Genotoxicity and cytotoxicity potential of organoselenium compounds in human leukocytes in vitro.

In the current work, cytotoxicity and genotoxicity of different organoselenium compounds were examined using Trypan blue exclusion and alkaline comet assays with silver staining respectively. Leukocytes were subjected to a 3-hour incubation with organoselenium compounds at concentrations of 1, 5, 10, 25, 50, and 75 µM, or with the control vehicle (DMSO), at a temperature of 37 °C. The viability of the cells was evaluated using the Trypan blue exclusion method, while DNA damage was analyzed through the alkaline comet assay with silver staining. The exposure of leukocytes to different organoselenium compounds including i.e. (Z)-N-(pyridin-2-ylmethylene)-1-(2-((2-(1-((E)-pyridin-2-ylmethyleneamino)ethyl)phenyl)diselanyl)phenyl)ethanamine (C1), 2,2'(1Z,1'E)-(1,1'-(2,2'-diselanediylbis(2,1-phenylene))bis(ethane-1,1-diyl)) bis(azan-1-yl-1-ylidene)bis -methan-1-yl-1-ylidene)diphenol (C2), and dinaphthyl diselenide (NapSe)2, At concentrations ranging from 1 to 5 µM, no significant DNA damage was observed, as indicated by the absence of a noteworthy increase in the Damage Index (DI). Our results suggest that the organoselenium selenium compounds tested were not genotoxic and cytotoxic to human leukocytes in vitro at lower concentration. This study offers further insights into the genotoxicity profile of these organochalcogens in human leukocytes. Their genotoxicity and cytotoxicity effects at higher concentration are probably mediated through reactive oxygen species generation and their ability to catalyze thiol oxidation.

Diphenyl diselenide protects against methylmercury-induced inhibition of thioredoxin reductase and glutathione peroxidase in human neuroblastoma cells: a comparison with ebselen.

Exposure to methylmercury (MeHg), an important environmental toxicant, may lead to serious health risks, damaging various organs and predominantly affecting the brain function. The toxicity of MeHg can be related to the inhibition of important selenoenzymes, such as glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). Experimental studies have shown that selenocompounds play an important role as cellular detoxifiers and protective agents against the harmful effects of mercury. The present study investigated the mechanisms by which diphenyl diselenide [(PhSe)2 ] and ebselen interfered with the interaction of mercury (MeHg) and selenoenzymes (TrxR and GPx) in an in vitro experimental model of cultured human neuroblastoma cells (SH-SY5Y). Our results established that (PhSe)2 and ebselen increased the activity and expression of TrxR. In contrast, MeHg inhibited TrxR activity even at low doses (0.5 µm). Coexposure to selenocompounds and MeHg showed a protective effect of (PhSe)2 on both the activity and expression of TrxR. When selenoenzyme GPx was evaluated, selenocompounds did not alter its activity or expression significantly, whereas MeHg inhibited the activity of GPx (from 1 µm). Among the selenocompounds only (PhSe)2 significantly protected against the effects of MeHg on GPx activity. Taken together, these results indicate a potential use for ebselen and (PhSe)2 against MeHg toxicity. Furthermore, for the first time, we have demonstrated that (PhSe)2 caused a more pronounced upregulation of TrxR than ebselen in neuroblastoma cells, likely reflecting an important molecular mechanism involved in the antioxidant properties of this compound. Copyright © 2017 John Wiley & Sons, Ltd.

Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment.

