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Distribution by Scientific Domains

Medical Sciences	50%
Life Sciences	33%

Selected Abstracts

Prolongation of Activation-Recovery Interval over a Preexcited Region before and after Catheter Ablation in Patients with Wolff-Parkinson-White Syndrome

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2001
YASUYA INDEN M.D.
Activation-Recovery Interval in WPW Syndrome. Introduction: Preexisting changes in repolarization properties play an important role in T wave abnormalities (cardiac memory) after ablation in patients with Wolff-Parkinson-White (WPW) syndrome. However, no report has provided direct evidence for prolongation of action potential duration (APD) over a preexcited region before and after ablation. Methods and Results: We studied 10 patients with ventricular preexcitation due to a left-sided accessory pathway (AP) (group M) and 12 patients with concealed left-sided AP (group C) to clarify prolongation of APD using activation-recovery intervals (ARIs) from epicardial and endocardial unipolar electrograms in patients with WPW syndrome. ARI was calculated from unipolar electrograms at the His bundle and the coronary sinus adjacent to the AP during atrial pacing (100 beats/min) before and 30 minutes after ablation. Before ablation, ARIs at the AP site were significantly longer in group M than in group C (255 ± 21 msec vs 211 ± 24 msec; P < 0.01), whereas ARIs at the His bundle did not differ between the two groups (255 ± 20 msec vs 245 ± 27 msec; P = NS). After ablation, group M showed no significant changes in ARIs at the AP and His bundle (256 ± 19 msec and 253 ± 15 msec) compared with before ablation. Conclusion: We found by direct analysis of ARIs from the epicardium that APD prolongation over the preexcited region was present before catheter ablation and persisted after catheter ablation. The gradual changes in repolarization properties, including APD prolongation after discontinuation of AP, may be one mechanism of cardiac memory after catheter ablation in patients with WPW syndrome. [source]

Structure of the endonuclease IV homologue from Thermotoga maritima in the presence of active-site divalent metal ions

ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 9 2010
Stephen J. Tomanicek
The most frequent lesion in DNA is at apurinic/apyrimidinic (AP) sites resulting from DNA-base losses. These AP-site lesions can stall DNA replication and lead to genome instability if left unrepaired. The AP endonucleases are an important class of enzymes that are involved in the repair of AP-site intermediates during damage-general DNA base-excision repair pathways. These enzymes hydrolytically cleave the 5,-phosphodiester bond at an AP site to generate a free 3,-hydroxyl group and a 5,-terminal sugar phosphate using their AP nuclease activity. Specifically, Thermotoga maritima endonuclease IV is a member of the second conserved AP endonuclease family that includes Escherichia coli endonuclease IV, which is the archetype of the AP endonuclease superfamily. In order to more fully characterize the AP endonuclease family of enzymes, two X-ray crystal structures of the T. maritima endonuclease IV homologue were determined in the presence of divalent metal ions bound in the active-site region. These structures of the T. maritima endonuclease IV homologue further revealed the use of the TIM-barrel fold and the trinuclear metal binding site as important highly conserved structural elements that are involved in DNA-binding and AP-site repair processes in the AP endonuclease superfamily. [source]

Accelerated repair and reduced mutagenicity of oxidative DNA damage in human bladder cells expressing the E. coli FPG protein

INTERNATIONAL JOURNAL OF CANCER, Issue 7 2006
Monica Ropolo
Abstract Repair of some oxidized purines such as 8-oxo-7,8-dihydroguanine (8-oxoG) is inefficient in human cells in comparison to repair of other major endogenous lesions (e.g. uracil, abasic sites or oxidized pyrimidines). This is due to the poor catalytic properties of hOGG1, the major DNA glycosylase involved in 8-oxoG removal. The formamidopyrimidine DNA glycosylase (FPG) protein from E. coli is endowed with a potent 8-oxoG glycolytic activity coupled with a ,,,-AP lyase. In this study, we have expressed FPG fused to the enhanced green fluorescent protein (EGFP) in human bladder cells to accelerate the repair of oxidative DNA damage. Cells expressing the fusion protein EGFP,FPG repaired 8-oxoG and AP sites at accelerated rates, in particular via the single-nucleotide insertion base excision repair (BER) pathway and were resistant to mutagenicity of the oxidizing carcinogen potassium bromate. FPG may stably protect human cells from some harmful effects of oxidative DNA damage. © 2005 Wiley-Liss, Inc. [source]

Induction of Oxidative DNA Damage in the Peri-Infarct Region After Permanent Focal Cerebral Ischemia

