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Background: Methylmercury (MeHg) and ethylmercury (EtHg) are potent toxicants affecting the environment and human healthy. In this way, the present study aimed to investigate and compare the effects of MeHg and EtHg exposure on human peripheral blood mononuclear cells (PBMCs), which are critical components of the mammalian immune system., Methods: PBMCs were exposed to 2.5 μM MeHg or 2.5 μM EtHg. The number of cells and incubation times varied according to each assay. After exposures, the PBMCs were subjected to different evaluations, including cell viability, morphological aspects, cell cycle phases, indices of apoptosis and necrosis, reactive species (RS) production, and mitochondrial functionality., Results: PBMCs exposed to EtHg were characterized by decreased viability and size, increased granularity, RS production, and apoptotic indexes accompanied by an intensification of Sub-G1 and reduction in G0-G1 cell cycle phases. Preceding these effects, we found mitochondrial dysfunctions, namely a reduction in the electron transport system related to mitochondrial complex I. In contrast, PBMCs exposed to MeHg showed only reduced viability. By ICP-MS, we found that PBMCs treated with EtHg accumulated Hg + levels ∼1.8-fold greater than MeHg-exposed cells., Conclusions and Significance: Taken together, our findings provide important insights about mercury immunotoxicity, showing that EtHg is more immunotoxic to human PBMCs than MeHg., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: We aimed to evaluate the prevalence, clinical determinants, and consequences (falls and hospitalization) of frailty in older adults with mental illness., Design: Retrospective clinical cohort study., Setting: We collected the data in a specialized psychogeriatric ward, in Boston, USA, between July 2018 and June 2019., Participants: Two hundred and fourty-four inpatients aged 65 years old and over., Measurements: Psychiatric diagnosis was based on a multi-professional consensus meeting according to DSM-5 criteria. Frailty was assessed according to two common instruments, that is, the FRAIL questionnaire and the deficit accumulation model (aka Frailty Index [FI]). Multiple linear regression analyses were conducted to evaluate the association between frailty and sample demographics (age, female sex, and non-Caucasian ethnicity) and clinical characteristics (dementia, number of clinical diseases, current infection, number of psychotropic, and non-psychotropic medications in use). Multiple regression between frailty assessments and either falls or number of hospital admissions in the last 6 and 12 months, respectively, were analyzed and adjusted for covariates., Results: Prevalence of frailty was high, that is, 83.6% according to the FI and 55.3% according to the FRAIL questionnaire. Age, the number of clinical (somatic) diseases, and the number of non-psychotropic medications were independently associated with frailty identified by the FRAIL. Dementia, current infection, the number of clinical (somatic) diseases, and the number of non-psychotropic medications were independently associated with frailty according to the FI. Falls were significantly associated with both frailty instruments. However, we found only a significant association for the number of hospital admissions with the FI., Conclusion: Frailty is highly prevalent among geriatric psychiatry inpatients. The FRAIL questionnaire and the FI may capture different forms of frailty dimensions, being the former probably more associated with the phenotype model and the latter more associated with multimorbidity.

Background: The surgical treatment of internal haemorrhoids is yet to be fully elucidated. Rubber band ligation (RBL) and injection sclerotherapy (IS) are less invasive alternative day-case treatment options with lower morbidity than excisional haemorrhoidectomy., Aims: This was a prospective study that compared the efficacy of RBL with 3% polidocanol IS in the treatment of Grades I to III internal haemorrhoids., Patients and Methods: Sodergren haemorrhoid symptom severity (SHSS) scores of consecutive adult patients with internal haemorrhoids were calculated before and after each of three therapy sessions with RBL and IS. Outcome measures included SHSS scores after treatment, post-procedure pain and complication rates. Data were collated and analysed using SPSS version 23., Results: A total of 74 patients participated in the study with 37 patients in each treatment group. The RBL and IS groups were not statistically different in age (P = 0.506), weight (P = 0.117), height (P = 0.462), BMI (P = 0.153) and gender (P = 0.639). The mean SHSS scores for both groups before therapy (P = 0.876), at 4 weeks (P = 0.669), 8 weeks (P = 0.168) and 12 weeks (P = 0.391) after commencement of therapy were not statistically different. The SHSS scores at 12 weeks after treatment were statistically significantly lower than before treatment in both the groups (P < 0.01). The post-procedure pain score was significantly higher in the RBL than IS group after the first (P < 0.001) and second (P < 0.006) but not after the third therapy session (P = 0.501). The complication rates were low and not significantly different for the RBL and IS groups (5.7% versus 8.1%; P = 0.643)., Conclusion: The study concluded that RBL and IS are both effective and safe in the treatment of Grades I, II and III internal haemorrhoids., Competing Interests: None

Most patients with acute pancreatitis will develop edematous pancreatitis with a mild course and spontaneous resolution within several days to a few weeks. However, about 20% of patients will develop necrotizing pancreatitis, which carries a high mortality. This case report focuses on a patient with infected necrosis of the pancreas, which is managed with endoscopic transluminal debridement, a safe alternative to open surgery.