BACKGROUND: There are several specific inflammatory and oxidative correlates among patients with hypothyroidism, but most studies are cross-sectional and do not evaluate the change in parameters during the treatment. The aim of this study was to investigate the effect of levothyroxine replacement therapy on biomarkers of oxidative stress (OS) and systemic inflammation in patients with hypothyroidism. METHODS: In this prospective open-label study, 17 patients with recently diagnosed primary hypothyroidism due to Hashimoto's thyroiditis who were not taking levothyroxine were included. The following parameters were measured before and at 6 and 12 months of levothyroxine treatment with an average dose of 1.5 to 1.7 µg/kg/day: thyroid-stimulating hormone (TSH), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP), interleukin 1 (IL-1), IL-6, IL-10, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), thiobarbituric acid-reactive substances (TBARS), activity of aminolevulinic acid dehydratase (δ-ALA-D), nonprotein and total thiol (NP-SH and T-SH) groups, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). Generalized estimating equation (GEE) modeling was used to analyze the effects of LRT (at pre-treatment, 6 months and 12 months) on those variables. The hypothyroidism status (i.e., overt or subclinical hypothyroidism) was included as a confounder in all analyses. An additional GEE post hoc analysis was made to compare time points. RESULTS: There was a significant decrease in TSH over time (P < 0.0001), (initial levels were on average 32.4 µIU/mL and 10.5 µIU/mL at 12 months). There was a significant increase in FT4 (P < 0.0001) (initial levels were on average 0,8 ng/dL and 2.7 ng/dL at 12 months). There were significant changes in interleukin levels over time, with a significant increase in IL-10 (P < 0.0001) and significant decreases in IL-1 (P < 0.0001), IL-6 (P < 0.0001), INF-γ (P < 0.0001) and TNF-α (P < 0.0001). No significant difference in hs-CRP over time was observed (P < 0.284). There was a significant reduction in NP-SH (P < 0.0001). CONCLUSIONS: This study observed significant changes in the inflammatory profile in hypothyroid patients under treatment, with reduction of pro-inflammatory cytokines and elevation of anti-inflammatory cytokine. In these patients, a decrease in low-grade chronic inflammation may have clinical relevance due to the known connection between chronic inflammation, atherosclerosis and cardiovascular events.

N-Acetylcysteine does not protect behavioral and biochemical toxicological effect after acute exposure of diphenyl ditelluride.

Diphenyl ditelluride (PhTe)2 is a versatile molecule used in the organic synthesis and it is a potential prototype for the development of novel biologically active molecules. The mechanism(s) involved in (PhTe)2 toxicity is(are) elusive, but thiol oxidation of critical proteins are important targets. Consequently, the possible remedy of its toxicity by thiol-containing compounds is of experimental and clinical interest. The present study aimed to investigate putative mechanisms underlying the toxicity of (PhTe)2 in vivo. We assessed behavioral and oxidative stress parameters in mice, including the modulation of antioxidant enzymatic defense systems. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered before (3 d) and simultaneously with (PhTe)2 (7 d). Mice were separated into six groups receiving daily injections of (1) TFK (2.5 ml/kg, intraperitonealy (i.p.)) plus canola oil (10 ml/kg, subcutaneously (s.c.)), (2) NAC (100 mg/kg, i.p.) plus canola oil s.c., (3) TFK i.p. plus (PhTe)2 (10 µmol/kg, s.c.), (4) TFK i.p. plus (PhTe)2 (50 µmol/kg, s.c.), (5) NAC plus (PhTe)2 (10 µmol/kg, s.c.), and (6) NAC plus (PhTe)2 (50 µmol/kg, s.c.). (PhTe)2 treatment started on the fourth day of treatment with NAC. Results demonstrated that (PhTe)2 induced behavioral alterations and inhibited important selenoenzymes (thioredoxin reductase and glutathione peroxidase). Treatments produced no or minor effects on the activities of antioxidant enzymes catalase and glutathione reductase. Contrary to expected, NAC co-administration did not protect against the deleterious effects of (PhTe)2. Other low-molecular-thiol containing molecules should be investigated to determine whether or not they can be effective against ditellurides.

Bauhinia forficata prevents vacuous chewing movements induced by haloperidol in rats and has antioxidant potential in vitro.

Classical antipsychotics can produce motor disturbances like tardive dyskinesia in humans and orofacial dyskinesia in rodents. These motor side effects have been associated with oxidative stress production in specific brain areas. Thus, some studies have proposed the use of natural compounds with antioxidant properties against involuntary movements induced by antipsychotics. Here, we examined the possible antioxidant activity of Bauhinia forficata (B. forficata), a plant used in folk medicine as a hypoglycemic, on brain lipid peroxidation induced by different pro-oxidants. B. forficata prevented the formation of lipid peroxidation induced by both pro-oxidants tested. However, it was effective against lipid peroxidation induced by sodium nitroprusside (IC50 = 12.08 µg/mL) and Fe(2+)/EDTA (IC50 = 41.19 µg/mL). Moreover, the effects of B. forficata were analyzed on an animal model of orofacial dyskinesia induced by long-term treatment with haloperidol, where rats received haloperidol each 28 days (38 mg/kg) and/or B. forficata decoction daily (2.5 g/L) for 16 weeks. Vacuous chewing movements (VCMs), locomotor and exploratory activities were evaluated. Haloperidol treatment induced VCMs, and co-treatment with B. forficata partially prevented this effect. Haloperidol reduced the locomotor and exploratory activities of animals in the open field test, which was not modified by B. forficata treatment. Our present data showed that B. forficata has antioxidant potential and partially protects against VCMs induced by haloperidol in rats. Taken together, our data suggest the protection by natural compounds against VCMs induced by haloperidol in rats.

