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Hypothyroidism is known to affect memory consolidation, and our prior research highlighted the potential of chrysin as a therapeutic agent to restore cognitive function. The present study aimed to investigate the action mechanism of chrysin on memory deficits in hypothyroid in C57BL/6 female mice. We assessed cognitive flexibility, declarative, working, and aversive memories while analyzing the BDNF/TrkB/AKT/Creb neuroplasticity signaling pathway and synaptic function in the hippocampus and prefrontal cortex. To induce hypothyroidism, mice were exposed to 0.1 % methimazole (MTZ) in the drinking water for 31 days. After confirming low thyroid hormones levels, the mice received either vehicle or chrysin (20 mg/kg) intragastrically once a day for 28 consecutive days. Memory tests were conducted in two separate experiments (experiment 1: Y-maze and reverse Morris water maze; experiment 2: object recognition task and step-down latency), ensuring no memories overlap. Following the tests, the brain samples were collected to analyses ex vivo. Hypothyroid mice exhibited deficits in cognitive flexibility and various memory types, along with altered protein expression related to the BDNF/TrkB/Creb signaling pathway and increased AKT levels in hippocampus and prefrontal cortex. Chrysin treatment effectively reversed these memory deficits, restored cognitive flexibility, and improved protein levels. Our findings suggest that hypothyroidism impairs cognitive flexibility and memory through the BDNF/TrkB/AKT/Creb pathway, which chrysin modulates, operating as a neuroprotector in hypothyroidism. This research sheds light on the potential therapeutic benefits of chrysin for memory-related issues in hypothyroidism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Amphetamine (AMPH) abuse represents a major global public health issue, highlighting the urgent need for effective therapeutic interventions to manage addiction caused by this psychostimulant. This study aimed to assess the potential of m-trifluoromethyl-diphenyldiselenide [(m-CF 3 -PhSe) 2 ] in preventing the addictive effects induced by AMPH through targeting dopamine metabolism proteins. (m-CF 3 -PhSe) 2 is of interest due to its demonstrated efficacy in mitigating opioid abuse, establishing it as a promising candidate for addiction treatment research. Initially, in silico studies examined the affinity of AMPH and (m-CF 3 -PhSe) 2 for dopamine 1, 2, and 3 receptors (D1R, D2R, D3R), and dopamine transporter (DAT). In our experimental design, male Wistar rats were divided into four groups: I) Control; II) (m-CF 3 -PhSe) 2 ; III) AMPH; IV) (m-CF 3 -PhSe) 2  + AMPH. Animals were administered (m-CF 3 -PhSe) 2 (0.1 mg/kg, by gavage) or canola oil (vehicle) 30 min before AMPH (4.0 mg/kg, i.p.) administration. Drug administration occurred for 8 days in the conditioned place preference (CPP) paradigm. Twenty-four hours after the last CPP conditioning section, preference for the drug-compartment was assessed, with anxiety-related effects and working memory were evaluated using the Y-maze test. Finally, animals were euthanized for striatal dissection to quantify D1R, D2R, D3R, and DAT levels in western blot. In silico findings suggest that (m-CF 3 -PhSe) 2 may prevent AMPH activation in DAT, interacting with Asp46 and Phe319, preventing possible addictive effects of AMPH in DAT. In vivo results showed that (m-CF 3 -PhSe) 2 attenuated AMPH effects, reducing preference for the drug-compartment in CPP test. Furthermore, (m-CF 3 -PhSe) 2 prevented AMPH-induced anxiogenic effects in the elevated plus maze (EPM) test, similarly to light/dark test. No differences in locomotion or working memory were observed among the experimental groups in the Y-maze test. Ex vivo western blot analyses of the entire striatum indicates that (m-CF 3 -PhSe) 2 prevented the AMPH-induced increase in D1R levels and decrease in D2R and DAT levels, with no changes in D3R levels. Overall, our study suggests that (m-CF 3 -PhSe) 2 may interact with DAT sites similarly to AMPH, reducing drug-compartment preference and anxiogenic behaviors while maintaining dopaminergic metabolism proteins in the striatum, a key region involved in the onset and perpetuation of addiction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Stress is triggered by a threatening event that alters the regulation of emotion, behavior, and cognition. The effects of stress on memory in animal models are well-documented. Firstly, this study aimed to determine whether the repeated forced swim stress (FSS) protocol induces memory impairment comparable to single prolonged stress (SPS) in the Y-maze test. The second objective was to evaluate whether (p-ClPhSe) 2 pretreatment mitigates stress-associated memory impairment and hippocampal glutamatergic neurotransmission in FSS-exposed mice. Mice subjected to FSS and SPS protocols reduced time spent in the novel arm of the Y-maze test compared to the control group, with no observed changes in locomotor or exploratory behavior. (p-ClPhSe) 2 was administered to mice at a dose of 5 mg/kg, 30 min before the first forced swimming session on days 1 and 2. Mice underwent a Y-maze test, after which they were euthanized, and hippocampal samples were collected. (p-ClPhSe) 2 pretreatment protected against the reduction in time spent in the novel arm by mice subjected to FSS. Repeated FSS exposure increased hippocampal protein levels of NMDAR subunits 2A, 2B, and EAAT1 compared to controls. (p-ClPhSe) 2 pretreatment prevented this increase. In conclusion, (p-ClPhSe) 2 mitigated stress-induced memory impairment in FSS-exposed mice, normalizing hippocampal NMDAR 2A, 2B, and EAAT1 protein levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Stress exposure can lead to post-traumatic stress disorder (PTSD) in male and female rats. Social-Single Prolonged Stress (SPS) protocol has been considered a potential PTSD model. This study aimed to pharmacologically validate the Social-SPS as a PTSD model in male and female rats. Male and female Wistar rats (60-day-old) were exposed to Social-SPS protocol and treated with fluoxetine (10 mg/Kg) or saline solution intraperitoneally 24 h before euthanasia. Two cohorts of animals were used; for cohort 1, male and female rats were still undisturbed until day 7 post-Social-SPS exposure, underwent locomotor and conditioned fear behaviors, and were euthanized on day 9. Animals of cohort 2 were subjected to the same protocol but were re-exposed to contextual fear behavior on day 14. Results showed that fluoxetine-treated rats gained less body weight than control and Social-SPS in both sexes. Social-SPS effectively increased the freezing time in male and female rats on day eight but not on day fourteen. Fluoxetine blocked the increase of freezing in male and female rats on day 8. Different mechanisms for fear behavior were observed in males, such as Social-SPS increased levels of glucocorticoid receptors and Beclin-1 in the amygdala. Social-SPS was shown to increase the levels of NMDA2A, GluR-1, PSD-95, and CAMKII in the amygdala of female rats. No alterations were observed in the amygdala of rats on day fourteen. The study revealed that Social-SPS is a potential PTSD protocol applicable to both male and female rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Diorganyl diselenides have emerged as privileged structures because they are easy to prepare, have distinct reactivity, and have broad biological activity. They have also been used in the synthesis of natural products as an electrophile in the organoselenylation of aromatic systems and peptides, reductions of alkenes, and nucleophilic substitution. This review summarizes the advancements in methods for the transformations promoted by diorganyl diselenides in the main functions of organic chemistry. Parallel, it will also describe the main findings on pharmacology and toxicology of diorganyl diselenides, emphasizing anti-inflammatory, hypoglycemic, chemotherapeutic, and antimicrobial activities. Therefore, an examination detailing the reactivity and biological characteristics of diorganyl diselenides provides valuable insights for academic researchers and industrial professionals., (© 2024 The Chemical Society of Japan and Wiley-VCH GmbH.)