Organoselenium compounds and isoquinoline derivatives have their toxicity linked to induction of pro-oxidant situations. δ-Aminolevulinate dehydratase (δ-ALA-D) and Na + , K + -ATPase have sulfhydryl groups susceptible to oxidation. Thus, we investigated toxicological effects of 4-organoseleno-isoquinoline derivatives, cerebral monoamine oxidase B inhibitors, on rat cerebral δ-ALA-D and Na + , K + -ATPase activities and the involvement of sulfhydryl groups in vitro. Compounds substituted with fluoro (4-(4-fluorophenylseleno)-3-phenylisoquinoline), chloro (4-(4-chlorophenylseleno)-3-phenylisoquinoline) and trifluoro (4-(3-trifluoromethylphenylseleno)-3-phenylisoquinoline) at the selenium-bonded aromatic ring inhibited δ-ALA-D (IC 50 values: 78.42, 92.27, 44.98 µM) and Na + , K + -ATPase (IC 50 values: 41.36, 89.43, 50.66 µM) activities, possibly due to electronic effects induced by these groups. 3-Phenyl-4-(phenylseleno) isoquinoline (without substitution at the selenium-bonded aromatic ring) and 4-(4-methylphenylseleno)-3-phenylisoquinoline (with a methyl group substituted at the selenium-bonded aromatic ring) did not alter the activity of these enzymes. Dithiothreitol, a reducing agent, restored the enzymatic activities inhibited by 4-(4-fluorophenylseleno)-3-phenylisoquinoline, 4-(4-chlorophenylseleno)-3-phenylisoquinoline and 4-(3-trifluoromethylphenylseleno)-3-phenylisoquinoline, suggesting the involvement of sulfhydryl residues in this effect. However, the release of essential zinc seems not to be related to the δ-ALA-D inhibition by these compounds. According to these data, the effect of oral administration (300 mg/kg, intragastric) of 3-phenyl-4-(phenylseleno) isoquinoline on markers of systemic toxicity in Wistar rats was evaluated. None signs of toxicity was observed during or after treatment. This study suggests that the insertion of electron-withdrawing groups in the aromatic ring bonded to the selenium atom of isoquinolines tested increased its inhibitory effect on sulfhydryl enzymes in vitro. 3-Phenyl-4-(phenylseleno) isoquinoline, which has documented pharmacological properties, had no toxicological effects on the parameters evaluated in this study. J. Cell. Biochem. 118: 1144-1150, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Parkinson's disease is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons. Diphenyl diselenide [(PhSe) 2 ] is a compound with pharmacological proprieties, such as antidepressant and neuroprotective. Therefore, this study investigated whether (PhSe) 2 reverses motor impairment and neurochemical alterations in a model of Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) in rats. For this, male Wistar rats received 20μg/3μl of 6-OHDA or vehicle into the right striatum. Three weeks later, animals were subjected to rotational behavioral test induced by D-amphetamine and randomly divided into four groups: Sham; (PhSe) 2 ; 6-OHDA and 6-OHDA+(PhSe) 2 . The rats received (PhSe) 2 (1mg/kg/day; i.g.) or vehicle (canola oil) during 30 days. After treatment, behavioral tests were performed in order to evaluate the motor function and the ipsilateral striatal tissue was collected for immunoblotting assay. (PhSe) 2 treatment restored the normal motor behavior of 6-OHDA-infused rats in the cylinder, stepping and bridge tests, but not in the rotarod test. The 6-OHDA infusion and/or (PhSe) 2 treatment did not alter the muscle strength and spontaneous locomotion in the forelimb support and open-field tests, respectively. Additionally, striatal brain-derived neurotrophic factor (BDNF), proBDNF and tyrosine hydroxylase (TH) levels of 6-OHDA-lesioned rats were decreased, while the tropomyosin-related kinase B (TrkB) levels were increased. (PhSe) 2 treatment restored striatal proBDNF, TrkB and TH levels. Thus, (PhSe) 2 treatment reversed some motor impairment and TH levels in a 6-OHDA model of Parkinson's disease in rats, demonstrating a potential neurorestorative role. Additionally, the BDNF/TrkB signaling recovery can be involved in its neurorestorative effect., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The present study investigated whether a p,p'-methoxyl-diphenyl diselenide (MeOPhSe)2-supplemented diet causes toxicity in rats. A second aim of this study was to determine whether a 10 ppm (MeOPhSe)2-supplemented diet has hypolipidemic effect on Triton WR-1339-induced hyperlipidemia in rats. To rule out the antioxidant property of (MeOPhSe)2 in its hypolipidemic action, parameters of oxidative stress were carried out. Wistar rats were fed with 3, 10, or 30 ppm of (MeOPhSe)2-supplemented diet for 30 days. None of (MeOPhSe)2-supplemented diets caused alteration in general parameters of toxicity and lipid profile of rats. The hypolipidemic effect of 10 ppm of (MeOPhSe)2-supplemented diet on rats treated with Triton WR-1339 (400 mg/kg, intraperitoneal) was investigated. The (MeOPhSe)2-supplemented diet partially protected against the levels of total cholesterol (TC) and non-HDL-C and reduced the atherogenic index (AI) increased by Triton WR-1339 in rats. A positive correlation between TC and triglyceride levels (r = 0.679) and non-HDL-C levels (r = 0.929) and AI (r = 0.889) was demonstrated. Triton WR-1339 altered parameters of oxidative stress in livers of rats but (MeOPhSe)2-supplemented diet did not protect against these alterations. The results demonstrated that the hypolipidemic action of (MeOPhSe)2-supplemented diet is not directly related to its antioxidant property and devoid of systemic toxicity in rats at the parameters analyzed.

