Search

Simple Summary: The rearing of calves is a challenging phase in the production of dairy cattle. These animals face challenges from birth, as they require ingestion of colostral immunoglobulins for transfer of passive immunity, given that their immune systems are still immature. If there is a failure in the transfer of passive immunity, they become vulnerable to disease. This vulnerability, combined with stressors such as weaning, can predispose them to cellular oxidative stress. Similarly, to the immune system, the antioxidant defense system is also in the developmental stage, therefore, providing antioxidant substances during this phase could be a valuable option. Considering this, our team proposed to assess the impact of prepartum maternal selenium supplementation on the offspring, given its established benefits and its transfer through the placenta, colostrum, and milk. Diphenyl diselenide, an organic analog, was selected because of its anti-inflammatory and antioxidant properties. It can be administered safely subcutaneously, ensuring the correct dosage and facilitating its use at strategic times without any risk of toxicity. Maternal supplementation with diphenyl diselenide has been found to significantly increase passive immunity transfer rates in calves, as well as help establish and improve humoral immunity. This provides new insight into the immunomodulatory capabilities of this molecule. This study aimed to assess the impact of prepartum maternal diphenyl diselenide (PhSe)2 supplementation on the development, biochemical, immune, and antioxidant parameters of calves. Eighteen Holstein breed calves were used, born to females who were or were not subjected to supplementation, at 42, 28, and 14 days prior to calving. The (PhSe)2 group (DDG) was administered 3 μmol/kg of (PhSe)2 in 4 mL of dimethyl sulfoxide (DMSO), while the DMSO and NaCl groups were administered 4 mL of DMSO and 0.9% NaCl, subcutaneously. The calves were evaluated based on their weight, withers height, body condition score 24 h post-birth (0), as well on days 14, 28, 42, 56, 70. Blood samples were also taken to determine serum variables. Calves on the DDG showed higher average levels of total protein, albumin, and globulins on day 0, and the immunoglobulin G level was significantly higher than the other groups on days 0, 14, 56, 70. Maternal supplementation showed immunomodulatory effect on calves, evidenced by the exceptional rates of passive immunity transfer, as well as the enhancement of humoral immunity. Our research offers fresh insights into the immunomodulatory potential of (PhSe)2, making it a viable alternative in facing this challenging phase, rearing dairy calves. [ABSTRACT FROM AUTHOR]

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the causative agent of the COVID-19 pandemic, a global public health problem. Despite the numerous studies for drug repurposing, there are only two FDA-approved antiviral agents (Remdesivir and Nirmatrelvir) for non-hospitalized patients with mild-to-moderate COVID-19 symptoms. Consequently, it is pivotal to search for new molecules with anti-SARS-CoV-2 activity and to study their effects in the human immune system. Ebselen (Eb) is an organoselenium compound that is safe for humans and has antioxidant, anti-inflammatory, and antimicrobial properties. Diphenyl diselenide ((PhSe)2) shares several pharmacological properties with Eb and is of low toxicity to mammals. Herein, we investigated Eb and (PhSe)2 anti-SARS-CoV-2 activity in a human pneumocytes cell model (Calu-3) and analyzed their toxic effects on human peripheral blood mononuclear cells (PBMCs). Both compounds significantly inhibited the SARS-CoV-2 replication in Calu-3 cells. The EC50 values for Eb and (PhSe)2 after 24 h post-infection (hpi) were 3.8 µM and 3.9 µM, respectively, and after 48 hpi were 2.6 µM and 3.4 µM. These concentrations are safe for non-infected cells, since the CC50 values found for Eb and (PhSe)2 on Calu-3 were greater than 200 µM. Importantly, the concentration rates tested on viral replication were not toxic to human PBMCs. Therefore, our findings reinforce the efficacy of Eb and demonstrate (PhSe)2 as a new candidate to be tested in future trials against SARS-CoV-2 infection/inflammation conditions. [ABSTRACT FROM AUTHOR]

The selenium element is essential to some life forms and its biological-chemistry function is mainly performed by the selenol/selenolate moiety (–SeH/–Se–) in a few selenoproteins. Many synthetic organoselenium compounds (OSeCs) have demonstrated important therapeutic applications, with the Ebselen and diphenyl diselenide being the most studied OSeCs. They could act as "hidden selenol" molecules, where the –SeH/–Se– are responsible for the reduction of dangerous peroxides and the protection against the neurotoxic methylmercury. However, their actual mechanisms of action at atomic/molecular level are still elusive. The main conundrum about OSeCs is how they can have quite different structures and similar in vivo action and at the same time modulate quite distinct physiological functions? The question is a hard one because we know little about the metabolism of OSeCs, the in vivo studies are always typically phenomenological, OSeCs have low selectivity and non-specific interactions with thiol-containing proteins. The use of in silico and in vitro models, followed by new analytical methodologies, will give important answers about the metabolism, reactivity, and specificity of OSeCs with specific biological targets, and a real advancement in the subfield of "pharmacological applications" of OSeCs. [ABSTRACT FROM AUTHOR]

Candida krusei is a candidiasis etiological agent of relevance in the clinical setting because of its intrinsic resistance to fluconazole. Also, it has opened up new paths in the area of alternative therapeutic techniques. This project demonstrated the effects of diphenyl diselenide (PhSe)2 and p-cloro diphenyl diselenide (pCl-PhSe)2, two organochalcogen compounds, on relevant virulence factors for the early stage of the C. krusei host interaction and infection process. Both compounds inhibited adherence of C. krusei to both polystyrene surfaces and cervical epithelial cells and biofilm formation; the structure of the biofilm was also changed in a dose-dependent manner. In addition, both compounds inhibited C. krusei growth, but (PhSe)2 significantly increased the time duration of the lag phase and delayed the start of the exponential phase in growth kinetics. (PhSe)2 has more potential antifungal activity than (pCl-PhSe)2 in inhibiting the adherence to epithelial cells, biofilm formation, and growth of C. krusei. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 μ m). 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 μ m). 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. [ABSTRACT FROM AUTHOR]