This study evaluated the effects of topically applied hydrogels (HG) containing nanoencapsulated indol-3-carbinol (I3C) and its free form in a rat model of skin wounds. Formulations were topically applied twice a day for five days to the wounds. On days 1, 3, and 6, the wound area was measured to verify the % of regression. On the sixth day, the animals were euthanized for the analysis of the inflammatory and oxidative profile in wounds. The nanocapsules (NC) exhibited physicochemical characteristics compatible with this kind of suspension. After five hours of exposure to ultraviolet C, more than 78% of I3C content in the suspensions was still observed. The NC-I3C did not modify the physicochemical characteristics of HG when compared to the HG base. In the in vivo study, an increase in the size of the wound was observed on the 3rd experimental day, which was lower in the treated groups (mainly in HG-NC-I3C) compared to the control. On the 6th day, HG-I3C, HG-NC-B, and HG-NC-I3C showed lower regression of the wound compared to the control. Additionally, HG-NC-I3C exhibited an anti-inflammatory effect (as observed by decreased levels of interleukin-1B and myeloperoxidase), reduced oxidative damage (by decreased reactive species, lipid peroxidation, and protein carbonylation levels), and increased antioxidant defense (by improved catalase activity and vitamin C levels) compared to the control. The current study showed more satisfactory results in the HG-NC-I3C group than in the free form of I3C in decreasing acute inflammation and oxidative damage in wounds.

Eating diets high in salt has been associated with alterations in the immune system and the potential development of neuropsychiatric disorders. This area of research shows promise, but there is currently a limited amount of research on this topic. The present study investigated whether a high salt diet (HSD) affects anhedonia and stress-coping response behaviors in young male and female Wistar rats. In this study, male and female Wistar rats were fed an HSD (8 % NaCl w/w) from weaning to post-natal day (PND) 64. From PND 60 to 64, the rats underwent a spontaneous locomotor activity test (SLA), sucrose splash test (SST), sucrose preference test (SPT), and forced swim test (FST), followed by euthanasia at PND 65. Male and female rats consuming the HSD exhibited an increase in water intake compared to the corresponding control diet (CD) groups. Male rats had lower body weight despite having similar food intakes compared to the CD group. Male rats displayed an active stress-coping behavior in the FST, characterized by increased mobility. Additionally, HSD-fed males exhibited a greater preference for sucrose solution in the SPT. However, no effect of diet and sex were detected in the SST and the SLA, and hypothalamic levels of leptin and ghrelin receptors. On the other hand, female rats were less susceptible to the experimental conditions applied in this protocol than males., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT 2A , 5-HT 3 , H 1 , NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe) 2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe) 2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe) 2 effects were also investigated. Our results demonstrate that (p-ClPhSe) 2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe) 2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe) 2 per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe) 2 . In conclusion, (p-ClPhSe) 2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aspartame (ASP) is a common sweetener, but studies show it can harm the nervous system, causing learning and memory deficits. β-caryophyllene (BCP), a natural compound found in foods, including bread, coffee, alcoholic beverages, and spices, has already described as a neuroprotector agent. Remarkably, ASP and BCP are commonly consumed, including in the same meal. Therefore, considering that (a) the BCP displays plenty of beneficial effects; (b) the ASP toxicity; and (c) that they can be consumed in the same meal, this study sought to investigate if the BCP would mitigate the memory impairment induced by ASP in rats and investigate the involvement of the brain-derived neurotrophic factor (BDNF)/ tropomyosin receptor kinase B (TrKB) signaling pathway and acetylcholinesterase (AChE) activity. Young male Wistar rats received ASP (75 mg/kg; i.g.) and/or BCP (100 mg/kg; i.p.) once daily, for 14 days. At the end of the treatment, the animals were evaluated in the open field and object recognition tests. The cerebral cortex and hippocampus samples were collected for biochemical and molecular analyses. Results showed that the BCP effectively protected against the cognitive damage caused by ASP in short and long-term memories. In addition, BCP mitigated the increase in AChE activity caused by ASP. Molecular insights revealed augmented BDNF and TrKB levels in the hippocampus of rats treated with BCP, indicating greater activation of this pathway. In conclusion, BCP protected against ASP-induced memory impairment. AChE activity and the BDNF/TrkB signaling pathway seem to be potential targets of BCP modulatory role in this study., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Tamoxifen (TAM), a Selective Estrogen Receptor Modulator (SERM), is commonly used to treat and prevent breast cancer. Memory impairment has been noticed in patients who experience hormone therapy in the case of TAM and other SERMs. Animal studies that mimic the TAM longer exposure effects are needed to better elucidate the adverse effects of continuous treatment in humans. This study evaluated the effects of TAM subchronic administration on the memory performance and hippocampal neural plasticity of intact female Wistar rats. Animals were treated intragastrically with TAM (0.25 and 2.5 mg/kg) for 59 days. The rats were subjected to the Object Location Test (OLT) and Object Recognition Test (ORT) to evaluate memory performance. After euthanasia, the hippocampus samples were excised and the protein levels of the BDNF/ERK/Akt/CREB pathway were evaluated. The rat's locomotor activity and hippocampal TrkB levels were similar among the experimental groups. TAM at both doses reduced the memory performance of female rats in the OLT and short-term memory of ORT, and impaired hippocampal levels of mBDNF, proBDNF, and pCREB/CREB. TAM only at the dose of 2.5 mg/kg reduced the memory performance of rats in the long-term memory of ORT and hippocampal pERK/ERK and pAkt/Akt ratios. TAM subchronic administration induced amnesic effects and modulated the hippocampal BDNF/ERK/Akt/CREB pathway in intact young adult female Wistar rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Parkinson's disease is a multisystemic neurodegenerative disorder that includes motor and non-motor symptoms, and common symptoms include memory loss and learning difficulties. Thus, we investigated the neuroprotective potential of a hydroalcoholic extract of Brazilian purple cherry (Eugenia uniflora) (HAE-BC) on memory impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats and the involvement of hippocampal BDNF/TrkB/p75 NTR pathway in its effects. Adult male Wistar rats were exposed to MPTP (1 mg/nostril) or vehicle. Twenty-four hours later, the HAE-BC treatments began at doses of 300 or 2000 mg/kg/day or vehicle for 14 days. From 7 days after the MPTP induction, the animals were subjected to behavioral tests to evaluate several cognitive paradigms. HAE-BC treatments, at both doses, blocked the MPTP-caused disruption in the social recognition memory, short- and long-term object recognition memories, and working memory. Furthermore, MPTP-induced motor deficit linked to striatal tyrosine hydroxylase levels decreased, which was blocked by HAE-BC. Our findings demonstrated that HAE-BC blocked the MPTP-induced increase in the hippocampal pro-BDNF, TrkB.t1, and p75 NTR levels. The pro-BDNF/p75 NTR interaction negatively regulates synaptic transmission and plasticity, and the neuroprotective effect of HAE-BC was related, at least partly, to the modulation of this hippocampal signaling pathway. Thus, our study reports the first evidence of the potential therapeutic of E. uniflora in a Parkinson's disease model in rodents., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lifestyle habits including energy-dense foods and ethanol intake are associated with anxiety disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF 3 -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-CF 3 -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-CF 3 -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-CF 3 -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-CF 3 -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-CF 3 -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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