Isoquinolines are formed endogenously as metabolites of neurotransmitters and are studied because they have structures similar to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and selegiline, a selective inhibitor of MAO-B. This study investigated a possible in vitro inhibitory activity of new 4-organochalcogen-isoquinoline derivatives, containing sulfur 1, selenium 2 or tellurium 3 on MAO-A and B activities. Considering that the non-substituted selenoisoquinoline derivative 2 showed the best inhibitory profile (IC50 = 36.45 μM), new compounds were synthesized by adding substituents (methyl 2a, fluorine 2b, chloro 2c and trifluoromethyl 2d) to the aromatic ring bonded to the selenium atom of compound 2. All tested compounds were selective MAO-B inhibitors, although only the substituted isoquinoline derivative 2b showed IC50 lower than the concentration of 100 μM (IC50 = 82.41 μM). Compounds 2 and 2b were chosen to study the inhibitory profile. These compounds demonstrated reversible and mixed inhibition by decreasing apparent V (app) max and increasing apparent K (app) m, however the non-substituted compound 2 was a more potent inhibitor than the substituted compound 2b (K i = 7.07 and 16.30 μM). In conclusion, selenoisoquinolines 2 and 2b fit in the profile of third generation MAO inhibitors (selective and reversible), which are promising alternatives for treatment of emotional and neurodegenerative disorders.

Depression is a disorder with symptoms manifested at the psychological, behavioral and physiological levels. Monosodium glutamate (MSG) is the most widely used additive in the food industry; however, some adverse effects induced by this additive have been demonstrated in experimental animals and humans, including functional and behavioral alterations. The aim of this study was to investigate the possible antidepressant-like effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, in the depressive-like behavior induced by MSG in rats. Male and female newborn Wistar rats were divided in control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4g/kg/day) from the 1st to 5th postnatal day. At 60th day of life, animals received (PhSe)2 (10mg/kg, intragastrically) 25min before spontaneous locomotor and forced swimming tests (FST). The cerebral cortices of rats were removed to determine [(3)H] serotonin (5-HT) uptake and Na(+), K(+)-ATPase activity. A single administration of (PhSe)2 was effective against locomotor hyperactivity caused by MSG in rats. (PhSe)2 treatment protected against the increase in the immobility time and a decrease in the latency for the first episode of immobility in the FST induced by MSG. Furthermore, (PhSe)2 reduced the [(3)H] 5-HT uptake and restored Na(+), K(+)-ATPase activity altered by MSG. In the present study a single administration of (PhSe)2 elicited an antidepressant-like effect and decrease the synaptosomal [(3)H] 5-HT uptake and an increase in the Na(+), K(+)-ATPase activity in MSG-treated rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The metabolic syndrome is a group of metabolic alterations considered a worldwide public health problem. Organic selenium compounds have been reported to have many different pharmacological actions, such as anti-hypercholesterolemic and anti-hyperglycemic. The aim of this study was to evaluate the effect of p-chloro-diphenyl diselenide (p-ClPhSe)2, an organic selenium compound, in a model of obesity induced by monosodium glutamate (MSG) administration in rats. The rats were treated during the first ten postnatal days with MSG and received (p-ClPhSe)2 (10 mg/kg, intragastrically) from 45th to 51 th postnatal day. Glucose, lipid and lactate levels were determined in plasma of rats. Glycogen levels and activities of tyrosine aminotransferase, hexokinase, citrate synthase and glucose-6-phosphatase (G-6-Pase) were determined in livers of rats. Renal G-6-Pase activity was also determined. The purine content [Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate] and mitochondrial functionality in the liver were also investigated. p-(ClPhSe)2 did not alter the reduction in growth performance and in the body weight caused by MSG but reduced epididymal fat deposition of rats. p-(ClPhSe)2 restored glycemia, triglycerides, cholesterol and lactate levels as well as the glucose metabolism altered in rats treated with MSG. p-(ClPhSe)2 restored hepatic mitochondrial dysfunction and the decrease in citrate synthase activity and ATP and ADP levels caused by MSG in rats. In summary, (p-ClPhSe)2 had homeostatic effects on glucose metabolism and mitochondrial function alterations induced by MSG administration to rats.