Methylmercury (MeHg) is a ubiquitous and persistent environmental pollutant that induces serious neurotoxic effects. Diphenyl diselenide [(PhSe)2], an organoseleno compound, exerts protective effects against MeHg toxicity, although the complete mechanism remains unclear. The aim of this study was to investigate the mechanisms involved in the protective effect of (PhSe)2 on the toxicity induced by MeHg using wild-type Saccharomyces cerevisiae and mutants with defects in enzymes and proteins of the antioxidant defense system (yap1Δ, ybp1Δ, ctt1Δ, cat1Δ, sod1Δ, sod2Δ, gsh1Δ, gsh2Δ, gtt1Δ, gtt2Δ, gtt3Δ, gpx1Δ, gpx2Δ, trx1Δ, trx2Δ, trx3Δ, and trr2Δ). In the wild-type strain, (PhSe)2 protected against the growth inhibition, reactive oxygen species production, and decrease in membrane integrity induced by MeHg and restored thiol levels to values indistinguishable from the control. Single deletions of yap1, sod1, sod2, gsh1, gsh2, gpx1, gpx2, trx1, trx2, and trx3 decreased the capacity of (PhSe)2 to prevent MeHg toxicity in yeast, indicating their involvement in (PhSe)2 protection. Together, these results suggest a role of (PhSe)2 in modulating the gene expression of antioxidant enzymes and ABC transporters through the action of the transcription factor YAP1, preventing the oxidative damage caused by MeHg in S. cerevisiae. [ABSTRACT FROM AUTHOR]

Project The opportunistic fungal Candida albicans can produce superficial and systemic infections in immunocompromised patients. An essential stage to both colonization and virulence by C. albicans is the transition from budding yeast form to filamentous form, producing biofilms. Procedure In this work, we studied the effect of the organochalcogenide compound (PhSe) 2 on both cell growth and biofilm formation by C. albicans . Results (PhSe) 2 inhibited both growth and biofilm formation by C. albicans . The inhibitory effects of (PhSe) 2 depended on the cell density and (PhSe) 2 concentration. We have also observed that (PhSe) 2 stimulated ROS production (67%) and increased cell membrane permeability (2.94-fold) in C. albicans . In addition, (PhSe) 2 caused a marked decrease in proteinase activity (6.8-fold) in relation to non-treated group. Conclusions (PhSe) 2 decreased both cell growth and biofilm development, decreasing the release of extracellular proteinases, which is an important facet of C. albicans pathogenicity. The toxicity of (PhSe) 2 towards C. albicans can be associated with an increase in ROS production, which can increase cell permeability. The permanent damage to the cell membranes can culminate in cell death. [ABSTRACT FROM AUTHOR]

Acute stroke is a major risk for morbidity and mortality in aging population. Mitochondrion has been the focus of a wide stroke-related research. This study investigated if treatment or pre-treatment with diphenyl diselenide (PhSe) can prevent mitochondrial damage in cerebral structures of rats induced by an ischemia and reperfusion (I/R) model. Adult male Wistar rats were assigned into five experimental groups: sham operation, ischemia/reperfusion, pre-treated + I/R, treated + I/R, and Sham + (PhSe). Neurological score showed the damage caused by I/R, which was partially prevented by (PhSe). Moreover, mitochondria of hippocampus and cortex were impaired by I/R through an increase of reactive oxygen species production, mitochondrial membrane potential (ΔΨm) and electrons flow alteration, activity of complex I deregulation as well as mitochondrial swelling. However, the ischemic damage did not induce an increase in pro-apoptotic proteins expression, but demonstrated an enhanced expression of Hsp70. The mitochondrial redox state was also altered (GSH/GSSG ratio, MnSOD, and GPx activities). Our results revealed that all treatments with (PhSe) significantly reduced the mitochondrial damage induced by I/R. These findings suggest that neuroprotective properties of (PhSe) may be attributed to the maintenance of mitochondrial redox balance. [ABSTRACT FROM AUTHOR]

Introduction: Cellular antioxidant signaling can be altered either by thyroid disturbances or by selenium status. Aims: To investigate whether or not dietary diphenyl diselenide can modify the expression of genes of antioxidant enzymes and endpoint markers of oxidative stress under hypothyroid conditions. Methods: Female rats were rendered hypothyroid by continuous exposure to methimazole (MTZ; 20 mg/100 ml in the drinking water) for 3 months. Concomitantly, MTZ-treated rats were either fed or not with a diet containing diphenyl diselenide (5 ppm). mRNA levels of antioxidant enzymes and antioxidant/oxidant status were determined in the cerebral cortex, hippocampus and striatum. Results: Hypothyroidism caused a marked upregulation in mRNA expression of catalase, superoxide dismutase (SOD-1, SOD-3), glutathione peroxidase (GPx-1, GPx-4) and thioredoxin reductase (TrxR-1) in brain structures. SOD-2 was increased in the cortex and striatum, while TrxR-2 increased in the cerebral cortex. The increase in mRNA expression of antioxidant enzymes was positively correlated with the Nrf-2 transcription in the cortex and hippocampus. Hypothyroidism caused oxidative stress, namely an increase in lipid peroxidation and reactive oxygen species levels in the hippocampus and striatum, and a decrease in nonprotein thiols in the cerebral cortex. Diphenyl diselenide was effective in reducing brain oxidative stress and normalizing most of the changes observed in gene expression of antioxidant enzymes. Conclusion: The present work corroborates and extends that hypothyroidism disrupts antioxidant enzyme gene expression and causes oxidative stress in the brain. Furthermore, diphenyl diselenide may be considered a promising molecule to counteract these effects in a hypothyroidism state. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives The present work aimed to investigate the effect of (PhSe)2 on cardiovascular age-related oxidative stress in hypercholesterolemic mice. Methods To this end, LDL receptor knockout (LDLr−/−) mice, 3 months (young adult) and 12 months (middle-aged) old, were orally treated with (PhSe)2. Key findings Hypercholesterolemia, regardless of age, impaired the mitochondrial antioxidant defence in the cardiac tissue, which was characterized by a decline in mitochondrial aortic glutathione (GSH) levels and increased reactive oxygen species production in the heart. (PhSe)2 treatment improved GSH levels, thioredoxin reductase (TRxR) and GSH reductase (GR) activity, and decreased malondialdehyde levels in the heart of young adult LDLr−/− mice. Moreover, (PhSe)2 increased GPx activity in both age groups, and GR activity in the aorta of middle-aged LDLr−/− mice. Conclusions Therefore, (PhSe)2 enhances the antioxidant defences in the cardiovascular system of LDLr−/− mice, which could explain its success as an anti-atherogenic compound. [ABSTRACT FROM AUTHOR]

