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1
Riche, Christian. "Xanthines : approches analytique, clinique, métabolique." Besançon, 1988. http://www.theses.fr/1988BESAA001.
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A partir de techniques de dosage des bases xanthiques par chromatographie en phase gazeuse, sur colonne capillaire de verre, avec détection thermoionique, et par chromatographie liquide de haute performance sur colonne C18, utilisant un gradient de solvant, sont abordés des problèmes de pharmacologie clinique et de métabolisme in vivo et in vitro. L'utilisation de la théophylline et de la caféine dans le cadre du traitement des apnées du nouveau-né est étudiée. Deux expérimentations cliniques, destinées à déterminer la zone thérapeutique de la théophylline et de la caféine sont rapportées. Le seuil minimal d'effecacité a été trouvé à 3 mg/l (17µmol/l) pour la théophylline et à 12 mg/l (63 µmol/l) pour la caféine. Pour la théophylline, le seuil de toxicité est de 8 mg/l (44µmol/l) et 20 mg/l (100 µmol/l) pour la caféine. Ce travail est complété par une approche du métabolisme in vitro, à l'aide d'hépatocytes en culture primaire d'homme adulte et de nouveau-né, en comparaison avec des résultats observés avec des hépatocytes de rat. Une transformation de la théophylline en caféine par les hépatocytes d'adulte a été mise en évidence. Le métabolisme du nouveau-né est limité. Pour la caféine chez l'adulte, on retrouve qualitativement et quantitativement les mêmes schémas métaboliques in vitro et in vivo, en ce qui concerne les déméthylations. D'autre part, il existe une différence importante entre espèces. Le modèle in vitro permet une bonne extrapolation de ce qui est connu in vivo.
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Perticarari, Sofia. "Atropisomeric xanthines: Synthesis, stereodynamics and absolute configuration." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amslaurea.unibo.it/9025/.
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During the thesis period a new class of atropisomeric xanthine derivatives has been studied. We decided to focus our attention on these purine bases because of their various biological activities, that could play an important role in the discovery of new bioactive atropisomers. The synthesized compounds bear an Aryl-N chiral axis in position 1 of the xanthine scaffold, around which the rotation is prevented by the presence of bulky ortho substituents. Through a retro synthetic analysis we synthesized three atropisomeric structures bearing in position 1 of the purine scaffold respectively an o-tolyl, o-nitrophenyl and a 1-naphthyl group. The conformational studies by DFT simulations showed that the interconversion energy barrier between the two available skewed conformations is higher enough to obtain thermally stable atropisomers. After the separation of the atropisomers, the experimental energy of interconversion was investigated by means of kinetic studies following the thermal racemization process using an enantioselective HPLC column. The absolute configuration of each atropisomer was assigned by experimental ECD analysis and TD-DFT simulations of the ECD spectra.
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Beauglehole, Anthony Robert, and anthony@adenrx com. "N3-substituted xanthines as irreversible adenosine receptor antagonists." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20080612.084330.
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8-Cyclopentyl-3-(3-(4-fluorosulfonylbenzoyl)oxy)propyl-propylxanthine (44, FSCPX) has been reported to exhibit potent and selective irreversible antagonism of the A1 adenosine receptor when using in vitro biological preparations. However, FSCPX (44) suffers from cleavage of the ester linkage separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine pharmacophore when used in in vivo biological preparations or preparations containing significant enzyme activity, presumably by esterases. Cleavage of the ester linkage renders FSCPX (44) inactive in terms of irreversible receptor binding. In order to obtain an irreversible A1 adenosine receptor antagonist with improved stability, and to further elucidate the effects of linker structure on pharmacological characteristics, several FSCPX (44) analogues incorporating the chemoreactive 4-(fluorosulfonyl)phenyl moiety were targeted, where the labile ester linkage has been replaced by more stable functionalites. In particular, ether, alkyl, amide and ketone linkers were targeted, where the length of the alkyl chain was varied from between one to five atoms.
Synthesis of the target compounds was achieved via direct attachment of the N-3 substituent to the xanthine. These compounds were then tested for their biological activity at the A1 adenosine receptor via their ability to irreversibly antagonise the binding of [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]DPCPX, ( 9) to the A1 adenosine receptor of DDT1 MF-2 cells. For comparison, the xanthines were also tested for their ability to inhibit the binding of [3H]-4-(2-[7-amino-2-{furyl} {1,2,4}- triazolo{2,3-a} {1,3,5}triazin-5-ylamino-ethyl)]phenol ([3H]ZM241385, 36) to the A2A adenosine receptor of PC-12 cells. The results suggest that the length and chemical composition of the linker separating the reactive 4-(fluorosulfonyl)phenyl moiety from the xanthine ring contribute to the potency and efficacy of the irreversible A1 adenosine receptor ligands. Like FSCPX (44, IC50 A1 = 11.8 nM), all derivatives possessed IC50 values in the low nM range under in vitro conditions. Compounds 94 (IC50 A1 = 165 nM), 95 (IC50 A1 = 112 nM) and 96 (IC50 A1 = 101 nM) possessing one, three and five methylene spacers within the linkage respectively, exhibited potent and selective binding to the A1 adenosine receptor versus the A2A adenosine receptor. Compound 94 did not exhibit any irreversible binding at A1 adenosine receptors, while 95 and 96 exhibit only weak irreversible binding at A1 adenosine receptors. Those compounds containing a benzylic carbonyl separating the 4-(fluorosulfonyl)phenyl moiety from the xanthine ring in the form of an amide (119, IC50 A1 = 24.9 nM, and 120, IC50 A1 = 21 nM) or ketone (151, IC50 A1 = 14 nM) proved to be the most potent, with compound 120 exhibiting the highest selectivity of 132-fold for the A receptor over the A2A receptor. compounds 119, 120 and 151 also strongly inhibited the binding of [3H]DPCPX irreversibly (82%, 83% and 78% loss of [3H]DPCPX binding at 100 nM respectively). compounds 120 and 151 are currently being evaluated for use in in vivo studies.
Structure-activity studies suggest that altering the 8-cycloalkyl group of A1 selective xanthines for a 3-substituted or 2,3-disubstituted styryl, combined with N-7 methyl substitution will produce a compound with high affinity and selectivity for the A2A adenosine receptor over the A1 adenosine receptor. Compound 167 (IC50 A2A = 264 nM) possessing 8-(m-chloro)styryl substitution and the reactive 4-(fluorosulfonyl)phenyl moiety separated from the xanthine ring via an amide linker in the 3-position (as for 119 and 120), exhibited relatively potent binding to the A2A adenosine receptor of PC-12 cells, with a 16-fold selectivity for that receptor over the A1 adenosine receptor. However, compound 167 exhibited only very weak irreversible binding at A2A adenosine receptors.
