Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new lustra research articles will be listed here shortly after becoming available to us.
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Medical research on lustra
Electron transfer reactivity of the Arabidopsis thaliana sulfhydryl oxidase AtErv1.
J Biol Chem. 2008 Nov 18;
Farver O, Vitu E, Wherland S, Fass D, Pecht I
The redox reactivity of the three disulfide bridges and the flavin present in each protomer of the wild type Arabidopsis thaliana mitochondrial sulfhydryl oxidase (AtErv1)* homodimer has been investigated. Pulse radiolytically produced CO2- radical ions were found to reduce the disulfide bridges to yield disulfide radicals, RSS*R-. Rates and absorption changes due to formation or decay of RSS*R- and the flavin quinone, semiquinone, and hydroquinone were measured and analyzed. During the first 100 micros following the pulse, the flavin was reduced to the semiquinone by intramolecular electron transfer from the active-site disulfide radical. The semiquinone and the remaining disulfide radicals then reacted by much slower, 40 ms to 40 s, inter-homodimer electron transfer reactions, culminating in reduced flavin and dithiols. The dithiols were then subject to oxidation by enzyme molecules via their intrinsic enzymatic activity, at a rate comparable to the slower intermolecular processes in the 10 s time regime. Mutants of AtErv1 lacking each of the three individual cysteine pairs were studied to determine the involvement of the respective disulfide groups in these reactions. Elimination of the active-site disulfide bridge increased the stability of the flavin semiquinone making it a long-lived product. Relevance of these observations to the design and function of the sulfhydryl oxidases is discussed.
Smoking and Parkinson's disease: Does nicotine affect alpha-synuclein fibrillation?
Biochim Biophys Acta. 2008 Oct 25;
Hong DP, Fink AL, Uversky VN
alpha-synuclein is a small presynaptic protein (14,460 D) that is abundantly distributed in the brain. Although, its function is unknown, the aggregated form of alpha-synuclein is a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease (PD). Epidemiological studies have shown that smoking can lessen the incidence of Parkinson's disease, indicating that smoke may contain chemicals that are neuro-protective. The fibrillation of alpha-synuclein was studied in relation to five different compounds found in cigarette smoke: anabasine, cotinine, hydroquinone, nicotine and nornicotine. Thioflavin T assays, gel electrophoresis, size exclusion chromatography-high performance liquid chromatography (SEC-HPLC) and atomic force microscopy (AFM) were utilized to monitor the rate of alpha-synuclein fibrillation and the inhibitory effects of the cigarette smoke components. We show that nicotine and hydroquinone inhibit alpha-synuclein fibril formation in a concentration-dependent manner, with nicotine being more effective. The SEC-HPLC data show that nicotine and hydroquinone stabilize soluble oligomers. The morphology of the oligomers stabilized by nicotine was evaluated by AFM, which showed the presence of three stable oligomers with an average height of 16 nm, 10 nm and 4 nm. Comparable results were obtained for the effect of the cigarette smoke components on the A53T mutant fibrillation. These results show that nicotine and hydroquinone inhibit alpha-synuclein fibrillation and stabilize soluble oligomeric forms. This information can be used to understand the molecular mechanism of the nicotine and hydroquinone action to develop therapeutic solutions for PD.
Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion.
Proc Natl Acad Sci U S A. 2008 Nov 18; 105(46): 17736-17741
Russell RJ, Kerry PS, Stevens DJ, Steinhauer DA, Martin SR, Gamblin SJ, Skehel JJ
The influenza surface glycoprotein hemagglutinin (HA) is a potential target for antiviral drugs because of its key roles in the initial stages of infection: receptor binding and the fusion of virus and cell membranes. The structure of HA in complex with a known inhibitor of membrane fusion and virus infectivity, tert-butyl hydroquinone (TBHQ), shows that the inhibitor binds in a hydrophobic pocket formed at an interface between HA monomers. Occupation of this site by TBHQ stabilizes the neutral pH structure through intersubunit and intrasubunit interactions that presumably inhibit the conformational rearrangements required for membrane fusion. The nature of the binding site suggests routes for the chemical modification of TBHQ that could lead to the development of more potent inhibitors of membrane fusion and potential anti-influenza drugs.
Sonolytic hydrolysis of peptides in aqueous solution upon addition of catechol.