Studies of our group has demonstrated that (PhSe)2 plays some pharmacologic activities. In addition, it is possible that this compound would be an alternative source of organic selenium in animal foods. However, previous works showed that diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2 are toxic for mammals, but their undesirable effects were never tested in avian models. Then, the present study was carried to examine the possible teratogenic effects of (PhSe)2 and (PhTe)2 on chicken embryo development. The eggs were injected with (PhSe)2 at 0, 1 and 10 nmol or with (PhTe)2 at 4 nmol. The control was injected with 10 µl of soya bean oil (vehicle). In order to determine the possible toxic effect of these chemicals, we measure the embryo dimensions, the encephalon, heart and liver weight, thiobarturic acid reactive species (TBARS) level and the δ-aminonevulinate dehydratase (ALA-D) activity. (PhSe)2 and (PhTe)2 did not affect the embryo dimensions. Treatment with (PhSe)2 at 10 nmol per egg caused a increase on TBARS level and on ALA-D activity of the liver tissue, whereas (PhTe)2 decreased encephalon weight, had a tendency to increase to increase TBARS level but did not affect ALA-D activity. Taken together, these results indicate that (PhSe)2 and (PhTe)2 are slightly toxic for chicken embryos. Furthermore, (PhTe)2 caused a decrease in encephalon, which indicates its neurotoxicity. Finally, these results indicate that (PhTe)2 seems not be promissory for therapeutic applications, whereas (PhSe)2 could be of clinical and/or nutritional concern, which will be target for further researches. [ABSTRACT FROM AUTHOR]

In this study, the authors evaluated the ability of diphenyl diselenide (PhSe)2 to reverse acute hepatic failure induced by acetaminophen (APAP) in mice. The animals received an APAP dose of 600 mg/kg intraperitoneally (i.p.), and then 1 hour later, they received 15.6 mg/kg i.p. of (PhSe)2. Three hours after (PhSe)2 administration, the animals were sacrificed and blood and liver samples were collected for analysis. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG), thiobarbituric acid-reactive substances (TBARS), 2’,7’-dichlorofluorescein (DFC), catalase activity (CAT), and myeloperoxidase (MPO) activity were determined in the liver. A methyl-tetrazolium reduction (MTT) assay was also performed on the liver. Histopathological studies were conducted in all groups. Exposure of animals to APAP induced oxidative stress, increased lipid peroxidation (LPO), and the generation of reactive species, reduced the levels of GSH, and caused an increase in the MPO activity. Treatment with (PhSe)2 reduced LPO and the formation of reactive species and inhibited the processes of inflammation, reducing the hepatic damage induced by APAP. The results of this study show that (PhSe)2 is a promising therapeutic option for the treatment of acute hepatic failure. [ABSTRACT FROM PUBLISHER]

Organoselenium compounds exhibit antioxidant activity, as well as a variety of biological activities, with potential pharmacological and therapeutic applications. The aim of this study was to investigate the effect of diphenyl diselenide (PhSe) in reversing oxidative brain damage and mitochondrial dysfunction caused by administration of acetaminophen (APAP) in mice. Mice received a toxic dose of APAP, followed by a dose of (PhSe) 1 h later. Four hours after the administration of APAP, plasma was withdrawn from the mice and used for biochemical assays of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatotoxicity. Brain homogenate was examined to determine oxidative stress. Isolated brain mitochondria were examined to quantify mitochondrial transmembrane's electrical potential and mitochondrial swelling and to estimate reactive oxygen species (ROS) production. APAP administration caused an increase in plasma ALT and AST activities. APAP administration also caused a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and dichlorofluorescein oxidation in brain homogenate. Similarly, mitochondrial swelling and ROS production increased after APAP administration. APAP treatment also caused a decrease in Na , K - ATPase activity and in mitochondrial membrane potential. These alterations observed in the brain of APAP-treated mice were restored by (PhSe). Glutathione levels were decreased by APAP, but (PhSe) did not reverse this change. Treatment with (PhSe) after APAP administration can reverse the neurotoxicity caused by a single toxic dose of APAP. The neuroprotective effect of (PhSe) is likely associated with its antioxidant properties. [ABSTRACT FROM AUTHOR]

Abstract: Thioredoxin reductase (TrxR) isoforms play important roles in cell physiology, protecting cells against oxidative processes. In addition to its endogenous substrates (Trx isoforms), hepatic TrxR can reduce organic selenium compounds such as ebselen and diphenyl diselenide to their selenol intermediates, which can be involved in their hepatoprotective properties. Taking this into account, the aim of the present study was to evaluate the hypothesis that ebselen, diphenyl diselenide and its analogs (4,4′-bistrifluoromethyldiphenyl diselenide, 4,4′-bismethoxydiphenyl diselenide, 4.4′-biscarboxy-diphenyl diselenide, 4,4′-bischlorodiphenyl diselenide, 2,4,6,2′,4′,6′-hexamethyldiphenyl diselenide) could be substrates of rat brain TrxR. In the presence of partially purified rat brain TrxR, diphenyl diselenide, bismethoxydiphenyl diselenide and bischlorodiphenyl diselenide (at 10, 15 and 20μM) stimulated NADPH oxidation, indicating that they are substrates of brain TrxR. In contrast, ebselen and bistrifluoromethyldiphenyl diselenide, that have been previously demonstrated to be substrate of hepatic TrxR, were not reduced by rat brain TrxR. The results presented here suggest that diphenyl diselenide can exert neuroprotective effects by mimicking glutathione peroxidase activity and also via its reduction by TrxR. However, ebselen was not reduced by brain TrxR, indicating that the neuroprotective properties of this compound is possibly mediate by its glutathione peroxidase-like activity. [Copyright &y& Elsevier]