Overall, at this stage of biological testing, compound 120 appears to possess the most advantageous characteristics as an irreversible antagonist for the A1 adenosine receptor. This can be attributed to its high selectivity for the A1 adenosine receptor as compared to the A2A adenosine receptor. It also has relatively high potency for the A1 adenosine receptor, a concentration-dependent and selective inactivation of A1 adenosine receptors, and unbound ligand is easily removed (washed out) from biological membranes. These characteristics mean compound 151 has the potential to be a useful tool for the further study of the structure and function of the A1 adenosine receptor.
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Duckworth, Megan Jane Medical Sciences Faculty of Medicine UNSW. "Characterisation of the xanthineguanine phosphoribosyltransferase of helicobacter pylori as a potential therapeutic target." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43418.
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Helicobacter pylori infects more than half of the global population and causes gastric disorders. The increasing development of antibiotic resistance by the bacterium continues to limit treatment options. The identification and characterisation of novel therapeutic targets are necessary for successful future treatment of the infection. One potential target for therapeutic intervention is the gpt gene encoded by hp0735 (jhp0672) in H. pylori strain 26695 (J99). This gene produces a putative xanthine-guanine phosphoribosyltransferase (XGPRTase), an enzyme of the purine salvage synthesis pathway. This project employed theoretical, molecular and biochemical approaches to investigate features of H. pylori gpt and XGPRTase that will serve to ascertain their therapeutic potential. The production of a functional XGPRTase by H. pylori was investigated in cell-free extracts, and the kinetic parameters of this activity were compared to those of purified rXGPRTase enzyme. The three 6-oxopurine substrates were recognised by rXGPRTase and allosteric kinetics were observed for some substrates of the enzyme in cell-free extracts and for purified enzyme. These observations indicate complex regulation and an influence of cellular interactions on activity. Bioinformatics were employed to analyse XGPRTase phylogeny, and threading techniques used to build a structural model of XGPRTase. The enzyme is significantly divergent from the equivalent mammalian enzyme, and modelling identified specific features of the enzyme. Molecular approaches were utilised to analyse the essential role of gpt in H. pylori survival. These included insertional inactivation of the gpt in wild-type H. pylori strains and in mutants possessing a complementing copy of the gene present at the rdxA locus. No mutants were recovered with inactivated gpt possibly as a result of pleiotropic effects. Plasmid-mediated complementation was attempted employing IPTG-inducible shuttle vectors and did not yield any mutants. Further characterisation of H. pylori XGPRTase was performed by determining the effects of nucleotide monophosphates and purine analogues on enzyme activity. Inhibition by GMP was observed in all cases, however differences in the inhibition by other nucleotide monophosphates were found between cell-free extracts and the recombinant enzyme. Inhibition of rXGPRTase activity was observed by the purine analogue 6-mercaptopurine ribose, a compound that previously has been shown to inhibit H. pylori growth in culture.
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Kascatan, Nebioglu Aysegul. "N-HETEROCYCLIC CARBENE SILVER(I) COMPLEXES FROM XANTHINES AND THEIR ANTIMICROBIAL APPLICATIONS." University of Akron / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=akron1176579309.
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Massip, Stéphane. "Synthèse de nouvelles xanthines, dérivées de 2-amino-2-oxazolines, antagonistes potentiels des récepteurs de l'adenosine." Bordeaux 2, 2005. http://www.theses.fr/2005BOR21206.
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Ce travail de thèse nous a permis de synthétiser un grand nombre de nouveaux dérivés de type 1- ou 3-[2-hydroxy-3-aryloxypropyl]xanthines. Ces composés ont été obtenus à partir d'un synthon original de type amidine, les 2-amino-2-oxazolines. Les différentes voies réaxtionnelles nous ont conduit à des diaminouraciles intermédiaires diversement substitués dont les possibilités réactionnelles nous ont permis l'accès à plus de 60 nouvelles xanthines et analogues. Différentes stratégies de synthèse ont été développées pour accéder à de nouvelles xanthines 3 différemment substituées en position 1 et 7. L'ensemble de ces composés originaux a fait l'objet d'études de liaison en tant qu'antagonistes potentiels vis-vis des récepteurs de l'adénosine. Ces tests ont pu êttre réalisés grâce à une collaboration établie avec l'équipe du professeur C. Muller de l'Institut Pharmaceutique de l'Université de Bonn. Ces études pharmacologiques nous ont permis de déceler de nouveaux dérivés possédant une affinité de l'ordre de 30 à 100 nM et présentant, pour certains, une sélectivité notable vis-à-vis des récepteurs de l'adénosine A1 ou A2A. Ainsi, un groupement cycloalkyle, de type cyclopentyle ou noradamantyle, substitué en position 8 et associé à une chaîne propylique en position 1 (xanthines 3e et 3g) semble constituer un bon pharmacophore pour l'affinité vis-à-vis du récepteur de l'adénosine A1. De plus, ce modèle de xanthine ne présente pas de substitution en position 7. Par ailleurs, les motifs xanthines présentant un groupement méthoxystyryle en position 8 associé à une chaîne propargyle en position 1 (composé 3f) et un groupe méthyle en position 7 (composé 3k) ont révélé une affinité remarquable vis-à-vis du récepteur A2A.
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Seddon, Gavin M. "Radiation effects on biochemical systems." Thesis, University of Salford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313912.
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Mapengo, Raphaël. "Cinétiques de méthylation et de deutérométhylation des xanthines : évaluation des effets isotopiques : essai de corrélation aux réactions de N-déméthylation biologique." Lyon 1, 1990. http://www.theses.fr/1990LYO1T168.
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Calenzo, Chappe Valérie (19. "Régulation et pharmacologie du canal chlorure CFTR : implication des récepteurs purinergiques de type P2Y dans l'activation du canal CFTR par les dérivés xanthines." Aix-Marseille 1, 1999. http://www.theses.fr/1999AIX11026.
