Showing papers on "Xanthine published in 2010"
TL;DR: The main mechanisms of action of caffeine on the vascular tissue are described, in which it is shown that caffeine has some cardiovascular properties and effects which could be considered beneficial.
Abstract: Caffeine is the most widely consumed stimulating substance in the world. It is found in coffee, tea, soft drinks, chocolate, and many medications. Caffeine is a xanthine with various effects and mechanisms of action in vascular tissue. In endothelial cells, it increases intracellular calcium stimulating the production of nitric oxide through the expression of the endothelial nitric oxide synthase enzyme. Nitric oxide is diffused to the vascular smooth muscle cell to produce vasodilation. In vascular smooth muscle cells its effect is predominantly a competitive inhibition of phosphodiesterase, producing an accumulation of cAMP and vasodilation. In addition, it blocks the adenosine receptors present in the vascular tissue to produce vasoconstriction. In this paper the main mechanisms of action of caffeine on the vascular tissue are described, in which it is shown that caffeine has some cardiovascular properties and effects which could be considered beneficial.
172 citations
TL;DR: Crystal structures of the bovine enzyme in complex with the physiological substrate hypoxanthine and the chemotherapeutic agent 6-mercaptopurine are determined, showing in each case two alternate orientations of substrate in the two active sites of the crystallographic asymmetric unit.
100 citations
TL;DR: Both diabetes-induced activation of NF-kappaB signalling cascade and subsequent over expression of inflammatory cytokines and enzymes were abolished by administration of allopurinol and a significant neutrophil infiltration in the liver of diabetic animals was found.
95 citations
TL;DR: Results indicated that S. brachyantha could protect against cell injury via induction of the antioxidant enzyme defences and might be valuable antioxidant natural sources and seemed to be applicable in both healthy medicine and food industry.
90 citations
TL;DR: The results imply that AtXDH1, which exhibits the most pronounced NADH oxidase activity among all xanthine dehydrogenase proteins studied thus far, is an efficient producer of superoxide also in vivo.
Abstract: Xanthine dehydrogenase AtXDH1 from Arabidopsis thaliana is a key enzyme in purine degradation where it oxidizes hypoxanthine to xanthine and xanthine to uric acid. Electrons released from these substrates are either transferred to NAD+ or to molecular oxygen, thereby yielding NADH or superoxide, respectively. By an alternative activity, AtXDH1 is capable of oxidizing NADH with concomitant formation of NAD+ and superoxide. Here we demonstrate that in comparison to the specific activity with xanthine as substrate, the specific activity of recombinant AtXDH1 with NADH as substrate is about 15-times higher accompanied by a doubling in superoxide production. The observation that NAD+ inhibits NADH oxidase activity of AtXDH1 while NADH suppresses NAD+-dependent xanthine oxidation indicates that both NAD+ and NADH compete for the same binding-site and that both sub-activities are not expressed at the same time. Rather, each sub-activity is determined by specific conditions such as the availability of substrates and co-substrates, which allows regulation of superoxide production by AtXDH1. Since AtXDH1 exhibits the most pronounced NADH oxidase activity among all xanthine dehydrogenase proteins studied thus far, our results imply that in particular by its NADH oxidase activity AtXDH1 is an efficient producer of superoxide also in vivo.
69 citations
TL;DR: Paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases because it is also reported to provide neuroprotection.
Abstract: CAFFEINE, IN THE FORM OF CAFFEINE-CONTAINING BEVERAGES OR OVER-THE-COUNTER CAFFEINE TABLETS (100 MG OR 200 MG), IS A WIDELY USED WAKE-promoting substance, used to reduce sleepiness in normal people.1,2 Caffeine is also widely used for patients with primary (such as narcolepsy) and secondary hypersomnia (hypersomnia associated with neurological diseases); these patients self-medicate with caffeine before they visit the sleep clinic to receive more potent medication.2
Caffeine is a non-selective antagonist for adenosine receptors (A1 and A2a receptors), and blockade of these receptors is believed to mediate its stimulant effects.1 One of the limitations of caffeine for treating hypersomnia is its low wake-promoting potency, while high doses may induce side effects such as anxiety, tremors, headache, and gastrointestinal irritation.
