g g{sup -1} dry weight) but exhibited relatively low levels of DNA adducts. Exposure to benzo[a]pyrene led to a dose-dependent accumulation of B[a]P (up to 7063 {mu}g g{sup -1} dry weight) and a clear induction of DNA adduct formation in the digestive gland of mussels (up to 1.13/10{sup 8} nucleotides). Comparisons with other bivalves exposed to the same model PAH, revealed similar levels of adducts and comparable adduct profiles with a main adduct spot and a second faint one. This study clearly demonstrated that zebra mussels are able to biotransform B[a]P and probably other PAH into reactive metabolites with DNA-binding activity. This work also demonstrated the applicability of the nuclease P1 enhanced {sup 32}P-postlabelling method for bulky adduct detection in the digestive gland of zebra mussels. DNA adduct measurement in

  9. Acetaldehyde Adducts in Alcoholic Liver Disease

    Directory of Open Access Journals (Sweden)

    Mashiko Setshedi

    2010-01-01

    Full Text Available Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD, with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC. Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2–15% versus cirrhosis (15–20% is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC.

  10. Wideband CMOS low noise amplifier including an active balun

    NARCIS (Netherlands)

    Blaakmeer, S.C.; Klumperink, Eric A.M.; Leenaerts, D.M.W.; Nauta, Bram

    2007-01-01

    An inductorless LNA with active balun is proposed for multi-standard radio applications between 100MHz and 6GHz [1]. It exploits a combination of a common-gate (CG) stage and an common-source (CS) stage with replica biasing to maximize balanced operation, while simultaneously canceling the noise and

  11. Information for Teachers (Including Classroom Activities), Skylab Student Project.

    Science.gov (United States)

    National Aeronautics and Space Administration, Washington, DC.

    This program is intended to directly involve the educational community in space experiments, many of which can be related to existing curricula. Included in this first packet are: 1) a brief description of the Skylab Program and the National Science Teachers Association-National Aeronautics and Space Administration (NSTA-NASA) Skylab Student…

  12. Formation of Hydroxymethyl DNA Adducts in Rats Orally Exposed to Stable Isotope Labeled Methanol

    Science.gov (United States)

    Lu, Kun; Gul, Husamettin; Upton, Patricia B.; Moeller, Benjamin C.; Swenberg, James A.

    2012-01-01

    Methanol is a large volume industrial chemical and widely used solvent and fuel additive. Methanol’s well known toxicity and use in a wide spectrum of applications has raised long-standing environmental issues over its safety, including its carcinogenicity. Methanol has not been listed as a carcinogen by any regulatory agency; however, there are debates about its carcinogenic potential. Formaldehyde, a metabolite of methanol, has been proposed to be responsible for the carcinogenesis of methanol. Formaldehyde is a known carcinogen and actively targets DNA and protein, causing diverse DNA and protein damage. However, formaldehyde-induced DNA adducts arising from the metabolism of methanol have not been reported previously, largely due to the absence of suitable DNA biomarkers and the inability to differentiate what was due to methanol compared with the substantial background of endogenous formaldehyde. Recently, we developed a unique approach combining highly sensitive liquid chromatography-mass spectrometry methods and exposure to stable isotope labeled chemicals to simultaneously quantify formaldehyde-specific endogenous and exogenous DNA adducts. In this study, rats were exposed daily to 500 or 2000 mg/kg [13CD4]-methanol by gavage for 5 days. Our data demonstrate that labeled formaldehyde arising from [13CD4]-methanol induced hydroxymethyl DNA adducts in multiple tissues in a dose-dependent manner. The results also demonstrated that the number of exogenous DNA adducts was lower than the number of endogenous hydroxymethyl DNA adducts in all tissues of rats administered 500 mg/kg per day for 5 days, a lethal dose to humans, even after incorporating an average factor of 4 for reduced metabolism due to isotope effects of deuterium-labeled methanol into account. PMID:22157354

  13. Chemical repair activity of free radical scavenger edaravone: reduction reactions with dGMP hydroxyl radical adducts and suppression of base lesions and AP sites on irradiated plasmid DNA.

    Science.gov (United States)

    Hata, Kuniki; Urushibara, Ayumi; Yamashita, Shinichi; Lin, Mingzhang; Muroya, Yusa; Shikazono, Naoya; Yokoya, Akinari; Fu, Haiying; Katsumura, Yosuke

    2015-01-01

    Reactions of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) with deoxyguanosine monophosphate (dGMP) hydroxyl radical adducts were investigated by pulse radiolysis technique. Edaravone was found to reduce the dGMP hydroxyl radical adducts through electron transfer reactions. The rate constants of the reactions were greater than 4 × 10(8) dm(3) mol(-1) s(-1) and similar to those of the reactions of ascorbic acid, which is a representative antioxidant. Yields of single-strand breaks, base lesions, and abasic sites produced in pUC18 plasmid DNA by gamma ray irradiation in the presence of low concentrations (10-1000 μmol dm(-3)) of edaravone were also quantified, and the chemical repair activity of edaravone was estimated by a method recently developed by the authors. By comparing suppression efficiencies to the induction of each DNA lesion, it was found that base lesions and abasic sites were suppressed by the chemical repair activity of edaravone, although the suppression of single-strand breaks was not very effective. This phenomenon was attributed to the chemical repair activity of edaravone toward base lesions and abasic sites. However, the chemical repair activity of edaravone for base lesions was lower than that of ascorbic acid. © The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  14. Hip adduction and abduction strength profiles in elite, sub-elite and amateur Australian footballers.

    Science.gov (United States)

    Prendergast, Ned; Hopper, Diana; Finucane, Mark; Grisbrook, Tiffany L

    2016-09-01

    It has been reported that obtaining an adduction-to-abduction strength ratio of 90-100%, and an adduction strength equal to that of the uninjured side, are suitable clinical milestones for return to sport following groin injury. Little is known about hip adduction and abduction strength profiles in Australian footballers. This study aimed to compare isometric hip adduction and abduction strength profiles between preferred and non-preferred kicking legs in elite, sub-elite and amateur Australian footballers. Cross sectional study 36 elite, 19 sub-elite and 18 amateur Australian footballers, with a mean age of 24, 19 and 23 years respectively, were included. Maximal hip isometric adduction and abduction strength were measured using a hand held dynamometer with external belt fixation. There were no significant differences in isometric hip adduction (p=0.262) or abduction (p=0.934) strength, or the adduction-to-abduction ratio (p=0.163), between preferred and non-preferred kicking legs, regardless of playing level. Elite players had significantly greater isometric hip adduction and abduction strength than both sub-elite (mean difference; adduction=46.01N, pamateur players (mean difference; adduction=78.72N, p<0.001, abduction=59.11N, p<0.001). There was no significant difference in the adduction-to-abduction ratio between the playing levels (p=0.165). No significant differences were found between preferred and non-preferred kicking legs across the playing levels for isometric hip adduction, abduction or the adduction-to-abduction ratio. This may have implications for developing groin injury prediction and return to sport criteria in Australian footballers. Copyright © 2015 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  15. Acetaminophen Adducts Detected in Serum of Pediatric Patients With Acute Liver Failure.

    Science.gov (United States)

    Alonso, Estella M; James, Laura P; Zhang, Song; Squires, Robert H

    2015-07-01

    Previous studies in patients with acute liver failure identified acetaminophen (APAP) protein adducts in the serum of 12% and 19% of children and adults, respectively, with acute liver failure of indeterminate etiology. This article details the testing of APAP adducts in a subset (n = 393) of patients with varied diagnoses in the Pediatric Acute Liver Failure Study Group (PALFSG). Serum samples were available from 393 participants included in the PALFSG registry. Adduct measurement was performed using validated methods. Participants were grouped by diagnostic category as known APAP overdose, known other diagnosis, and indeterminate etiology. Demographic and clinical characteristics and participant outcomes were compared by adduct status (positive or negative) within each group. APAP adduct testing was positive in 86% of participants with known APAP overdose, 6% with other known diagnoses, and 11% with an indeterminate cause of liver failure. Adduct-positive participants were noted to have marked elevation of serum alanine aminotransferase and aspartate aminotransferase coupled with total serum bilirubin that was significantly lower than adduct-negative patients. In the indeterminate group, adduct-positive patients had different outcomes than adduct-negative patients (P = 0.03); spontaneous survival was 16 of 21 (76%) in adduct-positive patients versus 75 of 169 (44%) in adduct-negative patients. Prognosis did not vary by adduct status in patients with known diagnoses. Furthermore, study is needed to understand the relation of APAP exposure, as determined by the presence of APAP adducts, to the clinical phenotype and outcomes of children with acute liver failure.

  16. Mass spectrometric analysis of sulfur mustard-induced biomolecular adducts: Are DNA adducts suitable biomarkers of exposure?

    Science.gov (United States)

    Zubel, Tabea; Bürkle, Alexander; Mangerich, Aswin

    2017-12-23

    The bi-functional chemical warfare agent sulfur mustard (SM), whose release in asymmetric conflicts or terrorist attacks represents a realistic threat, induces several kinds of biomolecular adducts, including highly toxic DNA adducts. Isotope dilution liquid chromatographic tandem mass spectrometry (ID-LC-MS/MS) is considered the gold standard for highly accurate, precise, specific and sensitive quantification of DNA adducts in general. Recently, a number of LC-MS/MS approaches have been established to analyze SM-induced protein and DNA adducts in cell culture and rodent animal models. As DNA adducts are mechanism-based biomarkers for SM exposure, results from such studies provide a deeper understanding of the etiology of SM-induced pathologies, especially of long-term effects such as cancer formation. As a result, medical treatment of SM-exposed individuals might be improved. Yet, despite the progress that has been made during the last years, there is still a need for advanced methods of ID-LC-MS/MS for the detection and quantitation of SM adducts. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. EMG evaluation of hip adduction exercises for soccer players: implications for exercise selection in prevention and treatment of groin injuries.

    Science.gov (United States)

    Serner, Andreas; Jakobsen, Markus Due; Andersen, Lars Louis; Hölmich, Per; Sundstrup, Emil; Thorborg, Kristian

    2014-07-01

    Exercise programmes are used in the prevention and treatment of adductor-related groin injuries in soccer; however, there is a lack of knowledge concerning the intensity of frequently used exercises. Primarily to investigate muscle activity of adductor longus during six traditional and two new hip adduction exercises. Additionally, to analyse muscle activation of gluteals and abdominals. 40 healthy male elite soccer players, training >5 h a week, participated in the study. Muscle activity using surface electromyography (sEMG) was measured bilaterally for the adductor longus during eight hip adduction strengthening exercises and peak EMG was normalised (nEMG) using an isometric maximal voluntary contraction (MVC) as reference. Furthermore, muscle activation of the gluteus medius, rectus abdominis and the external abdominal obliques was analysed during the exercises. There were large differences in peak nEMG of the adductor longus between the exercises, with values ranging from 14% to 108% nEMG (pinjuries. The Copenhagen Adduction and the hip adduction with an elastic band are dynamic high-intensity exercises, which can easily be performed at any training facility and could therefore be relevant to include in future prevention and treatment programmes. 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.

  18. Bypass of Aflatoxin B[subscript 1] Adducts by the Sulfolobus solfataricus DNA Polymerase IV

    Energy Technology Data Exchange (ETDEWEB)

    Banerjee, Surajit; Brown, Kyle L.; Egli, Martin; Stone, Michael P. (Vanderbilt)

    2012-07-18

    Aflatoxin B{sub 1} (AFB{sub 1}) is oxidized to an epoxide in vivo, which forms an N7-dG DNA adduct (AFB{sub 1}-N7-dG). The AFB{sub 1}-N7-dG can rearrange to a formamidopyrimidine (AFB{sub 1}-FAPY) derivative. Both AFB{sub 1}-N7-dG and the {beta}-anomer of the AFB{sub 1}-FAPY adduct yield G {yields} T transversions in Escherichia coli, but the latter is more mutagenic. We show that the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) bypasses AFB{sub 1}-N7-dG in an error-free manner but conducts error-prone replication past the AFB{sub 1}-FAPY adduct, including misinsertion of dATP, consistent with the G {yields} T mutations observed in E. coli. Three ternary (Dpo4-DNA-dNTP) structures with AFB{sub 1}-N7-dG adducted template:primers have been solved. These demonstrate insertion of dCTP opposite the AFB{sub 1}-N7-dG adduct, and correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB{sub 1}-N7-dG:dC pair. The insertion of dTTP reveals hydrogen bonding between the template N3 imino proton and the O{sup 2} oxygen of dTTP, and between the template T O{sup 4} oxygen and the N3 imino proton of dTTP, perhaps explaining why this polymerase does not efficiently catalyze phosphodiester bond formation from this mispair. The AFB{sub 1}-N7-dG maintains the 5'-intercalation of the AFB{sub 1} moiety observed in DNA. The bond between N7-dG and C8 of the AFB{sub 1} moiety remains in plane with the alkylated guanine, creating a 16{sup o} inclination of the AFB{sub 1} moiety with respect to the guanine. A binary (Dpo4-DNA) structure with an AFB{sub 1}-FAPY adducted template:primer also maintains 5'-intercalation of the AFB{sub 1} moiety. The {beta}-deoxyribose anomer is observed. Rotation about the FAPY C5-N{sup 5} bond orients the bond between N{sup 5} and C8 of the AFB{sub 1} moiety out of plane in the 5'-direction, with respect to the FAPY base. The formamide group extends in the 3'-direction. This improves

  19. Free flow electrophoresis separation and AMS quantitation of 14C-naphthalene-protein adducts

    Science.gov (United States)

    Buchholz, Bruce A.; Haack, Kurt W.; Sporty, Jennifer L.; Buckpitt, Alan R.; Morin, Dexter

    2010-04-01

    Naphthalene is a volatile aromatic hydrocarbon to which humans are exposed from a variety of sources including mobile air sources and cigarette smoke. Naphthalene produces dose-(concentration)dependent injury to airway epithelial cells of murine lung which is observed at concentrations well below the current occupational exposure standard. Toxicity is dependent upon the cytochrome P450 mediated metabolic activation of the parent substrate to unstable metabolites which become bound covalently to tissue proteins. Nearly 70 proteins have been identified as forming adducts with reactive naphthalene metabolites using in vitro systems but very little work has been conducted in vivo because reasonably large amounts (100 μCi) of 14C labeled parent compound must be administered to generate detectable adduct levels on storage phosphor screens following separation of labeled proteins by 2D gel electrophoresis. The work described here was done to provide proof of concept that protein separation by free flow electrophoresis followed by AMS detection of protein fractions containing protein bound reactive metabolites would provide adducted protein profiles in animals dosed with trace quantities of labeled naphthalene. Mice were administered 200 mg/kg naphthalene intraperitoneally at a calculated specific activity of 2 DPM/nmol (1 pCi/nmol) and respiratory epithelial tissue was obtained by lysis lavage 4 h post injection. Free flow electrophoresis (FFE) separates proteins in the liquid phase over a large pH range (2.5-11.5) using low molecular weight acids and bases to modify the pH. The apparatus separates fractions into standard 96-well plates that can be used in other protein analysis techniques. The buffers of the fractions have very high carbon content, however, and need to be dialyzed to yield buffers compatible with 14C-AMS. We describe the processing techniques required to couple FFE to AMS for quantitation of protein adducts.

  20. Free flow electrophoresis separation and AMS quantitation of {sup 14}C-naphthalene-protein adducts

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Bruce A., E-mail: bbuchholz@llnl.go [Center for AMS, LLNL, 7000 East Avenue, Livermore, CA 94551 (United States); Haack, Kurt W.; Sporty, Jennifer L. [Center for AMS, LLNL, 7000 East Avenue, Livermore, CA 94551 (United States); Buckpitt, Alan R.; Morin, Dexter [Department of Molecular Biosciences, School of Veterinary Medicine, UC Davis, Davis, CA 95616 (United States)

    2010-04-15

    Naphthalene is a volatile aromatic hydrocarbon to which humans are exposed from a variety of sources including mobile air sources and cigarette smoke. Naphthalene produces dose-(concentration)dependent injury to airway epithelial cells of murine lung which is observed at concentrations well below the current occupational exposure standard. Toxicity is dependent upon the cytochrome P450 mediated metabolic activation of the parent substrate to unstable metabolites which become bound covalently to tissue proteins. Nearly 70 proteins have been identified as forming adducts with reactive naphthalene metabolites using in vitro systems but very little work has been conducted in vivo because reasonably large amounts (100 muCi) of {sup 14}C labeled parent compound must be administered to generate detectable adduct levels on storage phosphor screens following separation of labeled proteins by 2D gel electrophoresis. The work described here was done to provide proof of concept that protein separation by free flow electrophoresis followed by AMS detection of protein fractions containing protein bound reactive metabolites would provide adducted protein profiles in animals dosed with trace quantities of labeled naphthalene. Mice were administered 200 mg/kg naphthalene intraperitoneally at a calculated specific activity of 2 DPM/nmol (1 pCi/nmol) and respiratory epithelial tissue was obtained by lysis lavage 4 h post injection. Free flow electrophoresis (FFE) separates proteins in the liquid phase over a large pH range (2.5-11.5) using low molecular weight acids and bases to modify the pH. The apparatus separates fractions into standard 96-well plates that can be used in other protein analysis techniques. The buffers of the fractions have very high carbon content, however, and need to be dialyzed to yield buffers compatible with {sup 14}C-AMS. We describe the processing techniques required to couple FFE to AMS for quantitation of protein adducts.

  1. Synthesis, characterization, and antifungal activity of novel (Z)-N-(2-cyano-3-phenylprop-2-en-1-yl)-alkyl/aryl-sulfonamides derived from a Morita-Baylis-Hillman adduct

    Science.gov (United States)

    Tavares, Eder C.; Rubinger, Mayura M. M.; Zacchi, Carlos H. C.; Silva, Simone A.; Oliveira, Marcelo R. L.; Guilardi, Silvana; Alcântara, Antônio F. de C.; Piló-Veloso, Dorila; Zambolim, Laércio

    2014-06-01

    A series of allyl sulfonamides prepared from the reaction of the Morita-Baylis-Hillman adduct 2-[hydroxy(phenyl)methyl]acrylonitrile with primary sulfonamides (RSO2NH2), where R = C6H5 (1), 4-Fsbnd C6H4 (2), 4-Clsbnd C6H4 (3), 4-Brsbnd C6H4 (4), 4-NO2sbnd C6H4 (5), CH3 (6), CH3CH2 (7), CH3(CH2)3 (8), and CH3(CH2)7 (9), were characterized by IR, 1H and 13C NMR spectroscopies, mass spectrometry and elemental analyses. BLYP/6-31G* calculations suggested stereoselective reactions, resulting in the exclusive formation of the thermodynamically more stable Z-products. The Z-configuration of the products was confirmed by NOE difference spectroscopy and single crystal X-ray diffraction measurements. The allyl sulfonamides were active against Colletotrichum gloeosporioides, an important agent of anthracnose in plants.

  2. DNA adducts: Mass spectrometry methods and future prospects

    International Nuclear Information System (INIS)

    Farmer, P.B.; Brown, K.; Tompkins, E.; Emms, V.L.; Jones, D.J.L.; Singh, R.; Phillips, D.H.

    2005-01-01

    Detection of DNA adducts is widely used for the monitoring of exposure to genotoxic carcinogens. Knowledge of the nature and amounts of DNA adducts formed in vivo also gives valuable information regarding the mutational effects that may result from particular exposures. The power of mass spectrometry (MS) to achieve qualitative and quantitative analyses of human DNA adducts has increased greatly in recent years with the development of improved chromatographic interfaces and ionisation sources. Adducts have been detected on nucleic acid bases, 2'-deoxynucleosides or 2'-deoxynucleotides, with LC-MS/MS being the favoured technique for many of these analyses. Our current applications of this technique include the determination of N7-(2-carbamoyl-2-hydroxyethyl)-guanine, which was postulated to be found as a DNA repair product in urine following exposure to acrylamide, and of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydro-2'-deoxyadenosine, as markers of oxidative damage in human lymphocyte DNA. Higher sensitivity (with a detection limit of 1-10 adducts/10 12 nucleotides) may be achieved by the use of accelerator mass spectrometry (AMS), although this requires the presence of certain isotopes, such as [ 14 C], in the material being analysed. In order to make this technique more amenable for studies of human exposure to environmental carcinogens, new postlabelling techniques, incorporating [ 14 C] into specific DNA adducts after formation, are being developed. It is expected that combining the use of advanced MS techniques with existing 32 P-postlabelling and immunochemical methodologies will contribute greatly to the understanding of the burden of human exposure to environmental carcinogens

  3. Comparative Error-Free and Error-Prone Translesion Synthesis of N(2)-2'-Deoxyguanosine Adducts Formed by Mitomycin C and Its Metabolite, 2,7-Diaminomitosene, in Human Cells.

    Science.gov (United States)

    Bose, Arindam; Surugihalli, Chaitra; Pande, Paritosh; Champeil, Elise; Basu, Ashis K

    2016-05-16

    Mitomycin C (MC) is a cytotoxic and mutagenic antitumor agent that alkylates DNA upon reductive activation. 2,7-Diaminomitosene (2,7-DAM) is a major metabolite of MC in tumor cells, which also alkylates DNA. MC forms seven DNA adducts, including monoadducts and inter- and intrastrand cross-links, whereas 2,7-DAM forms two monoadducts. Herein, the biological effects of the dG-N(2) adducts formed by MC and 2,7-DAM have been compared by constructing single-stranded plasmids containing these adducts and replicating them in human embryonic kidney 293T cells. Translesion synthesis (TLS) efficiencies of dG-N(2)-MC and dG-N(2)-2,7-DAM were 38 ± 3 and 27 ± 3%, respectively, compared to that of a control plasmid. This indicates that both adducts block DNA synthesis and that dG-N(2)-2,7-DAM is a stronger replication block than dG-N(2)-MC. TLS of each adducted construct was reduced upon siRNA knockdown of pol η, pol κ, or pol ζ. For both adducts, the most significant reduction occurred with knockdown of pol κ, which suggests that pol κ plays a major role in TLS of these dG-N(2) adducts. Analysis of the progeny showed that both adducts were mutagenic, and the mutation frequencies (MF) of dG-N(2)-MC and dG-N(2)-2,7-DAM were 18 ± 3 and 10 ± 1%, respectively. For both adducts, the major type of mutation was G → T transversions. Knockdown of pol η and pol ζ reduced the MF of dG-N(2)-MC and dG-N(2)-2,7-DAM, whereas knockdown of pol κ increased the MF of these adducts. This suggests that pol κ predominantly carries out error-free TLS, whereas pol η and pol ζ are involved in error-prone TLS. The largest reduction in MF by 78 and 80%, respectively, for dG-N(2)-MC and dG-N(2)-2,7-DAM constructs occurred when pol η, pol ζ, and Rev1 were simultaneously knocked down. This result strongly suggests that, unlike pol κ, these three TLS polymerases cooperatively perform the error-prone TLS of these adducts.

  4. Specific Function of the Met-Tyr-Trp Adduct Radical and Residues Arg-418 and Asp-137 in the Atypical Catalase Reaction of Catalase-Peroxidase KatG*

    Science.gov (United States)

    Zhao, Xiangbo; Khajo, Abdelahad; Jarrett, Sanchez; Suarez, Javier; Levitsky, Yan; Burger, Richard M.; Jarzecki, Andrzej A.; Magliozzo, Richard S.

    2012-01-01

    Catalase activity of the dual-function heme enzyme catalase-peroxidase (KatG) depends on several structural elements, including a unique adduct formed from covalently linked side chains of three conserved amino acids (Met-255, Tyr-229, and Trp-107, Mycobacterium tuberculosis KatG numbering) (MYW). Mutagenesis, electron paramagnetic resonance, and optical stopped-flow experiments, along with calculations using density functional theory (DFT) methods revealed the basis of the requirement for a radical on the MYW-adduct, for oxyferrous heme, and for conserved residues Arg-418 and Asp-137 in the rapid catalase reaction. The participation of an oxyferrous heme intermediate (dioxyheme) throughout the pH range of catalase activity is suggested from our finding that carbon monoxide inhibits the activity at both acidic and alkaline pH. In the presence of H2O2, the MYW-adduct radical is formed normally in KatG[D137S] but this mutant is defective in forming dioxyheme and lacks catalase activity. KatG[R418L] is also catalase deficient but exhibits normal formation of the adduct radical and dioxyheme. Both mutants exhibit a coincidence between MYW-adduct radical persistence and H2O2 consumption as a function of time, and enhanced subunit oligomerization during turnover, suggesting that the two mutations disrupting catalase turnover allow increased migration of the MYW-adduct radical to protein surface residues. DFT calculations showed that an interaction between the side chain of residue Arg-418 and Tyr-229 in the MYW-adduct radical favors reaction of the radical with the adjacent dioxyheme intermediate present throughout turnover in WT KatG. Release of molecular oxygen and regeneration of resting enzyme are thereby catalyzed in the last step of a proposed catalase reaction. PMID:22918833

  5. Redshift or adduct stabilization -- a computational study of hydrogen bonding in adducts of protonated carboxylic acids

    DEFF Research Database (Denmark)

    Olesen, Solveig Gaarn; Hammerum, Steen

    2009-01-01

    changes and the redshift favor the Z OH group, matching the results of NBO and AIM calculations. This reflects that the thermochemistry of adduct formation is not a good measure of the hydrogen bond strength in charged adducts, and that the ionic interactions in the E and Z adducts of protonated...

  6. Detection of carcinogenic etheno-DNA adducts in children and adolescents with non-alcoholic steatohepatitis (NASH).

    Science.gov (United States)

    Teufel, Ulrike; Peccerella, Teresa; Engelmann, Guido; Bruckner, Thomas; Flechtenmacher, Christa; Millonig, Gunda; Stickel, Felix; Hoffmann, Georg F; Schirmacher, Peter; Mueller, Sebastian; Bartsch, Helmut; Seitz, Helmut K

    2015-12-01

    Carcinogenic exocyclic-DNA adducts like 1,N(6)-etheno-2'-deoxyadenosine (εdA) are formed through reactive intermediates of 4-hydroxynonenal (4-HNE) or other lipid peroxidation (LPO) products with the DNA bases A, C, methyl-C and G. High levels of hepatic etheno-DNA adducts have been detected in cancer prone liver diseases including alcoholic liver disease (ALD). In ALD εdA levels correlated significantly with cytochrome P-450 2E1 (CYP2E1) expression which is also induced in non-alcoholic steatohepatitis (NASH). We investigated the occurrence of εdA adducts in children with NASH as a DNA damage marker. Liver biopsies from 21 children/adolescents with histologically proven NASH were analysed for hepatic fat content, inflammation, and fibrosis. εdA levels in DNA, CYP2E1-expression and protein bound 4-hydroxynonenal (HNE) were semi-quantitatively evaluated by immunohistochemistry. Among 21 NASH children, εdA levels in the liver were high in 3, moderate in 5, weak in 9 and not elevated in 4 patients. There was a positive correlation between CYP2E1 and protein-bound 4-HNE (r=0.60; P=0.008) and a trend for a positive relationship for CYP2E1 vs. staining intensity of εdA (r=0.45; P=0.06). Inflammatory activity and fibrosis correlated significantly (r=0.49, P=0.023). Our results demonstrate for the first time the presence of elevated carcinogenic etheno-DNA lesions (εdA) in the majority (17/21) of liver biopsies from young NASH patients. Our data suggest that LPO-derived etheno-adducts are implicated in NASH. Whether these adducts may serve as predictive risk markers in NASH children to develop hepatocellular cancer later in life remains to be investigated.

  7. Acetaminophen protein adducts: a review.

    Science.gov (United States)

    Bond, G Randall

    2009-01-01

    Significant controversy surrounds the clinical and legal implications of 3-para cysteinyl acetaminophen, the protein degradation product of acetaminophen protein adducts. Versions of this test have been used for several years in animal research to help understand acetaminophen toxicity. As human research papers have appeared, the allegation has been made that the presence of 3-para cysteinyl acetaminophen in a patient with hepatic injury proves causal association of acetaminophen with the injury. It has also been suggested that quantitative adduct assays can guide the management of acute overdose or repeated supra-therapeutic use of acetaminophen by determining the need for initiating therapy and the timing of the end of therapy. The purpose of this review is to discuss the nature of this molecule and the detection assay, the animal research linking it with injury, and to evaluate the human research--specifically the evidence regarding causality and clinical utility. At the current time there is inadequate evidence for the test alone to prove causal association between acetaminophen and hepatic injury. Also, since quantitative 3-para cysteinyl acetaminophen assays parallel other markers of liver injury, it is not clear that assays alone will guide therapy unless quantitative assay markers can be shown to precede other markers (in elevation or decline) or provide more specificity than the Rumack-Matthew risk categorization nomogram. These advantages have not been demonstrated.

  8. An ammonium bicarbonate-enhanced stable isotope dilution UHPLC-MS/MS method for sensitive and accurate quantification of acrolein-DNA adducts in human leukocytes.

    Science.gov (United States)

    Yin, Ruichuan; Liu, Shengquan; Zhao, Chao; Lu, Meiling; Tang, Moon-shong; Wang, Hailin

    2013-03-19

    Acrolein (Acr), a ubiquitous environmental pollutant, can react directly with genomic DNA to form mutagenic adducts without undergoing metabolic activation. To sensitively and accurately quantify Acr-DNA adducts (including structural isomers and stereoisomers) in human leukocytes, we developed an enhanced stable isotope dilution ultrahigh performance liquid chromatography (UHPLC)-tandem mass spectrometry (MS/MS) method using ammonium bicarbonate (NH4HCO3), which is thermally unstable and degrades readily to carbon dioxide and ammonia in heated gas phase. Interestingly, ammonium bicarbonate (as an additive to the mobile phase) not only improves the protonation of AcrdG adducts but also suppresses the formation of MS signal-deteriorating metal-AcrdG complexes during electrospray ionization, leading to the enhancement of their MS detection by 2.3-8.7 times. In contrast, routinely used ammonium salts (ammonium acetate and ammonium formate) and formic acid do not show similar enhancement. The developed method is potentially useful for enhancing ESI-MS detection of other modified 2'-deoxyribonucleosides that have difficulty in protonation and may form excess metal complexes during electrospray ionization. The limits of detection (LODs, S/N = 3) are estimated to be about 40-80 amol. By the use of the developed method, we found that the Acr adducts of three nucleotides (dG, dA, and dC) can be detected in human leukocytes. In addition to the known γ-AcrdG, α-AcrdA is also identified as an Acr-adduct of high abundance (2.5-20 adducts per10(8) nts).

  9. Catechol oxidase activity of a series of new dinuclear copper(II) complexes with 3,5-DTBC and TCC as substrates: syntheses, X-ray crystal structures, spectroscopic characterization of the adducts and kinetic studies.

    Science.gov (United States)

    Banu, Kazi Sabnam; Chattopadhyay, Tanmay; Banerjee, Arpita; Bhattacharya, Santanu; Suresh, Eringathodi; Nethaji, Munirathinam; Zangrando, Ennio; Das, Debasis

    2008-08-18

    A series of dinuclear copper(II) complexes has been synthesized with the aim to investigate their applicability as potential structure and function models for the active site of catechol oxidase enzyme. They have been characterized by routine physicochemical techniques as well as by X-ray single-crystal structure analysis: [Cu 2(H 2L2 (2))(OH)(H 2O)(NO 3)](NO 3) 3.2H 2O ( 1), [Cu(HL1 (4))(H 2O)(NO 3)] 2(NO 3) 2.2H 2O ( 2), [Cu(L1 (1))(H 2O)(NO 3)] 2 ( 3), [Cu 2(L2 (3))(OH)(H 2O) 2](NO 3) 2, ( 4) and [Cu 2(L2 (1))(N 3) 3] ( 5) [L1 = 2-formyl-4-methyl-6R-iminomethyl-phenolato and L2 = 2,6-bis(R-iminomethyl)-4-methyl-phenolato; for L1 (1) and L2 (1), R = N-propylmorpholine; for L2 (2), R = N-ethylpiperazine; for L2 (3), R = N-ethylpyrrolidine, and for L1 (4), R = N-ethylmorpholine]. Dinuclear 1 and 4 possess two "end-off" compartmental ligands with exogenous mu-hydroxido and endogenous mu-phenoxido groups leading to intermetallic distances of 2.9794(15) and 2.9435(9) A, respectively; 2 and 3 are formed by two tridentate compartmental ligands where the copper centers are connected by endogenous phenoxido bridges with Cu-Cu separations of 3.0213(13) and 3.0152(15) A, respectively; 5 is built by an end-off compartmental ligand having exogenous mu-azido and endogenous mu-phenoxido groups with a Cu-Cu distance of 3.133(2) A (mean of two independent molecules). The catecholase activity of all of the complexes has been investigated in acetonitrile and methanol medium by UV-vis spectrophotometric study using 3,5-di- tert-butylcatechol (3,5-DTBC) and tetrachlorocatechol (TCC) as substrates. In acetonitrile medium, the conversion of 3,5-DTBC to 3,5-di- tert-butylbenzoquinone (3,5-DTBQ) catalyzed by 1- 5 is observed to proceed via the formation of two enzyme-substrate adducts, ES1 and ES2, detected spectroscopically for the first time. In methanol medium no such enzyme-substrate adduct has been detected, and the 3,5-DTBC to 3,5-DTBQ conversion is observed to be catalyzed by 1- 5

  10. Photochemistry of psoralen-DNA adducts, biological effects of psoralen-DNA adducts, applications of psoralen-DNA photochemistry

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Yun-bo

    1988-03-01

    This thesis consists of three main parts and totally eight chapters. In Part I, The author will present studies on the photochemistry of psoralen-DNA adducts, specifically, the wavelength dependencies for the photoreversals of thymidine-HMT (4'-hydroxymethyl-4, 5', 8-trimenthylpsoralen) monoadducts and diadduct and the same adducts incorporated in DNA helices and the wavelength dependecies for the photocrossslinking of thymidine-HMT monoadducts in double-stranded helices. In Part II, The author will report some biological effects of psoralen-DNA adducts, i.e., the effects on double-stranded DNA stability, DNA structure, and transcription by E. coli and T7 RNA polymerases. Finally, The author will focus on the applications of psoralen-DNA photochemistry to investigation of protein-DNA interaction during transcription, which includes the interaction of E. coli and T7 RNA polymerases with DNA in elongation complexes arrested at specific psoralen-DNA adduct sites as revealed by DNase I footprinting experiments. 123 refs., 52 figs., 12 tabs.

  11. EMG evaluation of hip adduction exercises for soccer players

    DEFF Research Database (Denmark)

    Serner, Andreas; Jakobsen, Markus Due; Andersen, Lars Louis

    2014-01-01

    traditional and two new hip adduction exercises. Additionally, to analyse muscle activation of gluteals and abdominals. MATERIALS AND METHODS: 40 healthy male elite soccer players, training >5 h a week, participated in the study. Muscle activity using surface electromyography (sEMG) was measured bilaterally...... for the adductor longus during eight hip adduction strengthening exercises and peak EMG was normalised (nEMG) using an isometric maximal voluntary contraction (MVC) as reference. Furthermore, muscle activation of the gluteus medius, rectus abdominis and the external abdominal obliques was analysed during...... the exercises. RESULTS: There were large differences in peak nEMG of the adductor longus between the exercises, with values ranging from 14% to 108% nEMG (pEMG results for the gluteals...

  12. Imidazolidinone adducts of peptides and hemoglobin

    International Nuclear Information System (INIS)

    San George, R.C.; Hoberman, H.D.

    1986-01-01

    Acetaldehyde reacts selectively with the terminal amino groups of the α and β chains of hemoglobin to form stable adducts, the structures of which, based on 13 C NMR studies, are proposed to be diastereomeric 2-methyl imidazolidin-4-ones. In this scheme, acetaldelhyde forms a reversible Schiff base with the α-amino groups of the polypeptide chains which cyclize with the amide nitrogen of the first peptide bond to form the stable imidazolidinone adducts. In support of this mechanism, the authors found that in following the reaction of the peptide val-gly-gly with [1,2- 13 C] acetaldehyde, 13 C NMR resonances attributed to a Schiff base (δ = 170 ppm) were observed which slowly disappeared prior to appearance of resonances from a pair of stable adducts (δ = 70 and 71 ppm) believed to be the diastereomeric imidazolidinones. Schiff base formation appeared to limit the overall rate. Tetraglycine reacted in a similar manner but with a resonance from a single stable adduct observed representing the enantiomeric imidazolidinone adducts of this peptide. Peptides with proline in position 2 should be incapable of forming imidazolidinones, and the authors found that ala-pro-gly did in fact fail to form a stable adduct with acetaldehyde. The 2-methyl imidazolidin-4-one adducts of hemoglobin may be useful in determining the contribution of the amino terminal groups to the structure and functional properties of hemoglobins

  13. Hydrogen abstraction reactions by amide electron adducts

    International Nuclear Information System (INIS)

    Sevilla, M.D.; Sevilla, C.L.; Swarts, S.

    1982-01-01

    Electron reactions with a number of peptide model compounds (amides and N-acetylamino acids) in aqueous glasses at low temperature have been investigated using ESR spectroscopy. The radicals produced by electron attachment to amides, RC(OD)NDR', are found to act as hydrogen abstracting agents. For example, the propionamide electron adduct is found to abstract from its parent propionamide. Electron adducts of other amides investigated show similar behavior except for acetamide electron adduct which does not abstract from its parent compound, but does abstract from other amides. The tendency toward abstraction for amide electron adducts are compared to electron adducts of several carboxylic acids, ketones, aldehydes and esters. The comparison suggests the hydrogen abstraction tendency of the various deuterated electron adducts (DEAs) to be in the following order: aldehyde DEA > acid DEA = approximately ester DEA > ketone DEA > amide DEA. In basic glasses the hydrogen abstraction ability of the amide electron adducts is maintained until the concentration of base is increased sufficiently to convert the DEA to its anionic form, RC(O - )ND 2 . In this form the hydrogen abstracting ability of the radical is greatly diminished. Similar results were found for the ester and carboxylic acid DEA's tested. (author)

  14. Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

    Science.gov (United States)

    Goggin, Melissa; Sangaraju, Dewakar; Walker, Vernon E.; Wickliffe, Jeffrey; Swenberg, James A.; Tretyakova, Natalia

    2011-01-01

    1,3-butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen. The mechanism of BD-mediated cancer is of significant interest because of the widespread exposure of humans to BD from cigarette smoke and urban air. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is a highly genotoxic and mutagenic bis-alkylating agent believed to be the ultimate carcinogenic species of BD. We have previously identified several types of DEB-specific DNA adducts, including bis-N7-guanine cross-links (bis-N7-BD), N6-adenine-N7-guanine cross-links (N6A-N7G-BD), and 1,N6-dA exocyclic adducts. These lesions were detected in tissues of laboratory rodents exposed to BD by inhalation (Goggin et al. Cancer Res. 2009;69:2479–2486). In the present work, persistence and repair of bifunctional DEB-DNA adducts in tissues of mice and rats exposed to BD by inhalation were investigated. The half-lives of the most abundant cross-links, bis-N7G-BD, in mouse liver, kidney, and lungs were 2.3–2.4 days, 4.6–5.7 days, and 4.9 days, respectively. The in vitro half-lives of bis-N7G-BD were 3.5 days (S,S isomer) and 4.0 days (meso isomer) due to their spontaneous depurination. In contrast, tissue concentrations of the minor DEB adducts, N7G-N1A-BD and 1,N6-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t 1/2 of 36–42 days. No differences were observed between DEB-DNA adduct levels in BD-treated wild type mice and the corresponding animals deficient in methyl purine glycosylase or the Xpa gene. Our results indicate that DEB-induced N7G-N1A-BD and 1,N6-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure. PMID:21452897

  15. Base-Displaced Intercalated Structure of the N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone DNA Adduct.

    Science.gov (United States)

    Politica, Dustin A; Malik, Chanchal K; Basu, Ashis K; Stone, Michael P

    2015-12-21

    3-Nitrobenzanthrone (3-NBA), an environmental mutagen found in diesel exhaust and a suspected carcinogen, undergoes metabolic reduction followed by reaction with DNA to form aminobenzanthrone (ABA) adducts, with the major alkylation product being N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (C8-dG-ABA). Site-specific synthesis of the C8-dG-ABA adduct in the oligodeoxynucleotide 5'-d(GTGCXTGTTTGT)-3':5'-d(ACAAACACGCAC)-3'; X = C8-dG-ABA adduct, including codons 272-275 of the p53 gene, has allowed for investigation into the structural and thermodynamic properties of this adduct. The conformation of the C8-dG-ABA adduct was determined using NMR spectroscopy and was refined using molecular dynamics (MD) calculations restrained by experimentally determined interproton distance restraints obtained from NOE experiments. The refined structure revealed that the C8-dG-ABA adduct formed a base-displaced intercalated conformation. The adducted guanine was shifted into the syn conformation about the glycosidic bond. The 5'- and 3'-neighboring base pairs remained intact. While this facilitated π-stacking interactions between the ABA moiety and neighboring bases, the thermal melting temperature (Tm) of the adduct-containing duplex showed a decrease of 11 °C as compared to the corresponding unmodified oligodeoxynucleotide duplex. Overall, in this sequence, the base-displaced intercalated conformation of the C8-dG-ABA lesion bears similarity to structures of other arylamine C8-dG adducts. However, in this sequence, the base-displaced intercalated conformation for the C8-dG-ABA adduct differs from the conformation of the N(2)-dG-ABA adduct reported by de los Santos and co-workers, in which it is oriented in the minor groove toward the 5' end of the duplex, with the modified guanine remaining in the anti conformation about the glyosidic torsion angle, and the complementary base remaining within the duplex. The results are discussed in relationship to differences between the C8-d

  16. Protein modification by acrolein: Formation and stability of cysteine adducts

    OpenAIRE

    Cai, Jian; Bhatnagar, Aruni; Pierce, William M.

    2009-01-01

    The toxicity of the ubiquitous pollutant and endogenous metabolite, acrolein, is due in part to covalent protein modifications. Acrolein reacts readily with protein nucleophiles via Michael addition and Schiff base formation. Potential acrolein targets in protein include the nucleophilic side chains of cysteine, histidine, and lysine residues as well as the free amino terminus of proteins. Although cysteine is the most acrolein-reactive residue, cysteine-acrolein adducts are difficult to iden...

  17. Bond Strength and Reactivity Scales for Lewis Superacid Adducts: A Comparative Study with In(OTf)3 and Al(OTf)3.

    Science.gov (United States)

    Compain, Guillaume; Sikk, Lauri; Massi, Lionel; Gal, Jean-François; Duñach, Elisabet

    2017-03-17

    Metal triflates, often called Lewis superacids, are potent catalysts for organic synthesis. However, the reactivity of a given Lewis superacid toward a given base is difficult to anticipate. A systematic screening of catalysts is often necessary when developing synthetic methodologies. Presented herein is the development of quantitative reactivity and bond strength scales by using mass spectrometry (MS). By applying a collision-induced dissociation (CID) technique to the adducts formed between Lewis superacids Al(OTf) 3 or In(OTf) 3 with a series of amides bases, including monodentate and bidentate ligands, different dissociation pathways were observed. Quantitative relative energy scales were established by performing energy-resolved mass spectrometry (ERMS) analysis on the adducts. ERMS of the adducts affords a bond strength scale when the fragmentation leads to the loss of a ligand, and reactivity scales when the dissociation leads to the C-F bond activation of one triflate anion or the deprotonation of the ligand. Al(OTf) 3 was found to bind stronger to amides than In(OTf) 3 and to provide the most reactive adducts. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. The inactivation of cytochrome P450 3A5 by 17alpha-ethynylestradiol is cytochrome b5-dependent: metabolic activation of the ethynyl moiety leads to the formation of glutathione conjugates, a heme adduct, and covalent binding to the apoprotein.

    Science.gov (United States)

    Lin, Hsia-Lien; Hollenberg, Paul F

    2007-04-01

    17Alpha-ethynylestradiol (EE) inactivates cytochrome P450 3A5 (3A5) in the reconstituted system in a mechanism-based manner. The inactivation is dependent on NADPH, and it is irreversible. The inactivation of 3A5 by EE is also dependent on cytochrome b5 (b5). The values for the K(I) and k(inact) of the 7-benzyloxy-4-(trifluoromethyl)coumarin O-debenzylation activity of 3A5 are 26 microM and 0.06 min(-1), respectively. Incubation of 3A5 with EE resulted in a 62% loss of catalytic activity, 60% loss in the reduced CO difference spectrum, and 40% decrease in native heme with the formation of a heme adduct. The partition ratio was approximately 25, and the stoichiometry of binding was approximately 0.3 mol of EE metabolite bound/mol of P450 inactivated. Four major metabolites were formed during the metabolism of EE by 3A5. SDS-polyacrylamide gel electrophoresis analysis demonstrated that [3H]EE was irreversibly bound to 3A5 apoprotein. Liquid chromatography-tandem mass spectrometry analysis (LC-MS/MS) revealed that two glutathione (GSH) conjugates with m/z values of 620 were formed only in the presence of b5. These two conjugates are formed from the reaction of GSH with the ethynyl group with the oxygen being inserted into either the internal or terminal carbon. A heme adduct with the ion at m/z 927 and two dipyrrole adducts with ions at m/z 579 were detected by LC-MS/MS analysis. In conclusion, 3A5 can activate EE to a 17alpha-oxirene-related reactive species that can then partition the oxygen between the internal and terminal carbons of the ethynyl group to form heme and apoprotein adducts, resulting in the inactivation of P450 3A5.

  19. Chemistry and Chemical Equilibrium Dynamics of BMAA and Its Carbamate Adducts.

    Science.gov (United States)

    Diaz-Parga, Pedro; Goto, Joy J; Krishnan, V V

    2018-01-01

    Beta-N-methylamino-L-alanine (BMAA) has been demonstrated to contribute to the onset of the ALS/Parkinsonism-dementia complex (ALS/PDC) and is implicated in the progression of other neurodegenerative diseases. While the role of BMAA in these diseases is still debated, one of the suggested mechanisms involves the activation of excitatory glutamate receptors. In particular, the excitatory effects of BMAA are shown to be dependent on the presence of bicarbonate ions, which in turn forms carbamate adducts in physiological conditions. The formation of carbamate adducts from BMAA and bicarbonate is similar to the formation of carbamate adducts from non-proteinogenic amino acids. Structural, chemical, and biological information related to non-proteinogenic amino acids provide insight into the formation of and possible neurological action of BMAA. This article reviews the carbamate formation of BMAA in the presence of bicarbonate ions, with a particular focus on how the chemical equilibrium of BMAA carbamate adducts may affect the molecular mechanism of its function. Highlights of nuclear magnetic resonance (NMR)-based studies on the equilibrium process between free BMAA and its adducts are presented. The role of divalent metals on the equilibrium process is also explored. The formation and the equilibrium process of carbamate adducts of BMAA may answer questions on their neuroactive potency and provide strong motivation for further investigations into other toxic mechanisms.

  20. Boron Difluoride Adducts of a Flexidentate Pyridine-Substituted Formazanate Ligand: Property Modulation via Protonation and Coordination Chemistry.

    Science.gov (United States)

    Barbon, Stephanie M; Buddingh, Jasmine V; Maar, Ryan R; Gilroy, Joe B

    2017-10-02

    The synthesis and characterization of a flexidentate pyridine-substituted formazanate ligand and its boron difluoride adducts, formed via two different coordination modes of the title ligand, are described. The first adduct adopted a structure that was typical of other boron difluoride adducts of triarylformazanate ligands and contained a free pyridine subsituent, while the second was formed via the chelation of nitrogen atoms from the formazanate backbone and the pyridine substituent. Stepwise protonation of the pydridine-functionalized adduct, which is essentially nonemissive, resulted in a significant increase in the fluorescence quantum yield up to a maximum of 18%, prompting the study of this adduct as a pH sensor. The coordination chemistry of each adduct was explored through reactions with nickel(II) bromide [NiBr 2 (CH 3 CN) 2 ], triflate [Ni(OTf) 2 ], and 1,1,1,4,4,4-hexafluoroacetylacetonate [Ni(hfac) 2 (H 2 O) 2 ] salts. Coordination to nickel(II) ions altered the physical properties of the boron difluoride formazanate adducts, including red-shifted absorption maxima and less negative reduction potentials. Together, these studies have demonstrated that the physical and electronic properties of boron difluoride adducts of formazanate ligands can be readily modulated through protonation and coordination chemistry.

  1. Translesion Synthesis Past Acrolein-derived DNA Adducts by Human Mitochondrial DNA Polymerase γ*

    Science.gov (United States)

    Kasiviswanathan, Rajesh; Minko, Irina G.; Lloyd, R. Stephen; Copeland, William C.

    2013-01-01

    Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as γ-hydroxy-1,N2-propano-2′-deoxyguanosine (γ-HOPdG) and γ-hydroxy-1,N6-propano-2′-deoxyadenosine (γ-HOPdA). The bulky γ-HOPdG adduct blocks DNA synthesis by replicative polymerases but can be bypassed by translesion synthesis polymerases in the nucleus. Although acrolein-induced adducts are likely to be formed and persist in mitochondrial DNA, animal cell mitochondria lack specialized translesion DNA synthesis polymerases to tolerate these lesions. Thus, it is important to understand how pol γ, the sole mitochondrial DNA polymerase in human cells, acts on acrolein-adducted DNA. To address this question, we investigated the ability of pol γ to bypass the minor groove γ-HOPdG and major groove γ-HOPdA adducts using single nucleotide incorporation and primer extension analyses. The efficiency of pol γ-catalyzed bypass of γ-HOPdG was low, and surprisingly, pol γ preferred to incorporate purine nucleotides opposite the adduct. Pol γ also exhibited ∼2-fold lower rates of excision of the misincorporated purine nucleotides opposite γ-HOPdG compared with the corresponding nucleotides opposite dG. Extension of primers from the termini opposite γ-HOPdG was accomplished only following error-prone purine nucleotide incorporation. However, pol γ preferentially incorporated dT opposite the γ-HOPdA adduct and efficiently extended primers from the correctly paired terminus, indicating that γ-HOPdA is probably nonmutagenic. In summary, our data suggest that acrolein-induced exocyclic DNA lesions can be bypassed by mitochondrial DNA polymerase but, in the case of the minor groove γ-HOPdG adduct, at the cost of unprecedented high mutation rates. PMID:23543747

  2. Effect of Laterally Wedged Insoles on the External Knee Adduction Moment across Different Reference Frames.

    Directory of Open Access Journals (Sweden)

    Satoshi Yamaguchi

    Full Text Available Biomechanical effects of laterally wedged insoles are assessed by reduction in the knee adduction moment. However, the degree of reduction may vary depending on the reference frame with which it is calculated. The purpose of this study was to clarify the effect of reference frame on the reduction in the knee adduction moment by laterally wedged insoles.Twenty-nine healthy participants performed gait trials with a laterally wedged insole and with a flat insole as a control. The knee adduction moment, including the first and second peaks and the angular impulse, were calculated using four different reference frames: the femoral frame, tibial frame, laboratory frame and the Joint Coordinate System.There were significant effects of reference frame on the knee adduction moment first and second peaks (P < 0.001 for both variables, while the effect was not significant for the angular impulse (P = 0.84. No significant interaction between the gait condition and reference frame was found in either of the knee adduction moment variables (P = 0.99 for all variables, indicating that the effects of laterally wedged insole on the knee adduction moments were similar across the four reference frames. On the other hand, the average percent changes ranged from 9% to 16% for the first peak, from 16% to 18% for the second peak and from 17% to 21% for the angular impulse when using the different reference frames.The effects of laterally wedged insole on the reduction in the knee adduction moment were similar across the reference frames. On the other hand, Researchers need to recognize that when the percent change was used as the parameter of the efficacy of laterally wedged insole, the choice of reference frame may influence the interpretation of how laterally wedged insoles affect the knee adduction moment.

  3. Including students with moderate and severe intellectual disabilities in school extracurricular and community recreation activities.

    Science.gov (United States)

    Kleinert, Harold L; Miracle, Sally; Sheppard-Jones, Kathy

    2007-02-01

    We conducted an online statewide survey of teachers of students with moderate and severe intellectual disabilities to determine the extent to which their students were included in school extracurricular and community recreation activities. For the 252 teacher respondents who indicated that their primary caseload consisted of students with significant intellectual disabilities, we report the numbers of students participating in school and community activities and the primary type of support students required to participate in each activity. Finally, we identify implications for practitioners who want to increase the participation of students with significant disabilities in school and community activities.

  4. Repair of furocoumarin adducts in mammalian cells

    International Nuclear Information System (INIS)

    Zolan, M.E.; Smith, C.A.; Hanawalt, P.C.

    1984-01-01

    DNA repair was studied in cultured mammalian cells treated with the furocoumarins 8-methoxypsoralen (8-MOP), aminomethyl trioxsalen, or angelicin and irradiated with near UV light. The amount of DNA cross-linked by 8-MOP in normal human cells decreased by about one-half in 24 hours after treatment; no decrease was observed in xeroderma pigmentosum cells, group A. At present, it is not known to what extent this decrease represents complete repair events at the sites of cross-links. Furocoumarin adducts elicited excision repair in normal human and monkey cells but not in xeroderma pigmentosum group A cells. This excision repair resembled in several aspects that elicited by pyrimidine dimers, formed in DNA by irradiation with 254-nm UV light; however, it appeared that for at least 8-MOP and aminomethyl trioxsalen, removal of adducts was not as efficient as was the removal of pyrimidine dimers. A comparison was also made of repair in the 172-base-pair repetitive alpha-DNA component of monkey cells to repair in the bulk of the genome. Although repair elicited by pyrimidine dimers in alpha-DNA was the same as in the bulk DNA, that following treatment of cells with either aminomethyl trioxsalen or angelicin and near UV was markedly deficient in alpha-DNA. This deficiency reflected the removal of fewer adducts from alpha-DNA after the same initial adduct frequencies. These results could mean that each furocoumarin may produce several structurally distinct adducts to DNA in cells and that the capacity of cellular repair systems to remove these various adducts may vary greatly

  5. Flash kinetics in liquefied noble gases: Studies of alkane activation and ligand dynamics at rhodium carbonyl centers, and a search for xenon-carbene adducts

    Energy Technology Data Exchange (ETDEWEB)

    Yeston, Jake Simon [Univ. of California, Berkeley, CA (United States)

    2001-01-01

    A general introduction is given to place the subsequent chapters in context for the nonspecialist. Results are presented from a low temperature infrared (IR) flash kinetic study of C-H bond activation via photoinduced reaction of Cp*Rh(CO)2 (1) with linear and cyclic alkanes in liquid krypton and liquid xenon solution. No reaction was observed with methane; for all other hydrocarbons studied, the rate law supports fragmentation of the overall reaction into an alkane binding step followed by an oxidative addition step. For the binding step, larger alkanes within each series (linear and cyclic) interact more strongly than smaller alkanes with the Rh center. The second step, oxidative addition of the C-H bond across Rh, exhibits very little variance in the series of linear alkanes, while in the cyclic series the rate decreases with increasing alkane size. Results are presented from an IR flash kinetic study of the photoinduced chemistry of Tp*Rh(CO)2 (5; Tp* = hydridotris(3,5-dimethylpyrazolyl)borato) in liquid xenon solution at –50 °C. IR spectra of the solution taken 2 μs after 308 nm photolysis exhibit two transient bands at 1972-1980 cm-1 and 1992-2000 cm-1, respectively. These bands were assigned to (η3-Tp*)Rh(CO)•Xe and (η2-Tp*)Rh(CO)•Xe solvates on the basis of companion studies using Bp*Rh(CO)2 (9; Bp* = dihydridobis(3,5-dimethyl pyrazolyl)borato). Preliminary kinetic data for reaction of 5 with cyclohexane in xenon solution indicate that both transient bands still appear and that their rates of decay correlate with formation of the product Tp*Rh(CO)(C6H11)(H). The preparation and reactivity of the new complex Bp*Rh(CO)(pyridine) (11) are described. The complex reacts with CH3I to yield the novel Rh carbene hydride complex HB(Me2pz)2Rh(H)(I)(C5H5N)(C(O)Me) (12), resulting from formal addition of CH

  6. 7 CFR 981.441 - Credit for market promotion activities, including paid advertising.

    Science.gov (United States)

    2010-01-01

    ... activity including the handler's name or brand, or the words “California Almonds”, the amount allowed for... the handler's name, the handler's brand, or the words “California Almonds” on the primary, face label... payment on these dates, handler claims must be submitted, with all required elements, at least one month...

  7. Implementation of the Project "Including Disabled Senior Citizens in Creative Activities in 2013-2015"

    Science.gov (United States)

    Ploch, Leszek

    2015-01-01

    This paper made an attempt to indicate the findings of the author's research from the experiences of the implementation of the project "Including disabled senior citizens in creative activities in 2013-2015". The issues of disabled senior citizens have been an object of interest over the recent years though it still has not had a proper…

  8. DNA adduct formation by the ubiquitous environmental pollutant 3-nitrobenzanthrone and its metabolites in rats

    International Nuclear Information System (INIS)

    Arlt, Volker M.; Sorg, Bernd L.; Osborne, Martin; Hewer, Alan; Seidel, Albrecht; Schmeiser, Heinz H.; Phillips, David H.

    2003-01-01

    Diesel exhaust is known to induce tumours in animals and is suspected of being carcinogenic in humans. Of the compounds found in diesel exhaust, 3-nitrobenzanthrone (3-NBA) is an extremely potent mutagen and suspected human carcinogen forming multiple DNA adducts in vitro. 3-Aminobenzanthrone (3-ABA), 3-acetylaminobenzanthrone (3-Ac-ABA), and N-acetyl-N-hydroxy-3-aminobenzanthrone (N-Ac-N-OH-ABA) were identified as 3-NBA metabolites. In order to gain insight into the pathways of metabolic activation leading to 3-NBA-derived DNA adducts we treated Wistar rats intraperitoneally with 2 mg/kg body weight of 3-NBA, 3-ABA, 3-Ac-ABA, or N-Ac-N-OH-ABA and compared DNA adducts present in different organs. With each compound either four or five DNA adduct spots were detected by TLC in all tissues examined (lung, liver, kidney, heart, pancreas, and colon) using the nuclease P1 or butanol enrichment version of the 32 P-postlabelling method, respectively. Using HPLC co-chromatographic analysis we showed that all major 3-NBA-DNA adducts produced in vivo in rats are derived from reductive metabolites bound to purine bases and lack an N-acetyl group. Our results indicate that 3-NBA metabolites (3-ABA, 3-Ac-ABA and N-Ac-N-OH-ABA) undergo several biotransformations and that N-hydroxy-3-aminobenzanthrone (N-OH-ABA) appears to be the common intermediate in 3-NBA-derived DNA adduct formation. Therefore, 3-NBA-DNA adducts are useful biomarkers for exposure to 3-NBA and its metabolites and may help to identify enzymes involved in their metabolic activation

  9. Triple Active Antiretroviral Regimen Including Enfuvirtide Via the Biojector is Effective and Safe

    Directory of Open Access Journals (Sweden)

    Mona Loutfy

    2007-01-01

    Full Text Available For full HIV virological suppression, three fully active antiretroviral agents are required. New drug classes should be included to ensure that agents are fully active. The addition of enfuvirtide and efavirenz to the present patient’s new antiretroviral regimen ensured that two fully active agents were in use in the setting of a moderate degree of nucleoside resistance and a high level of protease resistance, and where non-nucleoside reverse transcriptase inhibitors were still fully active. Both viral load and CD4 count responded favourably to this regimen. The patient received support from physicians and clinic staff in the introduction and use of enfuvirtide. To reduce injection site reactions, a needle-free injection system (Biojector proved effective.

  10. Hip adduction and abduction strength profiles in elite soccer players

    DEFF Research Database (Denmark)

    Thorborg, Kristian; Serner, Andreas; Petersen, Jesper

    2011-01-01

    An ipsilateral hip adduction/abduction strength ratio of more than 90%, and hip adduction strength equal to that of the contralateral side have been suggested to clinically represent adequate strength recovery of hip adduction strength in athletes after groin injury. However, to what extent side-......-to-side symmetry in isometric hip adduction and abduction strength can be assumed in soccer players remains uncertain....

  11. Lewis acid adducts of [PCl2N]3.

    Science.gov (United States)

    Heston, Amy J; Panzner, Matthew J; Youngs, Wiley J; Tessier, Claire A

    2005-09-19

    Reaction of aluminum trichloride or gallium trichloride with the extremely weak base hexachlorotriphosphazene gives adducts in which the group 13 element is bound to a phosphazene nitrogen atom. In solution, the adducts exhibit fluxional behavior. The phosphazene ring of the adducts is distorted into a slight chair conformation.

  12. Hip adduction and abduction strength profiles in elite soccer players

    DEFF Research Database (Denmark)

    Thorborg, Kristian; Serner, Andreas; Petersen, Jesper

    2011-01-01

    An ipsilateral hip adduction/abduction strength ratio of more than 90%, and hip adduction strength equal to that of the contralateral side have been suggested to clinically represent adequate strength recovery of hip adduction strength in athletes after groin injury. However, to what extent side...

  13. 129I Moessbauer spectroscopic study of metallocene-iodine adducts

    International Nuclear Information System (INIS)

    Nakashima, Satoru; Sakai, Hiroshi; Watanabe, Masanobu; Maeda, Yutaka

    1994-01-01

    A 129 I Moessbauer spectroscopic study of iodine adducts of ferrocenophane, biruthenocene, and osmocene is reported. The spectra show the existence of iodine bonded to the central metals of metallocenes in addition to triiodide anions. The valence state of iron in the ferrocenophane-iodine adduct is the same as those of ruthenium and osmium in their adducts. (orig.)

  14. DNA Adducts aand Human Atherosclerotis Lesions

    Czech Academy of Sciences Publication Activity Database

    Strejc, Přemysl; Boubelík, O.; Stávková, Zdena; Chvátalová, Irena; Šrám, Radim

    2001-01-01

    Roč. 42, - (2001), s. 662 ISSN 0008-5472. [Annual Meeting of Proceedings /92./. 24.03.2001-28.03.2001, New Orleans] R&D Projects: GA MZd NM10 Keywords : DNA adducts * LDL cholesterol Subject RIV: DN - Health Impact of the Environment Quality

  15. Measuring Outcomes in Adult Weight Loss Studies That Include Diet and Physical Activity: A Systematic Review

    OpenAIRE

    Millstein, Rachel A.

    2014-01-01

    Background. Measuring success of obesity interventions is critical. Several methods measure weight loss outcomes but there is no consensus on best practices. This systematic review evaluates relevant outcomes (weight loss, BMI, % body fat, and fat mass) to determine which might be the best indicator(s) of success. Methods. Eligible articles described adult weight loss interventions that included diet and physical activity and a measure of weight or BMI change and body composition change. Resu...

  16. Synthesis and Characterization of the Adducts of Morpholinedithioccarbamate Complexes of Oxovanadium (IV, Nickel(II, and Copper(II with Piperidine and Morpholine

    Directory of Open Access Journals (Sweden)

    Mousami Sharma

    2012-01-01

    Full Text Available A series of 1:1 adducts of bis(morpholinedithiocarbamato complex of VO(IV, 1:1 and 1:2 adducts of bis(morpholinedithiocarbamato complexes of Ni(II and Cu(II with piperidine and morpholine have been synthesized and characterized by elemental analysis, molar conductance, magnetic susceptibility, IR, UV-Vis, and TGA/DTA techniques. Analytical data reveals that VO(IV complex forms only 1:1 adducts with the formula [VO(morphdtc2L].H2O while Ni(II and Cu(II complexes form both 1:1 and 1:2 adducts with 1:1 adducts having general formula Ni(morphdtc2.L and Cu(morphdtc2.L and 1:2 adducts having general formula Ni(morphdtc2.L2 and Cu(morphdtc2.L2 (morphdtc = morpholinedithiocarbamate, L = morpholine and piperidine. Antifungal activity of some complexes has been carried out against the fungal strain Fusarium oxysporium. Thermal studies indicate a continuous weight loss. A square pyramidal geometry has been proposed for the 1:1 adducts of Ni(II and Cu(II complexes while an octahedral geometry has been proposed for the 1:1 adducts of VO(IV and for the 1:2 adducts of Ni(II and Cu(II complexes.

  17. NITRO MUSK ADDUCTS OF RAINBOW TROUT ...

    Science.gov (United States)

    Rainbow trout and other fish species can serve as 'sentinel' species for the assessment of ecological status and the presence of certain environmental contaminants. As such they act as bioindicators of exposure. Here we present seminal data regarding dose-response and toxicokinetics of trout hemoglobin adduct formation from exposure to nitro musks that are frequently used as fragrance ingredients in formulations of personal care products. Hemoglobin adducts serve as biomarkers of exposure of the sentinel species as we have shown in previous studies of hemoglobin adducts formed in trout and environmental carp exposed to musk xylene (MX) and musk ketone (MK). Gas chromatography-electron capture negative ion chemical ionization-mass spectrometry (GC-NICI-MS) employing selected ion monitoring is used to measure 4-amino-MX (4-AMX), 2-amino-MX (2-AMX), and 2-amino-MK (2-AMK) released by alkaline hydrolysis from the sulfinamide adducts of hemoglobin. Dose-response and toxicokinetics were investigated using this sensitive method for analysis of these metabolites. In the dose-response investigation, the concentrations of 4-AMX and 2-2AMX are observed to pass through a maximum at 0.10 mg/g. In the case of 2-AMK, the adduct concentration is almost the same at dosages in the range of 0.030 to 0.10 mg/g. For toxicokinetics, the concentration of the metabolites in the Hb reaches a maximum in the 3-day sample after administration of MX or MK. Further elimination of the metabo

  18. Managing nuclear knowledge: IAEA activities and international coordination. Including resource material full text CD-ROM

    International Nuclear Information System (INIS)

    2005-06-01

    The present CD-ROM summarizes some activities carried out by the Departments of Nuclear Energy and Nuclear Safety and Security in the area of nuclear knowledge management in the period 2003-2005. It comprises, as open resource, most of the relevant documents in full text, including policy level documents, reports, presentation material by Member States and meeting summaries. The collection starts with a reprint of the report to the IAEA General Conference 2004 on Nuclear Knowledge [GOV/2004/56-GC(48)/12] summarizing the developments in nuclear knowledge management since the 47th session of the General Conference in 2003 and covers Managing Nuclear Knowledge including safety issues and Information and Strengthening Education and Training for Capacity Building. It contains an excerpt on Nuclear Knowledge from the General Conference Resolution [GC(48)/RES/13] on Strengthening the Agency's Activities Related to Nuclear Science, Technology and Applications. On the CD-ROM itself, all documents can easily be accessed by clicking on their titles on the subject pages (also printed at the end of this Working Material). Part 1 of the CD-ROM covers the activities in the period 2003-2005 and part 2 presents a resource material full text CD-ROM on Managing Nuclear Knowledge issued in October 2003

  19. Formation, Repair, and Genotoxic Properties of Bulky DNA Adducts Formed from Tobacco-Specific Nitrosamines

    Directory of Open Access Journals (Sweden)

    Lisa A. Peterson

    2010-01-01

    Full Text Available 4-(Methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and N′-nitrosonornicotine (NNN are tobacco-specific nitrosamines present in tobacco products and smoke. Both compounds are carcinogenic in laboratory animals, generating tumors at sites comparable to those observed in smokers. These Group 1 human carcinogens are metabolized to reactive intermediates that alkylate DNA. This paper focuses on the DNA pyridyloxobutylation pathway which is common to both compounds. This DNA route generates 7-[4-(3-pyridyl-4-oxobut-1-yl]-2′-deoxyguanosine, O2-[4-(3-pyridyl-4-oxobut-1-yl]-2′-deoxycytosine, O2-[4-(3-pyridyl-4-oxobut-1-yl]-2′-deoxythymidine, and O6-[4-(3-pyridyl-4-oxobut-1-yl]-2′-deoxyguanosine as well as unstable adducts which dealkylate to release 4-hydroxy-1-{3-pyridyl-1-butanone or depyriminidate/depurinate to generate abasic sites. There are multiple repair pathways responsible for protecting against the genotoxic effects of these adducts, including adduct reversal as well as base and nucleotide excision repair pathways. Data indicate that several DNA adducts contribute to the overall mutagenic properties of pyridyloxobutylating agents. Which adducts contribute to the carcinogenic properties of this pathway are likely to depend on the biochemistry of the target tissue.

  20. Novel approach of medialization thyroplasty with arytenoid adduction performed under general anesthesia with a laryngeal mask.

