(m-CF3-PhSe)2 counteracts metabolic disturbances and hypothalamic inflammation in a lifestyle rodent model.

An unhealthy lifestyle is associated with metabolic disorders and neuroinflammation. In this study, the efficacy of m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] against lifestyle model-related metabolic disturbances and hypothalamic inflammation in young mice was investigated. From postnatal day 25 (PND25) to 66, male Swiss mice were subjected to a lifestyle model, an energy-dense diet (20:20% lard: corn syrup) and sporadic ethanol (3x/week). Ethanol was administrated intragastrically (i.g., 2 g/kg) to mice from PND45 to 60. From PND60 to 66, mice received (m-CF3-PhSe)2 (5 mg/kg/day; i. g). (m-CF3-PhSe)2 reduced relative abdominal adipose tissue weight, hyperglycemia, and dyslipidemia in mice exposed to the lifestyle-induced model. (m-CF3-PhSe)2 normalized hepatic cholesterol and triglyceride levels, and the activity of G-6-Pase increased in lifestyle-exposed mice. (m-CF3-PhSe)2 was effective in modulating hepatic glycogen levels, citrate synthase and hexokinase activities, protein levels of GLUT-2, p-IRS/IRS, p-AKT/AKT, redox homeostasis, and inflammatory profile of mice exposed to a lifestyle model. (m-CF3-PhSe)2 counteracted hypothalamic inflammation and the ghrelin receptor levels in mice exposed to the lifestyle model. (m-CF3-PhSe)2 reversed the decreased levels of GLUT-3, p-IRS/IRS, and the leptin receptor in the hypothalamus of lifestyle-exposed mice. In conclusion, (m-CF3-PhSe)2 counteracted metabolic disturbances and hypothalamic inflammation in young mice exposed to a lifestyle model.

(m-CF3-PhSe)2 benefits against anxiety-like phenotype associated with synaptic plasticity impairment and NMDAR-mediated neurotoxicity in young mice exposed to a lifestyle model.

Lifestyle habits including energy-dense foods and ethanol intake are associated with anxiety disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] has been reported to modulate serotonergic and opioidergic systems and elicit an anxiolytic-like phenotype in animal models. This study investigated if the modulation of synaptic plasticity and NMDAR-mediated neurotoxicity contributes to the (m-CF3-PhSe)2 anxiolytic-like effect in young mice exposed to a lifestyle model. Swiss male mice (25-days old) were subjected to a lifestyle model, an energy-dense diet (20:20% lard: corn syrup) from the postnatal day (PND) 25-66 and sporadic ethanol (2 g/kg) (3 x a week, intragastrically, i.g.) from PND 45 to 60. From PND 60 to 66, mice received (m-CF3-PhSe)2 (5 mg/kg/day; i.g). The corresponding vehicle (control) groups were carried out. After, mice performed anxiety-like behavioral tests. Mice exposed only to an energy-dense diet or sporadic ethanol did not show an anxiety-like phenotype. (m-CF3-PhSe)2 abolished the anxiety-like phenotype in young mice exposed to a lifestyle model. Anxious-like mice showed increased levels of cerebral cortical NMDAR2A and 2B, NLRP3 and inflammatory markers, and decreased contents of synaptophysin, PSD95, and TRκB/BDNF/CREB signaling. (m-CF3-PhSe)2 reversed cerebral cortical neurotoxicity, the increased levels of NMDA2A and 2B, and decreased levels of synaptic plasticity-related signaling in the cerebral cortex of young mice exposed to a lifestyle model. In conclusion, the (m-CF3-PhSe)2 anxiolytic-like effect was associated with the modulation of NMDAR-mediated neurotoxicity and synaptic plasticity in the cerebral cortex of young mice exposed to the lifestyle model.

Potassium tert-Butoxide-Promoted Tandem Cyclization of Organoselenium Alkynyl Aryl Propargyl Ethers.