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Les epitheliums forment une barriere continue entre deux compartiments et permettent le transport d'ions, de solutes et de macromolecules. L'absorption de na + et la secretion de cl sont des elements majeurs de la fonction epitheliale. Le canal cftr (cystic fibrosis transmembrane conductance regulator), membre de la superfamille des transporteurs abc (atp binding cassette), est une des clefs de la regulation du transport de chlorure dans les epitheliums. La mucoviscidose est la maladie genetique la plus repandue dans les populations europeennes et nord-americaines. Elle se caracterise par une modification des transports ioniques epitheliaux due a un mauvais adressage ou un dysfonctionnement du canal cftr regule par l'ampc et l'atp. On ne possede pas de modeles structuraux ou moleculaires des canaux chlorure actives par le calcium, mais leur regulation par les recepteurs purinergiques de type p2 est bien connue. L'analyse des regulations par l'ampc et l'atp de ces canaux nous a permis de montrer l'importance des croisements entre ces voies de signalisation. Nous montrons que la permeabilite chlorure, activee par le calcium, des cellules frtl-5 (fischer rat thyroid) est controlee par une stimulation chronique de la voie ampc et que l'activite du canal cftr transfecte dans les cellules cho (chinese hamster ovary) est controlee par le recepteur purinergique p2u. L'etude pharmacologique du canal cftr montre que des formes actives, inactives et antagonistes de derives xanthines sont obtenues en modifiant des substitutions alkyl en position n1. La regulation du canal cftr par les seconds messagers suggere que l'activite des xanthines depend essentiellement de l'inhibition du recepteur p2u. Nos resultats montrent que les recepteurs purinergiques p2u jouent un role central dans la regulation du niveau intracellulaire de calcium et d'ampc, et donc de l'activite des canaux chlorure des cellules epitheliales.
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Essandoh, Ernest. "Structural studies of organic crystals of pharmaceutical relevance : correlation of crystal structure analysis with recognised non-bonded structural motifs in the organic solid state." Thesis, University of Bradford, 2009. http://hdl.handle.net/10454/4444.
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Pharmaceutical solids tend to exist in different physical forms termed as polymorphs. Issues about pharmaceutical systems are mainly concerned with the active ingredient's physico-chemical stability and bioavailability. The main aim of this study is to investigate the non-bonded interactions in pharmaceutical solids that govern the physical pharmaceutics performance of such materials and through the use of structural techniques and correlation of these results with crystal structural database to establish the presence of physical motifs in selected systems. Structural motifs were identified by the use of single crystal and crystal packing analysis on diverse range of pharma-relevant materials including chalcones, cryptolepines, biguanides and xanthines. These selected systems were validated using functional group and molecular analysis and correlating them to the Cambridge Structural Database. Crystallization studies are done on these selected systems as well as exploiting those using synthetic analogues. A total of 51 crystal structures were investigated including 16 new structure determinations. Addition synthesis of new xanthines to investigate novel intermolecular patterns was also undertaken. The understanding and exploitation of intermolecular interactions involving hydrogen bonds and coordination complexation during packing can be used in the design and synthesis of solid state molecular structures with desired physical and chemical properties.
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Lira, Eduardo Carvalho. "Efeito anticatabólico dos derivados de xantina no metabolismo de proteínas em músculos esqueléticos de ratos sépticos: um estudo de microdiálise." Faculdade de Medicina de São José do Rio Preto, 2006. http://bdtd.famerp.br/handle/tede/223.
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Previous issue date: 2006-04-20Introduction: The aim of the present study was to estimate the anticatabolic effect of xanthine derivatives on skeletal muscle protein metabolism from septic rats by using microdialysis. Methods: Sepsis was induced by cecal ligation and puncture (CLP). After 3, 6 and 10 hours of surgery, male Wistar rats (~250g) were anesthetized with thionembutal sodium (50mg/Kg body weight i.p.) and placed on heating pads to maintain adequate temperature (37oC). Microdialysis probe was inserted in the anterior tibial muscle and an equilibration period of 30 minutes was allowed. After connecting the catheter inlet to a microinjection pump, the system was perfused with 0,5% bovine serum albumin, 50 μM tyrosine and 1 mmol/l glucose in isotonic saline at a rate of 1.0 μl/min. Samples of the skeletal muscle interstitial fluid and arterial plasma from carotid artery were collected after 90 minutes of experiment and tyrosine was measured by fluorescence. The interstitial tyrosine concentration was estimated from the dialysate concentration. To calibrate catheters in vivo the internal reference calibration technique was used. The muscle blood flow was estimated by ethanol technique. Overall proteolysis was investigated in extensor digitorus longus (EDL) muscles from sham-operated and 3-hour septic rats (~70g) incubated in the presence or not of IBMX (1mM). Results: In sham-operated and septic rats, skeletal muscle interstitial tyrosine levels (μM) were significantly higher than arterial plasma tyrosine. Three-hour septic rats showed a 33% decrease in muscle blood flow and a 128% increase in the concentration of tyrosine in skeletal muscle interstitial (235 ± 16, n=10), when compared to sham-operated rats (95,5 ± 5,5, n=10). Interstitial (I) minus arterial (A) plasma tyrosine concentrations difference was also significantly increased after 3 hours of sepsis (117 ± 7 vs. 31 ± 6 in sham-operated, n=10). Pentoxifylline (PTX; 50mg/Kg body weigh, e.v.) treatment, during 1 hour immediately after CLP, reduced in 25% and 50% the interstitial tyrosine concentration and I-A difference, respectively. In situ isobutylmethylxanthine (IBMX; 1mM), but not PTX, reduced the interstitial tyrosine concentration (30-46%) and I-A difference (43-48%) in both groups. The increase of proteolysis induced by sepsis in EDL muscles was abolished by in vitro addition of IBMX (1mM). Conclusions: The data show that: (1) microdialysis is a perfectly adapted tool to investigate in vivo regulation of muscle protein metabolism during acute catabolic states; (2) the catabolic effect of sepsis on rat skeletal muscle protein metabolism in vivo can be observed 3 hours after CLP; (3) the xanthine derivatives reduce the muscle protein catabolism induced by sepsis in rats.
Objetivo: investigar o efeito anticatabólico dos derivados de xantinas no metabolismo de proteínas de ratos sépticos utilizando a técnica de microdiálise. Materiais e métodos: Ratos machos Wistar (~250g) foram anestesiados com tiopental (50mg/Kg, i.p.) e mantidos em mesa cirúrgica aquecida (37°C). A sepse foi induzida pela ligadura e punção do ceco (CLP) e os músculos estudados após 3, 6 e 10 horas da cirurgia. O cateter de microdiálise foi inserido no tibial anterior, o qual foi perfundido a um fluxo constante de 1,0μl/min com solução salina enriquecida com albumina bovina (0,5%), 50 μM de tirosina fria, 1 mmol/l de glicose e [14C]-tirosina. A tirosina foi quantificada por fluorescência no dialisado, sangue arterial e solução de perfusão, após 90 minutos de microdiálise. O cateter foi calibrado in situ pela técnica da referencia interna. O Fluxo Sanguíneo Muscular (FSM) foi avaliado pela técnica do clearance de etanol. A proteólise foi quantificada no extensor digitorus longus (EDL) de ratos (~70g) sham ou sépticos por meio da liberação de tirosina in vitro. Resultados: A concentração intersticial de tirosina foi sempre maior que a concentração arterial. A sepse de 3 horas reduziu em 33% o FSM e aumentou em 127% a concentração intersticial de tirosina (235 ± 16, n=10) em relação ao sham (95 ± 5, n=10). A diferença I-A também foi maior no grupo séptico (117 ± 16 vs. 31 ± 6 no sham, n=10). A infusão sistêmica da pentoxifilina (PTX; 50mg/Kg, e.v.), durante a primeira hora pós-CLP, reduziu em 25% e 50% a concentração intersticial e a diferença I-A de tirosina, respectivamente. O tratamento in situ com isobutil-metil-xantina (IBMX; 1mM), mas não com PTX, reduziu a concentração intersticial (30-46%) e a diferença I-A (43-48%) de tirosina, em ambos os grupos. O aumento da proteólise muscular induzido pela sepse foi abolido pela ação in vitro da IBMX (1mM) que reduziu a proteólise em 41%. Conclusões: os resultados mostram que: (1) a microdiálise é uma técnica perfeitamente adaptada ao estudo do metabolismo de proteínas em situações catabólicas; (2) o modelo da CLP de 3 horas ativa o catabolismo de proteínas em músculos esqueléticos de ratos; (3) As ações sistêmicas, in situ e in vitro dos derivados de xantinas reduzem o catabolismo de proteínas em músculos de ratos sépticos.