Monosodium glutamate (MSG) is a neuroexcitatory amino acid commonly used as flavoring of foods. MSG neonatal administration to animals leads to behavioral and physiological disorders in adulthood, including increased pain sensitivity. This study aimed to investigate the effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, on nociception induced by MSG. Newborn Wistar rats received 10 subcutaneous injections of MSG at a dose of 4.0g/kg or saline (once daily). At the 60th day of life, the rats were daily treated with (PhSe)2 (1mg/kg) or vehicle (canola oil) by the intragastric route for 7 days. The behavioral tests (locomotor activity, hot plate, tail-immersion and mechanical allodynia) were carried out. Ex vivo assays were performed in samples of hippocampus to determine Na(+), K(+)-ATPase and Ca(2+)-ATPase activities, cytokine levels and [(3)H]glutamate uptake. The results demonstrated that MSG increased nociception in the hot plate test and in the mechanical allodynia stimulated by Von-Frey hair but did not alter the tail immersion test. (PhSe)2 reversed all nociceptive behaviors altered by MSG. MSG caused an increase in Na(+),K(+)-ATPase and Ca(2+)-ATPase activities and in pro-inflammatory cytokine levels and a decrease in the anti-inflammatory cytokine and in the [(3)H]glutamate uptake. (PhSe)2 was effective in reversing all alterations caused by MSG. The results indicate that (PhSe)2 had a potential antinociceptive and anti-inflammatory action in the MSG model., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Anxiety is a serious disorder with symptoms manifested at the psychological, behavioral, and physiological levels, accompanied by alterations in the serotonergic system and monoaminergic signaling. In this study, the anxiolytic-like effect of 2-phenylethynyl butyltellurium (PEBT), in three well-consolidated anxiety mouse models (light-dark test, novelty suppressed-feeding, elevated plus-maze), was investigated. The involvement of the serotonergic system, synaptosomal [(3)H] serotonin (5-HT) uptake and monoamine oxidase (MAO A and B) activities on cerebral cortices of mice, was examined. Mice received PEBT (1mg/kg, by intragastric route, i.g.) or canola oil (10 ml/kg, i.g.) 30 min before behavioral tests. The results showed that PEBT was effective in increasing the time spent by mice in the illuminated side on the light-dark box and in the open arms on the elevated plus-maze. PEBT decreased the latency to begin eating on the novelty suppressed-feeding test, indicating an anxiolytic-like effect of PEBT. Furthermore, PEBT reduced [(3)H] 5-HT uptake and selectively inhibited MAO-A activity in cerebral cortex, suggesting the involvement of the serotonergic system in the mechanism of action of this tellurium compound., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The cognitive function decline is closely related with brain changes generated by age. The ability of caffeine and exercise to prevent memory impairment has been reported in animal models and humans. The purpose of the present study was to investigate whether swimming exercise and caffeine administration enhance memory in middle-aged Wistar rats. Male Wistar rats (18months) received caffeine at a dose of 30mg/kg, 5days per week by a period of 4weeks. Animals were subjected to swimming training with a workload (3% of body weight, 20min per day for 4weeks). After 4weeks, the object recognition test (ORT) and the object location test (OLT) were performed. The results of this study demonstrated that caffeine suppressed exercise-enhanced long-term (ORT) and spatial (OLT) memory in middle-aged and this effect may be related to a decrease in hippocampal p-CREB signaling. This study also provided evidence that the effects of this protocol on memory were not accompanied by alterations in the levels of activated Akt. The [(3)H] glutamate uptake was reduced in hippocampus of rats administered with caffeine and submitted to swimming protocol., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Monosodium glutamate (MSG) has been the target of research due to its toxicological effects., Aims: We investigated the depressive- and anxiogenic-like behaviors in rats exposed to neonatal subcutaneous injection of MSG. The involvement of the serotonergic system, by measuring [(3)H] serotonin (5-HT) uptake in cerebral cortices, and the hypothalamic pituitary adrenal (HPA) axis, by determining serum adrenocorticotropic hormone (ACTH) and corticosterone levels, was also examined., Materials and Methods: Male and female newborn Wistar rats were divided into control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 5th postnatal day. The behavioral tests [spontaneous locomotor activity, contextual fear conditioning, and forced swimming test (FST)] were performed from the 60th to 64th postnatal day. MSG-treated animals showed alteration in the spontaneous locomotor activity, an increase in the number of fecal pellets and the number of animal's vocalizations and urine occurrence, and a decrease in the grooming time., Key Findings: The MSG exposure increased the immobility time in the FST and the freezing reaction in the contextual fear conditioning. Additionally, MSG treatment increased the [(3)H]5-HT uptake in the cerebral cortices of rats and induced a deregulation of HPA axis function (by increasing serum ACTH and corticosterone levels)., Significance: In conclusion MSG-treated rats are more susceptible to develop anxiogenic- and depressive-like behaviors, which could be related to a dysfunction in the serotonergic system., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The levels of circulatory inflammatory markers, including interleukin (IL) IL-1β, IL-6, tumor necrosis factor-α (TNF-α) and interferon (INF-γ), are known to increase associated to aging. Caffeine has been reported to produce many beneficial effects for health. Exercise is considered to be a safe medicine to attenuate inflammation and cellular senescence. The purpose of the present study was to investigate the effects of a moderate-intensity swimming exercise (3 % of body weight, 20 min per day, 4 weeks) and sub-chronic supplementation with caffeine (30 mg/kg, 4 weeks) on the serum cytokine levels in middle-aged (18 months) Wistar rats. The effects of swimming exercise and caffeine on oxidative stress in muscle and liver of middle-aged rats were also investigated. The two-way ANOVA of pro-inflammatory cytokine levels demonstrated a significant exercise x caffeine interaction for IL-1β (F (1, 16) = 9.5772; p = 0.0069), IL-6 (F (1, 16) = 8.0463; p = 0.0119) and INF-γ (F (1, 16) = 15.078; p = 0.0013). The two-way ANOVA of TNF-α levels revealed a significant exercise × caffeine interaction (F (1, 16) = 9.6881; p = 0.00670). Swimming exercise and caffeine supplementation increased the ratio of reduced glutathione/oxidized glutathione in the rat liver and gastrocnemius muscle. Hepatic and renal markers of damage were not modified. In conclusion, a moderate-intensity swimming exercise protocol and caffeine supplementation induced positive adaptations in modulating cytokine levels without causing oxidative stress in muscle and liver of middle-aged rats.