    Science.gov (United States)

    Stow, Nicholas W; Lee, Jennifer W; Cole, Ian E

    2012-02-01

    To objectively assess the voice outcomes of patients with unilateral vocal fold paralysis treated with medialization thyroplasty and arytenoid adduction suture. Case series of patients who underwent medialization thyroplasty and arytenoid adduction suture. Preoperative and postoperative voice testing was performed and the data were compared by statistical analysis. Tertiary referral teaching hospital in Sydney, Australia. All patients had a unilateral vocal fold paralysis, with a large posterior glottic gap and vocal symptoms affecting their quality of life. Thirteen patients with a diagnosis of a unilateral vocal fold paralysis with a large posterior glottic gap, vocal symptoms, and total denervation of the vocal fold underwent medialization thyroplasty and arytenoid adduction suture. The surgery was performed in a novel method under a general anesthetic using a laryngeal mask and with direct intraoperative endoscopic feedback. Preoperative and postoperative measures of voice performance were compared, including acoustic analysis (fundamental frequency, speech intensity against quiet and loud background noise, speech rate) and aerodynamic assessment (airflow, maximum phonation time). Medialization thyroplasty with arytenoid adduction suture significantly improved aerodynamic assessment and phonation duration for both male and female subjects overall. There were 2 of 13 treatment failures. Median follow-up time was 6 months. Preliminary results indicate that in selected patients with vocal fold paralysis, medialization thyroplasty with arytenoid adduction suture leads to significant improvements in objective voice measures. Longer follow-up data are required to further quantify the voice outcomes after this procedure.

  1. Lifestyle, Environmental, and Genetic Predictors of Bulky DNA Adducts in a Study Population Nested within a Prospective Danish Cohort

    DEFF Research Database (Denmark)

    Eriksen, K. T.; Sørensen, M.; Autrup, H.

    2010-01-01

    Danish cohort. At enrollment, blood samples were collected and information on lifestyle, including dietary and smoking habits, obtained. Previously, bulky DNA adducts were measured in 245 individuals who developed lung cancer and 255 control members of the cohort. Of these 500 individuals, data on 375...... individuals were included in this study, excluding 125 cases, which developed lung cancer within the first 3 yr after blood sampling. Bulky DNA adduct levels were measured by 32P-postlabeling technique and polymorphisms in carcinogen metabolism and DNA repair genes were determined. Potential predictors...... found between dietary factors or smoking and DNA adduct levels. Further, the results showed no prominent associations between any of 12 genetic polymorphisms and adduct levels. Overall, our study showed only few associations between dietary, environmental, and genetic factors and levels of bulky DNA...

  2. DNA adduct measurements in zebra mussels, Dreissena polymorpha, Pallas. Potential use for genotoxicant biomonitoring of fresh water ecosystems.

    Science.gov (United States)

    Le Goff, J; Gallois, J; Pelhuet, L; Devier, M H; Budzinski, H; Pottier, D; André, V; Cachot, J

    2006-08-12

    The purpose of this study was to examine PAH accumulation and bulky DNA adduct formation in the digestive gland of zebra mussels exposed in their habitat or in controlled laboratory conditions to complex mixture of PAH. DNA adducts were measured using a 32P-postlabelling protocol with nuclease P1 enrichment adapted from Reddy and Randerath [Reddy, M.V., Randerath, K., 1986. Nuclease P1-mediated enhancement of sensitivity of 32P-postlabelling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551]. Specimens collected in the upper part of the Seine estuary were shown to accumulate higher levels of PAH (up to 1.6 microg g(-1) dry weight) in comparison to individuals from the reference site (0.053 microg g(-1) dry weight). The former exhibited elevated levels of DNA adducts (up to 4.0/10(8) nucleotides) and higher diversity of individual adducts with five distinct spots being specifically detected in individuals originating from the Seine estuary. Zebra mussels exposed for 5 days to 0.01% (v/v) of organic extract of sediment from the Seine estuary were shown to accumulate high amounts of PAH (up to 138 microg g(-1) dry weight) but exhibited relatively low levels of DNA adducts. Exposure to benzo[a]pyrene led to a dose-dependent accumulation of B[a]P (up to 7063 microg g(-1) dry weight) and a clear induction of DNA adduct formation in the digestive gland of mussels (up to 1.13/10(8) nucleotides). Comparisons with other bivalves exposed to the same model PAH, revealed similar levels of adducts and comparable adduct profiles with a main adduct spot and a second faint one. This study clearly demonstrated that zebra mussels are able to biotransform B[a]P and probably other PAH into reactive metabolites with DNA-binding activity. This work also demonstrated the applicability of the nuclease P1 enhanced 32P-postlabelling method for bulky adduct detection in the digestive gland of zebra mussels. DNA adduct measurement in zebra mussels could be a suitable

  3. Base-Displaced Intercalated Structure of the N-(2′-Deoxyguanosin-8-yl)-3-aminobenzanthrone DNA Adduct

    Science.gov (United States)

    Politica, Dustin A.; Malik, Chanchal K.; Basu, Ashis K.; Stone, Michael P.

    2016-01-01

    3-Nitrobenzanthrone (3-NBA), an environmental mutagen found in diesel exhaust and a suspected carcinogen, undergoes metabolic reduction followed by reaction with DNA to form aminobenzanthrone (ABA) adducts, with the major alkylation product being N-(2′-deoxyguanosin-8-yl)-3-aminobenzanthrone (C8-dG-ABA). Site-specific synthesis of the C8-dG-ABA adduct in the oligodeoxynucleotide 5'-d(GTGCXTGTTTGT)-3':5'-d(ACAAACACGCAC)-3'; X = C8-dG-ABA adduct, including codons 272-275 of the p53 gene, has allowed for investigation into the structural and thermodynamic properties of this adduct. The conformation of the C8-dG-ABA adduct was determined using NMR spectroscopy and was refined using molecular dynamics (MD) calculations restrained by experimentally determined interproton distance restraints obtained from NOE experiments. The refined structure revealed that the C8-dG-ABA adduct formed a base-displaced intercalated conformation. The adducted guanine was shifted into the syn conformation about the glycosidic bond. The 5'- and 3'-neighboring base pairs remained intact. While this facilitated π-stacking interactions between the ABA moiety and neighboring bases, the thermal melting temperature (Tm) of the adduct-containing duplex showed a decrease of 11 °C as compared to the corresponding unmodified oligodeoxynucleotide duplex. Overall, in this sequence, the base-displaced intercalated conformation of the C8-dG-ABA lesion bears similarity to structures of other arylamine C8-dG adducts. However, in this sequence, the base-displaced intercalated conformation for the C8-dG-ABA adduct differs from the conformation of the N2-dG-ABA adduct reported by de los Santos and co-workers, which oriented in the minor groove towards the 5' end of the duplex, with the modified guanine remaining in the anti conformation about the glyosidic torsion angle, and the complementary base remaining within the duplex. The results are discussed in relationship to differences between the C8-dG-ABA and

  4. Proteomic profiling of acrolein adducts in human lung epithelial cells

    Science.gov (United States)

    Spiess, Page C.; Deng, Bin; Hondal, Robert J.; Matthews, Dwight E.; van der Vliet, Albert

    2011-01-01

    Acrolein (2,3-propenal) is a major indoor and outdoor air pollutant originating largely from tobacco smoke or organic combustion. Given its high reactivity, the adverse effects of inhaled acrolein are likely due to direct interactions with the airway epithelium, resulting in altered epithelial function, but only limited information exists to date regarding the primary direct cellular targets for acrolein. Here, we describe a global proteomics approach to characterize the spectrum of airway epithelial protein targets for Michael adduction in acrolein-exposed bronchial epithelial (HBE1) cells, based on biotin hydrazide labeling and avidin purification of biotinylated proteins or peptides for analysis by LC-MS/MS. Identified protein targets included a number of stress proteins, cytoskeletal proteins, and several key proteins involved in redox signaling, including thioredoxin reductase, thioredoxin, peroxiredoxins, and glutathione S-transferase π. Because of the central role of thioredoxin reductase in cellular redox regulation, additional LC-MS/MS characterization was performed on purified mitochondrial thioredoxin reductase to identify the specific site of acrolein adduction, revealing the catalytic selenocysteine residue as the target responsible for enzyme inactivation. Our findings indicate that these approaches are useful in characterizing major protein targets for acrolein, and will enhance mechanistic understanding of the impact of acrolein on cell biology. PMID:21704744

  5. DNA adducts and cancer risk in prospective studies: a pooled analysis and a meta-analysis

    DEFF Research Database (Denmark)

    Veglia, Fabrizio; Loft, Steffen; Matullo, Giuseppe

    2008-01-01

    . In the pooled analysis, a weakly statistically significant increase in the risk of lung cancer was apparent (14% per unit standard deviation change in adduct levels, 95% confidence interval 1-28%; using the weighted mean difference method, 0.15 SD, units higher adducts in cases than in controls......). The association was evident only in current smokers and was absent in former smokers. Also the meta-analysis, which included both lung and bladder cancers, showed a statistically significant association in current smokers, whereas the results in never smokers were equivocal; in former smokers, no association...

  6. Should singing activities be included in speech and voice therapy for prepubertal children?

    Science.gov (United States)

    Rinta, Tiija; Welch, Graham F

    2008-01-01

    Customarily, speaking and singing have tended to be regarded as two completely separate sets of behaviors in clinical and educational settings. The treatment of speech and voice disorders has focused on the client's speaking ability, as this is perceived to be the main vocal behavior of concern. However, according to a broader voice-science perspective, given that the same vocal structure is used for speaking and singing, it may be possible to include singing in speech and voice therapy. In this article, a theoretical framework is proposed that indicates possible benefits from the inclusion of singing in such therapeutic settings. Based on a literature review, it is demonstrated theoretically why singing activities can potentially be exploited in the treatment of prepubertal children suffering from speech and voice disorders. Based on this theoretical framework, implications for further empirical research and practice are suggested.

  7. Characteristics of an β-N-Acetylhexosaminidase from Bacillus sp. CH11, Including its Transglycosylation Activity.

    Science.gov (United States)

    Kurakake, Masahiro; Amai, Yukari; Konishi, Mizuki; Ikehira, Kaho

    2018-04-06

    β-N-Acetylhexosaminidase was identified from Bacillus sp. CH11 and found to have relatively high transferring activity. In this study, its enzymatic properties and transglycosylation activity including its acceptor specificity were investigated. Its molecular weight was estimated to be 90 kDa by SDS-PAGE and its optimal pH was approximately 7 with good stability from pH 6 to 8. Its optimal temperature was 40 °C, and its activity was stable at temperatures of up to 40 °C. To analyze its acceptor specificity for transglycosylation, N, N'-diacetylchitobiose was used as a donor substrate and alcohols, sugar alcohols, sugars and polyphenols were used as acceptors. Dialcohols, which have 2 hydroxyl groups on the outside of the carbon chains, were good acceptors. The molecular size of the acceptor did not influence the transglycosylation up to at least 1,5-pentanediol (carbon number: C5). Glycerin (C3), erythritol (C4), and xylitol (C5), all small molecular weight sugar alcohols, had high acceptor specificity. Transglycosylation to mono- and disaccharides and polyphenols was not observed except for L-fucose. For the β-N-acetylhexosaminidase-catalyzed transglycosylation of chitin oligosaccharides and xylitol, the transfer product was identified as 1-O-β-D-N-acetylglucosaminyl xylitol. The optimal ratio of xylitol was 24% to 2% N, N'-diacetylchitobiose and 226 mg per 1 g N, N'-diacetylchitobiose was produced. CH11 β-N-acetylhexosaminidase efficiently produced 1-O-β-D-N-acetylglucosaminyl xylitol via transglycosylation. The new transfer products including 1-O-β-D-N-acetylglucosaminyl xylitol are attractive compounds for their potential physiological functions. 1-O-β-D-N-Acetylglucosaminyl xylitol was produced effectively from chitin-oligosaccharides and xylitol by β-N-acetylhexosaminidase from Bacillus sp. CH11. This enzyme may be useful for the development of food materials for health-related applications such as oligosaccharides with intestinal functions and

  8. Monitoring active volcanoes and mitigating volcanic hazards: the case for including simple approaches

    Science.gov (United States)

    Stoiber, Richard E.; Williams, Stanley N.

    1990-07-01

    Simple approaches to problems brought about eruptions and their ensuing hazardous effects should be advocated and used by volcanologists while awaiting more sophisticated remedies. The expedients we advocate have all or many of the following attributes: only locally available materials are required; no extensive training of operators or installation is necessary; they are affordable and do not require foreign aid or exports; they are often labor intensive and are sustainable without outside assistance. Where appropriate, the involvement of local residents is advocated. Examples of simple expedients which can be used in forecasting or mitigating the effects of crises emphasize the relative ease and the less elaborate requirements with which simple approaches can be activated. Emphasis is on visual observations often by untrained observers, simple meteorogical measurements, observations of water level in lakes, temperature and chemistry of springs and fumaroles, new springs and collapse areas and observations of volcanic plumes. Simple methods are suggested which can be applied to mitigating damage from mudflows, nuées ardentes, tephra falls and gas discharge. A review in hindsight at Ruiz includes the use of both chemical indicators and simple mudflow alarms. Simple expedients are sufficiently effective that any expert volcanologist called to aid in a crisis must include them in the package of advice offered. Simple approaches are a critical and logical complement to highly technical solutions to hazardous situations.

  9. Fluorogenic MMP activity assay for plasma including MMPs complexed to α2-macroglobulin

    NARCIS (Netherlands)

    Beekman, B.; Drijfhout, J.W.; Ronday, H.K.; TeKoppele, J.M.

    1999-01-01

    Elevated MMP activities are implicated in tissue degradation in, e.g., arthritis and cancer. The present study was designed to measure MMP enzyme activity in plasma. Free active MMP is unlikely to be present in plasma: upon entering the circulation, active MMP is expected to be captured by the

  10. The relationship between prenatal exposure to airborne polycyclic aromatic hydrocarbons (PAHs) and PAH-DNA adducts in cord blood.

    Science.gov (United States)

    Jedrychowski, Wieslaw A; Perera, Frederica P; Tang, Deliang; Rauh, Virginia; Majewska, Renata; Mroz, Elzbieta; Flak, Elzbieta; Stigter, Laura; Spengler, John; Camann, David; Jacek, Ryszard

    2013-07-01

    In a birth cohort study, we have assessed the dose-response relationship between individual measurements of prenatal airborne polycyclic aromatic hydrocarbon (PAH) exposure and specific PAH-DNA adducts in cord blood adjusted for maternal blood adducts and season of birth. The study uses data from an earlier established birth cohort of children in Krakow. The final analysis included 362 pregnant women who gave birth to term babies and had complete data on personal exposure in the second trimester of pregnancy to eight airborne PAHs including benzo[a]pyrene (B[a]P), as well as DNA adducts, both in maternal and cord blood. The relation between cord blood PAH-DNA adducts and airborne prenatal PAH exposure was non-linear. Although cord blood PAH-DNA adducts were significantly associated with the B[a]P exposure categorized by tertiles (non-parametric trend z=3.50, P<0.001), the relationship between B[a]P and maternal blood adducts was insignificant (z=1.63, P=0.103). Based on the multivariable linear regression model, we estimated the effect of the prenatal airborne B[a]P on the level of cord blood adducts. In total, 14.8% of cord blood adducts variance was attributed to the level of maternal adducts and 3% to a higher prenatal B[a] exposure above 5.70 ng/m(3). The calculated fetal/maternal blood adduct ratio (FMR) linearly increased with B[a]P exposure (z=1.99, P=0.047) and was highest at B[a]P concentrations exceeding 5.70 ng/m(3). In conclusion, the results support other findings that transplacental exposure to B[a]P from maternal inhalation produces DNA damage in the developing fetus. It also confirms the heightened fetal susceptibility to prenatal PAH exposure that should be a matter of public health concern, particularly in the highly polluted areas, because DNA adducts represent a pro-carcinogenic alteration in DNA. The continuation of this birth cohort study will assess the possible health effects of fetal DNA damage on the health of children and help in

  11. THE RELATIONSHIP BETWEEN PRENATAL EXPOSURE TO AIRBORNE POLYCYCLIC AROMATIC HYDROCARBONS (PAH) AND PAH-DNA ADDUCTS IN CORD BLOOD

    Science.gov (United States)

    Jedrychowski, Wieslaw; Perera, Frederica P.; Tang, Deliang; Rauh, Virginia; Majewska, Renata; Mroz, Elzbieta; Flak, Elzbieta; Stigter, Laura; Spengler, John; Camann, David; Jacek, Ryszard

    2013-01-01

    In a birth cohort study, we have assessed the dose-response relationship between individual measurements of prenatal airborne PAH exposure and specific PAH-DNA adducts in cord blood adjusted for maternal blood adducts and season of birth. The study uses data from an earlier established birth cohort of children in Krakow. The final analysis included 362 pregnant women who gave birth to term babies and had complete data on personal exposure in the second trimester of pregnancy to eight airborne polycyclic aromatic hydrocarbons (PAH) including benzo[a]pyrene (B[a]P), as well as DNA adducts, both in maternal and cord blood. The relation between cord blood PAH-DNA adducts and airborne prenatal PAH exposure was non-linear. While cord blood PAH-DNA adducts were significantly associated with the B[a]P exposure categorized by tertiles (nonparametric trend z = 3.50, p < 0.001), the relationship between B[a]P and maternal blood adducts was insignificant (z = 1.63, p = 0.103). Based on the multivariable linear regression model we estimated the effect of the prenatal airborne B[a]P on the level of cord blood adducts. In total, 14.8% of cord blood adducts variance was attributed to the level of maternal adducts and 3% to a higher prenatal B[a] exposure above 5.70 ng/m3. The calculated fetal/maternal blood adducts ratio (FMR) linearly increased with the B[a]P exposure (z = 1.99, p = 0.047) and was highest at B[a]P concentrations exceeding 5.70 ng/m3. In conclusion, the results support other findings that transplacental exposure to B[a[P from maternal inhalation produces DNA damage in the developing fetus. It also confirms the heightened fetal susceptibility to prenatal PAH exposure that should be a matter of public health concern particularly in the highly polluted areas because DNA adducts represent a pro-carcinogenic alteration in DNA The continuation of this birth cohort study will assess the possible health effects of fetal DNA damage on health of children and help in

  12. Mutagenic replication in human cell extracts of DNA containing site-specific N-2-acetylaminofluorene adducts.

    Science.gov (United States)

    Thomas, D C; Veaute, X; Kunkel, T A; Fuchs, R P

    1994-08-02

    We have analyzed the effects of site-specific N-2-acetylaminofluorene (AAF) adducts on the efficiency and frameshift fidelity of bidirectional replication of double-stranded DNA in a human cell extract. Plasmid vectors were constructed containing the simian virus 40 origin of replication and single AAF adducts at one of three guanines in the Nar I sequence GGCGCC in a lacZ reporter gene. The presence of an AAF adduct diminishes replication efficiency in HeLa cell extracts by 70-80%. Replication product analyses reveal unique termination sites with each damaged vector, suggesting that when the replication fork encounters an AAF adduct, it often stops before incorporation opposite the adduct. We also observed a higher proportion of products representing replication of the undamaged strand compared to the damaged strand. This suggests that the undamaged strand is replicated more readily, either by uncoupling the first fork to encounter the lesion or by replication using the fork arriving from the other direction. Also included among replication products are covalently closed monomer-length molecules resistant to cleavage at the AAF-modified Nar I site. This resistance is characteristic of substrates containing the AAF adduct, suggesting that translesion bypass had occurred. Transformation of Escherichia coli cells with the replicated damaged DNA yielded lacZ alpha revertant frequencies significantly above values obtained with undamaged DNA or with damaged DNA not replicated in vitro. This increase was only seen with the substrate modified at the third guanine position. Analysis of mutant DNA demonstrated the loss of a GC dinucleotide at the Nar I sequence. Generation of this position-dependent AAF-induced frameshift error in a human replication system is consistent with previous observations in E. coli suggesting that, after incorporation of dCMP opposite modified guanine in the third position, realignment of the template-primer occurs to form an intermediate with two

  13. VIDEO-ANALYSIS OF THE EFFECT OF DIFFERENT TYPES OF ADAPTED SHOES ON KNEE ADDUCTION MOMENT

    Directory of Open Access Journals (Sweden)

    Andrey Yu. Aksenov

    2017-03-01

    Full Text Available Background. The effect of different footwear profiles on knee adduction moment have not been fully studied. Methods. Fifteen healthy volunteer subjects, age 25.3 (±2.73, undertook a series of gait laboratory trials with adapted shoes. Kinematic and kinetic data were collect using 16 Oqus 3+ cameras and the walking speed was controlled using timing gates. High street shoes were adapted to include five different heel heights (varying from a 1.5 cm to 5.5 cm heels, two heel profile conditions (curved and semi-curved heels, three varying apex angles (10, 15, and 20 degrees, and barefoot and 3CR footwear conditions. The baseline shoe had no heel curve, a heel height of 3.5cm, an apex position of 62.5% of the shoe length, an apex angle of 15 deg, and a rigid forepart of the shoe. Results. The shoe with 5.5 cm heel height significantly increased the mean knee adduction moment during 50%–100% of the stance phase compared to the 1.5 cm heel (p = 0.008. The high heel shoe also significantly increased knee adduction impulse (area under the curve versus the 1.5, 2.5, and 3.5 cm heels, and the 10° toe angle and barefoot condition. Ten degrees of toe angle reduced mean knee adduction moment during 0%–50% of the stance phase versus 20° and significantly reduced mean knee adduction moment during the late stance phase versus 15° and 20° toe angle footwear conditions. Walking with the curved heel for the healthy subjects increased mean knee adduction moment during 0%–50% of the stance phase compared to the heel without curvature (p < 0.0009. Conclusion. Further study is required to investigate those changes in patients with high risk of knee osteoarthritis.

  14. Biomonitoring DNA Adducts of Cooked Meat Carcinogens in Human Prostate by Nano Liquid Chromatography-High Resolution Tandem Mass Spectrometry: Identification of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine DNA Adduct.

    Science.gov (United States)

    Xiao, Shun; Guo, Jingshu; Yun, Byeong Hwa; Villalta, Peter W; Krishna, Suprita; Tejpaul, Resha; Murugan, Paari; Weight, Christopher J; Turesky, Robert J

    2016-12-20

    Epidemiologic studies have reported an association between frequent consumption of well-done cooked meats and prostate cancer risk. However, unambiguous physiochemical markers of DNA damage from carcinogens derived from cooked meats, such as DNA adducts, have not been identified in human samples to support this paradigm. We have developed a highly sensitive nano-LC-Orbitrap MS n method to measure DNA adducts of several carcinogens originating from well-done cooked meats, tobacco smoke, and environmental pollution, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-9H-pyrido[2,3-b]indole (AαC), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (B[a]P), and 4-aminobiphenyl (4-ABP). The limit of quantification (LOQ) of the major deoxyguanosine (dG) adducts of these carcinogens ranged between 1.3 and 2.2 adducts per 10 9 nucleotides per 2.5 μg of DNA assayed. The DNA adduct of PhIP, N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP) was identified in 11 out of 35 patients, at levels ranging from 2 to 120 adducts per 10 9 nucleotides. The dG-C8 adducts of AαC and MeIQx, and the B[a]P adduct, 10-(deoxyguanosin-N 2 -yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (dG-N 2 -B[a]PDE) were not detected in any specimen, whereas N-(deoxyguanosin-8-yl)-4-ABP (dG-C8-4-ABP) was identified in one subject (30 adducts per 10 9 nucleotides). PhIP-DNA adducts also were recovered quantitatively from formalin fixed paraffin embedded (FFPE) tissues, signifying FFPE tissues can serve as biospecimens for carcinogen DNA adduct biomarker research. Our biomarker data provide support to the epidemiological observations implicating PhIP, one of the most mass-abundant heterocyclic aromatic amines formed in well-done cooked meats, as a DNA-damaging agent that may contribute to the etiology of prostate cancer.

  15. Nuclear magnetic resonance studies of an N2-guanine adduct derived from the tumorigen dibenzo[a,l]pyrene in DNA: impact of adduct stereochemistry, size, and local DNA sequence on solution conformations.

    Science.gov (United States)

    Rodríguez, Fabián A; Liu, Zhi; Lin, Chin H; Ding, Shuang; Cai, Yuqin; Kolbanovskiy, Alexander; Kolbanovskiy, Marina; Amin, Shantu; Broyde, Suse; Geacintov, Nicholas E

    2014-03-25

    The dimensions and arrangements of aromatic rings (topology) in adducts derived from the reactions of polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites with DNA influence the distortions and stabilities of double-stranded DNA, and hence their recognition and processing by the human nucleotide excision repair (NER) system. Dibenzo[a,l]pyrene (DB[a,l]P) is a highly tumorigenic six-ring PAH, which contains a nonplanar and aromatic fjord region that is absent in the structurally related bay region five-ring PAH benzo[a]pyrene (B[a]P). The PAH diol epoxide-DNA adducts formed include the stereoisomeric 14S and 14R trans-anti-DB[a,l]P-N(2)-dG and the stereochemically analogous 10S- and 10R-B[a]P-N(2)-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N(2)-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N(2)-dG adduct in two different sequence contexts using NMR methods with distance-restrained molecular dynamics simulations. In duplexes with dC opposite the adduct deleted, a well-resolved base-displaced intercalative adduct conformation can be observed. In full duplexes, in contrast to the intercalated 14R stereoisomeric adduct, the bulky DB[a,l]P residue in the 14S adduct is positioned in a greatly widened and distorted minor groove, with significant disruptions and distortions of base pairing at the lesion site and two 5'-side adjacent base pairs. These unique structural features are significantly different from those of the stereochemically analogous but smaller B[a]P-dG adduct. The greater size and different topology of the DB[a,l]P aromatic ring system lead to greater structurally destabilizing DNA distortions that are partially compensated by stabilizing DB[a,l]P-DNA van der Waals interactions, whose combined effects impact the NER response to the adduct. These structural results broaden our understanding of the structure-function relationship in NER.

  16. Facile Synthesis of 5-Hydroxy-3-pyrrolin-2-ones from Morita-Baylis-Hillman Adducts

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Cheol Hee; Kim, Sung Hwan; Kim, Jae Nyoung [Chonnam National University, Gwangju (Korea, Republic of)

    2012-05-15

    An efficient synthetic method of various 5-hydroxy-3-pyrrolin-2-one derivatives has been developed starting from the MBH adducts. In addition, some synthetic applicability of the prepared 5-hydroxy-3-pyrrolin-2-ones was demonstrated including the synthesis of lactam-fused tetrahydroisoquinolines.

  17. Active control of environmental noise, VIII: increasing the response to primary source changes including unpredictable noise

    Science.gov (United States)

    Wright, S. E.; Atmoko, H.; Vuksanovic, B.

    2004-07-01

    Conventional adaptive cancellation systems using traditional transverse finite impulse response (FIR) filters, together with least mean square (LMS) adaptive algorithms, well known in active noise control, are slow to adapt to primary source changes. This makes them inappropriate for cancelling rapidly changing noise, including unpredictable noise such as speech and music. Secondly, the cancelling structures require considerable computational processing effort to adapt to primary source and plant changes, particularly for multi-channel systems. This paper describes methods to increase the adaptive speed to primary source changes in large enclosed spaces and outdoor environments. A method is described that increases the response to time varying periodic noise using traditional transverse FIR filters. Here a multi-passband filter, with individual variable adaptive step sizes for each passband is automatically adjusted according to the signal level in each band. This creates a similar adaptive response for all frequencies within the total pass-band, irrespective of amplitude, minimizing the signal distortion and increasing the combined adaptive speed. Unfortunately, there is a limit to the adaptive speed using the above method as classical transverse FIR filters have a finite adaptive speed given by the stability band zero bandwidth. For rapidly changing periodic noise and unpredictable non-stationary noise, a rapid to instantaneous response is required. In this case the on-line adaptive FIR filters are dispensed with and replaced by a time domain solution that gives virtually instantaneous cancellation response (infinite adaptive speed) to primary source changes, and is computationally efficient.

  18. Measuring Outcomes in Adult Weight Loss Studies That Include Diet and Physical Activity: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Rachel A. Millstein

    2014-01-01

    Full Text Available Background. Measuring success of obesity interventions is critical. Several methods measure weight loss outcomes but there is no consensus on best practices. This systematic review evaluates relevant outcomes (weight loss, BMI, % body fat, and fat mass to determine which might be the best indicator(s of success. Methods. Eligible articles described adult weight loss interventions that included diet and physical activity and a measure of weight or BMI change and body composition change. Results. 28 full-text articles met inclusion criteria. Subjects, settings, intervention lengths, and intensities varied. All studies measured body weight (−2.9 to −17.3 kg, 9 studies measured BMI (−1.1 to −5.1 kg/m2, 20 studies measured % body fat (−0.7 to −10.2%, and 22 studies measured fat mass (−0.9 to −14.9 kg. All studies found agreement between weight or BMI and body fat mass or body fat % decreases, though there were discrepancies in degree of significance between measures. Conclusions. Nearly all weight or BMI and body composition measures agreed. Since body fat is the most metabolically harmful tissue type, it may be a more meaningful measure of health change. Future studies should consider primarily measuring % body fat, rather than or in addition to weight or BMI.

  19. Selective electrolytic removal of bis(alkoxycarbonyl)methano addends from C60 bis-adducts and electrochemical stability of C70 derivatives

    Science.gov (United States)

    Kessinger; Fender; Echegoyen; Thilgen; Echegoyen; Diederich

    2000-06-16

    The novel mixed bis-adducts of C60, (+/-)-4-(+/-)-8 and 9, with a bis(ethoxycarbonyl)methano addend (Bingel addend) and a second addend ([1,2]benzeno, but[2]eno, methaniminomethano, or diarylmethano) bridging 6,6-closed bonds of the carbon sphere were synthesized in two-step reactions. Each bis-adduct was exhaustively electrolyzed at the potential of the second fullerene-centered reduction step, resulting in the selective removal of the Bingel addend (retro-Bingel reaction) to produce the corresponding mono-adducts, which were isolated in yields of over 60%. These results open up the possibility of using the Bingel addend as a temporary protecting and directing group in the construction of multiple adducts of C60 with unusual addition patterns. The Bingel-type mono-adduct of C70 10 and the constitutionally isomeric bis-adducts 11, (+/-)-12, and (+/-)-13 were also included in this investigation. A large difference in the electrochemical behavior between C70 bis-adducts and the corresponding C60 derivatives was observed. Thus, the intramolecular "walk-on-the-sphere" isomerization which occurs readily with Bingel-type bis-adducts of C60 under the conditions of two-electron controlled potential electrolysis (CPE) is only a minor reaction pathway in the series of C70 derivatives. The latter preferentially undergo retro-Bingel reaction.

  20. Macroenvironmental factors including GDP per capita and physical activity in Europe

    NARCIS (Netherlands)

    Cameron, Adrian J.; van Stralen, Maartje M.; Kunst, Anton E.; te Velde, Saskia J.; van Lenthe, Frank J.; Salmon, Jo; Brug, Johannes

    2013-01-01

    Socioeconomic inequalities in physical activity at the individual level are well reported. Whether inequalities in economic development and other macroenvironmental variables between countries are also related to physical activity at the country level is comparatively unstudied. We examined the

  1. A kinetic and spectroscopic study of the CH3I-Cl and ICH2I-Cl adducts.

    Science.gov (United States)

    Gravestock, T J; Blitz, M A; Heard, D E

    2008-10-02

    Laser-induced fluorescence from the CH3I-Cl and ICH2I-Cl adducts formed in association reactions between chlorine atoms and CH3I and CH2I2 has been observed for the first time. The LIF excitation and dispersed fluorescence spectra have been measured in the range 345-375 nm and 380-480 nm, respectively, at 204 and 296 K. The excitation spectra exhibit vibrational fine structure, and a semiquantitative analysis of the spectra yields a similar binding energy for both adducts of approximately 60 kJ mol(-1). The adduct fluorescence is efficiently quenched by N2 and exhibits a zero-pressure lifetime of approximately 25-30 ns. Using LIF excited from the CH3I-Cl and ICH2I-Cl adducts, the kinetics of the reactions of atomic chlorine with methyl iodide and diiodomethane have been investigated, the results showing that both reactions proceed via two independent channels, an association reaction to form the adduct and a bimolecular abstraction reaction. At T approximately 200 K, the association reaction is predominant, and CH3I-Cl formation is irreversible, with rate coefficients for adduct formation found to be pressure-dependent and in reasonable agreement with the literature. At approximately 200 K, removal of the adduct is dominated by reaction with radical species (CH3 and ClSO) and by self-reaction, which proceed at close to the gas kinetic limit. At 296 K, CH3I-Cl formation is reversible, and the equilibrium constant, K(p) = (70.9 +/- 27.4) x 10(3) atm(-1), was determined, which is in excellent agreement with the literature, and the adduct does not significantly react with CH3I. The uncertainty is at the 95% confidence level (2sigma) and includes systematic errors. At approximately 200 K, the ICH2I-Cl adduct is again stabilized, with pressure-dependent rate coefficients reaching the high pressure limit at lower pressures than for the Cl + CH3I reaction. At room temperature, the ICH2I-Cl adduct is removed via an additional unimolecular decomposition channel, which

  2. Tumors and DNA adducts in mice exposed to benzo(a)pyrene and coal tars: implications for risk assessment

    Energy Technology Data Exchange (ETDEWEB)

    Goldstein, L.S.; Weyand, E.H.; Safe, S.; Steinberg, M.; Culp, S.J.; Gaylor, D.W.; Beland, F.A.; Rodriguez, L.V. [Electric Power Research Institute, Palo Alto, CA (United States)

    1998-12-01

    Current methods to estimate the quantitative cancer risk of complex mixtures of polycyclic aromatic hydrocarbons (PAH) such as coal tar assume that overall potency can be derived from knowledge of the concentration of a few carcinogenic components such as benzo(a)pyrene (B(a)P). Genotoxic damage, such as DNA adducts, is thought to be an essential aspect of PAH-induced tumorigenesis and could be a biomarker for exposure useful for estimating risk. However, the role of B(a)P and the relationship of adduct formation in tumorigenesis have not been tested rigorously in models appropriate for human health risk assessment. This paper compares tumor induction and adduct formation by B(a)P and coal tars in several experimental protocols, including one broadly accepted and used by regulators. It was found that B(a)P content did not account for tumor incidences after exposure to coal tars. DNA adducts were found in both tumors and tumor-free tissue and tumor outcomes were not predicted by either quantitation of total DNA adducts or by the DNA adduct formed by B(a)P. These data suggest that risk assessments based on B(a)P content may not predict accurately risk to human health posed by environmental PAH.

  3. Detection of human butyrylcholinesterase-nerve gas adducts by liquid chromatography-mass spectrometric analysis after in gel chymotryptic digestion.

    Science.gov (United States)

    Tsuge, Kouichiro; Seto, Yasuo

    2006-06-21

    To verify the exposure to nerve gas, a method for detecting human butyrylcholinesterase (BuChE)-nerve gas adduct was developed using LC-electrospray mass spectrometry (ESI-MS). Purified human serum BuChE was incubated with sarin, soman or VX, and the adduct was purified by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and digested in gel by treatment with chymotrypsin. The resulting peptide mixture was subjected to LC-ESI-MS. From the chymotryptic digest of untreated human BuChE, one peak corresponding to the peptide fragment containing the active center serine residue was detected on the extracted ion chromatogram at m/z 948.5, and the sequence was ascertained to be "GESAGAASVSL" by MS/MS analysis. From the chymotryptic digest of the human BuChE-sarin adduct, a singly charged peptide peak was detected on the extracted ion chromatogram at m/z 1,069.5, and the sequence was ascertained to be "GEXAGAASVSL" by MS/MS analysis (X denotes isopropylmethylphosphonylated serine). The difference in molecular weight (120.0 Da) between the active center peptide fragments corresponding to the untreated BuChE and BuChE-sarin adduct was assumed to be derived from the addition of an isopropyl methylphosphonyl moiety to the serine residue. The formation of human BuChE adducts with soman, VX and an aged soman adduct was confirmed by detecting the respective active center peptide fragments using LC-ESI-MS. To apply the established method to an actual biological sample, human serum was incubated with VX, and the adduct was purified by procainamide affinity chromatography followed by SDS-PAGE. After chymotryptic in gel digestion, the ethylphosphonylated active center peptide fragment could be detected, and the structure of the residue was ascertained by LC-ESI-MS analysis.

  4. Overview on extraction kinetics of metal adducts

    International Nuclear Information System (INIS)

    Aly, H.F.; Daoud, J.A.

    1995-01-01

    A overview of extraction kinetics solvent extraction of metal adducts is given. A kinetic regime, diffusional regime, and mixed diffusional-kinetic regime are analysed. The practical applications of kinetics of solvent extraction processes in connection with technical processes and counter-current modelling is discussed. Kinetic studies are essential for the development of new processes and the knowledge of factors governing the mass transfer and mechanism of extraction of metal ions is of major importance in the design, operation, control and optimization of reactors in chemical industry. 23 refs

  5. Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa.

    Science.gov (United States)

    Ho, Vikki; Brunetti, Vanessa; Peacock, Sarah; Massey, Thomas E; Godschalk, Roger W L; van Schooten, Frederik J; Ashbury, Janet E; Vanner, Stephen J; King, Will D

    2017-09-01

    Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32 P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY ® iPLEX ® Gold SNP Genotyping assay. PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Does limited virucidal activity of biocides include duck hepatitis B virucidal action?

    Directory of Open Access Journals (Sweden)

    Sauerbrei Andreas

    2012-10-01

    Full Text Available Abstract Background There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV or the modified vaccinia Ankara strain (MVA. Methods Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining. Results The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min. Conclusions Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV.

  7. Relationship between clinical results of total hip replacement and postoperative activities including weeding and snow shovelling.

    Science.gov (United States)

    Kijima, Hiroaki; Yamada, Shin; Konishi, Natsuo; Kubota, Hitoshi; Tazawa, Hiroshi; Tani, Takayuki; Suzuki, Norio; Kamo, Keiji; Okudera, Yoshihiko; Sasaki, Ken; Kawano, Tetsuya; Miyakoshi, Naohisa; Shimada, Yoichi

    2017-09-07

    Weeding or snow shovelling is indispensable for life in farm villages of northern countries. Clarifying the relationships between the degrees of these activities after total hip replacement (THR) and the clinical results of THR may enable us to predict the results of THR for high-level activity patients. The relationships between work activities after THR and the results were investigated. The subjects were 95 post-THR patients, who consulted 6 hospitals in August 2012. First, the Japanese Orthopaedic Association Hip-Disease Evaluation Questionnaire (JHEQ) and a questionnaire on postoperative activity were administered. Then, the Japanese Orthopaedic Association hip score (JOA score) was evaluated. The subjects' average age was 68 years. The average period after surgery was 4 years and 5 months. Weeding and snow shovelling were performed after THR in 44.2% and 40.0% of cases, respectively. The rate of farming after surgery (25.6%) was greater than that of swimming (21.1%). Both the JOA score and JHEQ were higher in those who played sports after THR than in those who did not (p = 0.003, p = 0.0046). The JOA score of those who performed work activities after THR was higher than that of those who did not (p = 0.0295). Nearly half of patients performed weeding or snow shovelling after THR, and about 1/4 of the patients engaged in farming after THR. The clinical results in cases doing sports and work activities after THR were better than those of cases not doing such activities. Therefore, these activities may be positively recommended.

  8. Nontargeted Identification of Reactive Metabolite Protein Adducts.

    Science.gov (United States)

    Leeming, Michael G; Donald, William A; O'Hair, Richard A J

    2017-06-06

    Metabolic bioactivation of many different chemicals results in the formation of highly reactive compounds (chemically reactive metabolites, CRMs) that can lead to toxicity via binding to macromolecular targets (e.g., proteins or DNA). There is a need to develop robust, rapid, and nontargeted analytical techniques to determine the identity of the protein targets of CRMs and their sites of modification. Here, we introduce a nontargeted methodology capable of determining both the identity of a CRM formed from an administered compound as well as the protein targets modified by the reactive metabolite in a single experiment without prior information. Acetaminophen (N-acetyl-p-aminophenol, APAP) and 13 C 6 -APAP were incubated with rat liver microsomes, which are known to bioactivate APAP to the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI). Global tryptic digestion followed by liquid chromatographic/mass spectrometric (LC/MS) analysis was used to locate "twin" ion peaks of peptides adducted by NAPQI and for shotgun proteomics via tandem mass spectrometry (MS/MS). By the development of blended data analytics software called Xenophile, the identity of the amino acid residue that was adducted can be established, which eliminates the need for specific parametrization of protein database search algorithms. This combination of experimental design and data analysis software allows the identity of a CRM, the protein target, and the amino acid residues that are modified to be rapidly established directly from experimental data. Xenophile is freely available from https://github.com/mgleeming/Xenophile .

  9. Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats.

    Science.gov (United States)

    Monien, Bernhard H; Müller, Carolin; Bakhiya, Nadiya; Donath, Claudia; Frank, Heinz; Seidel, Albrecht; Glatt, Hansruedi

    2009-07-28

    1-Methylpyrene (1-MP), an abundant alkylated polycyclic aromatic hydrocarbon, is activated by side-chain hydroxylation to 1-hydroxymethylpyrene (1-HMP) and subsequent sulfo-conjugation to electrophilic 1-sulfooxymethylpyrene (1-SMP). In rats, this activation mainly occurs in liver. 1-SMP may react with hepatic DNA or be exported into the blood circulation to reach other tissues, in particular kidneys. Findings with recombinant cell lines suggest that renal 1-SMP uptake proceeds via organic anion transporters (OATs). Here, we tested the hypothesis that probenecid, a characteristic OAT inhibitor, interferes with kidney damage brought about by 1-SMP formed in rats. 1-HMP was administered intraperitoneally to 30 rats, half of which were co-treated with probenecid. The tissue distribution of DNA adducts was analyzed using (32)P-postlabeling and isotope dilution LC-MS/MS for the detection of the adducts N(2)-(1-methylpyrenyl)-2'-deoxyguanosine and N(6)-(1-methylpyrenyl)-2'-deoxyadenosine. In rats treated solely with 1-HMP, adduct levels in kidney tissue were about 3-fold and 8-fold higher than those in liver and lung, respectively. After co-treatment with probenecid, hepatic and pulmonary adduct levels were 12-fold and 4-fold elevated, respectively, whereas renal adduct levels were slightly lower compared to those of rats receiving 1-HMP alone. Moreover, serum levels of 1-SMP were increased 23-fold in animals pre-treated with probenecid. The differential effects on hepatic and pulmonary adduct levels suggest that not only renal OATs, but also additional anion transporters, e.g. those mediating the hepatic export of 1-SMP into the bile, were inhibited. Thus, transmembrane transport proteins play a crucial role in the distribution of reactive phase II metabolites, and thereby in tissue allocation of DNA adducts.

  10. Adduct Formation in ESI/MS by Mobile Phase Additives.

    Science.gov (United States)

    Kruve, Anneli; Kaupmees, Karl

    2017-05-01

    Adduct formation is a common ionization method in electrospray ionization mass spectrometry (ESI/MS). However, this process is poorly understood and complicated to control. We demonstrate possibilities to control adduct formation via mobile phase additives in ESI positive mode for 17 oxygen and nitrogen bases. Mobile phase additives were found to be a very effective measure for manipulating the formation efficiencies of adducts. An appropriate choice of additive may increase sensitivity by up to three orders of magnitude. In general, sodium adduct [M + Na] + and protonated molecule [M + H] + formation efficiencies were found to be in good correlation; however, the former were significantly more influenced by mobile phase properties. Although the highest formation efficiencies for both species were observed in water/acetonitrile mixtures not containing additives, the repeatability of the formation efficiencies was found to be improved by additives. It is concluded that mobile phase additives are powerful, yet not limiting factors, for altering adduct formation. Graphical Abstract ᅟ.

  11. Using assistive technology adaptations to include students with learning disabilities in cooperative learning activities.

    Science.gov (United States)

    Bryant, D P; Bryant, B R

    1998-01-01

    Cooperative learning (CL) is a common instructional arrangement that is used by classroom teachers to foster academic achievement and social acceptance of students with and without learning disabilities. Cooperative learning is appealing to classroom teachers because it can provide an opportunity for more instruction and feedback by peers than can be provided by teachers to individual students who require extra assistance. Recent studies suggest that students with LD may need adaptations during cooperative learning activities. The use of assistive technology adaptations may be necessary to help some students with LD compensate for their specific learning difficulties so that they can engage more readily in cooperative learning activities. A process for integrating technology adaptations into cooperative learning activities is discussed in terms of three components: selecting adaptations, monitoring the use of the adaptations during cooperative learning activities, and evaluating the adaptations' effectiveness. The article concludes with comments regarding barriers to and support systems for technology integration, technology and effective instructional practices, and the need to consider technology adaptations for students who have learning disabilities.

  12. Three Peaks of 2011 Draconid Activity Including that Connected with Pre-1900 Material

    Science.gov (United States)

    Koten, Pavel; Vaubaillon, Jeremie; Tóth, Juraj; Margonis, Anastasios; Ďuriš, František

    2014-08-01

    A Draconid meteor shower outburst was observed from on board two scientific aircraft deployed above Northern Europe on 8th October 2011. The activity profile was measured using a set of photographic and video cameras. The main peak of the activity occurred around 20:15 ± 0:0.5 UT which is consistent with the model prediction as well as with the IMO network visual observations. The corrected hourly rates reached a value of almost 350. The brighter meteors peaked about 15-20 min earlier than the dimmer ones. This difference can be explained by different directions of the ejection of the meteoroids from the parent comet. One of the instruments was even able to detect meteors connected with the material ejected from the parent comet before 1900 and thus confirmed the prediction of the model, although it was based on uncertain pre-1900 cometary data. Another small peak of the activity, which was caused by material ejected during the 1926 perihelion passage of the parent comet, was detected around 21:10 UT. The mass distribution index determined using the narrow field-of-view video camera was 2.0 ± 0.1. This work shows that the observation of meteor outbursts can constrain the orbital elements, outgassing activity and existence of jets at the surface of a comet.

  13. Absence of a Classically Activated Macrophage Cytokine Signature in Peripheral Spondylarthritis, Including Psoriatic Arthritis

    NARCIS (Netherlands)

    Vandooren, Bernard; Noordenbos, Troy; Ambarus, Carmen; Krausz, Sarah; Cantaert, Tineke; Yeremenko, Nataliya; Boumans, Maartje; Lutter, Rene; Tak, Paul P.; Baeten, Dominique

    2009-01-01

    Objective. Peripheral spondylarthritis (SpA) is characterized by macrophages that express CD163, a marker of alternative activation (M2). The purpose of this study was to assess whether this differential infiltration with macrophage subsets was associated with a different local inflammatory milieu

  14. Sixty Minutes of Physical Activity per Day Included within Preschool Academic Lessons Improves Early Literacy

    Science.gov (United States)

    Kirk, Stacie M.; Kirk, Erik P.

    2016-01-01

    Background: The effects of increases in physical activity (PA) on early literacy skills in preschool children are not known. Methods: Fifty-four African-American preschool children from a low socioeconomic urban Head Start participated over 8 months. A 2-group, quasi-experimental design was used with one preschool site participating in the PA…

  15. 76 FR 10385 - Agency Information Collection Activities: Various Contract Related Forms That Will be Included in...

    Science.gov (United States)

    2011-02-24

    ... DEPARTMENT OF HOMELAND SECURITY Agency Information Collection Activities: Various Contract Related... that was indicated is the estimated annualized cost to the respondents for the hour burden for... additional 30-days for public comments and to correct the cost from $236,253.00 to zero. DATES: Comments are...

  16. 25 CFR 170.623 - How are IRR Program projects and activities included in a self-governance agreement?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false How are IRR Program projects and activities included in a self-governance agreement? 170.623 Section 170.623 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE... self-governance agreement? To include an IRR Program project or activity in a self-governance agreement...

  17. Activity behavior of a HPLC column including α-chymotrypsin immobilized monosized-porous particles

    International Nuclear Information System (INIS)

    Bilici, Z.; Camli, S.T.; Unsal, E.; Tuncel, A.

    2004-01-01

    In this study, a polymer-based, α-chymotrypsin (CT) immobilized HPLC column was prepared as a potential material for affinity-HPLC and chiral separation applications. Monosized-macroporous particles were synthesized as the support material by a relatively new polymerization protocol, the so-called, 'modified seeded polymerization'. The particles were obtained in the form of styrene-glycidyl methacrylate- divinylbenzene terpolymer approximately 11 μm in size. The particles were treated with aqueous ammonia to have primary amine groups on the porous surface. The amine functionalized particles were reacted by glutaraldehyde and the enzyme, CT, was covalently attached. CT carrying monosized-porous particles were slurry packed into the HPLC column 50 mmx4.6 mm in size. Since the activity behavior of immobilized CT played an important role in the enantiomeric separations performed by similar columns, the enzymatic activity behavior of the column produced by our protocol was determined. For this purpose, HPLC column was used as a packed bed reactor and the enzymatic reaction was continuously followed by measuring the absorbance of the output flow by the UV-detector of HPLC. S-shaped absorbance-time curves were obtained by monitoring the reactor output both in dynamic and steady-state periods. The columns with relatively lower immobilized enzyme content were more sensitive to the changes in the operating conditions and responded with more appreciable substrate conversion changes. The maximum reaction rate of the immobilized enzyme was estimated as approximately 25% of the free one by the mathematical model describing the activity behavior of the column. No significant loss was observed in the activity of the immobilized enzyme during the course of the experiments

  18. O6-pyridyloxobutylguanine adducts contribute to the mutagenic properties of pyridyloxobutylating agents.

    Science.gov (United States)

    Mijal, Renée S; Loktionova, Natalia A; Vu, Choua C; Pegg, Anthony E; Peterson, Lisa A

    2005-10-01

    The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are potent carcinogens in animal models and likely human carcinogens. Both NNK and NNN can be activated to a pyridyloxobutylating agent. This alkylating agent contributes to the carcinogenic effects of NNK and NNN via the formation of miscoding DNA adducts. One of these adducts, O6-[4-oxo-4-(3-pyridyl)butyl]guanine (O6-pobG) has been characterized as a mutagenic adduct which is a substrate for the repair protein O6-alkylguanine-DNA alkyltransferase (AGT). Repair of O6-alkylguanine adducts by AGT protects cells from the mutagenic and carcinogenic effects of alkylating agents and is likely to play a similar role in shielding cells from the adverse effects of pyridyloxobutylating agents. Therefore, we examined the mutagenicity of the model pyridyloxobutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanone (NNKOAc), in Salmonella typhimurium YG7108 expressing hAGT. Expression of hAGT protected cells from NNKOAc-induced mutagenicity. Interestingly, hAGT did not shield cells from the toxicity of this agent. To confirm that the repair of O6-pobG was increased in the bacteria expressing hAGT, we measured levels of this adduct in NNKOAc-treated cultures. The levels of O6-pobG were lower in DNA from bacteria expressing hAGT. This work establishes an important role for O6-pobG in mediating the mutagenic, and possibly carcinogenic, effects of pyridyloxobutylating compounds.

  19. Differences in micronucleus frequency and acrylamide adduct levels with hemoglobin between vegetarians and non-vegetarians.

    Science.gov (United States)

    Kotova, Natalia; Frostne, Cecilia; Abramsson-Zetterberg, Lilianne; Tareke, Eden; Bergman, Rolf; Haghdoost, Siamak; Paulsson, Birgit; Törnqvist, Margareta; Segerbäck, Dan; Jenssen, Dag; Grawé, Jan

    2015-10-01

    Nutrients and food constituents can prevent or contribute to genotoxicity. In this study, the possible influence of a vegetarian/non-vegetarian diet on genotoxic effects was investigated in 58 non-smoking healthy vegetarians (V) and non-vegetarians (NV), age 21-37 years from the Stockholm area in Sweden. Physical activity and dietary habits were similar in both groups, with the exception of the intake of meat and fish. Using flow cytometry, we determined the formation of micronuclei (MN) in transferrin-positive immature peripheral blood reticulocytes (Trf-Ret) (Total: n = 53; V: n = 27; NV: n = 26). Dietary exposure to acrylamide was measured through hemoglobin (Hb) adducts in peripheral erythrocytes (Total: n = 53; V: n = 29; NV: n = 24). Hb adducts of both acrylamide and its genotoxic metabolite glycidamide were monitored as a measure of the corresponding in vivo doses. Our data demonstrated that compared with the non-vegetarians, the vegetarians exhibited lower frequencies of MN (fMN) in the Trf-Ret (p vegetarians and non-vegetarians. Furthermore, there were no significant relationships between the adduct levels and fMN in the individuals. The ratio of the Hb adduct levels from glycidamide and acrylamide, however, showed a significant difference (p vegetarian diet might be beneficial in lowering genomic instability in healthy individuals. The measured Hb adduct levels indicate that the total intake of acrylamide does not differ between the two studied groups and does not contribute to the observed difference in fMN, although an influence of the diet on the metabolic rates of acrylamide was indicated. In addition, the observed significant difference in the background fMN in the two groups demonstrated that the MN analysis method has a sensitivity applicable to the biomonitoring of human lifestyle factors.

  20. Formation and persistence of DNA adducts from the carcinogen N-hydroxy-2-acetylaminofluorene in rat mammary gland in vivo

    International Nuclear Information System (INIS)

    Allaben, W.T.; Weis, C.C.; Fullerton, N.F.; Beland, F.A.

    1983-01-01

    The rat mammary carcinogen, N-hydroxy-2-acetylaminofluorene (N-hydroxy-2-AAF), has been proposed to be metabolically activated by mammary cytosolic N,O-acetyltransferase to a DNA binding species. To test this hypothesis, adult female Sprague-Dawley derived CD rats were treated, i.p., with 4.0 mg/kg [ring- 3 H]N-hydroxy-2-AAF. After 4 h, 1, 3, 14, and 28 days, the animals were killed, the mammary epithelium DNA was isolated and the carcinogen-deoxyribonucleoside adducts present were analyzed by high pressure liquid chromatography. At each time, only one adduct was detected and it was chromatographically identical to N-(deoxyguanosin-8-yl)-2-aminofluorene. The level of the adduct was maximal at 4 h (1.5 adducts/10(6) nucleotides) and then decreased, following first order kinetics with a t1/2 of 14.2 days. The detection of a single non-acetylated aminofluorene adduct is consistent with N,O-acyltransferase being involved in the metabolic activation of N-hydroxy-2-AAF in the rat mammary gland

  1. In vitro activity of Inula helenium against clinical Staphylococcus aureus strains including MRSA.

    LENUS (Irish Health Repository)

    O'Shea, S

    2009-01-01

    The present study aims to investigate the bactericidal activity (specifically antistaphylococcal) of Inula helenium. The antimicrobial activity of the extract is tested against 200 clinically significant Irish Staphylococcus aureus isolates consisting of methicillin-resistant (MRSA) and -sensitive (MSSA) S. aureus using a drop test method and a microbroth dilution method. The antibacterial effect is evaluated by measuring the area of the inhibition zone against the isolates. Results proved I. helenium to be 100% effective against the 200 staphylococci tested, with 93% of isolates falling within the ++ and +++ groups. The minimum bactericidal concentration of I. helenium was examined on a subset of isolates and values ranged from 0.9 mg\\/mL to 9.0 mg\\/mL. The extract was equally effective against antibiotic-resistant and -sensitive strains. This plant therefore possesses compounds with potent antistaphylococcal properties, which in the future could be used to complement infection control policies and prevent staphylococcal infection and carriage. This research supports other studies wherein herbal plants exhibiting medicinal properties are being examined to overcome the problems of antibiotic resistance and to offer alternatives in the treatment and control of infectious diseases.

  2. Active immunisation of horses against tetanus including the booster dose and its application.

    Science.gov (United States)

    Liefman, C E

    1981-02-01

    Successful active immunisation of horses against tetanus is dependent on a number of factors of which the toxoid preparation used, its method of application and the ability of the individual horse to respond are fundamental. Two immunisation schedules using an aluminium-based toxoid preparation were examined and the protection determined by monitoring the level of antitoxin afforded by each schedule. The results obtained demonstrated that 2 doses of this toxoid are necessary to ensure 12 months protection in all horses. These results are discussed in relation to the factors involved in active immunisation against tetanus. Reference is also made to the occurrence of a transient phase of reduced levels of antitoxin following booster doses of toxoid in immunised horses during which it is considered these horses could become more susceptible to tetanus. The effect of a booster dose on immunised horses was examined and while there can be a reduction in the level of antitoxin in some immunised horses following this dose its effect is minimal, short-lived and for all practical purposes can be disregarded. The application of the booster dose in practice is also discussed.

  3. 3-Nitropropionic Acid is a Suicide Inhibitor of MitochondrialRespiration that, Upon Oxidation by Complex II, Forms a Covalent AdductWith a Catalytic Base Arginine in the Active Site of the Enzyme

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Li-shar; Sun, Gang; Cobessi, David; Wang, Andy C.; Shen,John T.; Tung, Eric Y.; Anderson, Vernon E.; Berry, Edward A.

    2005-12-01

    We report three new structures of mitochondrial respiratory Complex II (succinate ubiquinone oxidoreductase, E.C. 1.3.5.1) at up to 2.1 {angstrom} resolution, with various inhibitors. The structures define the conformation of the bound inhibitors and suggest the residues involved in substrate binding and catalysis at the dicarboxylate site. In particular they support the role of Arg297 as a general base catalyst accepting a proton in the dehydrogenation of succinate. The dicarboxylate ligand in oxaloacetate-containing crystals appears to be the same as that reported for Shewanella flavocytochrome c treated with fumarate. The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297. The modification eliminates a trypsin cleavage site in the flavoprotein, and tandem mass spectroscopic analysis of the new fragment shows the mass of Arg 297 to be increased by 83 Da and to have potential of losing 44 Da, consistent with decarboxylation, during fragmentation.

  4. Nuclear Rocket Test Facility Decommissioning Including Controlled Explosive Demolition of a Neutron-Activated Shield Wall

    International Nuclear Information System (INIS)

    Michael Kruzic

    2007-01-01

    Located in Area 25 of the Nevada Test Site, the Test Cell A Facility was used in the 1960s for the testing of nuclear rocket engines, as part of the Nuclear Rocket Development Program. The facility was decontaminated and decommissioned (D and D) in 2005 using the Streamlined Approach For Environmental Restoration (SAFER) process, under the Federal Facilities Agreement and Consent Order (FFACO). Utilities and process piping were verified void of contents, hazardous materials were removed, concrete with removable contamination decontaminated, large sections mechanically demolished, and the remaining five-foot, five-inch thick radiologically-activated reinforced concrete shield wall demolished using open-air controlled explosive demolition (CED). CED of the shield wall was closely monitored and resulted in no radiological exposure or atmospheric release

  5. Sixty Minutes of Physical Activity per Day Included Within Preschool Academic Lessons Improves Early Literacy.

    Science.gov (United States)

    Kirk, Stacie M; Kirk, Erik P

    2016-03-01

    The effects of increases in physical activity (PA) on early literacy skills in preschool children are not known. Fifty-four African-American preschool children from a low socioeconomic urban Head Start participated over 8 months. A 2-group, quasi-experimental design was used with one preschool site participating in the PA intervention and a second site participating as the control site. The PA program was designed to promote 300 minutes/week of moderate to vigorous PA academic lessons. Academic achievement related to early literacy and phonological awareness in the areas of rhyming and alliteration were assessed at baseline, 4 and 8 months. Over 8 months, rhyming significantly (p literacy. © 2016, American School Health Association.

  6. Nuclear Rocket Test Facility Decommissioning Including Controlled Explosive Demolition of a Neutron-Activated Shield Wall

    Energy Technology Data Exchange (ETDEWEB)

    Michael Kruzic

    2007-09-01

    Located in Area 25 of the Nevada Test Site, the Test Cell A Facility was used in the 1960s for the testing of nuclear rocket engines, as part of the Nuclear Rocket Development Program. The facility was decontaminated and decommissioned (D&D) in 2005 using the Streamlined Approach For Environmental Restoration (SAFER) process, under the Federal Facilities Agreement and Consent Order (FFACO). Utilities and process piping were verified void of contents, hazardous materials were removed, concrete with removable contamination decontaminated, large sections mechanically demolished, and the remaining five-foot, five-inch thick radiologically-activated reinforced concrete shield wall demolished using open-air controlled explosive demolition (CED). CED of the shield wall was closely monitored and resulted in no radiological exposure or atmospheric release.

  7. Biocatalytic Reductions of Baylis - Hillman Adducts

    Energy Technology Data Exchange (ETDEWEB)

    A Walton; W Conerly; Y Pompeu; B Sullivan; J Stewart

    2011-12-31

    Baylis-Hillman adducts are highly useful synthetic intermediates; to enhance their value further, we sought enantiocomplementary alkene reductases to introduce chirality. Two solutions emerged: (1) a wild-type protein from Pichia stipitis (OYE 2.6), whose performance significantly outstrips that of the standard enzyme (Saccharomyces pastorianus OYE1), and (2) a series of OYE1 mutants at position 116 (Trp in the wild-type enzyme). To understand how mutations could lead to inverted enantioselectivity, we solved the X-ray crystal structure of the Trp116Ile OYE1 variant complexed with a cyclopentenone substrate. This revealed key protein-ligand interactions that control the orientation of substrate binding above the FMN cofactor.

  8. Individuals with varus thrust do not increase knee adduction when running with body borne load.

    Science.gov (United States)

    Brown, Tyler N; Kaplan, Jonathan T; Cameron, Sarah E; Seymore, Kayla D; Ramsay, John W

    2018-03-01

    Osteoarthritis (OA) is a common occupational hazard for service members. This study quantified how body borne load impacts knee biomechanics for participants who do and do not present varus thrust (range of knee adduction motion exhibited from heel strike to mid-stance (0-51%)) during over-ground running. Eighteen (9 varus thrust and 9 control) military personnel had knee biomechanics recorded when running with three load conditions (light, ∼6 kg, medium, 15% BW, and heavy, 30% BW). Subject-based means for knee biomechanics were calculated and submitted to a RM ANOVA to test the main effects and possible interactions between load and varus thrust group. The varus thrust group exhibited greater varus thrust (p = .001) and peak stance (PS, 0-100%) knee adduction (p = .009) posture compared to the control group with the light load, but not for the medium (p = .741 and p = .825) or heavy loads (p = .142 and p = .429). With the heavy load, varus thrust group reduced varus thrust (p = .023), whereas, the control group increased varus thrust (p = .037) compared to the light load, and increased PS knee adduction moment compared to light (p = .006) and medium loads (p = .031). The varus thrust group, however, exhibited no significant difference in knee adduction moment between any load (p = .174). With the addition of body borne load, varus thrust participants exhibited a significant reduction in knee biomechanics related to OA; whereas, control participants adopted knee biomechanics, including greater varus thrust and knee adduction moment, related to the development of OA. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene.

    Science.gov (United States)

    Wickramaratne, Susith; Banda, Douglas M; Ji, Shaofei; Manlove, Amelia H; Malayappan, Bhaskar; Nuñez, Nicole N; Samson, Leona; Campbell, Colin; David, Sheila S; Tretyakova, Natalia

    2016-11-01

    The important industrial and environmental carcinogen 1,3-butadiene (BD) forms a range of adenine adducts in DNA, including N 6 -(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine (N 6 -HB-dA), 1,N 6 -(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine (1,N 6 -HMHP-dA), and N 6 ,N 6 -(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (N 6 ,N 6 -DHB-dA). If not removed prior to DNA replication, these lesions can contribute to A → T and A → G mutations commonly observed following exposure to BD and its metabolites. In this study, base excision repair of BD-induced 2'-deoxyadenosine (BD-dA) lesions was investigated. Synthetic DNA duplexes containing site-specific and stereospecific (S)-N 6 -HB-dA, (R,S)-1,N 6 -HMHP-dA, and (R,R)-N 6 ,N 6 -DHB-dA adducts were prepared by a postoligomerization strategy. Incision assays with nuclear extracts from human fibrosarcoma (HT1080) cells have revealed that BD-dA adducts were recognized and cleaved by a BER mechanism, with the relative excision efficiency decreasing in the following order: (S)-N 6 -HB-dA > (R,R)-N 6 ,N 6 -DHB-dA > (R,S)-1,N 6 -HMHP-dA. The extent of strand cleavage at the adduct site was decreased in the presence of BER inhibitor methoxyamine and by competitor duplexes containing known BER substrates. Similar strand cleavage assays conducted using several eukaryotic DNA glycosylases/lyases (AAG, Mutyh, hNEIL1, and hOGG1) have failed to observe correct incision products at the BD-dA lesion sites, suggesting that a different BER enzyme may be involved in the removal of BD-dA adducts in human cells.

  10. PAH-DNA adducts in cord blood and fetal and child development in a Chinese cohort

    Energy Technology Data Exchange (ETDEWEB)

    Tang, D.L.; Li, T.Y.; Liu, J.J.; Chen, Y.H.; Qu, L.R.; Perera, F. [Columbia University, New York, NY (United States). Dept. for Environmental Health Science

    2006-08-15

    Polycyclic aromatic hydrocarbons (PAHs) are an important class of toxic pollutants released by fossil fuel combustion. Other pollutants include metals and particulate matter. PAH-DNA adducts, or benzo(a)pyrene (BaP) adducts as their proxy, provide a chemical-specific measure of individual biologically effective doses that have been associated with increased risk of cancer and adverse birth outcomes. In the present study we examined the relationship between prenatal PAH exposure and fetal and child growth and development in Tongliang, China, where a seasonally operated coal-fired power plant was the major pollution source. In a cohort of 150 nonsmoking women and their newborns enrolled between 4 March 2002 and 19 June 2002, BaP-DNA adducts were measured in maternal and umbilical cord blood obtained at delivery. High PAH-DNA adduct levels (above the median of detectable adduct level) were associated with decreased birth head circumference (p = 0.057) and reduced children's weight at 18 months, 24 months, and 30 months of age (p {lt} 0.05), after controlling for potential confounders. In addition, in separate models, longer duration of prenatal exposure was associated with reduced birth length (p = 0.033) and reduced children's height at 18 (p = 0.001), 24 (p {lt} 0.001), and 30 months of age (p {lt} 0.001). The findings suggest that exposure to elevated levels of PAHS, with the Tongliang power plant being a significant source, is associated with reduced fetal and child growth in this population.

  11. Steady-state analysis of activated sludge processes with a settler model including sludge compression.

    Science.gov (United States)

    Diehl, S; Zambrano, J; Carlsson, B

    2016-01-01

    A reduced model of a completely stirred-tank bioreactor coupled to a settling tank with recycle is analyzed in its steady states. In the reactor, the concentrations of one dominant particulate biomass and one soluble substrate component are modelled. While the biomass decay rate is assumed to be constant, growth kinetics can depend on both substrate and biomass concentrations, and optionally model substrate inhibition. Compressive and hindered settling phenomena are included using the Bürger-Diehl settler model, which consists of a partial differential equation. Steady-state solutions of this partial differential equation are obtained from an ordinary differential equation, making steady-state analysis of the entire plant difficult. A key result showing that the ordinary differential equation can be replaced with an approximate algebraic equation simplifies model analysis. This algebraic equation takes the location of the sludge-blanket during normal operation into account, allowing for the limiting flux capacity caused by compressive settling to easily be included in the steady-state mass balance equations for the entire plant system. This novel approach grants the possibility of more realistic solutions than other previously published reduced models, comprised of yet simpler settler assumptions. The steady-state concentrations, solids residence time, and the wastage flow ratio are functions of the recycle ratio. Solutions are shown for various growth kinetics; with different values of biomass decay rate, influent volumetric flow, and substrate concentration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. porewater chemistry experiment at Mont Terri rock laboratory. Reactive transport modelling including bacterial activity

    International Nuclear Information System (INIS)

    Tournassat, Christophe; Gaucher, Eric C.; Leupin, Olivier X.; Wersin, Paul

    2010-01-01

    Document available in extended abstract form only. An in-situ test in the Opalinus Clay formation, termed pore water Chemistry (PC) experiment, was run for a period of five years. It was based on the concept of diffusive equilibration whereby traced water with a composition close to that expected in the formation was continuously circulated and monitored in a packed off borehole. The main original focus was to obtain reliable data on the pH/pCO 2 of the pore water, but because of unexpected microbially- induced redox reactions, the objective was then changed to elucidate the biogeochemical processes happening in the borehole and to understand their impact on pH/pCO 2 and pH in the low permeability clay formation. The biologically perturbed chemical evolution of the PC experiment was simulated with reactive transport models. The aim of this modelling exercise was to develop a 'minimal-' model able to reproduce the chemical evolution of the PC experiment, i.e. the chemical evolution of solute inorganic and organic compounds (organic carbon, dissolved inorganic carbon etc...) that are coupled with each other through the simultaneous occurrence of biological transformation of solute or solid compounds, in-diffusion and out-diffusion of solute species and precipitation/dissolution of minerals (in the borehole and in the formation). An accurate description of the initial chemical conditions in the surrounding formation together with simplified kinetics rule mimicking the different phases of bacterial activities allowed reproducing the evolution of all main measured parameters (e.g. pH, TOC). Analyses from the overcoring and these simulations evidence the high buffer capacity of Opalinus clay regarding chemical perturbations due to bacterial activity. This pH buffering capacity is mainly attributed to the carbonate system as well as to the clay surfaces reactivity. Glycerol leaching from the pH-electrode might be the primary organic source responsible for

  13. Education outcomes related to including genomics activities in nursing practice in Singapore.

    Science.gov (United States)

    Pestka, Elizabeth; Lim, Swee Hia; Png, Hong Hock

    2010-06-01

    The purpose of this study was to describe the impact of a genomic educational intervention by measuring the extent participants could apply the class content to practice. A sample of 76 nurses employed by Singapore Health Services, Singapore, participated in a nursing genomics seminar in 2008 and completed a survey form with a response rate of 89%. Every respondent was able to identify use of a genomic assessment or intervention item with a patient from their clinical practice. The mean use of genomic assessment and intervention items was 5.8 out of a possible 10. The most frequently used items were assessment of family history information, environmental factors and genomic physical findings. Findings provide evidence that nurses are able to include genomic assessments and interventions in their practice following targeted education. This study highlights how informed nurses are able to apply genomic assessments and interventions to individualize patient care.