An unhealthy lifestyle is associated with metabolic disorders and neuroinflammation. In this study, the efficacy of m-trifluoromethyl-diphenyl diselenide [(m-CF 3 -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-CF 3 -PhSe) 2 (5 mg/kg/day; i. g). (m-CF 3 -PhSe) 2 reduced relative abdominal adipose tissue weight, hyperglycemia, and dyslipidemia in mice exposed to the lifestyle-induced model. (m-CF 3 -PhSe) 2 normalized hepatic cholesterol and triglyceride levels, and the activity of G-6-Pase increased in lifestyle-exposed mice. (m-CF 3 -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-CF 3 -PhSe) 2 counteracted hypothalamic inflammation and the ghrelin receptor levels in mice exposed to the lifestyle model. (m-CF 3 -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-CF 3 -PhSe) 2 counteracted metabolic disturbances and hypothalamic inflammation in young mice exposed to a lifestyle model., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Diphenyl diselenide (PhSe)2 is a stable organoselenium compound with promising in vitro antifungal activity against several fungi, including Sporothrix brasiliensis. This species is associated with feline and zoonotic sporotrichosis, an emergent mycosis in Latin America. We evaluated the activity of (PhSe)2, alone and in association with itraconazole, in the treatment of sporotrichosis caused by S. brasiliensis, in a murine model. Sixty mice were subcutaneously infected with S. brasiliensis in the footpad and treated by gavage for 30 consecutive days. The six treatment groups received: no active treatment, itraconazole (50 mg/kg), (PhSe)2 at 1, 5, and 10 mg/kg dosages, or itraconazole (50 mg/kg) + (PhSe)2 1 mg/kg, once a day, starting seven days post-inoculation. A significant reduction in the fungal burden of internal organs was achieved in the groups treated with (PhSe)2 1 mg/kg or itraconazole alone in comparison with the untreated group. Higher dosages (5 and 10 mg/kg) of (PhSe)2 increased the clinical manifestation of sporotrichosis and mortality rate. Treatment with both itraconazole and (PhSe)2 1 mg/kg was better than their activities alone (P < .001). This is the first demonstration of the potential use of (PhSe)2, alone or with the present drug of choice, in the treatment of sporotrichosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Excessive stress can precipitate depression and anxiety diseases, and damage gastrointestinal functionality and microbiota changes, favoring the development of functional gastrointestinal disorders (FGIDs) - defined by dysregulation in the brain-gut interaction. Therefore, the present study investigated if Emotional-Single Prolonged Stress (E-SPS) induces depressive/anxiety-like phenotype and gut dysfunction in adult Swiss male mice. For this, mice of the E-SPS group were subjected to three stressors sequential exposure: immobilization, swimming, and odor of the predator for 7 days (incubation period). Next, animals performed behavior tests and 24 h later, samples of feces, blood, and colon tissue were collected. E-SPS increased the plasma corticosterone levels, immobility time in the tail suspension and forced swim test, decreased the grooming time in the splash test, OAT%, and OAE% in the elevated plus-maze test, as well as increased anxiety index. Mice of E-SPS had increased % of intestinal transit rate, % of fecal moisture content, and fecal pellets number, and decreased Claudin1 content in the colon. E-SPS decreased the relative abundance of Bacteroidetes phylum, Bacteroidia class, Bacteroidales order, Muribaculaceae and Porphyromonadaceae family, Muribaculum, and Duncaniella genus. However, E-SPS increased Firmicutes and Actinobacteria phylum, Coriobacteriales order, and the ratio of Firmicutes/Bacteroidetes, and demonstrated Mucispirillum genus presence. The present study showed that E-SPS induced depressive/anxiety-like phenotype, predominant diarrhea gut dysfunction, and modulated the gut bacterial microbiota profile in male adult Swiss mice. E-SPS might be a promising model for future studies on the brain-gut interaction and the development of FGIDs with psychological comorbidities., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A method for the synthesis of 4-organoselanyl oxazinoindolone derivatives by the cascade cyclization of N-(alkoxycarbonyl)-2-alkynylindoles using iron(III) chloride and diorganyl diselenides as promoters was developed. This protocol was applied to a series of N-(alkoxycarbonyl)-2-alkynylindoles containing different substituents. The reaction conditions also tolerated a variety of diorganyl diselenides having both electron donating and electron withdrawing groups. However, the reaction did not work for diorganyl disulfides and ditellurides. The reaction mechanism seems to proceed via an ionic pathway and the cooperative action between iron(III) chloride and diorganyl diselenides is crucial for successful cyclization. We also found that using the same starting materials, by simply changing the electrophilic source to iodine, led to the formation of 4-iodo-oxazinoindolones. The high reactivity of Csp 2 -Se and Csp 2 -I bonds were tested under cross-coupling conditions leading to the preparation of a new class of functionalized indole derivatives. In addition, the absorption, emission and electrochemical properties of 4-organoselanyl oxazinoindolones showed an important relationship with the substituents of the aromatic rings. The advantages of the methodology include the use of electrophilic to promote the cyclization reaction and functionalization of the indole ring, and the electronic properties presented by the prepared compounds can be exploited as probes, analyte detectors and optical materials., (© 2022 Wiley-VCH GmbH.)

Stress is a triggering factor for anxious and depressive phenotypes. Exercise is known for its action on the central nervous system. This study aimed to evaluate the role of resistance exercise in an anxiety-depression-like dyad in a model of stress. Male Swiss mice (35-day-old) were exercised, three times a week for 4 weeks on nonconsecutive days. The resistance exercise consisted of climbing a 1-m-high ladder 15 times. After mice were subjected to an emotional single prolonged stress (Esps) protocol. Seven days later, they were subjected to anxiety and depression predictive behavioral tests. The results showed that exercised mice gain less weight than sedentary from weeks 3 to 5. Resistance exercise was effective against an increase in immobility time in the forced swim test and tail suspension test and a decrease in grooming time of mice subjected to Esps. Resistance exercise protected against the decrease in the percentage of open arms time and open arm entries, and the increase in the anxiety index in Esps mice. Four-week resistance exercise did not elicit an antidepressant/anxiolytic phenotype in non-stressed mice. Esps did not alter plasma corticosterone levels but increased the hippocampal glucocorticoid receptor content in mice. Resistance exercise protected against the decrease in hippocampal levels of tropomyosin kinase B (TRκB), the p-Akt/Akt, and the p-mTOR/mTOR ratios of Esps mice. Resistance exercise proved to be effective in decreasing hippocampal neuroinflammation in Esps mice. Resistance exercise protected against the increase in the hippocampal Akt/mTOR pathway and neuroinflammation, and anxiety/depression-like dyad in Esps exposed mice., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

This study describes the reaction of 2-amino arylalkynyl ketones with organoselenolates to form ( Z )-vinyl selenides, which lead to 4-organoselenyl quinolines via an intramolecular condensation. Using the optimized reaction conditions, the generality of this cyclization was studied with various arylalkynyl ketones and diorganyl diselenides. The study of the reaction mechanisms led to the isolation and identification of a vinyl selenide, which was the key intermediate for this cyclization. To expand the structural diversity and to demonstrate the applicability of the 4-organoselenyl quinolines prepared, we studied their application as substrates in the cleavage of the carbon-selenium bond using n -butyllithium followed by the capture of the lithium intermediate by electrophiles and Suzuki and Sonogashira cross-coupling reactions.