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Stockert, Amy L. "Spectroscopic and kinetic studies of bovine xanthine oxidase and Rhodobacter capsulatus xanthine dehydrogenase." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1089910515.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xv, 172 p.; also includes graphics. Includes bibliographical references (p. 165-172).
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Fujisawa(Morita), Yukari. "Identification of xanthine dehydrogenase/xanthine oxidase as a rat Paneth cell zinc-binding protein." Kyoto University, 2001. http://hdl.handle.net/2433/150188.
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Wilson, Wendy Lee. "Xanthine oxidase in the lung." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/26669.
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The generation of oxygen free radicals by the cytosolic enzyme, xanthine oxidase (XO), has been implicated in post-ischemic or reperfusion damage in several organs. XO catalyzes the conversion of hypoxanthine to urate with the concomitant production of superoxide anion free radical (0₂̅˙) and hydrogen peroxide (H₂O₂). Oxygen free radical-mediated injury has also been demonstrated in inflammatory lung disease. The possible involvement of XO in oxidative injury in the lung has not yet been studied. Therefore, this research project was designed to determine whether XO is present in the lung and to investigate its characteristics in porcine, bovine, rat and human lung and other tissues.
Immunochemical analysis of xanthine oxidase in the tissues employed on polyclonal antibody raised to bovine milk XO. Proteins were separated by SDS-polyacrylamide gel electrophoresis of tissue homogenates. Proteins were transfered from the gels to nitrocellulose filters by Western blotting. After incubating the filters with a antisera containing the antibody to the purified bovine XO. XO on the filter was detected by its reaction with an enzyme-conjugated second antibody. XO was immunologically detectable in bovine lung and milk. Rat lung, kidney and liver all showed XO reactivity. XO was detectable in porcine liver but not detectable in porcine lung or kidney. Thus, the antibody to bovine XO was cross-reactive with porcine and rat XO. XO protein was not immunologically detectable in human lung possibly because the antibody was not cross reactive with the bovine antibody. In vivo, xanthine oxidase exists predominantly as a dehydrogenase rather than an oxidase. In this form as xanthine dehydrogenase (XDH) the enxyme does not produce either 0₂̅˙ or
H₂O₂. The activity of both XDH and XO was measured in several
tissues using a fluorometric assay which uses an artifical substrate,
pterin which is catalytically converted to the fluorescent product
isoxanthopterin (IXP). XO activity in porcine liver was of 1.1 x 10⁻³ µg IXP/mg protein/min although XO activity was not detectable
in porcine lung and kidney, in rat lung of 1.7 x 10⁻² µg IXP/mg
protein/min, rat kidney of 1.5 x 10⁻² µg IXP/mg protein/min, and
rat liver of 2.2 x 10⁻² µg IXP/mg protein/min. Seven human lung biopsy samples were obtained after lung resection and initially tested for viability by determination of NADH oxidase activity and then assayed for XO-XDH. Three of these samples showed NADH oxidase activity indicating tissue viability, but only one of these three showed measurable XO activity of 5.35 x 10⁻⁶ µg IXP/mg protein/min.
Irreversible conversion of XDH to XO is thought to be the result of limited proteolysis by a Ca²⁺/calmodulin activated protease, whereas reversible conversion of the enzyme occurs by oxidation of critical thiol groups. Studies on the rate and nature of fluorescence assay to detect catalytic activities of both enzyme forms. Incubation of lung homogenates with trypsin for 60 min caused
irreverisble conversion of 90% of the XDH to XO. In contrast,
incubation of homogenates at 15°C for 10 hours caused conversion of
100% of the XDH to XO. This conversion was reversible to the extent
of 80% by reduction of thiol groups with dithiothreitol (DTT). The
effects of free Ca²⁺ on the conversion of XDH to X0 was examined by
using EDTA, a chelator of Ca²⁺ and other divalent cations; and EGTA,
a more specific chelator of Ca²⁺. The presence of these chelating agents during homogenization of either normoxic or ischemic rat lung tissue did not inhibit reversible enzyme conversion. Increased XO activity was reversible by DTT. In the normoxic rat lung, homogenates prepared with EDTA and EGTA showed a similar conversion of 95% of XDH to XO which was reversible to 70% with DTT. In the ischemic rat lung, samples prepared with EDTA and EGTA showed a'conversion of 80% and 95% XDH to XO which was similar to control samples. The extent of reversibility to XDH was 75% with DTT incubation. In addition, perfusion of rat lungs with EDTA and DTT via a pulmonary artery cannula prior to 60 min of ischemia and homogenization did not affect the extent of XDH to XO conversion.
These results indicate that irreversible Ca²⁺-mediated proteolytic conversion of XDH to XO does not occur to a great extent in the rat lung during either normoxia or ischemia. However, reversible conversion of XDH to XO does occur, suggesting that reversible thiol dependent conversion may play a role in the lung under both physiological and pathophysiological states.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Gibson, Elizabeth. "Porphyrin probes for xanthine oxidase." Thesis, University of York, 2007. http://etheses.whiterose.ac.uk/9915/.
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Martin, Hannah M. "Cellular expression of xanthine oxidoreductase." Thesis, University of Bath, 2003. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426176.
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Wang, Jinfang. "Xanthine-imprinted polymers for decaffeination applications." Thesis, University of Strathclyde, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431777.
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Pauff, James Michael. "Structure-Function Studies of Xanthine Oxidoreductase." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1227480976.
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Leigh, Maria. "Non purine inhibitors of xanthine oxidase." Thesis, University of York, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550273.