Ultrason Sonochem. 2008 Oct 2;
Sakakura M, Takayama M
The sonolytic hydrolysis of peptides with addition of phenolic reagents to aqueous solutions is described. Sonolysis of an aqueous solution of peptides to which catechol (o-dihydroxybenzene) had been added resulted in hydrolytic products reflecting the amino acid sequence without any side reactions, while sonolysis without any additives resulted in oxidation analytes and degradation products caused by side reactions. Although the use of additives such as resorcinol (m-dihydroxybenzene), hydroquinone (p-dihydroxybenzene) and phenol was also effective in producing sequence related products, several degradation products were produced by side reactions. A characteristic of the sonolysis of peptides is that the N-terminal side of proline, Xxx-Pro, is more susceptible than other amino acid residues to the process. This characteristic of sonolysis is superior to that of acid hydrolysis in which cleavage at the C-terminal side of proline, Pro-Xxx is difficult, and where dehydration products result due to side reactions.
Biochem J. 2008 Nov 6;
Zhang Y, Lucocq JM, Hayes JD
In rat liver RL-34 cells, endogenous Nrf1 (NF-E2-related factor 1) is localized in the endoplasmic reticulum (ER) where it exists as a glycosylated protein. Electron microscopy has demonstrated that ectopic Nrf1 in COS-1 cells is located in the ER and the nuclear envelope (NE). Subcellular fractionation, together with a membrane proteinase protection assay, revealed that Nrf1 is an integral membrane protein with both luminal and cytoplasmic domains. The N-terminal 65 residues of Nrf1 direct its integration into the ER and NE membranes and tether it to a Triton X-100-resistant membrane microdomain that is associated with lipid rafts. The activity of Nrf1 was increased by the electrophile tert-butyl hydroquinone (tBHQ) probably through an N-terminal domain-dependent process. We found that the NST (Asn/Ser/Thr-rich) domain, along with AD1 (acidic domain 1), contributes positively to the transactivation activity of full-length Nrf1. Further, the NST domain contains seven putative -Asn-X-Ser/Thr- glycosylation sites and when glycation was prevented by substituting all of the seven Asn to either Gln (Nrf11-7xN/Q) or Asp (Nrf11-7xN/D), the former multiple point mutant possessed less activity than the wild-type factor whereas the latter mutant exhibited substantially greater activity. Lastly, the ER stressors tunicamycin, thapsigargin and brefeldin A were found to inhibit basal Nrf1 activity by ~25%, and almost completely prevented induction of Nrf1-mediated transactivation by tBHQ. Collectively, these results suggest that the activity of Nrf1 critically depends on its topology within the ER, and that this is modulated by redox stressors, as well as its glycosylation status.
Dalton Trans. 2008 Nov 28; 6188-204
Stylianou M, Drouza C, Viskadourakis Z, Giapintzakis J, Keramidas AD
The reaction of Cu(2+) acetate monohydrate with 2-[N,N'-bis(carboxymethyl)aminomethyl]-4-carboxyphenol (H(4)cacp), 2-[N,N-bis(carboxymethyl)aminomethyl]hydroquinone (H(4)cah) and the dinucleating 2,5-bis[N,N-bis(carboxymethyl)aminomethyl]hydroquinone (H(6)bicah) in water results in the formation of several Cu(2+) species, which are in dynamic equilibrium in aqueous solution and their stability is pH dependent. A systematic crystallographic study of these species was pursued, resulting in the characterization of most of the species. Additional techniques were employed to characterize the molecules in the solid state (infrared spectroscopy) and in solution (UV-vis spectroscopy and electrochemistry). These measurements show that the Cu(2+) ions are ligated mainly to the iminodiacetate at pH < 6, exhibiting only weak interactions with the phenol oxygen. At pH > 6, the phenol oxygen was deprotonated and dinuclear-bridged species, from the phenolate oxygen complexes exhibiting a Cu(2+)(2)O(2) core, were isolated. The coordination environment around the copper ions varies between trigonal bipyramidal, tetragonal pyramidal and distorted octahedral geometries. The two unpaired electrons of the Cu(2+) ions are found to be antiferromagnetically coupled. A survey of the magnetic and structural properties of the dinuclear phenoxide bridged Cu(2+) complexes shows that the strength of the antiferromagnetic coupling is linearly dependent on the Cu-O(phenolate) bond lengths, at bond distances below 1.98 A. The effect of the Cu-O-Cu angles on the magnetic properties of the complexes is also discussed.