Parkinson's disease (PD) patients, in addition to motor dysfunction, also present alterations in pain sensation. The present study characterized the antinociceptive effects of diphenyl diselenide ((PhSe)2) in a model of nociception induced by unilateral, intrastriatal 6-hydroxydopamine (6-OHDA) injection in rats. Male adult Wistar rats received 20 μg/3 μl of 6-OHDA (in saline solution containing 0.02 % of ascorbic acid) or 3 μl of vehicle into the right striatum (1.0 mm anterior, 3.0 mm lateral, and 5.0 mm ventral-with respect to the bregma). Thirty days after injection, rats received (PhSe)2 intragastrically at a dose of 10 mg/kg 1 h before behavioral tests (von Frey hairs, hot plate, tail immersion, formalin, and open field). Our results demonstrated that 6-OHDA injection to rats augmented the response frequency of von Frey hairs (VHF) stimulation, besides reducing the thermal withdrawal latency in the hot plate test. Importantly, the (PhSe)2 treatment decreased the mechanical allodynia measured by the response frequency of VHF stimulation and diminished the thermal nociception in the hot plate test in 6-OHDA-injected rats. In conclusion, these results revealed that a single oral administration of (PhSe)2 1 h prior to the accomplishment of the behavioral tests was effective to attenuate the increased mechanical and thermal nociception caused by a single intrastriatal 6-OHDA injection to rats. Furthermore, other clarifying studies are warranted to improve the evidence bases for future clinical use of (PhSe)2 as a new alternative therapy for the treatment of painful symptoms associated to PD.

This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17β-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This study was designed to investigate the molecular effects of diphenyl diselenide ((PhSe)₂) on cholesterol metabolism in HepG2 cell line in a dose-dependent manner. The protein levels of both total and phosphorylated 3- hydroxy-3-methylglutaryl coenzyme A reductase (HMGR and P-HMGR), low-density lipoprotein receptors (LDLr) and the proteins involved in their regulatory network were analyzed by Western blotting, and the effect of (PhSe)₂ on HMGR activity was measured. Additionally, we also evaluated the effects of this compound on glucose transporter type 4 (GLUT4) translocation using fluorescence microscopy in L6 skeletal muscle cell line. Results demonstrated that (PhSe)₂ increased P-HMGR, HMGR, and LDLr protein levels as well as simvastatin treatment, which was used as positive control, without directly affecting HMGR activity. We observed that both long- and short-term HMGR regulation mechanisms are involved in the effects of (PhSe)₂, as this compound was able to augment Sterol regulatory element binding proteins (SREBP)-1 and Insulin induced gene (Insig)1 protein levels, and to increase AMP activated kinase (AMPK) activation state. We also found that, in L6 skeletal myotubes, 10 μM (PhSe)₂ increases GLUT4 translocation through AMPK activation. Taken together, these findings suggest that (PhSe)₂ can modulate the expression of some proteins involved in cholesterol and glucose cell metabolism.

A copper-catalyzed cyclization of (ortho-alkynyl)benzaldimines with diorganoyl dichalcogenides allowed the synthesis of 4-organochalcogen isoquinolines, whereas the presence of base in the reaction medium inhibited the product formation producing the undesirable isoquinoline without the organochalcogen atom at the 4-position. The cyclization reaction was carried out by using CuI (20 %) as a catalyst with diorganoyl dichalcogenides (1.5 equiv) in the presence of DMF at 100 °C. Furthermore, the reaction did not require an argon atmosphere and was carried out in an open flask. The cyclization reaction tolerated a variety of functional groups both in ortho-alkynylbenzaldimines and diorganoyl dichalcogenides, such as trifluoromethyl, chloro, fluorine, and methoxyl, to give the six-membered heterocyclic ring exclusively through a 6-endo-dig cyclization process. The organochalcogen group present at the 4-position of the isoquinoline ring was further subjected to a selective chalcogen-lithium exchange reaction followed by the addition of aldehydes to afford the desired secondary alcohols in good yields. The obtained isoquinolines also proved to be suitable substrates for the Suzuki and Sonogashira coupling conditions affording the corresponding products through C-C bond formation., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Køppe's proposition of four layers in theoretical building are used here in the exploration of a specific case of eclectic combination, the use of Piagetian and Vygotskian general approaches to the analysis of proportional reasoning as a cognitive mathematical ability. It is proposed here that the eclectic consideration of these contributions depends on the consideration of their specificity, in the sense that they highlight different aspects of the phenomenon under scrutiny, and also on the consideration of the coherence between this eclectic convergence and premises in terms of schools of thought under which each contribution is framed. We conclude proposing in accordance to S. Køppe's proposal that eclecticism can be valuable and heuristic in theory development, but this contribution will depend largely on the effort in establishing careful relations between the four layers of theory-building.

Ovarian hormone loss contributes to cognitive decline in postmenopausal women. Studies have demonstrated a positive role of the level of the element selenium in cognitive performance. The present study investigated the effects of the synthetic organoselenium compound diphenyl diselenide (PhSe)₂ on cognitive functions in ovariectomized rats. Ninety-day-old female Wistar rats were subjected to ovariectomy (OVX) or Sham operation. One week after surgery, rats were orally treated with (PhSe)₂ (5 mg/kg, per oral route) or vehicle once a day for 30 days. Next, the rats were evaluated in behavioral tests [Morris water maze (MWM) and open-field tests] and biochemical [cerebral acetylcholinesterase (AChE)] analyses were carried out. In MWM probe trial, (PhSe)₂ decreased the latency to reach the platform location and increased the number of crossings over the platform location, protecting against cognitive impairment induced by OVX. Furthermore, (PhSe)₂ prevented the stimulation of AChE activity caused by OVX. In conclusion, the present study showed a cognition-enhancing effect of (PhSe)₂ treatment for 30 days in ovariectomized rats in the MWM test, which could be related to its ability to prevent the stimulation of AChE activity caused by OVX in rats. These findings suggest that (PhSe)₂ might have a promising role in preventing the cognitive decline related to menopause.

