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The increase in fungal resistance is a major public health concern. In this context, Candida spp. is an important genus related to invasive diseases, especially in immunosuppressed patients. The relevance of alternative approaches to increasing fungal resistance stands out, in which products of natural origin demonstrate potential antifungal activity in vitro against Candida spp. In this sense, this work aimed to evaluate the in vitro activity of tannic acid against Candida spp. Minimum inhibitory concentration (MIC) was determined for tannic acid and the antifungals, and the checkerboard assay was performed to analyze the interactions between them. Furthermore, we evaluated the tannic acid antibiofilm activity and its possible mechanism of action. Tannic acid showed MIC ranging to 0.06 to 0.5 µg/ml and showed no loss of effectiveness when combined with antifungals. Also, is safe at the concentrations it exerts its antifungal activity in pre-formed biofilms, as demonstrated by IC50 in murine fibroblasts cells and the hemolytic assay. Additionally, its mechanisms of action can be related with induction of signals that lead to apoptosis in fungal cells.
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Candida species are among the priority pathogens in the area of research and development. Due to the problems associated with resistance to antifungals, new therapeutic alternatives are necessary. In this regard, drug repositioning has gained prominence. The objective of this study was to evaluate the activity of three tricyclic antidepressants (TCAs) - amitriptyline (AMT), nortriptyline (NOR) and clomipramine (CLO) - isolated or associated with antifungals against strains of Candida spp., as well as to analyze the possible mechanism of action. Among the methods used were broth microdilution tests, tolerance level assessment, checkerboard assays, flow cytometry and fluorescence microscopy. Furthermore, Candida cells were visualized after treatments by scanning electron microscopy (SEM). AMT presented MIC 50% in the range of 16 to 128 µg/mL, NOR from 8 to 128 µg/mL, and CLO from 8 to 64 µg/mL, with all three TCAs having a fungicidal inhibitory action profile. For these TCAs, there was synergism with amphotericin B (AMB) in 100% of the isolates. In association with fluconazole (FLC) and itraconazole (ITR), there were mostly indifferent interactions. TCAs isolated and associated with AMB reduced cell viability, promoted DNA fragmentation and damage, caused mitochondrial depolarization, externalization of phosphatidylserine, produced reactive oxygen species (ROS), decreased reduced glutathione (GSH) and increased carbonyl protein levels, causing morphological changes. The results suggest the antifungal mechanism of the TCAs works via the apoptotic pathway.
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Introduction. The development of new antifungal drugs has become a global priority, given the increasing cases of fungal diseases together with the rising resistance to available antifungal drugs. In this scenario, drug repositioning has emerged as an alternative for such development, with advantages such as reduced research time and costs.Gap statement. Propafenone is an antiarrhythmic drug whose antifungal activity is poorly described, being a good candidate for further study.Aim. This study aims to evaluate propafenone activity against different species of Candida spp. to evaluate its combination with standard antifungals, as well as its possible action mechanism.Methodology. To this end, we carried out tests against strains of Candida albicans, Candida auris, Candida parapsilosis, Candida tropicalis, Candida glabrata and Candida krusei based on the evaluation of the MIC, minimum fungicidal concentration and tolerance level, along with checkerboard and flow cytometry tests with clinical strains and cell structure analysis by scanning electron microscopy (SEM).Results. The results showed that propafenone has a 50% MIC ranging from 32 to 256 µg ml-1, with fungicidal activity and positive interactions with itraconazole in 83.3% of the strains evaluated. The effects of the treatments observed by SEM were extensive damage to the cell structure, while flow cytometry revealed the apoptotic potential of propafenone against Candida spp.Conclusion. Taken together, these results indicate that propafenone has the potential for repositioning as an antifungal drug.