J Cell Biochem. 2008 Nov 3;
Yagiz K, Snyder PW, Morré DJ, Morré DM
tNOX (ENOX2), a cancer-specific and growth-related cell surface protein with protein disulfide-thiol interchange and hydroquinone (NADH) oxidase activities was overexpressed in a transgenic mouse model. Female transgenic mice grew faster than wild type as did embryonic fibroblast cells prepared from the transgenic mice. The tissue expression of tNOX mRNA was greatest in heart, lung and liver. When these tissues were analyzed for cell size, the cells from the tissues of transgenic animals were, on average, 20% larger in surface area than cells from corresponding wild-type tissues. Also analyzed were cells of intestine, spleen and kidney in which tNOX overexpression was observed but to a lesser extent. Cell size was increased as well with intestine and kidney but less so with spleen. At the end of the study, carcass weights of the transgenic animals were greater than those of wild type. This increase in carcass weight was reflected in an increase in femur weight and thickness in both male and female transgenic mice but not in femur length. Other carcass parameters such as skin weight and body fat or body fluids were unchanged or changes were insufficient to account for the increased carcass weight. The findings are consistent with the property of tNOX observed in studies with cultured cells as contributing to the enlargement phase of cell growth. J. Cell. Biochem. (c) 2008 Wiley-Liss, Inc.
Carcinogenesis. 2008 Oct 31;
Lan Q, Zhang L, Shen M, Jo WJ, Vermeulen R, Li G, Vulpe C, Lim S, Ren X, Rappaport SM, Bernedt SI, Yeager M, Yuenger J, Hayes RB, Linet M, Yin S, Chanock S, Smith MT, Rothman N
Benzene is an established human hematotoxicant and leukemogen but its mechanism of action is unclear. To investigate the role of single nucleotide polymorphisms (SNPs) on benzene-induced hematotoxicity, we analyzed 1,395 SNPs in 411 genes using an Illumina GoldenGate assay in 250 benzene-exposed workers and 140 unexposed controls. Highly significant findings clustered in five genes (BLM, TP53, RAD51, WDR79, and WRN) that play a critical role in DNA repair and genomic maintenance, and these regions were then further investigated with tagSNPs. One or more SNPs in each gene were associated with highly significant 10-20% reductions (p values ranged from 0.0011 to 0.0002) in the white blood cell (WBC) count among benzene-exposed workers but not controls, with evidence for gene-environment interactions for SNPs in BLM, WRN, and RAD51. Further, among workers exposed to benzene, the genotype-associated risk of having a WBC count
Effect of the Cyclobutane Cytidine Dimer on the Properties of Escherichia coli DNA Photolyase.
J Phys Chem B. 2008 Oct 31;
Murphy AK, Tammaro M, Cortazar F, Gindt YM, Schelvis JP
Cyclobutane pyrimidine dimer (CPD) photolyases are structure specific DNA-repair enzymes that specialize in the repair of CPDs, the major photoproducts that are formed upon irradiation of DNA with ultraviolet light. The purified enzyme binds a flavin adenine dinucleotide (FAD), which is in the neutral radical semiquinone (FADH (*)) form. The CPDs are repaired by a light-driven, electron transfer from the anionic hydroquinone (FADH (-)) singlet excited state to the CPD, which is followed by reductive cleavage of the cyclobutane ring and subsequent monomerization of the pyrimidine bases. CPDs formed between two adjacent thymidine bases (TT) are repaired with greater efficiency than those formed between two adjacent cytidine bases (CC). In this paper, we investigate the changes in Escherichia coli photolyase that are induced upon binding to DNA containing CC lesions using resonance Raman, UV-vis absorption, and transient absorption spectroscopies, spectroelectrochemistry, and computational chemistry. The binding of photolyase to a CC lesion modifies the energy levels of FADH (*), the rate of charge recombination between FADH (-) and Trp 306 (*), and protein-FADH (*) interactions differently than binding to a TT lesion. However, the reduction potential of the FADH (-)/FADH (*) couple is modified in the same way with both substrates. Our calculations show that the permanent electric dipole moment of CC is stronger (12.1 D) and oriented differently than that of TT (8.7 D). The possible role of the electric dipole moment of the CPD in modifying the physicochemical properties of photolyase as well as in affecting CPD repair will be discussed.
Talanta. 2006 Jul 15; 69(5): 1265-8
Pistonesi MF, Di Nezio MS, Centurión ME, Palomeque ME, Lista AG, Fernández Band BS
The determination of phenolic compounds is of great importance owing to their high toxicity. Some of them are present in tobacco smoke and it is important for their monitoring in air of closed room. A simple, rapid and sensitive method was developed for simultaneous determination of hydroquinone, resorcinol and phenol in this kind of samples. Synchronous fluorescence technique was used and the data were processed by using the partial least-squares (PLS) chemometric algorithm. The concentrations for experimental calibration matrix were varied between 0.02 and 0.2mgL(-1) for hydroquinone, between 0.05 and 0.6mgL(-1) for resorcinol and between 0.05 and 0.4mgL(-1) for phenol in accordance with the national legislation. The cross-validation method was used to select the number of factors. To check the accuracy of the proposed method a recovery study on real samples was carried out.