Caffeine is demethylated to 3 active metabolites, paraxanthine, theobromine, and theophylline, and C-8 hydroxylated to 1,3,7-trimethyluric acid (TMU).3–5 The interspecies variations in caffeine metabolism, related to cytochrome P4501A enzyme, exist; and the percentages of the production of these 4 metabolites are reported to be 59.9%, 8.7%, 5.0%, and 26.4% in humans, and 19.1%, 10.8%, 21.7%, and 47.8% in mice.5
Like caffeine, paraxanthine is a central nervous stimulant. In addition, caffeine and paraxanthine have similar anti-adenosine actions, though the literature has consistently reported that paraxanthine exhibits slightly higher binding potencies for adenosine A1 and A2a receptors6 and both lower toxicity and lesser anxiogenic effects than caffeine.7 This may be explained by the pharmacological properties of other caffeine metabolites, such as theophylline, which often induce nausea, diarrhea, tachycardia, and arrhythmias.8 A recent study demonstrated that paraxanthine provides protection against dopaminergic cell death via ryanodine receptor stimulation.9 Therefore, paraxanthine may be more effective than caffeine for wake-promotion in normal people and treatment of hypersomnia in those with cardiovascular and neurological diseases.
Therefore, we evaluated the wake-promoting efficacy of paraxanthine in wild-type (WT) and narcoleptic mice models and compared it with those of caffeine and modafinil. Effects of these compounds on locomotor activity, core body temperature and anxiety levels were also compared. Narcoleptic mice were included since narcolepsy is the prototypical primary hypersomnia, and orexin/ataxin-3 narcoleptic mice share the major pathophysiology of human narcolepsy (hypocretin cell ablation).10,11 As such, the observed efficacy in narcoleptic mice is an accurate predictor of efficacy for treatment of pathological sleepiness.
50 citations
TL;DR: The crystal structures of the urate complexes of the demolybdo-form of the D428A mutant of rat xanthine oxidoreductase of the reduced bovine milk enzyme indicate the catalytically relevant binding mode of the substrate Xanthine.
Abstract: Two contradictory models have been proposed for the binding mode of the substrate xanthine to and its activation mechanism by xanthine oxidoreductase. In an effort to distinguish between the two models, we determined the crystal structures of the urate complexes of the demolybdo-form of the D428A mutant of rat xanthine oxidoreductase at 1.7 A and of the reduced bovine milk enzyme at 2.1 A, the latter representing a reaction intermediate. The results clearly indicate the catalytically relevant binding mode of the substrate xanthine.
42 citations
TL;DR: In situ experiments indicate that adenosine, adenine, guanosine, Guanine and inosine are better precursors than xanthosine, which is a direct precursor of a major pathway of caffeine biosynthesis.
Abstract: To determine the metabolic profiles of purine nucleotides and related compounds in leaves and roots of tea (Camellia sinensis), we studied the in situ metabolic fate of 10 different (14)C-labeled precursors in segments from tea seedlings. The activities of key enzymes in tea leaf extracts were also investigated. The rates of uptake of purine precursors were greater in leaf segments than in root segments. Adenine and adenosine were taken up more rapidly than other purine bases and nucleosides. Xanthosine was slowest. Some adenosine, guanosine and inosine was converted to nucleotides by adenosine kinase and inosine/guanosine kinase, but these compounds were easily hydrolyzed, and adenine, guanine and hypoxanthine were generated. These purine bases were salvaged by adenine phosphoribosyltransferase and hypoxanthine/guanine phosphoribosyltransferase. Salvage activity of adenine and adenosine was high, and they were converted exclusively to nucleotides. Inosine and hypoxanthine were salvaged to a lesser extent. In situ (14)C-tracer experiments revealed that xanthosine and xanthine were not salvaged, although xanthine phosphoribosyltransferase activity was found in tea extracts. Only some deoxyadenosine and deoxyguanosine was salvaged and utilized for DNA synthesis. However, most of these deoxynucleosides were hydrolyzed to adenine and guanine and then utilized for RNA synthesis. Purine alkaloid biosynthesis in leaves is much greater than in roots. In situ experiments indicate that adenosine, adenine, guanosine, guanine and inosine are better precursors than xanthosine, which is a direct precursor of a major pathway of caffeine biosynthesis. Based on these results, possible routes of purine metabolism are discussed.