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Antifúngicos , Candida , Testes de Sensibilidade Microbiana , Propafenona , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candida/crescimento & desenvolvimento , Propafenona/farmacologia , Humanos , Itraconazol/farmacologia , Sinergismo Farmacológico , Farmacorresistência Fúngica/efeitos dos fármacos , Candidíase/microbiologia , Candidíase/tratamento farmacológico , Reposicionamento de MedicamentosRESUMO
Introduction. Antibiotic resistance is a major threat to public health, particularly with methicillin-resistant Staphylococcus aureus (MRSA) being a leading cause of antimicrobial resistance. To combat this problem, drug repurposing offers a promising solution for the discovery of new antibacterial agents.Hypothesis. Menadione exhibits antibacterial activity against methicillin-sensitive and methicillin-resistant S. aureus strains, both alone and in combination with oxacillin. Its primary mechanism of action involves inducing oxidative stress.Methodology. Sensitivity assays were performed using broth microdilution. The interaction between menadione, oxacillin, and antioxidants was assessed using checkerboard technique. Mechanism of action was evaluated using flow cytometry, fluorescence microscopy, and in silico analysis.Aim. The aim of this study was to evaluate the in vitro antibacterial potential of menadione against planktonic and biofilm forms of methicillin-sensitive and resistant S. aureus strains. It also examined its role as a modulator of oxacillin activity and investigated the mechanism of action involved in its activity.Results. Menadione showed antibacterial activity against planktonic cells at concentrations ranging from 2 to 32 µg ml-1, with bacteriostatic action. When combined with oxacillin, it exhibited an additive and synergistic effect against the tested strains. Menadione also demonstrated antibiofilm activity at subinhibitory concentrations and effectively combated biofilms with reduced sensitivity to oxacillin alone. Its mechanism of action involves the production of reactive oxygen species (ROS) and DNA damage. It also showed interactions with important targets, such as DNA gyrase and dehydroesqualene synthase. The presence of ascorbic acid reversed its effects.Conclusion. Menadione exhibited antibacterial and antibiofilm activity against MRSA strains, suggesting its potential as an adjunct in the treatment of S. aureus infections. The main mechanism of action involves the production of ROS, which subsequently leads to DNA damage. Additionally, the activity of menadione can be complemented by its interaction with important virulence targets.
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Staphylococcus aureus Resistente à Meticilina , Oxacilina , Oxacilina/farmacologia , Vitamina K 3/farmacologia , Meticilina , Staphylococcus aureus , Espécies Reativas de Oxigênio , Antibacterianos/farmacologia , BiofilmesRESUMO
The emergence of antibiotic resistance poses a serious and challenging threat to healthcare systems, making it imperative to discover novel therapeutic options. This work reports the isolation and characterization of a thermostable trypsin inhibitor from chia (Salvia hispanica L.) seeds, with antibacterial activity against Staphylococcus aureus sensitive and resistant to methicillin. The trypsin inhibitor ShTI was purified from chia seeds through crude extract heat treatment, followed by affinity and reversed-phase chromatography. Tricine-SDS-PAGE revealed a single glycoprotein band of ~ 11 kDa under nonreducing conditions, confirmed by mass spectrometry analysis (11.558 kDa). ShTI was remarkably stable under high temperatures (100 °C; 120 min) and a broad pH range (2-10; 30 min). Upon exposure to DTT (0.1 M; 120 min), ShTI antitrypsin activity was partially lost (~ 38%), indicating the participation of disulfide bridges in its structure. ShTI is a competitive inhibitor (Ki = 1.79 × 10-8 M; IC50 = 1.74 × 10-8 M) that forms a 1:1 stoichiometry ratio for the ShTI:trypsin complex. ShTI displayed antibacterial activity alone (MICs range from 15.83 to 19.03 µM) and in combination with oxacillin (FICI range from 0.20 to 0.33) against strains of S. aureus, including methicillin-resistant strains. Overproduction of reactive oxygen species and plasma membrane pore formation are involved in the antibacterial action mode of ShTI. Overall, ShTI represents a novel candidate for use as a therapeutic agent for the bacterial management of S. aureus infections.
