RESUMO
Parkinson's disease (PD) is a common neurodegenerative disease characterized by movement disorders as well as loss of dopaminergic neurons. Moreover, genes affecting mitochondrial function, such as SNCA, Parkin, PINK1, DJ-1 and LRRK2, were demonstrated to be associated with PD and other neurodegenerative disease. Additionally, mitochondrial dysfunction and cellular energy imbalance are common markers found in PD. In this study, we used the pink1 null mutants of Drosophila melanogaster as a Parkinson's disease model to investigate how the energetic pathways and mitochondrial functions change during aging in a PD model. In our study, the loss of the pink1 gene decreased the survival percent and the decreased climbing index during aging in pink1-/- flies. Furthermore, there was an impairment in mitochondrial function demonstrated by a decrease in OXPHOS CI&CII-Linked and ETS CI&CII-Linked in pink1-/- flies at 3, 15 and 30 days of life. Interestingly, OXPHOS CII-Linked and ETS CII-Linked presented decreases only at 15 days of life in pink1-/- flies. Moreover, there was an increase in peroxide (H2O2) levels in pink1-/- flies at 15 and 30 days of life. Loss of the pink1 gene also decreased the activity of citrate synthase (CS) and increased the activity of lactate dehydrogenase (LDH) in pink1-/- flies head. Our results demonstrate a metabolic shift in ATP production in pink1-/- flies, which changed from oxidative to glycolytic pathways from 15 days of age, and is apparently more pronounced in the central nervous system.
Assuntos
Proteínas de Drosophila , Doenças Neurodegenerativas , Doença de Parkinson , Envelhecimento , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Cyclophosphamide (CPA) is an alkylating agent used for cancer chemotherapy, organ transplantation, and autoimmune disease treatment. Here, mRNA sequencing and high-resolution respirometry were performed to evaluate the alterations of Drosophila melanogaster gene expression fed with CPA under acute (0.1 mg/mL, for 24 h) and chronic (0.05 mg/mL, for 35 days) treatments. Differential expression analysis was performed using Cufflinks-Cuffdiff, DESeq2, and edgeR software. CPA affected genes are involved in several biological functions, including stress response and immune-related pathways, oxi-reduction and apoptotic processes, and cuticle and vitelline membrane formation. In particular, this is the first report of CPA-induced mitochondrial dysfunction caused by the downregulation of genes involved with mitochondria constituents. CPA treatment also changed the transcription pattern of transposable elements (TEs) from the gypsy and copia superfamilies. The results presented here provided evidence of CPA mitochondrial toxicity mechanisms and that CPA can modify TEs transcription in Drosophila flies.
Assuntos
Ciclofosfamida/toxicidade , Elementos de DNA Transponíveis/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Expressão Gênica , Mitocôndrias , Animais , Apoptose , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxirredução , Peptídeo Hidrolases/genética , Retroelementos/genéticaRESUMO
Exposure to chlorpyrifos (CPF) poses several harmful effects to human and animal health. The present study investigated the influence of diphenyl diselenide (DPDS) on CPF-induced toxicity in Drosophila melanogaster. Firstly, the time course lethality response of virgin flies (2- to 3-day-old) to CPF (0.075-0.6µg/g) and DPDP (5-40µmol/kg) in the diet for 28 consecutive days were investigated. Subsequently, the protective effect of DPDS (10, 20 and 40µmol/kg) on CPF (0.15µg/g)-induced mortality, locomotor deficits, neurotoxicity and oxidative stress was assessed in a co-exposure paradigm for 7 days. Results showed that CPF exposure significantly decreased the percent live flies in a time- and concentration-dependent manner, whereas the percent live flies with DPDS treatment was not statistically different from control following 28 days of treatment. In the co-exposure study, CPF significantly increased flies mortality while the survivors exhibited significant locomotor deficits with decreased acetylcholinesterase (AChE) activity. Dietary supplementation with DPDS was associated with marked decrease in mortality, improvement in locomotor activity and restoration of AChE activity in CPF-exposed flies. Moreover, CPF exposure significantly decreased catalase and glutathione-S-transferase activities, total thiol level with concomitant significant elevation in the levels of reactive oxygen species and thiobarbituric acid reactive substances in the head and body regions of the treated flies. Dietary supplementation with DPDS significantly improved the antioxidant status and prevented CPF-induced oxidative stress, thus demonstrating the protective effect of DPDS in CPF-treated flies.
