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We present our results on the synthesis and preliminary in silico and in vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2-aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20 % to 87 %. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated.

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AIMS: To conduct a systematic review and meta-analysis with the aim of synthesizing existing data on the efficacy and safety of topiramate as an adjunctive treatment for reducing second-generation antipsychotic (SGA)-associated weight gain in children aged 4-18 years. METHODS: We conducted a comprehensive search of PubMed, Embase, PsychNet and Web of Science from time of their inception up to 12 February 2024, including randomized controlled trials that compared SGA treatment with and without topiramate co-administration in children. The primary outcomes were changes in body weight and body mass index (BMI). Heterogeneity was assessed using I2 statistics. RESULTS: This systematic review included five randomized trials, totalling 139 participants (43.9% female; mean [SD] age 11.9 [3.5] years). Four of these trials were included in the meta-analysis, comprising 116 subjects. We found that topiramate was significantly effective both in reducing SGA-associated weight gain, with a mean difference of -2.80 kg (95% confidence interval [CI] -5.28 to -0.31; p = 0.037, I2 = 86.7%) and a standardized mean difference (SMD) of -1.33 (95% CI -2.14 to -0.51; p = 0.014, I2 = 31.7%), and in reducing BMI change compared to placebo (SMD -1.90, 95% CI -3.09 to -0.70; p = 0.02, I2 = 0%). Sedation risk was lower with topiramate than with placebo (odds ratio 0.19, 95% CI 0.11-0.32; p < 0.01, I2 = 0%). No significant differences were found in dropouts, any other side effects, and metabolic parameters, such as triglycerides, total cholesterol, low-density lipoprotein, high-density lipoprotein, and glucose. None of the included studies reported assessments on cognitive side effects. CONCLUSION: This meta-analysis suggests that topiramate is an effective and safe option for mitigating SGA-associated weight gain in children.

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Background: The relationship between cannabis use and the risk of returning to using opioids non-medically during treatment for opioid use disorder (OUD) remains unclear.Objective: We sought to quantify the impact of cannabis use on the risk of non-medical opioid use among people receiving pharmacotherapies for OUD.Methods: A comprehensive search was performed using multiple databases from March 1 to April 5 of 2023. Eligible studies longitudinally assessed the association between cannabis use and non-medical opioid use among people with OUD receiving treatment with buprenorphine, methadone, or naltrexone. We utilized a random-effects model employing the restricted maximum likelihood method. A sensitivity analysis was conducted to understand potential differences between each OUD treatment modality.Results: A total of 10 studies were included in the final meta-analysis. There were 8,367 participants (38% female). The average follow-up time across these studies was 9.7 months (SD = 3.77), ranging from 4 to 15 months. The pharmacotherapies involved were methadone (76.3%) buprenorphine (21.3%), and naltrexone (2.4%). The pooled odds ratio did not indicate that cannabis use significantly influenced non-medical opioid use (OR: 1.00, 95% CI: 0.97-1.04, p = .98). There is evidence of moderate heterogeneity and publication bias.Conclusion: There was no significant association between cannabis use and non-medical opioid use among patients receiving pharmacotherapies for OUD. These findings neither confirm concerns about cannabis increasing non-medical opioid use during MOUD, nor do they endorse its efficacy in decreasing non-medical opioid use with MOUD. This indicates a need for individualized approaches for cannabis use and challenges the requirement of cannabis abstinence to maintain OUD pharmacotherapies.

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SARS-CoV-2 infection triggers distinct patterns of disease development characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SLs) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n = 55), COVID-19 patients (n = 204), and convalescent individuals (n = 77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, a predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, and neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) species (d18:1/24:1) and (d18:1/24:0)were associated with increased risk. Moreover, we observed the enhanced expression of key enzymes involved in the SL pathway in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.

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Almost 90% of patients develop pain immediately after oxaliplatin (OXA) treatment. Here, the impact of aging on OXA-induced acute peripheral neuropathy and the potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) as a new therapeutic strategy were evaluated. In Swiss mice, the oxidative damage and its influence on Mg2+-ATPase and Na+, K+-ATPase activities were investigated. The relationship between the reactive oxygen species (ROS) and nitrate and nitrite (NOx) levels, the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) with the development of OXA-induced acute peripheral neuropathy was also studied. In this study, it was evidenced that OXA-induced acute peripheral neuropathy was exacerbated by aging through increased oxidative damage as well as Na+, K+-ATPase, and Mg+2-ATPase inhibition. 4-PSQ reversed hypersensitivity induced by OXA and aging-aggravated by reducing ROS and NOx levels, through modulation of GPx and SOD activities. 4-PSQ partially reestablish Na+, K+-ATPase activity, but not Mg 2+-ATPase activity. Locomotor and exploratory activities were not affected. This study is the first of its kind, providing new insight into the aging impact on mechanisms involved in OXA-induced acute peripheral neuropathy. Also, it provides evidence on promising 4-PSQ effects on this condition, mainly on aging.