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Oxacilina , Staphylococcus aureus , Oxacilina/farmacologia , Oxacilina/análise , Inibidores da Tripsina/farmacologia , Inibidores da Tripsina/análise , Salvia hispanica , Antibacterianos/farmacologia , Sementes/química , Combinação de MedicamentosRESUMO
Introduction. Candida spp. are commensal fungal pathogens of humans, but when there is an imbalance in the microbiota, or weak host immunity, these yeasts can become pathogenic, generating high medical costs.Gap Statement. With the increase in resistance to conventional antifungals, the development of new therapeutic strategies is necessary. This study evaluated the in vitro antifungal activity of chlorogenic acid against fluconazole-resistant strains of Candida spp. Mechanism of action through flow cytometry and in silico analyses, as well as molecular docking assays with ALS3 and SAP5, important proteins in the pathogenesis of Candida albicans associated with the adhesion process and biofilm formation.Results. The chlorogenic acid showed in vitro antifungal activity against the strains tested, causing reduced cell viability, increased potential for mitochondrial depolarization and production of reactive oxygen species, DNA fragmentation and phosphatidylserine externalization, indicating an apoptotic process. Concerning the analysis through docking, the complexes formed between chlorogenic acid and the targets Thymidylate Kinase, CYP51, 1Yeast Cytochrome BC1 Complex e Exo-B-(1,3)-glucanase demonstrated more favourable binding energy. In addition, chlorogenic acid presented significant interactions with the ALS3 active site residues of C. albicans, important in the adhesion process and resistance to fluconazole. Regarding molecular docking with SAP5, no significant interactions were found between chlorogenic acid and the active site of the enzyme.Conclusion. We concluded that chlorogenic acid has potential use as an adjuvant in antifungal therapies, due to its anti-Candida activity and ability to interact with important drug targets.
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Antifúngicos , Fluconazol , Antifúngicos/farmacologia , Apoptose , Biofilmes , Candida , Candida albicans , Ácido Clorogênico/farmacologia , Farmacorresistência Fúngica , Fluconazol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento MolecularRESUMO
The antimicrobial activity of an experimental solution containing essential oil of Lippia sidoides for denture cleaning was evaluated by (1) minimum inhibitory (MIC) and fungicidal/bactericidal concentration (MFC/MBC) tests against Candida albicans, Staphylococcus aureus, and Pseudomona aeruginosa; (2) the metabolic activity of C. albicans biofilm formed on flat-bottom microplates and denture base specimens based on the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); and (3) scanning electron microscopy, to evaluate the fungal biofilm morphology. The solution showed antimicrobial action against the pathogens tested (C. albicans - MIC and MFC: 19.53 µg ml-1, S. aureus - MIC and MBC: 78.12 µg ml-1, P. aeruginosa - MIC: 625 µg ml-1, MBC: 2,500 µg ml-1), reduced the metabolic activity of C. albicans biofilm up to 97%, and caused cell wall damage at low concentrations (195.3-390.6 µg ml-1) and in short time periods (20 min). Therefore, the experimental solution has the potential to be used as an alternative in the prevention and treatment of denture-induced infections.
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Lippia , Óleos Voláteis , Biofilmes , Candida albicans , Higienizadores de Dentadura , Óleos Voláteis/farmacologia , Staphylococcus aureusRESUMO
The genus Candida spp. has been highlighted as one of the main etiological agents causing fungal infections, with Candida albicans being the most prominent, responsible for most cases of candidemia. Due to its capacity for invasion and tissue adhesion, it is associated with the formation of biofilms, mainly in the environment and hospital devices, decreasing the effectiveness of available treatments. The repositioning of drugs, which is characterized by the use of drugs already on the market for other purposes, together with molecular-docking methods can be used aiming at the faster development of new antifungals to combat micro-organisms. This study aimed to evaluate the antifungal effect of diazepam on mature C. albicans biofilms in vitro and its action on biofilm in formation, as well as its mechanism of action and interaction with structures related to the adhesion of C. albicans, ALS3 and SAP5. To determine the MIC, the broth microdilution test was used according to protocol M27-A3 (CLSI, 2008). In vitro biofilm formation tests were performed using 96-well plates, followed by molecular-docking protocols to analyse the binding agent interaction with ALS3 and SAP5 targets. The results indicate that diazepam has antimicrobial activity against planktonic cells of Candida spp. and C. albicans biofilms, interacting with important virulence factors related to biofilm formation (ALS3 and SAP5). In addition, treatment with diazepam triggered a series of events in C. albicans cells, such as loss of membrane integrity, mitochondrial depolarization and increased production of EROs, causing DNA damage and consequent cell apoptosis.