Trichomoniasis is the most common nonviral sexually transmitted infection in the world, but its available therapies present low efficacy and high toxicity. Diphenyl diselenide (PhSe 2 ) is a pharmacologically active organic selenium compound; however, its clinical use is hindered by its lipophilicity and toxicity. Nanocarriers are an interesting approach to overcome the limitations associated with this compound. This study designed and evaluated a vaginal hydrogel containing PhSe 2 -loaded Eudragit ® RS100 and coconut oil nanocapsules for the treatment of trichomoniasis. Nanocapsules presented particle sizes in the nanometric range, positive zeta potential, a compound content close to the theoretical value, and high encapsulation efficiency. The nanoencapsulation maintained the anti- Trichomonas vaginalis action of the compound while improving the scavenger action in a DPPH assay. The hydrogels were prepared by thickening nanocapsule suspensions with locust bean gum (3%). The semisolids maintained the nanometric size of the particles and the PhSe 2 content at around the initial concentration (1.0 mg/g). They also displayed non-Newtonian pseudo-plastic behavior and a highly mucoadhesive property. The chorioallantoic membrane method indicated the absence of hemorrhage, coagulation, or lysis. The compound, from both non-encapsulated and nano-based hydrogel delivery systems, remained on the surface of the bovine vaginal mucosa. Therefore, the formulations displayed the intended properties and could be a promising alternative for the treatment of trichomoniasis.

Background: Single Prolonged Stress (SPS) is a valid animal model that reflects the core of post-traumatic stress disorder (PTSD) phenotypes. Although SPS has been a pivotal tool, it can bring ethics approval difficulties due to the use of ether as a stressor. The present study evaluated if changing a chemical (ether) with a social stressor resembles the PTSD hallmark symptoms., Methods: Female and male young adult rats were distributed in Sham and Social-SPS groups. Rats in Social-SPS groups were subjected to stress, whereas those in Sham groups remained undisturbed. One set of animals performed the behavioral tests, elevated plus-maze (EPM) and Y-maze. Plasma corticosterone levels and cortical and hippocampal molecular protein contents were analyzed. Another set of animals performed the dexamethasone suppression test., Results: A significant decrease in the percentage of time spent and the number of entries in open arms and an increase in anxiety index in the EPM were observed in rats of the social-SPS groups. In the Social-SPS groups, rats reduced the spontaneous alternations in Y-maze. The Social-SPS exposure enhanced the HPA-axis feedback and increased glucocorticoid receptor contents in the cerebral cortex and hippocampus of rats. A decrease in the content of synaptic integrity-related proteins, synaptophysin, and PSD-95, were found in the cortex and hippocampus of rats subjected to social-SPS. There were no statistical differences between males and females in any parameter analyzed., Limitations: The absence of a task to recap criterion E 'arousal' and predictive validity experiments., Conclusions: This study reveals that social-SPS recapitulated the main clusters required for a candidate animal model of PTSD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The organoselenium compounds belong to a class of synthetic molecules that displays a remarkable spectrum of promising pharmacological properties. Despite the huge amount of preclinical data that supports a bright outlook for organoselenium compounds, some toxicity issues and physicochemical limitations delay the development of more advanced studies. Currently, several scientific reports demonstrated that the association of nanotechnology has emerged as an alternative to improve solubility and safety issues of these molecules as well as enhance pharmacological properties. Therefore, our main objective was to address studies that reported the development and biological evaluations of nano-based formulations to synthetic organoselenium compounds incorporation by constructing an integrative literature review. The data survey was performed using the Science Direct, PubMed, Web of Science, and SCOPUS online databases, covering studies that were published from January 2011 up to October 2021. In the last decade, there has been an exponential growth in research regarding the incorporation of synthetic organoselenium compounds into distinct nanocarrier systems such as nanocapsules, nanoemulsions, micelles, and others, reinforcing that the association of such molecules and nanotechnology is a promising alliance. The reports investigated many nanosystems containing selenium organic molecules intending oral, intravenous, and cutaneous applications. Besides that, these systems were evaluated in a variety of in vitro techniques and in vivo models, concerning their pharmacological potential, biodistribution profile, and safety. In summary, the findings indicate that the production of nano-based formulations containing organoselenium compounds either improved physicochemical and biological properties or minimize toxicological issues of compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Amphetamine (AMPH) abuse results in neurobehavioral alterations related to the reward circuit. The hippocampus plays a role in cognition, reward, and drug addiction. There are no pharmacological approaches to prevent AMPH relapse. Physical exercise has been studied as a non-pharmacological promising influence to attenuate reward symptoms related to addictive drugs., Objective: This study aimed to compare the effects of non-weight-loaded and weight-loaded physical exercise on behavioral (relapse, memory and anxiety) and hippocampal molecular parameters associated with AMPH addiction in Wistar rats., Methods: Male rats were subjected to the AMPH-Conditioned Place Preference (CPP) paradigm. After 8-conditioning days, they were subjected to swimming physical exercise protocol (without or with weight-load). Behavioral evaluations were performed to assess the influence of both exercise protocols in addiction parameters, including relapse after AMPH reconditioning, working memory, locomotor activity, and anxiety-like symptoms. Subsequently, protein levels of Brain-Derived Neurotrophic Factor (BDNF) and pro-BDNF ex-vivo assays were carried out in samples of the hippocampus of the animals., Results: AMPH relapse and anxiety-like behaviors were reduced only in rats subjected to non-weight-loaded exercise. Hippocampal BDNF and pro-BDNF immunoreactivity were increased in non-weight-loaded exercise rats. Behavioral and molecular analyses were not modified in rats subjected to weight-loaded exercise., Conclusion: These findings demonstrate that non-weight-loaded exercise was more effective against relapse and anxiety-like behavior induced by AMPH. Non-weight-loaded exercise upregulated the hippocampal immunocontent levels in rats., (Copyright © 2022. Published by Elsevier Inc.)

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.

m -Trifluoromethyl diphenyl diselenide (TFDD) has antinociceptive and antidepressant-like properties and attenuates morphine withdrawal signs in mice. This study investigated if TFDD affects the development of morphine tolerance to its antinociceptive and antidepressant-like effects in mice. We also investigated whether TFDD modulates signaling pathways related to morphine tolerance, including the opioid receptors and some parameters of the nitrergic system. Male adult Swiss mice received morphine alone (5 mg/kg, subcutaneous) and in combination with TFDD (10 mg/kg, intragastric) for 7 days. Mice were subjected to hot plate and forced swim tests on days 1, 3, 5, and 7 of the experimental protocol. Repeated TFDD administrations avoided tolerance development mediated by morphine, including its antinociceptive and antidepressant-like effects. A single morphine dose increased MOR and NOx but decreased i NOS contents in the mouse cerebral cortex. In turn, single morphine and TFDD co-administration restored the MOR and i NOS protein levels. On the other hand, morphine repeated doses enhanced DOR and reduced MOR and NOx contents, whereas the morphine and TFDD association reestablished DOR and NOx levels in the mouse cerebral cortex. In conclusion, some opioid and nitrergic system parameters might contribute to TFDD attenuation of antinociceptive and antidepressant-like tolerance induced by morphine in mice.

Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1β (IL 1β), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na + ,K + -ATPase activity (specifically isoform α 2/3 ) followed by K m (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity., (Copyright © 2021. Published by Elsevier Inc.)