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The increase in the occurrence of hyperuricemia and gout in recent years, coupled with side- effects associated with use of the main anti-gout therapeutic, allopurinol, have triggered the search for non-purine alternatives. The first such inhibitor to be made available is Adenurlc", 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid. The aim of this work was to synthesise a small library of non-purine compounds and evaluate their inhibitory activity against the enzyme, xanthine oxidase. Successful inhibitors are marked as those that gave a comparable or lower ICso value than allopurinol (3 ± 0 J.1M), under conditions employed in this work. A range of five-membered heterocyclic compounds, including 1,2,4-triazole-3-thiones, 2- amino-1,3,4-thiadiazoles and 1,3-thiazoles were synthesised. On testing, the heterocyciic compounds did not reveal significant inhibition of XO. SAR analysis marked the presence of alkyl chains and para-cyano substituents as contributors to inhibition. The most successful heterocyciics investigated were highlighted as [17b), 4-(4-cyanophenyl)-1,3-thiazole-2- carboxylic acid, (ICso= 150 ± 14 J.1M) and [15), [4-(4-bromophenyl)-1,3-thiazole-2- sulfanyl]acetonitrile, (ICso= 29 ± 4 J.1M). A concise library of Schiff base compounds was then investigated, incorporating thiosemicarbazones, dithiocarbazates and hydrazones, with varied number and positioning of aromatic substituents. SAR analysis revealed important structural features affecting inhibition, such as a para-hydroxyl benzaldehyde substituent and a para-hydroxyl/cyano substituent on hydrazide/thiosemicarbazide rings. The position rather than the number of hydroxyl substituents proved significant for inhibition. The most potent compounds were thiosemicarbazones 8-Tz3 (0.6 ± 0.2 IlM), 10-Tz2 (0.5 ± 0 ~LM), 10-Tz3 (0.6 ± 0.1 IlM), 11- Tz2 (O.B ± 0.1 J.1M), 11-Tz3 (0.6 ± 0 J.1M) and 11•DTz1 (0.7 ± 0.1 J.1M), giving four times lower ICso than allopurinol. Potent uncomplexed Schiff bases as XO inhibitors have not been previously reported. Steady-state kinetic studies on 8-Tz3, 11-Tz3, 8-DTz1 and 11•DTz1 revealed mixed-type inhibition. As 11•DTz1 gave the lowest Kj value (0.4 ± 0 IlM), coupled with its low ICso value, highlight it as a promising lead compound. Upon reduction of the imine bond, 11•DTz1 reduced retained improved activity over allopurinol, though less potent than its parent Schiff base. Complexation to Mo{VI) and Cu{lI) centres occurred, with the ligands acting as tridentate ONS/ONO donors. The distorted octahedral coordination geometry of Mo(Vl) complexes was confirmed via crystal structure determination. The Cu(lI) complexes, [Cun(l10-TZ2)n) and [Cun(L S-HS)n), revealed a 3-fold increase in potency over their free ligands. The presence of Cu(lI) therefore appears to have a cooperative effect and warrants further investigation as means of improving potency and hydrolytic stability.
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Hewinson, James. "Vascular endothelial release of xanthine oxidoreductase." Thesis, University of Bath, 2005. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418883.
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Khan, Jamshad. "Purification and stability of bovine xanthine oxidase." Thesis, University of Bath, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307127.
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Bryant, Richard. "The immunoaffinity purification of human xanthine oxidase." Thesis, University of Bath, 2003. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398413.
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Rouquette, Magali. "Xanthine oxidoreductase : a role in cell signalling." Thesis, University of Bath, 1998. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300878.
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Page, Susanna. "Regulation and immunolocalisation of human xanthine oxidoreductase." Thesis, University of Bath, 1999. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300881.
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Powell, Debbie. "Purification, characterisation and regulation of human xanthine oxidase." Thesis, University of Bath, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307028.
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Choudhury, Sharmila. "Purification and characterisation of xanthine oxidoreductase from liver." Thesis, University of Bath, 2001. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760763.
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Lates, Vasilica-Adriana. "Systèmes bioanalytiques pour la détermination de la capacité antioxydante et l’ochratoxine A dans les denrées alimentaires." Perpignan, 2011. http://www.theses.fr/2011PERP1054.
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L'apport journalier en antioxydants (composés chimiques naturellement présents dans certains aliments) contribue à la diminution du stress oxydatif sur le métabolisme humain. Nous avons mis au point un nouvel outil pour la détermination de la capacité antioxydante, basé sur une série des réactions enzymatiques qui se déroulent dans un bioréacteur dont le produit principal, l’eau oxygénée, est suivi en temps réel par un biocapteur ampérométrique. Ce système analytique s'avère beaucoup plus adéquat pour l’analyse des échantillons réels que d’autres variantes déjà connues. La présence des mycotoxines (métabolites de certains champignons) dans différents aliments est une préoccupation majeure et d’actualité. Un dépistage rapide peut aider la prévention de la toxicité aigue provoquée par la consommation des produits alimentaires contaminés. La reconnaissance immunospécifique, en utilisant des anticorps immobilisés sur des différents supports (électrodes sérigraphiées, billes en verre), couplée soit avec une sonde redox soit avec une réaction enzymatique, est à la base d’une nouvelle technique utilisée pour la détection in situ de l'ochratoxine A dans des échantillons de vinDaily intake of antioxidants (natural constituents of foodstuffs) reduces the appearance of oxidative stress related diseases. A fast method for quantification of antioxidant activity could serve as an attractive criterion for aliments quality. In this work, a new analytical tool for antioxidant capacity determination was developed. Based on an original coupling between a enzymatic bioreactor and an amperometric biosensor, the system was included in a flow manifold, allowing the processing of real samples with a high throughput rate. Foodstuffs contamination with mycotoxins, secondary fungal metabolites, is an increasing worldwide concern because of the hazard that these compounds present. Together with preventive measures, a fast screening is a way of avoiding the toxic effects upon human health. Hence, we have developed a new analytical tool for the detection of ochratoxin A in wine samples. The immunospecific recognition based on immobilized antibodies on different supports (screen-printed electrodes, porous glass beads), monitored via a redox probe or an enzymatic reaction, is the principle of our technique, capable of in situ measurements
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Godber, Benjamin L. J. "Physicochemical and kinetic properties of human milk xanthine oxidoreductase." Thesis, University of Bath, 1998. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760718.
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Al-Gonaiah, Majed A. "Investigating xanthine oxidase toxicity models in cultured cerebellar granule neurons." Thesis, University of Glasgow, 2009. http://theses.gla.ac.uk/1057/.