Antioxidant properties of diorganoyl diselenides and ditellurides: modulation by organic aryl or naphthyl moiety.

Diorganoyl dichalcogenide compouds can have antioxidant activity in different in vitro and in vivo models. Here, we have compared the potential antioxidant activity of 1-dinaphthyl diselenide (1-NapSe)(2), 2-dinaphthyl diselenide (2-NapSe)(2), 1-dinaphthyl distelluride (1-NapTe)(2), 2-dinaphthyl ditelluride (2-NapTe)(2) with their well-studied analogs diphenyl diselenide ((PhSe)(2)) and diphenyl telluride ((PhTe)(2)). (PhSe)(2), (PhTe)(2), and naphthalene analogs-inhibited Fe(II)-induced lipid peroxidation, catalytically decomposed hydrogen peroxide and oxidized thiols, such as dithiothreitol (DTT), Cysteine (CYS), dimercaptopropionic acid (DMPS), and thiophenol (PhSH). (PhSe)(2) was the less potent of the tested compounds against Fe(II)-induced lipid peroxidation in brain homogenates and the change in the organic moiety from an aryl to naphthyl group increased considerably the antioxidant potency of diselenide compounds. However, the change from aryl to naphthyl had little effect on the thio-peroxidase-like activity of diorganoyl dichalcogenides. These results suggest that minor changes in the organic moiety of aromatic diselenide compounds can modify profoundly their capacity to inhibit iron-induced lipid peroxidation. The pharmacological properties of organochalcogens are thought to be linked to their capacity of modulating oxidative stress. Consequently, it becomes important to explore the toxicological properties of dinaphthyl diselenides and ditellurides.

Diphenyl ditelluride targets brain selenoproteins in vivo: inhibition of cerebral thioredoxin reductase and glutathione peroxidase in mice after acute exposure.

In this study, we investigated the effect of diphenyl ditelluride (PhTe)(2) administration (10 and 50 µmol/kg) on adult mouse behavioral performance as well as several parameters of oxidative stress in the brain and liver. Adult mice were injected with (PhTe)(2) or canola oil subcutaneously (s.c.) daily for 7 days. Results demonstrated that (PhTe)(2) induced prominent signs of toxicity (body weight loss), behavioral alterations and increased in lipid peroxidation in brain. 50 µmol/kg (PhTe)(2) inhibited blood δ-aminolevulinic acid dehydratase (δ-ALA-D), a redox sensitive enzyme. (PhTe)(2) caused an increase in cerebral non-protein thiol (NPSH) and protein thiol (PSH) groups. In the liver, 50 µmol/kg (PhTe)(2) decreased NPSH, but did not alter the content of protein thiol groups. (PhTe)(2) decreased cerebral antioxidant enzymes (catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), and thioredoxin reductase (TrxR). In liver, (PhTe)(2) increase SOD and GR and decreased GPx activity. Results obtained herein suggest that the brain was more susceptible to oxidative stress induced by (PhTe)(2) than the liver. Furthermore, we have demonstrated for the first time that TrxR is an in vivo target for (PhTe)(2.) Combined, these results highlight a novel molecular mechanism involved in the toxicity of (PhTe)(2). In particular the inhibition of important selenoenzymes (TrxR and GPx) seems to be involved in the neurotoxicity associated with (PhTe)(2) exposure in adult mice.

Evaluation of the biological effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative of aspartic acid.

(S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, showed remarkable glutathione peroxidase (GPx)-like activity, attesting to its antioxidant potential. However, the stability and toxicity of this compound has not yet been investigated. The present study was designed to investigate the pharmacological/toxicological properties of this compound in vitro and in vivo. In vitro, this telluroamino acid derivative significantly blocked spontaneous and Fe(II)-induced TBARS formation in rat brain homogenates, demonstrating high antioxidant activity. In addition, it exhibited GPx-like and thiol oxidase activities. However, when subcutaneously administered to mice, (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate indicated genotoxic and mutagenic effect in adult male mice. Considering the differential effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate in vitro and in vivo, additional experiments are needed to elucidate the mechanism(s) by which this compound displays its antioxidant/toxicological effects.

Toxicity of organochalcogens in human leukocytes is associated, but not directly related with reactive species production, apoptosis and changes in antioxidant gene expression.