Base-promoted cyclization of 3-organoselenyl-methylene-2-alkynyl aryl propargyl ethers has been developed for the synthesis of 3-butylselanyl-methylene benzofurans, 3-methyl-2-alkynyl-benzofurans, and 4-iodo-benzo[b]furan-fused selenopyrans. Under potassium tert-butoxide as the base and tetrahydrofuran as the solvent, at room temperature, 3-organoselenyl-methylene-2-alkynyl aryl propargyl ethers were converted into 3-butylselanyl-methylene benzofurans via a 5-exo-dig mode. Using the same substrate, changing the solvent to dimethylsulfoxide, 3-methyl-2-alkynyl-benzofurans were selectively obtained in good yields. From 3-butylselanyl-methylene benzofurans, 4-iodo-benzo[b]furan-fused selenopyrans were prepared through a nucleophilic cyclization promoted by molecular iodine. The optimization of the reaction conditions showed that the solvents governed the regioselectivity of this cyclization and the initial formation of the dimsyl anion by the reaction of dimethylsulfoxide with potassium tert-butoxide was crucial for the 3-methyl-2-alkynyl-benzofuran preparation. We also proposed the mechanism for the formation of the products, demonstrated that the methodology can be scaled up, and showed the application of the prepared compounds as substrate in further transformations.

p-Chloro-diphenyl diselenide modulates Nrf2/Keap1 signaling and counteracts renal oxidative stress in mice exposed to repeated dexamethasone administrations.

Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p-Chloro-diphenyl diselenide ((p-ClPhSe)2) is an antioxidant organoselenium compound. The present study evaluated whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1) signaling contributes to the (p-ClPhSe)2 antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (intraperitoneal) at a dose of 2 mg/kg or its vehicle for 21 days. After that, mice were treated with (p-ClPhSe)2 (intragastric) (1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. (p-ClPhSe)2 at a dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. (p-ClPhSe)2 at doses of 5 and 10 mg/kg was effective against the increase of thiobarbituric acid reactive substances, ROS, and CP, as well as the decrease of δ-aminolevulinic acid dehydratase activity and nonprotein sulfhydryl levels induced by dexamethasone. At 5 mg/kg, (p-ClPhSe)2 reduced the renal levels of 4-OH-2-HNE and heme oxygenase (HO-1), as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that (p-ClPhSe)2 antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone.

Females are more susceptible than male mice to thermal hypernociceptive behavior induced by early-life bisphenol-A exposure: Effectiveness of diphenyl diselenide.

Humans are ubiquitously exposed to bisphenol A (BPA), one of the most used synthetic monomers for manufacturing polycarbonate plastics. BPA exposure leads to abnormal nociceptive perception and neuroinflammation in rodents. This study investigated whether diphenyl diselenide (PhSe)2, a pleiotropic selenium-containing molecule, would be effective against the hypernociceptive behavior induced by the early-life BPA exposure to mice. Three-week-old male and female Swiss mice received intragastrically BPA (5 mg/kg) from 21st to 60th postnatal day. After, the mice received by the intragastric route (PhSe)2 (1 mg/kg) once a day for seven days. After the last day of treatment, the mice performed the hot plate and tail immersion tests. The cerebral cortex samples were used to determine the levels of proteins related to apoptosis and inflammation. The results demonstrated that females were more susceptible than male mice to thermal hypernociception induced by early-life exposure to BPA. (PhSe)2 was effective against the reduction in the latency to paw and tail withdrawal induced by BPA exposure in female mice. Furthermore, (PhSe)2 restored the impairment in the levels of inflammatory proteins (COX-2, IL-1ß, and p-JNK/JNK) but not those of apoptosis in the cerebral cortex of female mice exposed to BPA. Collectively, these data showed that females were more susceptible to thermal hypernociceptive behavior induced by early-life exposure to BPA than male mice. The administration of (PhSe)2 reduced thermal hypernociceptive behavior, a sex independent effect, in BPA-exposed mice. (PhSe)2 modulated inflammatory protein levels in the cerebral cortex of female mice exposed to BPA.

Contribution of cholinergic system and Nrf2/HO-1 signaling to the anti-amnesic action of 7-fluoro-1,3-diphenylisoquinoline-1-amine in mice.