Aging is characterized by several neurochemical modifications involving structural proteins and neurotransmitters. Exercise has been recognized as an enhancer of overall health; whereas, diphenyl diselenide (PhSe)2 has been reported to have antioxidant, anti-inflammatory, and neuroprotective effects in rodents. A combination of pharmacological and non-pharmacological interventions has been proposed to prevent the aging effects. This study aimed to determine the swimming exercise and (PhSe)2 dietary supplementation synergic effects on the [3H] γ-aminobutyric acid (GABA) uptake in aged rats. Male Wistar rats (24 months) received 1 ppm of (PhSe)2 supplemented in the standard chow for 4 weeks. Rats were subjected to swimming training (20 min per day for 4 weeks). After 4 weeks, the [3H]GABA uptake was determined in samples of cerebral cortex and striatum of rats. The results of the present study demonstrate that the association of (PhSe)2-supplemented diet and swimming exercise was effective against the decrease of cerebral cortical and striatal [3H]GABA uptake in aged rats. The association of (PhSe)2 dietary supplementation with swimming exercise modulated the GABA uptake in cerebral structures of aged rats.

Background: Behavioral sensitization, thought to underlie some aspects of drug dependence, is typically measured as increased locomotion in response to repeated administration of a drug. The study aimed to investigate the (m-CF3-PhSe) 2 effects on the acquisition, withdrawal, and re-exposure phases of morphine-induced behavioral locomotor sensitization., Methods: Swiss male mice were treated with saline or morphine at 10 mg/kg twice a day for 3 days; those of the morphine group were kept in the morphine withdrawal period (5 days). On day 9, mice were re-exposed to morphine. (m-CF3-PhSe) 2 (10 mg/kg) or vehicle was administered at all phases of morphine protocol, and mice performed locomotor activity test. Oxidative stress markers and the levels of opioid, dopamine, and glutamate receptors were determined in samples of the cerebral cortex. (m-CF3-PhSe) 2 administered at all phases of protocol attenuated morphine-induced locomotor sensitization., Results: Mice exposed to morphine showed reduced weight gain and increased locomotor activity, but (m-CF 3 -PhSe) 2 treatment attenuates the weight gain and behavioral hyperlocomotion effects. (m-CF3-PhSe) 2 , independent of the administration phase, modulated the increase of opioidergic (MOR, DOR, KOR) and glutamatergic (NMDA 2A and 2B) protein contents and attenuated redox imbalance in the cerebral cortex of mice exposed to morphine. However, (m-CF3-PhSe) 2 did not modulate cortical protein levels of dopaminergic (D1 and D2) receptors in the acquisition phase of morphine-induced locomotor sensitization protocol., Conclusion: (m-CF 3 -PhSe) 2 was effective against the behavioral and molecular alterations caused by morphine at all phases of locomotor sensitization., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Clinical and preclinical investigations have suggested a possible biological link betweenmajor depressive disorder (MDD) and Alzheimer's disease (AD). Therefore, a pharmacologic approach to treating MDD could be envisioned as a preventative therapy for some AD cases. In line with this, 1-(7-chloroquinolin-4-yl)-N-(4-methoxybenzyl)-5-methyl-1H-1,2,3-triazole-4 carboxamide (QTC-4-MeOBnE) is characterized as an inhibitor of β-secretase, glycogen synthase kinase 3β, and acetylcholinesterase and has also shown secondary effects underlying the modulation of neurogenesis and synaptic plasticity pathways. Therefore, we investigated the effects of QTC-4-MeOBnE treatment (0.1 or 1 mg/kg) on depressive-like behavior and cognitive impairments elicited by repeated injections of lipopolysaccharide (LPS; 250 μg/kg) in mice. Injections of LPS for seven days led to memory impairments and depressive-like behavior, as evidenced in the Y-maze/object recognition test and forced swimming/splash tests, respectively. However, these impairments were prevented in mice that, after the last LPS injection, were also treated with QTC-4-MeOBnE (1 mg/kg). This effect was associated with restoring blood-brain barrier permeability, reducing oxidative/nitrosative biomarkers, and decreasing neuroinflammation mediated NF-κB signaling in the hippocampus and cortex of the mice. To further investigate the involvement with NF-κB signaling, we evaluated the effects of QTC-4-MeOBnE on microglial cell activation through canonical and non-canonical pathways and the modulation of the involved components. Together, our findings highlight the pharmacological benefits of QTC-4-MeOBnE in a mouse model of sickness behavior and memory impairments, supporting the novel concept that since this molecule produces anti-depressant activity, it could also be beneficial for preventing AD onset and related dementias in subjects suffering from MDD through inflammatory pathway modulation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the in vitro antifungal action of a diphenyl diselenide-loaded poly(ε-caprolactone) nanocapsules suspension (NC-1) and incorporate it into a gellan gum hydrogel formulation in order to assess its in vivo efficacy in an animal model of vulvovaginal candidiasis. Nanocapsules suspensions containing the compound (NC-1 ∼ 5 mg/mL) or not (NC-B) were prepared by the interfacial deposition of preformed polymer method. To estimate in vitro antifungal effect, the broth microdilution test was applied. The results showed that NC-1 had equal or lower MIC values when compared to free compound against fifteen Candida strains. Following, the hydrogel was prepared by direct thickening of the nanocapsules suspension by gellan gum addition. The animal model of vulvovaginal candidiasis was induced by infecting female Swiss mice with Candida albicans strains. The animals were topically treated with 20 µL of hydrogels (NC-1 and free compound - 0.1 mg of diphenyl diselenide/once a day for seven days) and then the total fungal burden was assessed after the euthanasia. The results showed that the hydrogels presented pH in the acidic range, compound content close to theoretical value, homogeneous particle distribution with nanometric size, high physicochemical and microbiological stability as well as great bioadhesive property. The nano-based presented superior pharmacological action in comparison to the hydrogel containing non-encapsulated diphenyl diselenide. The results demonstrated that the nanoencapsulation maintained the effective antifungal action of diphenyl diselenide. The nano-based hydrogel formulation may be considered a promising approach against vulvovaginal candidiasis., (Copyright © 2021. Published by Elsevier B.V.)

Aflatoxin B 1 (AFB 1 ) is a mycotoxin highly toxic and carcinogenic to humans due to its potential to induce oxidative stress. The Beta-caryophyllene (BCP) have been highlighted for its broad spectrum of pharmacological effects. The present study aimed to investigate the beneficial effects of BCP against the susceptibility of hepatic and renal tissues to AFB 1 toxicity, in biochemical parameters to assess organ function, tissue oxidation, and the immunocontent of oxidative and inflammatory proteins. Male Wistar rats was exposed to AFB 1 (250 μg/kg, i.g.) and/or BCP (100 mg/kg, i.p.) for 14 successive days. It was found that exposure to AFB 1 did not change the measured renal toxicity parameters. Also, AFB 1 increased liver injury biomarkers (gamma glutamyl transferase and alkaline phosphatase) and reduced levels of non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol), however did not cause changes in the lipid peroxidation levels. Moreover, AFB 1 interfered in oxidative pathway regulated by Kelch-like ECH-associated protein (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2), overacting Glutathione-S-Transferase (GST) activity. Lastly, a main effect of AFB 1 on the total interleukin 1 beta (IL-1β) was observed. Remarkably, the associated treatment of AFB 1  + BCP improved altered liver parameters. In addition, BCP and AFB 1  + BCP groups showed an increase in the levels of inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). Thus, these results indicated that BCP has potential protective effect against AFB 1 induced hepatotoxicity., (Copyright © 2021. Published by Elsevier B.V.)