Assuntos
Derivados de Benzeno/farmacologia , Clorpirifos/toxicidade , Drosophila melanogaster/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Catalase/metabolismo , Drosophila melanogaster/enzimologia , Cabeça , Locomoção/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Análise de Sobrevida , Fatores de TempoRESUMO
The aim of this study was to analyze the effects of cryotherapy on the biochemical and morphological changes in ischemic and reperfused (I/R) gastrocnemius muscle of rats. Forty male Wistar rats were divided into control and I/R groups, and divided based on whether or not the rats were submitted to cryotherapy. Following the reperfusion period, biochemical and morphological analyses were performed. Following cryotherapy, a reduction in thiobarbituric acid-reactive substances and dichlorofluorescein oxidation levels were observed in I/R muscle. Cryotherapy in I/R muscle also minimized effects such as decreased cellular viability, levels of non-protein thiols and calcium ATPase activity as well as increased catalase activity. Cryotherapy also limited mitochondrial dysfunction and decreased the presence of neutrophils in I/R muscle, an effect that was corroborated by reduced myeloperoxidase activity in I/R muscle treated with cryotherapy. The effects of cryotherapy are associated with a reduction in the intensity of the inflammatory response and also with a decrease in mitochondrial dysfunction.
Assuntos
Crioterapia , Isquemia/terapia , Músculo Esquelético/irrigação sanguínea , Traumatismo por Reperfusão/terapia , Análise de Variância , Animais , Biomarcadores/metabolismo , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Isquemia/enzimologia , Isquemia/fisiopatologia , Masculino , Mitocôndrias Musculares/enzimologia , Músculo Esquelético/enzimologia , Estresse Oxidativo/fisiologia , Peroxidase/metabolismo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/fisiopatologiaRESUMO
Diorganoyl dichalcogenide compouds can have antioxidant activity in different in vitro and in vivo models. Here, we have compared the potential antioxidant activity of 1-dinaphthyl diselenide (1-NapSe)(2), 2-dinaphthyl diselenide (2-NapSe)(2), 1-dinaphthyl distelluride (1-NapTe)(2), 2-dinaphthyl ditelluride (2-NapTe)(2) with their well-studied analogs diphenyl diselenide ((PhSe)(2)) and diphenyl telluride ((PhTe)(2)). (PhSe)(2), (PhTe)(2), and naphthalene analogs-inhibited Fe(II)-induced lipid peroxidation, catalytically decomposed hydrogen peroxide and oxidized thiols, such as dithiothreitol (DTT), Cysteine (CYS), dimercaptopropionic acid (DMPS), and thiophenol (PhSH). (PhSe)(2) was the less potent of the tested compounds against Fe(II)-induced lipid peroxidation in brain homogenates and the change in the organic moiety from an aryl to naphthyl group increased considerably the antioxidant potency of diselenide compounds. However, the change from aryl to naphthyl had little effect on the thio-peroxidase-like activity of diorganoyl dichalcogenides. These results suggest that minor changes in the organic moiety of aromatic diselenide compounds can modify profoundly their capacity to inhibit iron-induced lipid peroxidation. The pharmacological properties of organochalcogens are thought to be linked to their capacity of modulating oxidative stress. Consequently, it becomes important to explore the toxicological properties of dinaphthyl diselenides and ditellurides.