42 citations
TL;DR: An efficient and versatile synthetic approach for the preparation of highly substituted xanthine derivatives has been developed by a combination of direct N7- and C8-arylation with significant fluorescence emission in a concentration-dependent response.
37 citations
TL;DR: The results suggest that AL effect on XOR activity is tissue dependent, and xanthine and hypoxanthine concentrations were greater in AL25 and AL50 birds compared to controls, whereas no differences were detected in allantoin concentrations.
Abstract: The purpose of this study was to determine the effects of allopurinol (AL) on xanthine oxidoreductase (XOR) activity and uric acid (UA) levels in chickens. Thirty 5-week-old broilers were divided into three groups and fed 0 (control), 25 (AL25) or 50 (AL50) mg AL per kg of body mass for 5 weeks. Chicks were weighed twice weekly and leukocyte oxidative activity (LOA) and plasma purine levels were determined weekly in five birds per group. Chicks were sacrificed after 2 or 5 weeks, and samples from tissues were taken for analysis of XOR activity. Plasma UA concentrations were lower (P 0.05) in XOR activity in the pancreas and intestine. These results suggest that AL effect on XOR activity is tissue dependent.
34 citations
TL;DR: It is suggested that IS acts as a novel endogenous antioxidant under normal‐physiological conditions and shows scavenging activity against cell‐derived generated from activated neutrophils.
Patent•
01 Sep 2010TL;DR: In this article, the authors proposed substituted xanthine derivatives that are derivatives of pentoxifylline and provided compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which these compounds are beneficial.
Abstract: This invention relates to novel compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted xanthine derivatives that are derivatives of pentoxifylline. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial.
TL;DR: The present results confirm the basic stepwise reaction mechanism and the orientation of the substrate that has been proposed in the previous QM/MM work on aldehyde oxidoreductase and xanthine oxidase and the calculated pathways for three different tautomers show great similarity to those found previously forxanthine.
Abstract: In continuation of our previous QM/MM study on the reductive half-reaction of wild-type xanthine oxidase, we consider the effects of variations in the cofactor, the substrate, and the active-site Glu802 residue on the reaction mechanism. Replacement of the sulfido ligand in the natural cofactor by an oxo ligand leads to a substantial increase in the computed barriers, consistent with the experimentally observed inactivity of this modified cofactor, whereas the selenido form is predicted to have lower barriers and hence higher activity. For the substrate 2-oxo-6-methylpurine, the calculated pathways for three different tautomers show great similarity to those found previously for xanthine, contrary to claims in the literature that the mechanisms for these two substrates are different. Compared with the wild-type enzyme, the conversion of xanthine to uric acid follows a somewhat different pathway in the Glu802 → Gln mutant which exhibits a lower overall activity, in agreement with recently published kinetic...
TL;DR: 3D modeling of Arthrobacter sp.
TL;DR: The results suggest that the aqueous extract of H. reticulatus aerial parts might have great potential as an antioxidant and a hypouricemic agent.
Abstract: Context: Xanthine oxidase (XO) is a key enzyme in the pathophysiological homeostasis of hyperuricemia. It catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid, the reaction involves the formation of free radical intermediates and superoxide byproducts.Objectives: This study was undertaken to investigate the antioxidant, antihyperuricemic, and xanthine oxidase inhibitory potentials of Hyoscyamus reticulatus L. (Solanaceae) extract.Materials and methods: The antioxidant potency was measured using the ABTS•+ scavenging capacity system, which includes Trolox as a standard. The xanthine oxidase inhibitory activity of the extract was quantitated in vitro by measuring the decline in the catalytic rate of xanthine oxidase following incubations with the plant extracts and using xanthine as a substrate. The hypouricemic potential of the extract was evaluated using an in vivo model for hyperuricemia. We tested three different doses of the extract and allopurinol was used as standard antihyperuri...
TL;DR: In this paper, a screen-printed three-electrode system was applied to fabricate a new type of disposable amperometric xanthine oxidase biosensor, which was used to detect xanthines and hypoxanthines.