One of the major causes of early pregnancy loss is heat stress. In ruminants, interferon tau (IFNT) is the embryo signal to the mother. Once the interferon signaling pathway is activated, it drives gene expression for interferon-stimulated genes (ISGs) and alters neutrophils responses. The aim of the present study was to evaluate interferon (IFN) pathway, ISGs and gene expression in polymorphonuclear leukocytes (PMN) and oxidative stress in dairy cows under heat stress. Pregnant cows had their estrous cycle synchronized and randomly assigned to a comfort or heat stress group. Blood samples were collected at artificial insemination (AI) and on Days 10, 14 and 18 following AI. Pregnant cows were pregnancy checked by ultrasound on Day 30 and confirmed on Day 60 post-AI. Results are presented as mean ± SEM. The corpus luteum (CL) diameter was not different between groups of pregnant cows; concentration of progesterone of pregnant cows on Day 18 following AI was greater in comfort group compared to heat stressed group. Comfort pregnant cows had higher expression of all analyzed genes from interferon pathway, except for IFNAR1, on both Days 14 and 18. Conversely, heat stressed cows did not show altered expression of IFNT pathway genes and ISGs between Days 10, 14, and 18 after AI. The oxidative stress, determined as malondialdehyde (MDA) levels, was greater in heat stress group on Days 10, 14 and 18, independent of pregnancy status. Heat stress negatively influences expression of ISGs, IFN pathway gene expression in neutrophils, and oxidative stress. Our data suggest that lower conception rates in cows under heat stress are multifactorial, with the association of interferon pathway activation and the unbalanced oxidative stress being main contributing factors., Competing Interests: The authors have declared that no competing interests exist.

Streptozotocin (STZ) is a substance used experimentally to induce a diabetes model, a metabolic disease associated with oxidative tissue damage. This study evaluated if 4-4'-dichloro-diphenyl diselenide ( p -ClPhSe) 2 modulates oxidative stress in peripheral tissues of diabetic mice. Male Swiss mice received a single STZ injection (i.p.) at a dose of 200 mg/kg or its vehicle and were treated with ( p -ClPhSe) 2 (7 days, 5 mg/kg) or metformin (200 mg/kg, twice per day). After, the mice were euthanized to collect liver, kidney, and skeletal muscle samples. In the liver, ( p -ClPhSe) 2 reduced thiobarbituric acid reactive substances (TBARS) and protein carbonyl levels and normalized the superoxide dismutase activity in STZ-treated mice. In the kidney, ( p -ClPhSe) 2 reversed the increase in the reactive species levels but not the catalase (CAT) activity reduction in STZ-treated mice. There was no evidence of oxidative damage in the skeletal muscle of STZ-treated mice, but an increase in the CAT activity and a reduction in non-protein thiol levels were found. ( p -ClPhSe) 2 did not reverse a decrease in hepatic and renal δ-aminolevulinic acid dehydratase activity in STZ-treated mice. The results show that the liver and kidney of STZ-treated mice were more susceptible to oxidative stress. This study reveals that ( p -ClPhSe) 2 modulated oxidative stress, which differently affected peripheral tissues of diabetic mice.

We evaluated the in vitro susceptibility of Sporothrix schenckii s.str. and Sporothrix globosa to diphenyl diselenide (PhSe) 2 alone and in association with itraconazole (ITZ). Eight clinical isolates were tested in microdilution and checkerboard assays. (PhSe) 2 alone inhibited all isolates in concentration ≤ 8 µg/mL and was effective in killing one S. schenckii isolate. Inhibitory and fungicidal beneficial effects in its interaction with ITZ were shown against 87.5% (7/8) and 50% (4/8) of the isolates tested, respectively. Our study demonstrates the in vitro antifungal activity of (PhSe) 2 against two pathogenic Sporothrix species, suggesting studies of in vivo applications are warranted., (© 2021. Sociedade Brasileira de Microbiologia.)

Prediabetes is the stage before diabetes in which not all the symptoms or signs required to diagnose diabetes are present, but blood glucose is abnormally high. This study investigates if memory impairment and depressive-like phenotype are accompanied by the hippocampal insulin and BDNF signaling in prediabetic mice. Male adult Swiss mice received streptozotocin (STZ, 200 mg/kg, ip) to induce prediabetes. Control mice were treated with citrate buffer (5 ml/kg, ip). To characterize prediabetes status, metabolic parameters were determined in mice. The behavioral test battery to assess memory consisted of object recognition (ORT), object location (OLT), and Morris water maze (MWM) tests. The mouse depressive-like phenotype was investigated using the forced swimming (FST) and tail suspension (TST) tests. The pIRS-1/Akt/GLUT4 and BDNF/TrkB/CREB protein contents were determined in the hippocampus of mice. Prediabetic mice showed mild hyperglycemia, reduced body weight gain, and an increase in glucose and insulin tolerance tests (AUCs). Prediabetic mice had smaller recognition and location indexes, in the ORT and OLT, than the control group. Prediabetic mice showed hippocampus-dependent spatial memory impairment, in the MWM test, and an increase in immobility time, in the TST and FST, compared to the control group. The molecular findings indicate the downregulation of hippocampal insulin and BDNF signaling in prediabetic mice. In conclusion, memory impairment and depressive-like phenotype were potentially linked to the downregulation of hippocampal pIRS-1/Akt/GLUT4 and BDNF/CREB signaling in prediabetic mice., (Copyright © 2021. Published by Elsevier Inc.)

Studies reveal that oxidative stress is associated with adverse effects of long-term morphine treatment. The m -trifluoromethyl-diphenyl diselenide (CF3) is a multi-target organoselenium compound that has antioxidant properties in different experimental models. This study aimed to investigate the CF3 effects against redox imbalance in peripheral and central tissues of mice, after single or multiple morphine doses. Swiss male mice received a single dose of morphine (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.), or morphine was repeatedly injected (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.) administered twice daily for 7 days. Oxidative stress was determined in the hippocampus, liver, and kidney. CF3 reversed the increase in reactive species caused by single and multiple morphine doses in the peripheral tissues. CF3 increased hepatic non-protein thiol levels and the superoxide dismutase (SOD) activity decreased by a single morphine dose. CF3 reversed the reduction in SOD activity in the kidney of mice repeatedly exposed to morphine. The study demonstrates that peripheral tissues were more susceptible than the hippocampus to oxidative stress induced by morphine in mice. The results show that CF3 modulated parameters of oxidative stress modified by single and multiple morphine administrations in peripheral and central tissues of mice.

