8-oxo-2--deoxyadenosine and Disease-Models--Animal

Increased production of reactive oxygen species (ROS) has long been recognized to play a pivotal role in carcinogenesis. Quercetin, a naturally occurring dietary flavonoid is known for its ROS scavenging properties. The present study was designed to investigate the chemopreventive and chemotherapeutic effects of quercetin based on cytochrome P450 (CYP) mediated ROS generation, ROS-induced cellular damage and activation of the NFκB signalling circuit during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Administration of quercetin inhibited the development of DMBA-induced HBP carcinomas by impairing CYP-mediated ROS production via downregulation of the expression of CYP1A1 and CYP1B1, and upregulation of antioxidant defences. Attenuation of ROS generation by quercetin in turn abrogated NFκB signalling by preventing the phosphorylation and degradation of IκB, nuclear translocation of NFκB and transactivation of its target genes associated with cell proliferation and apoptosis evasion. Thus dietary flavonoids such as quercetin that can block ROS generation and inhibit the redox regulated transcription factor NFκB, by virtue of their antioxidant potential are promising candidates for future antioxidant-based anticancer regimens.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Catalase; Cell Growth Processes; Cheek; Cricetinae; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Deoxyadenosines; Disease Models, Animal; Humans; Isoenzymes; Male; Mesocricetus; Mice; Mouth Neoplasms; NF-kappa B; Quercetin; Random Allocation; Reactive Oxygen Species; RNA, Messenger; Superoxide Dismutase

3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) is a free radical scavenger. We tested the hypothesis that combination treatment of Edaravone and recombinant tissue plasminogen activator (tPA) extends the therapeutic time window. Male Wistar rats were subjected to 1.5-, 3.0- or 4.5-hour middle cerebral artery (MCA) occlusion (MCAO) by a nylon thread. Animals were randomly divided into four groups. The Sham group rats were operated without MCAO and drug injection. In the Vehicle-treated group the same volume of saline was given every 1.5 hours from just after MCAO to just before reperfusion. In the Vehicle + tPA-treated group saline injection was given as above and tPA (5 mg/kg, i.v.) was given once just after reperfusion. Edaravone+tPA-treated group: Edaravone (3 mg/kg, i.v.) was given every 1.5 hours instead of saline and tPA injection as above. Survival rate, infarct size and evidence of apoptosis and hemorrhage were examined in the animals. Combining administration of Edaravone+tPA significantly increased survival rate after 3 hours of transient MCAO, and reduced infarct volume after 1.5 hours of transient MCAO compared with the vehicle or vehicle+tPA groups. In Edaravone+tPA-treated group, the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and 4-hydroxynonenal (4-HNE) positive cells were reduced at 16 hours after 3 hours of transient MCAO, but not in advanced glycation end products (AGEs) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Hemorrhage rate and the area decreased in the Edaravone+tPA-treated group. The combination therapy of Edaravone+tPA increased survival rate, and reduced the infarct volume and hemorrhage with reduction of lipid peroxidation. Therefore, Edaravone combination is expected to extend the therapeutic time window of tPA in the clinical situation.

Topics: Aldehydes; Animals; Antipyrine; Brain Ischemia; Cell Count; Deoxyadenosines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Edaravone; Fibrinolytic Agents; Free Radical Scavengers; Glycation End Products, Advanced; Hemorrhage; Immunohistochemistry; In Situ Nick-End Labeling; Male; Rats; Rats, Wistar; Survival Analysis; Tetrazolium Salts; Time Factors; Tissue Plasminogen Activator

Chronic exposure to lead results in sustained hypertension in humans and experimental animals. We investigated the possible role of reactive oxygen species (ROS) and their impact on DNA damage in lead-induced hypertension. Further the effect of short-term supplementation of vitamin C is also demonstrated.. Male Wistar rats were treated with either lead acetate (100 ppm) alone or lead acetate plus vitamin C (20 mg/rat/day). The control rats were fed regular rat chow. Blood pressure, antioxidants, total antioxidant status as measured by ferric-reducing antioxidant power, nitric oxide (NO) metabolites, malondialdehyde (MDA) and 8-hydroxy 2-deoxyguanosine were determined after 0, 1, 2 and 3 months.. The lead-exposed group showed a significant rise in blood pressure, lipid peroxidation (MDA) and a substantial oxidative damage to the DNA. A significant fall in NO metabolites, total antioxidant levels and ferric-reducing antioxidant power was also observed in this group. Concomitant administration of vitamin C ameliorated hypertension, normalized NO levels and abrogated lipid peroxidation. Also, it completely prevented oxidative damage to the DNA.. These findings point to enhanced ROS-mediated inactivation and sequestration of NO which can potentially contribute to hypertension, lipid peroxidation, reduced antioxidant status and oxidative DNA damage. The beneficial effects of vitamin C on these parameters support the role of increased ROS activity in the pathogenesis of these abnormalities in this model.

Topics: Animals; Antioxidants; Ascorbic Acid; Deoxyadenosines; Dietary Supplements; Disease Models, Animal; DNA Damage; Hypertension; Lead Poisoning; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide; Organometallic Compounds; Oxidation-Reduction; Random Allocation; Rats; Rats, Inbred WKY; Reactive Oxygen Species; Time Factors