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In the last few decades, evidence has been accumulating for a role for xanthine oxidoreductase (XOR)-generated toxic reactive oxygen species (ROS) in a variety of pathological conditions that affect different organ systems. This enzyme in mammals exists in two inter-convertible forms: xanthine dehydrogenase (XDH) (the predominant intracellular form under physiological conditions) and xanthine oxidase (XO). A combination of XO and its oxidizable substrate xanthine (X) (or hypoxanthine (HX)) is widely used as a model to produce ROS and to study their effects in a variety of cell culture studies. However, the effect of the combination of XOR and the reduced nicotinamide adenine dinucleotide (NADH) in cell cultures is much less studied. NADH is another oxidizable substrate for XOR that binds to a different site on the enzyme from that of X binding. The aim of this project was to investigate some aspects of the in vitro toxicity of XOR, which might provide more insights into its in vivo toxicity. The main investigation was a comparison between the well studied X / XO and the much less studied NADH / XO toxicity models. Also, secondary studies were undertaken to investigate those aspects of X / XO toxicity where there are uncertainties about them. These studies were performed using primary cell cultures. Cell cultures are now widely used to study different diseases, and although they have their drawbacks, they have their advantages over the in vivo studies. For this project, primary cultures of cerebellar granule neurons (CGNs) were used. In the beginning, some problems were encountered with CGNs. The main problem was the immediate damage induced to the neurons (including those in the control groups) at the intervention/experiments day (i.e. day 8 or 9 after plating) by manipulating the cultures (i.e. aspirating the culture medium, adding treatment and control vehicles, and adding the restoration medium). After several months of investigation, it was serendipitously discovered that the immediate damage seen in the neurons (including those in the control groups) when they are manipulated at the experiments/intervention day was due to glutamate excitotoxicity (through activating its N-methyl-D-aspartate (NMDA) receptors). The source of glutamate was the fresh serum which is present at 10% V/V in the fresh culture medium that is added to the cultures at that day. After solving this problem, it was possible to conduct reliable experiments to investigate XO toxicity models. Regarding investigating XO toxicity, it was found that both of the X / XO and NADH / XO combinations were toxic to cultures of CGNs. However, the concentration of NADH needed to cause the toxicity was much higher than that of the other substrate, X, which is in agreement with previous cell-free experiments that showed that NADH is a much weaker substrate than X for the bovine milk XO used here. Blocking the site of X binding on XO prevented X / XO toxicity, but did not prevent NADH / XO toxicity. On the other hand, blocking the site of NADH binding prevented both X / XO and NADH /XO toxicities. Another difference between the two systems was that deactivating either superoxide or hydrogen peroxide (both are ROS) generated by XO prevented NADH / XO toxicity, whereas although deactivating hydrogen peroxide prevented X / XO toxicity, deactivating superoxide generated from this combination did not. In the NADH / XO system, an extracellular metal contaminant (likely contaminating XO powder/preparation) seemed to be involved in the toxicity. The two toxicity models were similar in the mediation of toxicity by intracellular iron ion. In X / XO toxicity, although superoxide generated extracellularly from the combination has no role in the toxicity, intracellularly produced superoxide seemed to play a role. Conclusions: 1. Culturing/experimental conditions have been optimised for viability studies in CGNs cultures. 2. The combination of NADH and XO induces damage to CGNs, where although blocking the NADH binding site prevents this damage, blocking the X binding site does not. It is feasible that the oxidation of NADH by some forms of XOR (other than the one used here) that are known to be very efficient in oxidizing NADH might produce in vivo toxicity. 3. A possibility raised by this study is that a metal (like the metal contaminant proposed to play a role in NADH / XO toxicity in this study) might contribute to XOR toxicity in vivo. 4. Intracellular superoxide often mediates XOR toxicity. 5. The results add support to many previous studies which suggested that intracellular hydroxyl radical (or a similar species) is involved in XOR toxicity.
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Doyle, Wendy Anne. "Biochemical and molecular genetic studies of Drosophila melanogaster xanthine dehydrogenase." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239022.
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Millar, Timothy Marc. "Novel aspects of the activity and function of xanthine oxidase." Thesis, University of Bath, 1999. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311326.
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Urso, Edith-Marie d'. "Biocapteur ampérométrique pour la détection des ions phosphate : étude approfondie de l'immobilisation du système bienzymatique PNP-XOD, performances et applications." Lyon 1, 1992. http://www.theses.fr/1992LYO10145.
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Ce travail presente l'etude d'un biocapteur bienzymatique specifique des ions phosphate. La purine nucleoside phosphorylase (pnp) et la xanthine oxydase (xod) sont co-immobilisees sur une membrane synthetique preactivee placee au contact d'une electrode amperometrique en platine capable de detecter l'eau oxygenee et l'acide urique generes enzymatiquement. L'influence sur les performances du biocapteur du rapport des activites enzymatiques dans la solution de couplage et des activites totales deposees a ete etudiee. Nous demontrons que l'optimisation de ces deux parametres permet d'ameliorer non seulement la sensibilite mais aussi l'etendue du domaine de linearite de la reponse au phosphate par rapport aux resultats obtenus lorsque la proportion des deux enzymes dans la solution de couplage est fixee de facon arbitraire. La correlation entre la sensibilite et l'activite retenue pour les deux enzymes impliques nous a permis de mettre en evidence un comportement inattendu pour la xod. Nous avons alors compare les caracteristiques des electrodes monoenzymatiques obtenues en immobilisant seule la xod ou d'autres enzymes, la glucose oxydase et la choline oxydase. Les qualites du biocapteur (fiabilite, specificite, sensibilite et stabilite operationnelle) ont ete testees en systeme batch et en flux continu. Si l'on envisage une application dans le controle de l'environnement, le dispositif en flux continu semble plus adapte que le systeme en batch compte tenu de sa sensibilite plus elevee: la reponse au phosphate est lineaire entre 0,5 et 56 nanomoles (soit entre 1 et 250 m dans l'echantillon). Les reponses non specifiques du biocapteur dues aux interferences electrochimiques ou a la specificite large de la xod peuvent etre supprimees si l'on introduit, dans le dispositif, une deuxieme electrode munie d'une membrane neutre ou d'une membrane xod. Par contre, malgre la specificite de la nucleoside phosphorylase, la reponse du biocapteur a l'arseniate, analogue de structure du phosphate, ne peut pas etre contournee
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Richter, Tanja. "Entwicklung alternativer Methoden zur Nukleotid-Analytik in der Bioprozessüberwachung." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=959651853.
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Donyai, Parastou. "Xanthine oxidase in oxidative stress : design and evaluation of novel inhibitors." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300381.
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Harris, Christopher Peter David. "Lipoprotein quality, anti-(xanthine oxidase) antibodies and coronary heart disease risk." Thesis, University of Bath, 1995. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.760669.