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Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/efeitos dos fármacos , Diazepam/farmacologia , Farmacorresistência Fúngica/efeitos dos fármacos , Ácido Aspártico Endopeptidases/metabolismo , Candida/patogenicidade , Fluconazol/farmacologia , Proteínas Fúngicas/metabolismoRESUMO
Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the Candida genus. Here, 20 cinnamic and benzoic acid amides were synthesized and tested for inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019. Five compounds inhibited the Candida strains tested, with compound 16 (MIC = 7.8 µg/mL) producing stronger antifungal activity than fluconazole (MIC = 16 µg/mL) against C. krusei ATCC 14243. It was also tested against eight Candida strains, including five clinical strains resistant to fluconazole, and showed an inhibitory effect against all strains tested (MIC = 85.3-341.3 µg/mL). The MIC value against C. krusei ATCC 6258 was 85.3 mcg/mL, while against C. krusei ATCC 14243, it was 10.9 times smaller. This strain had greater sensitivity to the antifungal action of compound 16. The inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019 was also achieved by compounds 2, 9, 12, 14 and 15. Computational experiments combining target fishing, molecular docking and molecular dynamics simulations were performed to study the potential mechanism of action of compound 16 against C. krusei. From these, a multi-target mechanism of action is proposed for this compound that involves proteins related to critical cellular processes such as the redox balance, kinases-mediated signaling, protein folding and cell wall synthesis. The modeling results might guide future experiments focusing on the wet-lab investigation of the mechanism of action of this series of compounds, as well as on the optimization of their inhibitory potency.
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Amidas/farmacologia , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Modelos Moleculares , Amidas/química , Anti-Infecciosos/farmacologia , Halogenação , Testes de Sensibilidade Microbiana , TermodinâmicaRESUMO
The emergence of multidrug-resistant (MDR) bacteria is a global problem, by reducing the effectiveness of traditional antibiotics and decreasing the therapeutic arsenal to treat bacterial infections. This has led to an increase in researches about how to overcome this resistance to antibiotics. One strategy is the repositioning (or repurposing) of existing drugs not previously used to combat microorganisms, rather than the development of new drugs. Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRIs) and is considered one of the first highly selective antidepressants of the monoamine neurotransmitter serotonin (5-HT). The objective of this study is to prepare and physically characterize fluoxetine microparticles with galactomannan and evaluate their efficacy against strains of Staphylococcus aureus sensitive and resistant to methicillin. The microparticles were analyzed by differential scanning calorimetry (DSC), infrared analysis (IR) and X-ray diffraction (XRD). In addition, the percentage of encapsulation efficiency (EE%) and drug release kinetics were determined in vitro, along with the determination of the minimum inhibitory concentration (MIC) and evaluation of the action against biofilms. Physical tests were conducted to characterize galactomannan (GAL), FLX, oxacillin (OXA) and the galactomannan/fluoxetine microparticles (GFM). The EE% value was 98 % and, in regard the release, tests with the microparticles released about 60 % of the drug in 200 min. The isolated MIC results for FLX (255 µg/mL) and OXA MIC (1.97-15.62 µg/mL) showed that the strains were resistant. Furthermore, in the biofilms, microparticles showed statically significant improvement for all concentrations used. The study revealed that fluoxetine encapsulated in microparticles has the potential to act as an effective antimicrobial agent.
