Bioactivity of selenium-containing pyridinium salts: Prospecting future pharmaceutical constituents to treat liver diseases involving oxidative stress.

Redox imbalance leads to oxidative stress that causes irreversible cellular damage. The incorporation of the antioxidant element selenium (Se) in the structure of pyridinium salts has been used as a strategy in chemical synthesis and can be useful in drug development. We investigated the antioxidant activity of Se-containing pyridinium salts (named Compounds 3A, 3B, and 3C) through in vitro tests. We focused our study on liver protein carbonylation, liver lipoperoxidation, free radical scavenging activity (1,1-diphenyl-2-picryl-hydrazil [DPPH]; 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid [ABTS]), and enzyme-mimetic activity assays (glutathione S-transferase [GST]-like; superoxide dismutase [SOD]-like). In addition, 2-(4-chlorophenyl)-2-oxoethyl)-2-((phenylselanyl)methyl)pyridin-1-ium bromide (3C) was selected to evaluate the acute oral toxicity in mice due to the best antioxidant profile. The three compounds were effective in reducing the levels of protein carbonylation and lipoperoxidation in the liver in a µM concentration range. All compounds demonstrated scavenger activity of DPPH and ABTS radicals, and GST-like action. No significant effects were detected in the SOD-like assay. Experimental data also showed that the acute oral treatment of mice with Compound 3C (50 and 300 mg/kg) did not cause mortality or change markers of liver and kidney functions. In summary, our findings reveal the antioxidant potential of Se-containing pyridinium salts in liver tissue, which could be related to their radical scavenging ability and mimetic action on the GST enzyme. They also demonstrate a low toxicity potential for Compound 3C. Together, the promising results open space for future studies on the therapeutic application of these molecules.

Blueberry Extract Modulates Brain Enzymes Activities and Reduces Neuroinflammation: Promising Effect on Lipopolysaccharide-Induced Depressive-Like Behavior.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders with high rates of prevalence and mortality. MDD is pathophysiologically complex, and treatment options are limited. Blueberries are rich in polyphenols and have neuroprotective potential. The aim of this study was to investigate the effects of blueberry extract on neuroinflammatory and neuroplasticity parameters, as well as Na+/K+-ATPase, monoamine oxidase-A (MAO-A), and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus of mice subject to lipopolysaccharide (LPS)-induced depressive-like behavior. We also analyzed the interaction between anthocyanins and indoleamine 2 3-dioxygenase (IDO). Male Swiss mice (60-day-old) received vehicle, fluoxetine (20 mg/kg), or blueberry extract (100 or 200 mg/kg) intragastrically for 7 days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, the mice were subjected to behavioral tests. Both fluoxetine and blueberry extract (200 mg/kg) decreased the immobility time in the forced swim test, without affecting locomotor activity. Fluoxetine attenuated the decrease of Na+/K+-ATPase in the cerebral cortex, while blueberry extract promoted this same effect in the hippocampus. Additionally, fluoxetine and blueberry extract attenuated the decrease in the activity of MAO-A in the hippocampus. Blueberry extract (200 mg/kg) also prevented LPS-induced increase in AChE activity in the hippocampus as well as LPS upregulation of relative mRNA expression of tumor necrosis factor alpha, interleukin (IL)-1ß, and IL-10 in the cerebral cortex. Molecular docking analysis revealed binding sites for malvidin 3-galactoside (- 7.8 kcal/mol) and malvidin 3-glucoside (- 7.9 kcal/mol) residues with IDO. Taken together, these results indicate that blueberry extract improved depression-like behavior and attenuated the neurochemical and molecular changes in the brains of mice challenged with LPS.

Three -(pyridin-2-yl)-2-(pyridin-2-ylimino)thiazolidin-4-one as a novel inhibitor of cerebral MAO-B activity with antioxidant properties and low toxicity potential.

Some brain diseases are associated with oxidative stress and altered monoamine oxidase (MAO) activity. The objective of this study was to evaluate the antioxidant and neuroprotective actions through MAO inhibition of 3-(pyridin-2-yl)-2-(pyridine-2-ylimino) thiazolidin-4-one (PPIT, a synthetic molecule containing a thiazolidinone nucleus), as well as its effects on toxicity parameters in Swiss female mice. Five in vitro assays were carried out to verify the PPIT antioxidant capacity: protein carbonylation (PC), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1,1-diphenyl-2-picryl-hydrazil (DPPH), ferric ion (Fe3+ ) reducing antioxidant power (FRAP), and superoxide dismutase (SOD)-like activity. The results showed that PPIT reduced the level of PC in the homogenate of the brain. This compound did not demonstrate SOD mimetic activity, but it acted as a free radical scavenger (ABTS and DPPH) and exhibited reducing activity in the FRAP assay. In addition, the effects of PPIT on cerebral MAO activity (MAO-A and B isoforms) were investigated in vitro. Our data revealed inhibition of the MAO-B activity by PPIT with no effects on MAO-A. Lastly, an acute oral toxicity test was conducted in mice. No changes in food intake, body weight, and biochemical markers of kidney and liver damage were detected in mice treated with a high dose of PPIT (300 mg/kg). In conclusion, the present study demonstrated that PPIT exhibits antioxidant activity and selectively inhibits the MAO-B isoform without causing apparent toxicity. These findings suggest PPIT as a potential therapeutic candidate to be tested in preclinical models of brain diseases involving perturbations of MAO-B activity and redox status.