  14. Comparative antimicrobial activity of gatifloxacin tested against Campylobacter jejuni including fluoroquinolone-resistant clinical isolates.

    Science.gov (United States)

    Hayward, C L; Erwin, M E; Barrett, M S; Jones, R N

    1999-06-01

    Campylobacter jejuni is an important pathogen that causes gastroenteritis, as well as other disease states such as meningitis and septic arthritis. In this study, the Etest (AB BIODISK, Solna, Sweden) results were compared to a reference agar dilution method using gatifloxacin, a new 8-methoxyfluoroquinolone. A total of 53 strains of C. jejuni initially isolated from patients in California and Mexico were tested. Results demonstrated a high correlation (r = 0.88) between the two utilized in vitro dilution methods. In addition, gatifloxacin activity was compared to that of ciprofloxacin, metronidazole, amoxicillin, erythromycin, chloramphenicol, gentamicin, tetracycline, and trimethoprim/sulfamethoxazole using the Etest. Gatifloxacin (MIC90, 4 micrograms/ml) was approximately eight- to 16-fold more potent than ciprofloxacin (Mic90, > 32 micrograms/ml), a commonly used fluoroquinolone for Campylobacter infections. Eight strains highly resistant to ciprofloxacin (MIC90, > 32 micrograms/ml) were tested for cross resistance against the newer fluoroquinolones (gatifloxacin, levofloxacin, trovafloxacin) and the rank order of potency was: gatifloxacin (MIC50, 16 micrograms/ml) > trovafloxacin = levofloxacin (MIC50, > 32 micrograms/mL). However, only 25% ciprofloxacin-resistant strains were inhibited by < or = 1 microgram/mL of gatifloxacin or trovafloxacin. These results for gatifloxacin against C. jejuni strains must be further assessed in the context of in vivo trials before the clinical role of this new fluoroquinolone can be determined. The Etest appears to be a simple and precise susceptibility test method for testing C. jejuni isolates against fluoroquinolones and other alternative therapeutic agents.

  15. Design of a high-lift experiment in water including active flow control

    International Nuclear Information System (INIS)

    Beutel, T; Schwerter, M; Büttgenbach, S; Leester-Schädel, M; Sattler, S; El Sayed, Y; Radespiel, R; Zander, M; Sinapius, M; Wierach, P

    2014-01-01

    This paper describes the structural design of an active flow-control experiment. The aim of the experiment is to investigate the increase in efficiency of an internally blown Coanda flap using unsteady blowing. The system uses tailor-made microelectromechanical (MEMS) pressure sensors to determine the state of the oncoming flow and an actuated lip to regulate the mass flow and velocity of a stream near a wall over the internally blown flap. Sensors and actuators are integrated into a highly loaded system that is extremely compact. The sensors are connected to a bus system that feeds the data into a real-time control system. The piezoelectric actuators using the d 33 effect at a comparable low voltage of 120 V are integrated into a lip that controls the blowout slot height. The system is designed for closed-loop control that efficiently avoids flow separation on the Coanda flap. The setup is designed for water-tunnel experiments in order to reduce the free-stream velocity and the system’s control frequency by a factor of 10 compared with that in air. This paper outlines the function and verification of the system’s main components and their development. (technical note)

  16. Active packaging of chicken meats with modified atmosphere including oxygen scavengers.

    Science.gov (United States)

    Demirhan, B; Candoğan, K

    2016-10-19

    The effects of modified atmosphere packaging (MAP-70% CO 2 /30%N 2 ) and iron-based oxygen scavengers (OS) with various absorption capacities (Ageless ® ss100, ss300, and ss500) as an active packaging system on microbiological and oxidative changes in chicken thigh meats were evaluated during refrigerated storage (4°C) for 19 d at 3-day intervals. Total aerobic mesophilic bacteria counts exceeded the acceptability limit at d 7 in the control group without MAP (AIR), and at d 19 in MAP and OS containing samples. OS utilization resulted in around 1.5 and 1.0 log unit reductions in Pseudomonas spp. counts at d 7 and d 10 of storage, respectively, as compared with AIR and MAP groups (P < 0.05). MAP and OS groups had fewer (P < 0.05) coliform counts than did the AIR group, with an approximately 1.0 log reduction observed at d 10. Although in some cases OS utilization resulted in lower TBARS values and carbonyl and sulphydryl contents, particularly during later stages of refrigerated storage as compared to AIR and MAP groups, in general, these effects were not always apparent. The results of this study suggested that MAP suppressed microbiological growth and retarded lipid and protein oxidation in chicken thigh meats, with a 9-day shelf-life extention with insignificant effects of OS. © 2016 Poultry Science Association Inc.

  17. Multifunctional colloidal nanofiber composites including dextran and folic acid as electro-active platforms.

    Science.gov (United States)

    Rzayev, Zakir M O; Bunyatova, Ulviye; Şimșek, Murat

    2017-06-15

    This work presents the fabrication and characterization of novel colloidal multifunctional polymer nanofiber composites (NFCs) from water dispersion blends of intercalated silicate layered nanocomposites of poly (2-vinyl-N-pyrrolidone)/octadecyl amine-montmorillonite (ODA-MMT) and dextran/ODA-MMT as matrix and partner polymer intercalated nanocomposites in the presence of NaOH and folic acid (FA) as doping agents by green reactive electrospinning. Chemical and physical structures, surface morphology and electrical properties were investigated. Effects of matrix/partner polymer ratios, doping agents, absorption time of NaOH, and temperature on electrical parameters of NFCs were evaluated. The presence of FA and increasing dextran fraction in NFCs resulted in reducing fiber diameter and improving diameter distribution. High complexing behaviors of matrix/partner polymer chains, organoclay, FA, and NaOH significantly improved conductivity parameters, especially 5-min of absorption time (≈10 -2 -10 - 3 Sm -1 ). The conductivity of the samples decreased with increasing temperature. NFCs fabricated for the first time are promising candidates for various biomedical, electrochemical and electronic applications as electro-active platforms. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Mutagenicity of acrolein and acrolein-induced DNA adducts.

    Science.gov (United States)

    Liu, Xing-yu; Zhu, Mao-xiang; Xie, Jian-ping

    2010-01-01

    Acrolein mutagenicity relies on DNA adduct formation. Reaction of acrolein with deoxyguanosine generates alpha-hydroxy-1, N(2)-propano-2'-deoxyguanosine (alpha-HOPdG) and gamma-hydroxy-1, N(2)-propano-2'-deoxyguanosine (gamma-HOPdG) adducts. These two DNA adducts behave differently in mutagenicity. gamma-HOPdG is the major DNA adduct and it can lead to interstrand DNA-DNA and DNA-peptide/protein cross-links, which may induce strong mutagenicity; however, gamma-HOPdG can be repaired by some DNA polymerases complex and lessen its mutagenic effects. alpha-HOPdG is formed much less than gamma-HOPdG, but difficult to be repaired, which contributes to accumulation in vivo. Results of acrolein mutagenicity studies haven't been confirmed, which is mainly due to the conflicting mutagenicity data of the major acrolein adduct (gamma-HOPdG). The minor alpha-HOPdG is mutagenic in both in vitro and in vivo test systems. The role of alpha-HOPdG in acrolein mutagenicity needs further investigation. The inconsistent result of acrolein mutagenicity can be attributed, at least partially, to a variety of acrolein-DNA adducts formation and their repair in diverse detection systems. Recent results of detection of acrolein-DNA adduct in human lung tissues and analysis of P53 mutation spectra in acrolein-treated cells may shed some light on mechanisms of acrolein mutagenicity. These aspects are covered in this mini review.

  19. Linking the generation of DNA adducts to lung cancer.

    Science.gov (United States)

    Ceppi, Marcello; Munnia, Armelle; Cellai, Filippo; Bruzzone, Marco; Peluso, Marco E M

    2017-09-01

    Worldwide, lung cancer is the leading cause of cancer death. DNA adducts are considered a reliable biomarker that reflects carcinogen exposure to tobacco smoke, but the central question is what is the relationship of DNA adducts and cancer? Therefore, we investigated this relationship by a meta-analysis of twenty-two studies with bronchial adducts for a total of 1091 subjects, 887 lung cancer cases and 204 apparently healthy individuals with no evidence of lung cancer. Our study shows that these adducts are significantly associated to increase lung cancer risk. The value of Mean Ratio lung-cancer (MR) of bronchial adducts resulting from the random effects model was 2.64, 95% C.I. 2.00-3.50, in overall lung cancer cases as compared to controls. The significant difference, with lung cancer patients having significant higher levels of bronchial adducts than controls, persisted after stratification for smoking habits. The MR lung-cancer value between lung cancer patients and controls for smokers was 2.03, 95% C.I. 1.42-2.91, for ex-smokers 3.27, 95% C.I. 1.49-7.18, and for non-smokers was 3.81, 95% C.I. 1.85-7.85. Next, we found that the generation of bronchial adducts is significantly related to inhalation exposure to tobacco smoke carcinogens confirming its association with volatile carcinogens. The MR smoking estimate of bronchial adducts resulting from meta-regression was 2.28, 95% Confidence Interval (C.I.) 1.10-4.73, in overall smokers in respect to non-smokers. The present work provides strengthening of the hypothesis that bronchial adducts are not simply relate to exposure, but are a cause of chemical-induced lung cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Bulky carcinogen-DNA adducts and exposure to environmental and occupational sources of polycyclic aromatic hydrocarbons. Influence of susceptibility genotypes on adduct level

    Energy Technology Data Exchange (ETDEWEB)

    Sabro Nielsen, P.

    1996-12-31

    PAH exposure, whether it is of occupational or environmental origin, is thought to result in an elevated risk of cancer especially in the lungs. DNA damage is considered an important step in the carcinogenic effect of PAH. Hence, methods that elucidate the steps in the carcinogenic process are important to understand the action of PAH. It may prove useful in the exposure assessment and in combination with classical epidemiological methods give better basis for risk estimation. The objective in this thesis was to evaluate the feasibility of the {sup 32}P-postlabeling method to detect carcinogen-DNA adducts for assessing exposure to DNA damaging compounds in different occupationally and environmentally exposed groups. The studies included groups, that have an elevated cancer risk due to occupational exposure to PAH. Exposure levels were supposed to be relatively low according to reports on occupational and environmental air quality programs. Another aim was to evaluate the influence of polymorphisms in metabolizing enzyme genes on DNA adduct levels. A third objective was to establish some kind of baseline DNA adduct level for individuals with supposed low exposure, and compare it to the more exposed groups. A fourth aim in these studies was to examine if biomarkers of genotoxic exposure could be useful in epidemiological studies to identify groups at risk and thereby contribute with better exposure estimates in the study of PAH related cancer risk. (EG).

  1. Bulky carcinogen-DNA adducts and exposure to environmental and occupational sources of polycyclic aromatic hydrocarbons. Influence of susceptibility genotypes on adduct level

    International Nuclear Information System (INIS)

    Sabro Nielsen, P.

    1996-01-01

    PAH exposure, whether it is of occupational or environmental origin, is thought to result in an elevated risk of cancer especially in the lungs. DNA damage is considered an important step in the carcinogenic effect of PAH. Hence, methods that elucidate the steps in the carcinogenic process are important to understand the action of PAH. It may prove useful in the exposure assessment and in combination with classical epidemiological methods give better basis for risk estimation. The objective in this thesis was to evaluate the feasibility of the 32 P-postlabeling method to detect carcinogen-DNA adducts for assessing exposure to DNA damaging compounds in different occupationally and environmentally exposed groups. The studies included groups, that have an elevated cancer risk due to occupational exposure to PAH. Exposure levels were supposed to be relatively low according to reports on occupational and environmental air quality programs. Another aim was to evaluate the influence of polymorphisms in metabolizing enzyme genes on DNA adduct levels. A third objective was to establish some kind of baseline DNA adduct level for individuals with supposed low exposure, and compare it to the more exposed groups. A fourth aim in these studies was to examine if biomarkers of genotoxic exposure could be useful in epidemiological studies to identify groups at risk and thereby contribute with better exposure estimates in the study of PAH related cancer risk. (EG)

  2. Adducts of Oxylipin Electrophiles to Glutathione Reflect a 13 Specificity of the Downstream Lipoxygenase Pathway in the Tobacco Hypersensitive Response

    Science.gov (United States)

    Davoine, Céline; Falletti, Olivier; Douki, Thierry; Iacazio, Gilles; Ennar, Najla; Montillet, Jean-Luc; Triantaphylidès, Christian

    2006-01-01

    The response to reactive electrophile species (RES) is now considered as part of the plant response to pathogen and insect attacks. Thanks to a previously established high-performance liquid chromatography tandem mass spectrometry methodology, we have investigated the production of oxylipin RES adducts to glutathione (GSH) during the hypersensitive response (HR) of plants. We have observed that RES conjugation to GSH in tobacco (Nicotiana tabacum) leaves is facile and nonspecific. In cryptogein-elicited tobacco leaves, we show that the oxylipin RES adducts to GSH are produced in correlation with GSH consumption, increase in glutathione S-transferase activity, and the appearance of the cell death symptoms. In this model, the adducts arise mainly from the downstream 13 lipoxygenase (LOX) metabolism, although the induced 9 LOX pathway leads massively to the accumulation of upstream metabolites. The main adducts were obtained from 2-hexenal and 12-oxo-phytodienoic acid. They accumulate transiently as 1-hexanol-3-GSH, a reduced adduct, and 12-oxo-phytodienoic acid-GSH, respectively. RES conjugation does not initiate cell death but explains part of the GSH depletion that accompanies HR cell death. The nature of these GSH conjugates shows the key role played by the 13 LOX pathway in RES signaling in the tobacco HR. PMID:16500992

  3. Kinetic resolution of hindered Morita-Baylis-Hillman adducts by Rh(I)-catalyzed asymmetric 1,4-addition/β-hydroxyelimination.

    Science.gov (United States)

    Wang, Yazhou; Feng, Xiangqing; Du, Haifeng

    2011-09-16

    A kinetic resolution of hindered Morita-Baylis-Hillman adducts has been successfully achieved in excellent selectivities via Rh(I)-catalyzed asymmetric 1,4-addition/β-hydroxyelimination with the use of a chiral sulfinamide/olefin hybrid ligand. This study provides a novel and efficient access to both optically active hindered highly functionalized alkenes and Morita-Baylis-Hillman adducts. © 2011 American Chemical Society

  4. Should Physical Activity Be Included in Nutrition Education? A Comparison of Nutrition Outcomes with and without In-Class Activities

    Science.gov (United States)

    Palmer-Keenan, Debra M.; Corda, Kirsten

    2014-01-01

    Limited-resource adults' dietary intakes and nutrition behaviors improve as a result of Expanded Food and Nutrition Education Program (EFNEP)/Supplemental Nutrition Assistance Program Education (SNAP-Ed) participation; however, physical activity education is needed for improved health. The experimental study reported here assessed if spending time…

  5. Quantification of 3-nitrobenzanthrone-DNA adducts using online column-switching HPLC-electrospray tandem mass spectrometry.

    Science.gov (United States)

    Gamboa da Costa, Gonçalo; Singh, Rajinder; Arlt, Volker M; Mirza, Amin; Richards, Meirion; Takamura-Enya, Takeji; Schmeiser, Heinz H; Farmer, Peter B; Phillips, David H

    2009-11-01

    The aromatic nitroketone 3-nitrobenzanthrone (3-nitro-7H-benz[de]anthracen-7-one; 3-NBA) is an extremely potent mutagen and a suspected human carcinogen detected in the exhaust of diesel engines and in airborne particulate matter. 3-NBA is metabolically activated via reduction of the nitro group to the hydroxylamine (N-OH-3-ABA) to form covalent DNA adducts. Thus far, the detection and quantification of covalent 3-NBA-DNA adducts has relied solely on (32)P-postlabeling methodologies. In order to expand the range of available techniques for the detection and improved quantification of 3-NBA-DNA adducts, we have developed a method based upon online column-switching HPLC coupled to electrospray tandem mass spectrometry, with isotopic dilution of (15)N-labeled internal standards. This methodology was applied to the determination of three 3-NBA-derived adducts: 2-(2'-deoxyguanosin-N(2)-yl)-3-aminobenzanthrone (dG-N(2)-3-ABA), N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8-N-3-ABA) and 2-(2'-deoxyguanosine-8-yl)-3-aminobenzanthrone (dG-C8-C2-3-ABA). Dose-dependent increases were observed for all three adducts when salmon testis DNA was reacted with N-acetoxy-3-aminobenzanthrone (N-AcO-3-ABA). dG-C8-C2-3-ABA was detected at much lower levels (overall 1%) than the other two adducts. DNA samples isolated from tissues of rats treated either intratracheally with 3-NBA or intraperitoneally with N-OH-3-ABA were analyzed by mass spectrometry, and the results compared to those obtained by (32)P-postlabeling. The method required 50 microg of hydrolyzed animal DNA on column and the limit of detection was 2.0 fmol for each adduct. dG-C8-C2-3-ABA was not observed in any of the samples providing confirmation that it is not formed in vivo. Linear regression analysis of the levels of dG-N(2)-3-ABA and dG-C8-N-3-ABA in the rat DNA showed a reasonable correlation between the two methods (R(2) = 0.88 and 0.93, respectively). In summary, the mass spectrometric method is a faster, more

  6. Myeloperoxidase - 463A variant reduces benzo(a)pyrene diol epoxide DNA adducts in skin of coal tar treated patients

    Energy Technology Data Exchange (ETDEWEB)

    Rojas, M.; Godschalk, R.; Alexandrov, K.; Cascorbi, I.; Kriek, E.; Ostertag, J.; Van Schooten, F.J.; Bartsch, H. [German Cancer Research Center, Heidelberg (Germany). Div. of Toxicology & Cancer Risk Factors

    2001-07-01

    The skin of atopic dermatitis patients provides an excellent model to study the role of inflammation in benzo(a)pyrene (BaP) activation, since these individuals are often topically treated with ointments containing high concentrations of BaP. The authors determined, by HPLC with fluorescence detection, the BaP diol epoxide (BPDE)-DNA adduct levels in human skin after topical treatment with coal tar and their modulation by the -453G into A myeloperoxidase (MPO) polymorphism, which reduces MPO mRNA expression. The data show for the first time: (i) the in vivo formation of BPDE-DNA adducts in human skin treated with coal tar; (ii) that the MPO-463AA/AG genotype reduced BPDE-DNA adduct levels in human skin.

  7. RecBCD (Exonuclease V) is inhibited by DNA adducts produced by cisplatin and ultraviolet light.

    Science.gov (United States)

    Leung, Wai Y; Chung, Long H; Kava, Hieronimus W; Murray, Vincent

    2018-01-01

    The presence of adducts on the DNA double-helix can have major consequences for the efficient functioning of DNA repair enzymes. E. coli RecBCD (exonuclease V) is involved in recombinational repair of double-strand breaks that are caused by defective DNA replication, DNA damaging agents and other factors. The holoenzyme possesses a bipolar helicase activity which helps unwind DNA from both 3'- and 5'-directions and is coupled with a potent exonuclease activity that is also capable of digesting DNA from both 3'- and 5'-ends. In this study, DNA sequences were damaged with cisplatin or UV followed by RecBCD treatment. DNA damaging agents such as cisplatin and UV induce the formation of intrastrand adducts in the DNA template. It was demonstrated that RecBCD degradation was inhibited by either cisplatin-damaged or UV-damaged DNA sequences. This is the first occasion that RecBCD has been demonstrated to be inhibited by DNA adducts induced by cisplatin or UV. In addition, we quantified the amounts of DNA remaining after RecBCD treatment and observed that the level of inhibition was concentration and dose dependent. A DNA-targeted 9-aminoacridinecarboxamide cisplatin analogue was also found to inhibit RecBCD activity. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  8. Small-scale purification of butyrylcholinesterase from human plasma and implementation of a μLC-UV/ESI MS/MS method to detect its organophosphorus adducts.

    Science.gov (United States)

    John, Harald; Breyer, Felicitas; Schmidt, Christian; Mizaikoff, Boris; Worek, Franz; Thiermann, Horst

    2015-10-01

    Human butyrylcholinesterase (hBChE) is a serine hydrolase (EC 3.1.1.8) present in all mammalian tissues and the bloodstream. Similar to acetylcholinesterase, the enzyme reacts with organophosphorus compounds (OP) like nerve agents or pesticides that cause enzyme inhibition (BChE adducts). These adducts represent valuable biomarkers for analytical verification of OP exposure. For establishment of these mass spectrometry based methods sufficient amounts of hBChE in high purity are required. Unfortunately, commercial lots are of inappropriate purity thus favouring in-house isolation. Therefore, we developed a small scale procedure to isolate hBChE from citrate plasma. After precipitation by polyethylene glycol (8% w/v and 20% w/v PEG 6000) hBChE was purified from plasma by four consecutive chromatographic steps including anion exchange, affinity extraction and size exclusion. Protein elution was monitored on-line by UV-absorbance (280 nm) followed by continuous fractionation for off-line analysis of (1) hBChE enzyme activity by Ellman assay, (2) protein purity by gel electrophoresis, and (3) protein identity by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Numerous major impurities separated from hBChE were identified. The purified material was used for in vitro incubation with diverse OP to establish a μ-liquid chromatography-ultra violet detection/electrospray ionization tandem-mass spectrometric method (μLC-UV/ESI MS/MS) for detection of hBChE adducts suitable for verification analysis. Analytical data for diverse OP pesticides including deuterated analogues as well as G- and V-type nerve agents and their precursor are summarized. This method was successfully applied to plasma samples provided by the Organisation for the Prohibition of Chemical Weapons (OPCW) for the 4th Biomedical Exercise. Copyright © 2015 John Wiley & Sons, Ltd.

  9. Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives.

    Science.gov (United States)

    Jiang, Xiao; Wang, Shuguang; Zhao, Yuewei; Xia, Qingsu; Cai, Lining; Sun, Xin; Fu, Peter P

    2015-06-01

    Pyrrolizidine alkaloid-containing plants are widespread in the world and probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolic activation to form dehydropyrrolizidine alkaloids that bind to cellular proteins and DNA leading to hepatotoxicity, genotoxicity, and tumorigenicity. At present, it is not clear how dehydropyrrolizidine alkaloids bind to cellular amino acids and proteins to induced toxicity. We previously reported that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts that upon reaction with phenyl isothiocyanate (PITC) formed four DHP-valine-PITC adduct isomers. In this study, we report the absolute configuration and stability of DHP-valine and DHP-valine-PITC adducts, and the mechanism of interconversion between DHP-valine-PITC adducts. Copyright © 2015. Published by Elsevier B.V.

  10. Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives

    Directory of Open Access Journals (Sweden)

    Xiao Jiang

    2015-06-01

    Full Text Available Pyrrolizidine alkaloid-containing plants are widespread in the world and probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolic activation to form dehydropyrrolizidine alkaloids that bind to cellular proteins and DNA leading to hepatotoxicity, genotoxicity, and tumorigenicity. At present, it is not clear how dehydropyrrolizidine alkaloids bind to cellular amino acids and proteins to induced toxicity. We previously reported that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP-derived valine (DHP-valine adducts that upon reaction with phenyl isothiocyanate (PITC formed four DHP-valine-PITC adduct isomers. In this study, we report the absolute configuration and stability of DHP-valine and DHP-valine-PITC adducts, and the mechanism of interconversion between DHP-valine-PITC adducts.

  11. Fe(III)-Catalyzed Hydroallylation of Unactivated Alkenes with Morita-Baylis-Hillman Adducts.

    Science.gov (United States)

    Qi, Jifeng; Zheng, Jing; Cui, Sunliang

    2018-03-02

    An Fe(III)-catalyzed hydroallylation of unactivated alkenes with Morita-Baylis-Hillman adducts via an Fe-catalyzed process is described. A variety of alkenes, including mono-, di-, and trisubstituted alkenes, could all smoothly convert to structural diversified cinnamates in this protocol. Interestingly, when the hydroxyl-containing alkenes were used, various lactones could be rapidly assembled. Moreover, this protocol could be applied to late-stage functionalization of natural products.

  12. [Hemoglobin adducts as biomarkers of human exposure to selected xenobiotics].

    Science.gov (United States)

    Bukowska, Bożena

    2015-06-12

    In the living and working environments more and more new substances of anthropogenic origin exerting toxic properties appear. Simultaneously, the evaluation of human exposure is assessed. For many years adducts of hemoglobin (Hb) have been useful markers of the exposure of humans to various xenobiotics. These adducts are also termed biologically effective dose biomarkers. This paper focuses on a review of literature, mainly from the years 2010-2014, which refers to the hemoglobin adducts of toxic compounds with electrophilic properties. In the interactions of xenobiotics with hemoglobin, groups such as thiol, amino, carboxyl and hydroxyl of this hemoprotein are involved. These combinations occur most often in the reaction of xenobiotics with an N-terminal amino group of valine in Hb, imidazole nitrogen of histidine and cysteine sulfhydryl β93. Hb adducts are characterized by high availability, a long period of occurrence (up to 120 days) in the circulatory system, and high durability, and they have contact with all cells of the body. The measurement of hemoglobin adducts can be potentially used in the assessment of exposure to many xenobiotics such as acrylamide; substances present in tobacco smoke, e.g. benzo(α)pyrene and benzanthracene, ethylene oxide, aryl amines; and substances used on a large scale in industry such as glycidol and naphthalene and its derivatives. Recently the possibility of determination of hemoglobin adducts with estrogen metabolites has been postulated as indicators informing about heightened risk of breast cancer. Protein adducts are used as an alternative to DNA adducts for different classes of electrophilic substances.

  13. Condensed tannin-resorcinol adducts in laminating adhesives

    Science.gov (United States)

    Richard W. Hemingway; Roland E. Kreibich

    1985-01-01

    A condensed tannin-resorcinol adduct made by co-reaction of an extract from southern pine bark with resorcinol at a 2 to 1 weight ratio was used to prepare a laminating resin in which the entire amount of resorcinol normally used was replaced by this adduct. The resin was formulated into a room temperature setting adhesive that meets the basic criteria of product...

  14. Genotoxic Pyrrolizidine Alkaloids — Mechanisms Leading to DNA Adduct Formation and Tumorigenicity

    Directory of Open Access Journals (Sweden)

    Ming W. Chou

    2002-09-01

    Full Text Available Abstract: Plants that contain pyrrolizidine alkaloids are widely distributed in the world. Although pyrrolizidine alkaloids have been shown to be genotoxic and tumorigenic in experimental animals, the mechanisms of actions have not been fully understood. The results of our recent mechanistic studies suggest that pyrrolizidine alkaloids induce tumors via a genotoxic mechanism mediated by 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine (DHP-derived DNA adduct formation. This mechanism may be general to most carcinogenic pyrrolizidine alkaloids, including the retronecine-, heliotridine-, and otonecinetype pyrrolizidine alkaloids. It is hypothesized that these DHP-derived DNA adducts are potential biomarkers of pyrrolizidine alkaloid tumorigenicity. The mechanisms that involve the formation of DNA cross-linking and endogenous DNA adducts are also discussed.

  15. Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents.

    Science.gov (United States)

    Beranek, D T

    1990-07-01

    Alkylating agents, because of their ability to react directly with DNA either in vitro or in vivo, or following metabolic activation as in the case of the dialkylnitrosamines, have been used extensively in studying the mechanisms of mutagenicity and carcinogenicity. Their occurrence is widespread in the environment and human exposure from natural and pollutant sources is universal. Since most of these chemicals show varying degrees of both carcinogenicity and mutagenicity, and exhibit compound-specific binding patterns, they provide an excellent model for studying molecular dosimetry. Molecular dosimetry defines dose as the number of adducts bound per macromolecule and relates the binding of these adducts to the human mutagenic or carcinogenic response. This review complies DNA alkylation data for both methylating and ethylating agents in a variety of systems and discusses the role these alkylation products plays in molecular mutagenesis.

  16. Disulfiram generates a stable N,N-diethylcarbamoyl adduct on Cys-125 of rat hemoglobin beta-chains in vivo

    DEFF Research Database (Denmark)

    Erve, J C; Jensen, Ole Nørregaard; Valentine, H S

    2000-01-01

    with an active site Cys. This work aimed to determine if DSF generates monothiocarbamate adducts on cysteine residues in vivo by examining hemoglobin. Sprague-Dawley rats were treated with DSF po for 2, 4, and 6 weeks. Rats have four different globin beta-chains, of which three (beta-1-3) contain two cysteine...

  17. Multi trace element analysis of dry biological materials by neutron activation analysis including a chemical group separation

    International Nuclear Information System (INIS)

    Weers, C.A.

    1980-07-01

    Multi-element analysis of dry biological material by neutron activation analysis has to include radiochemical separation. The evaporation process is described in terms of the half-volume. The pretreatment of the samples and the development of the destruction-evaporation apparatus are described. The successive adsorption steps with active charcoal, Al 2 O 3 and coprecipitation with Fe(OH) 3 are described. Results obtained for standard reference materials are summarized. (G.T.H.)

  18. Benzene-derived N2-(4-hydroxyphenyl)-deoxyguanosine adduct: UvrABC incision and its conformation in DNA

    Energy Technology Data Exchange (ETDEWEB)

    Hang, Bo; Rodriguez, Ben; Yang, Yanu; Guliaev, Anton B.; Chenna, Ahmed

    2010-06-14

    Benzene, a ubiquitous human carcinogen, forms DNA adducts through its metabolites such as p-benzoquinone (p-BQ) and hydroquinone (HQ). N(2)-(4-Hydroxyphenyl)-2'-deoxyguanosine (N(2)-4-HOPh-dG) is the principal adduct identified in vivo by (32)P-postlabeling in cells or animals treated with p-BQ or HQ. To study its effect on repair specificity and replication fidelity, we recently synthesized defined oligonucleotides containing a site-specific adduct using phosphoramidite chemistry. We here report the repair of this adduct by Escherichia coli UvrABC complex, which performs the initial damage recognition and incision steps in the nucleotide excision repair (NER) pathway. We first showed that the p-BQ-treated plasmid was efficiently cleaved by the complex, indicating the formation of DNA lesions that are substrates for NER. Using a 40-mer substrate, we found that UvrABC incises the DNA strand containing N(2)-4-HOPh-dG in a dose- and time-dependent manner. The specificity of such repair was also compared with that of DNA glycosylases and damage-specific endonucleases of E. coli, both of which were found to have no detectable activity toward N(2)-4-HOPh-dG. To understand why this adduct is specifically recognized and processed by UvrABC, molecular modeling studies were performed. Analysis of molecular dynamics trajectories showed that stable G:C-like hydrogen bonding patterns of all three Watson-Crick hydrogen bonds are present within the N(2)-4-HOPh-G:C base pair, with the hydroxyphenyl ring at an almost planar position. In addition, N(2)-4-HOPh-dG has a tendency to form more stable stacking interactions than a normal G in B-type DNA. These conformational properties may be critical in differential recognition of this adduct by specific repair enzymes.

  19. Assessment of interactions between PAH exposure and genetic polymorphisms on PAH-DNA adducts in African American, Dominican, and Caucasian mothers and newborns.

    Science.gov (United States)

    Wang, Shuang; Chanock, Stephen; Tang, Deliang; Li, Zhigang; Jedrychowski, Wieslaw; Perera, Frederica P

    2008-02-01

    Polycyclic aromatic hydrocarbons (PAH) are widespread pollutants commonly found in air, food, and drinking water. Benzo[a]pyrene is a well-studied representative PAH found in air from fossil fuel combustion and a transplacental carcinogen experimentally. PAHs bind covalently to DNA to form DNA adducts, an indicator of DNA damage, and an informative biomarker of potential cancer risk. Associations between PAH-DNA adduct levels and both cancer risk and developmental deficits have been seen in previous experimental and epidemiologic studies. Several genes have been shown to play an important role in the metabolic activation or detoxification of PAHs, including the cytochrome P450 genes CYP1A1 and CYP1B1 and the glutathione S-transferase (GST) genes GSTM1, and GSTT2. Genetic variation in these genes could influence susceptibility to adverse effects of PAHs in polluted air. Here, we have explored interactions between prenatal PAH exposure and 17 polymorphisms in these genes (rs2198843, rs1456432, rs4646903, rs4646421, rs2606345, rs7495708, rs2472299, rs162549, rs1056837, rs1056836, rs162560, rs10012, rs2617266, rs2719, rs1622002, rs140194, and gene deletion GSTM1-02) and haplotypes on PAH-DNA adducts in cord blood of 547 newborns and in maternal blood of 806 mothers from three different self-described ethnic groups: African Americans, Dominicans, and Caucasians. PAHs were measured by personal air monitoring of mothers during pregnancy. Significant interactions (p < 0.05) were observed between certain genetic polymorphisms and CYP1A1 haplotype and PAHs in mothers and their newborns in the three ethnic groups. However, with our limited sample size, the current findings are suggestive only, warranting further study.

  20. Effects of Leisure Education Programme Including Sportive Activities on Perceived Freedom in Leisure of Adolescents with Intellectual Disabilities

    Science.gov (United States)

    Ertuzun, Ezgi

    2015-01-01

    The objective of this experimental study is to determine the effect of leisure education programme including sportive activities on the perceived freedom in leisure of adolescents with mild intellectual disabilities. The research was designed with an experimental group (n = 37) and a control group (n = 34), and was conducted among a total of 71…

  1. Partitioning of knee joint internal forces in gait is dictated by the knee adduction angle and not by the knee adduction moment.

    Science.gov (United States)

    Adouni, M; Shirazi-Adl, A

    2014-05-07

    Medial knee osteoarthritis is a debilitating disease. Surgical and conservative interventions are performed to manage its progression via reduction of load on the medial compartment or equivalently its surrogate measure, the external adduction moment. However, some studies have questioned a correlation between the medial load and adduction moment. Using a musculoskeletal model of the lower extremity driven by kinematics-kinetics of asymptomatic subjects at gait midstance, we aim here to quantify the relative effects of changes in the knee adduction angle versus changes in the adduction moment on the joint response and medial/lateral load partitioning. The reference adduction rotation of 1.6° is altered by ±1.5° to 3.1° and 0.1° or the knee reference adduction moment of 17Nm is varied by ±50% to 25.5Nm and 8.5Nm. Quadriceps, hamstrings and tibiofemoral contact forces substantially increased as adduction angle dropped and diminished as it increased. The medial/lateral ratio of contact forces slightly altered by changes in the adduction moment but a larger adduction rotation hugely increased this ratio from 8.8 to a 90 while in contrast a smaller adduction rotation yielded a more uniform distribution. If the aim in an intervention is to diminish the medial contact force and medial/lateral load ratio, a drop of 1.5° in adduction angle is much more effective (causing respectively 12% and 80% decreases) than a reduction of 50% in the adduction moment (causing respectively 4% and 13% decreases). Substantial role of changes in adduction angle is due to the associated alterations in joint nonlinear passive resistance. These findings explain the poor correlation between knee adduction moment and tibiofemoral compartment loading during gait suggesting that the internal load partitioning is dictated by the joint adduction angle. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Recognition and repair of the CC-1065-(N3-Adenine)-DNA adduct by the UVRABC nuclease

    International Nuclear Information System (INIS)

    Tang, M.; Lee, C.S.; Doisy, R.; Ross, L.; Needham-VanDevanter, D.R.; Hurley, L.H.

    1988-01-01

    The recognition and repair of the helix-stabilizing and relatively nondistortive CC-1065-(N3-adenine)-DNA adduct by UVRABC nuclease has been investigated both in vivo with phi X174RFI DNA by a transfection assay and in vitro by a site-directed adduct in a 117 base pair fragment from M13mp1. CC-1065 is a potent antitumor antibiotic produced by Streptomyces zelensis which binds within the minor groove of DNA through N3 of adenine. In contrast to the helix-destabilizing and distortive modifications of DNA caused by ultraviolet light or N-acetoxy-2-(acetylamino)fluorene, CC-1065 increases the melting point of DNA and decreases the S1 nuclease activity. Using a viral DNA-Escherichia coli transfection system, the authors have found that the uvrA, uvrB, and uvrC genes, which code for the major excision repair proteins for UV- and NAAAF-induced DNA damage, are also involved in the repair of CC-1065-DNA adducts. In contrast, the uvrD gene product, which has been found to be involved in the repair of UV damage, has no effect in repairing CC-1065-DNA adducts. Purified UVRA, UVRB, and UVRC proteins must work in concert to incise the drug-modified phi X174RFI DNA. Using a site-directed and multiple CC-1065 modified (MspI-BstNI) 117 base pair fragment from M13mp1, they have found that UVRABC nuclease incises at the eight phosphodiester bond on the 5' side of the CC-1065-DNA adduct on the drug-modified strand. The enzymes do not cut the noncovalently modified strand. The DNA sequence and/or helix-stabilizing effect of multiple adducts may determine the recognition and/or incision of the drug-DNA adduct by UVRABC nuclease. These results are discussed in relation to the structure of the CC-1065-DNA adduct and the effect of drug binding on local DNA structure

  3. Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation

    Directory of Open Access Journals (Sweden)

    Watson Andrew J

    2007-01-01

    Full Text Available Abstract Background Mechanisms that confer an ability to respond positively to environmental osmolarity are fundamental to ensuring embryo survival during the preimplantation period. Activation of p38 mitogen-activated protein kinase (MAPK occurs following exposure to hyperosmotic treatment. Recently, a novel scaffolding protein called Osmosensing Scaffold for MEKK3 (OSM was linked to p38 MAPK activation in response to sorbitol-induced hypertonicity. The human ortholog of OSM is cerebral cavernous malformation 2 (CCM2. The present study was conducted to investigate whether CCM2 is expressed during mouse preimplantation development and to determine whether this scaffolding protein is associated with p38 MAPK activation following exposure of preimplantation embryos to hyperosmotic environments. Results Our results indicate that Ccm2 along with upstream p38 MAPK pathway constituents (Map3k3, Map2k3, Map2k6, and Map2k4 are expressed throughout mouse preimplantation development. CCM2, MAP3K3 and the phosphorylated forms of MAP2K3/MAP2K6 and MAP2K4 were also detected throughout preimplantation development. Embryo culture in hyperosmotic media increased p38 MAPK activity in conjunction with elevated CCM2 levels. Conclusion These results define the expression of upstream activators of p38 MAPK during preimplantation development and indicate that embryo responses to hyperosmotic environments include elevation of CCM2 and activation of p38 MAPK.

  4. Using lysine adducts of human serum albumin to investigate the disposition of exogenous formaldehyde in human blood.

    Science.gov (United States)

    Regazzoni, Luca G; Grigoryan, Hasmik; Ji, Zhiying; Chen, Xi; Daniels, Sarah I; Huang, Deyin; Sanchez, Sylvia; Tang, Naijun; Sillé, Fenna C M; Iavarone, Anthony T; Williams, Evan R; Zhang, Luoping; Rappaport, Stephen M

    2017-02-15

    Formaldehyde is a human carcinogen that readily binds to nucleophiles, including proteins and DNA. To investigate whether exogenous formaldehyde produces adducts in extracellular fluids, we characterized modifications to human serum albumin (HSA) following incubation of whole blood, plasma, and saliva with formaldehyde at concentrations of 1, 10 and 100μM. The only HSA locus that showed the presence of formaldehyde modifications was Lys199. A N(6)-Lys adduct with added mass of 12Da, representing a putative intramolecular crosslink, was detected in biological fluids that had been incubated with formaldehyde but not in control fluids. An adduct representing N(6)-Lys formylation was detected in all fluids, but levels did not increase above control values over the tested range of formaldehyde concentrations. An adduct representing N(6)-Lys199 acetylation was also measured in all samples. We then applied the assay to repeated samples of human plasma from 6 nonsmoking volunteer subjects (from Berkeley, CA), and single samples of serum from 15 workers exposed to airborne formaldehyde at about 1.5ppm in a production facility and 15 control workers from Tianjin, China. Although all human plasma/serum samples contained basal levels of the products of N(6)-Lys formylation and acetylation, the putative crosslink product was not detected. Since the putative crosslink was observed in plasma incubated with formaldehyde at 1μM, this suggests that the endogenous concentration of formaldehyde in serum was much lower than reported in the literature. Furthermore, concentrations of the formyl adduct were not higher in workers exposed to formaldehyde at about 1.5ppm than in controls. Follow-up in vitro experiments with gaseous formaldehyde at 1.4ppm detected the putative crosslink in plasma but not whole blood. This combination of results suggests that N(6) formylation occurs within cells with subsequent release of adducted HSA to the systemic circulation. Comparing across human

  5. Characterization and reactivity of a terminal nickel(III)-oxygen adduct.

    Science.gov (United States)

    Pirovano, Paolo; Farquhar, Erik R; Swart, Marcel; Fitzpatrick, Anthony J; Morgan, Grace G; McDonald, Aidan R

    2015-02-23

    High-valent terminal metal-oxygen adducts are hypothesized to be the potent oxidizing reactants in late transition metal oxidation catalysis. In particular, examples of high-valent terminal nickel-oxygen adducts are scarce, meaning there is a dearth in the understanding of such oxidants. A monoanionic Ni(II)-bicarbonate complex has been found to react in a 1:1 ratio with the one-electron oxidant tris(4-bromophenyl)ammoniumyl hexachloroantimonate, yielding a thermally unstable intermediate in high yield (ca. 95%). Electronic absorption, electronic paramagnetic resonance, and X-ray absorption spectroscopies and density functional theory calculations confirm its description as a low-spin (S = 1/2), square planar Ni(III)-oxygen adduct. This rare example of a high-valent terminal nickel-oxygen complex performs oxidations of organic substrates, including 2,6-di-tert-butylphenol and triphenylphosphine, which are indicative of hydrogen atom abstraction and oxygen atom transfer reactivity, respectively. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Enzymology of repair of DNA adducts produced by N-nitroso compounds

    Energy Technology Data Exchange (ETDEWEB)

    Setlow, R.B.; Cao, E.H.; Delihas, N.C.

    1983-01-01

    The biological effects of DNA adducts depend on their nature, and on their half-lives relative to the rates of DNA replication and transcription. Their half-lives are determined by the rates of spontaneous decay, such as depurination, and the rates of enzymatic repair of the adducts or their decay products. The principle modes of repair of methylating and ethylating agents are by glycosylase catalyzed depurination of 7-alkylguanine and 3-alkyladenine and by the dealkalation of O/sup 6/-alkylguanine. Repair by dealkylation cannot be detected by the standard methods used to measure DNA repair, but it is easy to estimate the acceptor activity in cell extracts by measuring the transfer of radioactive O/sup 6/-alkyl groups in an exogenous DNA to protein. In extracts of cells treated with alkylating agents the activity is depressed because the endogenous DNA is rapidly dealkylated, using up the acceptor activity. In many cell types the decrease in activity is followed by an increase to the normal constitutive level. In other cells there is no such adaptive response. Differences in constitutive levels of methyl accepting activity in extracts of human lymphocytes and on the acceptor activity in lung macrophages from smokers (low activity) and non-smokers (high activity) have been observed. 46 references.

  7. Characterization of hemoglobin-benzo[a]pyrene adducts

    International Nuclear Information System (INIS)

    Haugen, D.A.; Myers, S.R.

    1987-01-01

    Cultures of Syrian hamster embryo (SHE) cells were supplemented with human Hb (0.2 mM heme) and [ 3 H]BP (1 μM). After a 24-h incubation, the medium was removed and subjected to cation-exchange liquid chromatography (CM-Sepharose) to resolve hemoglobins from serum proteins in the medium. The BP-treated Hb was subjected to analysis in each of three column chromatographic systems established for isolation and characterization of human hemoglobin and its genetic and post-translationally modified variants. Results demonstrate that hemoglobin-carcinogen adducts can be resolved from native hemoglobin by established conventional and high-performance liquid chromatographic procedures, suggesting the basis for development of general approaches for isolating and characterizing hemoglobin-carcinogen adducts. The results also suggest the basis for a model system in which adducts between carcinogens and human hemoglobin are formed in cultures of mammalian cells or tissues

  8. Chromospheric activity of periodic variable stars (including eclipsing binaries) observed in DR2 LAMOST stellar spectral survey

    Science.gov (United States)

    Zhang, Liyun; Lu, Hongpeng; Han, Xianming L.; Jiang, Linyan; Li, Zhongmu; Zhang, Yong; Hou, Yonghui; Wang, Yuefei; Cao, Zihuang

    2018-05-01

    The LAMOST spectral survey provides a rich databases for studying stellar spectroscopic properties and chromospheric activity. We cross-matched a total of 105,287 periodic variable stars from several photometric surveys and databases (CSS, LINEAR, Kepler, a recently updated eclipsing star catalogue, ASAS, NSVS, some part of SuperWASP survey, variable stars from the Tsinghua University-NAOC Transient Survey, and other objects from some new references) with four million stellar spectra published in the LAMOST data release 2 (DR2). We found 15,955 spectra for 11,469 stars (including 5398 eclipsing binaries). We calculated their equivalent widths (EWs) of their Hα, Hβ, Hγ, Hδ and Caii H lines. Using the Hα line EW, we found 447 spectra with emission above continuum for a total of 316 stars (178 eclipsing binaries). We identified 86 active stars (including 44 eclipsing binaries) with repeated LAMOST spectra. A total of 68 stars (including 34 eclipsing binaries) show chromospheric activity variability. We also found LAMOST spectra of 12 cataclysmic variables, five of which show chromospheric activity variability. We also made photometric follow-up studies of three short period targets (DY CVn, HAT-192-0001481, and LAMOST J164933.24+141255.0) using the Xinglong 60-cm telescope and the SARA 90-cm and 1-m telescopes, and obtained new BVRI CCD light curves. We analyzed these light curves and obtained orbital and starspot parameters. We detected the first flare event with a huge brightness increase of more than about 1.5 magnitudes in R filter in LAMOST J164933.24+141255.0.

  9. Lipid peroxidation-derived etheno-DNA adducts in human atherosclerotic lesions

    International Nuclear Information System (INIS)

    Nair, Jagadeesan; De Flora, Silvio; Izzotti, Alberto; Bartsch, Helmut

    2007-01-01

    Atherosclerosis and cancer are characterized by uncontrolled cell proliferation and share common risk factors, such as cigarette smoking, dietary habits and ageing. Growth of smooth muscle cells (SMCs) in atherosclerotic plaques may result from DNA damage, caused either by exogenous mutagens or by agents endogenously generated due to oxidative stress and lipid peroxidation (LPO). Hydroxy-2-nonenal (HNE), a major LPO product, binds covalently to cellular DNA to form the exocyclic etheno-DNA-base adducts, 1,N 6 -ethenodeoxyadenine (εdA) and 3,N 4 -ethenodeoxycytosine (εdC). By applying an ultrasensitive 32 P-postlabeling-immunoaffinity method, εdA and εdC were quantified in abdominal aorta SMCs from 13 atherosclerotic patients and 3 non-smoking subjects without atherosclerotic lesions. The levels of etheno-adducts ranged for εdA from 2.3 to 39.6/10 8 dA and for εdC from 10.7 to 157.7/10 8 dC, with a high correlation between εdA and εdC (r = 0.84, P = 0.0001). Etheno-adduct levels were higher in atherosclerotic smokers than in ex-smokers for both εdA (means 15.2 versus 7.3, P = 0.06) and εdC (71.9 versus 51.6, not significant). εdC levels were higher in either ex-smokers (P = 0.03) or smokers (P = 0.07) than in non-smokers. There was a poor correlation between either εdA or εdC and 8-hydroxy-2'-deoxyguanosine, whereas significant positive correlations were detected with the levels of several postlabeled bulky aromatic DNA adducts. In conclusion, two different types of DNA damage may be involved in atherosclerotic plaque formation and progression: (i) bulky aromatic compounds, to which aorta SMCs are chronically exposed in smokers, can either covalently bind to DNA, induce redox-cycling via quinone intermediates and/or activate local chronic inflammatory processes in the arterial wall; ii) this in turn leads to a self perpetuating generation of reactive oxygen species, LPO-products and increasing DNA-damage, as documented by the presence of high levels of

  10. Thermodynamics and kinetics of reduction and species conversion at a hydrophobic surface for mitochondrial cytochromes c and their cardiolipin adducts

    International Nuclear Information System (INIS)

    Ranieri, Antonio; Di Rocco, Giulia; Millo, Diego; Battistuzzi, Gianantonio; Bortolotti, Carlo A.; Lancellotti, Lidia; Borsari, Marco; Sola, Marco

    2015-01-01

    Highlights: • Cytochrome c and its adduct with cardiolipin can be immobilized on a hydrophobic SAM. • Adsorbed cytochrome c and its adduct undergo extensive unfolding and axial ligand substitution. • An equilibrium between a six-coordinated and a five-coordinated form is observed in both cases. • The reduced five-coordinated form is stabilized by cardiolipin binding. • Immobilized cytochrome c exchanges electrons more slowly upon cardiolipin binding. - Abstract: Cytochrome c (cytc) and its adduct with cardiolipin (CL) were immobilized on a hydrophobic SAM-coated electrode surface yielding a construct which mimics the environment experienced by the complex at the inner mitochondrial membrane where it plays a role in cell apoptosis. Under these conditions, both species undergo an equilibrium between a six-coordinated His/His-ligated and a five-coordinated His/- ligated forms stable in the oxidized and in the reduced state, respectively. The thermodynamics of the oxidation-state dependent species conversion were determined by temperature-dependent diffusionless voltammetry experiments. CL binding stabilizes the immobilized reduced His/- ligated form of cytc which was found previously to catalytically reduce dioxygen. Here, this adduct is also found to show pseudoperoxidase activity, catalysing reduction of hydrogen peroxide. These effects would impart CL with an additional role in the cytc-mediated peroxidation leading to programmed cell death. Moreover, immobilized cytc exchanges electrons more slowly upon CL binding possibly due to changes in solvent reorganization effects at the protein-SAM interface

  11. Pyrrolizidine Alkaloid-Protein Adducts: Potential Non-invasive Biomarkers of Pyrrolizidine Alkaloid-Induced Liver Toxicity and Exposure.

    Science.gov (United States)

    Xia, Qingsu; Zhao, Yuewei; Lin, Ge; Beland, Frederick A; Cai, Lining; Fu, Peter P

    2016-08-15

    Pyrrolizidine alkaloids (PAs) are phytochemicals present in hundreds of plant species from different families widely distributed in many geographical regions around the world. PA-containing plants are probably the most common type of poisonous plants affecting livestock, wildlife, and humans. There have been many large-scale human poisonings caused by the consumption of food contaminated with toxic PAs. PAs require metabolic activation to generate pyrrolic metabolites to exert their toxicity. In this study, we developed a novel method to quantify pyrrole-protein adducts present in the blood. This method involves the use of AgNO3 in acidic ethanol to cleave the thiol linkage of pyrrole-protein (DHP-protein) adducts, and the resulting 7,9-di-C2H5O-DHP is quantified by HPLC-ES-MS/MS multiple reaction monitoring analysis in the presence of a known quantity of isotopically labeled 7,9-di-C2D5O-DHP internal standard. Using this method, we determined that diester-type PAs administered to rats produced higher levels of DHP-protein adducts than other types of PAs. The results suggest that DHP-protein adducts can potentially serve as minimally invasive biomarkers of PA exposure.

  12. The underappreciated in vitro activity of tedizolid against Bacteroides fragilis species, including strains resistant to metronidazole and carbapenems.

    Science.gov (United States)

    Goldstein, Ellie J C; Citron, Diane M; Tyrrell, Kerin L; Leoncio, Elisa S; Merriam, C Vreni

    2017-02-01

    Because Bacteroides fragilis has the ability to develop mechanisms of resistance to almost all antibiotics, we studied the comparative in vitro activity of tedizolid against 124 Bacteroides group species clinical isolates, including carbapenem, metronidazole and piperacillin-tazobactam resistant strains. Tedizolid had an MIC 90 of 2 μg/ml (range, 0.5-4 μg/ml) and was 1-4 times more active than linezolid that had an MIC 90 of 8 μg/ml (range, 2-16 μg/ml). It was also active (MICs 0.5-2 μg/ml) against the 27 ertapenem, 2 metronidazole and 12 piperacillin-tazobactam resistant strains tested. This suggests that tedizolid may be useful treating infections, including bacteremias, due to resistant B. fragilis group species, as well as, mixed skin and soft tissue infections such as diabetic foot infections caused by Gram-positive aerobes and B. fragilis group species. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Possible rare congenital dysinnervation disorder: congenital ptosis associated with adduction.

    Science.gov (United States)

    Mendes, Sílvia; Beselga, Diana; Campos, Sónia; Neves, Arminda; Campos, Joana; Carvalho, Sílvia; Silva, Eduardo; Castro Sousa, João Paulo

    2015-01-01

    Ptosis is defined as an abnormally low position of the upper eyelid margin. It can be congenital or acquired, uni or bilateral, and isolated or associated with other ocular and nonocular defects. We report a case of a female child, aged 8 years, with congenital right ptosis increased on right adduction and with left ptosis on left adduction. There was no horizontal ocular movement limitation. Apparent underaction of the right inferior oblique muscle was also present. We believe that within the possible mechanisms it is more likely that it is a congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorder (CCDD).

  14. Quantitation of DNA Adducts Induced by 1,3-Butadiene

    Science.gov (United States)

    Sangaraju, Dewakar; Villalta, Peter W.; Wickramaratne, Susith; Swenberg, James; Tretyakova, Natalia

    2014-07-01

    Human exposure to 1,3-butadiene (BD) present in automobile exhaust, cigarette smoke, and forest fires is of great concern because of its potent carcinogenicity. The adverse health effects of BD are mediated by its epoxide metabolites such as 3,4-epoxy-1-butene (EB), which covalently modify genomic DNA to form promutagenic nucleobase adducts. Because of their direct role in cancer, BD-DNA adducts can be used as mechanism-based biomarkers of BD exposure. In the present work, a mass spectrometry-based methodology was developed for accurate, sensitive, and precise quantification of EB-induced N-7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) DNA adducts in vivo. In our approach, EB-GII adducts are selectively released from DNA backbone by neutral thermal hydrolysis, followed by ultrafiltration, offline HPLC purification, and isotope dilution nanoLC/ESI+-HRMS3 analysis on an Orbitrap Velos mass spectrometer. Following method validation, EB-GII lesions were quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of EB and in liver tissues of rats exposed to sub-ppm concentrations of BD (0.5-1.5 ppm). EB-GII concentrations increased linearly from 1.15 ± 0.23 to 10.11 ± 0.45 adducts per 106 nucleotides in HT1080 cells treated with 0.5-10 μM DEB. EB-GII concentrations in DNA of laboratory rats exposed to 0.5, 1.0, and 1.5 ppm BD were 0.17 ± 0.05, 0.33 ± 0.08, and 0.50 ± 0.04 adducts per 106 nucleotides, respectively. We also used the new method to determine the in vivo half-life of EB-GII adducts in rat liver DNA (2.20 ± 0.12 d) and to detect EB-GII in human blood DNA. To our knowledge, this is the first application of nanoLC/ESI+-HRMS3 Orbitrap methodology to quantitative analysis of DNA adducts in vivo.

  15. Identification of stable benzo[a]pyrene-7,8-dione-DNA adducts in human lung cells.

    Science.gov (United States)

    Huang, Meng; Blair, Ian A; Penning, Trevor M

    2013-05-20

    Metabolic activation of the proximate carcinogen benzo[a]pyrene-7,8-trans-dihydrodiol (B[a]P-7,8-trans-dihydrodiol) by aldo-keto reductases (AKRs) leads to B[a]P-7,8-dione that is both electrophilic and redox-active. B[a]P-7,8-dione generates reactive oxygen species resulting in oxidative DNA damage in human lung cells. However, information on the formation of stable B[a]P-7,8-dione-DNA adducts in these cells is lacking. We studied stable DNA adduct formation of B[a]P-7,8-dione in human lung adenocarcinoma A549 cells, human bronchoalveolar H358 cells, and immortalized human bronchial epithelial HBEC-KT cells. After treatment with 2 μM B[a]P-7,8-dione, the cellular DNA was extracted from the cell pellets subjected to enzyme hydrolysis and subsequent analysis by LC-MS/MS. Several stable DNA adducts of B[a]P-7,8-dione were only detected in A549 and HBEC-KT cells. In A549 cells, the structures of stable B[a]P-7,8-dione-DNA adducts were identified as hydrated-B[a]P-7,8-dione-N(2)-2'-deoxyguanosine and hydrated-B[a]P-7,8-dione-N1-2'-deoxyguanosine. In HBEC-KT cells, the structures of stable B[a]P-7,8-dione-DNA adducts were identified as hydrated-B[a]P-7,8-dione-2'-deoxyadenosine, hydrated-B[a]P-7,8-dione-N1- or N3-2'-deoxyadenosine, and B[a]P-7,8-dione-N1- or N3-2'-deoxyadenosine. In each case, adduct structures were characterized by MS(n) spectra. Adduct structures were also compared to those synthesized from reactions of B[a]P-7,8-dione with either deoxyribonucleosides or salmon testis DNA in vitro but were found to be different.

  16. Magnetic resonance imaging of differential compartmental function of horizontal rectus extraocular muscles during conjugate and converged ocular adduction.

    Science.gov (United States)

    Demer, Joseph L; Clark, Robert A

    2014-08-15

    Activity in horizontal rectus extraocular muscles (EOMs) was investigated by magnetic resonance imaging (MRI) of humans during asymmetric convergence to a monocularly aligned target at 15-cm distance or monocular fixation of afocal targets placed over a wide range of conjugate abduction through adduction. Cross sections and posterior partial volumes (PPVs) of EOMs were determined from quasi-coronal image planes and were separately analyzed in the inferior vs. superior compartments, defined by lines bisecting their maximum vertical dimensions. Both inferior and superior compartments of medial (MR) and lateral (LR) rectus exhibited contractile changes in PPV and maximum cross section for both asymmetric convergence and a comparable range of conjugate adduction. Both LR compartments, and the inferior MR compartment, exhibited similar decreases in contractility correlating with relaxation during both convergence and conjugate adduction. In contrast, the superior MR compartment exhibited roughly three times the contractility in conjugate adduction as in similar-magnitude convergence. In the aligned eye that did not move during convergence, summed contractility in all compartments of MR and LR exhibited corelaxation consistent with published EOM force measurements in this paradigm (Miller JM, Bockisch CJ, Pavlovski DS. J Neurophysiol 87: 2421-2433, 2002; Miller JM, Davison RC, Gamlin PD. J Neurophysiol 105: 2863-2873, 2011). The superior MR compartment also exhibited significantly greater contractility than the other compartments over the maximum achievable horizontal globe rotation from abduction to adduction. These findings suggest that the superior MR compartment is controlled differentially from the inferior compartment and suggest that its activity is reduced during convergence as a component of generally altered extraocular mechanics. Copyright © 2014 the American Physiological Society.

  17. A market based active/reactive dispatch including transformer taps and reactor and capacitor banks using Simulated Annealing

    International Nuclear Information System (INIS)

    Gomes, Mario Helder; Saraiva, Joao Tome

    2009-01-01

    This paper describes an optimization model to be used by System Operators in order to validate the economic schedules obtained by Market Operators together with the injections from Bilateral Contracts. These studies will be performed off-line in the day before operation and the developed model is based on adjustment bids submitted by generators and loads and it is used by System Operators if that is necessary to enforce technical or security constraints. This model corresponds to an enhancement of an approach described in a previous paper and it now includes discrete components as transformer taps and reactor and capacitor banks. The resulting mixed integer formulation is solved using Simulated Annealing, a well known metaheuristic specially suited for combinatorial problems. Once the Simulated Annealing converges and the values of the discrete variables are fixed, the resulting non-linear continuous problem is solved using Sequential Linear Programming to get the final solution. The developed model corresponds to an AC version, it includes constraints related with the capability diagram of synchronous generators and variables allowing the computation of the active power required to balance active losses. Finally, the paper includes a Case Study based on the IEEE 118 bus system to illustrate the results that it is possible to obtain and their interest. (author)

  18. A market based active/reactive dispatch including transformer taps and reactor and capacitor banks using Simulated Annealing

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Mario Helder [Departamento de Engenharia Electrotecnica, Instituto Politecnico de Tomar, Quinta do Contador, Estrada da Serra, 2300 Tomar (Portugal); Saraiva, Joao Tome [INESC Porto, Faculdade de Engenharia, Universidade do Porto, Campus da FEUP, Rua Dr. Roberto Frias, 4200-465 Porto (Portugal)

    2009-06-15

    This paper describes an optimization model to be used by System Operators in order to validate the economic schedules obtained by Market Operators together with the injections from Bilateral Contracts. These studies will be performed off-line in the day before operation and the developed model is based on adjustment bids submitted by generators and loads and it is used by System Operators if that is necessary to enforce technical or security constraints. This model corresponds to an enhancement of an approach described in a previous paper and it now includes discrete components as transformer taps and reactor and capacitor banks. The resulting mixed integer formulation is solved using Simulated Annealing, a well known metaheuristic specially suited for combinatorial problems. Once the Simulated Annealing converges and the values of the discrete variables are fixed, the resulting non-linear continuous problem is solved using Sequential Linear Programming to get the final solution. The developed model corresponds to an AC version, it includes constraints related with the capability diagram of synchronous generators and variables allowing the computation of the active power required to balance active losses. Finally, the paper includes a Case Study based on the IEEE 118 bus system to illustrate the results that it is possible to obtain and their interest. (author)

  19. Review of the IAEA nuclear fuel cycle and material section activities connected with nuclear fuel including WWER fuel

    International Nuclear Information System (INIS)

    Sokolov, F.

    2001-01-01

    Program activities on Nuclear Fuel Cycle and Materials cover the areas of: 1) raw materials (B.1.01); 2) fuel performance and technology (B.1.02); 3) pent fuel (B.1.03); 4) fuel cycle issues and information system (B.1.04); 5) support to technical cooperation activities (B.1.05). The IAEA activities in fuel performance and technology in 2001 include organization of the fuel experts meetings and completion of the Co-ordinate Research Projects (CRP). The special attention is given to the advanced post-irradiation examination techniques for water reactor fuel and fuel behavior under transients and LOCA conditions. An international research program on modeling of activity transfer in primary circuit of NPP is finalized in 2001. A new CRP on fuel modeling at extended burnup (FUMEX II) has planed to be carried out during the period 2002-2006. In the area of spent fuel management the implementation of burnup credit (BUC) in spent fuel management systems has motivated to be used in criticality safety applications, based on economic consideration. An overview of spent fuel storage policy accounting new fuel features as higher enrichment and final burnup, usage of MOX fuel and prolongation of the term of spent fuel storage is also given

  20. DNA polymerase eta participates in the mutagenic bypass of adducts induced by benzo[a]pyrene diol epoxide in mammalian cells.

    Directory of Open Access Journals (Sweden)

    Alden C Klarer

    Full Text Available Y-family DNA-polymerases have larger active sites that can accommodate bulky DNA adducts allowing them to bypass these lesions during replication. One member, polymerase eta (pol eta, is specialized for the bypass of UV-induced thymidine-thymidine dimers, correctly inserting two adenines. Loss of pol eta function is the molecular basis for xeroderma pigmentosum (XP variant where the accumulation of mutations results in a dramatic increase in UV-induced skin cancers. Less is known about the role of pol eta in the bypass of other DNA adducts. A commonly encountered DNA adduct is that caused by benzo[a]pyrene diol epoxide (BPDE, the ultimate carcinogenic metabolite of the environmental chemical benzo[a]pyrene. Here, treatment of pol eta-deficient fibroblasts from humans and mice with BPDE resulted in a significant decrease in Hprt gene mutations. These studies in mammalian cells support a number of in vitro reports that purified pol eta has error-prone activity on plasmids with site-directed BPDE adducts. Sequencing the Hprt gene from this work shows that the majority of mutations are G>T transversions. These data suggest that pol eta has error-prone activity when bypassing BPDE-adducts. Understanding the basis of environmental carcinogen-derived mutations may enable prevention strategies to reduce such mutations with the intent to reduce the number of environmentally relevant cancers.

  1. Modulation of the effect of prenatal PAH exposure on PAH-DNA adducts in cord blood by plasma antioxidants.

    Science.gov (United States)

    Kelvin, Elizabeth A; Edwards, Susan; Jedrychowski, Wieslaw; Schleicher, Rosemary L; Camann, David; Tang, Deliang; Perera, Frederica P

    2009-08-01

    The fetus is more susceptible than the adult to the effects of certain carcinogens, such as polycyclic aromatic hydrocarbons (PAH). Nutritional factors, including antioxidants, have been shown to have a protective effect on carcinogen-DNA adducts and cancer risk in adults. We investigated whether the effect of prenatal airborne PAH exposure, measured by personal air monitoring during pregnancy, on the level of PAH-DNA adducts in a baby's cord blood is modified by the concentration of micronutrients in maternal and cord blood. The micronutrients examined were: retinol (vitamin A), alpha-tocopherol and gamma-tocopherol (vitamin E), and carotenoids. With the use of multiple linear regression, we found a significant interaction between prenatal PAH exposure and cord blood concentration of alpha-tocopherol and carotenoids in predicting the concentration of PAH adducts in cord blood. The association between PAH exposure and PAH adducts was much stronger among those with low alpha-tocopherol (beta = 0.15; P = 0.001) and among those with low carotenoids (beta = 0.16; P < 0.001) compared with babies with high levels of these micronutrients (among those with high alpha-tocopherol: beta = 0.05; P = 0.165; among those with high carotenoids: beta = 0.06; P = 0.111). These results suggest a protective effect of micronutrients on the DNA damage and potential cancer risk associated with prenatal PAH exposure.

  2. Physical activity interventions in Latin America: what value might be added by including conference abstracts in a literature review?

    Science.gov (United States)

    Hoehner, Christine; Soares, Jesus; Parra, Diana C; Ribeiro, Isabela C; Pratt, Michael; Bracco, Mario; Hallal, Pedro C; Brownson, Ross C

    2010-07-01

    This review assessed whether conference abstracts yield useful information on the types and effectiveness of community-based physical activity (PA) interventions in Latin America, beyond that from interventions included in a recent systematic review of peer-reviewed literature. Abstracts from 9 conferences were searched for community-based interventions to promote PA in Latin America and summarized. Three reviewers classified and screened abstracts. Evaluated interventions that were not included in the previous review were assessed. Search of abstracts from 31 proceedings of 9 conferences identified 87 abstracts of studies on community-based interventions focused on increasing PA. Only 31 abstracts reported on studies with a control group and an outcome related to PA. Ten of these abstracts represented interventions that had not been included in the previous review of peer-reviewed literature, but the abstracts were insufficient in number or detail to make a practice recommendation for any single intervention. This review highlighted the challenges and low added value of including conference abstracts in a systematic review of community PA interventions in Latin America. Stronger evaluation design and execution and more published reports of evaluated interventions are needed to build an evidence base supporting interventions to increase PA in Latin America.

  3. Complex relationships between occupation, environment, DNA adducts, genetic polymorphisms and bladder cancer in a case-control study using a structural equation modeling.

    Directory of Open Access Journals (Sweden)

    Stefano Porru

    Full Text Available DNA adducts are considered an integrate measure of carcinogen exposure and the initial step of carcinogenesis. Their levels in more accessible peripheral blood lymphocytes (PBLs mirror that in the bladder tissue. In this study we explore whether the formation of PBL DNA adducts may be associated with bladder cancer (BC risk, and how this relationship is modulated by genetic polymorphisms, environmental and occupational risk factors for BC. These complex interrelationships, including direct and indirect effects of each variable, were appraised using the structural equation modeling (SEM analysis. Within the framework of a hospital-based case/control study, study population included 199 BC cases and 213 non-cancer controls, all Caucasian males. Data were collected on lifetime smoking, coffee drinking, dietary habits and lifetime occupation, with particular reference to exposure to aromatic amines (AAs and polycyclic aromatic hydrocarbons (PAHs. No indirect paths were found, disproving hypothesis on association between PBL DNA adducts and BC risk. DNA adducts were instead positively associated with occupational cumulative exposure to AAs (p = 0.028, whereas XRCC1 Arg 399 (p<0.006 was related with a decreased adduct levels, but with no impact on BC risk. Previous findings on increased BC risk by packyears (p<0.001, coffee (p<0.001, cumulative AAs exposure (p = 0.041 and MnSOD (p = 0.009 and a decreased risk by MPO (p<0.008 were also confirmed by SEM analysis. Our results for the first time make evident an association between occupational cumulative exposure to AAs with DNA adducts and BC risk, strengthening the central role of AAs in bladder carcinogenesis. However the lack of an association between PBL DNA adducts and BC risk advises that these snapshot measurements are not representative of relevant exposures. This would envisage new scenarios for biomarker discovery and new challenges such as repeated measurements at different

  4. Increasing resource allocation and research into tobacco control activities: a comprehensive approach including primary prevention, treatment and brief intervention.