Selenium (Se) containing organic compounds, such as ebselen (Ebs) and diphenyl diselenide [(PhSe)2], have been used as pharmacological agents due to their antioxidant properties. Tellurium (Te) does not have any biological function in mammals, but Te-containing organic compounds, such as diphenyl ditelluride [(PhTe)2], has been used both as an antioxidant or neurotoxic agent. At high concentrations, these compounds cause toxicity by oxidising thiol and selenol groups of proteins. Here, we analysed whether these compounds could modulate reactive species (RS) production, apoptosis and antioxidant gene expression profile of some selenoproteins and antioxidant enzymes or transcription factors in leukocytes isolated from human blood. Since no data is available about their accumulation in isolated leukocytes, we determine their concentration in the cells by CG-MS. Apoptosis (propidium iodide) and RS production (dichloro fluorescein) were determined by flow cytometry. The expression of CAT, SOD1, GPX3, GPX4, TRXR1, and NFLE2L2 genes were analysed by RT-PCR. (PhTe)2 was the only compound able to increase apoptosis rate. (PhSe)2 altered the expression of CAT and SOD1, and this was associated with a high RS production. All compounds decreased the expression of GPX3 but did not alter GPX4 and TRXR1 expression. All compounds decreased NFE2L2 expression (Ebs > (PhTe)2> (PhSe)2). We hypothesise that the toxicity induced by these organochalcogens is not directly related to their ability of inducing RS production.

High-sucrose diet induces diabetic-like phenotypes and oxidative stress in Drosophila melanogaster: Protective role of Syzygium cumini and Bauhinia forficata.

Diet is a key component for development and longevity of organisms. Here, the fruit fly was used to evaluate the detrimental effects caused by consumption of high-sucrose diets (HSD), namely phenotypic responses linked to insulin signaling and oxidative stress. The protective effects of extracts from medicinal plants Syzygium cumini and Bauhinia forficata were investigated. HSD intake (15% and 30%) delayed the time to pupation and reduced the number of white pupae. In adult flies, the intake of diets was associated with mortality and increased levels of glucose+trehalose, triacylglycerols and hydrogen peroxide. Indeed, 30% HSD induced body-weight loss, mitochondrial dysfunction and changes in acetylcholinesterase, δ-aminolevulinate dehydratase and antioxidant enzymes activity. Catalase, superoxide dismutase, keap1, HSP70, dILP-5 and Insulin receptor mRNA levels were over-expressed in flies emerged from 30% HSD. The extract treatments blunted the developmental alterations elicited by diets. Syzygium cumini extract was more efficient than B. forficata in reducing hyperglycaemia, redox disturbances and the changes in mRNA expression of insulin receptor.

Saponin from the fruit of Solanum anguivi protects against oxidative damage mediated by Fe2+ and sodium nitroprusside in rat brain synaptosome P2 fraction.

Solanum anguivi fruit saponin has antidiabetic property via interference with cellular energy metabolism and inhibition of reactive oxygen species (ROS) generation. In the current study, brain specific in vitro anti-oxidant role of S. anguivi saponin was investigated in the P2 synaptosomal fraction of rat brain. Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay, S. anguivi saponin concentration- dependently (10-200 µg/ml) reversed Fe2+ and sodium nitroprusside- induced decrease in mitochondrial activity via inhibition of ROS production, ROS-induced oxidation of protein and non-protein thiol-containing molecules and lipid peroxidation as measured by thiobarbituric acid reactive substances levels. Conclusively, S. anguivi fruit saponin represents a class of natural compounds with the ability to reverse synaptosomal disruption, loss of mitochondrial integrity and function often associated with the progression of Huntington's disease, Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis diseases.

Differential genotoxicity of diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2.

Organoselenium compounds have been pointed out as therapeutic agents. In contrast, the potential therapeutic aspects of tellurides have not yet been demonstrated. The present study evaluated the comparative toxicological effects of diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2 in mice after in vivo administration. Genotoxicity (as determined by comet assay) and mutagenicicity were used as end-points of toxicity. Subcutaneous administration of high doses of (PhSe)2 or (PhTe)2 (500 µmol/kg) caused distinct genotoxicity in mice. (PhSe)2 significantly decreased the DNA damage index after 48 and 96 h of its injection (p < 0.05). In contrast, (PhTe) caused a significant increase in DNA damage (p < 0.05) after 48 and 96 h of intoxication. (PhSe)2 did not cause mutagenicity but (PhTe)2 increased the micronuclei frequency, indicating its mutagenic potential. The present study demonstrated that acute in vivo exposure to ditelluride caused genotoxicity in mice, which may be associated with pro-oxidant effects of diphenyl ditelluride. In addition, the use of this compound and possibly other related tellurides must be carefully controlled.