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Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Reposicionamento de Medicamentos , Fluoxetina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Galactose/análogos & derivados , Mananas/química , Testes de Sensibilidade MicrobianaRESUMO
This study evaluated the effect of etomidate against biofilms of Candida spp. and analysed through molecular docking the interaction of this drug with ALS3, an important protein for fungal adhesion. Three fluconazole-resistant fungi were used: Candida albicans, Candida parapsilosis and Candida tropicalis. Growing biofilms were exposed to etomidate at 31.25-500 µg ml-1. Then, an ALS3 adhesive protein from C. albicans was analysed through a molecular mapping technique, composed of a sequence of algorithms to perform molecular mapping simulation based on classic force field theory. Etomidate showed antifungal activity against growing biofilms of resistant C. albicans, C. parapsilosis and C. tropicalis at all concentrations used in the study. The etomidate coupling analysis revealed three interactions with the residues of interest compared to hepta-threonine, which remained at the ALS3 site. In addition, etomidate decreased the expression of mannoproteins on the surface of C. albicans. These results revealed that etomidate inhibited the growth of biofilms.
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Candida/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Etomidato/farmacologia , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Etomidato/metabolismo , Fluconazol/farmacologia , Proteínas Fúngicas/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular/métodosRESUMO
The increased incidence of candidemia in terciary hospitals worldwide and the cross-resistance frequency require the new therapeutic strategies development. Recently, our research group demonstrated three semi-synthetic naphthofuranquinones (NFQs) with a significant antifungal activity in a fluconazole-resistant (FLC) C. tropicalis strain. The current study aimed to investigate the action's preliminary mechanisms of NFQs by several standardized methods such as proteomic and flow cytometry analyzes, comet assay, immunohistochemistry and confocal microscopy evaluation. Our data showed C. tropicalis 24 h treated with all NFQs induced an expression's increase of proteins involved in the metabolic response to stress, energy metabolism, glycolysis, nucleosome assembly and translation process. Some aspects of proteomic analysis are in consonance with our flow cytometry analysis which indicated an augmentation of intracellular ROS, mitochondrial dysfunction and DNA strand breaks (neutral comet assay and γ-H2AX detection). In conclusion, our data highlights the great contribution of ROS as a key event, probably not the one, associated to anti-candida properties of studied NFQs.
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Antifúngicos/farmacologia , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/metabolismo , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/fisiologia , Naftoquinonas/farmacologia , Proteômica , Espécies Reativas de Oxigênio/metabolismo , Antifúngicos/síntese química , Antifúngicos/química , Candida tropicalis/genética , Candidemia/microbiologia , Ciclo Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , DNA Fúngico/genética , Metabolismo Energético/efeitos dos fármacos , Fluconazol/farmacologia , Glicólise/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Naftoquinonas/síntese química , Naftoquinonas/química , Estresse PsicológicoRESUMO
O Brasil é um dos países sul-americanos com maior prevalência de acidentes ofídicos por ano, entretanto esses acontecimentos são considerados negligenciados por países tropicais e subtropicais em desenvolvimento. O objetivo deste artigo foi traçar o perfil epidemiológico dos acidentes ofídicos notificados no período 2011-2015, em um Centro de Assistência Toxicológica. Para tanto, fez-se uma pesquisa transversal de abordagem quantitativa realizada com dados epidemiológicos registrados e documentados nas fichas de notificação e de atendimento de acidentes ofídicos. Foram coletadas, para análise, nove variáveis, e os dados encontrados foram analisados por meio de estatística descritiva. Assim, os resultados indicaram a notificação de 183 casos, sendo 19,13% relativos aos acidentes botrópicos. O sexo masculino foi o mais acometido, com 67,76%, e predominou a faixa etária de 10 a 49 anos (73,22%), tendo os membros inferiores como a região anatômica mais afetada (74,32%). A maioria das ocorrências foi na zona rural (54,10%), principalmente agricultores (26,23%), na ocasião em que exerciam sua ocupação (13,66%). Concluiu-se que é necessário o desenvolvimento de pesquisas que contribuam para o (re)conhecimento do perfil epidemiológico desses acidentes como forma de favorecer o desenvolvimento de estratégias preventivas, bem como reforçar a importância da identificação das espécies responsáveis pelos acidentes para que haja um tratamento efetivo e menor risco de ocorrência de óbitos e sequelas nos indivíduos acometidos.