    Science.gov (United States)

    Richmond, R

    1993-01-01

    The range of tobacco control activities should be viewed as essential parts of a complex multi-component puzzle. Intervention strategies designed to address tobacco control should be comprehensive and include both primary and secondary prevention activities and be multi-faceted and capable of bringing about change at both the individual and broader social and cultural levels. In this paper I argue for a mutually inclusive framework in which the various components contribute in important and different ways. I examine the prevalence of smoking and identify the high risk groups, then I examine the range of available strategies and present the evidence for their success. I discuss the primary prevention approaches such as warning labels, taxes, price increases, workplace bans, education in schools, mass media and self-help materials, as well as brief interventions and treatment strategies which are conducted at the worksite, general practice and specialized cessation clinics. The areas for future research are delineated for increased resource allocation and include: the best ways to disseminate brief interventions to smokers, methods to motivate smokers; training of health professionals to deliver brief interventions; enhancing quitting and access to existing treatment resources among specific disadvantaged minority groups, e.g. migrants, unemployed youth, the effect on smoking prevalence of warning labels on cigarette packets and price rises on cigarettes.

  5. 78 FR 46260 - Sorbitan Monooleate Ethylene Oxide Adduct; Exemption From the Requirement of a Tolerance

    Science.gov (United States)

    2013-07-31

    ... Monooleate Ethylene Oxide Adduct; Exemption From the Requirement of a Tolerance AGENCY: Environmental...-ethanediyl) derivs., (Z)- (CAS Reg. No 9005-65-6) (also known as ``sorbitan monooleate ethylene oxide adduct... residues of sorbitan monooleate ethylene oxide adduct. DATES: This regulation is effective July 31, 2013...

  6. 40 CFR 721.3680 - Ethylene oxide adduct of fatty acid ester with pentaerythritol.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ethylene oxide adduct of fatty acid... New Uses for Specific Chemical Substances § 721.3680 Ethylene oxide adduct of fatty acid ester with... identified generically as ethylene oxide adduct of fatty acid ester with pentaerythritol (PMN P-91-442) is...

  7. [sup 129]I Moessbauer spectroscopic study of metallocene-iodine adducts

    Energy Technology Data Exchange (ETDEWEB)

    Nakashima, Satoru (Dept. of Chemistry, Faculty of Science, Hiroshima Univ. (Japan)); Sakai, Hiroshi (Dept. of Chemistry, Faculty of Science, Hiroshima Univ. (Japan)); Watanabe, Masanobu (Dept. of Chemistry, Coll. of Arts and Sciences, Univ. of Tokyo (Japan)); Maeda, Yutaka (Research Reactor Inst., Kyoto Univ., Osaka (Japan))

    1994-05-01

    A [sup 129]I Moessbauer spectroscopic study of iodine adducts of ferrocenophane, biruthenocene, and osmocene is reported. The spectra show the existence of iodine bonded to the central metals of metallocenes in addition to triiodide anions. The valence state of iron in the ferrocenophane-iodine adduct is the same as those of ruthenium and osmium in their adducts. (orig.)

  8. Comparison of estimated dietary intake of acrylamide with hemoglobin adducts of acrylamide and glycidamide

    DEFF Research Database (Denmark)

    Bjellaas, Thomas; Olesen, Pelle Thonning; Frandsen, Henrik Lauritz

    2007-01-01

    , a significant positive correlation was found between the AA-Hb adduct concentration and the intake of chips/snacks and crisp bread. GA-Hb adduct did not correlate with consumption of any of the main food groups. Neither AA-Hb nor GA-Hb adduct concentration correlated with total dietary intake of AA...

  9. Environmental, Dietary, Maternal, and Fetal Predictors of Bulky DNA Adducts in Cord Blood

    DEFF Research Database (Denmark)

    Pedersen, Marie; Mendez, Michelle A; Schoket, Bernadette

    2015-01-01

    BACKGROUND: Bulky DNA adducts reflect genotoxic exposures, have been associated with lower birth weight, and may predict cancer risk. OBJECTIVE: We selected factors known or hypothesized to affect in utero adduct formation and repair and examined their associations with adduct levels in neonates....

  10. An Antimicrobial Metabolite from Bacillus sp.: Significant activity against pathogenic bacteria including multidrug-resistant clinical strains

    Directory of Open Access Journals (Sweden)

    AJAY GHOSH CHALASANI

    2015-12-01

    Full Text Available In this study, the cell free modified trypticase soya broth (pH 7.4+0.2 of Bacillus subtilis URID 12.1 showed significant antimicrobial activity against multidrug-resistant strains of Staphylococcus aureus, S. epidermidis, Streptococcus pyogenes and Enterococcus faecalis. The partially purified antimicrobial molecule was found to be resistant to extremes of pH and temperatures and also to higher concentrations of trypsin and proteinase K. The antimicrobial molecule was purified by a three-step method that included reverse-phased high performance liquid chromatography (RP-HPLC. The minimum inhibitory concentration (MIC values were determined for 11 species of bacteria using a microbroth dilution technique. The HPLC-purified fraction showed the MICs ranging from 0.5 to 1 µg/ml for methicillin and vancomycin resistant Staphylococcus aureus (MVRSA and methicillin-resistant Staphylococcus epidermidis (MRSE strains. The molecular mass of the antimicrobial compound was determined to be 842.37 Da. The same antimicrobial fraction showed negligible haemolytic activity against human red blood cells even at a concentration as high as 100µg/ml. Because of its significant antimicrobial activity at low MIC values coupled with its non-haemolytic property, it may prove to be a novel antimicrobial lead molecule.

  11. The NLP toxin family in Phytophthora sojae includes rapidly evolving groups that lack necrosis-inducing activity.

    Science.gov (United States)

    Dong, Suomeng; Kong, Guanghui; Qutob, Dinah; Yu, Xiaoli; Tang, Junli; Kang, Jixiong; Dai, Tingting; Wang, Hai; Gijzen, Mark; Wang, Yuanchao

    2012-07-01

    Necrosis- and ethylene-inducing-like proteins (NLP) are widely distributed in eukaryotic and prokaryotic plant pathogens and are considered to be important virulence factors. We identified, in total, 70 potential Phytophthora sojae NLP genes but 37 were designated as pseudogenes. Sequence alignment of the remaining 33 NLP delineated six groups. Three of these groups include proteins with an intact heptapeptide (Gly-His-Arg-His-Asp-Trp-Glu) motif, which is important for necrosis-inducing activity, whereas the motif is not conserved in the other groups. In total, 19 representative NLP genes were assessed for necrosis-inducing activity by heterologous expression in Nicotiana benthamiana. Surprisingly, only eight genes triggered cell death. The expression of the NLP genes in P. sojae was examined, distinguishing 20 expressed and 13 nonexpressed NLP genes. Real-time reverse-transcriptase polymerase chain reaction results indicate that most NLP are highly expressed during cyst germination and infection stages. Amino acid substitution ratios (Ka/Ks) of 33 NLP sequences from four different P. sojae strains resulted in identification of positive selection sites in a distinct NLP group. Overall, our study indicates that expansion and pseudogenization of the P. sojae NLP family results from an ongoing birth-and-death process, and that varying patterns of expression, necrosis-inducing activity, and positive selection suggest that NLP have diversified in function.

  12. Characterization of a mutagenic DNA adduct formed from 1,2-dibromoethane by O6-alkylguanine-DNA alkyltransferase.

    Science.gov (United States)

    Liu, Liping; Hachey, David L; Valadez, Gerardo; Williams, Kevin M; Guengerich, F Peter; Loktionova, Natalia A; Kanugula, Sreenivas; Pegg, Anthony E

    2004-02-06

    It has been proposed that the DNA repair protein O6-alkylguanine-DNA alkyltransferase increases the mutagenicity of 1,2-dibromoethane by reacting with it at its cysteine acceptor site to form a highly reactive half-mustard, which can then react with DNA (Liu, L., Pegg, A. E., Williams, K. M., and Guengerich, F. P. (2002) J. Biol. Chem. 277, 37920-37928). Incubation of Escherichia coli-expressed human alkyltransferase with 1,2-dibromoethane and single-stranded oligodeoxyribonucleotides led to the formation of covalent transferaseoligo complexes. The order of reaction determined was Gua>Thy>Cyt>Ade. Mass spectrometry analysis of the tryptic digest of the reaction product indicated that some of the adducts led to depurination with the release of the Gly136-Arg147 peptide cross-linked to a Gua at the N7 position, with the site of reaction being the active site Cys145 as established by chromatographic retention time and the fragmentation pattern determined by tandem mass spectrometry of a synthetic peptide adduct. The alkyltransferase-mediated mutations produced by 1,2-dibromoethane were predominantly Gua to Ade transitions but, in the spectrum of such rifampicin-resistant mutations in the RpoB gene, 20% were Gua to Thy transversions. The latter are likely to have arisen from the apurinic site generated from the Gua-N7 adduct. Support exists for an additional adduct/mutagenic pathway because evidence was obtained for DNA adducts other than at the Gua N7 atom and for mutations other than those attributable to depurination. Thus, chemical and biological evidence supports the existence of at least two alkyltransferase-dependent pathways for 1,2-dibromoethane-induced mutagenicity, one involving Gua N7-alkylation by alkyltransferase-S-CH2CH2Br and depurination, plus another as yet uncharacterized system(s).

  13. An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

    Energy Technology Data Exchange (ETDEWEB)

    Kiwamoto, R., E-mail: reiko.kiwamoto@wur.nl; Spenkelink, A.; Rietjens, I.M.C.M.; Punt, A.

    2015-01-01

    Acyclic α,β-unsaturated aldehydes present in food raise a concern because the α,β-unsaturated aldehyde moiety is considered a structural alert for genotoxicity. However, controversy remains on whether in vivo at realistic dietary exposure DNA adduct formation is significant. The aim of the present study was to develop physiologically based kinetic/dynamic (PBK/D) models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes without 2- or 3-alkylation, and with no more than one conjugated double bond. Parameters for the PBK/D models were obtained using quantitative structure–activity relationships (QSARs) defined with a training set of six selected aldehydes. Using the QSARs, PBK/D models for the other 12 aldehydes were defined. Results revealed that DNA adduct formation in the liver increases with decreasing bulkiness of the molecule especially due to less efficient detoxification. 2-Propenal (acrolein) was identified to induce the highest DNA adduct levels. At realistic dietary intake, the predicted DNA adduct levels for all aldehydes were two orders of magnitude lower than endogenous background levels observed in disease free human liver, suggesting that for all 18 aldehydes DNA adduct formation is negligible at the relevant levels of dietary intake. The present study provides a proof of principle for the use of QSAR-based PBK/D modelling to facilitate group evaluations and read-across in risk assessment. - Highlights: • Physiologically based in silico models were made for 18 α,β-unsaturated aldehydes. • Kinetic parameters were determined by in vitro incubations and a QSAR approach. • DNA adduct formation was negligible at levels relevant for dietary intake. • The use of QSAR-based PBK/D modelling facilitates group evaluations and read-across.

  14. Comparison of Efficiency of Purification (from Human Plasma) of a Nerve Agent Adduct of Butyrylcholinesterase Between the Affinity Gel Method and Immunomagnetic Separation.

    Science.gov (United States)

    Lee, Jin Young

    2018-03-01

    O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) is a highly toxic chemical warfare agent because it inhibits cholinesterase (ChE) activity in the nervous system. Inhibition of butyrylcholinesterase (BChE) activity by VX is due to formation of a phosphorylated BChE adduct; this adduct in human plasma can serve as a biomarker of exposure to nerve agents. We compared purification efficiency between the procainamide affinity gel method and immunomagnetic separation (IMS) for the nerve agent adduct of BChE in plasma and then optimized the sample preparation by purifying BChE to measure biomarkers of human exposure to organophosphorus nerve agents. The purification efficiency of IMS was 5-fold greater than that of the procainamide affinity gel method because the antibody conjugate with protein G magnetic beads ensured highly selective capture and high recovery of VX-inhibited BChE from plasma. Protein isolation and extraction of the adduct of VX-inhibited BChE from plasma were made more specific by IMS. A 50 µL of the IMS solution was enough to bind VX-inhibited BChE in up to 0.5 mL of plasma. Nonetheless, the IMS method has a limitation in terms of reutilization of the complexes antibody-magnetic beads. We expect that this approach can be used to quantify other types of organophosphorus adducts in human plasma, thus serving as a possible general assay for biomarkers of exposure to nerve agents.

  15. Formation of BH 3 Adducts with Pyridine-2-Methylaminophosphine ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Chemical Sciences; Volume 128; Issue 1. Formation of BH3 Adducts with Pyridine-2-Methylaminophosphine ligands: An experimental and computational study. Harinath Adimulam Dwijendra P Kukri Bhabani S Mallik Tarun K Panda. Regular Articles Volume 128 Issue 1 January 2016 pp 53-60 ...

  16. Conformations of stereoisomeric base adducts to 4-hydroxyequilenin.

    Science.gov (United States)

    Ding, Shuang; Shapiro, Robert; Geacintov, Nicholas E; Broyde, Suse

    2003-06-01

    Exposure to estrogen through estrogen replacement therapy increases the risk of women developing cancer in hormone sensitive tissues. Premarin (Wyeth), which has been the most frequent choice for estrogen replacement therapy in the United States, contains the equine estrogens equilin and equilenin as major components. 4-Hydroxyequilenin (4-OHEN) is a phase I metabolite of both of these substances. This catechol estrogen autoxidizes to potent cytotoxic quinoids that can react with dG, dA, and dC to form unusual stereoisomeric cyclic adducts (Bolton, J. L., et al. (1998) Chem. Res. Toxicol. 11, 1113-1127). Like other bulky DNA adducts, these lesions may exhibit different susceptibilities to DNA repair and mutagenic potential, if not repaired in a structure-dependent manner. To ultimately gain insights into structure-function relationships, we computed conformations of stereoisomeric guanine, adenine, and cytosine base adducts using density functional theory. We find near mirror image conformations in stereoisomer adduct pairs for each modified base, suggesting opposite orientations with respect to the 5' --> 3' direction of the modified strand when the stereoisomer pairs are incorporated into duplex DNA. Such opposite orientations could cause stereoisomer pairs of lesions to respond differently to DNA replication and repair enzymes.

  17. Deuteration of triborane(7) adducts with anhydrous deuterium chloride

    International Nuclear Information System (INIS)

    Dodds, A.R.; Kodama, G.

    1977-01-01

    A hydrogen-deuterium exchange reaction between triborane(7) adducts and deuterium chloride is reported which involves all the hydrogen atoms in the B 3 H 7 moiety and proceeds rapidly even at low temperatures. The exchange reaction is reported to proceed much faster in dichloromethane solution than in tetrahydrofuran

  18. The fate of H atom adducts to 3'-uridine monophosphate.

    Science.gov (United States)

    Wang, Ran; Zhang, Ru Bo; Eriksson, Leif A

    2010-07-29

    The stabilities of the adducts deriving from H free radical addition to the O2, O4, and C5 positions of 3'-uridine monophosphate (3'UMP) are studied by the hybrid density functional B3LYP approach. Upon H atom addition at the O2 position, a concerted low-barrier proton-transfer process will initially occur, followed by the potential ruptures of the N-glycosidic or beta-phosphate bonds. The rupture barriers are strongly influenced by the rotational configuration of the phosphate group at the 3' terminal, and are influenced by bulk solvation effects. The O4-H adduct has the highest thermal stability, as the localization of the unpaired electron does not enable cleavage of either the C1'-N1 or the C3'-O(P) bonds. For the most stable adduct, with H atom added to the C5 position, the rate-controlled step is the H2'a abstraction by the C6 radical site, after which the subsequent strand rupture reactions proceed with low barriers. The main unpaired electron densities are presented for the transient species. Combined with previous results, it is concluded that the H atom adducts are more facile to drive the strand scission rather than N-glycosidic bond ruptures within the nucleic acid bases.

  19. Formation of BH3 Adducts with Pyridine-2-Methylaminophosphine ...

    Indian Academy of Sciences (India)

    tional theoretical (DFT) calculations were performed on the BH3 adducts 1a and 2a. The results are consistent with the experimental results. Keywords. Pyridine; Borane; DFT calculation; X-ray analysis; HOMO; LUMO. 1. Introduction. Various P-N ligands are often used in organometallic chemistry to achieve well-defined ...

  20. Effect of external electric field on Cyclodextrin-Alcohol adducts

    Indian Academy of Sciences (India)

    Effect of external electric fields on the interaction energy between cyclodextrin and alcohol was analyzed in the light of density functional theory (DFT) and density functional reactivity theory (DFRT). Stability of the cyclodextrin-alcohol adducts was measured in terms of DFT based reactivity descriptor, global hardness, ...

  1. Aldehyde and ketone adducts of the gaseous trifluoromethyl cation

    NARCIS (Netherlands)

    Oomens, J.; Morton, T.H.

    2011-01-01

    IR spectra of CF3+ adduct ions are reported for the first time using infrared multiple photon dissociation (IRMPD). Carbonyl stretches of ketone conjugate acids shift less than do those of ions containing C═OCF3+ groups. Carbonyl absorptions shift in proportion to the empirical softness of the

  2. Metal-isonitrile adducts for preparing radionuclide complexes

    International Nuclear Information System (INIS)

    Carpenter, A.P.; Linder, K.E.; Maheu, L.J.; Patz, M.A.; Thompson, J.S.; Tulip, T.H.; Subramanyam, V.

    1988-01-01

    An method for preparing a coordination complex of isonitrile ligand and a radioisotope of Te, Ru, Co, Pt, Re, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Nb and Ta from a non-radioactive metal adduct of the isonitrile

  3. Plasma and liver acetaminophen-protein adduct levels in mice after acetaminophen treatment: Dose–response, mechanisms, and clinical implications

    Energy Technology Data Exchange (ETDEWEB)

    McGill, Mitchell R.; Lebofsky, Margitta [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Norris, Hye-Ryun K.; Slawson, Matthew H. [Center for Human Toxicology, University of Utah, Salt Lake City, UT (United States); Bajt, Mary Lynn; Xie, Yuchao; Williams, C. David [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Wilkins, Diana G.; Rollins, Douglas E. [Center for Human Toxicology, University of Utah, Salt Lake City, UT (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2013-06-15

    At therapeutic doses, acetaminophen (APAP) is a safe and effective analgesic. However, overdose of APAP is the principal cause of acute liver failure in the West. Binding of the reactive metabolite of APAP (NAPQI) to proteins is thought to be the initiating event in the mechanism of hepatotoxicity. Early work suggested that APAP-protein binding could not occur without glutathione (GSH) depletion, and likely only at toxic doses. Moreover, it was found that protein-derived APAP-cysteine could only be detected in serum after the onset of liver injury. On this basis, it was recently proposed that serum APAP-cysteine could be used as diagnostic marker of APAP overdose. However, comprehensive dose–response and time course studies have not yet been done. Furthermore, the effects of co-morbidities on this parameter have not been investigated. We treated groups of mice with APAP at multiple doses and measured liver GSH and both liver and plasma APAP-protein adducts at various timepoints. Our results show that protein binding can occur without much loss of GSH. Importantly, the data confirm earlier work that showed that protein-derived APAP-cysteine can appear in plasma without liver injury. Experiments performed in vitro suggest that this may involve multiple mechanisms, including secretion of adducted proteins and diffusion of NAPQI directly into plasma. Induction of liver necrosis through ischemia–reperfusion significantly increased the plasma concentration of protein-derived APAP-cysteine after a subtoxic dose of APAP. While our data generally support the measurement of serum APAP-protein adducts in the clinic, caution is suggested in the interpretation of this parameter. - Highlights: • Extensive GSH depletion is not required for APAP-protein binding in the liver. • APAP-protein adducts appear in plasma at subtoxic doses. • Proteins are adducted in the cell and secreted out. • Coincidental liver injury increases plasma APAP-protein adducts at subtoxic doses

  4. Mechanism for Clastogenic Activity of Naphthalene

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Bruce A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-09-29

    Naphthalene incubations form DNA adducts in vitro in a dose dependent manner in both mouse and rat tissues. Rodent tissue incubations with naphthalene indicate that naphthalene forms as many DNA adducts as Benzo(a)pyrene, a known DNA binding carcinogen. The mouse airway has the greatest number of DNA adducts, corresponding to the higher metabolic activation of naphthalene in this location. Both rat tissues, the rat olfactory (tumor target) and the airways (non-tumor target), have similar levels of NA-DNA adducts, indicating that short term measures of initial adduct formation do not directly correlate with sites of tumor formation in the NTP bioassays.

  5. Mechanism for Clastogenic Activity of Naphthalene

    Energy Technology Data Exchange (ETDEWEB)

    Buchholz, Bruce A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2016-06-24

    Naphthalene incubations form DNA adducts in vitro in a dose dependent manner in both mouse and rat tissues. Rodent tissue incubations with naphthalene indicate that naphthalene forms as many DNA adducts as Benzo(a)pyrene, a known DNA binding carcinogen. The mouse airway has the greatest number of DNA adducts, corresponding to the higher metabolic activation of naphthalene in this location. Both rat tissues, the rat olfactory (tumor target) and the airways (non-tumor target), have similar levels of NA-DNA adducts, indicating that short term measures of initial adduct formation do not directly correlate with sites of tumor formation in the NTP bioassays.

  6. Two food-borne heterocyclic amines: Metabolism and DNA adduct formation of amino-alpha-carbolines

    DEFF Research Database (Denmark)

    Frederiksen, Hanne

    2005-01-01

    or proteins of animal or vegetable origin, furthermore they are found in many cooked foods, such as fish, meat, and chicken. The specific mutagenicity of the amino-a-carbolines are lower in the Ames Salmonella assay than other heterocyclic amines, but in rodent studies the carcinogenicity of the aminoa, alpha......-carbolines are comparable to other heterocyclic amines. The metabolic pathways of the amino-alpha-carbolines have been studied in vitro and in vivo, and the detoxified phase I and phase II metabolites characterized and quantified. The metabolic activation of the amino-a-carbolines and the formation of DNA-adducts have also...

  7. A mini-review on Biginelli adducts with notable pharmacological properties

    Directory of Open Access Journals (Sweden)

    Ângelo de Fátima

    2015-05-01

    Full Text Available Since the disclosure of Biginelli reaction by the chemist Pietro Biginelli, functionalized 3,4-dihydropyrimidin-2(1H-ones/thiones (DHPMs have emerged as prototypes for the design of compounds with a broad variety of biological activities. This mini-review describes over 100 Biginelli adducts demonstrated to be promising anticancer, inhibitors of calcium channel, anti-inflammatory, antimicrobial and antioxidant agents. Thus, this compilation presents the most notable in vitro and in vivo results for such fascinating class of organic compounds.

  8. Unexpected synthesis of cinnamaldehyde-dimedone adduct using samarium (III) chloride

    Science.gov (United States)

    Cahyana, A. H.; Nadila, A.; Ardiansah, B.

    2017-07-01

    In the present work, 1,8-dioxooctahydroxanthene cannot be obtained from the reaction between cinnamaldehyde and dimedone (ratio 1:2) using samarium(III) chloride as a Lewis acid catalyst. The unexpected product formed is 5,5-dimethyl-2-(3-phenylallylidene)cyclohexane-1,3-dione as a result of 1:1 adduct. The product is obtained in a low to good yield and the optimum protocol can be achieved by running the reaction using 10% mol SmCl3 in water at room temperature for 2 h. This product is preliminary screened for its radical scavenging test with moderate activity.

  9. Study protocol: Rehabilitation including Social and Physical activity and Education in Children and Teenagers with Cancer (RESPECT).

    Science.gov (United States)

    Thorsteinsson, Troels; Helms, Anne Sofie; Adamsen, Lis; Andersen, Lars Bo; Andersen, Karen Vitting; Christensen, Karl Bang; Hasle, Henrik; Heilmann, Carsten; Hejgaard, Nete; Johansen, Christoffer; Madsen, Marianne; Madsen, Svend Aage; Simovska, Venka; Strange, Birgit; Thing, Lone Friis; Wehner, Peder Skov; Schmiegelow, Kjeld; Larsen, Hanne Baekgaard

    2013-11-14

    During cancer treatment children have reduced contact with their social network of friends, and have limited participation in education, sports, and leisure activities. During and following cancer treatment, children describe school related problems, reduced physical fitness, and problems related to interaction with peers. The RESPECT study is a nationwide population-based prospective, controlled, mixed-methods intervention study looking at children aged 6-18 years newly diagnosed with cancer in eastern Denmark (n=120) and a matched control group in western Denmark (n=120). RESPECT includes Danish-speaking children diagnosed with cancer and treated at pediatric oncology units in Denmark. Primary endpoints are the level of educational achievement one year after the cessation of first-line cancer therapy, and the value of VO2max one year after the cessation of first-line cancer therapy. Secondary endpoints are quality of life measured by validated questionnaires and interviews, and physical performance. RESPECT includes a multimodal intervention program, including ambassador-facilitated educational, physical, and social interventions. The educational intervention includes an educational program aimed at the child with cancer, the child's schoolteachers and classmates, and the child's parents. Children with cancer will each have two ambassadors assigned from their class. The ambassadors visit the child with cancer at the hospital at alternating 2-week intervals and participate in the intervention program. The physical and social intervention examines the effect of early, structured, individualized, and continuous physical activity from diagnosis throughout the treatment period. The patients are tested at diagnosis, at 3 and 6 months after diagnosis, and one year after the cessation of treatment. The study is powered to quantify the impact of the combined educational, physical, and social intervention programs. RESPECT is the first population-based study to examine the

  10. Immunochemical detection of sulfur mustard-adducts with DNA and proteins: Exploratory research on adducts with proteins

    NARCIS (Netherlands)

    Schans, G.P. van der; Noort, D.; Mars-Groenendijk, R.H.; Dijk-Knijnenburg, H.C.M. van; Fidder, A.; Jong, L.P.A. de; Benschop, H.P.

    2000-01-01

    We have developed two modes of a standard operating procedure (SOP) for immunochemical detection of sulfur mustard adducts to DNA in human blood and skin. In the shortened mode data could be generated within 9 h after in vitro exposure of human blood to > 1 μM sulfur mustard. The sensitive mode

  11. Formation of DNA adducts in mouse tissues after 1-nitropyrene administration

    International Nuclear Information System (INIS)

    Mitchell, C.E.

    1986-01-01

    DNA adducts were isolated and characterized in mouse lung, liver and kidney after intratracheal instillation of [ 3 H]-1-nitropyrene (1-NP). HPLC analysis of the enzymatically digested DNA indicated the presence of multiple DNA adducts in mouse lung, liver and kidney. These results indicate that DNA adducts of 1-NP are formed in mouse lung, liver and kidney after intratracheal instillation of 1-NP; the HPLC profiles of the multiple adducts suggests that adducts may be formed via metabolic pathways that involve both nitroreduction and ring-oxidation. 6 references, 1 figure

  12. Detection of Adriamycin-DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations.

    Science.gov (United States)

    Coldwell, Kate E; Cutts, Suzanne M; Ognibene, Ted J; Henderson, Paul T; Phillips, Don R

    2008-09-01

    Limited sensitivity of existing assays has prevented investigation of whether Adriamycin-DNA adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin-DNA adducts/10(4) bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin-DNA adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We have used conditions previously validated (by less sensitive decay counting) to extract [(14)C]Adriamycin-DNA adducts from cells and adapted the methodology to AMS detection. Here we show the first direct evidence of Adriamycin-DNA adducts at clinically-relevant Adriamycin concentrations. [(14)C]Adriamycin treatment (25 nM) resulted in 4.4 +/- 1.0 adducts/10(7) bp ( approximately 1300 adducts/cell) in MCF-7 breast cancer cells, representing the best sensitivity and precision reported to date for the covalent binding of Adriamycin to DNA. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin-DNA adduct detection and revealed adduct formation within an hour of drug treatment. This method has been shown to be highly reproducible for the measurement of Adriamycin-DNA adducts in tumour cells in culture and can now be applied to the detection of these adducts in human tissues.

  13. Acetaminophen-cysteine adducts during therapeutic dosing and following overdose

    Directory of Open Access Journals (Sweden)

    Judge Bryan S

    2011-03-01

    Full Text Available Abstract Background Acetaminophen-cysteine adducts (APAP-CYS are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Methods Samples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated. Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection. Results Trial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20 nmol/ml, Trial 2- 0.1 (0.09 nmol/ml and Trial 3- 0.3 (0.12 nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml. No subject had detectable APAP

  14. Modelling knee flexion effects on joint power absorption and adduction moment.

    Science.gov (United States)

    Nagano, Hanatsu; Tatsumi, Ichiroh; Sarashina, Eri; Sparrow, W A; Begg, Rezaul K

    2015-12-01

    Knee osteoarthritis is commonly associated with ageing and long-term walking. In this study the effects of flexing motions on knee kinetics during stance were simulated. Extended knees do not facilitate efficient loading. It was therefore, hypothesised that knee flexion would promote power absorption and negative work, while possibly reducing knee adduction moment. Three-dimensional (3D) position and ground reaction forces were collected from the right lower limb stance phase of one healthy young male subject. 3D position was sampled at 100 Hz using three Optotrak Certus (Northern Digital Inc.) motion analysis camera units, set up around an eight metre walkway. Force plates (AMTI) recorded ground reaction forces for inverse dynamics calculations. The Visual 3D (C-motion) 'Landmark' function was used to change knee joint positions to simulate three knee flexion angles during static standing. Effects of the flexion angles on joint kinetics during the stance phase were then modelled. The static modelling showed that each 2.7° increment in knee flexion angle produced 2.74°-2.76° increments in knee flexion during stance. Increased peak extension moment was 6.61 Nm per 2.7° of increased knee flexion. Knee flexion enhanced peak power absorption and negative work, while decreasing adduction moment. Excessive knee extension impairs quadriceps' power absorption and reduces eccentric muscle activity, potentially leading to knee osteoarthritis. A more flexed knee is accompanied by reduced adduction moment. Research is required to determine the optimum knee flexion to prevent further damage to knee-joint structures affected by osteoarthritis. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Kinetics of hydroperoxy radical reactions with acetone/HO2 adduct and with acetonylperoxy radical

    Science.gov (United States)

    Grieman, F. J.; VanDerGeest, K.; Newenhouse, E.; Watkins, K.; Noell, A. C.; Hui, A.; Sander, S. P.; Okumura, M.

    2013-12-01

    Reactions of hydroperoxy radical, HO2, with acetone and with acetonylperoxy radical, CH3C(O)CH2OO, may play an important role in the oxidation chemistry of the troposphere. Using a temperature-controlled slow-flow tube cell and laser flash photolysis of Cl2 to produce HO2 and CH3C(O)CH2OO from methanol and acetone, respectively, we studied the chemical kinetics involved over the temperature range of 215 to 298 K at 100 Torr. Rates of chemical reactions were determined by monitoring the HO2 concentration as a function of time by near-IR diode laser wavelength modulation spectroscopy. (See Fig.1.) The primary reactions are rapid (reactions to form the adducts HO2-CH3OH and HO2-CH3C(O)CH3 followed by HO2 reactions with itself, the adducts (chaperone mechanisms), and acetonylperoxy radical. The equilibrium constants for adduct formation were determined in previous work.1,2 In this work, rate coefficients were determined for the acetone chaperone mechanism over the entire temperature range. (E.g., see Fig. 2.) The rate coefficients and energies obtained are very similar to those found for the methanol case.1 Rate coefficients for the CH3C(O)CH2OO/HO2 reaction were also determined over a smaller temperature range, extending the measured value beyond room temperature, and yielding an activation energy. 1. Christensen et al. J. Phys. Chem. A 2006, 110, 6948-6959. 2. Grieman et al. J. Phys. Chem. A 2011, 115, 10527-10538. Fig.1. HO2 decay for HO2/Acetone chemistry at T = 298 K. Fig.2. Determining rate coefficient (k") for HO2/acetone chaperone effect at T = 222.5 K.

  16. Pneumatic Multi-Pocket Elastomer Actuators for Metacarpophalangeal Joint Flexion and Abduction-Adduction

    Directory of Open Access Journals (Sweden)

    Tapio Veli Juhani Tarvainen

    2017-09-01

    Full Text Available During recent years, interest has been rising towards developing fluidic fiber-reinforced elastomer actuators for wearable soft robotics used in hand rehabilitation and power-assist. However, they do not enable finger abduction-adduction, which plays an important role in activities of daily living, when grasping larger objects. Furthermore, the developed gloves often do not have separate control of joints, which is important for doing various common rehabilitation motions. The main obstacle for the development of a fully-assisting glove is moving a joint with multiple degrees of freedom. If the functions are built into the same structure, they are naturally coupled and affect each other, which makes them more difficult to design and complex to control than a simple flexion-extension actuator. In this study, we explored the key design elements and fabrication of pneumatic multi-pocket elastomer actuators for a soft rehabilitation glove. The goal was to gain more control over the metacarpophalangeal joint’s response by increasing the degree of actuation. Three main functional designs were tested for achieving both flexion and abduction-adduction. Five prototypes, with four different actuator geometries and four different reinforcement types, were designed and fabricated. They were evaluated by recording their free motion with motion capture and measuring their torque output using a dummy finger. Results showed the strengths and weaknesses of each design in separating the control of the two functions. We discuss the different improvements that are needed in order to make each design plausible for developing an actuator that meets the requirements for full assist of the hand’s motions. In conclusion, we show that it is possible to produce multi-pocket actuators for assisting MCP joint motion in both flexion and abduction-adduction, although coupling between the separate functions is still problematic and should be considered further.

  17. Mechanisms of the different DNA adduct forming potentials of the urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone.

    Science.gov (United States)

    Stiborová, Marie; Martínek, Václav; Svobodová, Martina; Sístková, Jana; Dvorák, Zdenek; Ulrichová, Jitka; Simánek, Vilím; Frei, Eva; Schmeiser, Heinz H; Phillips, David H; Arlt, Volker M

    2010-07-19

    2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. We compared the efficiencies of human enzymatic systems [hepatic microsomes and cytosols, NAD(P)H:quinone oxidoreductase 1 (NQO1), xanthine oxidase, NADPH:cytochrome P450 reductase, N,O-acetyltransferases, and sulfotransferases] and human primary hepatocytes to activate 2-NBA and its isomer 3-NBA to species forming DNA adducts. In contrast to 3-NBA, 2-NBA was not metabolized at detectable levels by the tested human enzymatic systems and enzymes expressed in human hepatocytes, and no DNA adducts detectable by (32)P-postlabeling were generated by 2-NBA. Even NQO1, the most efficient human enzyme to bioactive 3-NBA, did not activate 2-NBA. Molecular docking of 2-NBA and 3-NBA to the active site of NQO1 showed similar binding affinities; however, the binding orientation of 2-NBA does not favor the reduction of the nitro group. This was in line with the inhibition of 3-NBA-DNA adduct formation by 2-NBA, indicating that 2-NBA can compete with 3-NBA for binding to NQO1, thereby decreasing the metabolic activation of 3-NBA. In addition, the predicted equilibrium conditions favor a 3 orders of magnitude higher dissociation of N-OH-3-ABA in comparison to N-OH-2-ABA. These findings explain the very different genotoxicity, mutagenicity, and DNA adduct forming potential of the two compounds. Collectively, our results suggest that 2-NBA possesses a relatively lower risk to humans than 3-NBA.

  18. Adduct ion-targeted qualitative and quantitative analysis of polyoxypregnanes by ultra-high pressure liquid chromatography coupled with triple quadrupole mass spectrometry.

    Science.gov (United States)

    Wu, Xu; Zhu, Lin; Ma, Jiang; Ye, Yang; Lin, Ge

    2017-10-25

    Polyoxypregnane and its glycosides (POPs) are frequently present in plants of Asclepiadaceae family, and have a variety of biological activities. There is a great need to comprehensively profile these phytochemicals and to quantify them for monitoring their contents in the herbs and the biological samples. However, POPs undergo extensive adduct ion formation in ESI-MS, which has posed a challenge for qualitative and quantitative analysis of POPs. In the present study, we took the advantage of such extensive adduct ion formation to investigate the suitability of adduct ion-targeted analysis of POPs. For the qualitative analysis, we firstly demonstrated that the sodium and ammonium adduct ion-targeted product ion scans (PIS) provided adequate MS/MS fragmentations for structural characterization of POPs. Aided with precursor ion (PI) scans, which showed high selectivity and sensitivity and improved peak assignment confidence in conjunction with full scan (FS), the informative adduct ion-targeted PIS enabled rapid POPs profiling. For the quantification, we used formic acid rather than ammonium acetate as an additive in the mobile phase to avoid simultaneous formation of sodium and ammonium adduct ions, and greatly improved reproducibility of MS response of POPs. By monitoring the solely formed sodium adduct ions [M+Na] + , a method for simultaneous quantification of 25 POPs in the dynamic multiple reaction monitoring mode was then developed and validated. Finally, the aforementioned methods were applied to qualitative and quantitative analysis of POPs in the extract of a traditional Chinses medicinal herb, Marsdenia tenacissima (Roxb.) Wight et Arn., and in the plasma obtained from the rats treated with this herb. The results demonstrated that adduct ion formation could be optimized for the qualitative and quantitative analysis of POPs, and our developed PI/FS-PIS scanning and sole [M+Na] + ion monitoring significantly improved the analysis of POPs in both herbal and

  19. The role of reactive oxygen species (ROS and cytochrome P-450 2E1 in the generation of carcinogenic etheno-DNA adducts

    Directory of Open Access Journals (Sweden)

    Kirsten Linhart

    2014-01-01

    Full Text Available Exocyclic etheno-DNA adducts are mutagenic and carcinogenic and are formed by the reaction of lipidperoxidation (LPO products such as 4-hydoxynonenal or malondialdehyde with DNA bases. LPO products are generated either via inflammation driven oxidative stress or via the induction of cytochrome P-450 2E1 (CYP2E1. In the liver CYP2E1 is induced by various compounds including free fatty acids, acetone and ethanol. Increased levels of CYP2E1 and thus, oxidative stress are observed in the liver of patients with non-alcoholic steatohepatitis (NASH as well as in the chronic alcoholic. In addition, chronic ethanol ingestion also increases CYP2E1 in the mucosa of the oesophagus and colon. In all these tissues CYP2E1 correlates significantly with the levels of carcinogenic etheno-DNA adducts. In contrast, in patients with non-alcoholic steatohepatitis (NASH hepatic etheno-DNA adducts do not correlate with CYP2E1 indicating that in NASH etheno-DNA adducts formation is predominately driven by inflammation rather than by CYP2E1 induction. Since etheno-DNA adducts are strong mutagens producing various types of base pair substitution mutations as well as other types of genetic damage, it is strongly believed that they are involved in ethanol mediated carcinogenesis primarily driven by the induction of CYP2E1.

  20. A single parameter representation of hygroscopic growth and cloud condensation nucleus activity – Part 2: Including solubility

    Directory of Open Access Journals (Sweden)

    M. D. Petters

    2008-10-01

    Full Text Available The ability of a particle to serve as a cloud condensation nucleus in the atmosphere is determined by its size, hygroscopicity and its solubility in water. Usually size and hygroscopicity alone are sufficient to predict CCN activity. Single parameter representations for hygroscopicity have been shown to successfully model complex, multicomponent particles types. Under the assumption of either complete solubility, or complete insolubility of a component, it is not necessary to explicitly include that component's solubility into the single parameter framework. This is not the case if sparingly soluble materials are present. In this work we explicitly account for solubility by modifying the single parameter equations. We demonstrate that sensitivity to the actual value of solubility emerges only in the regime of 2×10−1–5×10−4, where the solubility values are expressed as volume of solute per unit volume of water present in a saturated solution. Compounds that do not fall inside this sparingly soluble envelope can be adequately modeled assuming they are either infinitely soluble in water or completely insoluble.

  1. Antimicrobial Active Packaging including Chitosan Films with Thymus vulgaris L. Essential Oil for Ready-to-Eat Meat

    Directory of Open Access Journals (Sweden)

    Jesús Quesada

    2016-08-01

    Full Text Available An active packaging system has been designed for the shelf life extension of ready to eat meat products. The package included an inner surface coated with a chitosan film with thyme essential oil (0%, 0.5%, 1%, and 2% not in direct contact with the meat. Our aim was to reduce the impact of thyme essential oil (EO on meat sensory properties by using a chemotype with low odor intensity. The pH, color parameters, microbial populations, and sensory properties were assessed during 4 weeks of refrigerated storage. The presence of EO films reduced yeast populations, whereas aerobic mesophilic bacteria, lactic acid bacteria, and enterobacteria were not affected by the presence of the EO in the films. Meat color preservation (a * was enhanced in the presence of EO, giving a better appearance to the packaged meat. The presence of the chitosan-EO layer reduced water condensation inside the package, whereas packages containing only chitosan had evident water droplets. Thyme odor was perceived as desirable in cooked meat, and the typical product odor intensity decreased by increasing the EO concentration. Further studies should point towards developing oil blends or combinations with natural antimicrobial agents to be incorporated into the film to improve its antimicrobial properties.

  2. Gold Nanoparticles for the Detection of DNA Adducts as Biomarkers of Exposure to Acrylamide

    Science.gov (United States)

    Larguinho, Miguel Angelo Rodrigues

    The main objective of this thesis was the development of a gold nanoparticle-based methodology for detection of DNA adducts as biomarkers, to try and overcome existing drawbacks in currently employed techniques. For this objective to be achieved, the experimental work was divided in three components: sample preparation, method of detection and development of a model for exposure to acrylamide. Different techniques were employed and combined for de-complexation and purification of DNA samples (including ultrasonic energy, nuclease digestion and chromatography), resulting in a complete protocol for sample treatment, prior to detection. The detection of alkylated nucleotides using gold nanoparticles was performed by two distinct methodologies: mass spectrometry and colorimetric detection. In mass spectrometry, gold nanoparticles were employed for laser desorption/ionisation instead of the organic matrix. Identification of nucleotides was possible by fingerprint, however no specific mass signals were denoted when using gold nanoparticles to analyse biological samples. An alternate method using the colorimetric properties of gold nanoparticles was employed for detection. This method inspired in the non-cross-linking assay allowed the identification of glycidamide-guanine adducts and DNA adducts generated in vitro. For the development of a model of exposure, two different aquatic organisms were studies: a goldfish and a mussel. Organisms were exposed to waterborne acrylamide, after which mortality was recorded and effect concentrations were estimated. In goldfish, both genotoxicity and metabolic alterations were assessed and revealed dose-effect relationships of acrylamide. Histopathological alterations were verified primarily in pancreatic cells, but also in hepatocytes. Mussels showed higher effect concentrations than goldfish. Biomarkers of oxidative stress, biotransformation and neurotoxicity were analysed after prolonged exposure, showing mild oxidative stress in

  3. Detection of cysteine- and lysine-based protein adductions by reactive metabolites of 2,5-dimethylfuran.

    Science.gov (United States)

    Wang, Kai; Li, Weiwei; Chen, Jiaming; Peng, Ying; Zheng, Jiang

    2015-10-08

    Many furan-containing compounds are known to be toxic and/or carcinogenic. Metabolic activation of toxic furans to cis-enediones (cis-enedials or γ-ketoenals) is generally considered as the initial step towards the processes of their toxicities. Sequential modification of key proteins by the electrophilic reactive intermediates is suggested to be an important mechanism of the toxic actions. In the present study, we developed a novel and simple analytical platform to detect protein modification resulting from metabolic activation of model compound 2,5-dimethylfuran (DMF). 4-Bromobenzylamine and 4-bromobenzylmercaptan were employed to trap protein adductions at cysteine and lysine residues, respectively. The resulting protein samples were proteolytically digested by chymotrypsin and Pronase E, followed by LC-MS/MS analysis. Modifications of cysteine and lysine residues of proteins were observed in microsomal incubations and animals after exposure to DMF. In conclusion, the approach established has been proven highly selective and reliable. This advance allows us not only to detect the protein adductions but also to define the structural identities of amino acid residues modified. This technique provides a unique platform to assess protein modifications arising from metabolic activation of potentially harmful furan-containing compounds. Hepatic protein adductions were found to be proportional to the hepatotoxicity of DMF. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Bioanalytical verification of V-type nerve agent exposure: simultaneous detection of phosphonylated tyrosines and cysteine-containing disulfide-adducts derived from human albumin.

    Science.gov (United States)

    Kranawetvogl, Andreas; Küppers, Jim; Siegert, Markus; Gütschow, Michael; Worek, Franz; Thiermann, Horst; Elsinghorst, Paul W; John, Harald

    2018-02-01

    Modification of human serum albumin (HSA) by V-type nerve agents Chinese VX (CVX) and RussianVX (RVX). Various tyrosine residues (Tyr???)n (e.g. most reactive Tyr411) were phosphonylated and disulfide-adducts were formed between the thiol-containing leaving group 2-(diethylamino)ethanethiol (DEAET) and at least three cysteine residues (Cys34, Cys448 and Cys514). Pronase-mediated proteolysis produced low-molecular cleavage products including phosphonylated tyrosines, dipeptide (Cys34Pro) and tripeptide (MetProCys448, AspIleCys514) disulfide-adducts that were detected by microbore liquid chromatography-electrospray ionization mass spectrometry/high-resolution mass spectrometry (μLC-ESI MS/HR MS).

  5. DNA Adducts Formed by Aristolochic Acid Are Unique Biomarkers of Exposure and Explain the Initiation Phase of Upper Urothelial Cancer.

    Science.gov (United States)

    Stiborová, Marie; Arlt, Volker M; Schmeiser, Heinz H

    2017-10-14

    Aristolochic acid (AA) is a plant alkaloid that causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), unique renal diseases frequently associated with upper urothelial cancer (UUC). This review summarizes the significance of AA-derived DNA adducts in the aetiology of UUC leading to specific A:T to T:A transversion mutations (mutational signature) in AAN/BEN-associated tumours, which are otherwise rare in individuals with UCC not exposed to AA. Therefore, such DNA damage produced by AA-DNA adducts is one rare example of the direct association of exposure and cancer development (UUC) in humans, confirming that the covalent binding of carcinogens to DNA is causally related to tumourigenesis. Although aristolochic acid I (AAI), the major component of the natural plant extract AA, might directly cause interstitial nephropathy, enzymatic activation of AAI to reactive intermediates capable of binding to DNA is a necessary step leading to the formation of AA-DNA adducts and subsequently AA-induced malignant transformation. Therefore, AA-DNA adducts can not only be utilized as biomarkers for the assessment of AA exposure and markers of AA-induced UUC, but also be used for the mechanistic evaluation of its enzymatic activation and detoxification. Differences in AA metabolism might be one of the reasons for an individual's susceptibility in the multi-step process of AA carcinogenesis and studying associations between activities and/or polymorphisms of the enzymes metabolising AA is an important determinant to identify individuals having a high risk of developing AA-mediated UUC.

  6. Exposure of bus and taxi drivers to urban air pollutants as measured by DNA and protein adducts

    DEFF Research Database (Denmark)

    Hemminki, K.; Zhang, L.F.; Krüger, J.

    1994-01-01

    Urinary 1-hydroxypyrene, lymphocyte DNA adducts, serum protein-bound PAH and hemoglobin-bound alkene adducts were analysed from 4 groups of non-smoking men: urban and suburban bus drivers, taxi drivers and suburban controls. The only differences between the groups were in DNA adducts between...... suburban bus drivers and controls, and in DNA adduct and plasma protein PAH-adducts between taxi drivers and controls....

  7. The effects of rotator cuff tears, including shoulders without pain, on activities of daily living in the general population.

    Science.gov (United States)

    Nakajima, Daisuke; Yamamoto, Atsushi; Kobayashi, Tsutomu; Osawa, Toshihisa; Shitara, Hitoshi; Ichinose, Tsuyoshi; Takasawa, Eiji; Takagishi, Kenji

    2012-03-01

    Few reports have so far evaluated the possible restrictions of activities of daily living (ADL) in patients with asymptomatic rotator cuff tears (RCTs). The purpose of this study was to examine the effects of RCTs, including shoulders without pain, on ADL in the general population. We performed medical checkups on 462 individuals (924 shoulders). All participants completed a questionnaire regarding their background and medical history. We then assessed their shoulder functions with the Simple Shoulder Test (SST) and performed US (US) examinations of both shoulders to diagnose RCTs. We divided participants into tear and nontear groups and performed statistical analysis to compare total SST scores and each SST item between groups. Furthermore, we performed the same examinations for participants identified as having shoulders without pain. Among participants, those in the tear group showed significantly lower total SST scores than those in the nontear group. After examining each SST item, a significant difference was observed regarding the ability to sleep comfortably and to lift 3.6 kg to shoulder level. In shoulders without pain, the tear group showed significantly lower total SST scores than the nontear group. A significant difference was observed only regarding the ability to lift 3.6 kg to shoulder level. In the general population, ADL were restricted in participants with RCTs; they experienced night pain in the shoulder and muscle weakness during shoulder elevation. Furthermore, participants with RCTs, even if the condition itself did not induce any pain, tended to experience muscle weakness during shoulder elevation, thus resulting in restrictions of ADL.

  8. Poor oral health including active caries in 187 UK professional male football players: clinical dental examination performed by dentists.

    Science.gov (United States)

    Needleman, Ian; Ashley, Paul; Meehan, Lyndon; Petrie, Aviva; Weiler, Richard; McNally, Steve; Ayer, Chris; Hanna, Rob; Hunt, Ian; Kell, Steven; Ridgewell, Paul; Taylor, Russell

    2016-01-01

    The few studies that have assessed oral health in professional/elite football suggest poor oral health with minimal data on impact on performance. The aim of this research was to determine oral health in a representative sample of professional footballers in the UK and investigate possible determinants of oral health and self-reported impact on well-being, training and performance. Clinical oral health examination of senior squad players using standard methods and outcomes carried out at club training facilities. Questionnaire data were also collected. 8 teams were included, 5 Premier League, 2 Championship and 1 League One. 6 dentists examined 187 players who represented >90% of each senior squad. Oral health was poor: 37% players had active dental caries, 53% dental erosion and 5% moderate-severe irreversible periodontal disease. 45% were bothered by their oral health, 20% reported an impact on their quality of life and 7% on training or performance. Despite attendance for dental check-ups, oral health deteriorated with age. This is the first large, representative sample study in professional football. Oral health of professional footballers is poor, and this impacts on well-being and performance. Successful strategies to promote oral health within professional football are urgently needed, and research should investigate models based on best evidence for behaviour change and implementation science. Furthermore, this study provides strong evidence to support oral health screening within professional football. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  9. PHOSPHATO AND PHOSPHONATO ADDUCTS: SYNTHESIS AND SPECTROSCOPIC STUDY

    Directory of Open Access Journals (Sweden)

    Mouhamadou Birame Diop

    2014-05-01

    Full Text Available Two new adducts have been synthesized and studied by infrared and NMR spectroscopy. The suggested structures are discrete or of infinite chain type with a phosphate behaving as a bidentate ligand, a phosphonate acting as a monodentate ligand, the environments around the tin centre being tetrahedral or trigonal bipyramidal. In all the studied compounds, supramolecular architectures are obtained when hydrogen bonds are considered.

  10. Protein tyrosine adduct in humans self-poisoned by chlorpyrifos

    Energy Technology Data Exchange (ETDEWEB)

    Li, Bin, E-mail: binli@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States); Eyer, Peter, E-mail: peter.eyer@lrz.uni-muenchen.de [Walther-Straub-Institut Für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, 80336 München (Germany); Eddleston, Michael, E-mail: M.Eddleston@ed.ac.uk [Clinical Pharmacology Unit, University of Edinburgh, Edinburgh (United Kingdom); Jiang, Wei, E-mail: wjiang@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States); Schopfer, Lawrence M., E-mail: lmschopf@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States); Lockridge, Oksana, E-mail: olockrid@unmc.edu [Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198-5950 (United States)

    2013-06-15

    Studies of human cases of self-inflicted poisoning suggest that chlorpyrifos oxon reacts not only with acetylcholinesterase and butyrylcholinesterase but also with other blood proteins. A favored candidate is albumin because in vitro and animal studies have identified tyrosine 411 of albumin as a site covalently modified by organophosphorus poisons. Our goal was to test this proposal in humans by determining whether plasma from humans poisoned by chlorpyrifos has adducts on tyrosine. Plasma samples from 5 self-poisoned humans were drawn at various time intervals after ingestion of chlorpyrifos for a total of 34 samples. All 34 samples were analyzed for plasma levels of chlorpyrifos and chlorpyrifos oxon (CPO) as a function of time post-ingestion. Eleven samples were analyzed for the presence of diethoxyphosphorylated tyrosine by mass spectrometry. Six samples yielded diethoxyphosphorylated tyrosine in pronase digests. Blood collected as late as 5 days after chlorpyrifos ingestion was positive for CPO-tyrosine, consistent with the 20-day half-life of albumin. High plasma CPO levels did not predict detectable levels of CPO-tyrosine. CPO-tyrosine was identified in pralidoxime treated patients as well as in patients not treated with pralidoxime, indicating that pralidoxime does not reverse CPO binding to tyrosine in humans. Plasma butyrylcholinesterase was a more sensitive biomarker of exposure than adducts on tyrosine. In conclusion, chlorpyrifos oxon makes a stable covalent adduct on the tyrosine residue of blood proteins in humans who ingested chlorpyrifos. - Highlights: • Chlorpyrifos-poisoned patients have adducts on protein tyrosine. • Diethoxyphosphate-tyrosine does not lose an alkyl group. • Proteins in addition to AChE and BChE are modified by organophosphates.

  11. Dispersant additives derived from lactone modified amido-amine adducts

    Energy Technology Data Exchange (ETDEWEB)

    Gutierrez, A.; Lundberg, R.D.

    1990-10-16

    This patent describes a lactone modified dispersant additive. It comprises one adduct of a polyolefin of 300 to 10,000 number average molecular weight substituted with at least 0.8 (e.g., from about 1 to 4) dicarboxylic acid producing moieties (preferably acid or anhydride moieties) per polyolefin molecule, an amido-amine or thioamido-amine characterized by being a reaction product of at least a polyamine and an alpha, beta-unsaturated compound.

  12. Diagnosis and dosimetry of exposure to sulfur mustard: Development of a standard operating procedure for hemoglobin adducts: Exploratory research on albumin and keratin adducts

    NARCIS (Netherlands)

    Noort, D.; Fidder, A.; Jong, L.P.A. de; Schans, G.P. van der; Benschop, H.P.

    2000-01-01

    A standard operating procedure (SOP) for determination of the sulfur mustard adduct to the N-terminal valine in hemoglobin was developed. By using this SOP, it was found that the Nterminal valine adduct in globin of hairless guinea pigs and marmosets which had been exposed to sulfur mustard (0.5

  13. Diagnosis and dosimetry of exposure to sulfur mustard: Development of a standard operating procedure for mass spectrometric analysis of haemoglobin adducts - Exploratory research on albumin and keratin adducts

    NARCIS (Netherlands)

    Noort, D.; Fidder, A.; Hulst, A.G.; Jong, L.P.A. de; Benschop, H.P.

    2000-01-01

    Experiments were carried out to develop a standard operating procedure for analysis of sulfur mustard adducts to the N-terminal valine in haemoglobin and to explore adduct formation with albumin and keratin. In the first approach, gas chromatography-negative chemical ionization/mass spectrometry

  14. DYNAMIC HIP ADDUCTION, ABDUCTION AND ABDOMINAL EXERCISES FROM THE HOLMICH GROIN-INJURY PREVENTION PROGRAM ARE INTENSE ENOUGH TO BE CONSIDERED STRENGTHENING EXERCISES - A CROSS-SECTIONAL STUDY.

    Science.gov (United States)

    Krommes, Kasper; Bandholm, Thomas; Jakobsen, Markus D; Andersen, Lars L; Serner, Andreas; Hölmich, Per; Thorborg, Kristian

    2017-06-01

    Training intensity is an important variable in strength training and above 80% of one repetition maximum is recommended for promoting strength for athletes. Four dynamic and two isometric on-field exercises are included in the Hölmich groin-injury prevention study that initially failed to show a reduction in groin injuries in soccer players. It has been speculated that exercise-intensity in this groin-injury prevention program was too low to induce the strength gains necessary to protect against groin-related injuries. To estimate the intensity of the six exercises from the Hölmich program using electromyography (EMG) and possibly categorize them as strength-training exercises. Cross-sectional study. 21 adult male soccer players training >5 hours weekly were included. Surface-EMG was recorded from adductor longus, gluteus medius, rectus abdominis and external obliques during isometric adduction against a football placed between the ankles (IBA), isometric adduction against a football placed between the knees (IBK), folding knife (FK), cross-country skiing on one leg (CCS), adduction partner (ADP) and abduction partner (ABP). The EMG-signals were normalized (nEMG) to an isometric maximal voluntary contraction for each tested muscle. Adductor longus activity during IBA was 84% nEMG (95% CI: 70-98) and during IBK it was 118% nEMG (95% CI 106-130). For the dynamic exercises, ADP evoked 87% nEMG (95% CI 69-105) in adductor longus, ABP evoked 88% nEMG (95% CI 76-100) in gluteus medius, FK evoked 82% nEMG (95% CI 68-96) rectus abdominis, and 101% nEMG (95% CI 85-118) in external obliques. During CSS muscles. These data suggest that exercise-intensity of all the six investigated exercises in the Hölmich groin injury prevention program, except cross-county skiing, is sufficient to be considered strength-training for specific muscle groups in and around the groin region. 3.

  15. HEPS Inventory Tool: An Inventory Tool Including Quality Assessment of School Interventions on Healthy Eating and Physical Activity

    Science.gov (United States)

    Dadaczynski, Kevin; Paulus, Peter; de Vries, Nanne; de Ruiter, Silvia; Buijs, Goof

    2010-01-01

    The HEPS Inventory Tool aims to support stakeholders working in school health promotion to promote high quality interventions on healthy eating and physical activity. As a tool it provides a step-by-step approach on how to develop a national or regional inventory of existing school based interventions on healthy eating and physical activity. It…

  16. 25 CFR 170.137 - What types of activities can a recreation, tourism, and trails program include?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false What types of activities can a recreation, tourism, and... Eligibility Recreation, Tourism and Trails § 170.137 What types of activities can a recreation, tourism, and... may perform under a recreation, tourism, and trails program: (1) Transportation planning for tourism...

  17. Diastereoselective synthesis of {beta}-piperonyl-{gamma}-butyrolactones from morita-baylis-hillman adducts. highly efficient synthesis of ({+-})-yatein, ({+-})-podorhizol and ({+-})-epi-podorhizol

    Energy Technology Data Exchange (ETDEWEB)

    Trazzi, Giordano; Andre, Marcelo Fabiano; Coelho, Fernando, E-mail: coelho@iqm.unicamp.b [Universidade Estadual de Campinas (UNICAMP), SP (Brazil). Inst. de Quimica

    2010-07-01

    Starting from a Morita-Baylis-Hillman adduct we describe a simple and very efficient method for the diastereoselective preparation of hydroxylated beta-piperonyl-g-butyrolactones. To exemplify the efficiency of this approach we also describe a highly efficient synthesis for the biologically active lignans ({+-})-yatein, ({+-})-podorhizol and ({+-})-epi-podorhizol. (author)

  18. Persistence of DNA adducts, hypermutation and acquisition of cellular resistance to alkylating agents in glioblastoma.

    Science.gov (United States)

    Head, R J; Fay, M F; Cosgrove, L; Y C Fung, K; Rundle-Thiele, D; Martin, J H

    2017-12-02

    Glioblastoma is a lethal form of brain tumour usually treated by surgical resection followed by radiotherapy and an alkylating chemotherapeutic agent. Key to the success of this multimodal approach is maintaining apoptotic sensitivity of tumour cells to the alkylating agent. This initial treatment likely establishes conditions contributing to development of drug resistance as alkylating agents form the O 6 -methylguanine adduct. This activates the mismatch repair (MMR) process inducing apoptosis and mutagenesis. This review describes key juxtaposed drivers in the balance between alkylation induced mutagenesis and apoptosis. Mutations in MMR genes are the probable drivers for alkylation based drug resistance. Critical to this interaction are the dose-response and temporal interactions between adduct formation and MMR mutations. The precision in dose interval, dose-responses and temporal relationships dictate a role for alkylating agents in either promoting experimental tumour formation or inducing tumour cell death with chemotherapy. Importantly, this resultant loss of chemotherapeutic selective pressure provides opportunity to explore novel therapeutics and appropriate combinations to minimise alkylation based drug resistance and tumour relapse.

  19. Retardation of experimental tumorigenesis and reduction in DNA adducts by turmeric and curcumin.

    Science.gov (United States)

    Krishnaswamy, K; Goud, V K; Sesikeran, B; Mukundan, M A; Krishna, T P

    1998-01-01

    Turmeric and its active principle curcumin have been extensively investigated for their antimutagenic and antioxidant effects in bacterial and animal systems. Because oral cancers are common in India, an experimental model of 7,12-dimethylbenzanthracene-induced buccal pouch tumors in Syrian Golden hamsters was used to evaluate the tumor retardation effects of turmeric and curcumin. Turmeric and/or curcumin was administered in the diet and/or applied locally for 14 weeks along with 7,12-dimethylbenzanthracene. After the experimental period, the animals were sacrificed and oral pouches were examined for tumor number and size. DNA adducts were estimated by 32P postlabel assay in the cheek pouches. Neoplastic changes were graded by histopathology. The results of the study suggest that turmeric or curcumin in the diet and/or applied locally significantly reduced DNA adducts at the target site. Tumor number and tumor burden were significantly lower (p curcumin (p curcumin administered in the diet or applied as paint may have a plausible chemopreventive effect on oral precancerous lesions.

  20. Lysine- and cysteine-based protein adductions derived from toxic metabolites of 8-epidiosbulbin E acetate.

    Science.gov (United States)

    Lin, Dongju; Wang, Kai; Guo, Xiucai; Gao, Huiyuan; Peng, Ying; Zheng, Jiang

    2016-12-15

    Furanoid 8-epidiosbulbin E acetate (EEA) is a major constituent of herbal medicine Dioscorea bulbifera L. (DB), a traditional herbal medicine widely used in Asian nations. Our early studies demonstrated that administration of EEA caused acute hepatotoxicity in mice and the observed toxicity required P450-mediated metabolic activation. Protein modification by reactive metabolites of EEA has been suggested to be an important mechanism of EEA-induced hepatotoxicity. The objectives of the present study were to investigate the interaction of the electrophilic reactive metabolites derived from EEA with lysine and cysteine residues of proteins and to define the correlation of protein adductions of EEA and the hepatotoxicity induced by EEA. EEA-derived cis-enedial was found to modify both lysine and cysteine residues of proteins. The observed modifications increased with the increase in doses administered in the animals. The formation of protein adductions derived from the reactive metabolites of EEA were potentiated by buthionine sulfoximine, but were attenuated by ketoconazole. This work facilitated better understanding of the mechanisms of toxic action of EEA. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. Cysteine-Based Protein Adduction by Epoxide-Derived Metabolite(s) of Benzbromarone.

    Science.gov (United States)

    Wang, Hui; Feng, Yukun; Wang, Qian; Guo, Xiucai; Huang, Wenlin; Peng, Ying; Zheng, Jiang

    2016-12-19

    Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR-induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR-induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity.

  2. New insights into the chemistry of fac-[Ru(CO)₃]²⁺ fragments in biologically relevant conditions: the CO releasing activity of [Ru(CO)₃Cl₂(1,3-thiazole)], and the X-ray crystal structure of its adduct with lysozyme.

    Science.gov (United States)

    Santos, M F A; Seixas, J D; Coelho, A C; Mukhopadhyay, A; Reis, P M; Romão, M J; Romão, C C; Santos-Silva, T

    2012-12-01

    Complexes of the general formula fac-[Ru(CO)(3)L(3)](2+), namely CORM-2 and CORM-3, have been successfully used as experimental CO releasing molecules (CO-RMs) but their mechanism of action and delivery of CO remain unclear. The well characterized complex [Ru(CO)(3)Cl(2)(1,3-thiazole)] (1) is now studied as a potential model CO-RM of the same family of complexes using LC-MS, FTIR, and UV-vis spectroscopy, together with X-ray crystallography. The chemistry of [Ru(CO)(3)Cl(2)(1,3-thiazole)] is very similar to that of CORM-3: it only releases residual amounts of CO to the headspace of a solution in PBS7.4 and produces marginal increase of COHb after long incubation in whole blood. 1 also reacts with lysozyme to form Ru adducts. The crystallographic model of the lysozyme-Ru adducts shows only mono-carbonyl Ru species. [Ru(H(2)O)(4)(CO)] is found covalently bound to a histidine (His15) and to two aspartates (Asp18 and Asp119) at the protein surface. The CO release silence of both 1 and CORM-3 and their rapid formation of protein-Ru(CO)(x)(H(2)O)(y) (x=1,2) adducts, support our hypothesis that fac-[Ru(CO)(3)L(3)] CO-RMs deliver CO in vivo through the decay of their adducts with plasma proteins. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Mutagenicity of 5-hydroxymethylfurfural in V79 cells expressing human SULT1A1: identification and mass spectrometric quantification of DNA adducts formed.

    Science.gov (United States)

    Monien, Bernhard H; Engst, Wolfram; Barknowitz, Gitte; Seidel, Albrecht; Glatt, Hansruedi

    2012-07-16

    5-Hydroxymethylfurfural (HMF), a heterocyclic product of the Maillard reaction, is a ubiquitous food contaminant. It has demonstrated hepatocarcinogenic activity in female mice. This effect may originate from sulfo conjugation of the benzylic alcohol yielding 5-sulfooxymethylfurfural (SMF), which is prone to react with DNA via nucleophilic substitution. Indeed, we showed that HMF induces gene mutations in Chinese hamster V79 cells engineered for the expression of human (h) sulfotransferase (SULT)1A1 but not in parental V79 cells. In order to identify potential DNA adducts, we incubated DNA samples with SMF or HMF in aqueous solution. Modified DNA was digested and surveyed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) for adducts that may be formed by nucleosides either via nucleophilic substitution at the electrophilic carbon atom of SMF or via imine formation with the aldehyde group present in HMF and SMF. The most abundant adducts formed from SMF, N(6)-((2-formylfuran-5-yl)methyl)-2'-deoxyadenosine (N(6)-FFM-dAdo) and N(2)-((2-formylfuran-5-yl)methyl)-2'-deoxyguanosine (N(2)-FFM-dGuo), were synthesized, purified, and characterized by (1)H NMR. Imine adducts were only detected when DNA was incubated with very high levels of HMF following reduction of the imines to corresponding secondary amines by NaBH(3)CN. Sensitive techniques based on LC-MS/MS multiple reaction monitoring for the quantification of the adducts in DNA samples were devised using isotope-labeled [(15)N(5)]N(6)-FFM-dAdo and [(13)C(10),(15)N(5)]N(2)-FFM-dGuo as internal standards. Both 5-methylfurfuryl adducts were detected in DNA from V79-hSULT1A1 treated with HMF but not in DNA from V79 control cells. Considering the lack of other known mutagenic metabolites, we hypothesize that the hepatocarcinogenic potential of HMF originates from the formation of mutagenic SMF.

  4. The effects of low-dose Nepsilon-(carboxymethyllysine (CML and Nepsilon-(carboxyethyllysine (CEL, two main glycation free adducts considered as potential uremic toxins, on endothelial progenitor cell function

    Directory of Open Access Journals (Sweden)

    Zhu Jinzhou

    2012-08-01

    Full Text Available Abstract Background Patients with chronic kidney disease (CKD are at high risk of cardiovascular disease (CVD. Endothelial progenitor cell (EPCs dysfunction plays a key role in this pathogenesis. Uremic retention toxins have been reported to be in associated with EPC dysfunction. Advanced glycation end-products (AGEs free adducts, including Nepsilon-(carboxymethyllysine (CML and Nepsilon-(carboxyethyllysine (CEL, are formed by physiological proteolysis of AGEs and released into plasma for urinary excretion. They are retained in CKD patients and are considered to be potential uremic toxins. Though AGEs have been demonstrated to impair EPC function in various ways, the effect of AGE free adducts on EPC function has not been studied. Thus, we examined the role of CML and CEL in the regulation of growth-factor-dependent function in cultured human EPCs and the mechanisms by which they may affect EPC function. Methods Late outgrowth EPCs were incubated with different concentrations of CML or CEL for up to 72 hours. Cell proliferation was determined using WST-1 and BrdU assays. Cell apoptosis was tested with annexin V staining. Migration and tube formation assays were used to evaluate EPC function. Results Though CML and CEL were determined to have anti-proliferative effects on EPCs, cells treated with concentrations of CML and CEL in the range found in CKD patients had no observable impairment on migration or tube formation. CML and CEL did not induce EPC apoptosis. The reduced growth response was accompanied by significantly less phosphorylation of mitogen-activated protein kinases (MAPKs. Conclusions Our study revealed that CML and CEL at uremic concentrations have low biological toxicity when separately tested. The biologic effects of AGE free adducts on the cardiovascular system merit further study.