Brazilian nut consumption by healthy volunteers improves inflammatory parameters.

OBJECTIVE: The aim of this study was to investigate the effect of a single dose of Brazil nuts on the inflammatory markers of healthy individuals. METHOD: A randomized crossover study was conducted with 10 healthy individuals (mean age 24.7 ± 3.4 y). Each individual was tested four times regarding intake of different portions of Brazil nuts: 0, 5, 20 and 50 g. At each testing period, peripheral blood was collected before and at 1, 3, 6, 9, 24, and 48 h after intake of nuts, as well as at 5 and 30 d after intake of various Brazil nut portions. Blood samples were tested for high-sensitivity to C-reactive protein, interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, aspartate and alanine aminotransferases, albumin, total protein, alkaline phosphatase, gamma-glutamyltransferase, urea, and creatinine. RESULTS: Consumption of nuts did not affect biochemical parameters for liver and kidney function, indicating absence of hepatic and renal toxicity. A single intake of Brazil nuts (20 or 50 g) caused a significant decrease in serum IL-1, IL-6, TNF-α, and IFN-γ levels (P < 0.05), whereas serum levels of IL-10 were significantly increased (P < 0.05). CONCLUSION: The results indicate a long-term decrease in inflammatory markers after a single intake of large portions of Brazil nuts in healthy volunteers. Therefore, the long-term effect of regular Brazil nut consumption on inflammatory markers should be better investigated.

Cytotoxicity and genotoxicity evaluation of organochalcogens in human leucocytes: a comparative study between ebselen, diphenyl diselenide, and diphenyl ditelluride.

Organochalcogens, particularly ebselen, have been used in experimental and clinical trials with borderline efficacy. (PhSe)2 and (PhTe)2 are the simplest of the diaryl dichalcogenides and share with ebselen pharmacological properties. In view of the concerns with the use of mammals in studies and the great number of new organochalcogens with potential pharmacological properties that have been synthesized, it becomes important to develop screening protocols to select compounds that are worth to be tested in vivo. This study investigated the possible use of isolated human white cells as a preliminary model to test organochalcogen toxicity. Human leucocytes were exposed to 5-50 µM of ebselen, (PhSe)2, or (PhTe)2. All compounds were cytotoxic (Trypan's Blue exclusion) at the highest concentration tested, and Ebselen was the most toxic. Ebselen and (PhSe)2 were genotoxic (Comet Assay) only at 50 µM, and (PhTe)2 at 5-50 µM. Here, the acute cytotoxicity did not correspond with in vivo toxicity of the compounds. But the genotoxicity was in the same order of the in vivo toxicity to mice. These results indicate that in vitro genotoxicity in white blood cells should be considered as an early step in the investigation of potential toxicity of organochalcogens.

Hydrochlorothiazide and high-fat diets reduce plasma magnesium levels and increase hepatic oxidative stress in rats.

This study was designed to develop a rodent model of hydrochlorothiazide (HCTZ) toxicity by associating its intake with a high-fat (HF) diet. Rats were fed for 16 weeks with a control diet or with an HF diet supplemented or not with different doses of HCTZ. HCTZ, in a similar way to the HF diet, caused a significant increase in fructosamine levels. HCTZ and HF diet intake caused a significant reduction in magnesium and potassium levels, as well as an increase in lipid peroxidation and vitamin C in liver. Importantly, negative correlations were found between magnesium and glucose levels as well as between magnesium and fructosamine levels. The association between HCTZ and the HF diet caused additional worsening of biochemical parameters related to glucose homeostasis, and further increased hepatic oxidative stress. Our results suggest that chronic intake of HCTZ or an HF diet causes metabolic changes that are consistent with the development of insulin resistance. In addition, the association of an HF diet and HCTZ treatment can exacerbate some of these biochemical alterations, suggesting that this model might be useful for studying HCTZ metabolic toxicity.

Sub-acute administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate induces toxicity and oxidative stress in mice: unexpected effects of N-acetylcysteine.