Aims: Adrenomedullin (AM) is a peptide that displays cardiovascular protective activity. We investigated the effects of chronic ethanol consumption on arterial blood pressure, vascular reactivity to AM and the expression of AM system components in the rat mesenteric arterial bed (MAB)., Methods: Male Wistar rats were treated with ethanol (20% vol/vol) for 6 weeks. Systolic, diastolic and mean arterial blood pressure were monitored in conscious rats. Vascular reactivity experiments were performed on isolated rat MAB. Matrix metalloproteinase-2 (MMP-2) levels were determined by gelatin zymography. Nitrite and nitrate generation were measured by chemiluminescence. Protein and mRNA levels of pre-pro-AM, CRLR (calcitonin receptor-like receptor) and RAMP1, 2 and 3 (receptor activity-modifying proteins) were assessed by western blot and quantitative real-time polymerase chain reaction, respectively., Results: Ethanol consumption induced hypertension and decreased the relaxation induced by AM and acetylcholine in endothelium-intact rat MAB. Phenylephrine-induced contraction was increased in endothelium-intact MAB from ethanol-treated rats. Ethanol consumption did not alter basal levels of nitrate and nitrite, nor did it affect the expression of MMP-2 or the net MMP activity in the rat MAB. Ethanol consumption increased mRNA levels of pre-pro-AM and protein levels of AM in the rat MAB. Finally, no differences in protein levels or mRNA of CRLR and RAMP1, 2 and 3 were observed after treatment with ethanol., Conclusion: Our study demonstrates that ethanol consumption increases blood pressure and the expression of AM in the vasculature and reduces the relaxation induced by this peptide in the rat MAB.

