Influence of diphenyl diselenide on chlorpyrifos-induced toxicity in Drosophila melanogaster

Exposure to chlorpyrifos (CPF) poses several harmful effects to human and animal health. The present study investigated the influence of diphenyl diselenide (DPDS) on CPF-induced toxicity in Drosophila melanogaster. Firstly, the time course lethality response of virgin flies (2- to 3-day-old) to CPF (0.075–0.6 μg/g) and DPDP (5–40 μmol/kg) in the diet for 28 consecutive days were investigated. Subsequently, the protective effect of DPDS (10, 20 and 40 μmol/kg) on CPF (0.15 μg/g)-induced mortality, locomotor deficits, neurotoxicity and oxidative stress was assessed in a co-exposure paradigm for 7 days. Results showed that CPF exposure significantly decreased the percent live flies in a time- and concentration-dependent manner, whereas the percent live flies with DPDS treatment was not statistically different from control following 28 days of treatment. In the co-exposure study, CPF significantly increased flies mortality while the survivors exhibited significant locomotor deficits with decreased acetylcholinesterase (AChE) activity. Dietary supplementation with DPDS was associated with marked decrease in mortality, improvement in locomotor activity and restoration of AChE activity in CPF-exposed flies. Moreover, CPF exposure significantly decreased catalase and glutathione-S-transferase activities, total thiol level with concomitant significant elevation in the levels of reactive oxygen species and thiobarbituric acid reactive substances in the head and body regions of the treated flies. Dietary supplementation with DPDS significantly improved the antioxidant status and prevented CPF-induced oxidative stress, thus demonstrating the protective effect of DPDS in CPF-treated flies.     

Oral administration of diphenyl diselenide protects against cadmium-induced liver damage in rats

Cadmium is an environmental toxic metal implicated in human diseases. In the present study, the effect of diphenyl diselenide, (PhSe)(2), on sub-chronic exposure with cadmium chloride (CdCl(2)) was investigated in rats. Male adult Swiss albino rats received CdCl(2) (10 micromol/kg, orally) and (PhSe)(2) (5 micromol/kg, orally) for a period of 30 days. A number of parameters were examined as indicators of toxicity, including hepatic and renal damage, glucose and glycogen levels and markers of oxidative stress. Cadmium content, liver histology, delta-aminolevulinate dehydratase (delta-ALA-D) activity, metallothionein (MT) levels were also evaluated. Cadmium content determined in the tissue of rats exposed to CdCl(2) provides evidence that the liver is the major cadmium target where (PhSe)(2) acts. The concentration of cadmium in liver was about three fold higher than that in kidney, and (PhSe)(2) reduced about six fold the levels of this metal in liver of rats exposed. Rats exposed to CdCl(2) showed histological alterations abolished by (PhSe)(2) administration. (PhSe)(2) administration ameliorated plasma malondialdehyde (MDA) levels, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyl transferase (GGT) activities increased by CdCl(2) exposure. Urea and bilirubin levels increased by CdCl(2) exposure were also reduced by (PhSe)(2). In conclusion, this study demonstrated that co-treatment with (PhSe)(2) ameliorated hepatotoxicity and cellular damage in rat liver after sub-chronic exposure with CdCl(2). The proposed mechanisms by which (PhSe)(2) acts in this experimental protocol are its antioxidant properties and its capacity to form a complex with cadmium.     

Effect of diphenyl diselenide on the development of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory and demyelinating disease of the central nervous system with clinical and pathological similarities with multiple sclerosis. The oxidative stress is one of the major mediators of demyelination and axonal damage in both, multiple sclerosis and EAE. Therefore, several studies are being performed to assess whether treatment with antioxidants prevents the progression of these diseases. Some organic forms of selenium that exhibit glutathione peroxidase-like activity have become good candidates for disease prevention and therapy since they catalytically remove oxidative stressors. Particularly, diphenyl diselenide ((PhSe)₂) exerts antioxidant activity and has neuroprotective effects in several systems. The aim of the present study was to prove the therapeutic activity of (PhSe)₂ on the development of EAE. Intraperitoneally administered (PhSe)₂ (1-25 μmoles/kg body weight/day) reduced the incidence of the disease but was also deleterious for the animals. Conversely, (PhSe)₂ given orally (80 μmoles/kg body weight/day) produced a significant inhibition of EAE without any toxic effect. In addition, there was a reduction of the characteristic histological alterations and a diminished in vivo and in vitro T-cell response against the encephalitogenic myelin basic protein. These results show an effective suppression of the autoimmune response that could be the base for future developments of successful antioxidants therapies in EAE as well as in multiple sclerosis.     