Brazil is one of the South American countries with bigger prevalence of ophidian accidents by year, however these events are considered neglected by tropical and subtropical countries in development process. The objective of this article was to trace the epidemiological profile of ophidian accidents notified from 2011 to 2015 in a Toxicology Assistance Center. For this purpose, a cross-sectional research with quantitative approach was required, carried out with epidemiological data registered and documented to the notification and attention files of snakebite. Nine variables were collected for the research, and data found were analyzed by descriptive statistics. Thus, results indicate the notification of 183 events, 19.13% comprising Bothrops accidents. Male gender was the most affected, with 67,76%, and the age group from 10 to 49 was predominant (73,22%), lower limbs were the most affected body part (74,32%). The majority of the occurrences happened in rural area (54,10), mainly farmers (26,23%), as they were working (13,66%). In conclusion, it's necessary to develop researches that contribute to the (re)cognition of the epidemiological profile of such accidents as a way of favoring the development of preventive strategies, as well as to reinforce the importance of identifying the species responsible for the accidents in order to provide effective treatment and lower the risk of death occurrences and sequels to the individuals affected.
El Brasil es uno de los países sudamericanos con mayor prevalencia de accidentes ofídicos al año, sin embargo estos acontecimientos son considerados descuidados por países tropicales y subtropicales en desarrollo. El objetivo de este artículo fue trazar el perfil epidemiológico de los accidentes ofídicos notificados en el período de 2011 hasta 2015, en un Centro de Asistencia Toxicológica. Para ello, se ha hecho una investigación transversal de abordaje cuantitativo, realizado utilizando datos epidemiológicos registrados y documentados en las fichas de notificación y de atención de accidentes ofídicos. Fueron recogidas para el análisis nueve variables, y los datos encontrados fueron analizados por medio de la estadística descriptiva. Así, los resultados indicaron la notificación de 183 casos, siendo que el 19,13% comprende los accidentes botrópicos. El sexo masculino fue el más acometido, con el 67,76%, y ha predominado el grupo de edad de 10 hasta 49 años (73,22%), teniendo los miembros inferiores como la región anatómica más afectada (74,32%). La mayoría de las ocurrencias fue en la zona rural (54,10%), principalmente agricultores (26,23%), en la ocasión en que ejercían su ocupación (13,66%). Se concluyó que es necesario el desarrollo de investigaciones que contribuyan al (re)conocimiento del perfil epidemiológico de esos accidentes como forma de favorecer el desarrollo de estrategias preventivas, así como reforzar la importancia de la identificación de las especies responsables por los accidentes, para que haya un tratamiento efectivo y un menor riesgo de ocurrencia de muertes y secuelas en los individuos acometidos.
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Humanos , Animais , Mordeduras de Serpentes , Toxicologia , Perfil de Saúde , EpidemiologiaRESUMO
OBJECTIVES: The first drug repurposed for the treatment of depression was the tuberculostatic iproniazid. At present, drugs belonging to new classes of antidepressants still have antimicrobial effects. Dysbiosis of gut microbiota was implicated in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut-brain axis, the focus of this narrative review is to compile the available studies regarding the influences of gut microbiota in behavior and depression and to show the antimicrobial effect of antidepressant drugs. A discussion regarding the possible contribution of the antimicrobial effect of antidepressant drugs to its effectiveness/resistance is included. METHODS: The search included relevant articles from PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge. RESULTS: MDD is associated with changes in gut permeability and microbiota composition. In this respect, antidepressant drugs present antimicrobial effects that could also be related to the effectiveness of these drugs for MDD treatment. Conversely, some antimicrobials present antidepressant effects. CONCLUSION: Both antidepressants and antimicrobials present neuroprotective/antidepressant and antimicrobial effects. Further studies are needed to evaluate the participation of antimicrobial mechanisms of antidepressants in MDD treatment as well as to determine the contribution of this effect to antidepressant resistance.