The article presents a study which aims to assess the impact of organoselenium compound diphenyl diselenide (PhSe)2's acute administration on toxicological factors in rabbits. The study exposed the adult rabbits from New Zealand to (PhSe)2 one time daily within five days. The results suggests that rabbit's (PhSe)2 acute toxicology is dose-dependent, which should incite other experiments regarding the therapeutic properties of (PhSe)2.

In the present study we investigated the effects of Diphenyl Diselenide (DPDS) on behavioral and biochemical parameters in Drosophila melanogaster ( DM ). We also tried to explore the gender differences in response to DPDS treatment. One of the salient features of the present report is that, at the highest tested concentration (3.0 mmol/kg) the survival rate in females was significantly higher (65%) as compared with male subjects (27.5%). However in alive subjects, different results pattern was observed. The locomotor activity of females significantly decreased at all tested concentrations and no statistical difference was observed in males at 0.1 and 1.0 mM. To explore the toxicological pathway of DPDS, different arrays of experiments were performed. DPDS did not cause any significant alteration in total thiol contents (NPSH) in males. While, a significant decrease was observed in females at all tested concentrations (0.1, 1.0 and 3.0 mM; p<0.005). For gender comparison purpose, its important to note that females showed 2.1 and 1.63 folds increase in SOD and CAT m-RNA expression at the highest (3.0 mM) tested concentration (as compared with male subjects). In contrast to m-RNA levels of catalase, the lowest concentration (0.1 mM) of DPDS significantly decreased ( P <0.005) the enzymatic activity in females and a noticeable increase ( P <0.005) at highest tested concentration (3.0 mM) was observed in male subjects. Statistically no significant change was observed in Glutathione -S- transferase (GST) activity at all tested concentrations in females. However a marked increase at 1.0 and 3.0 mM was observed in males. Furthermore, we also evaluated, HSP70 mRNA levels in females, which were increased by approximately 10.6 fold ( P <0.005) as compared to male subjects. These results demonstrated significant gender-differences in terms of acute response to DPDS treatment. Mechanistically thiol oxidase (TOx) potential is one of the proposed pathways of DPDS toxicity, which can not be excluded in the present findings. [ABSTRACT FROM AUTHOR]

Abstract: Sepsis is a potentially deadly complication that can be caused by different factors. Actually, it is known that oxidative stress is involved in the pathogenesis of sepsis. Thus, the aim of this study was to evaluate the effect of diphenyl diselenide (PhSe)2, an emergent compound, on oxidative stress parameters induced by sepsis in rats. Animals were pre-injected with (PhSe)2 or vehicle. Twenty-four hours later, sepsis was induced by cecal ligation puncture (CLP). After 12h, liver was taken for thiobarbituric acid reactive species (TBARS) measurement, δ-aminolevunic acid dehydratase (δ-ALA-D), Cu/Zn superoxide dismutase (Cu/Zn SOD) and catalase (CAT) activities assay. The sepsis increased TBARS, inhibited δ-ALA-D, activated Cu/Zn SOD and had a tendency to decrease CAT activity. However, (PhSe)2 prevented the TBARS formation, but did not prevent the inhibition of δ-ALA-D activity in the animals with damage. Thus, this study showed that (PhSe)2 partially prevents the oxidative stress induced by sepsis, indicating the potential of this compound as a treatment for this pathology. Nevertheless, more tests should be performed to confirm the hypothesis suggested here. [Copyright &y& Elsevier]

Objetive The aim of this study was to evaluate the effects of diphenyl diselenide (PhSe) 2 and ebselen (EB) in ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in rats. Methods The effects of (PhSe) 2 and EB in rats submitted to DSS-induced colitis were determined by measurement of oxidative stress parameters, inflammatory response and bowel histopathological alterations. Results Animals developed moderate to severe neutrophil infiltration in histopathology assay in DSS rats and (PhSe) 2 improved this response. Moreover, the treatment with (PhSe) 2 decreased the oxidative damage in lipids and proteins, as well as reversed the superoxide dismutase (SOD) and catalase (CAT) levels in rats treated with DSS. EB was able only to reverse damage in lipids and the low levels of SOD in this animal model. Conclusions The organoselenium compounds tested demonstrated an anti-inflammatory and antioxidant activity reducing the colon damage, being (PhSe) 2 more effective than EB. [ABSTRACT FROM AUTHOR]

Diphenyl diselenide [(PhSe) 2 ] is an organoselenium compound that can mimic endogenous antioxidant enzymes, such as glutathione peroxidase (GPx), or be metabolized by thioredoxin reductase to form selenol intermediate, which can copy the function of the antioxidant selenoenzymes. This compound has shown potential role in preventing atherosclerosis and other oxidative stress-related diseases. The understanding of the underlying mechanism by which (PhSe) 2 modulates the glutathione-related antioxidant defenses is a relevant question. Therefore, we tested its ability to promote the nuclear translocation of the nuclear factor (erythroid 2-like)-related factor 2 (Nrf-2), increasing the expression of enzymes related to the antioxidant system, such as heme oxygenase 1 (HO-1) and peroxiredoxin 1 (Prx-1), in addition to the main enzyme in the glutathione synthesis - gamma glutamylcysteine synthetase (?-GCS) - in murine J774 macrophage cells. (PhSe) 2 (1 µM) was able to promote nuclear translocation and increased the expression of the Nrf-2 factor in the nucleus in a time-dependent manner (1-24 hours). In addition, this compound significantly increased the expression of HO-1 and Prx-1 at 24 hours and GPx-1 after the first hour. Furthermore, (PhSe) 2 was able to enhance GSH levels in a time-dependent manner, as well as GPx and GGCS activities. The increase in GPx and GGCS activities was dependent on the activation of PI3K, JNK, and p38MAPKs signaling pathways that may activate the Nrf2 factor. Altogether, these results show that (PhSe) 2 improved the antioxidant defense by increasing the expression of HO-1 and Prx-1 and the synthesis of GSH as a consequence of the activation and nuclear translocation of Nrf-2 factor. [ABSTRACT FROM AUTHOR]

Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major risk factors for atherosclerosis and cardiovascular morbidity. The early stages of atherosclerosis are initiated by the accumulation of oxLDL and the induction of toxic effects on endothelial cells, resulting in endothelial dysfunction. The aim of this study was to investigate how diphenyl diselenide (DD), an organoselenium compound, protect vascular endothelial cells against the toxic effects of oxLDL in vitro. Our data showed that the treatment of bovine endothelial aortic cells (BAEC) with DD (0.1–1 μM) for 24 h protected from oxLDL-induced reactive species (RS) production and reduced glutathione (GSH) depletion. Moreover, DD (1 μM) per se improved the maximal mitochondrial respiratory capacity and prevented oxLDL-induced mitochondrial damage. In addition, DD could prevent apoptosis induced by oxLDL in BAEC. Results from this study may provide insight into a possible molecular mechanism underlying DD suppression of oxLDL-mediated vascular endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Highlights: [•] The electron transfer chain is a sensitive target of MeHg toxicity. [•] MeHg-induced mitochondrial dysfunction could be prevented if (PhSe)2 is co-administered. [•] MeHg-exposed mice showed low cortical BDNF content and increased DNA damage. [•] (PhSe)2 protects from neurochemical MeHg-induced alterations. [•] (PhSe)2 could be consider as a new neuroprotectant. [Copyright &y& Elsevier]

Highlights: [•] Treatment with Hydrochlorothiazide (HCTZ) altered both glycemic and lipid profile. [•] High fructose diet (HFD) exaggerates metabolic end points of biochemical toxicity. [•] Consumption of HFD and HCTZ results in oxidative stress. [•] The use of HFD and HCTZ results in hypokalemia and hypomagnesemia. [•] Diphenyl Diselenide supplementation reduced oxidative damage. [Copyright &y& Elsevier]

Abstract: It has been reported that oxidized LDLs (oxLDL) are involved in the pathogenesis of atherosclerosis, and that macrophages as well as other cells of the arterial wall can oxidize LDL in vitro, depending on the balance between intracellular prooxidant generation and antioxidant defense efficiency. Because of their potential beneficial role in preventing atherosclerosis and other oxidative stress-related diseases, organoselenium compounds such as diphenyl diselenide (PhSe)2, are receiving increased attention. In the present work, we investigated the mechanisms underlying the protective effect exerted by (PhSe)2 on oxLDL-mediated effects in murine J774 macrophage-like cells. (PhSe)2 pretreatment reduced atherogenic signaling triggered by oxLDL in macrophages in vitro, namely: ROS generation, disturbance of NO homeostasis, activation of matrix metalloproteinase, foam cell formation, and mitochondrial dysfunction. Moreover, the redox signaling effects of (PhSe)2 presented herein were accompanied by a downregulation of NF-κB-binding activity. The relatively strong performance of (PhSe)2 makes it an ideal candidate for further, expanded trials as a new generation of antioxidants for preventing atherosclerotic lesion. [Copyright &y& Elsevier]

Highlights: [•] Organoselenium compounds efficiently protect endothelial cells against peroxynitrite toxicity. [•] The cytopropective effect of diphenyl diselenide could be related with its ability to activate the Nrf-2 cognate genes. [•] Diphenyl diselenide increases the expression and activity of GPx and the GSH content in endothelial cells. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial dysfunction plays a pivotal role in the cell toxicology and death decision. The aim of the present study was to investigate the effect of three organocompounds (ebselen [Ebs], diphenyl diselenide [(PhSe)2] and diphenyl ditelluride [(PhTe)2]) on mitochondrial complexes (I, II, I–III, II–III and IV) activity from rat liver and kidney to determine their potential role as molecular targets of organochalcogens. All studied organochalcogens caused a statistically significant inhibition of the mitochondrial complex I activity. Ebs and (PhTe)2 caused a statistically significant inhibition of the mitochondrial complex II activity in both hepatic and renal membranes. Hepatic mitochondrial complex II activity was practically unchanged by (PhSe)2, whereas it significantly inhibited renal complex II activity. Mitochondrial complex IV activity was practically unchanged by the organochalcogens. Furthermore, organochalcogens inhibited the mitochondrial respiration supported by complex I or complex II substrates. The inhibitory effect of Ebs, (PhSe)2 and (PhTe)2 on mitochondrial complex I was prevented by NADH, but it was not prevented by catalase (CAT) and/or superoxide dismutase (SOD). Additionally, the organochalcogens-induced inhibition of complex I and II was completely reversed by reduced glutathione (GSH). In conclusion, Ebs, (PhSe)2 and (PhTe)2 were more effective inhibitors of renal and hepatic mitochondrial complex I than complex II, whereas complexes III and IV were little modified by these compounds. Taking into account the presented results, we suggest that organochalcogen-induced mitochondrial complexes I and II inhibition can be mediated by their thiol oxidation activity, i.e., Ebs, (PhSe)2 and (PhTe)2 can oxidize critical thiol groups from mitochondrial complexes I and II. So, mitochondrial dysfunction can be considered an important factor in the toxicity of Ebs, (PhSe)2 and (PhTe)2. [Copyright &y& Elsevier]