We evaluated the in vitro activity of nikkomycin Z (NikZ) in combination with diphenyl diselenide (PhSe) 2 , two compounds previously shown to have anti-Sporothrix spp. activity. Eighteen isolates of Sporothrix spp. were tested in checkerboard assays. Synergism for inhibition and killing Sporothrix spp. occurred in 100% and 89% of the isolates, respectively. The anti-Sporothrix spp. activity of this combination provides a rationale for in vivo studies to evaluate the application of both compounds in sporotrichosis treatment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This study investigated whether swimming protocol induces adaptations to sex-specific oxidative stress and Nrf2/Keap-1 pathway in the liver of mice fed a high-calorie diet (HCD) during the early life period. Male and female Swiss mice were fed a standard or high-calorie (enriched with 20% lard and 20% corn syrup) diets, and the trained mice were subjected to a swimming protocol (5 days/week) from 21 st to 49 th postnatal days. Males fed a HCD had more pronounced alterations in all parameters evaluated than females. Although there was no increase in body weight, the fat deposition was higher in male mice exposed to diet. The intake of HCD induced dyslipidemia mainly in males. In a sex-dependent manner, the hepatic markers of oxidative damage, antioxidant defences, and a sensitive sulfhydryl protein were altered in mice fed a HCD. Swimming counteracted dyslipidemia, hepatic oxidative stress, and the Nrf2/Keap-1 signalling downregulation, in a sex-dependent manner, in mice exposed to a HCD. These findings demonstrate that a non-pharmacological therapy, swimming protocol, contributed to adaptations of sex-specific hepatic oxidative stress and Nrf2/Keap-1 regulation in male mice fed a HCD., (© 2021 John Wiley & Sons Ltd.)

Energy-dense foods and ethanol consumption are associated with mood disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF 3 -PhSe) 2 ] has been a prominent pharmacological target due to its antidepressant-like effects. This study investigated if the modulation of opioid and glucocorticoid receptors and its well-known antioxidant property contribute to the (m-CF 3 -PhSe) 2 antidepressant-like effect in young mice subjected to an energy-dense diet and ethanol intake. Swiss male mice [postnatal day (PND) 25] were exposed to an energy-dense diet (containing 20% fat and 20% carbohydrate) or standard chow until the PND 67. Mice received ethanol (2 g/kg) or water administration (3 times a week, intragastrically [i.g.]) from PND 45 to PND 60. After that, mice received (m-CF 3 -PhSe) 2 (5 mg/kg/day; i.g) or vegetal oil administration from PND 60 to 66. Mice performed the behavioral tests to evaluate the depressive-like phenotype. The results showed that individually neither an energy-dense diet nor ethanol group induced a depressive-like phenotype, but the association of both induced this phenotype in young mice. Oxidative stress was characterized by the increase of malondialdehyde, the decrease in the superoxide dismutase activity, and non-protein sulfhydryl levels in the cerebral cortex of depressive-like mice. Depressive-like mice showed an increase in the protein levels of opioid receptors and depletion in those of glucocorticoid. (m-CF 3 -PhSe) 2 abolished depressive-like phenotype and oxidative stress as well as modulated the levels of glucocorticoid and opioid receptors. In conclusion, the modulation of opioid and glucocorticoid receptors and the antioxidant property contributed to the (m-CF 3 -PhSe) 2 antidepressant-like effect in young mice exposed to an energy-dense diet and ethanol intake.

Here, we addressed the pharmacology and toxicology of synthetic organoselenium compounds and some naturally occurring organoselenium amino acids. The use of selenium as a tool in organic synthesis and as a pharmacological agent goes back to the middle of the nineteenth and the beginning of the twentieth centuries. The rediscovery of ebselen and its investigation in clinical trials have motivated the search for new organoselenium molecules with pharmacological properties. Although ebselen and diselenides have some overlapping pharmacological properties, their molecular targets are not identical. However, they have similar anti-inflammatory and antioxidant activities, possibly, via activation of transcription factors, regulating the expression of antioxidant genes. In short, our knowledge about the pharmacological properties of simple organoselenium compounds is still elusive. However, contrary to our early expectations that they could imitate selenoproteins, organoselenium compounds seem to have non-specific modulatory activation of antioxidant pathways and specific inhibitory effects in some thiol-containing proteins. The thiol-oxidizing properties of organoselenium compounds are considered the molecular basis of their chronic toxicity; however, the acute use of organoselenium compounds as inhibitors of specific thiol-containing enzymes can be of therapeutic significance. In summary, the outcomes of the clinical trials of ebselen as a mimetic of lithium or as an inhibitor of SARS-CoV-2 proteases will be important to the field of organoselenium synthesis. The development of computational techniques that could predict rational modifications in the structure of organoselenium compounds to increase their specificity is required to construct a library of thiol-modifying agents with selectivity toward specific target proteins.