The isoquinoline 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been studied due to its multitarget properties, such as modulation of GABAergic and glutamatergic systems, antioxidant, and anti-inflammatory. This study investigated the contribution of oxidative stress, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO-1) signaling, and the cholinergic system to the anti-amnesic action of FDPI in mice. Adult male Swiss mice received FDPI for 5 days (5-25 mg/kg, i.g.); the animals received scopolamine (1 mg/kg, i.p) from day 3-5. The vehicle-control group was carried out. Afterward, mice performed object recognition tests (ORTs). Scopolamine induced amnesia and cholinergic dysfunction by increasing the acetylcholinesterase (AChE) activity and content, decreasing the muscarinic M1 receptor levels in the prefrontal cortex and hippocampus of mice. This study reveals that scopolamine altered oxidative stress parameters differently in the prefrontal cortex and hippocampus of mice. Whereas the prefrontal cortex was susceptible to oxidative stress, none of the parameters evaluated was altered in the hippocampus of scopolamine-treated mice. FDPI at doses of 10 and 25 mg/kg had an anti-amnesic effect in the ORT tests. FDPI 10 mg/kg reversed the increase in the AChE activity and content, oxidative stress parameters, and modulated Nrf2/HO-1 signaling in the prefrontal cortex of scopolamine-exposed mice. Pearson's correlation analyses reinforced the contribution of the prefrontal cortical cholinergic system, oxidative stress as well as Nrf2/HO-1 signaling in the anti-amnesic effect of FDPI. Considering FDPI effects on the hippocampus, it was effective against the cholinergic dysfunction, AChE activity and content, and M1 receptor levels, which collectively could contribute to its anti-amnesic effect.

Diphenyl diselenide regulates Nrf2/Keap-1 signaling pathway and counteracts hepatic oxidative stress induced by bisphenol A in male mice.

Bisphenol A (BPA) is a chemical toxicant that has deleterious effects on human. BPA causes oxidative stress in tissues, including the liver. Diphenyl diselenide (PhSe)2 improves the antioxidant response via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein (keap 1) pathway in macrophage cells. In the present study, we investigated whether (PhSe)2 counteracts hepatic oxidative stress induced by BPA in male and female Swiss mice. Three-week-old mice received by the intragastric (i.g.) route BPA (5 mg/kg) from 21st to 60th postnatal day (PND). At PND 61, the mice were treated with (PhSe)2 (1 mg/kg, i.g.) for seven days. Parameters of hepatic damage and oxidative stress were determined in male and female mice. The results show that BPA increased the activity of aspartate aminotransferase in female mice, and in male mice the activity of alanine aminotranseferase was increased. Male and female mice had an increase in fat mass accumulation. Male mice showed an increase in hepatic oxidative damage of proteins and a decrease in non-enzymatic (ascorbic acid and non-protein thiol) and enzymatic (superoxide dismutase) defenses, which are consistent with oxidative stress status. Male mice were more susceptible than female mice to hepatic oxidative stress induced by BPA. BPA decreased Nrf2/Keap1 protein content in male mice. (PhSe)2 reduced hepatic oxidative stress induced by BPA in male mice. Our results demonstrate that male mice were more susceptible to hepatic oxidative stress induced by BPA than female mice. (PhSe)2 regulated Nrf2/Keap-1 signaling pathway and countered hepatic oxidative stress induced by BPA in male mice.

Bisphenol A impairs the memory function and glutamatergic homeostasis in a sex-dependent manner in mice: Beneficial effects of diphenyl diselenide.

Bisphenol A (BPA) is a compound integrated in commodities, which consequently increases the human exposure to this toxicant. The deleterious effects of BPA exposure during periods of brain development have been documented mainly concerning the impairment in memory functions. Diphenyl diselenide (PhSe)2, an organoselenium compound, shows protective/restorative effects against memory deficits in experimental models. Thus, this study investigated the effects of (PhSe)2 on the memory impairments induced by BPA exposure to male and female mice and the possible involvement of glutamatergic system in these effects. Three-week-old male and female Swiss mice received BPA (5mg/kg), intragastrically, from 21st to 60th postnatal day. After, the animals were intragastrically treated with (PhSe)2 (1mg/kg) during seven days. The mice performed the behavioral memory tests and the [3H] glutamate uptake and NMDA receptor subunits (2A and 2B) analyses were carried out in the hippocampus and cerebral cortex of mice. The results demonstrated that the BPA exposure induced impairment of object recognition memory in both sexes. However, it caused impairments in spatial memory in female and in the passive avoidance memory in male mice. Besides, BPA caused a decrease in the [3H] glutamate uptake and NMDA receptor subunit levels in the cortical and hippocampal regions depending on the sex. Treatment with (PhSe)2 reversed in a sex-independent manner the behavioral impairments and molecular alterations. In conclusion, BPA had a negative effect in different memory types as well as in the glutamatergic parameters in a sex-dependent manner and (PhSe)2 treatment was effective against these alterations.