Oxalate modulates thiobarbituric acid reactive species (TBARS) production in supernatants of homogenates from rat brain, liver and kidney: effect of diphenyl diselenide and diphenyl ditelluride

The aim of this paper was to investigate the mechanism(s) involved in the sodium oxalate pro-oxidative activity in vitro and the potential protection by diphenyl diselenide ((PhSe)(2)) and diphenyl ditelluride ((PhTe)(2)) using supernatants of homogenates from brain, liver and kidney. Oxalate causes a significant increase in the TBARS (thiobarbituric acid reactive species) production up to 4mmol/l and it had antioxidant activity from 8 to 16mmol/l in the brain and liver. Oxalate had no effect in kidney homogenates. The difference among tissues may be related to the formation of insoluble crystal of oxalate in kidney, but not in liver and brain homogenates. (PhSe)(2) and (PhTe)(2) reduced both basal and oxalate-induced TBARS in rat brain homogenates, whereas in liver homogenates they were antioxidant only on oxalate-induced TBARS production. (PhSe)(2) showed a modest effect on renal TBARS production, whereas (PhTe)(2) did not modulate TBARS in kidney preparations. Oxalate at 2mmol/l did not change deoxyribose degradation induced by Fe(2+) plus H(2)O(2), whereas at 20mmol/l it significantly prevents its degradation. Oxalate (up to 4mmol/l) did not alter iron (10micromol/l)-induced TBARS production in the brain preparations, whereas at 8mmol/l onwards it prevents iron effect. In liver preparations, oxalate amplifies iron pro-oxidant activity up to 4mmol/l, preventing iron-induced TBARS production at 16mmol/l onwards. These results support the antioxidant effect of organochalcogens against oxalate-induced TBARS production. In addition, our results suggest that oxalate pro- and antioxidant activity in vitro could be related to its interactions with iron ions.     

Diphenyl diselenide reduces temporarily hyperglycemia: possible relationship with oxidative stress

This study was designed to determine the effect of diphenyl diselenide and ebselen, synthetic organoselenium compounds with antioxidant properties, in diabetic rats. Diabetes was induced by the administration of streptozotocin (STZ) (45mg/kg, intravenous). In experimental trials, diphenyl diselenide, but not ebselen, caused a significant reduction in blood glucose levels of STZ-treated rats. This effect of diphenyl diselenide was accompanied by a reduction in the levels of glycated proteins. Diphenyl diselenide ameliorate superoxide dismutase activity (liver and erythrocytes) and Vitamin C levels (liver, kidney and blood), which were decreased in STZ-treated rats. In normal rats, diphenyl diselenide caused per se an increase in hepatic, renal and blood GSH levels. Similarly, treatment with diphenyl diselenide restored hepatic and renal GSH levels in STZ-treated rats. TBARS and protein carbonyl levels were not modified by STZ and/or diphenyl diselenide and ebselen treatments. Our findings suggest that diphenyl diselenide can be considered an anti-diabetogenic agent by exhibiting anti-hyperglycemic and antioxidant properties.     