Abstract: Oxidative stress has been pointed out as an important molecular mechanism in methylmercury (MeHg) intoxication. At low doses, diphenyl diselenide ((PhSe)2), a structurally simple organoselenium compound, has been shown to possess antioxidant and neuroprotective properties. Here we have examined the possible in vivo protective effect of diphenyl diselenide against the potential pro-oxidative effects of MeHg in mouse liver, kidney, cerebrum and cerebellum. The effects of MeHg exposure (2mg/(kgday) of methylmercury chloride 10ml/kg, p.o.), as well as the possible antagonist effect of diphenyl diselenide (1 and 0.4mg/(kgday); s.c.) on body weight gain and on hepatic, cerebellar, cerebral and renal levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), ascorbic acid content, mercury concentrations and activities of antioxidant enzymes (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) were evaluated after 35 days of treatment. MeHg caused an increase in TBARS and decreased NPSH levels in all tissues. MeHg also induced a decrease in hepatic ascorbic acid content and in renal GPx and CAT activities. Diphenyl diselenide (1mg/kg) conferred protection against MeHg-induced hepatic and renal lipid peroxidation and at both doses prevented the reduction in hepatic NPSH levels. Diphenyl diselenide also conferred a partial protection against MeHg-induced oxidative stress (TBARS and NPSH) in liver and cerebellum. Of particular importance, diphenyl diselenide decreased the deposition of Hg in cerebrum, cerebellum, kidney and liver. The present results indicate that diphenyl diselenide can protect against some toxic effects of MeHg in mice. This protection may be related to its antioxidant properties and its ability to reduce Hg body burden. We posit that formation of a selenol intermediate, which possesses high nucleophilicity and high affinity for MeHg, accounts for the ability of diphenyl diselenide to ameliorate MeHg-induced toxicity. [Copyright &y& Elsevier]

Abstract: Oxidative modification of low-density lipoprotein (LDL) represents an important factor in atherogenesis. In the present study, we have investigated the antioxidant capability of diphenyl diselenide (PhSe)2, a simple organoseleno compound, against copper (Cu2+) and peroxyl radical-induced human LDL oxidation in vitro. In initial studies using human serum, (PhSe)2 caused a dose-dependent inhibition of Cu2+-induced lipid peroxidation, which was correlated to thiol consumption. (PhSe)2 increased lipid peroxidation lag phase and decreased lipid peroxidation rate in isolated human LDL, evaluated by measuring both conjugated diene (CD) and thiobarbituric acid reactive substances (TBARS) levels. Consistent with these observations, (PhSe)2 showed a marked inhibitory effect on 2,2-azobis(2-amidinopropane dihydrochloride) (AAPH)-induced oxidation of LDL or parinaric acid (PnA) incorporated into LDL. (PhSe)2 also displayed a dose-dependent protective effect against Cu2+-induced lipid peroxidation in rat aortic slices. Interestingly, besides the antioxidant effects of (PhSe)2 toward the lipid moieties of LDL, which was related to its thiol-peroxidase activity, protein moieties from human isolated LDL were also protected against Cu2+-induced oxidation. The results presented herein are the first to show that (i) (PhSe)2 inhibits lipid peroxidation in human isolated LDL in vitro, (ii) this phenomenon is related to its thiol-peroxidase activity, and (iii) this chalcogen also prevents the oxidation of protein moieties of human LDL. Taken together, such data render (PhSe)2 a promising molecule for pharmacological studies with respect to the atherogenic process. [Copyright &y& Elsevier]

Abstract: Diphenyl diselenide [(PhSe)2] is an organoselenium compound which presents pharmacological antioxidant, anti-inflammatory, antinociceptive and antidepressant properties. The present study was designed to investigate the anxiolytic effect of (PhSe)2 in rats, employing the elevated plus maze task. The involvement of 5HT and GABA receptors in the anxiolytic-like effect was also evaluated. (PhSe)2 (5, 25 and 50 µmol/kg, i.p.) did not affect locomotor activity as evaluated in the open open-field test, and learning and memory when assessed in the inhibitory foot-shock avoidance task. However, (PhSe)2 at the 50 μmol/kg dose produced signs of an anxiolytic action, namely a decreased number of fecal boli in the open-field arena and an increased time spent in as well as an increased number of entries to the open arms of the elevated plus maze test. To evaluate the role of GABA and 5HT receptors in the anxiolytic-like effect of (PhSe)2, a selective GABAA receptor antagonist bicuculline, (0.75 mg/kg, i.p.), a non-selective 5HT2A/2C receptor antagonist, ritanserin (2 mg/kg, i.p.), a selective 5HT2A receptor antagonist, ketanserin (1 mg/kg, i.p.), and a selective 5HT1A receptor antagonist, WAY100635 (0.1 mg/kg, i.p.) were used. All the antagonists used were able to abolish the anxiolytic effect of (PhSe)2 suggesting that GABAA and 5HT receptors may play a role in the pharmacological property of this selenocompound in the central nervous system. [Copyright &y& Elsevier]

Abstract: Glutamate is the main excitatory neurotransmitter in brain involved in pathophysiology of several brain injuries. In this context, glutamate showed to stimulate ecto-nucleotidase activities in cerebellar granule cells increasing extracellular adenosine levels, an important neuromodulator in the CNS able to prevent cell damage. The organoselenium compounds, such as ebselen and diphenyl diselenide [(PhSe)2], display neuroprotective activities mediated at least in part by their antioxidant and anti-inflammatory properties. Ebselen was described to prevent glutamate-induced lipid peroxidation and cell death in cerebellar granule cells and (PhSe)2 modify glutamatergic synapse parameters in vitro and in vivo. In the present study, we investigated the effects of ebselen or (PhSe)2 on glutamate-induced stimulation of ecto-nucleotidase activities in rat cultured cerebellar granule cells. Glutamate increased nucleotide hydrolysis at lower concentrations (10 and 100 µM) than described in the literature and this effect was counteracted by both organoselenium compounds tested. Based on these results, we investigated the association of organoselenium effects with their antioxidant properties searching for redox site modulation by using the alkylant agent N-ethylmaleimide (NEM). Our results suggest that selenium compounds, as well as the well-known antioxidant trolox, can avoid the increase on glutamate-induced stimulation of ecto-nucleotidase activities probably due to their antioxidant properties. [Copyright &y& Elsevier]