Acute 2-phenyl-3-(phenylselanyl)benzofuran treatment reverses the neurobehavioral alterations induced by sleep deprivation in mice.

Sleep is a fundamental state for maintaining the organism homeostasis. Disruptions in sleep patterns predispose to the appearance of memory impairments and mental disorders, including depression. Recent pre-clinical studies have highlighted the antidepressant-like properties of the synthetic compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1). To further investigate the neuromodulatory effects of SeBZF1, this study aimed to assess its therapeutic efficacy in ameliorating neurobehavioral impairments induced by sleep deprivation (SD) in mice. For this purpose, a method known as multiple platforms over water was used to induce rapid eye movement (REM) SD. Two hours after acute SD (24 h), male Swiss mice received a single treatment of SeBZF1 (5 mg/kg, intragastric route) or fluoxetine (a positive control, 20 mg/kg, intraperitoneal route). Subsequently, behavioral tests were conducted to assess spontaneous motor function (open-field test), depressive-like behavior (tail suspension test), and memory deficits (Y-maze test). Brain structures were utilized to evaluate oxidative stress markers, monoamine oxidase (MAO) and acetylcholinesterase (AChE) activities. Our findings revealed that SD animals displayed depressive-like behavior and memory impairments, which were reverted by SeBZF1 and fluoxetine treatments. SeBZF1 also reverted the increase in lipoperoxidation levels and glutathione peroxidase activity in the pre-frontal cortex in mice exposed to SD. Besides, the increase in hippocampal AChE activity induced by SD was overturned by SeBZF1. Lastly, cortical MAO-B activity was reestablished by SeBZF1 in mice that underwent SD. Based on the main findings of this study, it can be inferred that the compound SeBZF1 reverses the neurobehavioral alterations induced by sleep deprivation in male Swiss mice.

Prevalence of Antimicrobial Resistance in Escherichia coli and Salmonella Species Isolates from Chickens in Live Bird Markets and Boot Swabs from Layer Farms in Timor-Leste.

The rapid emergence of antimicrobial resistance is a global concern, and high levels of resistance have been detected in chicken populations worldwide. The purpose of this study was to determine the prevalence of antimicrobial resistance in Escherichia coli and Salmonella spp. isolated from healthy chickens in Timor-Leste. Through a cross-sectional study, cloacal swabs and boot swabs were collected from 25 live bird markets and two layer farms respectively. E. coli and Salmonella spp. from these samples were tested for susceptibility to six antimicrobials using a disk diffusion test, and a subset was tested for susceptibility to 27 antimicrobials using broth-based microdilution. E. coli and Salmonella spp. isolates showed the highest resistance towards either tetracycline or ampicillin on the disk diffusion test. E. coli from layer farms (odds ratio:5.2; 95%CI 2.0-13.1) and broilers (odds ratio:18.1; 95%CI 5.3-61.2) were more likely to be multi-drug resistant than those from local chickens. Based on the broth-based microdilution test, resistance to antimicrobials in the Timor-Leste Antimicrobial Guidelines for humans were low, except for resistance to ciprofloxacin in Salmonella spp. (47.1%). Colistin resistance in E. coli was 6.6%. Although this study shows that antimicrobial resistance in chickens was generally low in Timor-Leste, there should be ongoing monitoring in commercial chickens as industry growth might be accompanied with increased antimicrobial use.

Antidepressant Potential of a Functionalized 3-Selanyl Benzo[b]Furan Compound in Mice: Focus on the Serotonergic System.