Towards the mechanism and comparative effect of diphenyl diselenide, diphenyl ditelluride and ebselen under various pathophysiological conditions in rat's kidney preparation

As an extension of our previous work we not only evaluated the relationship between acidosis and lipid peroxidation in rat's kidney homogenate, but also determined for the first time the potential anti-oxidant activity of diphenyl diselenide, diphenyl ditelluride and ebselen at a range of pH values (7.4–5.4). Because of the pH dependency of iron redox cycling, pH and iron need to be well controlled and for the reason we tested a number of pH values (from 7.4 to 5.4) to get a closer idea about the role of iron under various pathological conditions. Acidosis increased rate of lipid peroxidation in the absence Fe (II) in kidney homogenates especially at pH 5.4. This higher extent of lipid peroxidation can be explained by; the mobilized iron which may come from reserves where it is weakly bound. Addition of iron (Fe) chelator desferoxamine (DFO) to reaction medium completely inhibited the peroxidation processes at all studied pH values including acidic values (5.8–5.4). In the presence of Fe (II) acidosis also enhanced detrimental effect of Fe (II) especially at pH (6.4–5.4). Diphenyl diselenide significantly protected lipid peroxidation at all studied pH values, while ebselen offered only a small statistically non-significant protection. The highest anti-oxidant potency was observed for diphenyl ditelluride. These differences in potencies were explained by the mode of action of these compounds using their catalytic anti-oxidant cycles. However, changing the pH of the reaction medium did not alter the anti-oxidant activity of the tested compounds. This study provides evidence for acidosis catalyzed oxidative stress in kidney homogenate and for the first time anti-oxidant potential of diphenyl diselenide and diphenyl ditelluride not only at physiological pH but also at a range of acidic values.     

Attenuation of doxorubicin-induced hypothalamic-pituitary-testicular axis dysfunction by diphenyl diselenide involves suppression of hormonal deficits,oxido-inflammatory stress and caspase 3 activity in rats

BackgroundDoxorubicin (DOX) is one of the popular anti-cancer drugs in the world and several literatures have implicated it in various toxicities especially cardiotoxicity and reproductive toxicity. Diphenyl diselenide (DPDS) is well acknowledged for its compelling pharmacological effects in numerous disease models and chemically-mediated toxicity. This study was carried out to investigate the effect of DPDS on DOX-induced changes in the reproductive indices of male Wistar rats.MethodsRats were intraperitoneally injected with 7.5 mg/kg body weight of DOX alone once followed by treatment with DPDS at 5 and 10 mg/kg for seven successive days. Excised hypothalamus, testes and epididymis were processed for biochemical and histological analyses.ResultsDPDS treatment significantly (p < 0.05) abated DOX-induced oxidative damage by decreasing the levels of oxidative stress indices such as hydrogen peroxide, reactive oxygen and nitrogen species, and lipid peroxidation with a respective improvement in the level of glutathione in the hypothalamic, testicular and epididymal tissues of DOX-treated rats. The activities of antioxidant enzymes such as catalase, superoxide dismutase, glutathione S-transferase and glutathione peroxidase were upregulated in the DPDS co-treated group. DPDS co-treatment alleviates the burden of DOX-induced inflammation by significant reductions in myeloperoxidase activity, levels of nitric oxide and tumor necrosis factor alpha with concomitant decline in the activity of caspase-3, an apoptotic biomarker. Consequently, significant improvement in the spermiogram, levels of reproductive hormones (follicle stimulating hormone, luteinizing hormone, prolactin, serum testosterone and intra-testicular testosterone) levels in the DPDS co-treatment group in comparison to DOX alone-treated group were observed. Histology results of the testes and epididymis showed that DPDS significantly alleviated pathological lesions induced by DOX in the animals.ConclusionDPDS may modulate reproductive toxicity associated with DOX therapy in male cancer patients.     

Changes in biochemical parameters in rabbits blood after oral exposure to diphenyl diselenide for long periods

The concept that selenium-containing molecules may be better antioxidants than classical antioxidants, has led to the design of synthetic organoselenium compounds. The present study was conducted to evaluate the potential toxicity of long time oral exposure to diphenyl diselenide (PhSe)2 in rabbits. Male adult New Zealand rabbits were divided into four groups, group I served as control; groups II, III and IV received 0.3, 3.0 and 30 ppm of (PhSe)2 pulverized in the chow for 8 months. A number of parameters were examined in blood as indicators of toxicity, including delta-aminolevulinate dehydratase (delta-ALA-D), catalase, glutathione peroxidase (GPx), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine, TBARS, non-protein-SH, ascorbic acid and selenium. The results demonstrated that 6 and 8 months of 30 ppm (PhSe)2 intake caused a significant increase in blood delta-ALA-D activity. Erythrocyte non-protein thiol levels were significantly increased after 2 months of 30 ppm (PhSe)2 intake and then return to control levels after prolonged periods of intake. Ingestion of 3.0 ppm of (PhSe)2 for 8 months significantly increased catalase activity in erythrocytes. Conversely, no alterations in GPx, ALT, AST, TBARS and selenium levels were observed in rabbit serum, conversely, selenium levels in peri-renal adipose tissue were significantly increased after 8 months of 30 ppm (PhSe)2 intake, indicating its great lipophylicity. The present results suggest that diphenyl diselenide was not hepato- or renotoxic for rabbits, but caused some biochemical alterations that can be related to some pro-oxidant activity of the compound (particularly the reduction in Vitamin C).     