JOURNAL OF NEUROCHEMISTRY, Issue 4 2000
Tetsuya Nagayama
Abstract: To address the role of oxidative DNA damage in focal cerebral ischemia lacking reperfusion, we investigated DNA base and strand damage in a rat model of permanent middle cerebral artery occlusion (MCAO). Contents of 8-hydroxyl-2,-deoxyguanosine (8-OHdG) and apurinic/apyrimidinic abasic sites (AP sites), hallmarks of oxidative DNA damage, were quantitatively measured in nuclear DNA extracts from brains obtained 4-72 h after MCAO. DNA single- and double-strand breaks were detected on coronal brain sections using in situ DNA polymerase I-mediated biotin-dATP nick-translation (PANT) and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), respectively. Levels of 8-OHdG and AP sites were markedly elevated 16-72 h following MCAO in the frontal cortex, representing the peri-infarct region, but levels did not significantly change within the ischemic core regions of the caudateputamen and parietal cortex. PANT- and TUNEL-positive cells began to be detectable 4-8 h following MCAO in the caudate-putamen and parietal cortex and reached maximal levels at 72 h. PANT- and TUNEL-positive cells were also detected 16-72 h after MCAO in the lateral frontal cortex within the infarct border, where many cells also showed colocalization of DNA single-strand breaks and DNA fragmentation. In contrast, levels of PANT-positive cells alone were transiently increased (16 h after MCAO) in the medial frontal cortex, an area distant from the infarct zone. These data suggest that within peri-infarct brain regions, oxidative injury to nuclear DNA in the form of base and strand damage may be a significant and contributory cause of secondary expansion of brain damage following permanent focal ischemia. [source]

Lead promotes abasic site accumulation and co-mutagenesis in mammalian cells by inhibiting the major abasic endonuclease Ape1,

MOLECULAR CARCINOGENESIS, Issue 2 2007
Daniel R. McNeill
Abstract Lead is a widespread environmental toxin, found in contaminated water sources, household paints, and certain occupational settings. Classified as a probable carcinogen by the International Agency for Research on Cancer (IARC), lead promotes mutagenesis when combined with alkylating and oxidizing DNA-damaging agents. We previously reported that lead inhibits the in vitro repair activity of Ape1, the major endonuclease for repairing mutagenic and cytotoxic abasic sites in DNA. We investigated here whether lead targets Ape1 in cultured mammalian cells. We report a concentration-dependent inhibition of apurinic/apyrimidinic (AP) site incision activity of Chinese hamster ovary (CHO) AA8 whole cell extracts by lead. In addition, lead exposure results in a concentration-dependent accumulation of AP sites in the genomic DNA of AA8 cells. An increase in the oxidative base lesion 8-oxoguanine was observed only at high lead levels (500 µM), suggesting that non-specific oxidation plays little role in the production of lead-related AP lesions at physiological metal concentrations,a conclusion corroborated by "thiobarbituric acid reactive substances" assays. Notably, Ape1 overexpression in AA8 (hApe1-3 cell line) abrogated the lead-dependent increase in AP site steady-state levels. Moreover, lead functioned cooperatively to promote a further increase in abasic sites with agents known to generate AP sites in DNA (i.e., methyl methansulfonate (MMS) and hydrogen peroxide (H2O2)), but not the DNA crosslinking agent mitomycin C. Hypoxanthine guanine phosphoribosyltransferase (hprt) mutation analysis revealed that, whereas lead alone had no effect on mutation frequencies, mutagenesis increased in MMS treated, and to a greater extent lead/MMS treated, AA8 cells. With the hApe1-3 cell line, the number of mutant colonies in all treatment groups was found to be equal to that of the background level, indicating that Ape1 overexpression reverses MMS- and lead-associated hprt mutagenesis. Our studies in total indicate that Ape1 is a member of an emerging group of DNA surveillance proteins that are inhibited by environmental heavy metals, and suggest an underlying mechanism by which lead promotes co-carcinogenesis. Published 2006 Wiley-Liss, Inc., [source]

Folate deficiency followed by ionizing radiation perturbs hepatic dihydrofolate reducatse activity

BIOFACTORS, Issue 4 2008
Vipen Batra
Abstract There is lot of interest in the folate metabolism because of the essential role of folate coenzymes in nucleic acid synthesis. Gamma (,) radiation is well known for inducing damage in the DNA. To counteract these damage, a variety of DNA repair pathways have evolved that require regular supply of DNA bases whose biosynthesis in turn depends on sufficient pools of folate dependent enzymes like dihydrofolate reductase (DHFR). In the present study, we examined the ionizing radiation mediated perturbation of DHFR activity in folate deficient and folate sufficient conditions. In folate deficient animals a potent inhibition of liver DHFR activity was observed. Our results showed that combination of folate starvation and ionizing radiation might adversely affect the DHFR activity, compared to their individual treatments. Measurement of apurinic/apyrimidinic sites (AP sites), a major type of DNA damage generated by radiation induced loss of purine and/or pyrimidine base, indicated a dose dependent DNA damage in folate deficient animals. In conclusion our data suggest an interactive role of folate deficiency and radiation injury in inhibiting DHFR activity. [source]