This study aimed to evaluate the potential DNA photoprotection of nano-based hydrogels containing a novel benzofuroazepine molecule. Photoprotective property of three benzofuroazepine derivative compounds was assessed by determining a UV light absorptive profile. Nanocapsule suspensions (Eudragit® RS 100 as polymeric wall and medium-chain triglyceride or vitamin E as oil core) containing the benzofuroazepine compound that had the best UV spectral absorption were developed and physicochemically characterized. Photostability assay, bioadhesive property as well as preliminary toxicity parameters (HET-CAM and Artemia salina lethality assays) for free or nanoencapsulated forms were assessed. Among the molecules, the UV absorbance spectrum of free MBBA showed a broad and high intensity absorbance at UVB and UVA ranges. MBBA-nanocapsule suspensions had nanometric and homogeneous size distribution, bioadhesiveness property, and increased the UV light scattering in comparison to the free compound. Besides, all formulations triggered no irritative responses and the nanoencapsulation mitigated the toxic effect to Artemia salina observed to free MBBA. Following, hydrogels were prepared by thickening nanocapsule suspensions with gellan gum and their DNA photoprotection properties were determined by the exposure of DNA samples to the UVB and UVA radiation. Hydrogels showed acid pH values, compound content close to the theoretical value (3 mg/g), particle size in nanometric range, and spreadability profile suitable for cutaneous application. All MBBA hydrogels were effective against photoproducts formation induced by UVB and UVA radiation. In conclusion, these data show the identification of a compound with promising UV absorptive potential and the preparation of a final nano-based hydrogel for cutaneous application., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Increased energy food consumption during early-life has been associated with memory impairment. Swimming training has been reported to improve memory processes in rodent models. This study aimed to evaluate whether moderate-intensity swimming training counteracts learning and memory impairment in young mice fed a high-calorie diet during the early-life period. The contribution of hippocampal oxidative stress, as well as nuclear factor [erythroid-derived 2]-like 2/Kelch-like ECH-associated protein (NRF2/Keap-1/HO-1) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha/mitochondrial transcription factor A (PCG-1α/mtTFA) signaling, in memory effects was also investigated. Three-week-old male Swiss mice received a high-calorie diet (20% fat; 20% carbohydrate enriched) or a standard diet from 21 to 49 postnatal days. Mice performed a moderate-intensity swimming protocol (5 days/week) and behavioral tests predictive of memory function. Mice fed a high-calorie diet and subjected to the swimming protocol performed better on short- and long-term spatial and object recognition memory tests than those fed a high-calorie diet. The swimming protocol modulated the hippocampal NRF2/Keap-1/HO-1 and mtTFA pathways in mice fed a high-calorie diet. Swimming training positively affected location and long-term memory, fat mass content, as well as NRF2/Keap-1/HO-1 and mtTFA proteins of control-diet-fed mice. In conclusion, a moderate-intensity swimming training evoked an adaptive response in mice fed a high-calorie diet by restoring different types of memory-impaired and hippocampal oxidative stress as well as upregulated the NRF2/Keap-1/HO-1 and mtTFA pathways., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Bovine alphaherpesvirus 2 (BoHV-2) - the agent of bovine herpetic mamillitis (BHM) - is related to Human alphaherpesviruses 1 and 2 (HHV-1, HHV-2) and, as such, has been proposed as a model for vaccine and drug testing. We herein investigated the anti-viral activity in vitro against BoHV-2 of three anti-herpetic drugs: Cidofovir (CDV), Fanciclovir (FAM), Foscarnet (PFA), and diphenyl disselenide (Ph 2 Se 2 ) , a compound that has showed activity against HHV-2. Plaque reduction assays (PRA) revealed a significant reduction in viral plaques (p < 0.05) in cells treated with Ph 2 Se 2 (79.7% reduction) or CDV (62.8%). FAM treatment resulted in a slight decrease in plaque number (22.9%, p < 0.05); PFA showed no activity. The effects of Ph 2 Se 2 and CDV, alone or in combination, were investigated in ewes inoculated with BoHV-2 transdermally and submitted to daily topic treatment. Virus inoculated ewes developed lesions progressing through the stages of hyperemia, large papules or depressed dark areas, followed by scab formation. Treatment with Ph 2 Se 2 resulted in reduction in clinical score from day 10 pi onwards (P < 0.05), shortening of clinical course and reduction in duration of virus shedding (P < 0.05) compared to untreated controls. Combined treatment (Ph 2 Se 2  + CDV) and CDV alone, also led to clinical improvement (P < 0.05), yet less pronounced and delayed. These results are promising towards the use of Ph 2 Se 2 , alone or in combination with anti-herpetic drugs, in the treatment of udder and teat lesions produced by BoHV-2 in dairy cows., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nandrolone decanoate (ND) belongs to the class II of anabolic-androgenic steroids (AAS), which is composed of 19-nor-testosterone-derivatives. AAS represent a group of synthetic testosterone that is used in clinical treatment. However, these drugs are widely abused among individuals as a means of promoting muscle growth or enhancing athletic performance. AAS in general and ND in particular have been associated with several behavioral disturbances, such as anxiety, aggressiveness and depression. A factor that contributes to the development of depression is the brain activation of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of kynurenine pathway (KP). In the present study, we examined the involvement of KP in depressive phenotype induced by a ND treatment (10 mg/kg/day/s.c., for 28 days) that mimics human abuse system (e.g. supraphysiological doses) in C57B/6J mice. Our results showed that ND caused depressive like-behavior in the tail suspension test and anhedonic-like state measured in the sucrose preference test. ND administration decreased the levels of brain-derived neurotrophic factor and neurotrophin-3 and reduced Na + ,K + -ATPase activity in the hippocampus, striatum and prefrontal cortex. We also found that ND elicited KP activation, as reflected by the increase of IDO activity and kynurenine levels in these brain regions. Moreover, ND decreased serotonin levels and increased 5-hydroxyindoleacetic acid levels in the brain. Treatment with IDO inhibitor 1-methyl-dl-trypthophan (1 mg/kg/i.p.) reversed the behavioral and neurochemical alterations induced by ND. These results indicate for the first time that KP plays a key role in depressive-like behavior and neurotoxicity induced by supraphysiologicaldoses of ND in mice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diphenyl diselenide [(PhSe) 2 ] is a pleiotropic pharmacological agent, but it has low aqueous solubility. The nanoencapsulation of (PhSe) 2 allowed the preparation of an aqueous formulation as well as potentiated its in vitro antitumor effect and the effectiveness in a preclinical model of glioblastoma when administered by the intragastric route. Thus, aiming at maximizing the therapeutic potential of (PhSe) 2 , the present study designed a pegylated-formulation intending to intravenous administration of the (PhSe) 2 as a new approach for glioma therapy. The poly(Ɛ-caprolactone) nanocapsules containing (PhSe) 2 were physically coated with polyethyleneglycol (PEG) using the preformed polymer interfacial deposition technique and evaluated through physicochemical, morphological, spectroscopic, and thermal characteristics. Hemocompatibility was determined by the in vitro hemolysis test and cytotoxicity assays were performed in astrocytes and glioma C6 cells (10-100 μM). The pegylated-nanocapsules had an average diameter of 218 ± 25 nm, polydispersity index of 0.164 ± 0.046, zeta potential of - 8.1 ± 1.6 mV, pH 6.0 ± 0.09, (PhSe) 2 content of 102.00 ± 3.57%, and encapsulation efficiency around 98%. Besides, the (PhSe) 2 pegylated-nanocapsules were spherical, presented absence of chemical interaction among the constituents, and showed higher thermal stability than the non-encapsulated materials. PEG-coated nanocapsules did not cause hemolytic effect while formulations without PEG induced a hemolysis rate above 10%. Moreover, pegylated-nanocapsules had superior in vitro antiglioma effect in comparison to free compound (IC 50 : 24.10 μM and 74.83 μM, respectively). Therefore, the (PhSe) 2 -loaded pegylated-nanocapsule suspensions can be considered a hemocompatible formulation for the glioma treatment by the intravenous route.

Aim: The present work aimed at the DIM-loaded microparticles development and anti-hypernociceptive action evaluation., Method: The formulations were prepared by O/W solvent emulsion-evaporation method and characterised by particle diameter, content and DIM encapsulation efficiency, drug release profile, thermal behaviour and physicochemical state. The anti-hypernociceptive action was evaluated in the animal model of acute inflammatory pain., Result: The MPs had a mean diameter in the micrometric range (368 ± 31 μm), narrow size distribution, DIM content of 150 mg/g, encapsulation efficiency around 84% and prolonged compound release. Evaluations of the association form of DIM to MPs demonstrated the feasibility of the systems to incorporate DIM and increases its thermal stability. An improvement in the anti-hypernociceptive action of DIM was observed by its microencapsuation, because it was increased and prolonged., Conclusion: Therefore, the MPs developed represent a promising formulation for oral administration of the DIM in the treatment of inflammatory pain.

Cisplatin is an antineoplastic drug well recognized for its success in the battle against several types of cancer in adult, juvenile, and child populations. Meanwhile, this drug is also famous due to its serious side effects, such as hepatotoxicity. This study evaluated the hepatoprotective effectiveness of Diphenyl Diselenide (PhSe) 2 and Ebselen in a model of cisplatin-induced toxicity in juvenile rats. Juvenile Wistar rats received a single intraperitoneal (i.p) injection of cisplatin (6 mg/kg) or saline solution, at postnatal day (PND) 21. Ebselen (11 mg/kg) or (PhSe) 2 (12 mg/kg) was intragastrically (i.g) administered in rats from PND 21 to PND 25. At PND 26, the blood and liver were collected for the biochemistry assays. A single administration of cisplatin was enough to alter the makers of hepatic function (an increase of AST activity) and the blood lipid profile (an increase of cholesterol and triglycerides, TG). The cisplatin-induced metabolic disruption was demonstrated by the increase of hepatic glycogen and TG contents and hexokinase, glucose-6-phosphatase, and tyrosine aminotransferase activities; a decrease of citrate synthase activity and the levels of GLUT-2. Cisplatin-induced hepatic oxidative stress was characterized by an increase in reactive oxygen species, TBARS, protein carbonyl, and Nox levels as well as the decrease in NPSH levels. Ebselen and (PhSe) 2 were effective against all alterations caused by this chemotherapy medication. The present findings highlight the (PhSe) 2 and Ebselen similar hepatoprotective effectiveness against cisplatin-induced disruption of metabolic homeostasis and redox balance in juvenile rats., (Copyright © 2020 Elsevier B.V. All rights reserved.)