Induction of reactive oxygen species by diphenyl diselenide is preceded by changes in cell morphology and permeability in Saccharomyces cerevisiae

Organoselenium compounds, such as diphenyl diselenide (PhSe)₂ and phenylselenium zinc chloride (PhSeZnCl), show protective activities related to their thiol peroxidase activity. However, depending on experimental conditions, organoselenium compounds can cause toxicity by oxidising thiol groups of proteins and induce the production of reactive oxygen species (ROS). Here, we analysed the toxicity of (PhSe)₂ and PhSeZnCl in yeast Saccharomyces cerevisiae. Cell growth of S. cerevisiae after 1, 2, 3, 4, 6, and 16?h of treatment with 2, 4, 6, and 10?μM of (PhSe)₂ was evaluated. For comparative purpose, PhSeZnCl was analysed only at 16?h of incubation at equivalent concentrations of selenium (i.e. 4, 8, 12, and 20?μM). ROS production (DCFH-DA), size, granularity, and cell membrane permeability (propidium iodide) were determined by flow cytometry. (PhSe)₂ inhibited cell growth at 2?h (10?μM) of incubation, followed by increase in cell size. The increase of cell membrane permeability and granularity (10?μM) was observed after 3?h of incubation, however, ROS production occurs only at 16?h of incubation (10?μM) with (PhSe)₂, indicating that ROS overproduction is a more likely consequence of (PhSe)₂ toxicity and not its determinant. All tested parameters showed that only concentration of 20?μM induced toxicity in samples incubated with PhSeZnCl. In summary, the results suggest that (PhSe)₂ toxicity in S. cerevisiae is time and concentration dependent, presenting more toxicity when compared with PhSeZnCl.     

Effect of oral administration of diphenyl diselenide on antioxidant status,and activity of delta aminolevulinic acid dehydratase and isoforms of lactate dehydrogenase,in streptozotocin-induced diabetic rats

Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (45 mg/kg, i.v.) were treated with oral administration of diphenyl diselenide (DPDS) pre-dissolved in soya bean oil. A significant reduction in blood glucose levels was observed in STZ-induced diabetic rats treated with DPDS compared with an untreated STZ diabetic group. The pharmacological effect of DPDS was accompanied by a marked reduction in the level of glycated proteins, and restoration of the observed decreased levels of vitamin C and reduced glutathione (GSH; in liver and kidney tissues) of STZ-treated rats. DPDS also caused a marked reduction in the high levels of thiobarbituric acid reactive substances (TBARS) observed in STZ-induced diabetic group. Finally, the inhibition of catalase, delta aminolevulinic acid dehydratase (e-ALA-D) and isoforms of lactate dehydrogenase (LDH) accompanied by hyperglycemia were prevented by DPDS in all tissues examined. Hence, in comparison with our earlier report, the present findings suggests that, irrespective of the route of administration and the delivery vehicle, DPDS can be considered as an anti-diabetic agent due to its anti-hyperglycemic and antioxidant properties.     