We investigated the role of reactive oxygen species (ROS) and nitric oxide (NO) in ethanol-induced relaxation. Vascular reactivity experiments showed that ethanol (0.03-200 mmol/L) induced relaxation in endothelium-intact and denuded rat aortic rings isolated from male Wistar rats. Pre-incubation of intact or denuded rings with l-NAME (non selective NOS inhibitor, 100 μmol/L), 7-nitroindazole (selective nNOS inhibitor, 100 μmol/L), ODQ (selective inhibitor of guanylyl cyclase enzyme, 1 μmol/L), glibenclamide (selective blocker of ATP-sensitive K(+) channels, 3 μmol/L) and 4-aminopyridine (selective blocker of voltage-dependent K(+) channels, 4-AP, 1 mmol/L) reduced ethanol-induced relaxation. Similarly, tiron (superoxide anion (O(2)(-)) scavenger, 1 mmol/L) and catalase (hydrogen peroxide (H(2)O(2)) scavenger, 300 U/mL) reduced ethanol-induced relaxation to a similar extent in both endothelium-intact and denuded rings. Finally, prodifen (non-selective cytochrome P450 enzymes inhibitor, 10 μmol/L) and 4-methylpyrazole (selective alcohol dehydrogenase inhibitor, 10 μmol/L) reduced ethanol-induced relaxation. In cultured aortic vascular smooth muscle cells (VSMCs), ethanol stimulated generation of NO, which was significantly inhibited by l-NAME. In endothelial cells, flow cytometry studies showed that ethanol increased cytosolic Ca(2+) concentration ([Ca(2+)]c), O(2)(-) and cytosolic NO concentration ([NO]c). Tiron inhibited ethanol-induced increase in [Ca(2+)]c and [NO]c. The major new finding of this work is that ethanol induces relaxation via redox-sensitive and NO-cGMP-dependent pathways through direct effects on ROS production and NO signaling. These findings identify putative molecular mechanisms whereby ethanol, at pharmacological concentrations, influences vascular reactivity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Adrenomedullin (AM) is a peptide that displays cardiovascular protective activity. We investigated the effects of chronic ethanol consumption on vascular reactivity to AM and the expression of AM system components in the rat aorta. Male Wistar rats were treated with ethanol (20% vol/vol) for 6 weeks. Vascular reactivity experiments were performed in the isolated rat aorta. Metalloproteinase-2 (MMP-2) levels were determined by gelatin zymography. Nitrite and nitrate generation was measured by chemiluminescence. Protein and mRNA levels of pre-pro-AM, calcitonin receptor-like receptor (CRLR) and RAMP1, 2, and 3 (receptor-activity-modifying proteins) were assessed by western blot and quantitative real-time polymerase chain reaction, respectively. Ethanol intake reduced AM-induced relaxation in endothelium-intact rat aortas, whereas calcitonin gene-related peptide-, acetylcholine-, and sodium nitroprusside-induced relaxation were not affected by ethanol intake. N(G)-nitro-l-arginine-methyl-ester (l-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and tetraethylammonium reduced AM-induced relaxation in aortic rings from both control and ethanol-treated rats. Ethanol consumption did not alter basal levels of nitrate and nitrite, nor did it affect the expression of MMP-2 in the rat aorta. Ethanol consumption increased mRNA levels of pre-pro-AM and RAMP1. Protein levels of AM, CRLR, and RAMP1, 2, and 3 were not affected by ethanol consumption. The major findings of the present study are that ethanol consumption reduces the vascular relaxation induced by AM and changes the mRNA expression of the components of the AM system in the vasculature. This response could be one of the mechanisms by which ethanol predisposes individuals to vascular dysfunction and hypertension., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The present study evaluated if repeated malathion administration would cause behavioral impairment in rat pups. Na+K+ ATPase and acetylcholinesterase (AChE) activities were investigated in brains of rat pups. Malathion was administered (100 or 200 mg/kg) orally (p.o.), once a day for four consecutive days. Rat pups were submitted to behavioral tests on the 5th day, 24 h after the last malathion administration. Malathion at the dose of 200 mg/kg caused a significant increase in the negative geotaxis latency and a decrease in the rotarod latency of rat pups. Rat pups exposed to malathion at both doses showed a significant decrease in the forelimb support latency and an inhibition of brain AChE activity. Repeated exposure of rat pups to malathion caused a decrease in motor coordination, vestibular function and muscular strength/coordination. The brain activity of AChE is involved in the behavioral alterations caused by malathion in rat pups., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Alzheimer disease, a form of dementia in which loss of memory is the first and the most characteristic symptom, is frequently accompanied by affective symptoms. Intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) to rodents has been reported as an appropriate model for sporadic dementia of Alzheimer's type (SDAT), characterized by a progressive impairment of memory. However, very little or nothing is known about non-cognitive behavioral effects (e.g. anxiety-like behavior) in the STZ model. In this context, the hypothesis to be tested in this study is if i.c.v. injection of STZ (0.1mg/site, 4 μl) induces anxiety-like behavior in mice. The findings of the present study indicate that i.c.v. injection of STZ in mice resulted in an anxiogenic behavior. Mice spent less time and decreased the number of entries in the open arms in the elevated plus-maze task. The latency to the first entry in the dark side in the light-dark box task was reduced by STZ. No difference was found in anxiety-like behavior between early and late time (i.e., at 7 and 21 days after infusion, respectively). These results indicate that i.c.v. STZ injection caused an anxiogenic behavior in mice., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The present work investigates the mechanisms involved in the vasorelaxant effect of ent-16α-methoxykauran-19-oic acid (KA-OCH3), a semi-synthetic derivative obtained from the kaurane-type diterpene ent-kaur-16-en-19-oic acid (kaurenoic acid). Vascular reactivity experiments were performed in aortic rings isolated from male Wistar rats using standard muscle bath procedures. The cytosolic calcium concentration ([Ca2+]c) was measured by confocal microscopy using the fluorescent probe Fluo-3 AM. Blood pressure measurements were performed in conscious rats. KA-OCH3 (10, 50 and 100 μmol/l) inhibited phenylephrine-induced contraction in either endothelium-intact or endothelium-denuded rat aortic rings. KA-OCH3 also reduced CaCl2-induced contraction in a Ca2+-free solution containing KCl (30 mmol/l) or phenylephrine (0.1 μmol/l). KA-OCH3 (0.1-300 μmol/l) concentration-dependently relaxed endothelium-intact and endothelium-denuded aortas pre-contracted with either phenylephrine or KCl, to a greater extent than kaurenoic acid. Moreover, a Ca2+ mobilisation study showed that KA-OCH3 (100 μmol/l) inhibited the increase in Ca2+ concentration in smooth muscle and endothelial cells induced by phenylephrine or KCl. Pre-incubation of intact or denuded aortic rings with NG-nitro-L-arginine methyl ester (L-NAME, 100 μmol/l), 7-nitroindazole (100 μmol/l), wortmannin (0.5 μmol/l) and 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 μmol/l) produced a rightward displacement of the KA-OCH3 concentration-response curve. Intravenous administration of KA-OCH3 (1-10 mg/kg) reduced mean arterial blood pressure in normotensive rats. Collectively, our results show that KA-OCH3 induces vascular relaxation and hypotension. The mechanisms underlying the cardiovascular actions of KA-OCH3 involve blockade of Ca2+ influx and activation of the NO-cGMP pathway., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objectives: Ovarian hormone decline after menopause is linked to many pathophysiological reactions. Female rats submitted to ovariectomy are employed as a model of post-menopausal condition. This study investigated the effects of diphenyl diselenide (PhSe)(2) on body weight gain, intra-abdominal fat deposition, plasma lipid profile and hepatic oxidative stress in ovariectomized rats., Methods: Female adult Wistar rats were ovariectomized (OVX rats) or sham-operated and divided into four groups: (i) sham-operated, (ii) (PhSe)(2), (iii) OVX and (iv) OVX + (PhSe)(2). (PhSe)(2) (5 mg/kg; 5 ml/kg, p.o.) was administered once a day for 30 days to groups (ii) and (iv). After that, rats were anaesthetized for blood sample gathering and submitted to euthanasia., Key Findings: (PhSe)(2) (5 mg/kg) was effective in preventing the rise in body weight gain and intra-abdominal fat deposition induced in OVX rats. Although (PhSe)(2) was not effective in avoiding the increase in plasma total cholesterol and non-HDL levels induced in OVX rats, (PhSe)(2) reduced plasma triglycerides and augmented HDL levels in OVX rats. (PhSe)(2) also increased hepatic ascorbic acid levels, reduced glutathione content, glutathione S-transferase activity and restored catalase activity in liver of OVX rats., Conclusions: These findings suggest that (PhSe)(2) could be a promising alternative to minimize menopause related symptoms., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

The present study investigated whether the antioxidant activity of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)] is involved in its protective effect against cognitive impairment induced by streptozotocin (STZ) in a model of sporadic dementia of Alzheimer's type (SDAT). Swiss mice were treated with STZ or vehicle [2 µl of 2·5 mg ml(-1) solution; intracerebroventricularly (i.c.v.)] twice, 48 h apart. (MeOPhSe)(2) (25 mg kg(-1)) or vehicle was orally administered 30 min prior to each STZ treatment. Neuroprotector effect of (MeOPhSe)(2) on the behavioral performance of mice on spatial recognition memory consolidation was investigated in the Y-maze test. After that, mouse brains were removed for measuring antioxidant parameters. (MeOPhSe)(2) protected against the impairment in learning and memory caused by i.c.v. administration of STZ in mice. (MeOPhSe)(2) protected against the increase in reactive species and the reduction of glutathione levels, as well as, the increase in superoxide dismutase and glutathione S-transferase activities caused by STZ in whole brain. These results suggest that antioxidant property is involved, at least in part, in the neuroprotective effect of (MeOPhSe)(2) on SDAT induced by STZ in mice., (Copyright © 2011 John Wiley & Sons, Ltd.)