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Anti-Infecciosos/efeitos adversos , Antidepressivos/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/microbiologia , Disbiose/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Anti-Infecciosos/administração & dosagem , Antidepressivos/administração & dosagem , HumanosRESUMO
Tardive dyskinesia (TD) is an iatrogenic syndrome being a significant adverse outcome of typical and atypical antipsychotic therapy. Recently we demonstrated that vitamins B (B1, B6, B12 alone or in combination) were able to prevent haloperidol-induced orofacial dyskinesia (OD) possibly by their antioxidant activity in the striatum, using a well-established model of TD. Here, based on the fact that alterations in cholinergic neurotransmission are related to TD pathophysiology and that vitamins B seems to influence brain cholinergic neurotransmission, we decided to investigate the effects of vitamins B1, B6, B12 and their association, vitamin B cocktail in haloperidol-induced cholinergic alterations, evaluated by alterations in acetylcholinesterase (AChE) activity, in striatum, prefrontal cortex and hippocampus, as a way to determine the participation of cholinergic neurotransmission, in these vitamins antidyskinetic mechanism. Haloperidol 1 mg/kg i.p. daily administration during 21 days to Wistar rats caused OD while decreased AChE activity in all brain areas studied. Vitamins B administration (B1:B6:B12 at 60:60:0.6 mg/kg, s.c) alone and vitamin B cocktail co-administered with haloperidol prevented OD development and increased AChE activity in all brain areas studied, with the maximum activity increment observed in the hippocampus of the animals co-treated with vitamin B12 and vitamin B cocktail. The antidyskinetic drug, clozapine did not induce OD and increased AChE activity similarly to the groups coadministered with vitamin B and HAL. The present data suggest that vitamins B can prevent haloperidol-induced alterations in AChE activity what can be related to the mechanism underlying their antidyskinetic effect.
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Acetilcolinesterase/metabolismo , Antipsicóticos/toxicidade , Encéfalo/enzimologia , Haloperidol/toxicidade , Transtornos dos Movimentos/prevenção & controle , Complexo Vitamínico B/uso terapêutico , Animais , Masculino , Transtornos dos Movimentos/enzimologia , Ratos , Ratos WistarRESUMO
Previous experiments have shown that the generation of free radicals in rat brain homogenates is increased following pilocarpine-induced seizures and status epilepticus (SE). This study was aimed at investigating the changes in neurochemical mechanisms such as lipid peroxidation levels, nitrite content, glutathione reduced (GSH) concentration, superoxide dismutase and catalase activities in the frontal cortex and the striatum of Wistar adult rats after seizures and SE induced by pilocarpine. The control group was treated with 0.9% saline and another group of rats received pilocarpine (400 mg/kg, i.p.). Both groups were sacrificed 24 h after the treatments. Lipid peroxidation level, nitrite content, GSH concentration and enzymatic activities were measured by using spectrophotometric methods. Our findings showed that pilocarpine administration and its resulting seizures and SE produced a significant increase of lipid peroxidation level in the striatum (47%) and frontal cortex (59%). Nitrite contents increased 49% and 73% in striatum and frontal cortex in pilocarpine group, respectively. In GSH concentrations were decreases of 54% and 58% in the striatum and frontal cortex in pilocarpine group, respectively. The catalase activity increased 39% and 49% in the striatum and frontal cortex, respectively. The superoxide dismutase activity was not altered in the striatum, but it was present at a 24% increase in frontal cortex. These results suggest that there is a direct relationship between the lipid peroxidation and nitrite contents during epileptic activity that can be responsible for the superoxide dismutase and catalase enzymatic activity changes observed during the establishment of seizures and SE induced by pilocarpine.