Diphenyl Diselenide-Induced Seizures in Rat Pups: Possible Interaction with Glutamatergic System

The aims of the present study were to investigate the possible involvement of glutamatergic system in seizures induced by diphenyl diselenide in rat pups (postnatal day, 12-14) and to evaluate the role of oxidative stress in seizures induced by diphenyl diselenide/glutamate. Glutamate (4 g/kg of body weight) administered in association with diphenyl diselenide (500 mg/kg of body weight) increased the latency for the appearance of the first seizure episode, reduced lipid peroxidation levels and catalase, Na⁺,K⁺-ATPase and δ-ALA-D activities. At the lowest dose (5 mg/kg of body weight), diphenyl diselenide reduced the appearance of seizure episodes induced by glutamate but did not alter the latency for the onset of the first episode. Glutamate uptake was inhibited in glutamate, diphenyl diselenide (the highest dose) and in the association of diphenyl diselenide (both doses) and glutamate groups. Pre-treatment with a N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (5S,10R-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), significantly prolonged the latency for the onset for the first convulsive episode. A non-NMDA receptor antagonist, DNQX (6,7-dinitroquinoxaline-2,3-dione), did not protect seizures induced by diphenyl diselenide. The results of the present study demonstrated that: (a) when diphenyl diselenide and glutamate were administered concomitantly in pups, glutamate was the main responsible for the neurotoxic effects; (b) oxidative stress was not involved in glutamate-induced seizures; (c) NMDA glutamatergic receptors, were at least in part, involved in diphenyl diselenide- induced seizures; and (d) diphenyl diselenide, at the lowest dose, protected seizures induced by glutamate.     

Characterization of LY231617 protection against hydrogen peroxide toxicity

The compound LY231617 [2,6-bis(1,1-dimethylethyl)-4-[[(1-ethyl)amino]methyl]phenol hydrochloride] has been reported to afford significant neuroprotection against hydrogen peroxide (H2O2)-induced toxicity in vitro and global ischemia in vivo. We now report on further mechanistic studies of H2O2 toxicity and protection by LY231617. Brief exposure to H2O2 (15 min) elicited an oxidative insult comparable with that generated by overnight treatment. H2O2-mediated cellular degeneration was characterized using lactate dehydrogenase (LDH) release, changes in total glutathione, and a new marker of oxidative stress, 8-epiprostaglandin F2alpha (8-isoprostane). LY231617 attenuated H2O2-mediated degeneration under a variety of exposure conditions, including a more clinically relevant posttreatment paradigm. Levels of 8-isoprostane paralleled LDH release under various treatment paradigms of 100 microM H2O2 +/- 5 microM drug. In contrast, despite affording significant protection, LY231617 had modest to no effects on cellular levels of glutathione. Taken together, these results are consistent with a membrane site of action for LY231617 and suggest that the compound affords cytoprotection via its antioxidant properties.     

The role of the glutathione system in seizures induced by diphenyl diselenide in rat pups

The present study investigated the role of the glutathione system in seizures induced by diphenyl diselenide (PhSe)₂ (50 mg/kg) in rat pups (post natal day, 12–14). Reduced glutathione (GSH) (300 nmol/site; i.c.v.), administered 20 min before (PhSe)₂, abolished the appearance of seizures, protected against the inhibition of catalase and δ-aminolevulinic dehydratase (δ-ALA-D) activities and increased glutathione peroxidase (GPx) activity induced by (PhSe)₂. Administration of l-buthionine sulfoximine (BSO, a GSH-depleting compound) (3.2 μmol/site; i.c.v.) 24 h before (PhSe)₂ increased the percentage (42–100%) of rat pups which had seizure episodes, reduced the onset for the first convulsive episode. In addition, BSO increased thiobarbituric acid reactive species (TBARS) levels and decreased GSH content, catalase, δ-ALA-D and Na⁺, K⁺-ATPase activities. Treatment with sub effective doses of GSH (10 nmol/site) and d-2-amino-7-phosphonoheptanoic acid (AP-7, an antagonist of the glutamate site at the NMDA receptor; 5 mg/kg, i.p.) abolished the appearance of seizures induced by (PhSe)₂ in rat pups. Sub effective doses of GSH and kynurenic acid (an antagonist of strychnine-insensitive glycine site at the NMDA receptor; 40 mg/kg, i.p.) were also able in abolishing the appearance of seizures induced by (PhSe)₂. In conclusion, administration of GSH protected against seizure episodes induced by (PhSe)₂ in rat pups by reducing oxidative stress and, at least in part, by acting as an antagonist of glutamate and glycine modulatory sites in the NMDA receptor.     