  5. High-Confidence Qualitative Identification of Organophosphorus Nerve Agent Adducts to Human Butyrylcholinesterase.

    Science.gov (United States)

    Mathews, Thomas P; Carter, Melissa D; Johnson, Darryl; Isenberg, Samantha L; Graham, Leigh Ann; Thomas, Jerry D; Johnson, Rudolph C

    2017-02-07

    In this study, a data-dependent, high-resolution tandem mass spectrometry (ddHRMS/MS) method capable of detecting all organophosphorus nerve agent (OPNA) adducts to human butyrylcholinesterase (BChE) was developed. After an exposure event, immunoprecipitation from blood with a BChE-specific antibody and digestion with pepsin produces a nine amino acid peptide containing the OPNA adduct. Signature product ions of this peptic BChE nonapeptide (FGES*AGAAS) offer a route to broadly screen for OPNA exposure. Taking this approach on an HRMS instrument identifies biomarkers, including unknowns, with high mass accuracy. Using a set of pooled human sera exposed to OPNAs as quality control (QC) materials, the developed method successfully identified precursor ions with 15 ng/mL. The developed method was applied to a convenience set of 96 unexposed serum samples and a blinded set of 80 samples treated with OPNAs. OPNA biomarkers were not observed in convenience set samples and no false positive or negative identifications were observed in blinded samples. All biomarkers in the blinded serum set >15 ng/mL were correctly identified. For the first time, this study reports a ddHRMS/MS method capable of complementing existing quantitative methodologies and suitable for identifying exposure to unknown organophosphorus agents.

  6. Zinc acetylacetonate hydrate adducted with nitrogen donor ligands: Synthesis, spectroscopic characterization, and thermal analysis

    Science.gov (United States)

    Brahma, Sanjaya; Shivashankar, S. A.

    2015-12-01

    We report synthesis, spectroscopic characterization, and thermal analysis of zinc acetylacetonate complex adducted by nitrogen donor ligands, such as pyridine, bipyridine, and phenanthroline. The pyridine adducted complex crystallizes to monoclinic crystal structure, whereas other two adducted complexes have orthorhombic structure. Addition of nitrogen donor ligands enhances the thermal property of these complexes as that with parent metal-organic complex. Zinc acetylacetonate adducted with pyridine shows much higher volatility (106 °C), decomposition temperature (202 °C) as that with zinc acetylacetonate (136 °C, 220 °C), and other adducted complexes. All the adducted complexes are thermally stable, highly volatile and are considered to be suitable precursors for metal organic chemical vapor deposition. The formation of these complexes is confirmed by powder X-ray diffraction, Fourier transform infrared spectroscopy, mass spectroscopy, and elemental analysis. The complexes are widely used as starting precursor materials for the synthesis of ZnO nanostructures by microwave irradiation assisted coating process.

  7. Decay kinetics of nicotine/NNK-DNA adducts in vivo studied by accelerator mass spectrometry

    International Nuclear Information System (INIS)

    Sun, H.F.; He, L.; Liu, Y.F.; Liu, K.X.; Lu, X.Y.; Wang, J.J.; Ma, H.J.; Li, K.

    2000-01-01

    The decay kinetics of nicotine-DNA adducts and NNK-DNA adducts in mice liver after single dosing was studied by accelerator mass spectrometry (AMS). The decay is characterized by a two-stage process. The half-lives of nicotine-DNA adducts are 1.3 d (4-24 h) and 7.0 d (1-21 d), while for NNK-DNA adducts are 0.7 d (4-24 h) and 18.0 d (1-21 d). The relatively faster decay of nicotine-DNA adducts suggests that the genotoxicity of nicotine is weaker than that of NNK. The in vitro study shows that the metabolization of nicotine is necessary for the final formation of nicotine-DNA adducts, and nicotine Δ1'(5') iminium ion is a probable metabolite species that binds to DNA molecule covalently

  8. Fast repair of oxidizing OH adducts of DNA by hydroxycinnamic acid derivatives. A pulse radiolytic study

    International Nuclear Information System (INIS)

    Yue Jiang; Lin Weizhen; Yao Side; Lin Nianyun; Zhu Dayuan

    1999-01-01

    Using pulse radiolytic techniques, it has been demonstrated that the interactions of oxidizing OH adducts of DNA (ssDNA and dsDNA), polyA and polyG with hydroxycinnamic acid derivatives proceed via an electron transfer process (k=5-30x10 8 dm 3 mol -1 s -1 ). In addition, the rates for fast repair of OH adducts of dAMP, polyA and DNA (ssDNA and dsDNA) are slower than the corresponding rates for the rest OH adducts of DNA constituents. The slower rates for repair of oxidizing OH adducts of dAMP may be the rate determining step during the interaction of hydroxycinnamic acid derivatives with OH adducts of DNA containing the varieties of OH adducts of DNA constituents

  9. Retrospective detection of exposure to sulfur mustard: Improvements on an assay for liquid chromatography-tandem mass spectrometry analysis of albumin/sulfur mustard adducts

    NARCIS (Netherlands)

    Noort, D.; Fidder, A.; Hulst, A.G.; Woolfitt, A.R.; Ash, D.; Barr, J.R.

    2004-01-01

    We here report on the further development of the method comprising the pronase digestion of albumin alkylated by sulfur mustard and the subsequent mass spectrometric analysis of an adducted tripeptide. This includes significant improvements in both the albumin isolation procedure and the automation

  10. Detection of Emodin Derived Glutathione Adduct in Normal Rats Administered with Large Dosage of Polygoni Multiflori Radix

    Directory of Open Access Journals (Sweden)

    Li-Long Jiang

    2017-07-01

    Full Text Available Polygoni Multiflori Radix (PMR has been commonly used as a tonic in China for centuries. PMR-associated hepatotoxicity has been drawing increasingly more attention in recent years in parallel with its wide utilization. Anthraquinones (AQs are recognized as the main hepatotoxic components in PMR. However, the exact underlying mechanism of AQs poisoning is still not fully understood. Herein, we proposed a hypothesis that metabolic activation of AQs such as emodin was involved in PMR-induced liver injury, AQs followed to generate the electrophilic reactive metabolites and subsequently formed covalent adduct with cellular nucleophiles in the liver to exert hepatotoxicity. In the present study, the link of cytotoxicity of PMR in primary human hepatocytes and the depletion of glutathione (GSH was investigated by MTT assay and UHPLC-QqQ-MS/MS analysis. The results showed that PMR depleted GSH and therefore induced cytotoxicity. Then, emodin-GSH adduct was identified in bile of liver injured rats after intragastric administration of PMR or emodin with the aid of UHPLC-QTOF-MS/MS method. Our findings not only provided confirmative evidence that the mechanism of hepatotoxicity induced by AQs in PMR involved key metabolic steps, but also revealed that emodin-GSH adduct had potential to be further developed as a sensitive and traceable biomarker for the assessment of PMR-induced liver injury.

  11. Antimicrobial (including antimollicutes, antioxidant and anticholinesterase activities of Brazilian and Spanish marine organisms – evaluation of extracts and pure compounds

    Directory of Open Access Journals (Sweden)

    Éverson Miguel Bianco

    Full Text Available Abstract This work describes the antimicrobial, antioxidant and anticholinesterase activities in vitro of organic extracts from fourteen seaweeds, eleven sponges, two ascidians, one bryozoan, and one sea anemone species collected along the Brazilian and Spanish coast, as well as the isolation of the diterpene (4R, 9S, 14S-4α-acetoxy-9β,14α-dihydroxydolast-1(15,7-diene (1 and halogenated sesquiterpene elatol (2. The most promising antimicrobial results for cell wall bacteria were obtained by extracts from seaweeds Laurencia dendroidea and Sargassum vulgare var. nanun (MIC 250 μg/ml, and by the bryozoan Bugula neritina (MIC 62.5 μg/ml, both against Staphylococcus aureus. As for antimollicutes, extracts from seaweeds showed results better than the extracts from invertebrates. Almost all seaweeds assayed (92% exhibited some antimicrobial activity against mollicutes strains (Mycoplasma hominis,Mycoplasma genitalium,Mycoplasma capricolum and Mycoplasma pneumoniae strain FH. From these seaweeds, A1 (Canistrocarpus cervicornis, A11 (Gracilaria sp. and A4 (Lobophora variegata showed the best results for M. pneumoniae strain FH (MIC 250 μg/ml. Furthermore, compounds 1 and 2 were also assayed against mollicutes strains M. hominis,M. genitalium,M. capricolum,M. pneumoniae strain 129 and M. pneumoniae strain FH, which showed MIC > 100 μg/ml. Antioxidant activities of extracts from these marine organisms were inactive, except for E7 (from sponge Ircinia sp., which exhibited moderated antioxidant activities for two methods assayed (IC50 83.0 ± 0.1 μg/ml, and 52.0 ± 0.8 mg AA/g, respectively. Finally, for the anticholinesterase activity, all the 29 samples evaluated (100% exhibited some level of activity, with IC50 < 1000 μg/ml. From these, seaweeds extracts were considered more promising than marine invertebrate extracts [A10 (IC50 14.4 ± 0.1 μg/ml, A16 (IC50 16.4 ± 0.4 μg/ml and A8 (IC50 14.9 ± 0.5 μg/ml]. The findings of this work are useful

  12. Research on Chemical Composition and Biological Properties Including Antiquorum Sensing Activity of Angelica pancicii Vandas Aerial Parts and Roots.

    Science.gov (United States)

    Mileski, Ksenija S; Trifunović, Snežana S; Ćirić, Ana D; Šakić, Željana M; Ristić, Mihailo S; Todorović, Nina M; Matevski, Vlado S; Marin, Petar D; Tešević, Vele V; Džamić, Ana M

    2017-12-20

    The essential oil, different extracts, and isolated compounds of Angelica pancicii Vandas (Apiaceae) were investigated for the first time. The GC-FID and GC-MS analyses revealed sesquiterpenoids as the main constituents of A. pancicii essential oil of aerial parts with bornyl acetate (8.08%), n-octanol (5.82%), kessane (4.26%), and β-selinene (4.26%) as the main constituents. Analysis of methanol extracts, using an HPLC-DAD/ESI-ToF-MS system, showed a total of 52 compounds in the aerial parts and 53 in the roots, indicating coumarins as the main constituents. In addition, new chromone (1) and six known furanocoumarins (2-7) were isolated from the roots and structurally elucidated by combined spectroscopic methods. The aerial part extracts exhibited higher polyphenolic contents and antioxidant activity evaluated by three radical scavenging assays. Using a microwell dilution method, the strongest antibacterial activity profiles were determined for ethanol and methanol root extracts (minimum bactericidal concentrations (MBCs) = 0.25-3.00 mg/mL), which were comparable to the activity of streptomycin (MBCs = 0.34-1.24 mg/mL), while the strongest antibacterial compound of A. pancicii was oxypeucedanin hydrate (MBCs = 0.50-8.00 mg/mL). Antifungal potential was in moderate extent, and the highest activity was obtained for root methanol extract (minimum fungicidal concentrations (MFCs) = 4.00-14.00 mg/mL). Tested sub-minimum inhibitory concentrations (subMICs) of the extracts and isolated compounds inhibited selected Pseudomonas aeruginosa PAO1 virulence determinants. The most reduced growth of P. aeruginosa colony was in the presence of isolated oxypeucedanin. Ethanol (17.36-46.98%) and methanol (34.54-52.43%) root extracts showed higher anti-biofilm activity compared to streptomycin (49.40-88.36%) and ampicillin (56.46-92.16%).

  13. Temporal and spatial features of the formation of DNA adducts in sulfur mustard-exposed skin

    International Nuclear Information System (INIS)

    Batal, Mohamed; Boudry, Isabelle; Mouret, Stéphane; Wartelle, Julien; Emorine, Sandy; Bertoni, Marine; Bérard, Izabel; Cléry-Barraud, Cécile

    2013-01-01

    Sulfur mustard (SM) is a chemical warfare agent that targets skin where it induces large blisters. DNA alkylation is a critical step to explain SM-induced cutaneous symptoms. We determined the kinetics of formation of main SM–DNA adducts and compare it with the development of the SM-induced pathogenesis in skin. SKH-1 mice were exposed to 2, 6 and 60 mg/kg of SM and treated skin was biopsied between 6 h and 21 days. Formation of SM DNA adducts was dose-dependent with a maximum immediately after exposure. However, adducts were persistent and still detectable 21 days post-exposure. The time-dependent formation of DNA adducts was also found to be correlated with the appearance of apoptotic cells. This temporal correlation suggests that these two early events are responsible for the severity of the damage to the skin. Besides, SM–DNA adducts were also detected in areas located next to contaminated zone, thus suggesting that SM diffuses in skin. Altogether, this work provides for the first time a clear picture of SM-induced genotoxicity using DNA adducts as a marker. - Highlights: • Sulfur mustard adducts are formed in DNA after skin exposure. • DNA damage formation is an early event in the pathological process of skin burn. • The amount of SM–DNA adducts is maximal at the earliest time point investigated. • Adducts are still detected 3 weeks after exposure. • Sulfur mustard diffuses in skin especially when large doses are applied

  14. Temporal and spatial features of the formation of DNA adducts in sulfur mustard-exposed skin

    Energy Technology Data Exchange (ETDEWEB)

    Batal, Mohamed [Laboratoire «Lésions des Acides Nucléiques», Université Joseph Fourier – Grenoble 1, CEA/Institut Nanoscience et Cryogénie/SCIB, UMR-E3, Grenoble (France); Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche (France); Boudry, Isabelle; Mouret, Stéphane; Wartelle, Julien; Emorine, Sandy; Bertoni, Marine [Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche (France); Bérard, Izabel [Laboratoire «Lésions des Acides Nucléiques», Université Joseph Fourier – Grenoble 1, CEA/Institut Nanoscience et Cryogénie/SCIB, UMR-E3, Grenoble (France); Cléry-Barraud, Cécile [Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche (France); and others

    2013-12-15

    Sulfur mustard (SM) is a chemical warfare agent that targets skin where it induces large blisters. DNA alkylation is a critical step to explain SM-induced cutaneous symptoms. We determined the kinetics of formation of main SM–DNA adducts and compare it with the development of the SM-induced pathogenesis in skin. SKH-1 mice were exposed to 2, 6 and 60 mg/kg of SM and treated skin was biopsied between 6 h and 21 days. Formation of SM DNA adducts was dose-dependent with a maximum immediately after exposure. However, adducts were persistent and still detectable 21 days post-exposure. The time-dependent formation of DNA adducts was also found to be correlated with the appearance of apoptotic cells. This temporal correlation suggests that these two early events are responsible for the severity of the damage to the skin. Besides, SM–DNA adducts were also detected in areas located next to contaminated zone, thus suggesting that SM diffuses in skin. Altogether, this work provides for the first time a clear picture of SM-induced genotoxicity using DNA adducts as a marker. - Highlights: • Sulfur mustard adducts are formed in DNA after skin exposure. • DNA damage formation is an early event in the pathological process of skin burn. • The amount of SM–DNA adducts is maximal at the earliest time point investigated. • Adducts are still detected 3 weeks after exposure. • Sulfur mustard diffuses in skin especially when large doses are applied.

  15. Correlation between Quadriceps Endurance and Adduction Moment in Medial Knee Osteoarthritis.

    Directory of Open Access Journals (Sweden)

    Soon-Hyuck Lee

    Full Text Available It is not clear whether the strength or endurance of thigh muscles (quadriceps and hamstring is positively or negatively correlated with the adduction moment of osteoarthritic knees. This study therefore assessed the relationships between the strength and endurance of the quadriceps and hamstring muscles and adduction moment in osteoarthritic knees and evaluated predictors of the adduction moment. The study cohort comprised 35 patients with unilateral medial osteoarthritis and varus deformity who were candidates for open wedge osteotomy. The maximal torque (60°/sec and total work (180°/sec of the quadriceps and hamstring muscles and knee adduction moment were evaluated using an isokinetic testing device and gait analysis system. The total work of the quadriceps (r = 0.429, P = 0.037 and hamstring (r = 0.426, P = 0.045 muscles at 180°/sec each correlated with knee adduction moment. Preoperative varus deformity was positively correlated with adduction moment (r = 0.421, P = 0.041. Multiple linear regression analysis showed that quadriceps endurance at 180°/sec was the only factor independently associated with adduction moment (β = 0.790, P = 0.032. The adduction moment of osteoarthritic knees correlated with the endurance, but not the strength, of the quadriceps muscle. However, knee adduction moment did not correlate with the strength or endurance of the hamstring muscle.

  16. Synthesis and Characterization of the Adducts of Bis(O-ethyldithiocarbonatocopper(II with Substituted Pyridines

    Directory of Open Access Journals (Sweden)

    Gurpreet Kour

    2013-01-01

    Full Text Available Monomeric five coordinated adducts of bis(O-ethyldithiocarbonatocopper(II of general formula [Cu(C2H5OCS22(L], [L = 2-, 3-, 4-methylpyridines and 2-, 3-, 4-ethylpyridines] have been synthesized and characterized by elemental analysis, i.r. and electronic spectroscopy, magnetic and conductivity measurements. Analytical results show that the adducts have 1 : 1 stoichiometry. The adducts were found to be paramagnetic and their magnetic moments at room temperature lie within the 1.81–1.94 B.M. range and this indicates the presence of one unpaired electron. All the adducts have distorted square pyramidal geometry.

  17. Regiochemically Controlled Synthesis of a β-4-β' [70]Fullerene Bis-Adduct.

    Science.gov (United States)

    Cerón, Maira R; Castro, Edison; Neti, Venkata S Pavan K; Dunk, Paul W; Echegoyen, Luis A

    2017-01-20

    A β-4-β' C 70 bis-adduct regioisomer and an uncommon mono-adduct β-malonate C 70 derivative were synthesized by using a Diels-Alder cycloaddition followed by an addition-elimination of bromo-ethylmalonate and a retro-Diels-Alder cycloaddition reaction. We also report the regioselective synthesis and spectroscopic characterization of C s -symmetric tris- and C 2v -symmetric tetra-adducts of C 70 , which are the precursors of the mono- and bis-adduct final products.

  18. Weight management including dietary and physical activity advice provided by Australian physiotherapists: a pilot cross-sectional survey.

    Science.gov (United States)

    Snodgrass, Suzanne J; Carter, Amy E; Guest, Maya; Collins, Clare E; James, Carole; Kable, Ashley K; Ashby, Samantha E; Plotnikoff, Ronald C

    2014-08-01

    Physiotherapists may have an impact on obesity prevention and treatment by providing nutrition and physical activity advice to overweight or obese clients; yet little is known about physiotherapists' beliefs and practices related to client weight management. The aim of this pilot study was to determine the practices, beliefs, attitudes and knowledge of physiotherapists regarding the provision of weight management advice to overweight or obese clients. Physiotherapists (n = 65) working in multiple practice settings completed a self-administered questionnaire. Logistic regression determined factors associated with the provision of dietary and physical activity advice for weight management. The majority of physiotherapists (n = 53 [81.5%]) believed providing weight management advice was within their scope of practice, yet only a minority had received training during their professional entry level education (n = 13 [20%]) or through professional development (n = 7 [11%]). Most physiotherapists (n = 55 [84.6%]) provided physical activity advice for weight management, but a minority (n = 27 [41.5%]) provided dietary advice. Having received training in weight management during their professional entry level education was associated with providing dietary advice (Odds ratio 8.8, 95% confidence interval 2.0-38.9, p = 0.004). Training in weight management may increase the likelihood of physiotherapists providing dietary advice, improving physiotherapists' management of obesity.

  19. In vitro screening of 50 highly prescribed drugs for thiol adduct formation--comparison of potential for drug-induced toxicity and extent of adduct formation.

    Science.gov (United States)

    Gan, Jinping; Ruan, Qian; He, Bing; Zhu, Mingshe; Shyu, Wen C; Humphreys, W Griffith

    2009-04-01

    Reactive metabolite formation has been associated with drug-induced liver, skin, and hematopoietic toxicity of many drugs that has resulted in serious clinical toxicity, leading to clinical development failure, black box warnings, or, in some cases, withdrawal from the market. In vitro and in vivo screening for reactive metabolite formation has been proposed and widely adopted in the pharmaceutical industry with the aim of minimizing the property and thus the risk of drug-induced toxicity (DIT). One of the most common screening methods is in vitro thiol trapping of reactive metabolites. Although it is well-documented that many hepatotoxins form thiol adducts, there is no literature describing the adduct formation potential of safer drugs that are widely used. The objective of this study was to quantitatively assess the thiol adduct formation potential of 50 drugs (10 associated with DIT and 40 not associated) and document apparent differences in adduct formation between toxic and safer drugs. Dansyl glutathione was used as a trapping agent to aid the quantitation of adducts following in vitro incubation of drugs with human liver microsomes in the presence and absence of NADPH. Metabolic turnover of these drugs was also monitored by LC/UV. Overall, 15 out of the 50 drugs screened formed detectable levels of thiol adducts. There were general trends toward more positive findings in the DIT group vs the non-DIT group. These trends became more marked when the relative amount of thiol adducts was taken into account and improved further when dose and total daily reactive metabolite burdens were considered. In conclusion, there appears to be a general trend between the extent of thiol adduct formation and the potential for DIT, which would support the preclinical measurement and minimization of the property through screening of thiol adduct formation as part of an overall discovery optimization paradigm.

  20. Inhibition of azoxymethane-induced DNA adduct formation by Aloe arborescens var. natalensis.

    Science.gov (United States)

    Shimpo, Kan; Chihara, Takeshi; Beppu, Hidehiko; Ida, Chikako; Kaneko, Takaaki; Hoshino, Motoyuki; Kuzuya, Hiroshi

    2003-01-01

    To clarify the possible mechanisms of inhibition of azoxymethane (AOM)-induced aberrant crypt foci (ACF) in the rat colorectum by freeze-dried whole leaves of Aloe arborescens var. natalensis (Kidachi aloe) (hereinafter referred to as ALOE) and commercial crude aloin (Sigma A-0451; from Curacao aloe) (hereinafter ALOIN), we studied the effects of ALOE and ALOIN on the formation of AOM-induced DNA adducts (O6-methylguanine; O6-MeG) in rats. Male F344 rats (4 weeks old) were fed a basal diet, or experimental diets containing 5%ALOE or 0.25%ALOIN for 5 weeks. All rats were injected s.c. twice with 15 mg/kg AOM, once at the end of week 1, and once at the end of week 2. The animals were sacrificed 6 hours after the second injection to analyze DNA adducts (O6-MeG) in the colorectum. Dietary administration of ALOE significantly inhibited the O6-MeG levels (50% reduction) compared with controls, whereas the O6-MeG levels in the ALOIN-fed rats showed a tendency to decrease (by 30%), although not significantly. In this study, we also measured the enzyme activity and mRNA level of cytochrome (CYP) 2E1, known to be responsible for the activation of AOM, in rat liver. ALOE-fed rats showed significantly reduced CYP2E1 enzymatic activity (27% reduction) compared with controls. On the other hand, the activity in ALOIN-fed rats tended to decrease by 11%, although not significantly. The CYP2E1 mRNA levels in ALOE- and ALOIN-fed rats were slightly reduced (9.7% and 5.2%, respectively). These results may explain, at least in part, the previously observed inhibitory effects of ALOE and ALOIN, especially ALOE on AOM-induced ACF formation in the rat colorectum.

  1. Extended automated separation techniques in destructive neutron activation analysis; application to various biological materials, including human tissues and blood

    International Nuclear Information System (INIS)

    Tjioe, P.S.; Goeij, J.J.M. de; Houtman, J.P.W.

    1976-09-01

    Neutron activation analysis may be performed as a multi-element and low-level technique for many important trace elements in biological materials, provided that post-irradiation chemical separations are applied. This paper describes a chemical separation consisting of automated procedures for destruction, distillation, and anion-chromatography. The system developed enables the determination of 14 trace elements in biological materials, viz. antimony, arsenic, bromine, cadmium, chromium, cobalt, copper, gold, iron, mercury, molybdenum, nickel, selenium, and zinc. The aspects of sample preparation, neutron irradiation, gamma-spectrum evaluation, and blank-value contribution are also discussed

  2. Age-related changes in trunk neuromuscular activation patterns during a controlled functional transfer task include amplitude and temporal synergies.

    Science.gov (United States)

    Quirk, D Adam; Hubley-Kozey, Cheryl L

    2014-12-01

    While healthy aging is associated with physiological changes that can impair control of trunk motion, few studies examine how spinal muscle responses change with increasing age. This study examined whether older (over 65 years) compared to younger (20-45 years) adults had higher overall amplitude and altered temporal recruitment patterns of trunk musculature when performing a functional transfer task. Surface electromyograms from twelve bilateral trunk muscle (24) sites were analyzed using principal component analysis, extracting amplitude and temporal features (PCs) from electromyographic waveforms. Two PCs explained 96% of the waveform variance. Three factor ANOVA models tested main effects (group, muscle and reach) and interactions for PC scores. Significant (pactivity, demonstrated continuous activation levels in specific muscle sites despite changing external moments, and had altered temporal synergies within abdominal and back musculature. In summary both older and younger adults recruit highly organized activation patterns in response to changing external moments. Differences in temporal trunk musculature recruitment patterns suggest that older adults experience different dynamic spinal stiffness and loading compared to younger adults during a functional lifting task. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Aromatic DNA adducts in human white blood cells and skin after dermal application of coal tar

    Energy Technology Data Exchange (ETDEWEB)

    Godschalk, R.W.L.; Ostertag, J.U.; Moonen, E.J.C.; Neumann, H.A.M.; Kleinjans, J.C.S.; Schooten, F.J. van [University of Maastricht, Maastricht (Netherlands). Dept. of Health Risk Analysis and Toxicology

    1998-09-01

    A group of eczema patients topically treated with coal tar (CT) ointments was used as a model population to examine the applicability of DNA adducts in white blood cell (WBC) subpopulations as a measure of dermal exposure to polycyclic aromatic hydrocarbons (PAHs). Aromatic DNA adducts were examined by {sup 32}P-postlabeling in exposed skin and WBC subsets, and urinary excretion of PAH metabolites was determined to assess the whole-body burden. The median urinary excretion of 1-hydroxypyrene and 3-hydroxybenzo(a)pyrene was 0.39 and 0.01 {mu}mol/mol creatinine respectively, before the dermal application of CT ointments. After treatment for 1 week, these levels increased to 139.7 and 1.18 {mu}mol/mol creatinine respectively, indicating that considerable amounts of PAHs were absorbed. Median aromatic DNA adduct levels were significantly increased in skin from 2.9 adduct/10{sup 8} nucleotides before treatment to 63.3 adducts/10{sup 8} nt after treatment with CT, in monocytes from 0.28 to 0.86 adducts/10{sup 8} nt, in lymphocytes from 0.33 to 0.89 adducts/10{sup 8} nt and in granulocytes from 0.28 to 0.54 adducts/10{sup 8} nt. A week after stopping the CT treatment, the DNA adduct levels in monocytes and granulocytes were reduced to 0.38 and 0.38 adducts/10{sup 8} nt respectively, whereas the adduct levels in lymphocytes remained enhanced. Total DNA adduct levels in skin correlated with the adduct levels in monocytes and lymphocytes. Excretion of urinary metabolites during the first week of treatment was correlated with the percentage of the skin surface treated with CT ointment and decreased within a week after the cessation of treatment. 3-Hydroxybenzo(a)pyrene excretion, correlated with the levels of DNA adducts in skin that comigrated with benzo(a)pyrene-diol-epoxide-DNA. This study indicates that the DNA adduct levels in mononuclear WBCs can possibly be used as a surrogate for skin DNA after dermal exposure to PAHs. 34 refs., 4 figs., 1 tab.

  4. Detection of Riddelliine-Derived DNA Adducts in Blood of Rats Fed Riddelliine

    Directory of Open Access Journals (Sweden)

    Ming W. Chou

    2002-09-01

    Full Text Available Abstract: We have previously shown that riddelliine, a naturally occurring genotoxic pyrrolizidine alkaloid, induces liver tumors in rats and mice through a genotoxic mechanism mediated by the formation of a set of eight 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5Hpyrrolizine ( DHP-derived DNA adducts. In this study we report the formation of these DHP-derived DNA adducts in blood DNA of rats fed riddelliine. In an adduct formation and removal experiment, male and female F344 rats (8 weeks of age were administered riddelliine by gavage at a single dose of 10.0 mg/kg body weight in 0.1 M phosphate buffer. At 8, 24, 48, and 168 hrs after dosing, the levels of DHP-derived DNA adduct in blood and liver were determined by 32P-postlabeling/HPLC. Maximum DNA adduct formation occurred at 48 hr after treatment. From 48 to 168 hours, the adduct levels in female rat blood were 4-fold greater than those in male rats. In a dose response experiment, female rats were gavaged 0.1 and 1.0 mg/kg doses of riddelliine for three consecutive days and the DHPderived DNA adducts in blood DNA were assayed. The levels of the DHP-derived DNA adducts in blood of rats receiving 0.1 and 1.0 mg/kg doses were 12.9 and 51.8 adducts/107 nucleotides. These results suggest that: (i leucocyte DNA can bind with DHP to form a set of DHP-derived DNA adducts generated in liver; (ii DHP-derived DNA adducts in blood can serve as a potential non-invasive biomarkers for assessing the exposure to riddelliine.

  5. Ellipticine oxidation and DNA adduct formation in human hepatocytes is catalyzed by human cytochromes P450 and enhanced by cytochrome b5.

    Science.gov (United States)

    Stiborová, Marie; Poljaková, Jitka; Martínková, Eva; Ulrichová, Jitka; Simánek, Vilím; Dvořák, Zdeněk; Frei, Eva

    2012-12-16

    Ellipticine is an antineoplastic agent considered a pro-drug, the pharmacological and genotoxic effects of which are dependent on cytochrome P450 (CYP)- and/or peroxidase-mediated activation to covalent DNA adducts. We investigated whether ellipticine-DNA adducts are formed in human hepatic microsomes and human hepatocytes. We then identified which human CYPs oxidize ellipticine to metabolites forming DNA adducts and the effect of cytochrome b(5) on this oxidation. 13-Hydroxyellipticine, the metabolite forming the major ellipticine-DNA adduct, was generated mainly by CYP3A4 and 1A1, followed by CYP2D6>2C19>1B1>1A2>2E1 and >2C9. Cytochrome b(5) increased formation of this metabolite by human CYPs, predominantly by CYP1A1, 3A4, 1A2 and 2C19. Formation of 12-hydroxyellipticine is generated mainly by CYP2C19, followed by CYP2C9>3A4>2D6>2E1 and >2A6. Other CYPs were less active (CYP2C8 and 2B6) or did not oxidize ellipticine to this metabolite (CYP1A1, 1A2 and 1B1). CYP2D6 was the most efficient enzyme generating ellipticine N(2)-oxide. CYP3A4 and 1A1 in the presence of cytochrome b(5) are mainly responsible for bioactivation of ellipticine to DNA adduct 1 (formed by ellipticine-13-ylium from 13-hydroxyellipticine), while 12-hydroxyellipticine generated during the CYP2C19-mediated ellipticine oxidation is the predominant metabolite forming ellipticine-12-ylium that generates ellipticine-DNA adduct 2. These ellipticine-DNA adducts were also generated by human hepatic microsomes and in primary human hepatocytes exposed to ellipticine. Ellipticine is toxic to these hepatocytes, decreasing their viability; the IC(50) value of ellipticine in these cells was 0.7 μM. In liver CYP3A4 is the predominant ellipticine activating CYP species, which is expected to result in efficient metabolism after oral ingestion of ellipticine in humans. Copyright © 2012. Published by Elsevier Ireland Ltd.

  6. Short-Range Temporal Interactions in Sleep; Hippocampal Spike Avalanches Support a Large Milieu of Sequential Activity Including Replay.

    Directory of Open Access Journals (Sweden)

    J Matthew Mahoney

    Full Text Available Hippocampal neural systems consolidate multiple complex behaviors into memory. However, the temporal structure of neural firing supporting complex memory consolidation is unknown. Replay of hippocampal place cells during sleep supports the view that a simple repetitive behavior modifies sleep firing dynamics, but does not explain how multiple episodes could be integrated into associative networks for recollection during future cognition. Here we decode sequential firing structure within spike avalanches of all pyramidal cells recorded in sleeping rats after running in a circular track. We find that short sequences that combine into multiple long sequences capture the majority of the sequential structure during sleep, including replay of hippocampal place cells. The ensemble, however, is not optimized for maximally producing the behavior-enriched episode. Thus behavioral programming of sequential correlations occurs at the level of short-range interactions, not whole behavioral sequences and these short sequences are assembled into a large and complex milieu that could support complex memory consolidation.

  7. Fullerene–Carbene Lewis Acid–Base Adducts

    KAUST Repository

    Li, Huaping

    2011-08-17

    The reaction between a bulky N-heterocylic carbene (NHC) and C60 leads to the formation of a thermally stable zwitterionic Lewis acid-base adduct that is connected via a C-C single bond. Low-energy absorption bands with weak oscillator strengths similar to those of n-doped fullerenes were observed for the product, consistent with a net transfer of electron density to the C60 core. Corroborating information was obtained using UV photoelectron spectroscopy, which revealed that the adduct has an ionization potential ∼1.5 eV lower than that of C60. Density functional theory calculations showed that the C-C bond is polarized, with a total charge of +0.84e located on the NHC framework and -0.84e delocalized on the C 60 cage. The combination of reactivity, characterization, and theoretical studies demonstrates that fullerenes can behave as Lewis acids that react with C-based Lewis bases and that the overall process describes n-doping via C-C bond formation. © 2011 American Chemical Society.

  8. Kinetics, mechanism and thermodynamics of bisulfite-aldehyde adduct formation

    Energy Technology Data Exchange (ETDEWEB)

    Olson, T.M.; Boyce, S.D.; Hoffmann, M.R.

    1986-04-01

    The kinetics and mechanism of bisulfite addition to benzaldehyde were studied at low pH in order to assess the importance of this reaction in stabilizing S(IV) in fog-, cloud-, and rainwater. Previously, the authors established that appreciable concentrations of the formaldehyde-bisulfite adduct (HMSA) are often present in fogwater. Measured HMSA concentrations in fogwater often do not fully account for observed excess S(IV) concentrations, however, so that other S(IV)-aldehyde adducts may be present. Reaction rates were determined by monitoring the disappearance of benzaldehyde by U.V. spectrophotometry under pseudo-first order conditions, (S(IV))/sub T/ >>(phi-CHO)/sub T/, in the pH range 0 - 4.4 at 25/sup 0/C. The equilibrium constant was determined by dissolving the sodium salt of the addition compound in a solution adjusted to pH 3.9, and measuring the absorbance of the equilibrated solution at 250 nm. A literature value of the extinction coefficient for benzaldehyde was used to calculate the concentration of free benzaldehyde. All solutions were prepared under an N/sub 2/ atmosphere using deoxygenated, deionized water and ionic strength was maintained at 1.0 M with sodium chloride.

  9. Environmental air pollution and DNA adducts in Copenhagen bus drivers - effect of GSTM1 and NAT2 genotypes on adduct level

    DEFF Research Database (Denmark)

    Nielsen, Per Sabro; de Pater, Nettie; Okkels, Henrik

    1996-01-01

    The lymphocyte bulky PAH-DNA adduct levels have been studied in persons occupationally exposed to ambient air pollution. The exposure group consisted of 90 healthy, nonsmoking bus drivers from the Copenhagen area, divided into three exposure groups according to driving area, and 60 rural controls...... (smokers and non-smokers). PAH-DNA adducts were determined by 32P-postlabelling with the butanol enrichment procedure. The bus drivers answered a comprehensive questionnaire on passive smoking, residential area, diet and other potential confounding variables. A significantly higher adduct level...... was observed in bus drivers working in central Copenhagen (1.214 fmol/microg DNA, n = 49) compared with both those driving in the dormitory (median: 0.507 fmol/microg DNA, P = 0.046, n = 16) and suburban (median: 0.585 fmol/microg DNA, P = 0.041, n = 25) areas. All three groups had higher adduct levels than...

  10. 40 CFR 721.3700 - Fatty acid, ester with styrenated phenol, ethylene oxide adduct.

    Science.gov (United States)

    2010-07-01

    ... phenol, ethylene oxide adduct. 721.3700 Section 721.3700 Protection of Environment ENVIRONMENTAL..., ethylene oxide adduct. (a) Chemical substances and significant new uses subject to reporting. (1) The chemical substance identified generically as fatty acid, ester with styrenated phenol, ethylene oxide...

  11. Distribution of DNA adducts in the respiratory tract of rats exposed to diesel exhaust

    International Nuclear Information System (INIS)

    Bond, J.A.; Wolff, R.K.; Harkema, J.R.; Mauderly, J.L.; Henderson, R.F.; Griffith, W.C.; McClellan, R.O.

    1988-01-01

    Diesel exhaust, Inhaled chronically at high concentrations, induced tumors that were located exclusively In the peripheral lung of rats. The purpose of this study was to determine if differences in the level of DNA adducts among the regions of the respiratory tract paralleled the site of tumors. Groups of male F344/N rats were exposed 7 h/day, 5 day/wk for 12 wk to diesel engine exhaust at a soot concentration of 10 mg/m 3 or were sham-exposed to air. Respiratory tract tissues were dissected and DNA was isolated from the dissected samples and analyzed for the presence of adducts using the 32 P-postlabeling assay. The highest level of total DNA adducts occurred In peripheral lung tissue (∼ 18 adducts per 10 9 bases). About 1/4 to 1/5 the level of DNA adducts was detected in the nasal tissues as in peripheral lung. There were less than 3 adducts per 10 9 bases n each of the regions of the major conducting airways (.e., trachea, bronchi, axial airway). The data from this study indicate that higher levels of total DNA adducts were present In tissues where exhaust-induced tumors were located. These data suggest that DNA adduct levels in discrete locations of the respiratory tract may be good measures of the 'effective dose' of carcinogenic compounds. (author)

  12. Inert Reassessment Document for Poly(oxyethylene) adducts of mixed phytosterols

    Science.gov (United States)

    Poly(oxyethy1ene) adducts of mixed phytosterols is uncategorized as to list classification status. Based upon the reasonable certainty of no harm safety finding, the List 4B classification for poly(oxyethy1ene) adducts of mixed phytosterols is affirmed.

  13. Abundance of DNA adducts of 4-oxo-2-alkenals, lipid peroxidation-derived highly reactive genotoxins.

    Science.gov (United States)

    Kawai, Yoshichika; Nuka, Erika

    2018-01-01

    Reactive oxygen species and their reaction products can damage DNA to form mutagenic lesions. Among the reactive species, lipid peroxidation-derived aldehydes react with nucleobases and form bulky exocyclic adducts. Many types of aldehyde-derived DNA adducts have been characterized, identified and detected in vitro and in vivo , whereas relative quantitative and pathophysiological contributions of each adduct still remain unclear. In recent years, an abundant class of DNA adducts derived from 4-oxo-2-alkenals have been identified, in addition to classic aldehyde-derived adducts. The presence of 4-oxo-2-alkenal-derived DNA adducts associated with age-related diseases has been revealed in rodents and humans. In vitro studies have demonstrated that 4-oxo-2-alkenals, as compared with other classes of lipid peroxidation-derived aldehydes, are highly reactive with nucleobases. It has been generally recognized that 4-oxo-2-alkenals are generated through oxidative degradation of the corresponding 4-hydroperoxy-2-alkenals, homolytic degradation products of polyunsaturated fatty acid hydroperoxides. Our recent results have also shown an alternative pathway for the formation of 4-oxo-2-alkenals, in which 2-alkenals could undergo the metal-catalyzed autoxidation resulting in the formation of the corresponding 4-oxo-2-alkenals. This review summarizes the basis of the formation of lipid peroxidation-derived genotoxic aldehydes and their covalent adduction to nucleobases, especially focusing on the abundance of 4-oxo-2-alkenal-derived DNA adducts.

  14. Immunochemical detection of sulfur mustard adducts with keratins in the stratum corneum of human skin

    NARCIS (Netherlands)

    Schans, G.P. van der; Noort, D.; Mars-Groenendijk, R.H.; Fidder, A.; Chau, L.F.; Jong, L.P.A. de; Benschop, H.P.

    2002-01-01

    As part of a program to develop methods for diagnosis of exposure to chemical warfare agents, we developed immunochemical methods for detection of adducts of sulfur mustard to keratin in human skin. Three partial sequences of keratins containing glutamine or asparagine adducted with a

  15. γIrradiation induced formation of PCB-solvent adducts in aliphatic solvents

    International Nuclear Information System (INIS)

    Lepine, F.; Milot, S.; Gagne, N.

    1990-01-01

    γIrradiation induced formation of PCB-solvent adducts was investigated as a model for PCB residues in irradiated food. Formation of cyclohexyl adducts of PCBs was found to be significant when pure PCB congeners and Aroclor mixture were irradiated in cyclohexane and cyclohexene. Reaction pathways were investigated, and the effects of oxygen and electron scavenger were studied

  16. Condensed tannin-resorcinol adducts and their use in wood-laminating adhesives: An exploratory study

    Science.gov (United States)

    Richard W. Hemingway; R.E. Kreibich

    1984-01-01

    The reaction of a tannin extract (containing about 30% carbohydrate) from loblolly pine (Pinus taeda L.) bark (two parts) and resorcinol (one part) at 120°C for 24 h with acetic acid catalyst gave a product containing predominantly oligomeric procyanidin-4-resorcinol adducts (39%), unreacted resorcinol (22%), carbohydrate (20%). the resorcinol adduct...

  17. Genetic polymorphisms in catalase and CYP1B1 determine DNA adduct formation by bento(a)pyrene ex vivo

    NARCIS (Netherlands)

    Schults, Marten A.; Chiu, Roland K.; Nagle, Peter; Kleinjans, J C; van Schooten, Frederik Jan; Godschalk, Roger W.

    Genetic polymorphisms can partially explain the large inter-individual variation in DNA adduct levels following exposure to polycyclic aromatic hydrocarbons. Effects of genetic polymorphisms on DNA adduct formation are difficult to assess in human studies because exposure misclassification

  18. Quantitation of 4,4′-methylene diphenyl diisocyanate human serum albumin adducts

    Directory of Open Access Journals (Sweden)

    Leah G. Luna

    2014-01-01

    Full Text Available 4,4′-Methylene diphenyl diisocyanate (herein 4,4′-MDI is used in the production of polyurethane foams, elastomers, coatings, adhesives and the like for a wide range of commercial products. Occupational exposure to MDI levels above current airborne exposure limits can elicit immune mediated hypersensitivity reactions such as occupational asthma in sensitive individuals. To accurately determine exposure, there has been increasing interest in developing analytical methods to measure internal biomarkers of exposure to MDI. Previous investigators have reported methodologies for measuring MDI diamine metabolites and MDI-Lysine (4,4′-MDI-Lys adducts. The purpose of this study was to develop and validate an ultra performance liquid chromatography isotope dilution tandem mass spectrometry (UPLC-ID/MS/MS quantitation method via a signature peptide approach to enable biomonitoring of 4,4′-MDI adducted to human serum albumin (HSA in plasma. A murine, anti-4,4′-MDI monoclonal IgM antibody was bound to magnetic beads and utilized for enrichment of the MDI adducted HSA. Following enrichment, trypsin digestion was performed to generate the expected 414 site (primary site of adduction 4,4′-MDI-adducted HSA signature peptide that was quantified by UPLC-ID/MS/MS. An Agilent 6530 UPLC/quadrupole time of flight MS (QTOF system was utilized for intact adducted protein analysis and an Agilent 6490 UPLC/MS/MS system operated in multiple reaction monitoring (MRM mode was utilized for quantification of the adducted signature peptide biomarker both for in chemico and worker serum samples. Worker serum samples were initially screened utilizing the previously developed 4,4′-MDI-Lys amino acid method and results showed that 12 samples were identified as quantifiable for 4,4′-MDI-Lys adducts. The signature peptide adduct approach was applied to the 12 worker samples identified as quantifiable for 4,4′-MDI-Lys adducts. Results indicated no positive results

  19. High water-stressed population estimated by world water resources assessment including human activities under SRES scenarios

    Science.gov (United States)

    Kiguchi, M.; Shen, Y.; Kanae, S.; Oki, T.

    2009-04-01

    In an argument of the reduction and the adaptation for the climate change, the evaluation of the influence by the climate change is important. When we argue in adaptation plan from a damage scale and balance with the cost, it is particularly important. Parry et al (2001) evaluated the risks in shortage of water, malaria, food, the risk of the coast flood by temperature function and clarified the level of critical climate change. According to their evaluation, the population to be affected by the shortage of water suddenly increases in the range where temperature increases from 1.5 to 2.0 degree in 2080s. They showed how much we need to reduce emissions in order to draw-down significantly the number at risk. This evaluation of critical climate change threats and targets of water shortage did not include the water withdrawal divided by water availability. Shen et al (2008a) estimated the water withdrawal of projection of future world water resources according to socio-economic driving factors predicted for scenarios A1b, A2, B1, and B2 of the Special Report on Emission Scenarios (SRES). However, these results were in function of not temperature but time. The assessment of the highly water-stressed population considered the socioeconomic development is necessary for a function of the temperature. Because of it is easy to understand to need to reduce emission. We present a multi-GCM analysis of the global and regional populations lived in highly water-stressed basin for a function of the temperature using the socioeconomic data and the outputs of GCMs. In scenario A2, the population increases gradually with warming. On the other hand, the future projection population in scenario A1b and B1 increase gradually until the temperature anomaly exceeds around from +1 to +1.5 degree. After that the population is almost constant. From Shen et al (2008b), we evaluated the HWSP and its ratio in the world with temperature function for scenarios A1B, A2, and B1 by the index of W

  20. Line narrowing spectroscopic studies of DNA-carcinogen adducts and DNA-dye complexes

    Energy Technology Data Exchange (ETDEWEB)

    Suh, Myungkoo [Iowa State Univ., Ames, IA (United States)

    1995-12-06

    Laser-induced fluorescence line narrowing and non-line narrowing spectroscopic methods were applied to conformational studies of stable DNA adducts of the 7β, 8α-dihydoxy-9α, l0α-epoxy-7,8,9, 10-tetrahydrobenzo[α]pyrene (anti-BPDE). Stereochemically distinct (+)-trans-, (-)-trans-, (+)-cis- and (-)-cis adducts of anti-BPDE bound to exocyclic amino group of the central guanine in an 11-mer oligonucleotide, exist in a mixture of conformations in frozen aqueous buffer matrices. The (+)-trans adduct adopts primarily an external conformation with a smaller fraction ( ~25 %) exists in a partially base-stacked conformation. Both cis adducts were found to be intercalated with significant π-π stacking interactions between the pyrenyl residues and the bases. Conformations of the trans-adduct of (+)-anti -BPDE in 11-mer oligonucleotides were studied as a function of flanking bases. In single stranded form the adduct at G2 or G3 (5 ft-flanking, base guanine) adopts a conformation with strong, interaction with the bases. In contrast, the adduct with a 5ft-flanking, thymine exists in a primarily helixexternal conformation. Similar differences were observed in the double stranded oligonucleotides. The nature of the 3ft-flanking base has little influence on the conformational equilibrium of the (+)-trans-anti BPDE-dG adduct. The formation and repair of BPDE-N2-dG in DNA isolated from the skin of mice treated topically with benzo[α]pyrene (BP) was studied. Low-temperature fluorescence spectroscopy of the intact DNA identified the major adduct as (+)-trans-anti-BPDE-N-dG, and the minor adduct fraction consisted mainly of (+)-cis-anti-BPDE-N2-dG.

  1. Line narrowing spectroscopic studies of DNA-carcinogen adducts and DNA-dye complexes

    International Nuclear Information System (INIS)

    Suh, Myungkoo.

    1995-01-01

    Laser-induced fluorescence line narrowing and non-line narrowing spectroscopic methods were applied to conformational studies of stable DNA adducts of the 7β, 8α-dihydoxy-9α, l0α-epoxy-7,8,9, 10-tetrahydrobenzo[α]pyrene (anti-BPDE). Stereochemically distinct (+)-trans-, (-)-trans-, (+)-cis- and (-)-cis adducts of anti-BPDE bound to exocyclic amino group of the central guanine in an 11-mer oligonucleotide, exist in a mixture of conformations in frozen aqueous buffer matrices. The (+)-trans adduct adopts primarily an external conformation with a smaller fraction ( ∼ 25 %) exists in a partially base-stacked conformation. Both cis adducts were found to be intercalated with significant π-π stacking interactions between the pyrenyl residues and the bases. Conformations of the trans-adduct of (+)-anti -BPDE in 11-mer oligonucleotides were studied as a function of flanking bases. In single stranded form the adduct at G 2 or G 3 (5 ft-flanking, base guanine) adopts a conformation with strong, interaction with the bases. In contrast, the adduct with a 5ft-flanking, thymine exists in a primarily helixexternal conformation. Similar differences were observed in the double stranded oligonucleotides. The nature of the 3ft-flanking base has little influence on the conformational equilibrium of the (+)-trans-anti BPDE-dG adduct. The formation and repair of BPDE-N 2 -dG in DNA isolated from the skin of mice treated topically with benzo[α]pyrene (BP) was studied. Low-temperature fluorescence spectroscopy of the intact DNA identified the major adduct as (+)-trans-anti-BPDE-N-dG, and the minor adduct fraction consisted mainly of (+)-cis-anti-BPDE-N 2 -dG

  2. Retrospective detection of sulfur mustard exposure by mass spectrometric analysis of adducts to albumin and hemoglobin: An in vivo study

    NARCIS (Netherlands)

    Noort, D.; Fidder, A.; Degenhardt-Langelaan, C.E.A.M.; Hulst, A.G.

    2008-01-01

    The persistence in rats of sulfur mustard adducts to albumin and hemoglobin was studied in vivo after exposure (intravenously; 0.3 mg/kg; approximately 0.1 LD50) of rats to sulfur mustard. The albumin adduct (S-HETE)Cys-Pro-Tyr was detectable up to 7 days after the exposure, while the adduct to the

  3. Stability, accumulation and cytotoxicity of an albumin-cisplatin adduct

    DEFF Research Database (Denmark)

    Møller, Charlotte; Tastesen, Hanne Sørup; Gammelgaard, Bente

    2010-01-01

    significant amount within 24 h incubation. The accumulation and cytotoxicity of HSA-Pt was compared to 10 µmol L¿¹ cisplatin for which a larger accumulation and cytotoxicity were observed in EATC compared to Lettré. The experiment was performed with cell medium exchange every fourth hour as HSA......-Pt and cisplatin were not stable in RPMI-1640 with 10% serum. The stability was determined using size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and after 4 h new platinum peaks were observed. These findings indicate that before conducting cell experiments, the stability......The accumulation and cytotoxicity of a 10 µmol L¿¹ equimolar human serum albumin-cisplatin adduct (HSA-Pt) was investigated in suspension Ehrlich Ascites Tumor Cells (EATC) and adherent Ehrlich Lettré Ascites Cells (Lettré). HSA-Pt did not induce apoptosis nor was it taken up by the cells to any...

  4. Vitamin A-aldehyde adducts: AMD risk and targeted therapeutics.

    Science.gov (United States)

    Sparrow, Janet R

    2016-04-26

    Although currently available treatment options for age-related macular degeneration (AMD) are limited, particularly for atrophic AMD, the identification of predisposing genetic variations has informed clinical studies addressing therapeutic options such as complement inhibitors and anti-inflammatory agents. To lower risk of early AMD, recommended lifestyle interventions such as the avoidance of smoking and the intake of low glycemic antioxidant-rich diets have largely followed from the identification of nongenetic modifiable factors. On the other hand, the challenge of understanding the complex relationship between aging and cumulative damage leading to AMD has fueled investigations of the visual cycle adducts that accumulate in retinal pigment epithelial (RPE) cells and are a hallmark of aging retina. These studies have revealed properties of these compounds that provide insights into processes that may compromise RPE and could contribute to disease mechanisms in AMD. This work has also led to the design of targeted therapeutics that are currently under investigation.

  5. Non Covalent Interactions and Internal Dynamics in Adducts of Freons

    Science.gov (United States)

    Caminati, Walther; Gou, Qian; Evangelisti, Luca; Feng, Gang; Spada, Lorenzo; Vallejo-López, Montserrat; Lesarri, Alberto; Cocinero, Emilio J.

    2014-06-01

    The complexation of chlorofluorocarbons (CFCs) with atmospheric water and pollutants of the atmosphere affects their reactivity and it seems to accelerate, for example, the decomposition rate of freons in the atmosphere [1]. For this reason we characterized shapes, stabilities, nature of the non-covalent interactions, structures and internal dynamics of a number of complexes of CFCs with water and of their dimers or oligomers by rotational spectroscopy. It has been found that hydrogenated CFCs form adducts with other molecules through weak hydrogen bonds (WHBs). Their C-H groups can act as proton donors, enhanced by the electron withdrawing of the halogen atoms, interacting with the electron rich regions of the partner molecules [2]. Also in adducts or oligomers of hydrogenated CFCs the monomer units are held together by nets of WHBs [3]. When CFCs are perhalogenated, the positive electrostatic region ("σ-hole") can interact electrostatically with negative sites of another, or of the same molecular entity, giving rise, according to IUPAC, to the so called halogen bond (HaB). However, it has been observed that when the perhalogenated CFCs has a Π electron system, a lone pair•••Π interaction (Bürgi-Dunitz) is favoured [4]. We describe here the HaBs that CF4 and CF3Cl form with a variety of partner molecules such as water, ammonia, dimethyl ether, etc. Important spectroscopic features outline strong dynamics effects taking place in this kind of complex. References [1] V. Vaida, H. G. Kjaergaard, K. J. Feierabend, Int. Rev. Phys. Chem. 22 (2003) 203. [2] See, for example: W. Caminati, S. Melandri, A. Maris, P. Ottaviani, Angew. Chem. Int. Ed. 45 (2006) 2438. [3] G. Feng, L. Evangelisti, I. Cacelli, L. Carbonaro, G. Prampolini, W. Caminati, Chem. Commun. 50 (2014) 171. [4] Q. Gou, G. Feng, L. Evangelisti, W. Caminati, Angew. Chem. Int. Ed. 52 (2013) 52 11888.

  6. Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation

    DEFF Research Database (Denmark)

    Mancini, Sarah J; White, Anna D; Bijland, Silvia

    2017-01-01

    Inflammation of adipose tissue in obesity is associated with increased IL-1β, IL-6 and TNF-α secretion and proposed to contribute to insulin resistance. AMP-activated protein kinase (AMPK) regulates nutrient metabolism and is reported to have anti-inflammatory actions in adipose tissue, yet the m...

  7. Measuring DNA nucleobase adducts using neutral hydrolysis and liquid chromatography-mass spectrometry.

    Science.gov (United States)

    Tarun, Maricar; Rusling, James F

    2005-01-01

    The detection and identification of DNA adducts is important for predicting human cancer risk posed by chemicals and for uncovering potential genotoxicity of new drug and agricultural chemical candidates. For compounds that react with DNA to form N7-guanine and/or N3-adenine adducts, neutral thermal hydrolysis provides a simple procedure for sample preparation. The N7-guanine and N3-adenine adducts are selectively ejected from the DNA chain, resulting in a clean sample matrix enriched in nucleobase adducts. Coupling neutral thermal hydrolysis with liquid chromatography-mass spectrometry (LC-MS) provides sensitive methods to detect and quantitate DNA adducts, and structural information is provided by MS. Combining these technologies with capillary liquid chromatography sample preconcentration systems can provide exquisitely sensitive detection. In this review, we first summarize the chemistry of nucleobase adduct formation, briefly summarize modern methods to detect DNA adducts, and then describe neutral thermal hydrolysis coupled to LC-MS/MS and some of its applications to DNA damage studies. Finally, we review recent applications of neutral thermal hydrolysis and LC-MS to toxicity screening of chemicals.

  8. Polycyclic aromatic hydrocarbon-DNA adducts and survival among women with breast cancer

    International Nuclear Information System (INIS)

    Sagiv, Sharon K.; Gaudet, Mia M.; Eng, Sybil M.; Abrahamson, Page E.; Shantakumar, Sumitra; Teitelbaum, Susan L.; Bell, Paula; Thomas, Joyce A.; Neugut, Alfred I.; Santella, Regina M.; Gammon, Marilie D.

    2009-01-01

    Polycyclic aromatic hydrocarbons (PAH) are mammary carcinogens in animal studies, and a few epidemiologic studies have suggested a link between elevated levels of PAH-DNA adducts and breast cancer incidence. An association between PAH-DNA adducts and survival among breast cancer cases has not been previously reported. We conducted a survival analysis among women with newly diagnosed invasive breast cancer between 1996 and 1997, enrolled in the Long Island Breast Cancer Study Project. DNA was isolated from blood samples that were obtained from cases shortly after diagnosis and assayed for PAH-DNA adducts using ELISA. Among the 722 cases with PAH-DNA adduct measurements, 97 deaths (13.4%) from all causes and 54 deaths (7.5%) due to breast cancer were reported to National Death Index (NDI) by December 31, 2002. Using Cox proportional hazards models and controlling for age at diagnosis, we did not find evidence that all-cause mortality (hazard ratio (HR)=0.88; 95% confidence interval (CI): 0.57-1.37), or breast cancer mortality (HR=1.20; 95% CI: 0.63-2.28) was strongly associated with detectable PAH-DNA adduct levels compared with non-detectable adducts; additionally, no dose-response association was observed. Among a subgroup with treatment data (n=520), adducts were associated with over a two-fold higher mortality among those receiving radiation, but mortality for adducts was reduced among hormone therapy users. Results from this large population-based study do not provide strong support for an association between detectable PAH-DNA adducts and survival among women with breast cancer, except perhaps among those receiving radiation treatment

  9. DNA-nicotine adduction of lung and liver of mice exposed to passive smoking studied by AMS

    International Nuclear Information System (INIS)

    Hou Qin; Sun Hongfang; Shi Jingyuan; Liu Yuanfang; Wang Jianjun; Lu Xiangyang; Li Kun; Zhao Qiang

    1997-01-01

    The author presents the measurement of adduction of mice lung or liver DNA with nicotine by accelerator mass spectrometry (AMS). Mice were exposed in a toxicity infecting chamber filled up with cigarette smoke for a period of time of simulate the exposure of mice to passive smoking. The dose of nicotine inhaled by mice was determined. The results of AMS showed, when the dose of inhaled nicotine ranged from 33 μg/kg to 330 μg/kg, the adducts number of lung DNA was 10 3 -10 4 adducts/10 12 nucleotides, and the adducts increased linearly with increasing dose of nicotine; the adducts number of liver DNA reached to 10 4 -10 5 adducts/10 12 nucleotides, when the dose of nicotine ranged from 99 μg/kg to 330 μg/kg, and the adducts increased vigorously as dose of nicotine increased. Comparing the DNA adducts levels of the same nicotine dose, liver DNA adducts were more than lung DNA adducts. This study also suggested that the other components of cigarette smoke have synergic effect on the formation of nicotine derived DNA adducts

  10. Replication of acetylaminofluorene-adducted plasmids in human cells: Spectrum of base substitutions and evidence of excision repair

    Energy Technology Data Exchange (ETDEWEB)

    Mah, M.C.; Boldt, J.; Maher, V.M.; McCormick, J.J. (Michigan State Univ., East Lansing (United States)); Culp, S.J. (National Center for Toxicological Research, Jefferson, AR (United States))

    1991-11-15

    In rats fed the liver carcinogen 2-acetylaminofluorene (AAF), the two most abundant types of DNA adduct are N-(deoxyguanosin-8-yl)-2-acetylaminofluorene and its deacetylated derivative. When plasmids carrying AAF adducts replicate in bacteria, the predominant mutations are frameshifts, whereas with deacetylated (AF) adducts, they are mainly base substitutions, just as the authors found when plasmids carrying AF adducts replicated in human cells. The authors have investigated the frequency and spectrum of mutations induced when a shuttle vector carrying AAF adducts (85% bound to the C8 position of guanine, 15% to the N{sup 2} position) replicated in human cells. The frequency induced per initial AAF adduct was higher than with AF adducts, but the kinds of mutations were similar - i.e., 85% base substitutions, principally G {center dot} C {yields} T {center dot} A transversions. There was good correlation between the hot spots for mutations and hot spots for AAF adduct formation, suggesting that mutational hot spots reflect preferential binding of the carcinogen to DNA. {sup 32}P-postlabeling analysis of the adducts before and after the DNA was transfected of AAF adducts and that 85% of both types of adducts were removed within 3.5 hours, most probably by excision repair.

  11. Pulse radiolysis studies of the interaction of tea polyphenol derivatives with oxidizing OH adduct of thymine

    International Nuclear Information System (INIS)

    Jiang Yue; Li Hucheng; Yao Side; Zuo Zhihua; Wang Zailan; Zhang Jiashan; Lin Nianyun

    1996-01-01

    The electron transfer reactions between oxidizing OH adduct of thymine with tea polyphenol derivatives has been investigated by pulse radiolysis. The tea polyphenol derivatives are identified as good antioxidants for reduction of oxidizing OH adducts of thymine. From buildup kinetic analysis of radical phenoxyl product, the rate constants for reactions of the N 3 radical with tea polyphenol derivatives have been determined to be (8-9) x 10 9 dm 3 /mol s, while the rate constants of electron transfer from tea polyphenol derivatives to oxidizing OH adducts of thymine was obtained to be around 10 9 dm 3 /mol s. Copyright direct C 1996 Elsevier Science Ltd

  12. Mutagenic replication in human cell extracts of DNA containing site-specific N-2-acetylaminofluorene adducts.

    OpenAIRE

    Thomas, D C; Veaute, X; Kunkel, T A; Fuchs, R P

    1994-01-01

    We have analyzed the effects of site-specific N-2-acetylaminofluorene (AAF) adducts on the efficiency and frameshift fidelity of bidirectional replication of double-stranded DNA in a human cell extract. Plasmid vectors were constructed containing the simian virus 40 origin of replication and single AAF adducts at one of three guanines in the Nar I sequence GGCGCC in a lacZ reporter gene. The presence of an AAF adduct diminishes replication efficiency in HeLa cell extracts by 70-80%. Replicati...

  13. Analysis of hemoglobin adducts from acrylamide, glycidamide, and ethylene oxide in paired mother/cord blood samples from Denmark

    DEFF Research Database (Denmark)

    von Stedingk, Hans; Vikström, Anna C; Rydberg, Per

    2011-01-01

    for analysis of Hb adducts by liquid chromatography-mass spectrometry, the adduct FIRE procedure, was applied to measurements of adducts from these compounds in maternal blood samples (n = 87) and umbilical cord blood samples (n = 219). The adduct levels from the three compounds, acrylamide, glycidamide......, and ethylene oxide, were increased in tobacco smokers. Highly significant correlations were found between cord and maternal blood with regard to measured adduct levels of the three compounds. The mean cord/maternal hemoglobin adduct level ratios were 0.48 (range 0.27-0.86) for acrylamide, 0.38 (range 0.......20-0.73) for glycidamide, and 0.43 (range 0.17-1.34) for ethylene oxide. In vitro studies with acrylamide and glycidamide showed a lower (0.38-0.48) rate of adduct formation with Hb in cord blood than with Hb in maternal blood, which is compatible with the structural differences in fetal and adult Hb. Together...

  14. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    Energy Technology Data Exchange (ETDEWEB)

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H

    2007-05-23

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  15. Including Youth with Intellectual Disabilities in Health Promotion Research: Development and Reliability of a Structured Interview to Assess the Correlates of Physical Activity among Youth

    Science.gov (United States)

    Curtin, Carol; Bandini, Linda G.; Must, Aviva; Phillips, Sarah; Maslin, Melissa C. T.; Lo, Charmaine; Gleason, James M.; Fleming, Richard K.; Stanish, Heidi I.

    2016-01-01

    Background: The input of youth with intellectual disabilities in health promotion and health disparities research is essential for understanding their needs and preferences. Regular physical activity (PA) is vital for health and well-being, but levels are low in youth generally, including those with intellectual disabilities. Understanding the…

  16. Correlation between base-excision repair gene polymorphisms and levels of in-vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes.

    Directory of Open Access Journals (Sweden)

    Hongping Yu

    Full Text Available In vitro benzo[a]pyrene diol epoxide (BPDE-induced DNA adducts in cultured peripheral lymphocytes have been shown to be a phenotypic biomarker of individual's DNA repair phenotype that is associated with cancer risk. In this study, we explored associations between genotypes of base-excision repair genes (PARP1 Val762Ala, APEX1 Asp148Glu, and XRCC1 Arg399Gln and in vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes in 706 cancer-free non-Hispanic white subjects. We found that levels of BPDE-induced DNA adducts were significantly higher in ever smokers than in never smokers and that individuals with the Glu variant genotypes (i.e., Asp/Glu and Glu/Glu exhibited lower levels of BPDE-induced DNA adducts than did individuals with the common Asp/Asp homozygous genotype (median RAL levels: 32.0 for Asp/Asp, 27.0 for Asp/Glu, and 17.0 for Glu/Glu, respectively; P(trend = 0.030. Further stratified analysis showed that compared with individuals with the common APEX1-148 homozygous Asp/Asp genotype, individuals with the APEX1-148Asp/Glu genotype or the Glu/Glu genotype had a lower risk of having higher-level adducts (adjusted OR = 0.60, 95% CI: 0.36-0.98 and adjusted OR = 0.47, 95% CI: 0.26-0.86, respectively; P(trend = 0.012 among smokers. Such an effect was not observed in non-smokers. However, there was no significant interaction between the APEX1 Asp148Glu polymorphism and smoking exposure in this study population (P = 0.512. Additional genotype-phenotype analysis found that the APEX1-148Glu allele had significantly increased expression of APEX1 mRNA in 270 Epstein-Barr virus-transformed lymphoblastoid cell lines, which is likely associated with more active repair activity. Our findings suggest that the functional APEX1-148Glu allele is associated with reduced risk of having high levels of BPDE-induced DNA adducts mediated with high levels of mRNA expression.

  17. Ruthenium—Arene Complexes Derived from NHC•CO2 and NHC•CS2 Zwitterionic Adducts and Their Use in Olefin Metathesis

    Science.gov (United States)

    Delaude, Lionel; Demonceau, Albert

    A range of imidazol(in)ium-2-carboxylates and -dithiocarboxylates bearing alkyl or aryl groups on their nitrogen atoms were prepared by reacting the corresponding N-heterocyclic carbenes (NHCs) with either carbon dioxide or carbon disulfide. All the zwitterionic products were characterized by various analytical techniques, including thermogravimetric analysis (TGA). Their ability to act as NHC ligand precursors for in situ catalytic applications was investigated in the ruthenium-promoted ring-opening metathesis polymerization (ROMP) of cyclo-octene. Upon exposure to the [RuCl2(p-cymene)]2 dimer, the NHC CO2 adducts readily dissociated to generate [RuCl2(p-cymene)(NHC)] complexes that were highly active catalyst precursors for olefin metathesis. Conversely, the NHC CS2 betaines retained their zwitterionic nature and led to new cationic complexes of the [RuCl(p-cymene)(NHC CS2)]+PF6 - type that were devoid of any significant catalytic activity in the reaction under consideration

  18. NEW THIO S2- ADDUCTS WITH ANTIMONY (III AND V HALIDE: SYNTHESIS AND INFRARED STUDY

    Directory of Open Access Journals (Sweden)

    HASSAN ALLOUCH

    2013-12-01

    Full Text Available Five new S2- adducts with SbIII and SbV halides have been synthesized and studied by infrared. Discrete structures have been suggested, the environment around the antimony being tetrahedral, trigonal bipyramidal or octahedral.

  19. Development of methods to measure hemoglobin adducts by gel electrophoresis - Preliminary results

    International Nuclear Information System (INIS)

    Sun, J.D.; McBride, S.M.

    1988-01-01

    Chemical adducts formed on blood hemoglobin may be a useful biomarker for assessing human exposures to these compounds. This paper reports preliminary results in the development of methods to measure such adducts that may be generally applicable for a wide variety of chemicals. Male F344/N rats were intraperitoneally injected with 14 C-BaP dissolved in corn oil. Twenty-four hours later, the rats were sacrificed. Blood samples were collected and globin was isolated. Globin protein was then cleaved into peptide fragments using cyanogen bromide and the fragments separated using 2-dimensional gel electrophoresis. The results showed that the adducted 14 C-globin fragments migrated to different areas of the gel than did unadducted fragments. Further research is being conducted to develop methods that will allow quantitation of separated adducted globin fragments from human blood samples without the use of a radiolabel. (author)

  20. Second vowel formant relationship to adduction: A preliminary study

    Science.gov (United States)

    Hanrahan, Kevin G.