The present study investigated the antidepressant-like potential of a functionalized 3-selanyl benzo[b]furan (SeBZF) in male Swiss mice. To evaluate possible antidepressant-like actions, the compounds SeBZF1-5 (50 mg/kg, intragastric, i.g., route) were acutely screened in the tail suspension tests (TSTs). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) was then selected. Dose-response and time-response curves revealed that SeBFZ3 exerts antidepressant-like effects in the TST (5-50 mg/kg) and forced swimming test (FST; 50 mg/kg). Additional tests demonstrated that pretreatment with receptor antagonists WAY100635 (5-HT1A; 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/C; 1 mg/kg, intraperitoneal, i.p.), or ondansetron (5-HT3; 1 mg/kg, i.p.) blocked the SeBZF3 antidepressant-like effects (50 mg/kg) in the TST. In addition, the coadministration of subeffective doses of SeBZF3 (1 mg/kg, i.g.) and fluoxetine (a selective serotonin reuptake inhibitor; 5 mg/kg, i.p.) produced synergistic action. A high dose of SeBZF3 (300 mg/kg) did not produce oral acute toxicity. The present results provide evidence for the antidepressant-like action of SeBZF3 and its relative safety, as well as predict the possible interactions with the serotonergic system, aiding in the development of novel options to alleviate psychiatric disabilities.

Knowledge, attitudes and practices of government animal health workers on antibiotic use and antibiotic resistance in Timor-Leste.

Introduction: Antibiotic resistance is a global health threat, and there is growing concern on the inappropriate use of antibiotics in the livestock sector especially in low and middle income countries. The purpose of the study was to understand the knowledge, attitudes and practices on antibiotic use and antibiotic resistance of government animal health workers in Timor-Leste. Method: A cross-sectional survey using a census approach was conducted between August 2021 and January 2022 focusing on government animal health workers involved in field work and access to antibiotics. Interviews were face-to-face in the local Tetun language. Descriptive and regression analysis informed by causal diagrams were performed. Result: The study found poor knowledge of antibiotics among participants, with only 8.0% (13/162) able to correctly answer questions on how antibiotics worked. Knowledge of antibiotic resistance was poor as only 29.0% (47/162) of participants had heard of antibiotic resistance and were able to accurately identify that it made antibiotics less effective. Knowledge of antibiotics and knowledge of antibiotic resistance were crudely associated with being a veterinary technician and having university education. Attitude scores were positively influenced by knowledge of antibiotics and antibiotic resistance. Antibiotics were most commonly used in pigs, cattle and buffalo, with oxytetracycline being the most commonly used antibiotics in pigs and chicken. However, most participants reported a lack in supply of this antibiotic (137/162, 78.4%) and other antibiotics. Empiric use of antibiotics in sick animals was common, and some participants used antibiotics for parasitic diseases. Less than a fifth of participants reported ever using human antibiotics, and use of antibiotics for growth promotion was uncommon. Conclusion: There is a need to develop Timor-Leste specific treatment guidelines, strengthen veterinary diagnostic support, improve antibiotic procurement, and develop training programs to address knowledge gaps and poor practices found in this study.

2-Phenyl-3-(phenylselanyl)benzofuran elicits acute antidepressant-like action in male Swiss mice mediated by modulation of the dopaminergic system and reveals therapeutic efficacy in both sexes.

RATIONALE: Depression is a psychiatric disorder that constitutes one of the leading causes of disability worldwide. 2-Phenyl-3-(phenylselanyl)benzofuran (SeBZF1) has been studied as a potential antidepressant drug, but its pharmacological action needs more investigation. OBJECTIVES AND METHODS: Our aim was to extend information about the antidepressant-like action of SeBZF1 using the mouse tail suspension test (TST). Initial experiments investigated the mechanisms involved in the acute antidepressant-like action of SeBZF1 in male Swiss mice. For this purpose, males received noradrenergic or dopaminergic receptor antagonists before acute SeBZF1 administration (50 mg/kg, per oral). In parallel, effects of combined treatment with SeBZF1 and bupropion at sub-effective doses (1 and 3 mg/kg, respectively) were tested. The next experiments were designed to determine the acute effects of SeBZF1 in females through a dose-response curve (5-50 mg/kg). Lastly, the efficacy of a 7-day repeated treatment with SeBZF1 (1 and 5 mg/kg) in mice of both sexes and its safety were evaluated. TST and the open-field test (OFT) were employed in all behavioral experiments. RESULTS: Pre-administration of dopaminergic antagonists (SCH23390, a selective D1R antagonist; sulpiride, a selective D2/D3R antagonist; and haloperidol, a non-selective antagonist), but not of adrenergic α1, α2, and ß-R antagonists, blocked the acute antidepressant-like effects of SeBZF1 in males. Co-administration of sub-effective doses of SeBZF1 and bupropion reduced the depressive phenotype. In addition, acute treatment with SeBZF1 at 50 mg/kg produced a reduction of female immobility. Finally, repeated treatment with SeBZF1 (1 and 5 mg/kg) was effective in causing antidepressant-like effects in both sexes. Locomotor activity, plasma transaminases, and urea levels remained unaltered after SeBZF1 exposure. CONCLUSION: Our findings provide evidence of the involvement of the dopaminergic system in the acutely antidepressant-like action of SeBZF1 in male mice and reveal the compound efficacy when acute or repeatedly administered in both sexes.