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The present review describes the successful application of organoboron compounds in transition-metal-free C-S, C-Se, and C-Te bond formations. We presented studies regarding these C-Chalcogen bond formations using organoboron reagents, such as boronic acids, boronic esters, borate anions, and several sources of chalcogen atoms/moieties. Moreover, a broad range of transition-metal-free approaches to synthesize sulfides, selenides, and tellurides were described using conventional heating methods, which are sometimes green since they use green solvents, safe reagents, among others. Furthermore, protocols using alternative energy sources, including ultrasound, microwave irradiation, photocatalysis, and electrolytic processes, were also shown to be suitable. These protocols were applied to prepare a broad scope of functionalized chalcogenides with high molecular diversity. These studies and their proposed mechanisms were also reported herein in addition to the reuse of reaction promoters.

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In this study, the deposition of platinum in oxaliplatin (OXA)-exposed mice and the effects of the oxidative damage on the central nervous system were investigated. The relationship between the reactive species (RS) levels as well as the expression and activity of enzymes, such as catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and acetylcholinesterase (AChE), in the development of peripheral neuropathy after OXA exposure, was evidenced. The effects of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on OXA-induced peripheral neuropathy was also investigated. Swiss mice received OXA (10 mg kg-1) or vehicle by intraperitoneal route (days 0 and 2). Oral administration of 4-PSQ (1 mg kg-1) or vehicle was performed on days 2 to 14. Behavioural tasks started on day 9, after the first OXA administration. It was observed that 4-PSQ reduced the mechanical and thermal hypersensitivity induced by OXA. 4-PSQ and OXA did not affect locomotor and exploratory activities. The results revealed, for the first time, a high concentration of platinum in the spinal cord of mice exposed to OXA. 4-PSQ reversed the increased levels of RS in the spinal cord, cerebral cortex and hippocampus of mice exposed to OXA. The alterations in the activity and expression of the GPx, SOD, CAT and AChE induced by OXA exposure were normalized by 4-PSQ. Therefore, the 4-PSQ might be a good prototype for the development of a more effective drug for the treatment of OXA-induced peripheral neuropathy. The results obtained by the present study expanded the knowledge about the mechanisms involved in the physiopathology of peripheral neuropathy. Graphical abstract.

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Growing evidence demonstrates that Oxaliplatin (OXA) is commonly associated with neurotoxicity that leads to emotional and cognitive impairments. The aim of the present study was to evaluate the OXA and Na+, K+-ATPase interaction and to correlate anxious behavior and cognitive impairment induced by this chemotherapeutic in Swiss mice. Also, considering the pharmacological modulation of Na+, K+-ATPase as a potential target for OXA-induced neurotoxicity, the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) was evaluated. Mice received OXA (10 mg kg-1) or vehicle by intraperitoneal route (days 0 and 2). Oral administration of 4-PSQ (1 mg kg-1) or vehicle was performed from days 2-14. Behavioral tasks started from day 12 onwards. On day 15, the animals were sacrificed, and the tissues collected. The effects of OXA and 4-PSQ on activity and expression level of Na+, K+-ATPase in the hippocampus and cerebral cortex, and the plasmatic corticosterone levels were determined. The findings demonstrated a significant positive correlation between anxious behavior and cognitive impairment induced by OXA. OXA caused an increase on the plasmatic corticosterone levels and reduced activity and expression level of Na+, K+-ATPase. 4-PSQ reduced both anxious behavior and cognitive impairment induced by OXA. 4-PSQ effect seems to be due to the modulation of Na+, K+-ATPase and reduction of corticosterone levels. Our results helped to expand knowledge about the mechanisms involved in the physiopathology of the OXA-induced neurotoxicity and strongly indicated that 4-PSQ may be a good prototype for the treatment of anxious behavior and cognitive impairment induced by OXA exposure.

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We described here our results on the use of thiourea as a ligand in the copper catalysed azide-alkyne cycloaddition (CuAAC) of 2-azidobenzaldehyde with alkynes. Reactions were performed reacting 2-azidobenzaldehyde with a range of terminal alkynes using 10 mol % of copper iodide as a catalyst, 20 mol % of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 °C under nitrogen atmosphere. The corresponding 2-(1H-1,2,3-triazoyl)-benzaldehydes (2-TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: ß-secretase (BACE), glycogen synthase kinase (GSK-3ß) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5 a (2-(4-phenyl-1H-1,2,3-triazol-1-yl)benzaldehyde), 5 b (2-(4-(p-tolyl)-1H-1,2,3-triazol-1-yl)benzaldehyde), and 5 d (2-(4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-1-yl)benzaldehyde) were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation. Due the antioxidant potential ally to the affinity with BACE, GSK-3ß and AChE, compound 5 b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5 b (1 mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK-3ß expression.

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A simple method for the direct mono- and bis-organylselenylation of N-substituted pyrroles through a multicomponent reaction promoted by ultrasonic radiation was described. These sonochemical promoted reactions were performed between different primary amines, 2,5-hexanedione and dialkyl, diheteroaryl, or diaryl diselenides, using catalytic amounts of copper iodide. Depending on the amount of copper iodide and diorganyl diselenide used in the reactions, mono- or bis-organylselenylation products were efficiently synthesized in high yields.