    The relationship between the vocal tract and the larynx in the formation of vowels has been debated for decades. Vowels were first thought to have been formed in the larynx; then later it was believed that they were formed solely in the vocal tract. In the 1960s Fant formalized this belief into the Source-Filter Theory of Vowel Formation. The theory was interpreted by voice teachers to mean that the larynx had very little to do with the formation of vowels, and this interpretation has dominated voice teaching for decades. Recent research, however, is now suggesting that the larynx and the vocal tract are interactive with each other, meaning that a change of muscular function in the larynx will create a change of resonator function in the vocal tract, and vice versa. This conclusion is drawn mainly on the work of Titze, Story, Laukkanen, et.al. They have found that a relationship exists between laryngeal function and the first vowel formant (F1). When examining research on the second vowel formant (F2), this author discovered that there may be a relationship between F2 and adduction. Therefore, based on present evidence, it was hypothesized that an elevated frequency of F2 corresponded to an increase in adduction. The hypothesis was examined by comparing the resonance output and glottal closure between vowels where F2 was elevated and vowels without modification of F2. Subjects were asked to sing [i], [a], and [u] at a medium dynamic level on D4, G#4, and D5 for the female subjects and an octave below for the male subjects, once using a "generic" version of the vowel, meaning what they considered a "nice, easy, and generic" version of the vowel to be, and then again modifying the vowel to increase the frequency of the upper harmonics. Electroglottogram, pitch, intensity, and formant data were collected and compared. An increase in the frequency of F2 corresponded to an increase in the Closed Quotient (CQ), the length of time the vocal folds are closed, in a few

  1. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    Energy Technology Data Exchange (ETDEWEB)

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2012-11-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  2. Mass Spectrometric Characterization of Circulating Covalent Protein Adducts Derived from a Drug Acyl Glucuronide Metabolite: Multiple Albumin Adductions in Diclofenac Patients

    Science.gov (United States)

    Hammond, Thomas G.; Meng, Xiaoli; Jenkins, Rosalind E.; Maggs, James L.; Castelazo, Anahi Santoyo; Regan, Sophie L.; Bennett, Stuart N. L.; Earnshaw, Caroline J.; Aithal, Guruprasad P.; Pande, Ira; Kenna, J. Gerry; Stachulski, Andrew V.; Park, B. Kevin

    2014-01-01

    Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2–8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein’s 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug’s AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association. PMID:24902585

  3. Synthesis and structural studies of flavin and alloxazine adducts with O-nucleophiles

    Czech Academy of Sciences Publication Activity Database

    Ménová, P.; Eigner, V.; Čejka, J.; Dvořáková, H.; Šanda, Miloslav; Cibulka, R.

    2011-01-01

    Roč. 1004, 1/3 (2011), s. 178-187 ISSN 0022-2860 R&D Projects: GA ČR(CZ) GA203/07/1246 Institutional research plan: CEZ:AV0Z40550506 Keywords : alloxazine adducts * flavin adducts * flavoenzymes * X-ray structural analysis * NMR spectroscopy * UV-VIS spectroscopy Subject RIV: CC - Organic Chemistry Impact factor: 1.634, year: 2011

  4. Structure and Oxidation of Pyrrole Adducts Formed between Aflatoxin B2aand Biological Amines.

    Science.gov (United States)

    Rushing, Blake R; Selim, Mustafa I

    2017-06-19

    Aflatoxin B 2a has been shown to bind to proteins through a dialdehyde intermediate under physiological conditions. The proposed structure of this adduct has been published showing a Schiff base interaction, but adequate verification using structural elucidation instrumental techniques has not been performed. In this work, we synthesized the aflatoxin B 2a amino acid adduct under alkaline conditions, and the formation of a new product was determined using high performance liquid chromatography-time-of-flight mass spectrometry. The resulting accurate mass was used to generate a novel proposed chemical structure of the adduct in which the dialdehyde forms a pyrrole ring with primary amines rather than the previously proposed Schiff base interaction. The pyrrole structure was confirmed using 1 H, 13 C, correlation spectroscopy, heteronuclear single quantum correlation, and heteronuclear multiple bond correlation NMR and tandem mass spectrometry. Reaction kinetics show that the reaction is overall second order and that the rate increases as pH increases. Additionally, this study shows for the first time that aflatoxin B 2a dialdehyde forms adducts with phosphatidylethanolamines and does so through pyrrole ring formation, which makes it the first aflatoxin-lipid adduct to be structurally identified. Furthermore, oxidation of the pyrrole adduct produced a product that was 16 m/z heavier. When the aflatoxin B 2a -lysine (ε) adduct was oxidized, it gave a product with an accurate mass, mass fragmentation pattern, and 1 H NMR spectrum that match aflatoxin B 1 -lysine, which suggest the transformation of the pyrrole ring to a pyrrolin-2-one ring. These data give new insight into the fate and chemical properties of biological adducts formed from aflatoxin B 2a as well as possible interferences with known aflatoxin B 1 exposure biomarkers.

  5. Base-Resolution Analysis of Cisplatin–DNA Adducts at the Genome Scale

    OpenAIRE

    Shu, Xiaoting; Xiong, Xushen; Song, Jinghui; He, Chuan; Yi, Chengqi

    2016-01-01

    Cisplatin, one of the most widely used anticancer drugs, crosslinks DNA and ultimately induces cell death. However, the genomic pattern of cisplatin–DNA adducts has remained unknown owing to the lack of a reliable and sensitive genome-wide method. Herein we present “cisplatin-seq” to identify genome-wide cisplatin crosslinking sites at base resolution. Cisplatin-seq reveals that mitochondrial DNA is a preferred target of cisplatin. For nuclear genomes, cisplatin–DNA adducts are enriched withi...

  6. Correlation of tumors with DNA adducts from methyl eugenol and tamoxifen in rats.

    Science.gov (United States)

    Waddell, William J; Crooks, Neil H; Carmichael, Paul L

    2004-05-01

    Data on percent tumors in male rats after administration of methyl eugenol, obtained from the National Toxicology Program, or tamoxifen were plotted on a linear scale for percent tumors against the dose on a logarithmic scale. Data on (32)P-postlabelled DNA adducts were plotted on the same graphs for each of these two compounds in order to correlate adduct formation and tumor incidence with dose. The resulting graph for methyl eugenol showed a linear response for both adduct formation and tumor incidence. The threshold dose of administered methyl eugenol for adduct formation (zero adducts) was 10(19.3) molecules of methyl eugenol/kg/day, which compared with a threshold of 10(20.1) molecules of methyl eugenol/kg/day for tumor formation; however, 30 adducts/10(8) nucleotides was the threshold for tumor formation. The dose of tamoxifen for adduct formation fit an exponential plot slightly better than a linear plot, but reached minimal values close to the threshold of 10(18.7) molecules of tamoxifen/kg/day for tumor formation. These data confirm that tumor formation coincides with adduct formation and that both have thresholds, or at least reach minimal values, above levels to which humans are exposed. Although the threshold dose for tumor formation from tamoxifen is only about 10x above the dose received by women at risk for breast cancer, this should be an adequate safety margin. The safety factor for methyl eugenol is several orders of magnitude; therefore, there should be no cause for concern for humans at current levels of exposure.

  7. Mechanism-based inactivation of cytochromes P450 2E1 and 2E1 T303A by tert-butyl acetylenes: characterization of reactive intermediate adducts to the heme and apoprotein.

    Science.gov (United States)

    Blobaum, Anna L; Kent, Ute M; Alworth, William L; Hollenberg, Paul F

    2002-12-01

    The kinetics for the inactivation of cytochrome P450 2E1 and the mutant P450 2E1 T303A by tert-butyl acetylene (tBA) and tert-butyl 1-methyl-2-propynyl ether (tBMP) were investigated. The two acetylenes inactivated the 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) O-deethylation activity of purified rabbit P450s 2E1 and 2E1 T303A in a reconstituted system in a time-, concentration-, and NADPH-dependent manner. The K(I) values for the inactivation of P450s 2E1 and 2E1 T303A by tBA were 1.0 and 2.0 mM, the k(inact) values were 0.20 and 0.38 min(-)(1), and the t(1/2) values were 3.5 and 1.8 min, respectively. The K(I) values for the tBMP-inactivated P450s were 0.1 and 1.0 mM, the k(inact) values were 0.12 and 0.07 min(-)(1), and the t(1/)(2) values were 5.9 and 10.2 min, respectively. Losses in enzyme activity occurred with concurrent losses in the P450 CO spectrum and P450 heme, which were accompanied by the appearance of two different tBA- or tBMP-modified heme products in each inactivated sample. LC-MS analysis of the adducts showed masses of 661 or 705 Da, consistent with the mass of an iron-depleted heme plus the masses of a tBA or tBMP reactive intermediate and one oxygen atom, respectively. Only the tBA-inactivated P450 2E1 revealed a tBA-adducted apoprotein with an increase in mass of 99 Da, corresponding to the mass of tBA plus one oxygen atom. Surprisingly, the inactivation, CO spectral and heme loss, and heme adduct formation of the tBA-inactivated T303A mutant were completely reversible after dialysis. In addition, metabolism of para-nitrophenol was not compromised by the tBA-inactivated T303A mutant. Therefore, our studies on the inactivation of P450s 2E1 and 2E1 T303A by tBA and tBMP suggest the existence of three distinct mechanisms for inactivation, among which includes a novel, reversible heme alkylation that has not been previously described with P450 enzymes.

  8. DNA adduct profiling of in vitro colonic meat digests to map red vs. white meat genotoxicity.

    Science.gov (United States)

    Hemeryck, Lieselot Y; Rombouts, Caroline; De Paepe, Ellen; Vanhaecke, Lynn

    2018-02-16

    The consumption of red meat has been linked to an increased colorectal cancer (CRC) risk. One of the major hypotheses states that heme iron (present in red meat) stimulates the formation of genotoxic N-nitroso compounds (NOCs) and lipid peroxidation products (LPOs). By means of DNA adductomics, chemically induced DNA adduct formation can be mapped in relation to e.g. dietary exposures. In this study, this state-of-the-art methodology was used to investigate alkylation and (lipid per)oxidation induced DNA adduct formation in in vitro red vs. white meat digests. In doing so, 90 alkylation and (lipid per)oxidation induced DNA adduct types could be (tentatively) identified. Overall, 12 NOC- and/or LPO-related DNA adduct types, i.e. dimethyl-T (or ethyl-T), hydroxymethyl-T, tetramethyl-T, methylguanine (MeG), guanidinohydantoin, hydroxybutyl-C, hydroxymethylhydantoin, malondialdehyde-x3-C, O 6 -carboxymethylguanine, hydroxyethyl-T, carboxyethyl-T and 3,N 4 -etheno-C were singled out as potential heme-rich meat digestion markers. The retrieval of these DNA adduct markers is in support of the heme, NOC and LPO hypotheses, suggesting that DNA adduct formation may indeed contribute to red meat related CRC risk. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. DNA adduct quantification in Eisenia fetida after subchronic exposures to creosote contaminated soils

    Energy Technology Data Exchange (ETDEWEB)

    Charrois, J.W.A.; McGill, W.B. [Alberta Univ., Dept. of Renewable Resources, Edmonton, AB (Canada)

    1999-07-01

    Within soil ecosystems contaminant toxicity can vary from acute and chronic, depending on the time of exposure. Due to the long times involved chronic toxicity is difficult to determine. DNA adducts fall into the category of biochemical markers that act as an early warning system in environmental monitoring. It has been proposed that they could be used as a sensitive method to determine environmental exposures to compounds such as polycyclic aromatic hydrocarbons (PAHs), which can occur, although not exclusively, in creosote. In this connection, Benzo[a]pyrene (BaP) is a PAH that can be transformed into an electrophilic metabolite, which ultimately results in DNA adduct formation. Use was made of a 32P postlabeling method to quantify the number of DNA adducts occurring in the earthworm Eisenia fetida after exposure to weathered creosote contaminated- and biotreated-soils with and without additions of extra BaP. DNA adducts can be measured in earthworms exposed to creosote contaminated- and biotreated-soils. E. fetida exposed to weathered creosote contaminated soils had significantly more DNA adducts than those exposed to a pristine control soil. Exposures to creosote contaminated soils with additional BaP (1000 mg/kg) or biotreatment did not yield statistically significant increases in DNA adducts compared to the pristine control. (Abstract only)

  10. Scavenging of Toxic Acrolein by Resveratrol and Hesperetin and Identification of Adducts.

    Science.gov (United States)

    Wang, Weixin; Qi, Yajing; Rocca, James R; Sarnoski, Paul J; Jia, Aiqun; Gu, Liwei

    2015-11-04

    The objective of this study was to investigate the ability of resveratrol and hesperetin to scavenge acrolein at pH 7.4 and 37 °C. About 6.4 or 5.2% of acrolein remained after reaction with resveratrol or hesperetin for 12 h at equimolar concentrations. An acrolein-resveratrol adduct and two acrolein-hesperetin adducts were isolated. Their structures were elucidated using mass and NMR spectroscopy. Acrolein reacted with resveratrol at the C-2 and C-3 positions through nucleophilic addition and formed an additional heterocyclic ring. Two similar monoacrolein-conjugated adducts were identified for hesperetin. Spectroscopic data suggested each acrolein-hesperetin adduct was a mixture of four stereoisomers due to the existence of two chiral carbon atoms. Yield of adducts was low at pH 5.4 but increased at pH 7.4 and 8.4. Higher pH also promoted the formation of diacrolein adducts. Results suggest that resveratrol and hesperetin exert health benefits in part through neutralizing toxic acrolein in vivo.

  11. DYNAMIC HIP ADDUCTION, ABDUCTION AND ABDOMINAL EXERCISES FROM THE HOLMICH GROIN-INJURY PREVENTION PROGRAM ARE INTENSE ENOUGH TO BE CONSIDERED STRENGTHENING EXERCISES – A CROSS-SECTIONAL STUDY

    Science.gov (United States)

    Bandholm, Thomas; Jakobsen, Markus D.; Andersen, Lars L.; Serner, Andreas; Hölmich, Per; Thorborg, Kristian

    2017-01-01

    Background Training intensity is an important variable in strength training and above 80% of one repetition maximum is recommended for promoting strength for athletes. Four dynamic and two isometric on-field exercises are included in the Hölmich groin-injury prevention study that initially failed to show a reduction in groin injuries in soccer players. It has been speculated that exercise-intensity in this groin-injury prevention program was too low to induce the strength gains necessary to protect against groin-related injuries. Purpose To estimate the intensity of the six exercises from the Hölmich program using electromyography (EMG) and possibly categorize them as strength-training exercises. Study Design Cross-sectional study. Methods 21 adult male soccer players training >5 hours weekly were included. Surface-EMG was recorded from adductor longus, gluteus medius, rectus abdominis and external obliques during isometric adduction against a football placed between the ankles (IBA), isometric adduction against a football placed between the knees (IBK), folding knife (FK), cross-country skiing on one leg (CCS), adduction partner (ADP) and abduction partner (ABP). The EMG-signals were normalized (nEMG) to an isometric maximal voluntary contraction for each tested muscle. Results Adductor longus activity during IBA was 84% nEMG (95% CI: 70-98) and during IBK it was 118% nEMG (95% CI 106-130). For the dynamic exercises, ADP evoked 87% nEMG (95% CI 69-105) in adductor longus, ABP evoked 88% nEMG (95% CI 76-100) in gluteus medius, FK evoked 82% nEMG (95% CI 68-96) rectus abdominis, and 101% nEMG (95% CI 85-118) in external obliques. During CSS muscles. Conclusion These data suggest that exercise-intensity of all the six investigated exercises in the Hölmich groin injury prevention program, except cross-county skiing, is sufficient to be considered strength-training for specific muscle groups in and around the groin region. Level of Evidence 3 PMID:28593090

  12. Cellulose based hybrid hydroxylated adducts for polyurethane foams

    Science.gov (United States)

    De Pisapia, Laura; Verdolotti, Letizia; Di Mauro, Eduardo; Di Maio, Ernesto; Lavorgna, Marino; Iannace, Salvatore

    2012-07-01

    Hybrid flexible polyurethane foams (HPU) were synthesized by using a hybrid hydroxilated adduct (HHA) based on renewable resources. In particular the HHA was obtained by dispersing cellulose wastes in colloidal silica at room temperature, pressure and humidity. The colloidal silica was selected for its ability of modifying the cellulose structure, by inducing a certain "destructurization" of the crystalline phase, in order to allow cellulose to react with di-isocyanate for the final synthesis of the polyurethane foam. In fact, cellulose-polysilicate complexes are engaged in the reaction with the isocyanate groups. This study provides evidence of the effects of the colloidal silica on the cellulose structure, namely, a reduction of the microfiber cellulose diameter and the formation of hydrogen bonds between the polysilicate functional groups and the hydroxyl groups of the cellulose, as assessed by IR spectroscopy and solid state NMR. The HHA was added to a conventional polyol in different percentages (between 5 and 20%) to synthesize HPU in presence of catalysts, silicone surfactant and diphenylmethane diisocyanate (MDI). The mixture was expanded in a mold and cured for two hours at room temperature. Thermal analysis, optical microscopy and mechanical tests were performed on the foams. The results highlighted an improvement of thermal stability and a decrease of the cell size with respect neat polyurethane foam. Mechanical tests showed an improvement of the elastic modulus and of the damping properties with increasing HHA amount.

  13. Stability, accumulation and cytotoxicity of an albumin-cisplatin adduct.

    Science.gov (United States)

    Møller, Charlotte; Tastesen, Hanne Sørup; Gammelgaard, Bente; Lambert, Ian Henry; Stürup, Stefan

    2010-12-01

    The accumulation and cytotoxicity of a 10 μmol L⁻¹ equimolar human serum albumin-cisplatin adduct (HSA-Pt) was investigated in suspension Ehrlich Ascites Tumor Cells (EATC) and adherent Ehrlich Lettré Ascites Cells (Lettré). HSA-Pt did not induce apoptosis nor was it taken up by the cells to any significant amount within 24 h incubation. The accumulation and cytotoxicity of HSA-Pt was compared to 10 μmol L⁻¹ cisplatin for which a larger accumulation and cytotoxicity were observed in EATC compared to Lettré. The experiment was performed with cell medium exchange every fourth hour as HSA-Pt and cisplatin were not stable in RPMI-1640 with 10% serum. The stability was determined using size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and after 4 h new platinum peaks were observed. These findings indicate that before conducting cell experiments, the stability of the compound in the cell medium should be investigated especially when long exposure times are applied. Furthermore, HSA-Pt was found to be stable in Hanks Balanced Saline Solution (HBSS) and in Phosphate Buffered Saline (PBS) at pH 5.3, 6.1 and 7.4. Thus, the shift in pH when HSA-cisplatin passes from blood (pH 7.4) to tumor tissue (pH 5-6) is not capable of releasing cisplatin from HSA.

  14. Eukaryotic Catalase-Peroxidase: The Role of the Trp-Tyr-Met Adduct in Protein Stability, Substrate Accessibility, and Catalysis of Hydrogen Peroxide Dismutation.

    Science.gov (United States)

    Gasselhuber, Bernhard; Carpena, Xavi; Graf, Michael M H; Pirker, Katharina F; Nicolussi, Andrea; Sündermann, Axel; Hofbauer, Stefan; Zamocky, Marcel; Furtmüller, Paul G; Jakopitsch, Christa; Oostenbrink, Chris; Fita, Ignacio; Obinger, Christian

    2015-09-08

    Recently, it was demonstrated that bifunctional catalase-peroxidases (KatGs) are found not only in archaea and bacteria but also in lower eukaryotes. Structural studies and preliminary biochemical data of the secreted KatG from the rice pathogen Magnaporthe grisea (MagKatG2) suggested both similar and novel features when compared to those of the prokaryotic counterparts studied so far. In this work, we demonstrate the role of the autocatalytically formed redox-active Trp140-Tyr273-Met299 adduct of MagKatG2 in (i) the maintenance of the active site architecture, (ii) the catalysis of hydrogen peroxide dismutation, and (iii) the protein stability by comparing wild-type MagKatG2 with the single mutants Trp140Phe, Tyr273Phe, and Met299Ala. The impact of disruption of the covalent bonds between the adduct residues on the spectral signatures and heme cavity architecture was small. By contrast, loss of its integrity converts bifunctional MagKatG2 to a monofunctional peroxidase of significantly reduced thermal stability. It increases the accessibility of ligands due to the increased flexibility of the KatG-typical large loop 1 (LL1), which contributes to the substrate access channel and anchors at the adduct Tyr. We discuss these data with respect to those known from prokaryotic KatGs and in addition present a high-resolution structure of an oxoiron compound of MagKatG2.

  15. Limonene protects osteoblasts against methylglyoxal-derived adduct formation by regulating glyoxalase, oxidative stress, and mitochondrial function.

    Science.gov (United States)

    Suh, Kwang Sik; Chon, Suk; Choi, Eun Mi

    2017-12-25

    Methylglyoxal (MG) is a potent protein glycating agent and an important precursor of advanced glycation end products, which are involved in the pathogenesis of diabetic osteopathy. In this study, we investigated the effects of limonene on MG-induced damage in osteoblastic MC3T3-E1 cells. Pretreating cells with limonene prevented MG-induced protein adduct formation, tumor necrosis factor alpha and interleukin-6 release, mitochondrial superoxide production, and cardiolipin peroxidation. In addition, limonene increased glyoxalase I activity, and glutathione and heme oxygenase-1 levels in the presence of MG. Pretreatment with limonene prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation and adenosine triphosphate loss, and reduced the levels of adenosine monophosphate-activated protein kinase, peroxisome proliferator activated receptor γ coactivator 1α, and nitric oxide. These results demonstrate that limonene may prevent the development of diabetic osteopathy. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Acetonitrile/water gas-phase reaction products observed by use of atmospheric pressure chemical ionization: adducts formed with sulfonamides.

    Science.gov (United States)

    Ross, Charles W; Coddington, Arthur B; Murphy, Joan S; Wisnoski, David D; Zartman, C Blair; Ramjit, Harri G

    2005-01-01

    Electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) are the two most common mass spectrometric ionization methods used in the pharmaceutical industry. However, APCI analysis can sometimes lead to ambiguity in compound characterization and quantitation due to gas-phase reactions occurring between acetonitrile and water in the plasma, and between these plasma-generated compounds and the analyte. During the analysis of various sultams and sulfonamides we observed signals corresponding to m/z [M+44](+) and [M+60](+). Various solvent conditions and collisionally activated dissociation MS(n) experiments revealed that under the high-energy plasma conditions of APCI, the acetonitrile/water solvent mixture reacts undergoing acid-catalyzed hydrolysis producing acetamide, 59 Da. Further, the highly reactive 43 Da species ethanimine is also produced. These two compounds, normally not observed in APCI analysis, are stabilized by the sulfonamide and appear as adduct species in the mass spectra. The sulfone oxygens and the lone pair of electrons on the amide nitrogen play a role in stabilizing this adduct.

  17. The inflammatory/cancer-related IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and maintains the active state of breast myofibroblasts.

    Science.gov (United States)

    Hendrayani, Siti-Fauziah; Al-Harbi, Bothaina; Al-Ansari, Mysoon M; Silva, Gabriela; Aboussekhra, Abdelilah

    2016-07-05

    The IL-6/STAT3/NF-κB positive feedback loop links inflammation to cancer and maintains cells at a transformed state. Similarly, cancer-associated myofibroblats remains active even in absence of cancer cells. However, the molecular basis of this sustained active state remains elusive. We have shown here that breast cancer cells and IL-6 persistently activate breast stromal fibroblasts through the stimulation of the positive IL-6/STAT3/NF-κB feedback loop. Transient neutralization of IL-6 in culture inhibited this signaling circuit and reverted myofibrobalsts to a normalized state, suggesting the implication of the IL-6 autocrine feedback loop as well. Importantly, the IL-6/STAT3/NF-κB pro-inflammatory circuit was also active in cancer-associated fibroblasts isolated from breast cancer patients. Transient inhibition of STAT3 by specific siRNA in active fibroblasts persistently reduced the level of the RNA binding protein AUF1, blocked the loop and normalized these cells. Moreover, we present clear evidence that AUF1 is also part of this positive feedback loop. Interestingly, treatment of breast myofibroblasts with caffeine, which has been previously shown to persistently inhibit active breast stromal fibroblasts, blocked the positive feedback loop through potent and sustained inhibition of STAT3, AKT, lin28B and AUF1. These results indicate that the IL-6/STAT3/NF-κB positive feedback loop includes AUF1 and is responsible for the sustained active status of cancer-associated fibroblasts. We have also shown that normalizing myofibroblasts, which could be of great therapeutic value, is possible through the inhibition of this procarcinogenic circuit.

  18. S-(3-Aminobenzanthron-2-yl)cysteine in the globin of rats as a novel type of adduct and possible biomarker of exposure to 3-nitrobenzanthrone, a potent environmental carcinogen.

    Science.gov (United States)

    Linhart, Igor; Hanzlíková, Iveta; Mráz, Jaroslav; Dušková, Šárka

    2017-10-01

    3-Nitrobenzanthrone (3-NBA), a potent environmental mutagen and carcinogen, is known to be activated in vivo to 3-benzanthronylnitrenium ion which forms both NH and C2-bound adducts with DNA and also reacts with glutathione giving rise to urinary 3-aminobenzanthron-2-ylmercapturic acid. In this study, acid hydrolysate of globin from rats dosed intraperitoneally with 3-NBA was analysed by HPLC/MS to identify a novel type of cysteine adduct, 3-aminobenzanthron-2-ylcysteine (3-ABA-Cys), confirmed using a synthesised standard. The 3-ABA-Cys levels in globin peaked after single 3-NBA doses of 1 and 2 mg/kg on day 2 to attain 0.25 and 0.49 nmol/g globin, respectively, thereafter declining slowly to 70-80% of their maximum values during 15 days. After dosing rats for three consecutive days with 1 mg 3-NBA/kg a significant cumulation of 3-ABA-Cys in globin was observed. 3-ABA-Cys was also found in the plasma hydrolysate. Herein, after dosing with 1 and 2 mg 3-NBA/kg the adduct levels peaked on day 1 at 0.15 and 0.51 nmol/ml plasma, respectively, thereafter declining rapidly to undetectable levels on day 15. In addition, sulphinamide adducts were also found in the exposed rats, measured indirectly as 3-aminobenzanthrone (3-ABA) split off from globin by mild acid hydrolysis. Levels of both types of adducts in the globin samples parallelled very well with 3-ABA/3-ABA-Cys ratio being around 1:8. In conclusion, 3-ABA-Cys is the first example of arylnitrenium-cysteine adduct in globin representing a new promising class of biomarkers to assess cumulative exposures to aromatic amines, nitroaromatics and heteroaromatic amines.

  19. Effects of thiourea and ammonium bicarbonate on the formation and stability of bifunctional cisplatin-DNA adducts : consequences for the accurate quantification of adducts in (cellular) DNA

    NARCIS (Netherlands)

    Fichtinger-Schepman, A.M.J.; Dijk-Knijnenburg, H.C.M. van; Dijt, F.J.; Velde-Visser, S.D. van der; Berends, F.; Baan, R.A.

    1995-01-01

    Cisplatin reacts with DNA by forming mainly bifunctional adducts via reactive monofunctional intermediates. When freshly platinated DNA was postincubated with thiourea (10 mM, at 23 or 37°C) for periods of up to 24 h, followed by determination of mono- and diadducts, a rapid initial decrease was

  20. Ion mobility studies of carbohydrates as group I adducts: isomer specific collisional cross section dependence on metal ion radius.

    Science.gov (United States)

    Huang, Yuting; Dodds, Eric D

    2013-10-15

    Carbohydrates play numerous critical roles in biological systems. Characterization of oligosaccharide structures is essential to a complete understanding of their functions in biological processes; nevertheless, their structural determination remains challenging in part due to isomerism. Ion mobility spectrometry provides the means to resolve gas phase ions on the basis of their shape-to-charge ratios, thus providing significant potential for separation and differentiation of carbohydrate isomers. Here, we report on the determination of collisional cross sections for four groups of isomeric carbohydrates (including five isomeric disaccharides, four isomeric trisaccharides, two isomeric pentasaccharides, and two isomeric hexasaccharides) as their group I metal ion adducts (i.e., [M + Li](+), [M + Na](+), [M + K](+), [M + Rb](+), and [M + Cs](+)). In all, 65 collisional cross sections were measured, the great majority of which have not been previously reported. As anticipated, the collisional cross sections of the carbohydrate metal ion adducts generally increase with increasing metal ion radius; however, the collisional cross sections were found to scale with the group I cation size in isomer specific manners. Such measurements are of substantial analytical value, as they illustrate how the selection of charge carrier influences carbohydrate ion mobility determinations. For example, certain pairs of isomeric carbohydrates assume unique collisional cross sections upon binding one metal ion, but not another. On the whole, these data suggest a role for the charge carrier as a probe of carbohydrate structure and thus have significant implications for the continued development and application of ion mobility spectrometry for the distinction and resolution of isomeric carbohydrates.

  1. [Antibacterial actin of vinegar against food-borne pathogenic bacteria including Escherichia coli O157:H7 (Part 2). Effect of sodium chloride and temperature on bactericidal activity].

    Science.gov (United States)

    Entani, E; Asai, M; Tsujihata, S; Tsukamoto, Y; Ohta, M

    1997-05-01

    Bactericidal effects of various kinds of AWASEZU (processed vinegar, 2.5% acidity) on food-borne pathogenic bacteria including Escherichia coli O157:H7 and other bacteria were examined. the order of bactericidal activities was NIHAIZU (3.5% NaCl was added) > SANBA-IZU (3.5% NaCl and 10% sucrose were added) > plain vinegar (spirit vinegar) > AMAZU (10% sucrose was added). This indicates that their activities were enhanced by the addition of sodium chloride and suppressed by the addition of sugar. On the other hand, when soy sauce was used instead of sodium chloride, the order of bactericidal activities was plain vinegar > AMAZU > NIHAIZU > SANBAIZU. This is mainly because their activities were suppressed by the increase in the pH value. The effect of sodium chloride (0.01-15%) and temperature (10-50 degrees C) on bactericidal activities against E. coli O157:H7 in spirit vinegar (0.5-2.5% acidity) was further examined. When vinegar was used in combination with sodium chloride, predominant synergism on the bactericidal activity was observed. Their activities were markedly enhanced by the addition of sodium chloride in proportion to the concentration. In addition to this, at higher temperatures spirit vinegar killed bacteria much more rapidly. It should be noted that the bactericidal activity of spirit vinegar was extremely enhanced by the combined use of the addition of sodium chloride and the rise of temperature. For example, in 2.5% acidity vinegar, the time required for 3 log decrease in viable cell numbers at 20 degrees C was shortened to 1/140-fold by the addition of 5% sodium chloride, shortened to 1/51-fold by the rise of the reaction temperature at 40 degrees C, and shortened to 1/830-fold; 0.89 minutes by both the addition of 5% sodium chloride and the rise of temperature at 40 degrees C. In order to propose the methods to prevent food poisoning by bacterial infection, bactericidal activities of vinegar solution containing sodium chloride on cooking tools and

  2. Applying the Model of Goal-Directed Behavior, Including Descriptive Norms, to Physical Activity Intentions: A Contribution to Improving the Theory of Planned Behavior.

    Science.gov (United States)

    Esposito, Gabriele; van Bavel, René; Baranowski, Tom; Duch-Brown, Néstor

    2016-08-01

    The theory of planned behavior (TPB) has received its fair share of criticism lately, including calls for it to retire. We contribute to improving the theory by testing extensions such as the model of goal-directed behavior (MGDB, which adds desire and anticipated positive and negative emotions) applied to physical activity (PA) intention. We also test the inclusion of a descriptive norms construct as an addition to the subjective norms construct, also applied to PA, resulting in two additional models: TPB including descriptive norms (TPB + DN) and MGDB including descriptive norms (MGDB + DN). The study is based on an online survey of 400 young adult Internet users, previously enrolled in a subject pool. Confirmatory factor analysis (CFA) showed that TPB and TPB + DN were not fit for purpose, while MGDB and MGDB + DN were. Structural equation modelling (SEM) conducted on MGDB and MGDB + DN showed that the inclusion of descriptive norms took over the significance of injunctive norms, and increased the model's account of total variance in intention to be physically active. © The Author(s) 2016.

  3. Genetic modifiers of carcinogen DNA adducts in target lung and peripheral blood mononuclear cells.

    Science.gov (United States)

    Lee, Mi-Sun; Su, Li; Mark, Eugene J; Wain, John C; Christiani, David C

    2010-12-01

    Measurement of carcinogen DNA adducts in blood has been used as a surrogate for the target lung tissue. We aimed to examine whether genetic polymorphisms in several metabolic pathway genes modify the relation between DNA adducts in target lung and blood. One hundred and thirty-five early-stage lung cancer patients from the Massachusetts General Hospital were studied. DNA adducts were measured by the (32)P-postlabeling assay in lung and blood mononuclear cells (MNCs) in a subset of 53 who had paired blood samples. Single-nucleotide polymorphisms (SNPs) were assessed in genes involved in phase II (GSTs, NAT2, EPHX and NQO1), DNA repair (ERCC1, ERCC2 and XRCC1) and DNA methylation (MTHFR C677T and A1298C) pathways. There was a significant correlation between DNA adduct levels in lung and blood within the different genotypes, with one exception. Significant modifications in adducts were found by variants in genes for phase II metabolism [NAT2 (1.51 for rapid versus 0.76 for slow, P = 0.022)], DNA repair [ERCC1 C118T (P = 0.014), ERCC2 (P = 0.003) and XRCC1 (P = 0.025)] and MTHFR [C677T (P = 0.005) and A1298C (P = 0.005)]. The relation between DNA adducts in blood MNCs and target lung tissue was significantly modified by the single-nucleotide polymorphisms in the three main pathways. Despite the relatively small sample size, our results suggest that genetic factors may need to be considered when assessing the association of DNA adducts using surrogate tissue in studies of lung cancer. Further studies are needed to better understand their role and the mechanisms.

  4. Protective effects of selenium against DNA adducts formation in Inuit environmentally exposed to PCBs

    Science.gov (United States)

    Ravoori, Srivani; Srinivasan, Cidambi; Pereg, Daria; Robertson, Larry W; Ayotte, Pierre; Gupta, Ramesh C

    2012-01-01

    Dietary habits that expose populations to potential toxicants as well as protective agents simultaneously is a realistic scenario where a meaningful assessment of the interactions and net benefit or damage can be made. A group of Inuit from Salluit, Northern Canada are exposed to high levels of PCBs and selenium, both present in the Inuit traditional foods such as blubber from sea mammals and fatty fish. Blood samples were collected from 83 Inuit, 22–70 years old. Blood selenium and PCB levels were determined previously and ranged from 227 to 2,069 µg/L and 1.7 to 143 µg/L, respectively. DNA isolated from white blood cells were analyzed by modified 32P-postlabeling adductomics technology that detects a multitude of highly polar to lipophilic adducts. The levels of 8-oxodG adducts ranged from 470 to 7,400 adducts/109 nucleotides. Other as yet unidentified polar adducts showed a 30 to 800–fold inter-individual variability. Adduct levels were negatively associated with PCB and selenium levels. The subjects were classified into high and low ratio groups, with respect to selenium/PCB. In the high ratio group, the coefficient of selenium is significantly negatively correlated with 8-oxodG (r = −0.38, p = 0.014) and total adducts (r = −0.41, p = 0.009) while there was no correlation within the low selenium/PCB group. This study suggests increasing selenium has mitigating effect in reducing DNA adducts and therefore, possible negative effects of PCB were not rendered. A protective effect of selenium is highlighted. PMID:19735942

  5. Protonation reactions of electron adducts of acrylamide derivatives. A pulse radiolytic-kinetic spectrophotometric study

    International Nuclear Information System (INIS)

    Madhavan, V.; Lichtin, N.N.; Hayon, E.

    1974-01-01

    The absorption spectra of electron adducts of a number of α,β-unsaturated carboxamides and of methyl methacrylate, as well as of two isomeric types of protonated electron adducts, have been characterized by means of the technique of pulse radiolysis-kinetic absorption spectrophotometry. Spectra of the electron adducts are characterized by bands in the uv (epsilon/sub max/ approximately 10 4 M -1 cm -1 ) and in the visible (epsilon/sub max/ approximately 10 3 M -1 cm -1 ). The position of the uv band shifts 10--30 nm to shorter wavelength upon reversible protonation. Fast reversible protonation of electron adducts takes place at the carbonyl oxygen. The pK/sub a/ values of the electron adducts vary linearly with the pK/sub a/ values of the corresponding carboxylic acids: for acrylamide, 7.9; methacrylamide, 8.0; trans-crotonamide, 8.5; β,β-dimethylacrylamide, 9.5; N,N-dimethylacrylamide, 8.5; trans-cinnamamide, 7.2; methyl methacrylate, approximately7. Slower irreversible protonation of the electron adducts takes place at the β-carbon atom and is subject to general acid catalysis which obeys the Bronsted catalysis law. Uncatalyzed specific rates of β protonation of anion radicals (in units of 10 5 sec -1 ) are: for acrylamide, 1.4; for methacrylamide, 13; for trans-crotonamide, 0.22; for β,β-dimethylacrylamide, 0.21; for N,N-dimethylacrylamide, 3.7; for trans-cinnamamide, less than or equal to approximately .01; for methyl methacrylate, 4.5. The second-order decay of reversibly protonated electron adducts competes with irreversible β protonation. (U.S.)

  6. Comparative synchronous fluorescence spectrophotometry and 32P-postlabeling analysis of PAH-DNA adducts in human lung and the relationship to TP53 mutations

    DEFF Research Database (Denmark)

    Andreassen, Åshild; Kure, Elin H.; Nielsen, Per Sabro

    1996-01-01

    )-DNA adducts detected by SFS and the BPDE co-migrating spot detected by 32P-postlabeling. We have also analyzed the relationship between adduct levels and TP53 mutations. By postlabeling diagonal radioactive zone (DRZ) adducts were detected in 37 of 39 (95%) lung tissues from lung cancer patients......Polycyclic aromatic hydrocarbon (PAH)-DNA adducts were studied in human lung from 39 lung cancer patients by synchronous fluorescence spectrophotometric (SFS) and 32P-postlabeling assays. Regression analysis of the samples failed to detect any correlation between benzo[a]pyrene-diolepoxide (BPDE...... and the adduct level ranged from 6.81 to 108.50 adducts/10(8) nucleotide. Thirty-three of 39 (85%) had detectable levels of BPDE-DNA adducts (> 1 adduct/10(9) nucleotide). Current heavy smokers (> 20 cigarettes/day) have significantly higher DRZ adduct levels compared to individuals smoking less than 20...

  7. Reaction of aryne with aza-Morita–Baylis–Hillman adducts: Synthesis of 4-quinolones and N-arylation products

    Directory of Open Access Journals (Sweden)

    Li-Li Liu

    2017-05-01

    Full Text Available The reaction of aryne with aza-Morita–Baylis–Hillman (aza-MBH adducts has been studied. Aryne reacts with aza-MBH adducts through a cascade insertion–cyclization–ene reaction to produce 4-quinolones in 18–44% yields; meanwhile, aza-MBH adducts undergo N-insertion reaction with aryne to afford N-arylation products in 27–77% yields.

  8. Direct reduction of N-acetoxy-PhIP by tea polyphenols: a possible mechanism for chemoprevention against PhIP-DNA adduct formation

    International Nuclear Information System (INIS)

    Lin Dongxin; Thompson, Patricia A.; Teitel, Candee; Chen Junshi; Kadlubar, Fred F.

    2003-01-01

    The chemopreventive effect of tea against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adduct formation and its mechanism were studied. Rats were exposed to freshly prepared aqueous extracts of green tea (3% (w/v)) as the sole source of drinking water for 10 days prior to administration with a single dose of PhIP (10 mg/kg body weight) by oral gavage. PhIP-DNA adducts in the liver, colon, heart, and lung were measured using the 32 P-postlabelling technique. Rats pre-treated with tea and given PhIP 20 h before sacrifice had significantly reduced levels of PhIP-DNA adducts as compared with controls given PhIP alone. The possible mechanism of protective effect of tea on PhIP-DNA adduct formation was then examined in vitro. It was found that an aqueous extract of green and black tea, mixtures of green and black tea polyphenols, as well as purified polyphenols could strongly inhibit the DNA binding of N-acetoxy-PhIP, a putative ultimate carcinogen of PhIP formed in vivo via metabolic activation. Among these, epigallocatechin gallate was exceptionally potent. HPLC analyses of these incubation mixtures containing N-acetoxy-PhIP and the tea polyphenols each revealed the production of the parent amine, PhIP, indicating the involvement of a redox mechanism. In view of the presence of relatively high levels of tea polyphenols in rat and human plasma after ingestion of tea, this study suggests that direct reduction of the ultimate carcinogen N-acetoxy-PhIP by tea polyphenols is likely to be involved in the mechanism of chemoprotection of tea against this carcinogen

  9. Catalytic-site conformational equilibrium in nerve-agent adducts of acetylcholinesterase: possible implications for the HI-6 antidote substrate specificity.

    Science.gov (United States)

    Artursson, Elisabet; Andersson, Per Ola; Akfur, Christine; Linusson, Anna; Börjegren, Susanne; Ekström, Fredrik

    2013-05-01

    Nerve agents such as tabun, cyclosarin and Russian VX inhibit the essential enzyme acetylcholinesterase (AChE) by organophosphorylating the catalytic serine residue. Nucleophiles, such as oximes, are used as antidotes as they can reactivate and restore the function of the inhibited enzyme. The oxime HI-6 shows a notably low activity on tabun adducts but can effectively reactivate adducts of cyclosarin and Russian VX. To examine the structural basis for the pronounced substrate specificity of HI-6, we determined the binary crystal structures of Mus musculus AChE (mAChE) conjugated by cyclosarin and Russian VX and found a conformational mobility of the side chains of Phe338 and His447. The interaction between HI-6 and tabun-adducts of AChE were subsequently investigated using a combination of time resolved fluorescence spectroscopy and X-ray crystallography. Our findings show that HI-6 binds to tabun inhibited Homo sapiens AChE (hAChE) with an IC50 value of 300μM and suggest that the reactive nucleophilic moiety of HI-6 is excluded from the phosphorus atom of tabun. We propose that a conformational mobility of the side-chains of Phe338 and His447 is a common feature in nerve-agent adducts of AChE. We also suggest that the conformational mobility allow HI-6 to reactivate conjugates of cyclosarin and Russian VX while a reduced mobility in tabun conjugated AChE results in steric hindrance that prevents efficient reactivation. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Hip abduction-adduction strength and one-leg hop tests: test-retest reliability and relationship to function in elite ice hockey players.

    Science.gov (United States)

    Kea, J; Kramer, J; Forwell, L; Birmingham, T

    2001-08-01

    Single group, test-retest. To determine: (1) hip abduction and adduction torques during concentric and eccentric muscle actions, (2) medial and lateral one-leg hop distances, (3) the test-retest reliability of these measurements, and (4) the relationship between isokinetic measures of hip muscle strength and hop distances in elite ice hockey players. The skating motion used in ice hockey requires strong contractions of the hip and knee musculature. However, baseline scores for hip strength and hop distances, their test-retest reliability, and measures of the extent to which these tests are related for this population are not available. The dominant leg of 27 men (mean age 20 +/- 3 yrs) was tested on 2 occasions. Hip abduction and adduction movements were completed at 60 degrees.s(-1) angular velocity, with the subject lying on the non-test side and the test leg moving vertically in the subject's coronal plane. One-leg hops requiring jumping from and landing on the same leg without losing balance were completed in the medial and lateral directions. Hip adduction torques were significantly greater than abduction torques during both concentric and eccentric muscle actions, while no significant difference was observed between medial and lateral hop distances. Although hop test scores produced excellent ICCs (> 0.75) when determined using scores on 1 occasion, torques needed to be averaged over 2 test occasions to reach this level. Correlations between the strength and hop tests ranged from slight to low (r = -0.26 to 0.27) and were characterized by wide 95% confidence intervals (-0.54 to 0.61). Isokinetic tests of hip abduction and adduction did not provide a strong indication of performance during sideways hop tests. Although isokinetic tests can provide a measure of muscular strength under specific test conditions, they should not be relied upon as a primary indicator of functional abilities or readiness to return to activity.

  11. Conformational sensitivity of conjugated poly(ethylene oxide)-poly(amidoamine) molecules to cations adducted upon electrospray ionization – A mass spectrometry, ion mobility and molecular modeling study

    Energy Technology Data Exchange (ETDEWEB)

    Tintaru, Aura [Aix-Marseille Université – CNRS, UMR 7273, Institut de Chimie Radicalaire, Marseille (France); Chendo, Christophe [Aix-Marseille Université – CNRS, FR 1739, Fédération des Sciences Chimiques de Marseille, Spectropole, Marseille (France); Wang, Qi [Aix-Marseille Université – CNRS, UMR 6114, Centre Interdisciplinaire de Nanosciences de Marseille, Marseille (France); Viel, Stéphane [Aix-Marseille Université – CNRS, UMR 7273, Institut de Chimie Radicalaire, Marseille (France); Quéléver, Gilles; Peng, Ling [Aix-Marseille Université – CNRS, UMR 6114, Centre Interdisciplinaire de Nanosciences de Marseille, Marseille (France); Posocco, Paola [University of Trieste, Molecular Simulation Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), Trieste (Italy); National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste (Italy); Pricl, Sabrina, E-mail: sabrina.pricl@di3.units.it [University of Trieste, Molecular Simulation Engineering (MOSE) Laboratory, Department of Engineering and Architecture (DEA), Trieste (Italy); National Interuniversity Consortium for Material Science and Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste (Italy); Charles, Laurence, E-mail: laurence.charles@univ-amu.fr [Aix-Marseille Université – CNRS, UMR 7273, Institut de Chimie Radicalaire, Marseille (France)

    2014-01-15

    Graphical abstract: -- Highlights: •ESI-MS/MS, IMS and molecular modeling were combined to study PEO-PAMAM conformation. •Protonated and lithiated molecules were studied, with charge states from 2 to 4. •Protonation mostly occurred on PAMAM, with PEO units enclosing the protonated group. •Lithium adduction on PEO units lead to more expanded conformations. •Charge location strongly influenced PEO-PAMAM dissociation behavior. -- Abstract: Tandem mass spectrometry and ion mobility spectrometry experiments were performed on multiply charged molecules formed upon conjugation of a poly(amidoamine) (PAMAM) dendrimer with a poly(ethylene oxide) (PEO) linear polymer to evidence any conformational modification as a function of their charge state (2+ to 4+) and of the adducted cation (H{sup +}vs Li{sup +}). Experimental findings were rationalized by molecular dynamics simulations. The G0 PAMAM head-group could accommodate up to three protons, with protonated terminal amine group enclosed in a pseudo 18-crown-6 ring formed by the PEO segment. This particular conformation enabled a hydrogen bond network which allowed long-range proton transfer to occur during collisionally activated dissociation. In contrast, lithium adduction was found to mainly occur onto oxygen atoms of the polyether, each Li{sup +} cation being coordinated by a 12-crown-4 pseudo structure. As a result, for the studied polymeric segment (M{sub n} = 1500 g mol{sup −1}), PEO-PAMAM hybrid molecules exhibited a more expanded shape when adducted to lithium as compared to proton.

  12. Mechanism of Error-Free Bypass of the Environmental Carcinogen N-(2'-Deoxyguanosin-8-yl)-3-aminobenzanthrone Adduct by Human DNA Polymerase η.

    Science.gov (United States)

    Patra, Amritraj; Politica, Dustin A; Chatterjee, Arindom; Tokarsky, E John; Suo, Zucai; Basu, Ashis K; Stone, Michael P; Egli, Martin

    2016-11-03

    The environmental pollutant 3-nitrobenzanthrone produces bulky aminobenzanthrone (ABA) DNA adducts with both guanine and adenine nucleobases. A major product occurs at the C8 position of guanine (C8-dG-ABA). These adducts present a strong block to replicative polymerases but, remarkably, can be bypassed in a largely error-free manner by the human Y-family polymerase η (hPol η). Here, we report the crystal structure of a ternary Pol⋅DNA⋅dCTP complex between a C8-dG-ABA-containing template:primer duplex and hPol η. The complex was captured at the insertion stage and provides crucial insight into the mechanism of error-free bypass of this bulky lesion. Specifically, bypass involves accommodation of the ABA moiety inside a hydrophobic cleft to the side of the enzyme active site and formation of an intra-nucleotide hydrogen bond between the phosphate and ABA amino moiety, allowing the adducted guanine to form a standard Watson-Crick pair with the incoming dCTP. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Outcomes of medialization laryngoplasty with and without arytenoid adduction.

    Science.gov (United States)

    Chang, Joseph; Schneider, Sarah L; Curtis, James; Langenstein, Jonelyn; Courey, Mark S; Yung, Katherine C

    2017-11-01

    To evaluate the effect of medialization laryngoplasty (ML) performed alone compared to ML with arytenoid adduction (AA) on glottic gap and voice quality in unilateral vocal fold paralysis (UVFP) patients. Retrospective case series. UVFP patients treated with ML alone and ML with AA at the University of California San Francisco Voice and Swallowing Center were identified. Demographic information and history of laryngeal procedures were collected. Preoperative and postoperative examinations were digitally analyzed using ImageJ for normalized anterior and posterior glottic gap and voice samples graded with CAPE-V scores. Forty-seven patients underwent ML and 27 patients underwent ML with AA. Normalized anterior gap (AG) improved in both ML (preop: 4.4 pixel units (u), postop: 0.8 u; P < 0.001) and ML with AA groups (preop: 3.3 u, postop 0.6 u; P < 0.001). There was no statistically significant difference in normalized AG values between treatment groups. Postoperative normalized posterior gap (PG) improved in the ML with AA group only (preop: 1.8 u, postop: 0.5 u; P = 0.01). Overall severity, roughness, and strain voice parameters had acceptable reliability for analysis. Overall severity improved in ML (preop: 54, postop: 27; P < 0.001) and ML with AA (preop: 44, postop: 24; P = 0.005). There was no statistically significant difference in any voice parameter between treatment groups. UVFP patients undergoing ML may benefit from addition of AA when a large posterior glottic gap is present. In this study, ML with AA but not ML alone resulted in statistically significant improvement in PG. 4. Laryngoscope, 127:2591-2595, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  14. Wakame and Nori in restructured meats included in cholesterol-enriched diets affect the antioxidant enzyme gene expressions and activities in Wistar rats.

    Science.gov (United States)

    Moreira, Adriana Schultz; González-Torres, Laura; Olivero-David, Raul; Bastida, Sara; Benedi, Juana; Sánchez-Muniz, Francisco J

    2010-09-01

    The effects of diets including restructured meats (RM) containing Wakame or Nori on total liver glutathione status, and several antioxidant enzyme gene expressions and activities were tested. Six groups of ten male growing Wistar rats each were fed a mix of 85% AIN-93 M diet and 15% freeze-dried RM for 35 days. The control group (C) consumed control RM, the Wakame (W) and the Nori (N) groups, RM with 5% Wakame and 5% Nori, respectively. Animals on added cholesterol diets (CC, CW, and CN) consumed their corresponding basal diets added with cholesterol (2%) and cholic acid (0.4%). Alga and dietary cholesterol significantly interact (P Nori-RM is a hypocholesterolemic food while Wakame-RM is an antioxidant food. This should be taken into account when including this kind of RM as potential functional foods in human.

  15. Kinetic structure of large-conductance Ca2+-activated K+ channels suggests that the gating includes transitions through intermediate or secondary states. A mechanism for flickers.

    Science.gov (United States)

    Rothberg, B S; Magleby, K L

    1998-06-01

    Mechanisms for the Ca2+-dependent gating of single large-conductance Ca2+-activated K+ channels from cultured rat skeletal muscle were developed using two-dimensional analysis of single-channel currents recorded with the patch clamp technique. To extract and display the essential kinetic information, the kinetic structure, from the single channel currents, adjacent open and closed intervals were binned as pairs and plotted as two-dimensional dwell-time distributions, and the excesses and deficits of the interval pairs over that expected for independent pairing were plotted as dependency plots. The basic features of the kinetic structure were generally the same among single large-conductance Ca2+-activated K+ channels, but channel-specific differences were readily apparent, suggesting heterogeneities in the gating. Simple gating schemes drawn from the Monod- Wyman-Changeux (MWC) model for allosteric proteins could approximate the basic features of the Ca2+ dependence of the kinetic structure. However, consistent differences between the observed and predicted dependency plots suggested that additional brief lifetime closed states not included in MWC-type models were involved in the gating. Adding these additional brief closed states to the MWC-type models, either beyond the activation pathway (secondary closed states) or within the activation pathway (intermediate closed states), improved the description of the Ca2+ dependence of the kinetic structure. Secondary closed states are consistent with the closing of secondary gates or channel block. Intermediate closed states are consistent with mechanisms in which the channel activates by passing through a series of intermediate conformations between the more stable open and closed states. It is the added secondary or intermediate closed states that give rise to the majority of the brief closings (flickers) in the gating.

  16. Differential immune responses to albumin adducts of reactive intermediates of trichloroethene in MRL+/+ mice

    International Nuclear Information System (INIS)

    Cai Ping; Koenig, Rolf; Khan, M. Firoze; Kaphalia, Bhupendra S.; Ansari, G.A.S.

    2007-01-01

    Trichloroethene (TCE) is an industrial degreasing solvent and widespread environmental contaminant. Exposure to TCE is associated with autoimmunity. The mode of action of TCE is via its oxidative metabolism, and most likely, immunotoxicity is mediated via haptenization of macromolecules and subsequent induction of immune responses. To better understand the role of protein haptenization through TCE metabolism, we immunized MRL+/+ mice with albumin adducts of various TCE reactive intermediates. Serum immunoglobulins and cytokine levels were measured to determine immune responses against haptenized albumin. We found antigen-specific IgG responses of the IgG subtypes IgG 1 , IgG 2a , and IgG 2b , with IgG 1 predominating. Serum levels of G-CSF were increased in immunized mice, suggesting macrophage activation. Liver histology revealed lymphocyte infiltration in the lobules and the portal area following immunization with formyl-albumin. Our findings suggest that proteins haptenized by metabolites of TCE may act as neo-antigens that can induce humoral immune responses and T cell-mediated hepatitis

  17. SYNTHESIS AND PHARMACOLOGICAL EFFECTS OF BUTADIENE AND CYCLOPENTADIENE ADDUCTS OF METHANDROSTENOLONE IN RATS

    Directory of Open Access Journals (Sweden)

    FAZEL SHAMSA

    2006-06-01

    Full Text Available In this study the reactivity of methandrostenolone or [(17b-17-hydroxy-17-methylandrosta-1, 4-diene-3-one], as a dienophil in a Diels-Alder type cycloaddition reaction was investigated. The purpose of this approach was to investigate whether the 1-dehydro position of methandrostenolone 1 undergoes a cycloaddition reaction with dienes, such as 1, 3 butadiene or cyclopentadiene, and to investigate the biological behavior of the reaction adducts, i.e, compound 3 {(17b-17-hydroxy-17-methyl androsta [1a, 2a] cyclohex 3’, 4-diene-3-one} and compound 4 {(17b-17-hydroxy-17-methyl androsta [1a, 2a] cyclohex (2’,5’ methylene 3’, 4-diene-3-one}, relative to compound 1. The results indicated that thedDiels-Alder reactionddid notpproceed under the usual circumstances of high pressure and temperature, but could proceed in the presence of a Lewis acid (AlCl3. The structures of compounds 3 and 4 were confirmed by spectroscopic methods. The androgenic behavior of compounds 3 and 4 in comparison to compound 1 in the apomorphine test indicated that both compounds were almost devoid of androgenic activity, but prevented apomorphine mediated penile erection in male rats in a similar manner as cyproterone acetate.

  18. Optical modulator including grapene

    Science.gov (United States)

    Liu, Ming; Yin, Xiaobo; Zhang, Xiang

    2016-06-07

    The present invention provides for a one or more layer graphene optical modulator. In a first exemplary embodiment the optical modulator includes an optical waveguide, a nanoscale oxide spacer adjacent to a working region of the waveguide, and a monolayer graphene sheet adjacent to the spacer. In a second exemplary embodiment, the optical modulator includes at least one pair of active media, where the pair includes an oxide spacer, a first monolayer graphene sheet adjacent to a first side of the spacer, and a second monolayer graphene sheet adjacent to a second side of the spacer, and at least one optical waveguide adjacent to the pair.

  19. Elucidating the Key Role of a Lewis Base Solvent in the Formation of Perovskite Films Fabricated from the Lewis Adduct Approach.

    Science.gov (United States)

    Cao, Xiaobing; Zhi, Lili; Li, Yahui; Fang, Fei; Cui, Xian; Yao, Youwei; Ci, Lijie; Ding, Kongxian; Wei, Jinquan

    2017-09-27

    High-quality perovskite films can be fabricated from Lewis acid-base adducts through molecule exchange. Substantial work is needed to fully understand the formation mechanism of the perovskite films, which helps to further improve their quality. Here, we study the formation of CH 3 NH 3 PbI 3 perovskite films by introducing some dimethylacetamide into the PbI 2 /N,N-dimethylformamide solution. We reveal that there are three key processes during the formation of perovskite films through the Lewis acid-base adduct approach: molecule intercalation of solvent into the PbI 2 lattice, molecule exchange between the solvent and CH 3 NH 3 I, and dissolution-recrystallization of the perovskite grains during annealing. The Lewis base solvents play multiple functions in the above processes. The properties of the solvent, including Lewis basicity and boiling point, play key roles in forming smooth perovskite films with large grains. We also provide some rules for choosing Lewis base additives to prepare high-quality perovskite films through the Lewis adduct approach.

  20. DNA adduct formation and mutation induction by aristolochic acid in rat kidney and liver

    International Nuclear Information System (INIS)

    Mei, Nan; Arlt, Volker M.; Phillips, David H.; Heflich, Robert H.; Chen, Tao

    2006-01-01

    Aristolochic acid (AA) is a potent nephrotoxin and carcinogen and is the causative factor for Chinese herb nephropathy. AA has been associated with the development of urothelial cancer in humans, and kidney and forestomach tumors in rodents. To investigate the molecular mechanisms responsible for the tumorigenicity of AA, we determined the DNA adduct formation and mutagenicity of AA in the liver (nontarget tissue) and kidney (target tissue) of Big Blue rats. Groups of six male rats were gavaged with 0, 0.1, 1.0 and 10.0 mg AA/kg body weight five times/week for 3 months. The rats were sacrificed 1 day after the final treatment, and the livers and kidneys were isolated. DNA adduct formation was analyzed by 32 P-postlabeling and mutant frequency (MF) was determined using the λ Select-cII Mutation Detection System. Three major adducts (7-[deoxyadenosin-N 6 -yl]-aristolactam I, 7-[deoxyadenosin-N 6 -yl]-aristolactam II and 7-[deoxyguanosin-N 2 -yl]-aristolactam I) were identified. There were strong linear dose-responses for AA-induced DNA adducts in treated rats, ranging from 25 to 1967 adducts/10 8 nucleotides in liver and 95-4598 adducts/10 8 nucleotides in kidney. A similar trend of dose-responses for mutation induction also was found, the MFs ranging from 37 to 666 x 10 -6 in liver compared with the MFs of 78-1319 x 10 -6 that we previously reported for the kidneys of AA-treated rats. Overall, kidneys had at least two-fold higher levels of DNA adducts and MF than livers. Sequence analysis of the cII mutants revealed that there was a statistically significant difference between the mutation spectra in both kidney and liver of AA-treated and control rats, but there was no significant difference between the mutation spectra in AA-treated livers and kidneys. A:T → T:A transversion was the predominant mutation in AA-treated rats; whereas G:C → A:T transition was the main type of mutation in control rats. These results indicate that the AA treatment that eventually

  1. 1-(2-aminophenyl)-1H-1,2,3-triazole-4-carboxylic acid: activity against Gram-positive and Gram-negative pathogens including Vibrio cholerae

    Science.gov (United States)

    Maji, Krishnendu; Haldar, Debasish

    2017-10-01

    We report a new synthetic aromatic ε-amino acid containing a triazole moiety with antimicrobial potential against Gram-positive, Gram-negative and pathogenic bacteria including Vibrio cholerae. Structure-property relationship studies revealed that all the functional groups are essential to enhance the antimicrobial activity. The 1-(2-aminophenyl)-1H-1,2,3-triazole-4-carboxylic acid was synthesized by click chemistry. From X-ray crystallography, the amino acid adopts a kink-like structure where the phenyl and triazole rings are perpendicular to each other and the amine and acid groups maintain an angle of 60°. The agar diffusion test shows that the amino acid has significant antibacterial activity. The liquid culture test exhibits that the minimum inhibitory concentration (MIC) value for Bacillus subtilis and Vibrio cholerae is 59.5 µg ml-1. FE-SEM experiments were performed to study the morphological changes of bacterial shape after treatment with compound 1. The antimicrobial activity of the amino acid was further studied by DNA binding and degradation study, protein binding, dye-binding assay and morphological analysis. Moreover, the amino acid does not have any harmful effect on eukaryotes.

  2. Kinetic and Mechanistic Study of the pH-Dependent Activation (Epoxidation) of Prodrug Treosulfan Including the Reaction Inhibition in a Borate Buffer.

    Science.gov (United States)

    Romański, Michał; Ratajczak, Whitney; Główka, Franciszek

    2017-07-01

    A prodrug treosulfan (T) undergoes a pH-dependent activation to epoxide derivatives. The process seems to involve an intramolecular Williamson reaction (IWR) but clear kinetic evidence is lacking. Moreover, a cis-diol system present in the T structure is expected to promote complexation with boric acid. As a result, the prodrug epoxidation would be inhibited; however, this phenomenon has not been investigated. In this article, the effect of pH on the kinetics of T conversion to its monoepoxide was studied from a mechanistic point of view. Also, the influence of boric acid on the reaction kinetics was examined. The rate constants observed for the activation of T (k obs ) in acetate, phosphate, and carbonate buffers satisfied the equation logk obs  = -7.48 + 0.96 pH. The reaction was inhibited in the excess of boric acid over T, and the k obs decreased with increasing borate buffer concentration. The experimental results were consistent with the inhibition model that included the formation of a tetrahedral, anionic T-boric acid monoester. To conclude, in nonborate buffers, the T activation to (2S,3S)-1,2-epoxybutane-3,4-diol 4-methanesulfonate follows IWR mechanism. A borate buffer changes the reaction kinetics and complicates kinetic analysis. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  3. Targeted mutations induced by a single acetylaminofluorene DNA adduct in mammalian cells and bacteria

    Energy Technology Data Exchange (ETDEWEB)

    Moryia, M.; Takeshita, M.; Johnson, F.; Peden, K.; Will, S.; Grollman, A.P.

    1988-03-01

    Mutagenic specificity of 2-acetylaminofluorene (AAF) has been established in mammalian cells and several strains of bacteria by using a shuttle plasmid vector containing a single N-(deoxyguanosin-8-yl)acetylaminofluorene (C8-dG-AAF) adduct. The nucleotide sequence of the gene conferring tetracycline resistance was modified by conservative codon replacement so as to accommodate the sequence d(CCTTCGCTAC) flanked by two restriction sites, Bsm I and Xho I. The corresponding synthetic oligodeoxynucleotide underwent reaction with 2-(N-acetoxy-N-acetylamino)-fluorene (AAAF), forming a single dG-AAF adduct. This modified oligodeoxynucleotide was hybridized to its complementary strand and ligated between the Bsm I and Xho I sites of the vector. Plasmids containing the C8-dG-AAF adduct were used to transfect simian virus 40-transformed simian kidney (COS-1) cells and to transform several AB strains of Escherichia coli. Colonies containing mutant plasmides were detected by hybridization to /sup 32/P-labeled oligodeoxynucleotides. Presence of the single DNA adduct increased the mutation frequency by 8-fold in both COS cells and E. coli. Over 80% of mutations detected in both systems were targeted and represented G x C ..-->.. C x G or G x C ..-->.. T x A transversions or single nucleotide deletions. The authors conclude that modification of a deoxyguanosine residue with AAF preferentially induces mutations targeted at this site when a plasmid containing a single C8-dG-AAF adduct is introduced into mammalian cells or bacteria.

  4. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy.

    Science.gov (United States)

    Dzagnidze, Anna; Katsarava, Zaza; Makhalova, Julia; Liedert, Bernd; Yoon, Min-Suk; Kaube, Holger; Limmroth, Volker; Thomale, Juergen

    2007-08-29

    The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy (PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct (guanine-guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair (NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion (DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.

  5. Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N-oxides.

    Science.gov (United States)

    He, Xiaobo; Xia, Qingsu; Woodling, Kellie; Lin, Ge; Fu, Peter P

    2017-10-01

    There are 660 pyrrolizidine alkaloids (PAs) and PA N-oxides present in the plants, with approximately half being possible carcinogens. We previously reported that a set of four PA-derived DNA adducts is formed in the liver of rats administered a series of hepatocarcinogenic PAs and a PA N-oxide. Based on our findings, we hypothesized that this set of DNA adducts is a common biological biomarker of PA-induced liver tumor formation. In this study, we determined that rat liver microsomal metabolism of five hepatocarcinogenic PAs (lasiocarpine, retrorsine, riddelliine, monocrotaline, and heliotrine) and their corresponding PA N-oxides produced the same set of DNA adducts. Among these compounds, lasiocarpine N-oxide, retrorsine N-oxide, monocrotaline N-oxide, and heliotrine N-oxide are for first time shown to be able to produce these DNA adducts. These results further support the role of these DNA adducts as potential common biomarkers of PA-induced liver tumor initiation. Copyright © 2017. Published by Elsevier B.V.

  6. Pyrrolizidine alkaloid-derived DNA adducts are common toxicological biomarkers of pyrrolizidine alkaloid N-oxides

    Directory of Open Access Journals (Sweden)

    Xiaobo He

    2017-10-01

    Full Text Available There are 660 pyrrolizidine alkaloids (PAs and PA N-oxides present in the plants, with approximately half being possible carcinogens. We previously reported that a set of four PA-derived DNA adducts is formed in the liver of rats administered a series of hepatocarcinogenic PAs and a PA N-oxide. Based on our findings, we hypothesized that this set of DNA adducts is a common biological biomarker of PA-induced liver tumor formation. In this study, we determined that rat liver microsomal metabolism of five hepatocarcinogenic PAs (lasiocarpine, retrorsine, riddelliine, monocrotaline, and heliotrine and their corresponding PA N-oxides produced the same set of DNA adducts. Among these compounds, lasiocarpine N-oxide, retrorsine N-oxide, monocrotaline N-oxide, and heliotrine N-oxide are for first time shown to be able to produce these DNA adducts. These results further support the role of these DNA adducts as potential common biomarkers of PA-induced liver tumor initiation.

  7. Differential protein adduction by seven organophosphorus pesticides in both brain and thymus.

    Science.gov (United States)

    Carter, Wayne G; Tarhoni, Mabruka; Rathbone, Alexandra J; Ray, David E

    2007-04-01

    There is a need for mechanistic understanding of the lasting ill health reported in several studies of workers exposed to organophosphorus (OP) pesticide. Although the acute toxicity is largely explicable by acetylcholinesterase inhibition and the lasting effects of frank poisoning by direct excitotoxicity or indirect consequences of the cholinergic syndrome, effects at lower levels of exposure would not be predicted from these mechanisms. Similarly, reversible interactions with nicotinic and muscarinic receptors in adults would not predict continuing ill health. Many OP pesticides produce protein adduction, and the lasting nature of this makes it a candidate mechanism for the production of continuing ill health. We found significant adduction of partially characterized protein targets in both rat brain and thymus by azamethiphos, chlorfenvinphos, chlorpyrifos-oxon, diazinon-oxon, dichlorvos and malaoxon, in vitro and pirimiphos-methyl in vivo. The diversity in the adduction pattern seen across these agents at low dose levels means that any longer term effects of adduction would be specific to specific organophosphates, rather than generic. This presents a challenge to epidemiology, as most exposures are to different agents over time. However, some adducted proteins are also expressed in blood, notably albumin, and so may provide exposure measures to increase the power of future epidemiological studies.