Mitochondrial Respiratory Dysfunction and Oxidative Stress after Chronic Malathion Exposure

Malathion is a pesticide used on a large scale and with high potential risk for human exposure. However, it is reasonable to hypothesize that while the malathion is metabolizing reactive oxygen species (ROS) can be generated and subsequently there is onset of an oxidative stress in central nervous system (CNS) structures: hippocampus, cortex, striatum and cerebellum of intoxicated rats due to mitochondrial respiratory chain disfunctions. The present study was therefore undertaken to evaluate malathion-induced lipid peroxidation (LPO), superoxide production from sub-mitochondrial particles and the activity of complexes II and IV of the mitochondrial respiratory chain. Malathion was administered in doses of 25, 50, 100 and 150 mg malathion/kg. After malathion administration LPO increased in hippocampus and striatum. This was accompanied by an increase in the formation of superoxide in submitochondrial particles in the hippocampus. Complex IV suffered significant inhibition of its activity. We could demonstrate in this study that malathion induces oxidative stress and it could be due to inactivation of mitochondrial respiratory complexes.     

Effectiveness of (PhSe)2 in protect against the HgCl2 toxicity

This work investigated the preventive effect of diphenyl diselenide [(PhSe)₂] on renal and hepatic toxicity biomarkers and oxidative parameters in adult mice exposed to mercury chloride (HgCl₂). Selenium (Se) and mercury (Hg) determination was also carried out. Mice received a daily oral dose of (PhSe)₂ (5.0 mg/kg/day) or canola oil for five consecutive days. During the following five days, the animals were treated with a daily subcutaneous dose of HgCl₂ (5.0 mg/kg/day) or saline (0.9%). Twenty-four hours after the last HgCl₂ administration, the animals were sacrificed and biological material was obtained. Concerning toxicity biomarkers, Hg exposure inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), serum alanine aminotransferase (ALT) activity and also increased serum creatinine levels. (PhSe)₂ partially prevented blood δ-ALA-D inhibition and totally prevented the serum creatinine increase. Regarding the oxidative parameters, Hg decreased kidney TBARS levels and increased kidney non-protein thiol levels, while (PhSe)₂ pre-treatment partially protected the kidney thiol levels increase. Animals exposed to HgCl₂ presented Hg content accumulation in blood, kidney and liver. The (PhSe)₂ pre-treatment increased Hg accumulation in kidney and decreased in blood. These results show that (PhSe)₂ can be efficient in protecting against these toxic effects presented by this Hg exposure model.     

Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression

Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Life stressors contribute in some fashion to depression and are an extension of what occurs normally. In this context, chronic stress has been used as an animal model of depression. Based on the hypothesis that metabolism impairment might be involved in the pathophysiology of depression, in the present work we evaluated the activities of mitochondrial respiratory chain complexes and creatine kinase in brain of rats subjected to chronic stress. After 40 days of mild stress, a reduction in sweet food ingestion was observed, as well as increased adrenal gland weight, when compared to control group. We also verified that control group gained weight after 40 days, but stressed group did not. Moreover, our findings showed that complex I, III and IV were inhibited in stress group only in cerebral cortex and cerebellum. On the other hand, complex II and creatine kinase were not affected in stressed group. Although it is difficult to extrapolate our findings to the human condition, the inhibition of mitochondrial respiratory chain by chronic stress may be one mechanism in the pathophysiology of depressive disorders.     

Protective effects of taxifolin on pazopanib-induced liver toxicity: an experimental rat model