The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) exhibits thiol-peroxidase activity that could potentially offer protection against oxidative stress. However, data from the literature show that tellurium is a toxic agent to rodents. In order to mitigate such toxicity, N-acetylcysteine (NAC) was administered in parallel with TeAsp during 10 days. Mice were separated into four groups receiving daily injections of (A) vehicle (PBS 2.5 ml/kg, i.p. and DMSO 1 ml/kg, s.c.), (B) NAC (100 mg/kg, i.p. and DMSO s.c.), (C) PBS i.p. and TeAsp (92.5 µmol/kg, s.c), or (D) NAC plus TeAsp. TeAsp treatment started on the fourth day. Vehicle or NAC-treated animals showed an increase in body weight whereas TeAsp caused a significant reduction. Contrary to expected, NAC co-administration potentiated the toxic effect of TeAsp, causing a decrease in body weight. Vehicle, NAC or TeAsp did not affect the exploratory and motor activity in the open-field test at the end of the treatment, while the combination of NAC and TeAsp produced a significant decrease in these parameters. No DNA damage or alterations in cell viability were observed in leukocytes of treated animals. Treatments produced no or minor effects on the activities of antioxidant enzymes catalase, glutathione peroxidase and glutathione reductase, whereas the activity of the thioredoxin reductase was decreased in the brain and increased the liver of the animals in the groups receiving TeAsp or TeAsp plus NAC. In conclusion, the toxicity of TeAsp was potentiated by NAC and oxidative stress appears to play a central role in this process.

Diphenyl diselenide supplementation reduces biochemical alterations associated with oxidative stress in rats fed with fructose and hydrochlorothiazide.

The study evaluated whether a diet containing diphenyl diselenide (PhSe)2, a synthetic antioxidant, could reduce the biochemical alterations induced by chronic consumption of highly enriched fructose diet and/or hydrochlorothiazide (HCTZ). Rats were fed a control diet (CT) or a high fructose diet (HFD), supplemented with or not HCTZ (4.0g/kg) and/or (PhSe)2 (3ppm) for 18weeks. HFD intake increased significantly plasma glucose, fructosamine, triglycerides and cholesterol levels. (PhSe)2 supplementation significantly reduced triglycerides and cholesterol but could not restore them to control levels. The combination of HFD and HCTZ significantly altered plasma glucose, fructosamine, triglycerides and cholesterol levels which were not restore by (PhSe)2 supplementation. Lipid peroxidation, protein carbonyl formation, vitamin C level and catalase activity decreased after HFD, HCTZ or HFD plus HCTZ ingestion. Remarkably (PhSe)2 supplementation restored the oxidative stress parameters. HCTZ decreased renal superoxide dismutase (SOD) activity, which was restored to control levels by (PhSe)2. Furthermore, the association of HFD and HCTZ decreased plasma potassium levels and aggravated HCTZ-induced hypomagnesemia and hypertriglyceridemia. Here we provided evidence of the involvement of oxidative stress and metabolic disorders in a rat model of HFD associated or not with HTCZ. (PhSe)2 supplementation reduced the oxidative stress and this compound should be considered for the treatment of biochemical disturbances and oxidative stress in other animal models of metabolic disorders.

Ethanol-induced oxidative stress: the role of binaphthyl diselenide as a potent antioxidant.

It is widely accepted that oxidative stress plays a central role in alcohol-induced pathogenesis. The protective effect of binaphthyl diselenide (NapSe)2 was investigated in ethanol (Etoh)-induced brain injury. Thirty male adult Wistar rats were divided randomly into five groups of six animals each and treated as follows: (1) The control group received the vehicle (soy bean oil, 1 mL/kg, p.o.). (2) Ethanol group of animals was administered with ethanol (70% v/v, 2 mL/kg, p.o.). (3) (NapSe)2 1 mg/kg, 1 mL/kg plus ethanol 70% (v/v, 2 mL/kg, p.o. (5) (NapSe)2 10 mg/kg, 1 mL/kg) plus ethanol 70% (v/v, 2 mL/kg, p.o). After acute treatment, all rats were sacrificed by decapitation. Evidence for oxidative stress in rat brain was obtained from the observed levels of thiobarbituric acid reactive species, of non-protein thiol (NPSH) groups, and of ascorbic acid, as well as from the activities of catalase (CAT) and of superoxide dismutase (SOD). (NapSe)2 compensated the deficits in the antioxidant defense mechanisms (CAT, SOD, NPSH, and ascorbic acid), and suppressed lipid peroxidation in rat brain resulting from Etoh administration. It was concluded that ethanol exposure causes alterations in the antioxidant defense system and induces oxidative stress in rat brain. (NaPSe)2 at 5 mg/kg restored the antioxidant defenses in rat brain and mitigated the toxic effects of alcohol, suggesting that could be used as a potential therapeutic agent for alcohol-induced oxidative damage in rat brain.