Response of arsenic-induced oxidative stress,DNA damage,and metal imbalance to combined administration of DMSA and monoisoamyl-DMSA during chronic arsenic poisoning in rats

Arsenic and its compounds cause adverse health effects in humans. Current treatment employs administration of thiol chelators, such as meso-2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised by number of limitations due to their lipophobic nature, particularly in case of chronic poisoning. Combination therapy is a new approach to ensure enhanced removal of metal from the body, reduced doses of potentially toxic chelators, and no redistribution of metal from one organ to another, following chronic metal exposure. The present study attempts to investigate dose-related effects of two thiol chelators, DMSA and one of its new analogues, monoisoamyl dimercaptosuccinic acid (MiADMSA), when administered in combination with the aim of achieving normalization of altered biochemical parameters suggestive of oxidative stress and depletion of inorganic arsenic following chronic arsenic exposure. Twenty-five adult male Wistar rats were given 25 ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 0.3 mmol/kg (orally) when administered individually or 0.15 mmol/kg and 0.3 mmol/kg (once daily for 5 consecutive days), respectively, when administered in combination. Arsenic exposure led to the inhibition of blood δ-aminolevulinic acid dehydratase (ALAD) activity and depletion of glutathione (GSH) level. These changes were accompanied by significant depletion of hemoglobin, RBC and Hct as well as blood superoxide dismutase (SOD) acitivity. There was an increase in hepatic and renal levels of thiobarbituric acid-reactive substances, while GSH:GSSG ratio decreased significantly, accompanied by a significant increase in metallothionein (MT) in hepatocytes. DNA damage based on denaturing polyacrylamide gel electrophoresis revealed significant loss in the integrity of DNA extracted from the liver of arsenic-exposed rats compared to that of normal animals. These changes were accompanied by a significant elevation in blood and soft-tissue arsenic concentration. Co-administration of DMSA and MiADMSA at lower dose (0.15 mmol/kg) was most effective not only in reducing arsenic-induced oxidative stress but also in depleting arsenic from blood and soft tissues compared to other treatments. This combination was also able to repair DNA damage caused following arsenic exposure. We thus recommend combined administration of DMSA and MiADMSA for achieving optimum effects of chelation therapy.     

Effects of taurine on oxidative stress parameters and chromium levels altered by acute hexavalent chromium exposure in Mice Kidney tissue

The kidney has been regarded as a critical organ of toxicity induced by acute exposure to hexavalent chromium [Cr(VI)] compounds. Reactive intermediates and free radicals generated during reduction process might be responsible for Cr(VI) toxicity. In this study, the effects of pretreatment or posttreatment of taurine on Cr(VI)-induced oxidative stress and chromium accumulation in kidney tissue of Swiss albino mice were investigated. Single intraperitoneal (ip) potassium dichromate treatment (20 mgCr/kg), as Cr(VI) compound, significantly elevated the level of lipid peroxidation as compared with the control group (p<0.05). This was accompanied by significant decreases in nonprotein sulfhydryls (NPSH) level, superoxide dismutase (SOD), and catalase (CAT) enzyme activities as well as a significant chromium accumulation (p<0.05). Taurine administration (1 g/kg, ip) before or after Cr(VI) exposure resulted in reduction of lipid peroxidation levels and improvement in SOD enzyme activity (p<0.05). On the other hand, administration of the antioxidant before Cr(VI) exposure restored the NPSH level and CAT enzyme activity and also reduced tissue chromium levels (p<0.05), whereas postreatment had only slight effects on these parameters. In view of the results, taurine seems to exert some beneficial effects against Cr(VI)-induced oxidative stress and chromium accumulation in mice kidney tissue.     

Uptake by rice seedlings and in-plant degradation of atrazine as influenced by the oxidative stress induced by added arsenic or phosphate deficiency

The uptake and degradation of atrazine (ATR) by rice seedlings (Oryza sativa L.) was investigated with and without arsenate and phosphate nutrient in the cultured solution over a period of 48 h. The hydrogen peroxide (H₂O₂) contents in plants under different treatments were measured to evaluate the oxidative stress of the plant cell and its influence on the plant uptake and degradation of ATR. Results indicated that the ATR levels and main degradation products, deethylatrazine (DEA) and deisopropylatrazine (DIA), in plants varied significantly in different treatments. Added arsenate in solution increased the level of DEA and the ratios of DEA to the total (ATR, DEA, and DIA) in roots, while it either increased or decreased the H₂O₂ content in roots. Added arsenate increased the ratios of degradation products to the total in shoots, which corresponded to the 110%–285% increase of the H₂O₂ content. In phosphate-deficient systems, the H₂O₂ contents in shoots increased significantly, especially when exposed to a low level of ATR while the ratios of DIA and DEA to the total in shoots increased. The oxidative stress in rice seedlings induced by arsenic coexisting with ATR and by phosphate deficiency affected the plant uptake and degradation of ATR.     