Abstract: The screen-printed three-electrode system was applied to fabricate a new type of disposable amperometric xanthine oxidase biosensor. Carbon-working, carbon-counter and Ag/AgCl reference electrodes were all manually printed on the polyethylene terephthalate substrate forming the screen-printed three-electrode system by the conventional screen-printing process. As a mediator, Prussian blue could not only catalyze the electrochemical reduction of hydrogen peroxide produced from the enzyme reaction, but also keep the favorable potential around 0 V. The optimum operational conditions, including pH, potential and temperature, were investigated. The sensitivities of xanthine and hypoxanthine detections were 13.83 mA/M and 25.56 mA/M, respectively. A linear relationship was obtained in the concentration range between 0.10 μM and 4.98 μM for xanthine and between 0.50 μM and 3.98 μM for hypoxanthine. The small Michaelis-menten constant value of the xanthine oxidase biosensor was calculated to be 3.90 μM. The results indicate that the fabricated xanthine oxidase biosensor is effective and sensitive for the detection of xanthine and hypoxanthine.
TL;DR: Among copper complexes, 2-hydroxy-4-methoxyacetophenone semicarbazone analog was the most active compounds and exhibited the most potent SOD-like activities with the IC(50) values ranging from 0.2 to 4 microM.
TL;DR: Observations provide evidence that isorhamnetin 3‐O‐neohesperidoside isolated from the leaves of A. salicina is able to protect cells against the consequences of oxidative stress.
Abstract: Antioxidant activity of isorhamnetin 3-O-neohesperidoside, isolated from the leaves of Acacia salicina, was determined by the ability of this compound to inhibit xanthine oxidase activity and to scavenge the free radical 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS(.-)) diammonium salt. Antigenotoxic activity was assessed using the SOS chromotest assay. This compound has the ability to scavenge the ABTS(.+) radical by a hydrogen donating mechanism. We also envisaged the study of the antioxidant effect of this compound by the enzymatic xanthine/xanthine oxidase (X/XOD) assay. Results indicated that isorhamnetin 3-O-neohesperidoside was a potent inhibitor of xanthine oxidase and superoxide anion scavengers. Moreover, this compound induced an inhibitory activity against nifuroxazide and aflatoxine B1 (AFB1) induced genotoxicity. Taken together, these observations provide evidence that isorhamnetin 3-O-neohesperidoside isolated from the leaves of A. salicina is able to protect cells against the consequences of oxidative stress.
TL;DR: It is indicated that Yerba Mate possesses potent antioxidant effects against hydroxyl and superoxide radicals in both chemical and cell culture systems, as well as DNA-protective properties.
Abstract: Mate (MT) is a popular South American beverage that has been used as a traditional medicine for centuries, spurring recent interest in its nutraceutical properties. MT is prepared as an infusion of leaves from the Yerba Mate (llex paraguriensis) tree. MT has been reported to have antioxidant properties in vitro and in vivo, but these have not been fully characterized in terms of effects against specific radicals. Accordingly, we examined the antioxidant effects of an MT infusion against hydroxyl and superoxide radicals in both chemical and cell culture assays. MT infusions were prepared at 3.10 g/L in boiling water and diluted to experimental dilutions from this stock. Electron spin resonance (ESR) experiments indicated that MT scavenged hydroxyl radicals (produced via the Fenton reaction) and superoxide radicals (produced via the xanthine/xanthine oxidase enzymatic reaction) at all concentrations tested (P < 0.05). Further controls indicated that superoxide radical scavenging was not due to xanthine oxidase inhibition. MT scavenged hydroxyl radicals and decreased cellular oxygen consumption in a dose-dependent manner in Cr(VI)-stimulated RAW 264.7 cells, based on ESR and oxygraph measurements (P < 0.05). Similarly, MT also inhibited hydroxyl-radical-induced lipid peroxidation and DNA damage in a dose-dependent manner in RAW 264.7 cells, based on malondialdehyde and Comet assay data (P < 0.05). This study indicates that MT possesses potent antioxidant effects against hydroxyl and superoxide radicals in both chemical and cell culture systems, as well as DNA-protective properties. These data further clarify the reported antioxidant effects of Yerba Mate infusions.