Design and synthesis of organoselenium compounds with high thiol peroxidase (TPx) and low thiol oxidase (TOx) activities have been a difficult task and remains a synthetic-activity relationship dilemma. In this regard we are reporting for the first time a detail experimental data (both in vitro and in vivo) about the anti-oxidant and toxicological profile of an Imine (-N) containing organoselenium compound (Compound A). The TPx activity of Compound A was significantly higher than diphenyl diselenide (DPDS). Both Compound A and DPDS protected sodium nitropruside (SNP) induced thiobarbituric acid reactive species (TBARS) production in rats tissue homogenate with significantly higher activity observed for Compound A than DPDS (p<0.05). The Compound A also exhibited strong antioxidant activity in the DPPH and ABTS radical scavenging assays. This study reveals that an imine group close to selenium atom drastically enhances the catalytic activities in the aromatic thiol (PhSH) assay systems. The oxidation of biologically significant thiols reflects the toxicity of the compounds. However, the present data showed that treatment with Compound A at 0, 10, 25 or 50mg/kg was not associated with mortality or body weight loss. Similarly it did not inhibit α-ALA-D and Na(+1)/K(+1) ATPase (sulfhydryl group containing enzymes) activities after acute oral treatment; rather it enhanced non-protein thiols (NPSH) concentration. The Compound A did not cause any oxidative stress as measured by TBARS production in rat's tissue preparation. Our data also indicate that exposure to Compound A did not affect plasma transaminase activities or levels of urea and creatinine in rats. Ascorbic acid is always considered a marker of oxidative stress and the reduction of its content may indicate an increase in oxidative stress. Treatment with Compound A did not alter Ascorbic acid levels in rats. The conducted in vitro and in vivo tests show the versatile therapeutic potential of this compound in the area of free radical induced damages, will undoubtedly enhance our understanding of the mechanism of model compounds and may ultimately yield insights that result in improved GPx mimics., (2011 Elsevier Ireland Ltd. All rights reserved.)

The present study was designed to investigate the possible neuroprotective effect of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)] in a model of sporadic dementia of Alzheimer's type (SDAT) induced by intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) in mice. Mice were divided into four groups: (I) control, (II) (MeOPhSe)(2), (III) STZ, and (IV) (MeOPhSe)(2)+STZ. Mice were exposed to (MeOPhSe)(2) (25mg/kg, by gavage) and STZ (2mul of 2.5mg/ml solution; i.c.v.) or vehicles. 48 after that the exposure was repeated. Learning and memory were assessed with the step-down-type passive-avoidance (SDPA) and Morris water-maze (MWM) tests at the days 5-6 and 6-9, respectively. At the end of the experimental protocol animals were euthanized and cerebral cortex was removed for acetylcholinesterase (AChE) activity assay. Our results confirmed that i.c.v. STZ caused learning and memory deficits in mice, which were verified using the MWM and SDPA tasks. Furthermore, this study showed that AChE activity was increased in mice that received i.c.v. STZ. The most important findings of the present study are that (MeOPhSe)(2) was able to reverse the learning and memory impairments induced by STZ, and to protect against the increase in AChE activity. All these findings support the neuroprotective role of (MeOPhSe)(2) in a mice model of SDAT induced by i.c.v. STZ., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: A significant association between the trace element selenium and hypercholesterolaemia has been reported. This study was designed to investigate a potential hypolipidaemic effect of diphenyl diselenide ((PhSe)(2)) in Triton WR-1339-induced hyperlipidaemia in mice., Methods: Triton was administered intraperitoneally (400 mg/kg) to overnight-fasted mice to develop acute hyperlipidaemia. (PhSe)(2) was administered orally (10 mg/kg) 30 min before Triton. At 24 h after Triton injection, blood samples were collected to measure plasma lipid levels. The hepatic thiobarbituric acid reactive substances and ascorbic acid levels as well as catalase and glutathione peroxidase activity were recorded., Key Findings: (PhSe)(2) administration significantly lowered total cholesterol, non-high-density lipoprotein-cholesterol and triglycerides, whilst it increased high-density lipoprotein-cholesterol levels in plasma of hyperlipidaemic mice. Neither oxidative stress nor the antioxidant effect of (PhSe)(2) was observed in the mouse liver in this experimental protocol., Conclusions: These findings indicated that (PhSe)(2) was able to lower plasma lipid concentrations. Further studies are needed to elucidate the exact mechanism by which (PhSe)(2) exerted its hypolipidaemic effect in the management of hyperlipidaemia and atherosclerosis.

We present here our results of the efficient copper-catalyzed cyclizations of chalcogenoenynes and establish a route to obtain 3-substituted chalcogenophenes in good to excellent yields. In addition, the obtained chalcogenophenes were readily transformed to more complex products using the palladium-catalyzed cross-coupling reactions with boronic acids to give Suzuki-type products in good yields.