替米沙坦及吡哆胺对自发性高血压大鼠脑组织氧化应激的影响

目的:探讨替米沙坦及吡哆胺对自发性高血压大鼠脑组织氧化应激的影响。方法:自发性高血压大鼠24只随机分为4组(n=6):高血压对照组(HC组);替米沙坦组(T组);吡哆胺组(P组);联合治疗组(TP组)。同龄WKY大鼠作为正常对照组(NC组)。药物干预16周,测定各组脑组织中丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性及烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶p47phox mRNA表达。结果:与NC组比较,HC组脑组织中MDA含量明显升高、SOD活性明显减低(P<0.05);与HC组比较T组、P组、TP组MDA含量明显减低,SOD活性明显升高(P<0.05);与NC组比较HC组(NADPH)氧化酶p47phox mRNA表达显著上调(P<0.01);与HC组比较T组、TP组NADPH氧化酶p47phox mRNA表达明显下调(P<0.01);HC组与P组比较NADPH氧化酶p47phox mRNA表达无统计学差异(P>0.05)。结论:自发性高血压大鼠脑组织处于氧化应激状态,替米沙坦及吡哆胺可抑制自发性高血压大鼠脑组织的氧化应激水平,联合治疗并不优于替米沙坦单药治疗。     

Effects of individual and combined exposure to sodium arsenite and sodium fluoride on tissue oxidative stress, arsenic and fluoride levels in male mice

Arsenic and fluoride are potent toxicants, widely distributed through drinking water and food and often result in adverse health effects. The present study examined the effects of sodium meta-arsenite (100 mg/l in drinking water) and sodium fluoride (5 mg/kg, oral, once daily), administered either alone or in combination for 8 weeks, on various biochemical variables indicative of tissue oxidative stress and cell injury in Swiss albino male mice. A separate group was first exposed to arsenic for 4 weeks followed by 4 weeks of fluoride exposure. Exposure to arsenic or fluoride led to a significant depletion of blood delta-aminolevulinic acid dehydratase (ALAD) activity and glutathione (GSH) level. These changes were accompanied by increased level of blood and tissues reactive oxygen species (ROS) level. An increase in the level of liver and kidney thiobarbituric acid reactive substance (TBARS) along with a concomitant decrease in the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) and reduced GSH content were observed in both arsenic and fluoride administered mice. The changes were significantly more pronounced in arsenic exposed animals than in fluoride. It was interesting to observe that during combined exposure the toxic effects were less pronounced compared to the effects of arsenic or fluoride alone. In some cases antagonistic effects were noted following co-exposure to arsenic and fluoride. Arsenic and fluoride concentration increased significantly on exposure. Interestingly, their concentration decreased significantly on concomitant exposure for 8 weeks. However, the group which was administered arsenic for 4 weeks followed by 4 weeks of fluoride administration showed no such protection suggesting that the antagonistic effect of fluoride on arsenic or vice versa is possible only during interaction at the gastro intestinal sites. These results are new and interesting and require further exploration.     

The impact of experimentally elevated energy expenditure on oxidative stress and lifespan in the short-tailed field vole Microtus agrestis

Life-history theory assumes that animal life histories are a consequence of trade-offs between current activities and future reproductive performance or survival, because resource supply is limited. Empirical evidence for such trade-offs in the wild are common, yet investigations of the underlying mechanisms are rare. Life-history trade-offs may have both physiological and ecological mediated costs. One hypothesized physiological mechanism is that elevated energy metabolism may increase reactive oxygen species production, leading to somatic damage and thus compromising future survival. We investigated the impact of experimentally elevated energy expenditure on oxidative damage, protection and lifespan in short-tailed field voles (Microtus agrestis) maintained in captivity to remove any confounding ecological factor effects. Energy expenditure was elevated via lifelong cold exposure (7+/-2 degrees C), relative to siblings in the warm (22+/-2 degrees C). No treatment effect on cumulative mortality risk was observed, with negligible effects on oxidative stress and antioxidant protection. These data suggest that in captive animals physiologically mediated costs on life history do not result from increased energy expenditure and consequent elevations in oxidative stress and reduced survival.     

Protective effects of a new metalloporphyrin on paraquat-induced oxidative stress and apoptosis in N27 cells

Paraquat （PQ, 1,1′-dimethyl-4,4′-bipyridinium）,awidely-used herbicide, has been suggested as a potential etiologic factor for the development of Parkinson＇s disease. In recent years, many studies have focused on the mechanism（s） of PQ neurotoxicity. In this study, we examined the neuroprotective effect of manganese （Ⅲ） meso-tetrakis （N,N′-diethylimi- dazolium） porphyrin （MnTDM）, a superoxide dismutase/ catalase mimetic, on PQ-induced oxidative stress and apoptosis in 1 RB3AN27 （N27） cells, a dopaminergic neuronal cell line. The results indicated that MnTDM significantly attenuated PQ-induced loss of cell viability, glutathione depletion, and reactive oxygen species production. MnTDM also ameliorated PQ-induced morphological nuclear changes of apoptosis and increased rates of apoptosis. In addition, our data provide direct evidence that MnTDM suppressed PQ- induced caspase-3 cleavage, possibly a key event of PQ neurotoxicity. These observations suggested that oxidative stress and apoptosis are implicated in PQ-induced neurotoxicity and this toxicity could be prevented by MnTDM. These findings also proposed a novel therapeutic approach for Parkinson＇s disease and other disorders associated with oxidative stress.