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Cultrone, Antonietta. "La xanthine dioxygénase α-kétoglutarate dépendante : une enzyme caractéristique des champignons." Paris 11, 2004. http://www.theses.fr/2004PA112069.
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Le sujet de cette thèse est le clonage du gène xanA et le caractérisation de la protéine XanA d'Aspergillus nidulans. XanA est une enzyme qui hydroxyle la xanthine en acide urique. Dans une souche sauvage la purine hydroxylase I (HxA) catalyse l'hydroxylation de l'hypoxanthine en xanthine et de la xanthine en acide urique. L'hypoxanthine peut aussi être hydroxylée par la purine hydroxylase II codée par le gène hxnS. Les purines hydroxylases I et II sont des enzymes associées à un cofacteur à molybdène, alors que XanA ne l'est pas. Nous avons cloné et séquencé le gène xanA. Il code une protéine de 370 acides aminés. XanA présente des similarités avec les protéines de la famille des dioxygénases. Des protéines fortement similaires à XanA n'ont été trouvées que chez les champignons (N. Crassa, S. Pombe, F. Graminearum, P. Chrysosporium, C. Cinereus, U. Maydis, C. Albicans). Une mutation dans le gène xanA a été isolée. Cette mutation (xanA1) est une transversion de C à A qui se traduit par le remplacement d'une alanine par une asparagine au niveau du codon 167. Le phénotype de la délétion du gène xanA est identique à celui de xanA1. La surexpression de xanA chez A. Nidulans a permis de caractériser l'enzyme. Nous avons démontré qu'il s'agit d'une xanthine dioxygénase dépendante de l'a-kétoglutarate. Le gène xanA (chromosome VIII) et son promoteur sont partiellement dupliqués sur le chromosome II. L'homologue de xanA chez S. Pombe (TC3962) ne complémente pas la mutation xanA1 d'A. Nidulans, tandis que cette mutation est complementée par l'homologue de xanA chez N. Crassa (xan1). L'expression de xanA est soumise au contrôle du facteur GATA AreA et est dépendante du facteur UaYThis work comprises the cloning of the xanA gene and the biochemical characterization of the XanA protein of aspergillus nidulans. This enzyme catalyses the oxidation of xanthine to uric acid. In the wild type strain, purine hydroxylase I (HxA) catalyses both the hydroxylation of hypoxanthine to xanthine and that of xanthine to uric acid. Hypoxanthine is also oxidized to xanthine by a second purine hydroxylase (purine hydroxylase II), which is coded by the hxnS gene. Both purine hydroxylases contain a molybdopterin co-factor while XanA does not. We have cloned and sequenced the xanA gene. XanA encodes a protein 370 amino acids long. The sequence of XanA has confirmed that it's not a molybdenum-containing enzyme; we found some similarities with proteins of the dioxygenase family. Proteins with high similarity to XanA were found only in fungi in N. Crassa, S. Pombe, F. Graminearum, p: chrysosporium, C. Cinereus, U. Maydis, C. Albicans. One mutation (xanA1) has been isolated. The xanA1 allele is a C to A transversion resulting in an alanine to asparagine change in codon 167. The phenotype of the xanA1 mutation is identical to that of xanA deletion. Overexpression of the xanAgene in A. Nidulans has permitted a preliminary characterization of the enzyme. We have shown it is an a-ketoglutarate dependent xanthine dioxygenase. The xanA gene (chromosome VIII), including its promoter is partially duplicated in chromosome II. The S. Pombe homologue of xanA, TC3962, is not able to complement the mutation xanA1. As all other enzymes of the purine utilization pathway xanA expression is under the control of the GATA factor AreA and the pathway specific transcription factor UaY
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Mokfi, Moloud [Verfasser]. "Xanthine-derived N-heterocyclic carbenes and their metal complexes / Moloud Mokfi." Wuppertal : Universitätsbibliothek Wuppertal, 2021. http://d-nb.info/1240266960/34.
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Sayin, Hasan McKee Michael L. "Quantum chemical studies and kinetics of gas reactions." Auburn, Ala, 2006. http://repo.lib.auburn.edu/2006%20Fall/Dissertations/SAYIN_HASAN_39.pdf.
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Jawed, Shahid. "The role of the redox enzyme xanthine oxido-reductase in rheumatoid arthritis." Thesis, Queen Mary, University of London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391624.
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Aburas, Omaro A. Emhmed. "Investigation of aldehyde oxidase and xanthine oxidoreductase in rainbow trout (Oncorhynchus mykiss)." Thesis, University of Huddersfield, 2014. http://eprints.hud.ac.uk/id/eprint/23543/.
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Molybdo-flavoenzymes (MFEs), aldehyde oxidase (AOX) and xanthine oxidoreductase (XOR) are involved in the oxidation of N-heterocyclic compounds and aldehydes, many of which are environmental pollutants, drugs and vitamins. This biotransformation generally generates more polar compounds that are more easily excreted, thus MFEs have been classed as detoxication enzymes. To date there has been scant study of the properties, substrate and inhibitor specificities of MFEs in non-mammalian vertebrate organisms. This investigation focuses on MFEs in rainbow trout (Oncorhynchus mykiss) as it belongs to a class of fish that host a single AOX (AOXβ) and one XOR. In this study the substrate specificity of rainbow trout liver AOX and XOR was investigated using HPLC and spectrophotometric assays. AOX in hepatic cytosol was found to be able to catalyse the oxidation of azanaphthalenes belonging to a group of compounds that are environmental pollutants such as phenanthridine, phthalazine and cinchonine. In addition, xenobiotic aromatic aldehydes (vanillin and dimethylaminocinnamaldehyde) and drugs such as allopurinol and pyrazinamide were substrates. Several endogenous vitamins including pyridoxal (vitamin B6), all-trans retinal (vitamin A) and N1-methylnicotinamide were also biotransformed by the rainbow trout AOX. In contrast to liver no AOX activity was detectable in kidney and gill tissue. XOR activity in rainbow trout liver was measurable with the endogenous purine xanthine, purine drug metabolites (1-methylxanthine and 6-thioxanthine) and N-heterocyclic drugs (allopurinol and pyrazinamide). Unlike mammalian XOR that can utilise both NAD+ and O2 as electron acceptors, trout XOR was exclusively NAD+-dependent with no activity being detected with O2. Eadie-Hofstee plots were using to determine the Km and Vmax of rainbow trout AOX and XOR with different substrates and it was found the Vmax of the rainbow trout enzymes were generally lower and Km generally higher than mammalian AOX and XOR. Inhibitors of mammalian AOX were tested to determine if they could interact with the piscine AOX. Environmental pollutants (17α-ethinyl estradiol and phenanthridine), an endogenous steroid (estradiol) and drugs (chlorpromazine and menadione) were found to be effective inhibitors and were classed as competitive, non-competitive and uncompetitive respectively using Lineweaver-Burk plots. The drug metabolite, oxipurinol, was a non-competitive inhibitor of rainbow trout XOR. In order to further characterise trout AOX protein purification was carried out. In contrast to mammalian AOX, the piscine enzyme was not thermotolerant at 55°C nor was it inhibited by benzamidine, thus heat treatment and affinity chromatography could not be used as a purification steps. Trout AOX was purified 210-fold using ammonium sulphate fractionation, together with ion exchange and gel filtration chromatography. The native molecular mass of the piscine AOX was 295 kDa, which is similar to mammalian AOXs. In conclusion this study yields new insight into groups of anthropogenic environmental pollutants, drugs and vitamins that are substrates and inhibitors of an ancestral vertebrate AOX. The toxicological relevance of these findings is discussed.