TL;DR: In general, methylation of the purine does not significantly affect inhibition, and an intact purine ring with anionic character favors inhibition.
TL;DR: It is concluded that the production of active oxygen species through the XO system plays an important role in the induction of defense reactions in wheat against the RWA.
Abstract: The role of xanthine oxidase (XO) in the defense response of wheat (Triticum aestivum L.) against the Russian wheat aphid (RWA) (Diuraphis noxia) was studied. Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine to uric acid, and oxygen radicals that are formed as a by-product at both of these oxidation steps may participate in plant defense reactions. A resistant wheat cultivar (Tugela DN), and a close isogenic susceptible cultivar (Tugela), were infested with 20–30 aphids per plant before inhibiting xanthine oxidase by adding allopurinol as a soil drench to the resistant plants. Increases in H2O2 content were detected early after infestation in the resistant wheat, and the downstream defense related responses, chitinase and peroxidase activities, were selectively induced by RWA infestation. These downstream defense responses were substantially inhibited in allopurinol treated-resistant wheat, presumably as a response to inhibition of XO, and superoxide dismutase (SOD). We conclude that the production of active oxygen species through the XO system plays an important role in the induction of defense reactions in wheat against the RWA.
TL;DR: In this paper, single crystal X-ray structures of new perchlorate salts of a series of xanthine alkaloids, for example, Xanthine (xt), caffeine (cf), theophylline (tp), and theobromine (tb) are reported.
Abstract: Single crystal X-ray structures of new perchlorate salts of a series of four xanthine alkaloids, for example, xanthine (xt), caffeine (cf), theophylline (tp), and theobromine (tb) are reported. The treatment of xanthine derivatives with 70% of HClO4 afforded their salts Hxt·ClO4·2(H2O), 1; Htp·ClO4, 2; Htb·ClO4, 3; and Hcf·ClO4·H2O, 4. Xanthine form dimers via N(9)−H···O−C(6) hydrogen bond in the crystal structure. Of the two possible resonance structures of the protonated imidazoles, one of the structures was found to be major in xanthine, theobromine, and caffeine salts, while both structures are of equal contribution in theophylline salts. These observations also have been verified by using the structural information available in the Cambridge Structural Database. Interestingly, xanthine 1 is present as a dihydrate and 4 as a monohydrate, whereas 2 and 3 are crystallized without any water. Thus, proton transfer from the strong acid HClO4 to the weakly basic imidazole ring of xanthines occurs which lead...
TL;DR: The data suggest that residues crucial for the transport mechanism cluster in two conserved motifs, at the cytoplasmic end of TM8 (EXXGDXXAT) and in TM9a (GXXXDG).
TL;DR: It is concluded that concentration differences between uridine, inosine, guanosine and adenosine in the frontal cortex and cerebral white matter suggest that nucleoside metabolism is altered with aging and regulated differently between men and women.
TL;DR: During renal transplantation, significant changes in XME occur that are associated with early post-transplant graft function and have potential value to discern between EGF and SGF/DGF.
Abstract: Background Xanthine oxidoreductase (XOR) and its active forms, dehydrogenase (XD) and oxidase (XO), act as double-edged swords during ischemia-reperfusion injury. On the one hand, their action generates antioxidants, such as uric acid (UA); however, they may strongly enhance production of free radicals. In this study, we examined the association between post-transplant graft function and perioperative xanthine metabolizing enzymes (XME) activity in kidney transplant recipients divided into early (EGF), slow (SGF), and delayed graft function (DGF) groups. Study Design XME activity and UA levels were measured in blood samples collected directly before and during the first and fifth minutes of reperfusion. Results Results demonstrated an increase in XO and XOR activity in all groups; however, these parameters were lower in the EGF than in the DGF group (p Conclusions During renal transplantation, significant changes in XME occur that are associated with early post-transplant graft function and have potential value to discern between EGF and SGF/DGF.
TL;DR: In this paper, the thermodynamic properties of imidazolium salts derived from the natural methylated xanthines theophylline, theobromine, and caffeine were investigated.