  8. Aflatoxin B1-lysine adduct in dried blood spot samples of animals and humans.

    Science.gov (United States)

    Xue, Kathy S; Cai, Wenjie; Tang, Lili; Wang, Jia-Sheng

    2016-12-01

    Dried blood spots (DBS) were proposed as potentially viable method for exposure assessment of environmental toxicants in infant and young children. For this study, we validated an experimental protocol to quantify AFB 1 -lysine adduct in DBS samples of AFB 1 -treated F344 rats, as well as samples from human field study. Significant dose-response relationships in AFB 1 -lysine adduct formation were found in DBS samples of rats treated with single- and repeated-dose AFB 1 . AFB 1 -lysine levels in DBS samples were highly correlated with corresponding serum sample levels. The Person coefficients were 0.997 for the single-dose exposure, and 0.996 for the repeated-dose exposure. Levels of AFB 1 -lysine adduct had also good agreement between DBS and serum samples as shown by Bland-Altman plot analysis. For human field study samples (n = 36), a Pearson correlation coefficient of 0.784 was found between AFB 1 -lysine adduct levels of DBS and corresponding serum samples. Bland-Altman plots showed the distribution of the log differences between DBS and serum AFB 1 -lysine levels are within 95% confidence intervals. These results showed AFB 1 -lysine adduct levels in DBS cards and serum samples from animals and human samples are comparable, and the DBS technique and analytical protocol is a good means to assess AFB 1 exposure in infant and children populations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Characterization of model peptide adducts with reactive metabolites of naphthalene by mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Nathalie T Pham

    Full Text Available Naphthalene is a volatile polycyclic aromatic hydrocarbon generated during combustion and is a ubiquitous chemical in the environment. Short term exposures of rodents to air concentrations less than the current OSHA standard yielded necrotic lesions in the airways and nasal epithelium of the mouse, and in the nasal epithelium of the rat. The cytotoxic effects of naphthalene have been correlated with the formation of covalent protein adducts after the generation of reactive metabolites, but there is little information about the specific sites of adduction or on the amino acid targets of these metabolites. To better understand the chemical species produced when naphthalene metabolites react with proteins and peptides, we studied the formation and structure of the resulting adducts from the incubation of model peptides with naphthalene epoxide, naphthalene diol epoxide, 1,2-naphthoquinone, and 1,4-naphthoquinone using high resolution mass spectrometry. Identification of the binding sites, relative rates of depletion of the unadducted peptide, and selectivity of binding to amino acid residues were determined. Adduction occurred on the cysteine, lysine, and histidine residues, and on the N-terminus. Monoadduct formation occurred in 39 of the 48 reactions. In reactions with the naphthoquinones, diadducts were observed, and in one case, a triadduct was detected. The results from this model peptide study will assist in data interpretation from ongoing work to detect peptide adducts in vivo as markers of biologic effect.

  10. Serendipitous compositional and structural diversity in urotropine adducts of binary cadmium xanthates

    International Nuclear Information System (INIS)

    Tan, Yee Seng; Azizuddin, Aliaa Diyana; Campian, Marius V.; Haiduc, Ionel; Tiekink, Edward R.T.

    2016-01-01

    Three new compounds, Cd(S 2 COMe) 2 (hmta) (1), Cd(S 2 COEt) 2 (hmta)0.5 (2) and Cd(S 2 COiPr) 2 (hmta) (3), have been isolated from a systematic study of adduct formation between Cd(S 2 COR) 2 , R = Me, Et and iPr, precursors and potentially polydentate hmta; hmta is urotropine (hexamethylenetetramine). The compounds have been characterised by a variety of spectroscopic techniques including a photoluminescence study in both solution and the solid-state, as well as by thermal methods. Crystallography shows 1 to have μ 2 -bridging hmta leading to a one-dimensional coordination polymer. This framework is essentially repeated in 2 but with a μ 3 -bridging hmta so that Cd(S 2 COEt) 2 entities decorate the chain. By contrast, a binuclear zero-dimensional aggregate with terminally bound hmta is found in 3. The influence of steric bulk of the alkyl substituents in Cd(S 2 COR) 2 is pivotal in determining the ultimate structural outcome.

  11. Serendipitous compositional and structural diversity in urotropine adducts of binary cadmium xanthates

    Energy Technology Data Exchange (ETDEWEB)

    Tan, Yee Seng; Azizuddin, Aliaa Diyana [Malaya Univ., Kuala Lumpur (Malaysia). Dept. of Chemistry; Campian, Marius V.; Haiduc, Ionel [Babes-Bolyai Univ., Cluj-Napoca (Romania). Dept. of Chemistry; Tiekink, Edward R.T. [Sunway Univ., Bandar Sunway (Malaysia). Centre for Crystalline Material

    2016-05-01

    Three new compounds, Cd(S{sub 2}COMe){sub 2}(hmta) (1), Cd(S{sub 2}COEt){sub 2}(hmta)0.5 (2) and Cd(S{sub 2}COiPr){sub 2}(hmta) (3), have been isolated from a systematic study of adduct formation between Cd(S{sub 2}COR){sub 2}, R = Me, Et and iPr, precursors and potentially polydentate hmta; hmta is urotropine (hexamethylenetetramine). The compounds have been characterised by a variety of spectroscopic techniques including a photoluminescence study in both solution and the solid-state, as well as by thermal methods. Crystallography shows 1 to have μ{sub 2}-bridging hmta leading to a one-dimensional coordination polymer. This framework is essentially repeated in 2 but with a μ{sub 3}-bridging hmta so that Cd(S{sub 2}COEt){sub 2} entities decorate the chain. By contrast, a binuclear zero-dimensional aggregate with terminally bound hmta is found in 3. The influence of steric bulk of the alkyl substituents in Cd(S{sub 2}COR){sub 2} is pivotal in determining the ultimate structural outcome.

  12. PXR (NR1I2): splice variants in human tissues, including brain, and identification of neurosteroids and nicotine as PXR activators

    International Nuclear Information System (INIS)

    Lamba, Vishal; Yasuda, Kazuto; Lamba, Jatinder K.; Assem, Mahfoud; Davila, Julio; Strom, Stephen; Schuetz, Erin G.

    2004-01-01

    To gain insight on the expression of pregnane X receptor (PXR), we analyzed PXR.1 and PXR alternatively spliced transcripts in a panel of 36 human tissues. PXR.1 was expressed in many more tissues than previously determined, including human bone marrow and select regions of the human brain. In each of these tissues, we observed alternative splicing of various exons of PXR that generated multiple distinct PXR isoforms. The most abundant PXR alternative mRNA transcripts lacked 111 nucleotides, deleting 37 amino acids from the PXR LBD (PXR.2), or lacked 123 nt, deleting 41 amino acids from the PXR LBD (PXR.3). CYP3A4, a gene transcriptionally regulated by PXR, showed incomplete overlap with PXR in its tissue distribution. Quantitation of PXR mRNAs in human liver demonstrated that PXR.2 and PXR.3 represented 6.7% and 0.32% of total PXR mRNA transcripts. Brain expression of PXR prompted analysis of whether some brain acting chemicals were PXR ligands. The neurosteroids allopregnanolone and pregnanolone activated PXR and induced transcription of a CYP3A4-luciferase reporter. Nicotine, the psychoactive and addictive chemical in cigarettes, and a known inducer of brain CYP2B6, was an efficacious activator of PXR and inducer of CYP3A4 transcription. Because nicotine activation of PXR will enhance metabolism of nicotine to the non-psychoactive cotinine, these results provide one molecular mechanism for the development of tolerance to nicotine. Moreover, the identification of PXR in many human tissues, such as brain, and activation by tissue specific ligands (such as neurosteroids) suggests additional biological roles for this receptor in these tissues

  13. The influence of antagonist muscle electrical stimulation on maximal hip adduction force.

    Science.gov (United States)

    Nakano, Sota; Wada, Chikamune

    2016-01-01

    [Purpose] The aim of this study was to determine whether electrical stimulation of the tensor fascia lata muscle decreases voluntary maximum resistance to passive abduction motion in participants without disease of the central nervous system. [Subjects] The participants were 16 healthy men. [Methods] The hip joint was moved from 10° adduction to 0° adduction with an angular velocity of 7°/s. During the passive leg motion, the subject was asked to resist the motion with maximum force. Two experimental conditions were prepared: (1) electrical stimulation provided to the tensor fascia lata muscle during the passive motion; and (2) no electrical stimulation provided. [Results] The force was 10.2 ± 3.5 kgf with electrical stimulation and 12.2 ± 3.8 kgf without electrical stimulation. [Conclusion] The results suggested that the maximum hip adduction force decreased in participants because of electrical stimulation of the tensor fascia lata muscle.

  14. Hemoglobin adducts in workers exposed to 1,6-hexamethylene diisocyanate

    Science.gov (United States)

    Flack, Sheila L.; Fent, Kenneth W.; Gaines, Linda G. T.; Thomasen, Jennifer M.; Whittaker, Stephen G.; Ball, Louise M.; Nylander-French, Leena A.

    2014-01-01

    We investigated the utility of 1,6-hexamethylene diamine (HDA) hemoglobin adducts as biomarkers of exposure to 1,6-hexamethylene diisocyanate (HDI) monomer. Blood samples from 15 spray painters applying HDI-containing paint were analyzed for hemoglobin HDA (HDA-Hb) and N-acetyl-1,6-hexamethylene diamine (monoacetyl-HDA-Hb) by GC-MS. HDA-Hb was detected in the majority of workers (≤1.2–37 ng/g Hb), whereas monoacetyl-HDA-Hb was detected in one worker (0.06 ng/g Hb). The stronger, positive association between HDA-Hb and cumulative HDI exposure (r2 = 0.3, p < 0.06) than same day exposure (p ≥ 0.13) indicates long-term elimination kinetics for HDA-Hb adducts. This association demonstrates the suitability of HDA-Hb adducts for further validation as a biomarker of HDI exposure. PMID:21506697

  15. Quantitative measurement of DNA adducts using neutral hydrolysis and LC-MS. Validation of genotoxicity sensors.

    Science.gov (United States)

    Tarun, Maricar; Rusling, James F

    2005-04-01

    Neutral hydrolysis and LC-MS/MS analysis of 6-nm-thick DNA-polyion films used in voltammetric genotoxicity screening sensors showed that concentrations of N7-guanine DNA adducts with methyl methanesulfonate and styrene oxide increased with incubation time with the same trends as found for sensor response. Results show that the genotoxicity sensors can be used to estimate relative DNA damage rates for chemical toxicity screening. Neutral thermal hydrolysis provided a relatively clean sample matrix allowing quantitative estimates of nucleobase adducts after several minutes of incubation with damage agents. In addition, an approximate standardization procedure for neutral thermal hydrolysis was developed and validated that avoids need for a pure standard and should be useful in cases where nucleobase adduct standards are unavailable or where their identities are unknown.

  16. Synthesis of Cyclopropane Derivatives Starting from the Baylis-Hillman Adducts Using Sulfur Ylide Chemistry

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ka Young; Kim, Seung Chan; Kim, Jae Nyoung [Chonnam National University, Gwangju (Korea, Republic of)

    2006-02-15

    During the extensive studies on the chemical transformations of Baylis-Hillman adducts, we examined the introduction of cyclopropane moiety at the primary position of Baylis-Hillman adducts to form vinyl cyclopropane derivatives. Such vinyl cyclopropane backbone is an important entity in many naturally occurring and synthetic pyrethroidal insectides, and could be used for further chemical transformations. Our synthetic rationale is shown in Scheme 1. The starting cinnamyl bromide was prepared from the Baylis-Hillman adduct and HBr according to the reported method. The reaction of and dimethyl sulfide in CH{sub 3}CN generated the sulfonium salt, which was converted into the corresponding sulfur ylide by treatment with NaOH.

  17. Microwave-assisted convenient syntheses of 2-indolizine derivatives from Morita-Baylis-Hillman adducts: new in silico potential ion channel modulators

    International Nuclear Information System (INIS)

    Cunha, Saraghina M.D.; Oliveira, Ramon G. de; Vasconcellos, Mario L.A.A.

    2013-01-01

    In this work, a microwave-assisted synthesis study by microwave irradiation to produce indolizine-2-carbonitrile and indolizine-2-carboxylate in good to high yields (70 and 81%, respectively) in one step from Morita-Baylis-Hillman adducts (MBHA) is presented. These compounds were subsequently transformed to high yields (94 to 100%, respectively) in three 2-indolizine derivatives. The five synthesized compounds were designed in silico aiming to present potential selective activities as ion channel modulators. These activities were suggested by the score values using Molinspiration Cheminformatics program. (author)

  18. Microwave-assisted convenient syntheses of 2-indolizine derivatives from Morita-Baylis-Hillman adducts: new in silico potential ion channel modulators

    Energy Technology Data Exchange (ETDEWEB)

    Cunha, Saraghina M.D.; Oliveira, Ramon G. de; Vasconcellos, Mario L.A.A., E-mail: mlaav@quimica.ufpb.br [Universidade Federal da Paraiba (UFPB), Joao Pessoa, PB (Brazil). Departamento de Quimica

    2013-03-15

    In this work, a microwave-assisted synthesis study by microwave irradiation to produce indolizine-2-carbonitrile and indolizine-2-carboxylate in good to high yields (70 and 81%, respectively) in one step from Morita-Baylis-Hillman adducts (MBHA) is presented. These compounds were subsequently transformed to high yields (94 to 100%, respectively) in three 2-indolizine derivatives. The five synthesized compounds were designed in silico aiming to present potential selective activities as ion channel modulators. These activities were suggested by the score values using Molinspiration Cheminformatics program. (author)

  19. In Vitro Antibacterial and Antibiofilm Activities of Chlorogenic Acid against Clinical Isolates of Stenotrophomonas maltophilia including the Trimethoprim/Sulfamethoxazole Resistant Strain

    Science.gov (United States)

    Karunanidhi, Arunkumar; Thomas, Renjan; van Belkum, Alex; Neela, Vasanthakumari

    2013-01-01

    The in vitro antibacterial and antibiofilm activity of chlorogenic acid against clinical isolates of Stenotrophomonas maltophilia was investigated through disk diffusion, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time-kill and biofilm assays. A total of 9 clinical S. maltophilia isolates including one isolate resistant to trimethoprim/sulfamethoxazole (TMP/SMX) were tested. The inhibition zone sizes for the isolates ranged from 17 to 29 mm, while the MIC and MBC values ranged from 8 to 16 μg mL−1 and 16 to 32 μg mL−1. Chlorogenic acid appeared to be strongly bactericidal at 4x MIC, with a 2-log reduction in viable bacteria at 10 h. In vitro antibiofilm testing showed a 4-fold reduction in biofilm viability at 4x MIC compared to 1x MIC values (0.085 chlorogenic acid. The data from this study support the notion that the chlorogenic acid has promising in vitro antibacterial and antibiofilm activities against S. maltophilia. PMID:23509719

  20. MTHFR polymorphisms, folate intake and carcinogen DNA adducts in the lung.

    Science.gov (United States)

    Lee, Mi-Sun; Asomaning, Kofi; Su, Li; Wain, John C; Mark, Eugene J; Christiani, David C

    2012-09-01

    The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was completed for MTHFR C677T (rs1801133) and A1298C (rs1801131). Information on dietary intake for one-carbon related micronutrients, folate and other B vitamin was derived from a validated food frequency questionnaire. DNA adducts in lung were measured by (32) P-postlabeling. After adjusting for potential confounders, DNA adduct levels in lung significantly increased by 69.2% [95% confidence interval (CI), 5.5% to 171.5%] for the MTHFR 1298AC+CC genotype. The high risk group, combining the A1298C (AC+CC) plus C677T (CT+TT) genotypes, had significantly enhanced levels of lung adducts by 210.7% (95% CI, 21.4% to 695.2%) in contrast to the A1298C (AA) plus C677T (CC) genotypes. Elevation of DNA adduct was pronounced-111.3% (95% CI, -3.0 to 360.5%) among 1298AC+CC patients, who consumed the lowest level of folate intake as compared to 1298AA individuals with highest tertile of intake. These results indicate that DNA adducts levels are influenced by MTHFR polymorphisms and low folate consumption, suggesting an important role of genetic and nutritional factors in protecting DNA damage from lung carcinogen in at-risk populations. Copyright © 2011 UICC.

  1. Proteomic analysis of acrylamide-protein adduct formation in rat brain synaptosomes

    International Nuclear Information System (INIS)

    Barber, David S.; LoPachin, Richard M.

    2004-01-01

    Evidence suggests that the neurological defects (gait abnormalities, foot splay, and skeletal muscle weakness) associated with acrylamide (ACR) intoxication are mediated by impaired neurotransmission at central and peripheral synapses. ACR can form adducts with nucleophilic residues on proteins and thereby alter corresponding structure and function. To evaluate protein adduction in nerve terminals as a possible mechanism of action, recombinant N-ethylmaleimide sensitive factor (NSF) was exposed in vitro to ACR (10 μmol) and mass spectrometry (MS) was used to identify adduct sites. MS analyses demonstrated that ACR formed adducts with sulfhydryl groups on cysteine residues (carbamoylethylcysteine, or CEC) of NSF. Ex vivo incubation of whole brain synaptosomes with ACR (0.001-1.0 M) produced concentration-dependent increases in CEC that were inversely correlated to reductions in neurotransmitter release that occurred over the same neurotoxicant concentration range. In synaptosomes isolated from rats intoxicated at a higher (50 mg/kg per day x 3, 5, 8, or 11 days) or a lower (21 mg/kg per day x 14, 21, or 28 day) ACR dose rate, CEC levels increased progressively up to a moderate level of neurotoxicity. To identify protein adducts, synaptosomal proteins labeled by ex vivo 14 C-ACR exposure were separated by gel electrophoresis and probed by immunoblot analysis. Results showed that NSF and the SNARE protein, SNAP-25, were tentative ACR targets. Subsequent experiments indicated that ACR exposure increased synaptosomal levels of the 7S SNARE core complex, which is consistent with inhibition of NSF, SNAP-25 function, or both. These data suggest that adduction of cysteine residues on NSF and certain SNARE proteins might be causally involved in the nerve terminal dysfunction induced by ACR

  2. PREFACE: 9th International Fröhlich's Symposium: Electrodynamic Activity of Living Cells (Including Microtubule Coherent Modes and Cancer Cell Physics)

    Science.gov (United States)

    Cifra, Michal; Pokorný, Jirí; Kucera, Ondrej

    2011-12-01

    This volume contains papers presented at the International Fröhlich's Symposium entitled 'Electrodynamic Activity of Living Cells' (1-3 July 2011, Prague, Czech Republic). The Symposium was the 9th meeting devoted to physical processes in living matter organized in Prague since 1987. The hypothesis of oscillation systems in living cells featured by non-linear interaction between elastic and electrical polarization fields, non-linear interactions between the system and the heat bath leading to energy downconversion along the frequency scale, energy condensation in the lowest frequency mode and creation of a coherent state was formulated by H Fröhlich, founder of the theory of dielectric materials. He assumed that biological activity is based not only on biochemical but also on biophysical mechanisms and that their disturbances form basic links along the cancer transformation pathway. Fröhlich outlined general ideas of non-linear physical processes in biological systems. The downconversion and the elastic-polarization interactions should be connected in a unified theory and the solution based on comprehensive non-linear characteristics. Biochemical and genetic research of biological systems are highly developed and have disclosed a variety of cellular and subcellular structures, chemical reactions, molecular information transfer, and genetic code sequences - including their pathological development. Nevertheless, the cancer problem is still a big challenge. Warburg's discovery of suppressed oxidative metabolism in mitochondria in cancer cells suggested the essential role of physical mechanisms (but his discovery has remained without impact on cancer research and on the study of physical properties of biological systems for a long time). Mitochondria, the power plants of the cell, have several areas of activity-oxidative energy production is connected with the formation of a strong static electric field around them, water ordering, and liberation of non

  3. Apiaceous Vegetable Consumption Decreases PhIP-Induced DNA Adducts and Increases Methylated PhIP Metabolites in the Urine Metabolome in Rats123

    Science.gov (United States)

    Kim, Jae Kyeom; Gallaher, Daniel D; Chen, Chi; Yao, Dan; Trudo, Sabrina P

    2015-01-01

    Background: Heterocyclic aromatic amines, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are carcinogenic compounds produced during heating of protein-containing foods. Apiaceous vegetables inhibit PhIP-activating enzymes, whereas cruciferous vegetables induce both PhIP-activating and -detoxifying enzymes. Objective: We investigated the effects of these vegetables, either alone or combined, on PhIP metabolism and colonic DNA adduct formation in rats. Methods: Male Wistar rats were fed cruciferous vegetables (21%, wt:wt), apiaceous vegetables (21%, wt:wt), or a combination of both vegetables (10.5% wt:wt of each). Negative and positive control groups were fed an AIN-93G diet. After 6 d, all groups received an intraperitoneal injection of PhIP (10 mg · kg body weight−1) except for the negative control group, which received only vehicle. Urine was collected for 24 h after the injection for LC–tandem mass spectrometry metabolomic analyses. On day 7, rats were killed and tissues processed. Results: Compared with the positive control, cruciferous vegetables increased the activity of hepatic PhIP-activating enzymes [39.5% and 45.1% for cytochrome P450 (CYP) 1A1 (P = 0.0006) and CYP1A2 (P vegetables did not inhibit PhIP-activating enzymes, yet reduced colonic PhIP-DNA adducts by 20.4% (P = 0.0496). Metabolomic analyses indicated that apiaceous vegetables increased the relative abundance of urinary methylated PhIP metabolites. The sum of these methylated metabolites inversely correlated with colonic PhIP-DNA adducts (r = −0.43, P = 0.01). We detected a novel methylated urinary PhIP metabolite and demonstrated that methylated metabolites are produced in the human liver S9 fraction. Conclusions: Apiaceous vegetables did not inhibit the activity of PhIP-activating enzymes in rats, suggesting that the reduction in PhIP-DNA adducts may involve other pathways. Further investigation of the importance of PhIP methylation in carcinogen metabolism is warranted

  4. Apiaceous vegetable consumption decreases PhIP-induced DNA adducts and increases methylated PhIP metabolites in the urine metabolome in rats.

    Science.gov (United States)

    Kim, Jae Kyeom; Gallaher, Daniel D; Chen, Chi; Yao, Dan; Trudo, Sabrina P

    2015-03-01

    Heterocyclic aromatic amines, such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are carcinogenic compounds produced during heating of protein-containing foods. Apiaceous vegetables inhibit PhIP-activating enzymes, whereas cruciferous vegetables induce both PhIP-activating and -detoxifying enzymes. We investigated the effects of these vegetables, either alone or combined, on PhIP metabolism and colonic DNA adduct formation in rats. Male Wistar rats were fed cruciferous vegetables (21%, wt:wt), apiaceous vegetables (21%, wt:wt), or a combination of both vegetables (10.5% wt:wt of each). Negative and positive control groups were fed an AIN-93G diet. After 6 d, all groups received an intraperitoneal injection of PhIP (10 mg · kg body weight(-1)) except for the negative control group, which received only vehicle. Urine was collected for 24 h after the injection for LC-tandem mass spectrometry metabolomic analyses. On day 7, rats were killed and tissues processed. Compared with the positive control, cruciferous vegetables increased the activity of hepatic PhIP-activating enzymes [39.5% and 45.1% for cytochrome P450 (CYP) 1A1 (P = 0.0006) and CYP1A2 (P vegetables did not inhibit PhIP-activating enzymes, yet reduced colonic PhIP-DNA adducts by 20.4% (P = 0.0496). Metabolomic analyses indicated that apiaceous vegetables increased the relative abundance of urinary methylated PhIP metabolites. The sum of these methylated metabolites inversely correlated with colonic PhIP-DNA adducts (r = -0.43, P = 0.01). We detected a novel methylated urinary PhIP metabolite and demonstrated that methylated metabolites are produced in the human liver S9 fraction. Apiaceous vegetables did not inhibit the activity of PhIP-activating enzymes in rats, suggesting that the reduction in PhIP-DNA adducts may involve other pathways. Further investigation of the importance of PhIP methylation in carcinogen metabolism is warranted, given the inverse correlation of methylated Ph

  5. Synthesis, characterisation and optical studies of new tetraethyl- rubyrin-graphene oxide covalent adducts

    Science.gov (United States)

    Garg, Kavita; Shanmugam, Ramakrishanan; Ramamurthy, Praveen C.

    2018-02-01

    Tetrathia-rubyrin and graphene oxide (GO) covalent adduct was synthesized, characterised and optical properties were studied. GO-Rubyrin adducts showed fluorescence quenching of rubyrin due to electron or energy transfer from rubyrin to graphene oxide, which also reflected in UV-vis absorbance spectroscopy. The non-linear optical responses were measured through Z scan technique in nano-second regime. The enhanced optical non-linearity was observed after attachment of GO with rubyrin, can be ascribed to the photo-induced electron or energy transfer from the electron rich rubyrin moiety to the electron deficient GO.

  6. NanoLC/ESI+ HRMS3 quantitation of DNA adducts induced by 1,3-butadiene.

    Science.gov (United States)

    Sangaraju, Dewakar; Villalta, Peter W; Wickramaratne, Susith; Swenberg, James; Tretyakova, Natalia

    2014-07-01

    Human exposure to 1,3-butadiene (BD) present in automobile exhaust, cigarette smoke, and forest fires is of great concern because of its potent carcinogenicity. The adverse health effects of BD are mediated by its epoxide metabolites such as 3,4-epoxy-1-butene (EB), which covalently modify genomic DNA to form promutagenic nucleobase adducts. Because of their direct role in cancer, BD-DNA adducts can be used as mechanism-based biomarkers of BD exposure. In the present work, a mass spectrometry-based methodology was developed for accurate, sensitive, and precise quantification of EB-induced N-7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) DNA adducts in vivo. In our approach, EB-GII adducts are selectively released from DNA backbone by neutral thermal hydrolysis, followed by ultrafiltration, offline HPLC purification, and isotope dilution nanoLC/ESI(+)-HRMS(3) analysis on an Orbitrap Velos mass spectrometer. Following method validation, EB-GII lesions were quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of EB and in liver tissues of rats exposed to sub-ppm concentrations of BD (0.5-1.5 ppm). EB-GII concentrations increased linearly from 1.15 ± 0.23 to 10.11 ± 0.45 adducts per 10(8) nucleotides in HT1080 cells treated with 0.5-10 μM EB. EB-GII concentrations in DNA of laboratory rats exposed to 0.5, 1.0, and 1.5 ppm BD were 0.17 ± 0.05, 0.33 ± 0.08, and 0.50 ± 0.04 adducts per 10(8) nucleotides, respectively [corrected]. We also used the new method to determine the in vivo half-life of EB-GII adducts in rat liver DNA (2.20 ± 0.12 d) and to detect EB-GII in human blood DNA. To our knowledge, this is the first application of nanoLC/ESI(+)-HRMS(3) Orbitrap methodology to quantitative analysis of DNA adducts in vivo.

  7. Mechanisms of formation of adducts from reactions of glycidaldehyde with 2'-deoxyguanosine and/or guanosine.

    Science.gov (United States)

    Golding, B T; Slaich, P K; Kennedy, G; Bleasdale, C; Watson, W P

    1996-01-01

    Convenient synthesis of rac-glycidaldehyde from rac-but-3-ene-1,2-diol and (R)-glycidaldehyde from D-mannitol are described. (R)-Glycidaldehyde (1) reacts with guanosine in water (pH 4-11, faster reaction at higher pH) to give initially 6(S)-hydroxy-7(S)-(hydroxymethyl)-3-(beta-D-ribofuranosyl)-5,6,7- trihydroimidazo[1,2-alpha]purin-9(3H)-one (7a) and 6(S),7(R)-dihydroxy-3-(beta-D-ribofuranosyl)-5,6,7,8- tetrahydropyrimido[1,2- alpha]purin-10(3H)-one (8a). The former decomposes to 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2- alpha]purine (3a), 5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2-alpha]purine (5a, 1,N2-ethenoguanosine), and formaldehyde, while the latter adduct is relatively stable. The position of the hydroxymethyl group on the imidazo ring of 7-(hydroxymethyl)-5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo-[1,2 - alpha]purine was proved by 13C NMR analysis of adducts derived from [1-15N]guanosine and [amino-15N]guanosine. At longer reaction times, the adduct 7,7'-methylenebis[5,9-dihydro-9-oxo-3-(beta-D-ribofuranosyl)imidazo[1,2- alpha]purine (4a) is formed from guanosine and glycidaldehyde. The structure analysis of this adduct was also aided by 13C NMR analysis of the 15N-labeled adduct derived from [1-15N]guanosine. Analogous adducts were obtained from the reaction between glycidaldehyde and deoxyguanosine. Mechanisms of formation of the adducts from glycidaldehyde and guanosine/deoxyguanosine are proposed and supported by model studies with simple amines. The formaldehyde produced in the reactions described reacts with guanosine to give the known adduct N2-(hydroxymethyl)guanosine (9).

  8. Identification and quantification of drug-albumin adducts in serum samples from a drug exposure study in mice

    NARCIS (Netherlands)

    Switzar, L.; Kwast, L.M.; Lingeman, H.; Giera, M.; Pieters, R.H.H.; Niessen, W.M.A.

    2013-01-01

    The formation of drug-protein adducts following the bioactivation of drugs to reactive metabolites has been linked to adverse drug reactions (ADRs) and is a major complication in drug discovery and development. Identification and quantification of drug-protein adducts in vivo may lead to a better

  9. Electrophilic aldehyde products of lipid peroxidation selectively adduct to heat shock protein 90 and arylsulfatase A in stallion spermatozoa.

    Science.gov (United States)

    Hall, Sally E; Aitken, R John; Nixon, Brett; Smith, Nathan D; Gibb, Zamira

    2017-01-01

    Oxidative stress is a major determinant of mammalian sperm function stimulating lipid peroxidation cascades that culminate in the generation of potentially cytotoxic aldehydes. The aim of this study was to assess the impact of such aldehydes on the functionality of stallion spermatozoa. The impact of exposure to exogenous acrolein (ACR) and 4-hydroxynonenal (4HNE) was manifested in a highly significant dose- and time-dependent increase in mitochondrial reactive oxygen species (ROS), total cellular ROS, a decrease in sperm motility, and a time-dependent increase in lipid peroxidation. Notably, low doses of ACR and 4HNE also caused a significant decrease in zona binding. In contrast, exogenous malondialdehyde, a commonly used marker of oxidative stress, had little impact on the various sperm parameters assessed. In accounting for the negative physiological impact of ACR and 4HNE, it was noted that both aldehydes readily adducted to sperm proteins located predominantly within the head, proximal centriole, and tail. The detoxifying activity of mitochondrial aldehyde dehydrogenase 2 appeared responsible for a lack of adduction in the midpiece; however, this activity was overwhelmed by 24 h of electrophilic aldehyde exposure. Sequencing of the dominant proteins targeted for ACR and 4HNE covalent modification identified heat shock protein 90 alpha (cytosolic) class A member 1 and arylsulfatase A, respectively. These collective findings may prove useful in the identification of diagnostic biomarkers of stallion fertility and resolving the mechanistic basis of sperm dysfunction in this species. © The Authors 2016. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please journals.permissions@oup.com.

  10. Environmental Toxin Acrolein Alters Levels of Endogenous Lipids, Including TRP Agonists: A Potential Mechanism for Headache Driven by TRPA1 Activation.

    Science.gov (United States)

    Leishman, Emma; Kunkler, Phillip E; Manchanda, Meera; Sangani, Kishan; Stuart, Jordyn M; Oxford, Gerry S; Hurley, Joyce H; Bradshaw, Heather B

    2017-01-01

    Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1), a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1) agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N -acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N -arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization.

  11. Environmental toxin acrolein alters levels of endogenous lipids, including TRP agonists: A potential mechanism for headache driven by TRPA1 activation

    Directory of Open Access Journals (Sweden)

    Emma Leishman

    2017-01-01

    Full Text Available Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1, a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1 agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N-acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N-arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization. Keywords: Lipidomics, Endogenous cannabinoid, TRPA1, TRPV1, Lipoamine, Acrolein, Migraine

  12. [Association of etheno-DNA adduct and DNA methylation level among workers exposed to diesel engine exhaust].

    Science.gov (United States)

    Shen, M L; He, Z N; Zhang, X; Duan, H W; Niu, Y; Bin, P; Ye, M; Meng, T; Dai, Y F; Yu, S F; Chen, W; Zheng, Y X

    2017-06-06

    Objective: To investigate the association between etheno-DNA adduct and the promoter of DNA methylation levels of cyclin dependent kinase inhibitor 2A (P16), Ras association domain family 1 (RASSF1A) and O-6-methylguanine-DNA methyltransferase (MGMT) in workers with occupational exposure to diesel engine exhaust (DEE). Methods: We recruited 124 diesel engine testing workers as DEE exposure group and 112 water pump operator in the same area as control group in Henan province in 2012 using cluster sampling. The demographic data were obtained by questionnaire survey; urine after work and venous blood samples were collected from each subject. The urinary etheno-DNA adducts were detected using UPLC-MS/MS, including 1,N6-etheno-2'-deoxyadenosine (εdA) and 3,N4-etheno-2'-deoxycytidine(εdC). The DNA methylation levels of P16, RASSF1A, and MGMT were evaluated using bisulfite-pyrosequencing assay. The percentage of methylation was expressed as the 5-methylcytosine (5mC) over the sum of cytosines (%5mC). Spearman correlation and multiple linear regression were applied to analyze the association between etheno-DNA adducts and DNA methylation of P16, RASSF1A, and MGMT. Results: The median ( P (25)- P (75)) of urinary εdA level was 230.00 (98.04-470.91) pmol/g creatinine in DEE exposure group, and 102.10 (49.95-194.48) creatinine in control group. The level of εdA was higher in DEE exposure group than control group ( P 0.05) . Multiple linear regression confirmed the negative correlation between εdA and DNA methylation levels of P16, RASSF1A, and MGMT in non-smoking group (β (95 %CI ) was -0.068 (-0.132--0.003), -0.082 (-0.159--0.004) and -0.048 (-0.090--0.007), P values were 0.039, 0.039 and 0.024, respectively). Moreover, εdC was negative associated with DNA methylation level of MGMT in non-smoking group (β (95 %CI ) was -0.094 (-0.179--0.008), P= 0.032). Conclusion: DEE exposure could induce the increased of εdA and decreased of DNA methylation levels of P16, RASSF1A

  13. The potential of platinum-DNA adduct determination in ex vivo treated tumor fragments for the prediction of sensitivity to cisplatin chemotherapy

    NARCIS (Netherlands)

    Welters, M.J.P.; Braakhuis, B.J.M.; Jacobs-Bergmans, A.J.; Kegel, A.; Baan, R.A.; Vijgh, W.J.F. van der; Fichtinger-Schepman, A.M.J.

    1999-01-01

    Background: Response to cisplatin-therapy is assumed to be related to the formation of platinum (Pt)-DNA adducts. Measurement of these adducts prior to therapy could be of value to improve cisplatin based cancer therapy. Materials and methods: We determined Pt-GG and Pt-AG adduct levels by use of

  14. Differences in Butadiene Adduct Formation between Rats and Mice Not Due to Selective Inhibition of CYP2E1 by Butadiene Metabolites

    Science.gov (United States)

    Pianalto, Kaila M.; Hartman, Jessica H.; Boysen, Gunnar; Miller, Grover P.

    2013-01-01

    CYP2E1 metabolizes 1,3-butadiene (BD) into genotoxic and possibly carcinogenic 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane (DEB), and 1,2-epoxy-3,4-butanediol (EB-diol). The dose response of DNA and protein adducts derived from BD metabolites increase linearly at low BD exposures and then saturate at higher exposures in rats, but not mice. It was hypothesized that differences in adduct formation between rodents reflect more efficient BD oxidation in mice than rats. Herein, we assessed whether BD-derived metabolites selectively inhibit rat but not mouse CYP2E1 activity using B6C3F1 mouse and Fisher 344 rat liver microsomes. Basal CYP2E1 activities toward 4-nitrophenol were similar between rodents. Through IC50 studies, EB was the strongest inhibitor (IC50 54 μM, mouse; 98 μM, rat), BD-diol considerably weaker (IC50 1200 μM, mouse; 1000 μM, rat), and DEB inhibition nonexistent (IC50 >25 mM). Kinetic studies showed that in both species EB and BD-diol inhibited 4-nitrophenol oxidation through two-site mechanisms in which inhibition constants reflected trends observed in IC50 studies. None of the reactive epoxide metabolites inactivated CYP2E1 irreversibly. Thus, there was no selective inhibition or inactivation of rat CYP2E1 by BD metabolites relative to mouse Cyp2e1, and it can be inferred that CYP2E1 activity toward BD between rodent species would similarly not be impacted by the presence of BD metabolites. Inhibition of CYP2E1 by BD metabolites is then not responsible for the reported species difference in BD metabolism, formation of BD-derived DNA and protein adducts, mutagenicity and tumorigenesis. PMID:24021170

  15. How Y-Family DNA polymerase IV is more accurate than Dpo4 at dCTP insertion opposite an N2-dG adduct of benzo[a]pyrene.

    Science.gov (United States)

    Sholder, Gabriel; Creech, Amanda; Loechler, Edward L

    2015-11-01

    To bypass DNA damage, cells have Y-Family DNA polymerases (DNAPs). One Y-Family-class includes DNAP κ and DNAP IV, which accurately insert dCTP opposite N(2)-dG adducts, including from the carcinogen benzo[a]pyrene (BP). Another class includes DNAP η and DNAP V, which insert accurately opposite UV-damage, but inaccurately opposite BP-N(2)-dG. To investigate structural differences between Y-Family-classes, regions are swapped between DNAP IV (a κ/IV-class-member) and Dpo4 (a η/V-class-member); the kinetic consequences are evaluated via primer-extension studies with a BP-N(2)-dG-containing template. Four key structural elements are revealed. (1) Y-Family DNAPs have discreet non-covalent contacts between their little finger-domain (LF-Domain) and their catalytic core-domain (CC-Domain), which we call "non-covalent bridges" (NCBs). Arg37 and Arg38 in DNAP IV's CC-Domain near the active site form a non-covalent bridge (AS-NCB) by interacting with Glu251 and Asp252, respectively, in DNAP IV's LF-Domain. Without these interactions dATP/dGTP/dTTP misinsertions increase. DNAP IV's AS-NCB suppresses misinsertions better than Dpo4's equivalent AS-NCB. (2) DNAP IV also suppresses dATP/dGTP/dTTP misinsertions via a second non-covalent bridge, which is ∼8Å from the active site (Distal-NCB). Dpo4 has no Distal-NCB, rendering it inferior at dATP/dGTP/dTTP suppression. (3) dCTP insertion is facilitated by the larger minor groove opening near the active site in DNAP IV versus Dpo4, which is sensible given that Watson/Crick-like [dCTP:BP-N(2)-dG] pairing requires the BP-moiety to be in the minor groove. (4) Compared to Dpo4, DNAP IV has a smaller major groove opening, which suppresses dGTP misinsertion, implying BP-N(2)-dG bulk in the major groove during Hoogsteen syn-adduct-dG:dGTP pairing. In summary, DNAP IV has a large minor groove opening to enhance dCTP insertion, a plugged major groove opening to suppress dGTP misinsertion, and two non-covalent bridges (near and distal

  16. Insulin Activates Vagal Afferent Neurons Including those Innervating Pancreas via Insulin Cascade and Ca(2+ Influx: Its Dysfunction in IRS2-KO Mice with Hyperphagic Obesity.

    Directory of Open Access Journals (Sweden)

    Yusaku Iwasaki

    Full Text Available Some of insulin's functions, including glucose/lipid metabolism, satiety and neuroprotection, involve the alteration of brain activities. Insulin could signal to the brain via penetrating through the blood-brain barrier and acting on the vagal afferents, while the latter remains unproved. This study aimed to clarify whether insulin directly regulates the nodose ganglion neurons (NGNs of vagal afferents in mice. NGs expressed insulin receptor (IR and insulin receptor substrate-2 (IRS2 mRNA, and some of NGNs were immunoreactive to IR. In patch-clamp and fura-2 microfluorometric studies, insulin (10(-12∼10(-6 M depolarized and increased cytosolic Ca(2+ concentration ([Ca(2+]i in single NGNs. The insulin-induced [Ca(2+]i increases were attenuated by L- and N-type Ca(2+ channel blockers, by phosphatidylinositol 3 kinase (PI3K inhibitor, and in NGNs from IRS2 knockout mice. Half of the insulin-responsive NGNs contained cocaine- and amphetamine-regulated transcript. Neuronal fibers expressing IRs were distributed in/around pancreatic islets. The NGNs innervating the pancreas, identified by injecting retrograde tracer into the pancreas, responded to insulin with much greater incidence than unlabeled NGNs. Insulin concentrations measured in pancreatic vein was 64-fold higher than that in circulation. Elevation of insulin to 10(-7 M recruited a remarkably greater population of NGNs to [Ca(2+]i increases. Systemic injection of glibenclamide rapidly released insulin and phosphorylated AKT in NGs. Furthermore, in IRS2 knockout mice, insulin action to suppress [Ca(2+]i in orexigenic ghrelin-responsive neurons in hypothalamic arcuate nucleus was intact while insulin action on NGN was markedly attenuated, suggesting a possible link between impaired insulin sensing by NGNs and hyperphagic obese phenotype in IRS2 knockout mice These data demonstrate that insulin directly activates NGNs via IR-IRS2-PI3K-AKT-cascade and depolarization-gated Ca(2+ influx. Pancreas

  17. Low-dose DNA adduct dosimetry by accelerator mass spectrometry (AMS)

    International Nuclear Information System (INIS)

    Turteltaub, K.W.; Felton, J.S.; Vogel, J.S.; Gledhill, B.L.; Davis, J.C.; Snyderwine, E.G.; Thorgeirsson, S.S.; Adamson, R.H.

    1991-01-01

    DNA adduction was measured following exposure to low doses of [2- 14 C]-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) [2- 14 C]-2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and [U- 14 C]-2,3,7,8-tetrachlorodibenzo-p-dioxin by AMS, a technique used in the earth sciences but not previously in toxicological research. The ability to measure low concentrations of rare isotopes suggested that biomedical research was a potentially powerful application for this technology. Sensitivity of the method was found to be one adduct per 10 11 nucleotides. No DNA adduct formation could be detected in TCDD treated rodents. DNA adducts in cynomolgus monkey lymphocytes following exposure to 500 μg/kg IQ peaked between 6 and 18 hrs following exposure. Sensitivity was limited mainly by the abundance of 14 C in contemporary carbon. Hosts depleted in radiocarbon are being developed, potentially increasing sensitivity another 3 orders of magnitude. These results demonstrate the high sensitivity of AMS for tracing molecules following administration of low levels of isotopically-labeled xenobiotics. In addition to 14 C measurement, AMS offers potential to conduct studies with other isotopes, particularly 3 H and 41 Ca

  18. Role of CYP1B1 in PAH-DNA Adduct Formation and Breast Cancer Risk

    National Research Council Canada - National Science Library

    Goth-Goldstein, Regine

    2002-01-01

    ...) to reactive intermediates appears to be the cytochrome P45O enzyme CYPlB1. High CYPlB1 enzyme levels may result in increased formation of PAH-DNA adducts in breast tissue and lead to subsequent development of breast cancer...

  19. In vitro adduct formation of phosgene with albumin and hemoglobin in human blood

    NARCIS (Netherlands)

    Noort, D.; Hulst, A.G.; Fidder, A.; Gurp, R.A. van; Jong, L.P.A. de; Benschop, H.P.

    2000-01-01

    The development of procedures for retrospective detection and quantitation of exposure to phosgene, based on adducts to hemoglobin and albumin, is described. Upon incubation of human blood with [14C]phosgene (0-750 μM), a significant part of radioactivity (0-13%) became associated with globin and

  20. Eccentric hip adduction and abduction strength in elite soccer players and matched controls

    DEFF Research Database (Denmark)

    Thorborg, Kristian; Couppé, C; Petersen, J

    2011-01-01

    Eccentric hip adduction and abduction strength plays an important role in the treatment and prevention of groin injuries in soccer players. Lower extremity strength deficits of less than 10% on the injured side, compared to the uninjured side, have been suggested as the clinical milestone before...... returning to sports following injury....

  1. Formation of a Hydroxymethylfurfural-Cysteine Adduct and Its Absorption and Cytotoxicity in Caco-2 Cells.

    Science.gov (United States)

    Zhao, Qianzhu; Zou, Yueyu; Huang, Caihuan; Lan, Ping; Zheng, Jie; Ou, Shiyi

    2017-11-15

    Adducts of 5-hydroxymethylfurfural (HMF)-amino acids are formed during food processing and digestion; the elimination capacity of in vitro intestinal digests of biscuits, instant noodles, and potato crisps for HMF is 652, 727, and 540 μg/g, respectively. However, the safety of these adducts is unknown. In this study, an HMF-cysteine adduct named 1-dicysteinethioacetal-5-hydroxymehtylfurfural (DCH), which was found to be produced in the gastrointestinal tract after HMF intake, was prepared to test its effect toward Caco-2 cells. Compared with HMF, the adduct displayed lower cytotoxicity against Caco-2 cells with an IC 50 value of 31.26 mM versus 14.95 mM (HMF). The DCH did not induce cell apoptosis, whereas HMF significantly increased the apoptosis rate after incubation at concentrations of 16, 32, and 48 mM for 72 h. DCH showed an absorption rate considerably lower than that of HMF by Caco-2 cells. Lower absorption of DCH may result in lower toxicity compared with HMF against Caco-2 cells. Intracellular transformation of DCH has been observed.

  2. Hemoglobin adducts in 1,3-butadiene exposed Czech workers: Female–male comparisons

    Czech Academy of Sciences Publication Activity Database

    Vacek, P. M.; Albertini, R. J.; Šrám, Radim; Upton, P.; Swenberg, J. A.

    2010-01-01

    Roč. 188, č. 3 (2010), s. 668-676 ISSN 0009-2797 Institutional research plan: CEZ:AV0Z50390512 Keywords : 3-Butadiene * metabolism * THB-Val hemoglobin adducts Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.832, year: 2010

  3. Cisplatin-DNA adduct formation in rat spermatozoa and its effect on fetal development

    NARCIS (Netherlands)

    Hooser, S.T.; Dijk-Knijnenburg, C.M. van; Waalkens-Berendsen, I.D.H.; Smits-van Prooije, A.E.; Snoeij, N.J.; Baan, R.A.; Fichtinger-Schepman, M.J.

    2000-01-01

    Exposure of males to some genotoxic chemicals causes DNA damage in spermatozoa resulting in embryotoxicity and developmental defects in their offspring. This study demonstrates that cisplatin-DNA adducts could be measured in spermatozoa following treatment with the antineoplastic drug, cisplatin.

  4. Comprehensive DNA Adduct Analysis Reveals Pulmonary Inflammatory Response Contributes to Genotoxic Action of Magnetite Nanoparticles

    Directory of Open Access Journals (Sweden)

    Kousuke Ishino

    2015-02-01

    Full Text Available Nanosized-magnetite (MGT is widely utilized in medicinal and industrial fields; however, its toxicological properties are not well documented. In our previous report, MGT showed genotoxicity in both in vitro and in vivo assay systems, and it was suggested that inflammatory responses exist behind the genotoxicity. To further clarify mechanisms underlying the genotoxicity, a comprehensive DNA adduct (DNA adductome analysis was conducted using DNA samples derived from the lungs of mice exposed to MGT. In total, 30 and 42 types of DNA adducts were detected in the vehicle control and MGT-treated groups, respectively. Principal component analysis (PCA against a subset of DNA adducts was applied and several adducts, which are deduced to be formed by inflammation or oxidative stress, as the case of etheno-deoxycytidine (εdC, revealed higher contributions to MGT exposure. By quantitative-LC-MS/MS analysis, εdC levels were significantly higher in MGT-treated mice than those of the vehicle control. Taken together with our previous data, it is suggested that inflammatory responses might be involved in the genotoxicity induced by MGT in the lungs of mice.

  5. Immunomagnetic separation and quantification of butyrylcholinesterase nerve agent adducts in human serum

    NARCIS (Netherlands)

    Sporty, J.L.S.; Lemire, S.W.; Jakubowski, E.M.; Renner, J.A.; Evans, R.A.; Williams, R.F.; Schmidt, J.G.; Schans, M.J. van der; Noort, D.; Johnson, R.C.

    2010-01-01

    A novel method for extracting butyrylcholinesterase (BuChE) from serum as a means of identifying and measuring nerve agent adducts to human BuChE is presented here. Antibutyrylcholinesterase monoclonal antibodies were conjugated to protein-G ferromagnetic particles and mixed with 500 μL serum

  6. Effect of external electric field on Cyclodextrin-Alcohol adducts: A ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Chemical Sciences; Volume 127; Issue 6. Effect of external electric field on Cyclodextrin-Alcohol adducts: A DFT study. Kundan Baruah Pradip Kr Bhattacharyya. Regular Articles Volume 127 Issue 6 June 2015 pp 1109-1117 ... Keywords. Membrane; electric field; DFT; reactivity descriptor; MHP.

  7. ANTIMONY HALIDES AND HgX2 (X = Cl, Br AMINE ADDUCTS: SYNTHESIS AND INFRARED STUDY

    Directory of Open Access Journals (Sweden)

    NDONGO GUEYE

    2013-12-01

    Full Text Available Eight new SbF3, SbCl5 and HgX2 (X = Cl, Br amine adducts have been synthesized and their infrared study carried out. Discrete structures have been suggested on the basis of elemental analysis and infrared data, the coordination number of antimony varying from five to nine, while the environment around Hg is tetrahedral.

  8. Eccentric hip adduction and abduction strength in elite soccer players and matched controls

    DEFF Research Database (Denmark)

    Thorborg, K; Couppé, C; Petersen, J

    2011-01-01

    Eccentric hip adduction and abduction strength plays an important role in the treatment and prevention of groin injuries in soccer players. Lower extremity strength deficits of less than 10% on the injured side, compared to the uninjured side, have been suggested as the clinical milestone before...

  9. Effect of external electric field on Cyclodextrin-Alcohol adducts: A ...

    Indian Academy of Sciences (India)

    Keywords. Membrane; electric field; DFT; reactivity descriptor; MHP. 1. Introduction. Cyclodextrins (CDs) are natural ... for membrane preparations, which are used extensively in separation science offering a good choice .... culated BSSE corrected gas phase interaction energies in adducts (figure 1) are found to be −33.737, ...

  10. Kinetics of formation of specific styrene oxide adducts in double-stranded DNA

    Czech Academy of Sciences Publication Activity Database

    Koskinen, M.; Vodičková, L.; Vodička, Pavel; Warner, S. C.; Hemminki, K.

    2001-01-01

    Roč. 138, č. 2 (2001), s. 111-124 ISSN 0009-2797 R&D Projects: GA ČR GA313/99/1460 Grant - others:EU(XC) QLK4-1999-01368 Institutional research plan: CEZ:AV0Z5039906 Keywords : biomonitoring * DNA adducts Subject RIV: EA - Cell Biology Impact factor: 1.706, year: 2001

  11. 32P-Postlabelling/HPLC analysis of various styrene-induced DNA adducts in mice

    Czech Academy of Sciences Publication Activity Database

    Koskinen, M.; Vodička, Pavel; Vodičková, L.; Hemminki, K.

    2001-01-01

    Roč. 6, č. 3 (2001), s. 175-189 ISSN 1354-750X R&D Projects: GA ČR GA313/99/1460 Grant - others:GA-(EU) QLK4-1999-01368 Institutional research plan: CEZ:AV0Z5039906 Keywords : DNA adducts Subject RIV: EA - Cell Biology Impact factor: 1.118, year: 2001

  12. Effect of Nanoemitters on Suppressing the Formation of Metal Adduct Ions in Electrospray Ionization Mass Spectrometry.

    Science.gov (United States)

    Hu, Jun; Guan, Qi-Yuan; Wang, Jiang; Jiang, Xiao-Xiao; Wu, Zeng-Qiang; Xia, Xing-Hua; Xu, Jing-Juan; Chen, Hong-Yuan

    2017-02-07

    In the work, we showed that the use of nanoemitters (tip dimension metal adduction to peptide or protein ions as well as improve the matrix tolerance of electrospray ionization mass spectrometry (ESI-MS). The proton-enriched smaller initial droplets are supposed to have played a significant role in suppressing the formation of metal adduct ions in nanoemitters. The proton-enrichment effect in the nanoemitters is related to both the exclusion-enrichment effect (EEE) and the ion concentration polarization effect (ICP effect), which permit the molecular ions to be regulated to protonated ones. Smaller initial charged droplets generated from nanoemitters need less fission steps to release the gas-phase ions; thus, the enrichment effect of salt was not as significant as that of microemitters (tip dimension >1 μm), resulting in the disappearing of salt cluster peaks in high mass-to-charge (m/z) region. The use of nanoemitters demonstrates a novel method for tuning the distribution of the metal-adducted ions to be in a controlled manner. This method is also characterized by ease of use and high efficiency in eliminating the formation of adduct ions, and no pretreatment such as desalting is needed even in the presence of salt at millimole concentration.

  13. Crystal structure of the pyridine-diiodine (1/1) adduct.

    Science.gov (United States)

    Tuikka, Matti; Haukka, Matti

    2015-07-01

    In the title adduct, C5H5N·I2, the N-I distance [2.424 (8) Å] is remarkably shorter than the sum of the van der Waals radii. The line through the I atoms forms an angle of 78.39 (16)° with the normal to the pyridine ring.

  14. Crystal structure of the pyridine–diiodine (1/1 adduct

    Directory of Open Access Journals (Sweden)

    Matti Tuikka

    2015-07-01

    Full Text Available In the title adduct, C5H5N·I2, the N—I distance [2.424 (8 Å] is remarkably shorter than the sum of the van der Waals radii. The line through the I atoms forms an angle of 78.39 (16° with the normal to the pyridine ring.

  15. Poly(acrylic acid)/poly(ethylene glycol) adduct for attaining multifunctional cellulosic fabrics.

    Science.gov (United States)

    Ibrahim, N A; Amr, A; Eid, B M; Mohamed, Z E; Fahmy, H M

    2012-06-20

    Aqueous polymerization of partially neutralized acrylic acid (AA) along with polyethylene glycol (PEG-600) at AA/PEG-600 mass ratio 3/1 using ammonium persulfate as initiator under proper conditions results in formation of PAA/PEG-600 adduct. The structure of the adduct was confirmed by FT-IR spectra. The potential applications of the prepared adduct in: sizing, durable hand building of cotton cellulose, as well as in functional finishing of cellulose containing fabrics, i.e. cotton, viscose and cotton/polyester, with Ag- or TiO2-nanoparticles were investigated. The modified substrates using the prepared adduct showed a remarkable improvement in their sizing, hand building and/or functional properties, i.e. antibacterial, anti-UV, and self cleaning, in addition to durability to wash. TEM images of the prepared nano-particles, SEM images of the untreated and treated substrates, as well as EDX spectra to analyze the surface elemental compositions were examined. The tentative mechanisms were also suggested. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Adducts compounds of lanthanides (III) trifluoreacetates and yttrium and the N,N - dimenthylformamide

    International Nuclear Information System (INIS)

    Silva, M. das G. da.

    1983-01-01

    Some studies on lanthanides, f transition elements, and yttrium are presented. Adducts of lanthanides trifluoroacetates and N,N -dimethylformamide are described. The characterization of complexes from elementar analysis, conductance measurements, X-ray patterns, vibrational, electronics and fluorescence spectra are analysed. (M.J.C.) [pt

  17. Bulky DNA adducts in white blood cells: a pooled analysis of 3600 subjects

    Czech Academy of Sciences Publication Activity Database

    Ricceri, F.; Godschalk, R. W.; Peluso, M.; Philips, D. H.; Agudo, A.; Georgiadis, P.; Loft, S.; Tjonneland, A.; Raaschau-Nielsen, O.; Palli, D.; Perera, F.; Vermeulen, R.; Taioli, E.; Šrám, Radim; Munnia, A.; Rosa, F.; Allione, A.; Matullo, G.; Vineis, P.

    2010-01-01

    Roč. 19, č. 12 (2010), s. 3174-3181 ISSN 1055-9965 Grant - others:European Union ECNIS(XE) FOOD-CT-2005-513943 Institutional research plan: CEZ:AV0Z50390512 Keywords : DNA adducts * biomarkers of exposure * air pollution Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 4.190, year: 2010

  18. DNA adducts and atherosclerotic: A study of accidental and sudden death males in the Czech Republic

    Czech Academy of Sciences Publication Activity Database

    Binková, Blanka; Šmerhovský, Zdeněk; Strejc, P.; Boubelík, O.; Stávková, Zdena; Chvátalová, Irena; Šrám, Radim

    č. 501 (2002), s. 115-128 ISSN 0027-5107 R&D Projects: GA MŽP SI/340/1/97 Institutional research plan: CEZ:AV0Z5039906 Keywords : atherosclerosis * DNA-adducts * GSTM1 and CYP1A1 polymorphism Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 3.158, year: 2002

  19. Hemoglobin adducts of epoxybutene in workers occupationally exposed to 1,3-butadiene

    Czech Academy of Sciences Publication Activity Database

    Begemann, P.; Šrám, Radim; Neumann, H. G.

    2001-01-01

    Roč. 74, - (2001), s. 680-687 ISSN 0340-5761 Grant - others:EU(XC) CIPA-CT93-0228 Institutional research plan: CEZ:AV0Z5039906 Keywords : biomonitoring * hemoglobin adducts Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 1.558, year: 2001

  20. Kinetics of Hydrogen Radical Reactions with Toluene Including Chemical Activation Theory Employing System-Specific Quantum RRK Theory Calibrated by Variational Transition State Theory.

    Science.gov (United States)

    Bao, Junwei Lucas; Zheng, Jingjing; Truhlar, Donald G

    2016-03-02

    Pressure-dependent reactions are ubiquitous in combustion and atmospheric chemistry. We employ a new calibration procedure for quantum Rice-Ramsperger-Kassel (QRRK) unimolecular rate theory within a chemical activation mechanism to calculate the pressure-falloff effect of a radical association with an aromatic ring. The new theoretical framework is applied to the reaction of H with toluene, which is a prototypical reaction in the combustion chemistry of aromatic hydrocarbons present in most fuels. Both the hydrogen abstraction reactions and the hydrogen addition reactions are calculated. Our system-specific (SS) QRRK approach is adjusted with SS parameters to agree with multistructural canonical variational transition state theory with multidimensional tunneling (MS-CVT/SCT) at the high-pressure limit. The new method avoids the need for the usual empirical estimations of the QRRK parameters, and it eliminates the need for variational transition state theory calculations as a function of energy, although in this first application we do validate the falloff curves by comparing SS-QRRK results without tunneling to multistructural microcanonical variational transition state theory (MS-μVT) rate constants without tunneling. At low temperatures, the two approaches agree well with each other, but at high temperatures, SS-QRRK tends to overestimate falloff slightly. We also show that the variational effect is important in computing the energy-resolved rate constants. Multiple-structure anharmonicity, torsional-potential anharmonicity, and high-frequency-mode vibrational anharmonicity are all included in the rate computations, and torsional anharmonicity effects on the density of states are investigated. Branching fractions, which are both temperature- and pressure-dependent (and for which only limited data is available from experiment), are predicted as a function of pressure.

  1. Comparison of Bile Acids and Acetaminophen Protein Adducts in Children and Adolescents with Acetaminophen Toxicity.

    Directory of Open Access Journals (Sweden)

    Laura James

    Full Text Available Metabolomics approaches have enabled the study of new mechanisms of liver injury in experimental models of drug toxicity. Disruption of bile acid homeostasis is a known mechanism of drug induced liver injury. The relationship of individual bile acids to indicators of oxidative drug metabolism (acetaminophen protein adducts and liver injury was examined in children with acetaminophen overdose, hospitalized children with low dose exposure to acetaminophen, and children with no recent exposure to acetaminophen. Nine bile acids were quantified through targeted metabolomic analysis in the serum samples of the three groups. Bile acids were compared to serum levels of acetaminophen protein adducts and alanine aminotransferase. Glycodeoxycholic acid, taurodeoxycholic acid, and glycochenodeoxycholic acid were significantly increased in children with acetaminophen overdose compared to healthy controls. Among patients with acetaminophen overdose, bile acids were higher in subjects with acetaminophen protein adduct values > 1.0 nmol/mL and modest correlations were noted for three bile acids and acetaminophen protein adducts as follows: taurodeoxycholic acid (R=0.604; p<0.001, glycodeoxycholic acid (R=0.581; p<0.001, and glycochenodeoxycholic acid (R=0.571; p<0.001. Variability in bile acids was greater among hospitalized children receiving low doses of acetaminophen than in healthy children with no recent acetaminophen exposure. Compared to bile acids, acetaminophen protein adducts more accurately discriminated among children with acetaminophen overdose, children with low dose exposure to acetaminophen, and healthy control subjects. In children with acetaminophen overdose, elevations of conjugated bile acids were associated with specific indicators of acetaminophen metabolism and non-specific indicators of liver injury.

  2. Detection of Pyrrolizidine Alkaloid DNA Adducts in Livers of Cattle Poisoned with Heliotropium europaeum.

    Science.gov (United States)

    Fu, Peter P; Xia, Qingsu; He, Xiaobo; Barel, Shimon; Edery, Nir; Beland, Frederick A; Shimshoni, Jakob A

    2017-03-20

    Pyrrolizidine alkaloids are among the most common poisonous plants affecting livestock, wildlife, and humans. Exposure of humans and livestock to toxic pyrrolizidine alkaloids through the intake of contaminated food and feed may result in poisoning, leading to devastating epidemics. During February 2014, 73 mixed breed female beef cows from the Galilee region of Israel were accidently fed pyrrolizidine alkaloid contaminated hay for 42 days, resulting in the sudden death of 24 cows over a period of 63 days. The remaining cows were slaughtered 2.5 months after the last ingestion of the contaminated hay. In this study, we report the histopathological analysis of the livers from five of the slaughtered cows and quantitation of pyrrolizidine alkaloid-derived DNA adducts from their livers and three livers of control cows fed with feed free of weeds producing pyrrolizidine alkaloids. Histopathological examination revealed that the five cows suffered from varying degrees of bile duct proliferation, fibrosis, and megalocytosis. Selected reaction monitoring HPLC-ES-MS/MS analysis indicated that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts were formed in all five livers. The livers from the three control cows did not have any liver damage nor any indication of DHP-DNA adduct formed. These results confirm that the toxicity observed in these cattle was caused by pyrrolizidine alkaloid poisoning and that pyrrolizidine alkaloid-derived DNA adducts could still be detected and quantified in the livers of the chronically poisoned cows 2.5 months after their last exposure to the contaminated feed, suggesting that DHP-derived DNA adducts can serve as biomarkers for pyrrolizidine alkaloid exposure and poisoning.

  3. Full structure assignments of pyrrolizidine alkaloid DNA adducts and mechanism of tumor initiation.

    Science.gov (United States)

    Zhao, Yuewei; Xia, Qingsu; Gamboa da Costa, Gonçalo; Yu, Hongtao; Cai, Lining; Fu, Peter P

    2012-09-17

    Pyrrolizidine alkaloid-containing plants are widespread in the world and are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids are among the first chemical carcinogens identified in plants. Previously, we determined that metabolism of pyrrolizidine alkaloids in vivo and in vitro generated a common set of DNA adducts that are responsible for tumor induction. Using LC-ESI/MS/MS analysis, we previously determined that four DNA adducts (DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4) were formed in rats dosed with riddelliine, a tumorigenic pyrrolizidine alkaloid. Because of the lack of an adequate amount of authentic standards, the structures of DHP-dA-3 and DHP-dA-4 were not elucidated, and the structural assignment for DHP-dG-4 warranted further validation. In this study, we developed an improved synthetic methodology for these DNA adducts, enabling their full structural elucidation by mass spectrometry and NMR spectroscopy. We determined that DHP-dA-3 and DHP-dA-4 are a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl) dehydrosupinidine, while DHP-dG-4 is 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine, an epimer of DHP-dG-3. With the structures of these DNA adducts unequivocally elucidated, we conclude that cellular DNA preferentially binds dehydropyrrolizidine alkaloid, for example, dehydroriddelliine, at the C9 position of the necine base, rather than at the C7 position. We also determined that DHP-dA-3 and DHP-dA-4, as well as DHP-dG-3 and DHP-dG-4, are interconvertible. This study represents the first report with detailed structural assignments of the DNA adducts that are responsible for pyrrolizidine alkaloid tumor induction on the molecular level. A mechanism of tumor initiation by pyrrolizidine alkaloids is consequently fully determined.

  4. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

    2010-04-01

    This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

  5. Effect Of Five Proteases Including Alcalase, Flavourzyme, Papain, Proteinase K And Trypsin On Antioxidative Activities Of Casein Hydrolysate From Goat Milk

    OpenAIRE

    Shu Guowei; Zhang Qian; Chen He; Wan Hongchang; Li Hong

    2015-01-01

    Oxidation was related to the pathogenesis of human diseases. Adequate intake of antioxidant activity of food can reduce the levels of free radicals, prevent lipid peroxidation, and help the body against diseases. In the paper, casein from goat milk was hydrolyzed by five commercial proteases, namely, Alcalase, flavourzyme, papain, proteinase K and trypsin. The antioxidant activities of casein hydrolysates were assessed by evaluating hydrolysis degree, DPPH radical-scavenging activity, metal-c...

  6. Effect Of Five Proteases Including Alcalase, Flavourzyme, Papain, Proteinase K And Trypsin On Antioxidative Activities Of Casein Hydrolysate From Goat Milk

    Directory of Open Access Journals (Sweden)

    Shu Guowei

    2015-12-01

    Full Text Available Oxidation was related to the pathogenesis of human diseases. Adequate intake of antioxidant activity of food can reduce the levels of free radicals, prevent lipid peroxidation, and help the body against diseases. In the paper, casein from goat milk was hydrolyzed by five commercial proteases, namely, Alcalase, flavourzyme, papain, proteinase K and trypsin. The antioxidant activities of casein hydrolysates were assessed by evaluating hydrolysis degree, DPPH radical-scavenging activity, metal-chelating activity and superoxide radical scavenging activity. The results showed as follows: the DH of proteinase K, Alcalase, and trypsin were higher significantly than those of papain and flavourzyme. The Fe2+-chelation activity and superoxide radical scavenging activity of casein hydrolysates from goat milk by Alcalase was higher than the others, the DPPH scavenging activities of casein hydrolysates by Alcalase and papain was higher than the others and the DPPH scavenging activities by Alcalase and papain had no significant diffierence (p<0.05, so the optimal proteinase for hydrolysis casein from goat milk to produce antioxidant peptide was Alcalase.

  7. Changes in abdominal muscle thickness measured by ultrasound are not associated with recovery in athletes with longstanding groin pain associated with resisted hip adduction.