Knowledge and Practices on Antibiotic Use and Antibiotic Resistance Among Smallholder Pig Farmers in Timor-Leste.

Antibiotic resistance is an emerging global health threat which is linked to the overuse and misuse of antibiotics. This study was conducted to understand the knowledge and practices of smallholder pig farmers on antibiotic use and resistance in Timor-Leste. A cross-sectional study using a structured face-to-face interview was conducted in three municipalities. The interview was piloted and implemented in the local Tetun language. This study found that knowledge of antibiotics was very poor as only 12.7% (95% CI: 6.3-23.9) of farmers reported knowing what antibiotics were, and of these only one was able to correctly explain how an antibiotic worked. None of the farmers knew about antibiotic resistance and were able to explain the concept correctly. After the definition of antibiotic was explained to the farmer, only 3.6% (95% CI: 0.8-14.9) reported that their pigs had ever received antibiotics, and the majority of farmers whose pigs had not received antibiotics reported the lack of access to veterinary services. When used, antibiotics were only used for treatment with no reported use for disease prevention or growth promotion. None of the commonly used antibiotics were critically important antimicrobials. Compliance with withdrawal periods was not routinely followed. There is a need to improve access to government veterinary services for farmers in Timor-Leste, while addressing identified knowledge gaps on antibiotics and promoting prudent use practices. The findings from this study serve as baseline information to inform future interventions.

Antimicrobial Use in Animals in Timor-Leste Based on Veterinary Antimicrobial Imports between 2016 and 2019.

Monitoring veterinary antimicrobial use is part of the global strategy to tackle antimicrobial resistance. The purpose of this study was to quantify veterinary antimicrobials imported into Timor-Leste between 2016 and 2019 and describe the antimicrobial import profile of importers. Data were obtained from import applications received by the Ministry of Agriculture and Fisheries (MAF) of Timor-Leste. Import quantities were analysed by antimicrobial class, importance for human medicine, recommended route of administration and type of importer. An average of 57.4 kg (s.d. 31.0 kg) and 0.55 mg/kg (s.d. 0.27 mg/kg) animal biomass of antimicrobials was imported per year. Tetracyclines (35.5%), penicillins (23.7%), and macrolides (15.9%) were the commonly imported antimicrobial classes. Antimicrobials imported for parenteral administration were most common (60.1%). MAF was the largest importer (52.4%). Most of the critically important antimicrobials for human medicine were imported by poultry farms for oral administration and use for growth promotion could not be ruled out. In conclusion, the use of antimicrobials in animals in Timor-Leste is very low, in keeping with its predominantly subsistence agriculture system. Farmer education, development of treatment guidelines, and strengthening of the veterinary service is important for addressing the potential future misuse of antimicrobials especially in the commercial poultry industry.

Insights into serotonergic and antioxidant mechanisms involved in antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran in mice.

Monoaminergic and oxidative dysfunctions have been reported to play a role in depression. The present study investigated the antioxidant potential as well as the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in male Swiss mice. Time and dose-response curves were analyzed with the forced swim (FST) and tail suspension (TST) tests, in which SeBZF1 elicited antidepressant-like effects. Serotonergic mechanisms were investigated in the TST. The pre-administration of WAY100635 (selective 5-HT1A receptor antagonist, 0.1 mg/kg, subcutaneous route), ketanserin (5-HT2A/2C receptor antagonist, 1 mg/kg, intraperitoneal route, i.p.), and chlorophenylalaninemethyl ester (p-CPA) (selective tryptophan hydroxylase inhibitor, 100 mg/kg, i.p., for 4 days), but not of ondansetron (selective 5-HT3 receptor antagonist, 1 mg/kg, i.p.), abolished the antidepressant-like action of SeBZF1 (50 mg/kg, intragastric route, i.g.). Co-administration of sub-effective doses of SeBZF1 (1 mg/kg, i.g.) and fluoxetine (5 mg/kg, i.p., selective serotonin reuptake inhibitor) was effective in producing anti-immobility effects in the TST, revealing a synergistic effect. Besides, p-CPA induced hippocampal oxidative stress, characterized by a reduction of total thiols and lipoperoxidation, which was reversed by SeBZF1 (50 mg/kg). The in vitro screening of the antioxidant action of SeBZF1 in brain tissue reinforced these results. Lastly, SeBZF1 did not cause systemic toxicity at a high dose (300 mg/kg). In summary, the present study demonstrated that SeBZF1 exerted antidepressant-like action in male mice which appears to be mediated by the serotonergic system. Moreover, SeBZF1 elicited in vitro antioxidant action in brain tissue, attenuated the hippocampal oxidative damage induced by 5-HT depletion in mice and showed no toxic signs.