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Dong, Liang. "Novel xanthine and oxanine DNA glycosylase activities in yeast and mammalian systems." Connect to this title online, 2008. http://etd.lib.clemson.edu/documents/1239895528/.
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Perino, Isabelle. "Café, thé, maté, guarana : drogues végétales à bases xanthiques." Paris 5, 1990. http://www.theses.fr/1990PA05P044.
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Liu, Shiu Cheong Patrick. "Effects of xanthine oxidase inhibitors in pulmonary hypertension associated with chronic lung disease." Thesis, University of Dundee, 2019. https://discovery.dundee.ac.uk/en/studentTheses/ee8678d8-e7c7-498c-b501-ff5522f32ae5.
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Chronic lung diseases are often complicated with pulmonary hypertension (PH). This can lead to disability and poor prognosis. Oxidative stress has been implicated in the development of PH and right ventricular hypertrophy (RVH).A possible new way to treat lung disease related pulmonary hypertension is allopurinol (a xanthine oxidase inhibitor) which decreases both uric acid and oxidative stress. We hypothesised that allopurinol could regress RVH in patients with pulmonary hypertension associated with chronic lung disease (PH-CLD).In a double-blind, randomised controlled clinical trial, 72 patients with PH-CLD (93% diagnosed with chronic obstructive pulmonary disease and 17% with interstitial lung disease) were randomised to receive either allopurinol 300 mg twice daily or placebo for twelve months. The primary outcome was the mean change in right ventricular mass (RVM) as assessed by cardiac magnetic resonance imaging (CMRI) at twelve months. The secondary outcomes were the change in other cardiac parameters measured by CMRI, St George's Respiratory Questionnaire, Short Form 36, spirometry and six-minute walk test (6MWT).The mean age was 71 years, the mean FEV1 was 60% with mean resting SaO2 of 96%. After 12 months, there was no significant change in RVM. There were also no significant changes in other cardiac parameters measured on CMRI, quality of life questionnaires, spirometry and 6MWT. Post-hoc subgroup analysis showed that allopurinol reduced RVM (allopurinol -6.16 g vs placebo 0.75 g, p = 0.02) in COPD patients with more severe airflow limitation. Patients with higher NT-proBNP (> 489 pg/ml) had a greater improvement in left ventricular ejection fraction with allopurinol 5.12 vs placebo -1.62, p = 0.02.In summary, allopurinol had no overall impact but reduced RV mass in COPD patients with more severe airflow limitation. Further studies are warranted to assess the longer term impact of allopurinol in more severe COPD.
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Choi, Eun-Young. "Studies on the reaction mechanism of the reductive half-reaction of Xanthine Oxidase /." The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu148819366523445.
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Abooali, Maryam. "Crucial involvement of xanthine oxidoreductase in the biological responses of myeloid hematopoietic cells." Thesis, University of Kent, 2015. https://kar.kent.ac.uk/49841/.
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Xanthine oxidoreductase (XOR) is one of the main purine catabolising enzymes which converts hypoxanthine into xanthine and further into uric acid. The enzyme has a homodimeric structure and contains two FeS centres, one FAD molecule and one molybdenum atom per monomer. Recent evidence clearly demonstrated that XOR activity is highly increased in human hematopoietic cells of myeloid lineage during their pathogen-induced and endogenously generated biological responses. The integrative signalling role and especially involvement of XOR in cross-talk of metabolic and signalling machinery of human leukocytes remains poorly understood. We have demonstrated that XOD is activated in human myeloid cells in response to pro-inflammatory and growth factor stimulation. Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP1) transcription complexes were found responsible for maintaining XOR catalytic activity and protein levels. Importantly, the mammalian target of rapamycin (mTOR), a major myeloid cell translation regulator, appeared to be essential for XOR activation. Specific inhibition of XOR led to an increase in intracellular AMP levels triggering downregulation of mTOR activation. Taken together, these results show that XOD is not only activated by pro-inflammatory stimuli or SCF (growth factors), but also plays a crucial role in maintaining mTOR-dependent translational control during the biological responses of hematopoietic cells of myeloid lineage. Findings reported in this thesis open a new field in human myeloid cell research and translational medicine. XOR is an easily accessible therapeutic target, which could be pharmacologically corrected using non-toxic drugs.
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Hoare, Catherine Anne. "The localisation and activity of xanthine oxidoreductase in human endothelial and epithelial cells." Thesis, University of Bath, 2002. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268383.
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Tao, Li. "Expression and distribution of butyrophilin 1A1 and xanthine dehydrogenase-oxidase in lactating mammary gland." College Park, Md. : University of Maryland, 2006. http://hdl.handle.net/1903/3698.
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Thesis (M.S.) -- University of Maryland, College Park, 2006.Thesis research directed by: Dept. of Cell Biology and Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Rajendra, N. S. "Exploring the therapeutic potential of xanthine oxidase inhibitor-AUopurinol, in stable coronary artery disease." Thesis, University of Dundee, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521663.
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Mbewe, Boniface. "Cloning, expression, purification and drug targeting of Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT)." Doctoral thesis, University of Cape Town, 2005. http://hdl.handle.net/11427/2696.
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Includes bibliographical references.The research concerns sub-cloning the gene for HGXPRT from Plasmodium falciparum from a vector with a His-tag facility to one without, expression of the protein in E. coli, and purification. On an analytical scale (40 ml culture), a purification procedure was developed that involves extraction of contaminating proteins by anion exchange chromatography (HGXPRT does not bind under the conditions used), followed by Reactive Red 120 agarose affinity chromatography.
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Watanabe, Koji. "Pterin-6-aldehyde, an Inhibitor of Xanthine Oxidase, Has Superoxide Anion Radical Scavenging Activity." Kyoto University, 2000. http://hdl.handle.net/2433/151411.
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