    Science.gov (United States)

    Jansen, J A C G; Mens, J M A; Backx, Frank J G; Stam, Henk J

    2009-10-01

    Longitudinal single-cohort study. Athletes with longstanding groin pain associated with resisted hip adduction have been shown to have abnormal activation of the transversus abdominis (TA). Therefore, exercises targeting the TA to help stabilize the lumbopelvic area are generally used in the rehabilitation of these athletes. To investigate if (1) changes in abdominal muscle resting thickness and changes in relative thickness during lower extremity tasks after 14 weeks of intervention are related to changes in clinical status and (2) the changes in abdominal muscle resting/relative thickness are significant postintervention. In 21 athletes with longstanding groin pain associated with resisted hip adduction, ultrasound imaging of the abdominal musculature on the right side was performed at rest, during the active straight-leg raise (left and right), and during bilateral isometric hip adduction. Athletes then followed a 14-week rehabilitation protocol. Clinical outcome measured by self-reported sports restriction and change in abdominal muscle resting and relative thickness during lower extremity tasks were evaluated. There was an overall significant decrease in self-reported sports restriction after intervention for this group of athletes. Apart from a significant negative correlation for changes in TA resting thickness, no significant association between changes in abdominal muscle thickness and change in self-reported sports restriction were found. Postintervention, TA resting thickness was significantly increased but relative thickness during the lower extremity tasks was found not to be statistically different for all muscles, except for a decreased relative thickness of obliquus externus abdominus (OE) during the active straight-leg raise for the left lower extremity. There was no association between changes in abdominal muscle resting thickness and relative thickness during lower extremity tasks, and change in self-reported sports restriction after a period of

  8. DNA adduct formation in B6C3F1 mice and Fischer-344 rats exposed to 1,2,3-trichloropropane.

    Science.gov (United States)

    La, D K; Lilly, P D; Anderegg, R J; Swenberg, J A

    1995-06-01

    1,2,3-Trichloropropane (TCP) is a multispecies, multisite carcinogen which has been found to be an environmental contaminant. In this study, we have characterized and measured DNA adducts formed in vivo following exposure to TCP. [14C]TCP was administered to male B6C3F1 mice and Fischer-344 rats by gavage at doses used in the NTP carcinogenesis bioassay. Both target and nontarget organs were examined for the formation of DNA adducts. Adducts were hydrolyzed from DNA by neutral thermal or mild acid hydrolysis, isolated by HPLC, and detected and quantitated by measurement of radioactivity. The HPLC elution profile of radioactivity suggested that one major DNA adduct was formed. To characterize this adduct, larger yields were induced in rats by intraperitoneal administration of TCP (300 mg/kg). The DNA adduct was isolated by HPLC based on coelution with the radiolabeled adduct, and compared to previously identified adducts. The isolated adduct coeluted with S-[1-(hydroxymethyl)-2-(N7-guanyl)-ethyl]glutathione, an adduct derived from the structurally related carcinogen 1,2-dibromo-3-chloropropane (DBCP). Analysis by electrospray mass spectrometry suggested that the TCP-induced adduct and the DBCP-derived adduct were identical. The 14C-labeled DNA adduct was distributed widely among the organs examined. Adduct levels varied depending on species, organ, and dose. In rat organs, adduct concentrations for the low dose ranged from 0.8 to 6.6 mumol per mol guanine and from 7.1 to 47.6 mumol per mol guanine for the high dose. In the mouse, adduct yields ranged from 0.32 to 28.1 mumol per mol guanine for the low dose and from 12.2 to 208.1 mumol per mol guanine for the high dose. The relationship between DNA adduct formation and organ-specific tumorigenesis was unclear. Although relatively high concentrations of DNA adducts were detected in target organs, several nontarget sites also contained high adduct levels. Our data suggest that factors in addition to adduct formation

  9. Syntheses, characterization and crystal structures of novel amine adducts of metal saccharinates, orotates and salicylates

    Science.gov (United States)

    Icbudak, Hasan; Olmez, Halis; Yesilel, Okan Z.; Arslan, Figen; Naumov, Pance; Jovanovski, Gligor; Ibrahim, Abdul Razak; Usman, Anwar; Fun, Hoong-Kun; Chantrapromma, Suchada; Ng, Seik Weng

    2003-09-01

    Seven novel adducts of ethylenediamine (en), N, N'-dimethylethylenediamine (dmen) and N, N-dimethylethylenediamine (ndmen) with saccharinate, orotate and salicylate as counter-ions were synthesized and characterized with physico-chemical methods (IR and UV/vis spectroscopy, magnetic susceptibility and thermoanalytical measurements) and X-ray diffraction. Reaction of dmen with tetraaquabis(saccharinato- N)copper(II) dihydrate yielded diaquabis(dmen)copper(II) saccharinate, whereas with the corresponding nickel derivative it afforded bis(dmen)bis(saccharinato- O)nickel(II). In the copper complex the coordinated water and the primary nitrogen end of the donor ligand interact with the saccharinate anion [O1w⋯O3=2.833(2), N1⋯N2=2.992(2) Å]. Adjacent molecules are linked by two more hydrogen bonds into a layer structure. In the nickel compound, the dmen ligand also chelates the metal atom, which is bonded to the carbonyl oxygen of the anionic group. The negatively-charged nitrogen atom of the anion is intramolecularly linked to the dmen [N1⋯N2=2.968(2) Å]; hydrogen bonds link the molecules into layers. Under mildly basic conditions, the reaction of orotic acid with cobalt(II) afforded tetraaqua(2,6-dioxo-1,2,6-trihydropyrimidine-4-carboxylato- N, O)cobalt(II) hydrate. The complex was oxidatively reacted with en to give a mixed-ligand cobalt(III) adduct which includes both mono- and bisdeprotonated orotate ions. The metal atom in tetraaqua(2,6-dioxo-1,2,6-trihydropyrimidine-4-carboxylato- N, O)cobalt(II) hydrate is chelated by the orotato dianion through the carboxyl oxygen and 3-pyrimidyl nitrogen atoms, and its octahedral geometry is completed by four water molecules. The 1-pyrimidyl nitrogen atom engages in hydrogen bonding with the lattice water molecule. The cobalt atom is similarly chelated by the orotato dianion in bis(en)(2,6-dioxo-1,2,6-trihydropyrimidine-4-carboxylato- N, O)cobalt(III) 2,6-dioxo-1,2,3,6-tetrahydropyridimidine-4-carboxylate

  10. o-Toluidine blood protein adducts: HPLC analysis with fluorescence detection after a single dose in the adult male rat

    International Nuclear Information System (INIS)

    Cheever, K.L.; DeBord, G.D.; Swearengin, T.F.

    1991-01-01

    Hemoglobin (Hb) and albumin (Alb) adducts of the suspect human carcinogen o-toluidine (OT) were quantified in blood samples collected from rats after a single i.p. injection. Mild alkaline hydrolysis of Hb-adducted [ 14 C]OT followed by extraction with ethylacetate resulted in recovery of 66% of the bound radioactivity. HPLC analysis revealed a single radiolabeled peak which was identified as OT by GC-MS. In subsequent experiments the Hb and Alb adduct levels were determined by HPLC analysis of this split product using fluorescence detection. 4-Ethylaniline was used as internal standard. The detection limit for OT was approximately 450 pg/injection of 5 pmol. mg Hb. Mean adduct levels for Hb increased rapidly over the first 4 hr with the highest (ng/mg Hb ± SD) 3.7 ± 0.5 detected 24 hr after OT (50 mg/kg body wt). In contrast, adduct levels for pooled Alb samples increased from 0.7 ng/mg Alb at 2 hr to 2.5 ng/mg Alb at 4 hr, but were not detectable 24 hr after OT (50 mg/kg body wt). In contrast, adduct levels for pooled Alb samples increased from 0.7 ng/mg Alb at 2 hr to 2.5 ng/mg Alb at 4 hr, but were not detectable 24 hr after dosing. Hb adducts showed a linear relationship for OT doses of 10, 20, 40, 50, and 100 mg/kg body wt. The Hb adduct t 1/2 (11.2 days) was determined after a single 100 mg/kg OT dose. Hb adduct levels were quantifiable (1.3 ± 0.2 ng/mg Hb) by HPLC/fluorescence 28 days after 100 mg/kg OT

  11. Effectiveness of interventions on physical activity in overweight or obese children: a systematic review and meta-analysis including studies with objectively measured outcomes.

    Science.gov (United States)

    Nooijen, C F J; Galanti, M R; Engström, K; Möller, J; Forsell, Y

    2017-02-01

    There is no consensus on interventions to be recommended in order to promote physical activity among overweight or obese children. The objective of this review was to assess the effects on objectively measured physical activity, of interventions promoting physical activity among overweight or obese children or adolescents, compared to no intervention or to interventions without a physical activity component. Publications up to December 2015 were located through electronic searches for randomized controlled trials resulting in inclusion of 33 studies. Standardized mean differences from baseline to post-intervention and to long-term follow-up were determined for intervention and control groups and meta-analysed using random effects models. The meta-analysis showed that interventions had no effect on total physical activity of overweight and obese children, neither directly post-intervention (-0.02 [-0.15, 0.11]) nor at long-term follow-up (0.07 [-0.27, 0.40]). Separate analyses by typology of intervention (with or without physical fitness, behavioural or environmental components) showed similar results (no effect). In conclusion, there is no evidence that currently available interventions are able to increase physical activity among overweight or obese children. This questions the contribution of physical activity to the treatment of overweight and obesity in children in the studied interventions and calls for other treatment strategies. © 2017 World Obesity Federation.

  12. Pharmacokinetics of digoxin cross-reacting substances in patients with acute yellow Oleander (Thevetia peruviana) poisoning, including the effect of activated charcoal.

    Science.gov (United States)

    Roberts, Darren M; Southcott, Emma; Potter, Julia M; Roberts, Michael S; Eddleston, Michael; Buckley, Nick A

    2006-12-01

    Intentional self-poisonings with seeds from the yellow oleander tree (Thevetia peruviana) are widely reported. Activated charcoal has been suggested to benefit patients with yellow oleander poisoning by reducing absorption and/or facilitating elimination. Two recent randomized controlled trials (RCTs) assessing the efficacy of activated charcoal yielded conflicting outcomes in terms of mortality. The effect of activated charcoal on the pharmacokinetics of Thevetia cardenolides has not been assessed. This information may be useful for determining whether further studies are necessary. Serial blood samples were obtained from patients enrolled in an RCT assessing the relative efficacy of single-dose and multiple-dose activated charcoal (SDAC and MDAC, respectively) compared with no activated charcoal (NoAC). The concentration of Thevetia cardenolides was estimated with a digoxin immunoassay. The effect of activated charcoal on cardenolide pharmacokinetics was compared between treatment groups by determining the area under the curve for each patient in the 24 hours following admission, the 24-hour mean residence time, and regression lines obtained from serial concentration points, adjusted for exposure. Erratic and prolonged absorption patterns were noted in each patient group. The apparent terminal half-life was highly variable, with a median time of 42.9 hours. There was a reduction in 24-hour mean residence time and in the apparent terminal half-life estimated from linear regression in patients administered activated charcoal, versus the control group (NoAC). This effect was approximately equal in patients administered MDAC or SDAC. Activated charcoal appears to favorably influence the pharmacokinetic profile of Thevetia cardenolides in patients with acute self-poisoning and may have clinical benefits. Given the conflicting clinical outcomes noted in previous RCTs, these mechanistic data support the need for further studies to determine whether a particular subgroup

  13. Isolation, structural elucidation and in vitro activity of 2-acetyl-2-decarboxamido-oxytetracycline against environmental relevant bacteria, including tetracycline-resistant bacteria

    DEFF Research Database (Denmark)

    Lykkeberg, Anne Kruse; Sengeløv, Gitte; Cornett, Claus

    2004-01-01

    i.d., 5 microm), and the mobile phase contained methanol-water (27:73 (v/v)) with 0.08 M formic acid added. The flow rate was 9.0 ml/min. It was possible to isolate few milligram ADOTC in a day. The compound was unambiguously identified using NMR and MS-MS. The anti-microbial activity against...... activated sludge bacteria was determined giving a potency of only 3% of that of OTC. With tetracycline-resistant bacteria, no anti-microbial activity was observed, indicating a mode of action similar to that of OTC....

  14. Personal Hearing Protection including Active Noise Reduction (Les dispositifs de protection de l'ouie, y compris l'attenuation du bruit actif) (CD-ROM)

    National Research Council Canada - National Science Library

    Steeneken, H. J; Dancer, A; McKinley, R; Buck, K; James, S

    2005-01-01

    .... SYSTEMS DETAIL NOTE: Adobe Acrobat Reader is included on disc. ABSTRACT: Personal hearing protection and speech communication facilities are essential for optimal performance in military operations...

  15. Self-reported activity in tortured refugees with long-term sequelae including pain and the impact of foot pain from falanga - a cross-sectional study

    DEFF Research Database (Denmark)

    Prip, Karen; Persson, Ann L; Sjölund, Bengt H

    2011-01-01

    Purpose. To describe activity limitations in tortured refugees referred for rehabilitation, particularly the impact of neuropathic pain resulting from falanga (beatings under the feet). Methods. Physiotherapists assessed 103 consecutively referred torture victims with a long history of sequelae......, among them pain and mobility problems. All had been subjected to various forms of physical and psychological torture and 71 victims had also suffered falanga. Main outcome measures used were: the Disability Rating Index (DRI; 12 items) to assess self-reported capacity to carry out daily activities...... of victims who had chronic pain for at least 5 years after torture, all perceived activity limitations, but pain from falanga had a greater overall impact on disability assessed in terms of daily activities....

  16. Attenuation of autoimmune responses to oxidative specific epitopes, but not nitroso-adducts, is associated with a better clinical outcome in Myalgic Encephalomyelitis/chronic fatigue syndrome.

    Science.gov (United States)

    Maes, Michael; Leunis, Jean-Claude

    2014-01-01

    There is evidence that inflammatory, oxidative and nitrosative stress (IO&NS) pathways participate in the pathophysiology of a subgroup of patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Increased IgM-related autoimmune responses to oxidative specific epitopes (OSEs), including malondialdehyde (MDA), oleic acid and phosphatidyl inositol (Pi), and nitroso-(NO)-adducts, including NO-tryptophan (NOW), NO-arginine and NO-cysteinyl, are frequently observed in ME/CFS. Autoimmune responses in ME/CFS may be driven by increased bacterial translocation as measured by IgM and IgA responses to LPS of gram negative bacteria. The aim of this study is to examine whether IgM responses to OSEs and NO-adducts are related to a better outcome as measured by the Fibromyalgia and Fatigue Rating Scale (FF). 76 ME/CFS patients with initially abnormal autoimmune responses were treated with care-as-usual, including nutraceuticals with anti-IO&NS effects (NAIOS), such as L-carnitine, coenzyme Q10, taurine + lipoic acid, with or without curcumine + quercitine or N-acetyl-cysteine, zinc + glutamine. We found that use of these NAIOS was associated with highly significant reductions in initially increased IgM-mediated autoimmune responses to OSEs and NO-adducts. A greater reduction in autoimmune responses to OSEs during intake of these NAIOS was associated with a lower FF score. Reductions in IgM responses to oleic acid, MDA and Pi, but not in any of the NO-adducts, were associated with reductions in severity of illness. These associations remained significant after adjusting for possible effects of increased bacterial translocation (leaky gut). Our results show that autoimmune responses to OSEs are involved in the pathophysiology of ME/CFS and that these pathways are a new drug target in a subgroup of ME/CFS patients. Although hypernitrosylation and nitrosative stress play a role in ME/CFS, reductions in these pathways are not associated with lowered severity of

  17. Isolation, structural elucidation and in vitro activity of 2-acetyl-2-decarboxamido-oxytetracycline against environmental relevant bacteria, including tetracycline-resistant bacteria

    DEFF Research Database (Denmark)

    Lykkeberg, Anne Kruse; Sengeløv, Gitte; Cornett, Claus

    2004-01-01

    2-Acetyl-2-decarboxamido-oxytetracycline (ADOTC) is a major impurity of oxytetracycline (OTC) produced as a side product during fermentation. ADOTC was isolated from OTC and other impurities using preparative HPLC. The preparative column was an Xterra MS. C-18 chromatographic column (100 mm x 19...... turn W., 5 mum), and the mobile phase contained methanol-water (27:73 (v/v)) with 0.08 M formic acid added. The flow rate was 9.0 ml/min. It was possible to isolate few milligram ADOTC in a day. The compound was unambiguously identified using NMR and MS-MS. The anti-microbial activity against activated...... sludge bacteria was deter-mined giving a potency of only 3% of that of OTC. With tetracycline-resistant bacteria, no anti-microbial activity was observed, indicating a mode of action similar to that of OTC....

  18. The Recombinant Bacteriophage Endolysin HY-133 Exhibits In Vitro Activity against Different African Clonal Lineages of the Staphylococcus aureus Complex, Including Staphylococcus schweitzeri.

    Science.gov (United States)

    Idelevich, Evgeny A; Schaumburg, Frieder; Knaack, Dennis; Scherzinger, Anna S; Mutter, Wolfgang; Peters, Georg; Peschel, Andreas; Becker, Karsten

    2016-04-01

    HY-133 is a recombinant bacteriophage endolysin with bactericidal activity againstStaphylococcus aureus Here, HY-133 showedin vitroactivity against major African methicillin-susceptible and methicillin-resistantS. aureuslineages and ceftaroline/ceftobiprole- and borderline oxacillin-resistant isolates. HY-133 was also active againstStaphylococcus schweitzeri, a recently described species of theS. aureuscomplex. The activity of HY-133 on the tested isolates (MIC50, 0.25 μg/ml; MIC90, 0.5 μg/ml; range, 0.125 to 0.5 μg/ml) was independent of the species and strain background or antibiotic resistance. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  19. Update of the BIPM.RI(II)-K1.Rn-222 comparison of activity measurements for the radionuclide {sup 222}Rn to include the LNE-LNHB, France

    Energy Technology Data Exchange (ETDEWEB)

    Michotte, C.; Ratel, G. [Bureau International de Poids et Mesures, Pavillon de Breteuil, F-92312 Sevres cedex (France); Cassette, P. [Bureau International de Poids et Mesures, Pavillon de Breteuil, F-92312 Sevres cedex (France); Laboratoire national de metrologie et d' essais -Laboratoire national Henri Becquerel, 91191 Gif-sur-Yvette cedex (France)

    2012-02-15

    In 2007, the Laboratoire national de metrologie et d'essais - Laboratoire national Henri Becquerel (LNE-LNHB), France submitted a sample of known activity of {sup 222}Rn to the International Reference System (SIR) for comparison. The value of the activity submitted was about 90 kBq. This key comparison result joins that of Switzerland and Germany in the key comparison database that now contains three results, identifier BIPM.RI(II)-K1.Rn-222. Consequently, the KCRV has been updated and the degrees of equivalence with the KCRV have been evaluated. (authors)

  20. Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation.

    Science.gov (United States)

    Carruthers, Nicholas J; Stemmer, Paul M; Chen, Ben; Valeriote, Frederick; Gao, Xiaohua; Guatam, Subhash C; Shaw, Jiajiu

    2017-09-15

    UTL-5g is a novel small-molecule TNF-alpha modulator. It reduces cisplatin-induced side effects by protecting kidney, liver, and platelets, thereby increasing tolerance for cisplatin. UTL-5g also reduces radiation-induced acute liver toxicity. The mechanism of action for UTL-5g is not clear at the present time. A phosphoproteomic analysis to a depth of 4943 phosphopeptides and a luminescence-based transcription factor activity assay were used to provide complementary analyses of signaling events that were disrupted by UTL-5g in RAW 264.7 cells. Transcriptional activity downstream of the interferon gamma, IL-6, type 1 Interferon, TGF-β, PKC/Ca 2+ and the glucocorticoid receptor pathways were disrupted by UTL-5g. Phosphoproteomic analysis indicated that hyperphosphorylation of proteins involved in actin remodeling was suppressed by UTL-5g (gene set analysis, FDR 5g. This global characterization of UTL-5g activity in a macrophage cell line discovered that it disrupts selected aspects of LPS signaling including Stat3 activation and actin remodeling providing new insight on how UTL-5g acts to reduce cisplatin-induced side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Spectra and structure of gallium compounds. Part IX . Infrared and Raman spectra of trimethylphosphinegallium trichloride and normal coordinate calculations of gallium trichloride and the adduct

    Science.gov (United States)

    Durig, J. R.; Chatterjee, K. K.

    1982-05-01

    The infrared (3200-50 cm -1)and the Raman (3200-30 cm -1) spectra of (CH 3) 3PGaCI 3 have been recorded for the solid state. The spectra are interpreted on the basis of an effective C3v molecular symmetry for the crystalline state and a complete vibrational assignment except for the torsional modes is presented. The frequencies and potential energy distribution for GaCl 3 and those of the adduct have been calculated utilizing a modified valence force field model. A comparison of the calculated potential constants for the adduct with those of the free Lewis acid and base is made and the differences are shown to be consistent with structural changes upon adduct formation and explained in terms of the VSEPR model. Extensive coupling is observed between the GaP stretching mode and the GaCI 3 and the PC 3 stretching and symmetric deformational modes. Various degrees of coupling are also observed between other skeletal modes of vibration, including coupling between the PC 3 and GaCI 3 rocking motions. The value of 2.01 mdyn Å -1 for the GaP stretching force constant is the same as that previously determined for the same constant for (CH 3) 3PGaH 3. Several weak bands, observed in the low frequency region of the infrared and Raman spectra of crystalline (CH 3) 3PGaCl 3, are characterized as lattice modes arising from intermolecular librations. These results are compared to the similar quantities in some corresponding molecules.

  2. A probiotic mixture including galactooligosaccharides decreases fecal β-glucosidase activity but does not affect serum enterolactone concentration in men during a two-week intervention.

    Science.gov (United States)

    Kekkonen, Riina A; Holma, Reetta; Hatakka, Katja; Suomalainen, Tarja; Poussa, Tuija; Adlercreutz, Herman; Korpela, Riitta

    2011-05-01

    A high serum concentration of enterolactone, an enterolignan produced by colonic microbiota from precursors in cereals, vegetables, and fruits, is associated with reduced risk of acute coronary events. Probiotics and prebiotics modify colonic metabolism and may affect the serum enterolactone concentration. The effects of a probiotic mixture alone and with galactooligosaccharides (GOS) on serum enterolactone concentration and fecal metabolism were investigated in 18 healthy men. Participants received 3 interventions, each for 2 wk: 1) probiotics [Lactobacillus rhamnosus strains GG (LGG) and LC705, Propionibacterium freudenreichii ssp. shermanii JS, and Bifidobacterium breve Bb99, for a total amount of 2 × 10(10) CFU/d]; 2) probiotics and GOS 3.8 g/d; 3) probiotics, GOS, and rye bread (minimum 120 g/d). Serum enterolactone and fecal dry weight, enzyme activities, pH, SCFA, lactic acid bacteria, bifidobacteria, propionibacteria, and the strains LGG and LC705 were determined. The serum enterolactone concentration (nmol/L) tended to be decreased from baseline [mean (95% CI) 18.6 (10.8-26.4)] by probiotics alone [15.2 (7.8-22.7); P = 0.095], was not significantly affected by probiotics with GOS [21.5 (13.2-29.8)], and was increased by probiotics with GOS and rye bread [24.6 (15.4-33.7); P < 0.05]. Probiotics alone did not affect fecal β-glucosidase activity and bifidobacteria, but probiotics with GOS decreased β-glucosidase activity and increased bifidobacteria compared with baseline (P < 0.05) and with probiotics alone (P < 0.01). In conclusion, this probiotic mixture with or without GOS does not significantly affect serum enterolactone concentration. Because probiotics with GOS decreased fecal β-glucosidase activity but not serum enterolactone, the reduced fecal β-glucosidase, within the range of activities measured, does not seem to limit the formation of enterolactone.

  3. Determination of Catechol Estrogen Adducts by High-Performance Liquid Chromatography: Establishing Biomarkers for the Early Detection of Breast Cancer

    National Research Council Canada - National Science Library

    Stack, Douglas

    2002-01-01

    In order to better understand the role of estrogen metabolism as it relates to breast cancer etiology, a new analytical technique that can measure CE and CE-DNA adducts at low endogenous levels is being developed...

  4. Determination of Catechol Estrogen Adducts by High-Performance Liquid Chromatography: Establishing Biomarkers for the Early Detection of Breast Cancer

    National Research Council Canada - National Science Library

    Stack, Douglas

    2001-01-01

    In order to better understand the role of estrogen metabolism as it relates to breast cancer etiology, a new analytical technique that can measure CE and CE-DNA adducts at low endogenous levels is being developed...

  5. SYNTHESIS AND INFRARED STUDY OF SOME NEW MOLYBDATO AND HYDROGENOMOLYBDATO ADDUCTS AND COMPLEXES OF COBALT, ZINC, ANTIMONY AND CADMIUM CHLORIDES

    Directory of Open Access Journals (Sweden)

    SERIGNE FALLOU POUYE

    2014-01-01

    Full Text Available Five new molybdato (four and hydrogenomolybdato (one adducts and complexes have been synthesized and studied by infrared spectroscopy. The suggested structures are all discrete, the molybdate anion behaving as a trichelating, a monochelating, a bridging, a tetrachelating and a bichelating ligand. The environment around Zn, Co, Cd is tetrahedral or trigonal bipyramidal also for Zn - while being octahedral for Sb. The Cd pentanuclear adduct has a two metallic components structure, a tetranuclear anionic one with a tetrachelating molybdate, the second being a neutral dehydrated adduct component. The suggested structure for the hydrogenomolybdato adduct is discrete, the hydrogenomolybdate being present as a hydrogen bonded dimer behaves as a bridging bidentate ligand. The water molecules can be considered as a coordinating ligand or lattice. When secondary interactions through hydrogen bonds involving the water molecules are considered supramolecular architectures are obtained.

  6. The association between submaximal quadriceps force steadiness and the knee adduction moment during walking in patients with knee osteoarthritis

    DEFF Research Database (Denmark)

    Sørensen, Tina Juul; Langberg, Henning; Aaboe, Jens

    2011-01-01

    , and knee pain was assessed using the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale and a visual analog scale. RESULTS: Regression analyses showed that quadriceps force steadiness did not predict the peak knee adduction moment (adjusted R2 = 0.05, P = .41). Inclusion of covariates did......STUDY DESIGN: Cross-sectional study. OBJECTIVES: To investigate the relationship between quadriceps force steadiness and knee adduction moment during walking in patients with knee osteoarthritis (OA). BACKGROUND: Studies have shown that quadriceps force steadiness is impaired in patients with knee...... OA. Furthermore, patients with knee OA, compared to healthy controls, have also demonstrated a significantly higher external knee adduction moment during walking. However, no studies have examined the relationship between quadriceps force steadiness and the peak knee adduction moment during walking...

  7. Diagnosis and Dosimetry of Exposure to Sulfur Mustard: Development of Standard Operating Procedures; Further Exploratory Research on Protein Adducts

    National Research Council Canada - National Science Library

    Benschop, H

    1999-01-01

    .... Both procedures could be substantially shortened, while their sensitivities were improved. Furthermore, exploratory research is performed aiming at the development of a fieldable immunochemical assay for sulfur mustard adducts with proteins, i.e...

  8. U.S. Geological Survey Scientific Activities in the Exploration of Antarctica: Introduction to Antarctica (Including USGS Field Personnel: 1946-59)

    Science.gov (United States)

    Tony K. Meunier Edited by Williams, Richard S.; Ferrigno, Jane G.

    2007-01-01

    INTRODUCTION Antarctica is the planet's fifth largest continent [13.2 million km2 (5.1 million mi2)]; it contains the Earth's largest (of two) remaining ice sheets; it is considered to be one of the most important scientific laboratories on Earth. This report is the introduction to a series that covers 60 years of U.S. Geological Survey (USGS) scientific activity in Antarctica. It will concentrate primarily on three major topics:

  9. Evaluation of a Self-Administered Intravaginal Swab for PCR Detection of Genitourinary Tract Infections Including Chlamydia, Gonorrhea, Trichomonas and Human Papillomavirus in Active Duty Military Women

    Science.gov (United States)

    1998-10-01

    Baltimore, Maryland’ Cayetano Heredia University, Lima , Peru ;2 National Institute of Allergy and Infectious Diseases, National Institutes of Health...STDs or gynecologic infection, drug or alcohol use pattern relative to sexual activity, and drug and alcohol use pattern among sexual partners. The... adolescents and pregnancy outcome. Lancet ii: prompt transport, and laboratory processing before the organ- 333-337. ism lyses or loses motility. In

  10. EspC, an Autotransporter Protein Secreted by Enteropathogenic Escherichia coli, Causes Apoptosis and Necrosis through Caspase and Calpain Activation, Including Direct Procaspase-3 Cleavage

    Directory of Open Access Journals (Sweden)

    Antonio Serapio-Palacios

    2016-06-01

    Full Text Available Enteropathogenic Escherichia coli (EPEC has the ability to antagonize host apoptosis during infection through promotion and inhibition of effectors injected by the type III secretion system (T3SS, but the total number of these effectors and the overall functional relationships between these effectors during infection are poorly understood. EspC produced by EPEC cleaves fodrin, paxillin, and focal adhesion kinase (FAK, which are also cleaved by caspases and calpains during apoptosis. Here we show the role of EspC in cell death induced by EPEC. EspC is involved in EPEC-mediated cell death and induces both apoptosis and necrosis in epithelial cells. EspC induces apoptosis through the mitochondrial apoptotic pathway by provoking (i a decrease in the expression levels of antiapoptotic protein Bcl-2, (ii translocation of the proapoptotic protein Bax from cytosol to mitochondria, (iii cytochrome c release from mitochondria to the cytoplasm, (iv loss of mitochondrial membrane potential, (v caspase-9 activation, (vi cleavage of procaspase-3 and (vii an increase in caspase-3 activity, (viii PARP proteolysis, and (ix nuclear fragmentation and an increase in the sub-G1 population. Interestingly, EspC-induced apoptosis was triggered through a dual mechanism involving both independent and dependent functions of its EspC serine protease motif, the direct cleavage of procaspase-3 being dependent on this motif. This is the first report showing a shortcut for induction of apoptosis by the catalytic activity of an EPEC protein. Furthermore, this atypical intrinsic apoptosis appeared to induce necrosis through the activation of calpain and through the increase of intracellular calcium induced by EspC. Our data indicate that EspC plays a relevant role in cell death induced by EPEC.

  11. Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of pyrrolizidine alkaloid-induced tumorigenicity.

    Science.gov (United States)

    Xia, Qingsu; Zhao, Yuewei; Von Tungeln, Linda S; Doerge, Daniel R; Lin, Ge; Cai, Lining; Fu, Peter P

    2013-09-16

    Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic pyrrolizidine alkaloid, platyphylliine, a pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of

  12. Monitoring of environmental cancer initiators through hemoglobin adducts by a modified Edman degradation method

    International Nuclear Information System (INIS)

    Toernqvist, M.M.; Mowrer, J.; Jensen, S.; Ehrenberg, L.

    1986-01-01

    Tissue doses of cancer initiators/mutagens are suitably monitored through hemoglobin adducts formed in vivo, but the use of this method has been hampered by a lack of sufficiently simple and fast procedures. It was previously observed that when the N-terminal amino acid in hemoglobin, valine, is alkylated it is cleaved off by the Edman sequencing reagent, phenyl isothiocyanate, in the neutral-alkaline coupling medium, as opposed to the acidic medium required by normal amino acids. Based on this principle, conditions for a functioning procedure for gas chromatography/mass spectrometry (GC/MS) determination of N-terminal alkylvalines in hemoglobin were worked out. Derivatizing the protein in formamide solution with pentafluorophenyl isothiocyanate, using a 2 H-alkylated protein as internal standard, and applying on-column injection during analysis, permit reproducible determination of hydroxyethylvaline and other adducts down into the dose range where cancer risks may be considered acceptably low

  13. Lactone modified mono-or dicarboxylic acid based adduct dispersant compositions

    Energy Technology Data Exchange (ETDEWEB)

    Gutierrez, A.; Lundberg, R.D.

    1990-03-06

    This patent describes a C{sub 5}-C{sub 9} lactone adduct material useful as an oil additive formed by reacting an aliphatic hydrocarbyl saturated or unsaturated, natural or synthetic, straight chain or branched chain monocarboxylic or dicarboxylic acylating agent heaving from about 1 to about 165 total carbon atoms with the reaction product of a C{sub 5}-C{sub 9} lactone with a member selected from the group consisting of a polyamine having from bout 2 to 60 total carbon atoms and from about 2 to about 12 nitrogen atoms, an amino alcohol containing up to about 50 total carbon atoms, from 1 to about 5 nitrogen atoms and from 1 to about 15 hydroxyl groups, and mixtures thereof. The aliphatic acylating agent having at least about twelve carbon atoms in said straight or branched chain to produce lactone adduct material that is hydrocarbon soluble.

  14. Morphological changes of calcite single crystals induced by graphene-biomolecule adducts

    Science.gov (United States)

    Calvaresi, Matteo; Di Giosia, Matteo; Ianiro, Alessandro; Valle, Francesco; Fermani, Simona; Polishchuk, Iryna; Pokroy, Boaz; Falini, Giuseppe

    2017-01-01

    Calcite has the capability to interact with a wide variety of molecules. This usually induces changes in shape and morphology of crystals. Here, this process was investigated using sheets of graphene-biomolecule adducts. They were prepared and made dispersible in water through the exfoliation of graphite by tip sonication in the presence tryptophan or N-acetyl-D-glucosamine. The crystallization of calcium carbonate in the presence of these additives was obtained by the vapor diffusion method and only calcite formed. The analysis of the microscopic observations showed that the graphene-biomolecule adducts affected shape and morphology of rhombohedral {10.4} faced calcite crystals, due to their stabilization of additional {hk.0} faces. The only presence of the biomolecule affected minimally shape and morphology of calcite crystals, highlighting the key role of the graphene sheets as 2D support for the adsorption of the biomolecules.

  15. Diastereoselective synthesis of substituted 2-amino-1,3-propanediols from Morita-Baylis-Hillman adducts

    Energy Technology Data Exchange (ETDEWEB)

    Paioti, Paulo H.S.; Rezende, Patricia; Coelho, Fernando [Laboratorio de Sintese de Produtos Naturais e Farmacos, Instituto de Quimica, Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2012-07-01

    We report herein a new diastereoselective approach to substituted 2-amino-1,3-propanediols with anti relative stereochemistry from Morita-Baylis-Hillman (MBH) adducts. These structural moieties have been used as intermediates for the synthesis of several compounds with relevant pharmacological and commercial interest. In this strategy, substituted anti 2-amino-1,3-propanediols were readily prepared via ozonolysis of allylic diols obtained from MBH adducts, followed by a diastereoselective reductive amination of the substituted 2-oxo-1,3-propanediols. To demonstrate the synthetic utility of these aminodiols, they were transformed into substituted oxazolidine-2-ones, which were also used in the indirect determination of the relative stereochemistry of the aminodiols. (author)

  16. TLC surface integrity affects the detection of alkali adduct ions in TLC-MALDI analysis.

    Science.gov (United States)

    Dong, Yonghui; Ferrazza, Ruggero; Anesi, Andrea; Guella, Graziano; Franceschi, Pietro

    2017-09-01

    Direct coupling of thin-layer chromatography (TLC) with matrix-assisted laser desorption ionization (MALDI) mass spectrometry allows fast and detailed characterization of a large variety of analytes. The use of this technique, however, presents great challenges in semiquantitative applications because of the complex phenomena occurring at the TLC surface. In our laboratory, we recently observed that the ion intensities of several alkali adduct ions were significantly different between the top and interior layer of the TLC plate. This indicates that the integrity of the TLC surface can have an important effect on the reproducibility of TLC- MALDI analyses. Graphical Abstract MALDI imaging reveals that surface integrity affects the detection of alkali adductions in TLC-MALDI.

  17. Applying the model of Goal-Directed Behavior, including descriptive norms, to physical activity intentions: A contribution to improving the Theory of Planned Behavior

    Science.gov (United States)

    The theory of planned behavior (TPB) has received its fair share of criticism lately, including calls for it to retire. We contributed to improving the theory by testing extensions such as the model of goal-directed behavior (MGDB, which adds desire and anticipated positive and negative emotions) ap...

  18. Sugar beet activities of the USDA-ARS East Lansing conducted in cooperation with Saginaw Valley Bean and Beet Farm during 2011 (including Project 905)

    Science.gov (United States)

    Evaluation and rating plots were planted at the Saginaw Valley Research & Extension Center in Frankenmuth, MI in 2011 that focused on Cercospora leaf spot performance, conducted in conjunction with Beet Sugar Development Foundation and including USDA-ARS cooperators. 263 breeding lines were tested i...

  19. Pulse radiolysis study of reaction of bull serum albumin electron adduct with oxygen. Polychromatic kinetics of reaction with adsorbed oxygen

    International Nuclear Information System (INIS)

    Pribush, A.G.

    1986-01-01

    By the method of pulse radiolysis the reaction of bull serum albumin electron adduct with oxygen is investigated. As pulsed radiation source electron linear accelerators with particle energy of 8.0 and 4.5 MeV and pulse time of 40 ns and 2.2 μs, respectively have been used. It is assumed that the disappearance of protein electron adduct occurs in the course of its interaction with oxygen adsorbed on protein globular molecule

  20. An alternative approach to aminodiols from Baylis-Hillman adducts. Stereoselective synthesis of chloramphenicol, fluoramphenicol and thiamphenicol

    Energy Technology Data Exchange (ETDEWEB)

    Mateus, Cristiano R.; Coelho, Fernando [Universidade Estadual de Campinas, SP (Brazil). Inst. de Quimica]. E-mail: coelho@iqm.unicamp.br

    2005-05-15

    We describe herein a new approach for the stereoselective synthesis of broad spectrum antibiotics from Baylis-Hillman adducts. The strategy is based on the preparation of an ene-carbamate directly from a Baylis-Hillman adduct using a Curtius rearrangement reaction. Stereoselective hydroboration furnished a mixture of diastereoisomeric aminoalcohols (syn and anti). After chromatographic separation, the syn diastereoisomer was directly transformed into the antibiotics. (author)

  1. MTHFR Polymorphisms, Folate Intake, and Carcinogen DNA Adducts in the Lung

    OpenAIRE

    Lee, Mi-Sun; Asomaning, Kofi; Su, Li; Wain, John C.; Mark, Eugene J.; Christiani, David C.

    2012-01-01

    The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was complet...

  2. Analytical determination of specific 4,4'-methylene diphenyl diisocyanate hemoglobin adducts in human blood.

    Science.gov (United States)

    Gries, Wolfgang; Leng, Gabriele

    2013-09-01

    4,4'-Methylene diphenyl diisocyanate (MDI) is one of the most important isocyanates in the industrial production of polyurethane and other MDI-based synthetics. Because of its high reactivity, it is known as a sensitizing agent, caused by protein adducts. Analysis of MDI is routinely done by determination of the nonspecific 4,4'-methylenedianiline as a marker for MDI exposure in urine and blood. Since several publications have reported specific adducts of MDI and albumin or hemoglobin, more information about their existence in humans is necessary. Specific adducts of MDI and hemoglobin were only reported in rats after high-dose MDI inhalation. The aim of this investigation was to detect the hemoglobin adduct 5-isopropyl-3-[4-(4-aminobenzyl)phenyl]hydantoin (ABP-Val-Hyd) in human blood for the first time. We found values up to 5.2 ng ABP-Val-Hyd/g globin (16 pmol/g) in blood samples of workers exposed to MDI. Because there was no information available about possible amounts of this specific MDI marker, the analytical method focused on optimal sensitivity and selectivity. Using gas chromatography-high-resolution mass spectrometry with negative chemical ionization, we achieved a detection limit of 0.02 ng ABP-Val-Hyd/g globin (0.062 pmol/g). The robustness of the method was confirmed by relative standard deviations between 3.0 and 9.8 %. Combined with a linear detection range up to 10 ng ABP-Val-Hyd/g globin (31 pmol/g), the enhanced precision parameter demonstrates that the method described is optimized for screening studies of the human population.

  3. Genotoxicity induced by xenobiotics:the role of DNA adducts, individual susceptibility and DNA repair

    Czech Academy of Sciences Publication Activity Database

    Vodička, Pavel; Koskinen, M.; Štětina, R.; Vodičková, L.; Kuricová, M.; Hemminki, K.

    2002-01-01

    Roč. 10, č. 1 (2002), s. 322 ISSN 1107-3756. [World Congress on Advances in Oncology /7./ and International Symposium on Molecular Medicine /5./. Hersonissos, 10.10.2002-12.10.2002] R&D Projects: GA ČR GA310/01/0802 Institutional research plan: CEZ:AV0Z5039906 Keywords : DNA adducts Subject RIV: FM - Hygiene Impact factor: 2.063, year: 2002

  4. Quantitation of acrolein-protein adducts: potential biomarker of acrolein exposure.

    Science.gov (United States)

    Li, Hui; Wang, Jianling; Kaphalia, Bhupendra; Ansari, G A S; Khan, M Firoze

    2004-03-26

    Acrolein, an alpha,beta-unsaturated aldehyde, is a ubiquitous environmental toxic pollutant. Because of potential human exposure, there is a need for a sensitive, reliable, and specific method to monitor acrolein exposure. Acrolein is a potent electrophile and reacts with proteins mainly through Michael addition reaction, leading to acrolein-protein adducts (APA). The present study aimed to develop a competitive enzyme-linked immunosorbent assay (ELISA) method for the quantitation of APA in biological samples. Antibody to acrolein-keyhole limpet hemocyanin adduct was raised in rabbits, and the specificity of the antibody was determined by ELISA using acrolein-albumin adduct (AAA) or native albumin. A dose-dependent response was observed with AAA, but no immunoreactivity with native albumin. Further, lack of cross-reactivity of anti-acrolein antibody with formaldehyde-, malondialdehyde-, or 4-hydroxynonenal-albumin adducts indicates its specificity for acrolein. For the competitive ELISA, 1:16,000 diluted antisera was used with varying concentrations of AAA, which provided a linear detection range between 250 and 10,000 pg. To test the efficacy of the method for possible use as a biomarker of acrolein exposure, SD rats were orally administered 1 or 7 doses of 9.2 mg/kg/d acrolein. APA levels, quantitated in the serum, showed significantly greater formation (32% and 58% after 1 and 7 doses, respectively) in acrolein-treated rats as compared to the controls. Western blot analyses of APA in the sera from acrolein-treated rats showed APA bands (especially 29, 31, and 100 kD) with greater intensity in comparison to controls, further supporting our ELISA results. These results suggest that quantitation of APA has potential to be used as biomarker of acrolein exposure and eventually for molecular dosimetry and risk assessment.

  5. The 1:1 adduct of caffeine and 2-(1,3-dioxoisoindolin-2-ylacetic acid

    Directory of Open Access Journals (Sweden)

    Moazzam H. Bhatti

    2011-09-01

    Full Text Available In the crystal structure of the title adduct [systematic name: 2-(1,3-dioxoisoindolin-2-ylacetic acid–1,3,7-trimethyl-1,2,3,6-tetrahydro-7H-purine-2,6-dione (1/1], C8H10N4O2·C10H7NO4, the components are linked by an O—H...N hydrogen-bond and no proton transfer occurs.

  6. Preparation and characterization of the adducts between lanthanide methanesulfonates and thioxane oxide

    International Nuclear Information System (INIS)

    Castro e Silva, E. de.

    1983-01-01

    The preparation and characterization of the adduct between lanthanide methanesulphonates and thioxane oxide are presented. The compounds characterization by conductance measurements, X-ray powder patterns, infrared, visible and fluorescence spectra, TG, DTG and DTA curves was made. According to the X-ray patterns, three isomorphous series were obtained: a-La-Gd b-Tb-Dy and c-Ho-Lu, Y. (M.J.C.) [pt

  7. Mass-spectrometric investigation of rare earth acetylacetonates dipivaloylmethanates and their adducts

    International Nuclear Information System (INIS)

    Gavrishzhuk, E.M.; Dzyubenko, N.G.; Martynenko, L.I.

    1985-01-01

    Peculiarities of fragmentation of molecular ions of rare earth acetylacetonates and dipivaloylmethanates under mass-spectrometric investigation of these compounds as well as their adducts with o-phenanthroline, α,α'-dipyridyl, triphenylphosphine oxide are considered in the given review. Similar data for identical derivants of some transitions metals are presented. Data on potentials of appearance and dissociation energy of basic ions in mass-spectra of the studied β-diketonates are analyzed

  8. Electrochemical oxidation and protein adduct formation of aniline: a liquid chromatography/mass spectrometry study.

    Science.gov (United States)

    Melles, Daniel; Vielhaber, Torsten; Baumann, Anne; Zazzeroni, Raniero; Karst, Uwe

    2012-04-01

    Historically, skin sensitization tests are typically based on in vivo animal tests. However, for substances used in cosmetic products, these tests have to be replaced according to the European Commission regulation no. 1223/2009. Modification of skin proteins by electrophilic chemicals is a key process associated with the induction of skin sensitization. The present study investigates the capabilities of a purely instrumental setup to determine the potential of commonly used non-electrophilic chemicals to cause skin sensitization by the generation of electrophilic species from the parent compound. In this work, the electrophiles were generated by the electrochemical oxidation of aniline, a basic industrial chemical which may also be released from azo dyes in cosmetics. The compound is a known sensitizer and was oxidized in an electrochemical thin-layer cell which was coupled online to electrospray ionization-mass spectrometry. The electrochemical oxidation was performed on a boron-doped diamond working electrode, which is able to generate hydroxyl radicals in aqueous solutions at high potentials. Without any pretreatment, the oxidation products were identified by electrospray ionization/time-of-flight mass spectrometry (ESI-ToF-MS) using their exact masses. A mass voltammogram was generated by plotting the obtained mass spectra against the applied potential. Oligomerization states with up to six monomeric units in different redox states of aniline were observed using this setup. This approach was extended to generate adducts between the oxidation products of aniline and the tripeptide glutathione. Two adducts were identified with this trapping experiment. Protein modification was carried out subsequently: Aniline was oxidized at a constant potential and was allowed to react with β-lactoglobulin A (β-LGA) or human serum albumin (HSA), respectively. The generated adducts were analyzed by liquid chromatography coupled to ESI-ToF-MS. For both β-LGA and HSA, aniline

  9. Arabidopsis cpFtsY mutants exhibit pleiotropic defects including an inability to increase iron deficiency-inducible root Fe(III) chelate reductase activity.

    Science.gov (United States)

    Durrett, Timothy P; Connolly, Erin L; Rogers, Elizabeth E

    2006-08-01

    All plants, except for the grasses, must reduce Fe(III) to Fe(II) in order to acquire iron. In Arabidopsis, the enzyme responsible for this reductase activity in the roots is encoded by FRO2. Two Arabidopsis mutants, frd4-1 and frd4-2, were isolated in a screen for plants that do not induce Fe(III) chelate reductase activity in their roots in response to iron deficiency. frd4 mutant plants are chlorotic and grow more slowly than wild-type Col-0 plants. Additionally, frd4 chloroplasts are smaller in size and possess dramatically fewer thylakoid membranes and grana stacks when compared with wild-type chloroplasts. frd4 mutant plants express both FRO2 and IRT1 mRNA normally in their roots under iron deficiency, arguing against any defects in systemic iron-deficiency signaling. Further, transgenic frd4 plants accumulate FRO2-dHA fusion protein under iron-deficient conditions, suggesting that the frd4 mutation acts post-translationally in reducing Fe(III) chelate reductase activity. FRO2-dHA appears to localize to the plasma membrane of root epidermal cells in both Col-0 and frd4-1 transgenic plants when grown under iron-deficient conditions. Map-based cloning revealed that the frd4 mutations reside in cpFtsY, which encodes a component of one of the pathways responsible for the insertion of proteins into the thylakoid membranes of the chloroplast. The presence of cpFtsY mRNA and protein in the roots of wild-type plants suggests additional roles for this protein, in addition to its known function in targeting proteins to the thylakoid membrane in chloroplasts.

  10. Capillary HPLC-accurate mass MS/MS quantitation of N7-(2,3,4-trihydroxybut-1-yl)-guanine adducts of 1,3-butadiene in human leukocyte DNA.

    Science.gov (United States)

    Sangaraju, Dewakar; Villalta, Peter; Goggin, Melissa; Agunsoye, Maria O; Campbell, Colin; Tretyakova, Natalia

    2013-10-21

    1,3-Butadiene (BD) is a high volume industrial chemical commonly used in polymer and rubber production. It is also present in cigarette smoke, automobile exhaust, and urban air, leading to widespread exposure of human populations. Upon entering the body, BD is metabolized to electrophilic epoxides, 3,4-epoxy-1-butene (EB), diepoxybutane (DEB), and 3,4-epoxy-1,2-diol (EBD), which can alkylate DNA nucleobases. The most abundant BD epoxide, EBD, modifies the N7-guanine positions in DNA to form N7-(2, 3, 4-trihydroxybut-1-yl) guanine (N7-THBG) adducts, which can be useful as biomarkers of BD exposure and metabolic activation to DNA-reactive epoxides. In the present work, a capillary HPLC-high resolution ESI⁺-MS/MS (HPLC-ESI⁺-HRMS/MS) methodology was developed for accurate, sensitive, and reproducible quantification of N7-THBG in cell culture and in human white blood cells. In our approach, DNA is subjected to neutral thermal hydrolysis to release N7-guanine adducts from the DNA backbone, followed by ultrafiltration, solid-phase extraction, and isotope dilution HPLC-ESI⁺-HRMS/MS analysis on an Orbitrap Velos mass spectrometer. Following method validation, N7-THBG was quantified in human fibrosarcoma (HT1080) cells treated with micromolar concentrations of DEB and in DNA isolated from blood of smokers, nonsmokers, individuals participating in a smoking cessation program, and occupationally exposed workers. N7-THBG concentrations increased linearly from 31.4 ± 4.84 to 966.55 ± 128.05 adducts per 10⁹ nucleotides in HT1080 cells treated with 1-100 μM DEB. N7-THBG amounts in leukocyte DNA of nonsmokers, smokers, and occupationally exposed workers were 7.08 ± 5.29, 8.20 ± 5.12, and 9.72 ± 3.80 adducts per 10⁹ nucleotides, respectively, suggesting the presence of an endogenous or environmental source for this adduct. The availability of sensitive HPLC-ESI⁺-HRMS/MS methodology for BD-induced DNA adducts in humans will enable future population studies of

  11. Differential repair of platinum-DNA adducts in human bladder and testicular tumor continuous cell lines

    International Nuclear Information System (INIS)

    Bedford, P.; Fichtinger-Schepman, A.M.; Shellard, S.A.; Walker, M.C.; Masters, J.R.; Hill, B.T.

    1988-01-01

    The formation and removal of four platinum-DNA adducts were immunochemically quantitated in cultured cells derived from a human bladder carcinoma cell line (RT112) and from two lines derived from germ cell tumors of the testis (833K and SUSA), following exposure in vitro to 16.7 microM (5 micrograms/ml) cisplatin. RT112 cells were least sensitive to the drug and were proficient in the repair of all four adducts, whereas SUSA cells, which were 5-fold more sensitive, were deficient in the repair of DNA-DNA intrastrand cross-links in the sequences pApG and pGpG. Despite expressing a similar sensitivity to SUSA cells, 833K cells were proficient in the repair of all four adducts, although less so than the RT112 bladder tumor cells. In addition, SUSA cells were unable to repair DNA-DNA interstrand cross-links whereas 50-85% of these lesions were removed in RT112 and 833K cells 24 h following drug exposure. It is possible that the inability of SuSa cells to repair platinated DNA may account for their hypersensitivity to cisplatin

  12. Thermochemistry of adducts of some bivalent transition metal bromides with aniline

    International Nuclear Information System (INIS)

    Dunstan, Pedro Oliver

    2006-01-01

    The compounds [MBr 2 (an) 2 ] (where M is Mn(II), Fe(II), Co(II), Ni(II), Cu(II) or Zn(II); an=aniline) were synthesized and characterized by melting points, elemental analysis, thermal studies, and electronic and IR spectroscopy. The enthalpies of dissolution of the adducts, metal(II) bromides and aniline in methanol, aqueous 1.2M HCl or 25% (v/v) aqueous 1.2M HCl in methanol were measured. The following thermochemical parameters for the adducts have been determined by thermochemical cycles: the standard enthalpies for the Lewis acid/base reactions (Δ r H o ), the standard enthalpies of formation (Δ f H o ), the standard enthalpies of decomposition (Δ D H o ), the lattice standard enthalpies (Δ M H o ) and the standard enthalpies of the Lewis acid/base reactions in the gaseous phase (Δ r H o (g)). The mean bond dissociation enthalpies of the M(II)-nitrogen bonds (D-bar (M?N) ) and the enthalpies of formation of the adducts from the ions in the gaseous phase: M 2+ (g) +Br - (g) +an (g) ->[MBr 2 (an) 2 ] (g) (Δ fi H o ) have been estimated

  13. Suicide of EMT-6 tumor cells by decays from radioactively-labelled sensitizer adducts

    International Nuclear Information System (INIS)

    Roa, W.H.Y.; Chapman, J.D.

    1987-01-01

    Nitroaromatic radiosensitizers become metabolically bound preferentially to hypoxic cells and at least 10/sup 9/ adducts/cell can be tolerated as non-toxic. EMT-6 tumor cells have been incubated in hypoxia in the presence of /sup 3/H-Misonidazole and /sup 125/I-Azomycin Riboside for various times and the amount of /sup 3/H or /sup 125/I bound/cell was determined. Cells were stored as monolayers at 25 0 C for up to 96 hr to accumulate radioactive decays and transferred at various times to 37 0 C for colony-forming assays. No radiation inactivation was measured in cells which had incorporated at least 10/sup 6/ /sup 3/H or 10/sup 5/ /sup 125/I atoms. Previous studies had shown that -- 1% of MISO adducts to EMT-6 cells was associated with cellular DNA. These data indicate that the radiation-induced damage produced by these quantities of bound /sup 3/H or /sup 125/I causes little or not cell inactivation. The results of current studies to measure the colony-forming ability of sensitizer-labelled cells which have been stored in liquid nitrogen to facilitate the accumulation of more decays will be reported. These data suggest that a ''sensitizer-adduct suicide technique'' as a hypoxic cell selective adjunct to other cancer therapies is not feasible. These data are also instructive for those who attempt to develop radiolabelled ''tumor specific'' antibodies for therapeutic purposes

  14. Unprecedented solvent induced inter-conversion between monomeric and dimeric silylene-zinc iodide adducts.

    Science.gov (United States)

    Yadav, Sandeep; Sangtani, Ekta; Dhawan, Diksha; Gonnade, Rajesh G; Ghosh, Debashree; Sen, Sakya S

    2017-08-29

    Usually, when a silylene reacts with a transition metal Lewis acid, it forms an adduct which could be either monomeric or dimeric. However, we present here that a silylene, [PhC(NtBu) 2 SiN(SiMe 3 ) 2 ] can form both monomeric [PhC(NtBu) 2 Si{N(SiMe 3 ) 2 } → ZnI 2 ]·THF (1) and dimeric [{PhC(NtBu) 2 }(N(SiMe 3 ) 2 )SiZnI,(μ-I)] 2 (2) adducts upon reaction with ZnI 2 . The formation of 1 and 2 relies upon the solvent used for the reaction or crystallization. When the crystallization is carried out in THF complex 1 is formed, however, when the reaction and crystallization are performed in acetonitrile complex 2 is obtained. Both 1 and 2 were structurally authenticated and the nature of the Si-Zn bond in these complexes was determined by quantum chemical calculations. In addition, a spontaneous inter-conversion between 1 and 2 just by changing the solvents has been also observed; a feature presently not known for silylene-transition metal Lewis adducts.

  15. Detection of benzo[a]pyrene-guanine adducts in single-stranded DNA using the α-hemolysin nanopore

    Science.gov (United States)

    Perera, Rukshan T.; Fleming, Aaron M.; Johnson, Robert P.; Burrows, Cynthia J.; White, Henry S.

    2015-02-01

    The carcinogenic precursor benzo[a]pyrene (BP), a polycyclic aromatic hydrocarbon, is released into the environment through the incomplete combustion of hydrocarbons. Metabolism of BP in the human body yields a potent alkylating agent (benzo[a]pyrene diol epoxide, BPDE) that reacts with guanine (G) in DNA to form an adduct implicated in cancer initiation. We report that the α-hemolysin (αHL) nanopore platform can be used to detect a BPDE adduct to G in synthetic oligodeoxynucleotides. Translocation of a 41-mer poly-2‧-deoxycytidine strand with a centrally located BPDE adduct to G through αHL in 1 M KCl produces a unique multi-level current signature allowing the adduct to be detected. This readily distinguishable current modulation was observed when the BPDE-adducted DNA strand translocated from either the 5‧ or 3‧ directions. This study suggests that BPDE adducts and other large aromatic biomarkers can be detected with αHL, presenting opportunities for the monitoring, quantification, and sequencing of mutagenic compounds from cellular DNA samples.

  16. The presence of aflatoxin B₁-FAPY adduct and human papilloma virus in cervical smears from cancer patients in Mexico.

    Science.gov (United States)

    Carvajal, Magda; Berumen, Jaime; Guardado-Estrada, Mariano

    2012-01-01

    The carcinogenic biomarker aflatoxin B(1)-formamidopyrimidine 2,3-dihydro-2-(N-formyl)-2',5',6'-triamino-4'-4'-oxy-N-pyrimidyl-3-hydroxy-AFB(1) called AFB(1)-FAPY adduct, and Human Papilloma Virus (HPV) types 16 and 18 were quantified from DNA cervical scrapes from 40 women with cervical cancer (CC) and 14 healthy women as controls. The relationship between the AFB(1)-FAPY adduct and HPV types 16 and 18 was determined. Competitive inhibitory indirect ELISA was validated with 94% inhibition to quantify the AFB(1)-FAPY adducts in picograms per milligram of DNA (limit of detection = 0.1 pg/mg, and limit of quantification = 10 pg/mg), polymerase chain reaction and DNA sequencing to identify HPV types. The average concentration of AFB(1)-FAPY adducts/mg DNA in the CC cases was 1025 pg, 1420 pg with HPV16 and 630 pg sharing HPV18 (p = 0.03). In comparison, healthy controls had ≤ 2.6 pg/mg DNA, a statistically significant difference (p = 0.00006). The presence of AFB(1)-FAPY adduct increased six-fold the risk for CC between cases and controls, the odds ratio was 6.1 (95% CI = 1.4-25.4). There was a close relationship between the AFB(1)-FAPY adducts and HPV16 in CC samples.

  17. Structural and chemical characterization of S-[2-(N7-guanyl)-ethyl]glutathione, the major DNA adduct formed from 1,2-dibromoethane

    International Nuclear Information System (INIS)

    Inskeep, P.B.; Koga, N.; Cmarik, J.L.; Peterson, L.A.; Guengerich, F.P.

    1986-01-01

    Glutathione (GSH) S-transferase catalyzes the reaction of the carcinogen 1,2-dibromoethane (DBE) with DNA, resulting in the formation of a major DNA adduct which can be released by thermal hydrolysis at neutral pH and purified by octadecylsilyl- and propylamino high performance liquid chromatography. This adduct was also the only major liver and kidney DNA adduct isolated from rats treated with [1,2- 14 C]-DBE. Administration of 1,2-dichloroethane to rats also led to the production of this and other DNA adducts. The DNA adduct was assigned the structure S-[2-(N'-guanyl)ethyl]GSH as determined by positive and negative ion mass spectrometry and two-dimensional NMR correlated spectroscopy (COSY). Consistently, the chromatographic characteristics of the adduct could be altered upon treatment with γ-glutamic transpeptidase or pronase. No evidence for in vitro or in vivo guanyl imidazole ring opening was observed under these experimental conditions. Additionally, S-[2-(N 7 -guanyl)ethyl]GSH was found to be stable to further reaction with DNA to generate new DNA adducts. The structure of the isolated adduct is consistent with a proposed bioactivation pathway of DBE which involves enzyme catalyzed conjugation of DBE with GSH followed by attack of the N 7 -position of DNA guanine residues to generate this major adduct. The chemical stability of the adduct suggests that it may be important to the carcinogenicity of this compound

  18. Fumigant toxicity of Oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components, including their acetylcholinesterase inhibitory activity, against Japanese termites (Reticulitermes speratus).

    Science.gov (United States)

    Park, Il-Kwon

    2014-08-19

    This study investigated the fumigant toxicity of oriental sweetgum (Liquidambar orientalis) and valerian (Valeriana wallichii) essential oils and their components against the Japanese termite (Reticulitermes speratus). The fumigant toxicity of oriental sweetgum and valerian oil differed significantly according to exposure time. Oriental sweetgum showed toxicity at short exposure times (2 days), and the toxicity of valerian oil was high 7 days after treatment. The main constituents of oriental sweetgum and valerian oils were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, benzyl alcohol, acetophenone, 1-phenyl-1-ethanol, hydrocinnamyl alcohol, trans-cinnamyl aldehyde, trans-cinnamyl alcohol, cis-asarone, styrene, and cis-ocimene showed toxicity against Japanese termites 7 days after treatment. Hydrocinnamyl alcohol and trans-cinnamyl alcohol were found to be the major contributors to the fumigant antitermitic toxicity of oriental sweetgum oil. The acetylcholinesterase (AChE) inhibition activity of two oils and their constituents was tested to determine their mode of action. Only cis-ocimene showed strong AChE inhibition activity with an IC50 value of 0.131 mg/mL. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control.

  19. Fumigant Toxicity of Oriental Sweetgum (Liquidambar orientalis and Valerian (Valeriana wallichii Essential Oils and Their Components, Including Their Acetylcholinesterase Inhibitory Activity, against Japanese Termites (Reticulitermes speratus

    Directory of Open Access Journals (Sweden)

    Il-Kwon Park

    2014-08-01

    Full Text Available This study investigated the fumigant toxicity of oriental sweetgum (Liquidambar orientalis and valerian (Valeriana wallichii essential oils and their components against the Japanese termite (Reticulitermes speratus. The fumigant toxicity of oriental sweetgum and valerian oil differed significantly according to exposure time. Oriental sweetgum showed toxicity at short exposure times (2 days, and the toxicity of valerian oil was high 7 days after treatment. The main constituents of oriental sweetgum and valerian oils were tested individually for their fumigant toxicity against Japanese termites. Among the test compounds, benzyl alcohol, acetophenone, 1-phenyl-1-ethanol, hydrocinnamyl alcohol, trans-cinnamyl aldehyde, trans-cinnamyl alcohol, cis-asarone, styrene, and cis-ocimene showed toxicity against Japanese termites 7 days after treatment. Hydrocinnamyl alcohol and trans-cinnamyl alcohol were found to be the major contributors to the fumigant antitermitic toxicity of oriental sweetgum oil. The acetylcholinesterase (AChE inhibition activity of two oils and their constituents was tested to determine their mode of action. Only cis-ocimene showed strong AChE inhibition activity with an IC50 value of 0.131 mg/mL. Further studies are warranted to determine the potential of these essential oils and their constituents as fumigants for termite control.

  20. Consumption of Dairy Yogurt Containing Lactobacillus paracasei ssp. paracasei, Bifidobacterium animalis ssp. lactis and Heat-Treated Lactobacillus plantarum Improves Immune Function Including Natural Killer Cell Activity

    Directory of Open Access Journals (Sweden)

    Ayoung Lee

    2017-05-01

    Full Text Available The aim of this study was to investigate the impact of consuming dairy yogurt containing Lactobacillus paracasei ssp. paracasei (L. paracasei, Bifidobacterium animalis ssp. lactis (B. lactis and heat-treated Lactobacillus plantarum (L. plantarum on immune function. A randomized, open-label, placebo-controlled study was conducted on 200 nondiabetic subjects. Over a twelve-week period, the test group consumed dairy yogurt containing probiotics each day, whereas the placebo group consumed milk. Natural killer (NK cell activity, interleukin (IL-12 and immunoglobulin (Ig G1 levels were significantly increased in the test group at twelve weeks compared to baseline. Additionally, the test group had significantly greater increases in serum NK cell activity and interferon (IFN-γ and IgG1 than placebo group. Daily consumption of dairy yogurt containing L. paracasei, B. lactis and heat-treated L. plantarum could be an effective option to improve immune function by enhancing NK cell function and IFN-γ concentration (ClinicalTrials.gov: NCT03051425.

  1. ComparativeIn VitroActivities of Relebactam, Imipenem, the Combination of the Two, and Six Comparator Antimicrobial Agents against 432 Strains of Anaerobic Organisms, Including Imipenem-Resistant Strains.

    Science.gov (United States)

    Goldstein, Ellie J C; Citron, Diane M; Tyrrell, Kerin L; Leoncio, Eliza; Merriam, C Vreni

    2018-02-01

    Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested. Copyright © 2018 American Society for Microbiology.

  2. Effect of pH, water activity and gel micro-structure, including oxygen profiles and rheological characterization, on the growth kinetics of Salmonella Typhimurium.

    Science.gov (United States)

    Theys, T E; Geeraerd, A H; Verhulst, A; Poot, K; Van Bree, I; Devlieghere, F; Moldenaers, P; Wilson, D; Brocklehurst, T; Van Impe, J F

    2008-11-30

    In this study, the growth of Salmonella Typhimurium in Tryptic Soy Broth was examined at different pH (4.50-5.50), water activity a(w) (0.970-0.992) and gelatin concentration (0%, 1% and 5% ) at 20 degrees C. Experiments in TSB with 0% gelatin were carried out in shaken erlenmeyers, in the weak 1% gelatin media in petri plates and in the firm 5% gelatin media in gel cassettes. A quantification of gel strength was performed by rheological measurements and the influence of oxygen supply on the growth of S. Typhimurium was investigated. pH, as well as a(w) as well as gelatin concentration had an influence on the growth rate. Both in broth and in gelatinized media, lowering pH or water activity caused a decrease of growth rate. In media with 1% gelatin a reduction of growth rate and maximal cell density was observed compared to broth at all conditions. However, the effects of decreasing pH and a(w) were less pronounced. A further increase in gelatin concentration to 5% gelatin caused a small or no additional drop of growth rate. The final oxygen concentration dropped from 5.5 ppm in stirred broth to anoxic values in petri plates, also when 0% and 5% gelatin media were tested in this recipient. Probably, not stirring the medium, which leads to anoxic conditions, has a more pronounced effect on the growth rate of S. Typhimurium then medium solidness. Finally, growth data were fitted with the primary model of Baranyi and Roberts [Baranyi, J. and Roberts, T. A., 1994. A dynamic approach to predicting bacterial growth in food. International Journal of Food Microbiology 23, 277-294]. An additional factor was introduced into the secondary model of Ross et al. [Ross, T. and Ratkowsky, D. A. and Mellefont, L. A. and McMeekin, T. A., 2003. Modelling the effects of temperature, water activity, pH and lactic acid concentration on the growth rate of Escherichia coli. International Journal of Food Microbiology 82, 33-43.] to incorporate the effect of gelatin concentration, next to

  3. ANALYSIS OF EFFICIENCY OF R&D ACTIVITIES AMONG COUNTRIES WITH DEVELOPED AND DEVELOPING ECONOMIES INCLUDING REPUBLIC OF BELARUS WITH STOCHASTIC FRONTIER APPROACH

    Directory of Open Access Journals (Sweden)

    I. V. Zhukovski

    2016-01-01

    Full Text Available This study evaluates efficiency of R&D activities based on the stochastic frontier analysis across 69 counties with developed and developing economies. Gross domestic expenditures on R&D in purchasing power parity, researchers per million inhabitants, technicians per million inhabitants are treated as inputs while patents granted to residents and scientific and technical journal articles are considered as outputs. According to the analysis results Costa Rica, Israel and Singapore are the most efficient in terms of transformation of available resources into the R&D results. What concerns Belarus it is necessary that additional investments in R&D go together with increasing efficiency of available resources’ usage. 

  4. Synthesis, Structure, and Reactivity of the Ethyl Yttrium Metallocene, (C5Me5)2Y(CH2CH3), Including Activation of Methane.

    Science.gov (United States)

    MacDonald, Matthew R; Langeslay, Ryan R; Ziller, Joseph W; Evans, William J

    2015-11-25

    (C5Me5)2Y(μ-Ph)2BPh2, 1, reacted with ethyllithium at -15 °C to make (C5Me5)2Y(CH2CH3), 2, which is thermally unstable at room temperature and formed the C-H bond activation product, (C5Me5)2Y(μ-H)(μ-η(1):η(5)-CH2C5Me4)Y(C5Me5), 3, containing a metalated (C5Me5)(1-) ligand. Spectroscopic evidence for 2 was obtained at low temperature, and trapping experiments with (i)PrNCN(i)Pr and CO2 gave the Y-CH2CH3 insertion products, (C5Me5)2Y[(i)PrNC(Et)N(i)Pr-κ(2)N,N'], 4, and [(C5Me5)2Y(μ-O2CEt)]2, 5. Although 2 is highly reactive, low temperature isolation methods allowed the isolation of single crystals which revealed an 82.6(2)° Y-CH2-CH3 bond angle consistent with an agostic structure in the solid state. Complex 2 reacted with benzene and toluene to make (C5Me5)2YPh, 7, and (C5Me5)2YCH2Ph, 8, respectively. The reaction of 2 with [(C5Me5)2YCl]2 formed (C5Me5)2Y(μ-Cl)(μ-η(1):η(5)-CH2C5Me4)Y(C5Me5) in which a (C5Me5)(1-) ligand was metalated. C-H bond activation also occurred with methane which reacted with 2 to make [(C5Me5)2YMe]2, 9.

  5. Heterogeneity in Pseudomonas aeruginosa Biofilms Includes Expression of Ribosome Hibernation Factors in the Antibiotic-Tolerant Subpopulation and Hypoxia-Induced Stress Response in the Metabolically Active Population

    Science.gov (United States)

    Williamson, Kerry S.; Richards, Lee A.; Perez-Osorio, Ailyn C.; Pitts, Betsey; McInnerney, Kathleen; Stewart, Philip S.

    2012-01-01

    Bacteria growing in biofilms are physiologically heterogeneous, due in part to their adaptation to local environmental conditions. Here, we characterized the local transcriptome responses of Pseudomonas aeruginosa growing in biofilms by using a microarray analysis of isolated biofilm subpopulations. The results demonstrated that cells at the top of the biofilms had high mRNA abundances for genes involved in general metabolic functions, while mRNA levels for these housekeeping genes were low in cells at the bottom of the biofilms. Selective green fluorescent protein (GFP) labeling showed that cells at the top of the biofilm were actively dividing. However, the dividing cells had high mRNA levels for genes regulated by the hypoxia-induced regulator Anr. Slow-growing cells deep in the biofilms had little expression of Anr-regulated genes and may have experienced long-term anoxia. Transcripts for ribosomal proteins were associated primarily with the metabolically active cell fraction, while ribosomal RNAs were abundant throughout the biofilms, indicating that ribosomes are stably maintained even in slowly growing cells. Consistent with these results was the identification of mRNAs for ribosome hibernation factors (the rmf and PA4463 genes) at the bottom of the biofilms. The dormant biofilm cells of a P. aeruginosa Δrmf strain had decreased membrane integrity, as shown by propidium iodide staining. Using selective GFP labeling and cell sorting, we show that the dividing cells are more susceptible to killing by tobramycin and ciprofloxacin. The results demonstrate that in thick P. aeruginosa biofilms, cells are physiologically distinct spatially, with cells deep in the biofilm in a viable but antibiotic-tolerant slow-growth state. PMID:22343293

  6. The ethanol extract of Scutellaria baicalensis and the active compounds induce cell cycle arrest and apoptosis including upregulation of p53 and Bax in human lung cancer cells

    International Nuclear Information System (INIS)

    Gao Jiayu; Morgan, Winston A.; Sanchez-Medina, Alberto; Corcoran, Olivia

    2011-01-01

    Despite a lack of scientific authentication, Scutellaria baicalensis is clinically used in Chinese medicine as a traditional adjuvant to chemotherapy of lung cancer. In this stud