Abstract: The present study aimed at investigating the potential in vitro protective effect of the organochalcogenide diphenyl diselenide – (PhSe)2 – against hydrogen peroxide (H2O2)-induced toxicity in rat hippocampal slices. Hippocampal slices were treated for 1 h with H2O2 (2 mM) in the presence or absence of (PhSe)2 (0.1–10 μM). H2O2 treatment significantly decreased cell viability (measured by MTT test) and the co-incubation with (PhSe)2 (10 μM) significantly blunted such phenomenon. The non permeable thiol compounds dithiothreitol (DTT) (100 μM) or reduced glutathione (GSH) (100 μM), which did not display protective effects against H2O2-induced loss of cell viability per se, significantly improved the protective effects elicited by (PhSe)2. Conversely, the permeable form of GSH (GSH monoethyl ester) was unable to alter the neuroprotection mediated by (PhSe)2. The treatment of rat hippocampal slices with H2O2 also increased the lipid peroxidation and decreased the intracellular GSH levels. Moreover, (PhSe)2 (from 0.1 μM) significantly decreased H2O2-induced lipid peroxidation. Interestingly, H2O2 decreased GSH levels and this phenomenon was partially prevented by (PhSe)2. The potential effects of H2O2 on MAPKs phosphorylation (ERK1/2, p38MAPK and JNK1/2) were also evaluated. Even though H2O2 (2 mM) did not alter p38MAPK and JNK1/2 phosphorylation in hippocampal slices, it stimulated ERK1/2 phosphorylation and the co-incubation with (PhSe)2 (10 μM) blocked this effect. Taken together, the present results indicate that (PhSe)2 exerts protective effects against H2O2-induced oxidative damage in hippocampal slices and avoided the increase in ERK1/2 phosphorylation promoted by H2O2. The neuroprotective effect of compound seems to be related to its thiol-peroxidase-like activity and appears to occur at the extracellular milieu because a permeable form of GSH was unable to improve the protective effect of the compound as did the impermeable GSH. [Copyright &y& Elsevier]

Abstract: The present study was designed to investigate further the mechanisms involved in the antinociception caused by diphenyl diselenide in behavioral model of pain in mice. Diphenyl diselenide (1–100 mg/kg), given orally, produced significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate (175 nmol/site) and N-methyl-d-aspartate (NMDA; 450 pmol/site), with mean ID50 values of 45.92 (39.74–60.4) and 55.77 (36.52–77.5) mg/kg respectively. However, diphenyl diselenide completely failed to affect the nociception induced by α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA; 135 pmol/site), (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 50 nmol/site) and kainate (110 pmol/site). This compound also reduced the nociceptive response induced by substance P (SP) (135 ng/site, i.t.), interleukin 1β (IL-1β; 1 pg/site), tumor necrosis factor-α (TNF-α; 0.1 pg/site), bradykinin (BK; 0.1 μg/site) and capsaicin (30 ng/site) with mean ID50 values of 16.22, 7.06, 6.06, 4.18 and 7.90 mg/kg, respectively. Together, these results indicate that diphenyl diselenide produced antinociception at spinal sites, with a possible interaction with glutamatergic pathways, more specifically via interaction with NMDA receptors, peptidergic or vanilloid systems. [Copyright &y& Elsevier]

Abstract: An in vitro evaluation on the antioxidant effect of diphenyl diselenide (PhSe)2, an organochalcogenide, against sodium nitroprusside (SNP)-induced lipid peroxidation (LPO) was conduced. Human platelets and erythrocyte membranes (ghosts), as well as rat brain homogenates (S1), were pre-incubated with different concentrations of SNP (0–10μM). All SNP concentrations tested significantly increased LPO in human platelets and S1. Platelets were more sensitive to SNP-induced peroxidative damage when compared to S1. SNP 10μM decreased glutathione peroxidase (GPx) activity and did not affect glutathione reductase (GR) and catalase (CAT) activities in human platelets. However, ghosts were insensitive to SNP-induced LPO and no changes on GPx, GR and CAT activities were observed. Diphenyl diselenide significantly protected human platelets against SNP-induced LPO and recovered GPx inactivation. This effect was more evident at (PhSe)2 concentrations above 2μM. The presented results indicate that (PhSe)2 exerts protective effects on SNP-induced oxidative damage in human blood components and in rat brain. These phenomena seem to be related to its thiol peroxidase-like activity and to a possible direct interaction with SNP and derivatives. Based on our results and on literature, diphenyl diselenide can be pointed as a promising antioxidant molecule. [Copyright &y& Elsevier]

Abstract: Diphenyl diselenide, (PhSe)2, is an organoselenium compound that affects a number of neuronal processes. The effect of maternal subcutaneous (s.c.) injection of 25 mg/kg (PhSe)2 once daily during early postnatal development (from PND 1 to 21) was evaluated in offspring of Wistar rats. The physical and neural reflexes were recorded at pre-weaning period. The behavioral changes in the elevated plus-maze (EPM), open-field and rotarod tasks were performed in 28-day-old pups. Selenium brain status was significantly increased (∼ 41%) in rat pups. Statistically significant decreases in body weight were observed during lactation period in male and female pups exposed to 25 mg/kg (PhSe)2. There were no dose-related changes on landmarks indicative of physical and reflexologic parameters of development in rats. (PhSe)2 induced a disinhibitory effect in EPM behavior according to gender. Specifically, exposure to (PhSe)2 increased entries and duration in the open arms of the EPM in females but not in males. Locomotor activity and rearing increased by (PhSe)2 exposure in both male and female offspring in the open field. Both groups were similar in response to motor coordination in the rotarod. We concluded that maternal (PhSe)2 exposure during lactation increased selenium levels in the pup brain and caused changes on developmental and behavioral parameters of Wistar rat offspring. [Copyright &y& Elsevier]