Abstract: New imidazolium salts derived from the natural methylated xanthines theophylline, theobromine and caffeine, namely 1,3-dimethyl-9-benzylxanthinium bromide (tphBzBr, 1a), 3,7-dimethyl-9-benzylxanthinium bromide (tbrBzBr, 2a) and 1,3,7-trimethyl-9-benzylxanthinium bromide (caffBzBr, 3a), are reported. Also, the disubstituted analog of 1a, 1,3-dimethyl-7,9-dibenzylxanthinium bromide (tphBz2Br, 1a′) was identified and characterized by NMR. The coordination chemistry of ligands 1a–3a toward palladium, and some theoretical aspects of the unmodified theophylline, theobromine and caffeine are studied. Our results prove that the theophylline derivative has the thermodynamic tendency to form N-bonded species, even when an equilibrium between the Pd–NHC and the “theophyllinate” was observed spectroscopically, due to the anisotropy of the NHC ligand. To confirm the N-coordination, the solid state structure of the new “theophyllinate” species PdBr2(tphBz-H)2 (4), derived from 1a, was determined by X-ray diffraction. The analog with theobromine, ligand 2a, coordinates to palladium via N1, in an analogous manner to 1a, and a mixture of the cis/trans isomers of its palladium complex is obtained. On the other hand, since there is no possibility of N-coordination in 3a, this caffeine derivative forms a Pd-NHC compound after deprotonation with a strong base. Both the theoretical results and the experimental evidence are in accordance, in terms of the predicted coordination sites or possibility of modification of the selected methylated xanthines to obtain new ligands.
TL;DR: Reactive oxygen species increased portal pressure via stimulation of TXA2 production by KCs and a subsequent Rho kinase-dependent contraction of the intrahepatic vasculature, indicating that the KCs that are well known to produce H2O2 could also be activated by H2 O2.
Abstract: This study aimed to investigate the effects of reactive oxygen species on the hepatic macrophages, the Kupffer cells (KC), and to identify the relevant targets of vasoconstrictors involved in the regulation of intrahepatic microcirculation and therefore portal pressure. The effects of hydrogen peroxide (H2O2), xanthine/xanthine oxidase or a thromboxane (TX) analogue (U46619; 0.1 microM) were tested in sham-operated and fibrotic livers (bile duct ligation over 4 weeks) during isolated rat liver perfusion and in vivo with or without additional KC blockade (gadolinium chloride, 10 mg kg(-1) body weight, 48 and 24 h, i.p.). To investigate downstream mechanisms, a TXA2 antagonist (BM 13.177; 20 microM) or a Rho kinase inhibitor (Y27632; 10 microM) was infused additionally. TXB2 efflux was measured by enzyme-linked immunosorbent assay. The phosphorylation state of moesin (p-moesin), as indicator for Rho kinase activity, was assessed by Western blot analyses. Portal pressure was dose-dependently increased by H2O2 (maximum, 0.5 mM) and, to a lower extent, by xanthine/xanthine oxidase together with catalase. The portal pressure increase by H2O2 was attenuated by previous KC blockade. TXA2 efflux increased after H2O2 infusion and was reduced by KC blockade. The TXA2 antagonist counteracted the H2O2-induced increase in portal pressure. The Rho kinase inhibitor attenuated portal pressure increase after TXA2 analogue or H2O2 infusion. Hepatic levels of p-moesin were increased after H2O2 infusion. Reactive oxygen species increased portal pressure via stimulation of TXA2 production by KCs and a subsequent Rho kinase-dependent contraction of the intrahepatic vasculature. In conclusion, the KCs that are well known to produce H2O2 could also be activated by H2O2. This vicious cycle may best be interrupted at the earliest time point.
TL;DR: The optimized (1:10 Hb/PEG) crosslinked conjugates with antioxidant enzymes showed protective properties from severe free radical stresses when incubated with hydrogen peroxide and xanthine/xanthine oxidase system.
TL;DR: It is found that the in vitro activity of 8 of the XO variants toward 6-TX was functionally affected, suggesting that polymorphism in the gene encoding XO may increase the toxicity of thiopurine drugs such as 6-mercaputopurine.