Pazopanib is a tyrosine kinase inhibitor that is generally used for the treatment of metastatic renal cell cancer and advanced soft tissue sarcoma. It can cause various degrees of hepatotoxicity. Our study aimed to investigate the effect of taxifolin on pazopanib-induced liver toxicity. A total of 18 rats were divided into three groups: the pazopanib (PP), pazopanib plus taxifolin (TPP), and control (C) group. Taxifolin was administered to the TPP (n=6) group with a dose of 50 mg/kg. Distilled water was orally admnistered to the C (n=6) and PP (n=6) groups as a solvent. Subsequently, pazopanib 200 mg/kg was administered to the TPP and PP groups via the stomach. This procedure was repeated once a day for four weeks. Then, all rats were sacrificed, and their livers were removed. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), and total antioxidant status (TAS) levels were evaluated. MDA and TOS levels were higher in the PP group compared with the levels of the other parameters (P<0.001). tGSH and TAS levels were lower in the PP group than in the TPP and C groups (P<0.001), and the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) levels were higher. Furthermore, liver tissue damage, including hemorrhage, hydropic degeneration, and necrosis was observed in the PP group. Administration of taxifolin before pazopanib significantly improved degenerative changes. Our study demonstrated that the administration of taxifolin is significantly effective in preventing pazopanib-induced hepatotoxicity in rats.     

Influence of pH on the reactivity of diphenyl ditelluride with thiols and anti-oxidant potential in rat brain

Thiol oxidation by diphenyl ditelluride is a favorable reaction and may be responsible for alteration in regulatory or signaling pathways. We have measured rate constants for reactions of diphenyl ditelluride with cysteine, dimercaptosuccinic acid, glutathione and dithiothreitol in phosphate buffer. The relative reactivities of the different thiols with diphenyl ditelluride were independent of the pK_a of the thiol group, such that at pH 7.4, cysteine and dithiothreitol were the most reactive and low reactivity was observed with glutathione and dimercaptosuccinic acid. The reactivity of diphenyl ditelluride was not modified by change in pH. Rate of oxidation increased with increasing pH for all thiols except dimercaptosuccinic acid, where the rate of oxidation was faster at low pH. The lipid peroxidation product malonaldehyde (MDA) was measured in rat brain homogenate and phospholipids extract from egg yolk after incubation in phosphate buffer at various pHs ranging from 7.4 to 5.4. TBARS production increased when homogenates were incubated in the pH (5.4-6.8) medium both in the absence and presence of Fe(II). These data indicate that lipid peroxidation processes, mediated by iron, are enhanced with decreasing pH. The iron mobilization may come from reserves where it is weakly bound. Diphenyl ditelluride significantly protected TBARS production at all studied pH values in a concentration dependent manner in brain homogenate. This study provides in vitro evidence for acidosis induced oxidative stress and anti-oxidant action of diphenyl ditelluride.     

Involvement of oxidative stress in 4-vinylcyclohexene-induced toxicity in Drosophila melanogaster

4-Vinylcyclohexene (VCH) is a dimer of 1,3-butadiene produced as a by-product of pesticides, plastic, rubber, flame retardants, and tire production. Although, several studies have reported the ovotoxicity of VCH, information on a possible involvement of oxidative stress in the toxicity of this occupational chemical is scarce. Hence, this study was carried out to investigate further possible mechanisms of toxicity of VCH with a specific emphasis on oxidative stress using a Drosophila melanogaster model. D. melanogaster (both genders) of 1 to 3 days old were exposed to different concentrations of VCH (10 µM–1 mM) in the diet for 5 days. Subsequently, the survival and negative geotaxis assays and the quantification of reactive oxygen species (ROS) generation were determined. In addition, we evaluated RT-PCR expressions of selected oxidative stress and antioxidant mRNA genes (HSP27, 70, and 83, SOD, Nrf-2, MAPK2, and catalase). Furthermore, catalase, glutathione-S-transferase (GST), delta aminolevulinic acid dehydratase (δ-ALA-D), and acetylcholinesterase (AChE) activities were determined. VCH exposure impaired negative geotaxic behavior and induced the mRNA of SOD, Nrf-2, and MAPK2 genes expressions. There were increases in catalase and ROS production, as well as inhibitions of GST, δ-ALA-D, and AChE activities (P<0.05). Our results suggest that the VCH mechanism of toxicity is associated with oxidative damage, as evidenced by the alteration in the oxidative stress-antioxidant balance, and possible neurotoxic consequences due to decreased AChE activity, and impairments in negative geotaxic behavior. Thus, we conclude that D. melanogaster is a useful model for investigating the toxicity of VCH exposure, and here, we have provided further insights on the mechanism of VCH-induced toxicity.