Abstract: 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 30ppm of (PhSe)2 pulverized in the chow for 8 months. A number of parameters were examined in blood as indicators of toxicity, including δ-aminolevulinate dehydratase (δ-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 30ppm (PhSe)2 intake caused a significant increase in blood δ-ALA-D activity. Erythrocyte non-protein thiol levels were significantly increased after 2 months of 30ppm (PhSe)2 intake and then return to control levels after prolonged periods of intake. Ingestion of 3.0ppm 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 30ppm (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). [Copyright &y& Elsevier]

Abstract: Recently, we have described the beneficial effects of Diphenyl diselenide, an organochalcogen with glutathione peroxidase-like activity, on reserpine-induced orofacial dyskinesia in old rats. In this study, our aim was to examine the effects of diselenide on haloperidol-induced orofacial dyskinesia in rats. Male wistar rats received one single dose of Haloperidol decanoate (57mg/kg/im) or control. After this dose, the animals received daily administration of diphenyl diselenide (1, 5 or 10mg/kg/sc) or control, during 28 days. Twenty-four hours after the last diselenide or control solution injection, all the rats were observed for quantification of oral dyskinesia through the frequency of vacuous chewing movements (VCM) and tongue protrusion (TP) and the duration of facial twitching (FT). Haloperidol caused a significant increase in VCM, TP and FT observed in the 4 weekly evaluations (p <0.05). The co-administration of diselenide (5mg/kg) reversed this effect for all the parameters in four behavioral sessions. The results of the present study demonstrate the possible protective activity of diphenyl diselenide on haloperidol-induced orofacial diskinesia. This effect is in accordance to the involvement of neurotoxicity in orofacial dyskinesia and suggest that studies be continued with new antioxidant compounds. [Copyright &y& Elsevier]

Abstract: The present study was conducted to evaluate the toxicity of the exposure to diphenyl diselenide [(PhSe)2] and diphenyl ditelluride [(PhTe)2] on reproductive system in Wistar rats. Adult male rats were exposed intraperitonealy (acute) or subcutaneously (sub-chronic, during 4 or 8weeks) to (PhSe)2 or (PhTe)2 prior to mating. A number of biochemical parameters in rat testes were examined, such as δ-aminolevulinate dehydratase (δ-ALA-D) activity, lipid peroxidation, glycogen content and components of the antioxidant defenses (superoxide dismutase (SOD) activity and ascorbic acid concentration). Furthermore, a possible effect on fertility and reproductive performance in male rats were studied. Sperm counts of caudal epididymis were also evaluated. No lethality was noted in any group. Reduction on body weight in rats which received (PhTe)2 was only evidenced in acute exposure, while (PhSe)2-exposed rats presented significant loss of body weight in acute and 4week-exposure. Mating and fertility indexes were not affected after acute and sub-chronic exposure. Regarding other parameters studied, except for a decrease in testes glycogen content in acutely (PhSe)2-treated group, no alterations were found in treated groups. Sperm counts of rats treated acutely and sub-chronically were unaffected by drugs exposure. Histological evaluation revealed no modification on testicular tissue in rats exposed to (PhSe)2 and (PhTe)2. The results suggest the absence of the male reproductive toxicity induced by (PhSe)2 and (PhTe)2 administered intraperitonealy (acute) or subcutaneously (sub-chronical) to adult rats Wistar. [Copyright &y& Elsevier]

Abstract: Ethanol toxicity is affected by both environmental and inherited features. Since oxidative stress is an important molecular mechanism for ethanol-induced cellular damage, the concomitant exposure to ethanol and pro-oxidative or antioxidant compounds can alter its toxicity. Here, we investigate the effects of exposure to ethanol and/or diphenyl diselenide, an organochalcogen with antioxidant properties, on parameters related to oxidative stress (thiobarbituric acid reactive species—TBARS—and δ-aminolevulinate dehydratase—δ-ALA-D activity) in mouse liver and brain. In addition, the in vitro effects of ethanol and acetaldehyde on the activity of δ-ALA-D from human erythrocytes were also investigated. Both ethanol and diphenyl diselenide decreased hepatic δ-ALA-D activity and DL-dithiothreitol (DTT) reactivated this enzyme only after ethanol-induced inhibition. Moreover, ethanol increased liver TBARS levels, independently of the presence of diphenyl diselenide treatment. Brain δ-ALA-D activity and TBARS levels were not changed by ethanol or diphenyl diselenide exposure. Under in vitro conditions, acetaldehyde was a more potent inhibitor of δ-ALA-D from human erythrocytes when compared to ethanol, demonstrating a dose-dependent effect. This study indicates that (1) hepatic δ-ALA-D is a molecular target for the damaging effect of ethanol under in vivo conditions; (2) diphenyl diselenide and ethanol seem to inhibit δ-ALA-D by different mechanisms; (3) acetaldehyde, a metabolite of ethanol, is probably the main molecule responsible for the inhibitory effects of the parent compound on δ-ALA-D. [Copyright &y& Elsevier]

Abstract: In this study, we described the local peripheral antinociceptive activity produced by diphenyl diselenide in the formalin test as compared to ebselen, an amply studied organoselenium compound. A second objective was to evaluate, the possible mechanisms underlying the antinociceptive effect caused by diphenyl diselenide. Administration of diphenyl diselenide or ebselen produced a significant antinociceptive local effect on the late phase (15–30min) of the formalin test. As well, diphenyl diselenide and ebselen injected in the contra lateral paw produced a significant decrease in licking time on the late phase (15–30min). The mechanisms underlying the analgesic action of diphenyl diselenide seem to be unlike the activation of opioid, dopaminergic D2, muscarinic cholinergic receptors or the interaction with α1 and α2 adrenoceptors. Furthermore, the effect of a 5-HT3 receptor antagonist in abolishing the antinociception induced by diphenyl diselenide suggests the involvement of serotonergic pathways. [Copyright &y& Elsevier]