Assuntos
Antioxidantes/farmacologia , Derivados de Benzeno/farmacologia , Naftalenos/farmacologia , Compostos Organometálicos/farmacologia , Compostos Organosselênicos/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxirredução , Estresse Oxidativo , Peroxidase/metabolismo , Fenóis/farmacologia , Ratos , Ratos Wistar , Compostos de Sulfidrila/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
This study investigated the cadmium (Cd) intoxication on cognitive, motor and anxiety performance of rats subjected to long-term exposure to diet with Cd salt or with Cd from contaminated potato tubers. Potato plantlets were micropropagated in MS medium and transplanted to plastic trays containing sand. Tubers were collected, planted in sand boxes and cultivated with 0 or 10 µM Cd and, after were oven-dried, powder processed and used for diet. Rats were divided into six groups and fed different diets for 5 months: control, potato, potato+Cd, 1, 5 or 25 mg/kg CdCl2. Cd exposure increased Cd concentration in brain regions. There was a significant decrease in the step-down latency in Cd-intoxicated rats and, elevated plus maze task revealed an anxiolytic effect in rats fed potato diet per se, and an anxiogenic effect in rats fed 25 mg/kg Cd. The brain structures of rats exposed to Cd salt or Cd from tubers showed an increased AChE activity, but Na+,K+-ATPase decreased in cortex, hypothalamus, and cerebellum. Therefore, we suggest an association between the long-term diet of potato tuber and a clear anxiolytic effect. Moreover, we observed an impaired cognition and enhanced anxiety-like behavior displayed by Cd-intoxicated rats coupled with a marked increase of brain Cd concentration, and increase and decrease of AChE and Na+,K+-ATPase activities, respectively.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/enzimologia , Cádmio/toxicidade , Contaminação de Alimentos/análise , Solanum tuberosum/química , Acetilcolinesterase/metabolismo , Animais , Dieta , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Distribuição Aleatória , Ratos , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Treatment with classical neuroleptics in humans can produce a serious side effect, known as tardive dyskinesia (TD). Here, we examined the possible neuroprotective effects of resveratrol, a polyphenol compound contained in red grapes and red wine, in an animal model of orofacial dyskinesia (OD) induced by acute treatment with fluphenazine. Adult male rats were treated during 3 weeks with fluphenazine enantate (25 mg/kg, i.m., single administration) and/or resveratrol (1 mg/kg, s.c., 3 times a week). Vacuous chewing movements (VCMs), locomotor and exploratory performance were evaluated. Fluphenazine treatment produced VCM in 70% of rats and the concomitant treatment with resveratrol decreased the prevalence to 30%, but did not modify the intensity of VCMs. Furthermore, the fluphenazine administration reduced the locomotor and exploratory activity of animals in the open field test. Resveratrol co-treatment was able to protect the reduction of both parameters. Taken together, our data suggest that resveratrol could be considered a potential neuroprotective agent by reducing motor disorders induced by fluphenazine treatment.
Assuntos
Flufenazina/toxicidade , Mastigação/efeitos dos fármacos , Transtornos dos Movimentos/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Estilbenos/uso terapêutico , Animais , Flufenazina/administração & dosagem , Flufenazina/antagonistas & inibidores , Masculino , Transtornos dos Movimentos/fisiopatologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Wistar , Resveratrol , Estilbenos/farmacologiaRESUMO
The aim of the present study was to investigate whether the in vitro pro-oxidant effect of ascorbic acid towards thiol groups could be mediated by free radicals formed during its auto-oxidation and/or by a direct oxidation of -SH groups by its oxidized form (dehydroascorbic acid). This hypothesis was examined by measuring the rate of AA (ascorbic acid) oxidation in MOPS (3-morpholinepropanesulfonic acid buffer) and phosphate buffer (PB). Here we have used dithiothreitol (DTT) as model of vicinal thiol-containing enzymes, namely δ-aminolevulinate dehydratase. The rate of AA and DTT oxidation was more pronounced in the presence of PB than in the MOPS. AA oxidation induced by iron/EDTA complex was significantly reduced by addition of superoxide dismutase, catalase and DTT to the reaction medium. H2O2 alone did not stimulate the oxidation of AA; however, AA oxidation was enhanced significantly with the addition of crescent concentrations of iron. Conversely, in DTT oxidation assay (without AA) the addition of iron, EDTA and H2O2, did not promote the oxidation of -SH groups. Our findings suggest that in the presence of physiological concentrations of AA and thiols, the oxidation of -SH groups is mediated by AA conversion to dehydroascorbic acid with the participation of iron. Furthermore, free radical species formed during the auto-oxidation of AA apparently did not oxidize thiol groups to a significant extent.
RESUMO
Alloxan is a compound widely used in models of diabetes mellitus due to its ability for damage insulin-producing ß-cells. The aim of this study was to investigate acute (after 24h) and sub-acute (after seven days) effects of 200mg/kg alloxan administration on mice. Biochemical parameters as liver, kidney, and blood δ-ALA-D activity, total sulfhydryl content of hepatic and renal tissues, and hepatic and renal content of malondialdehyde (MDA) were evaluated. The histopathology of hepatic and renal tissues of alloxan-treated and control animals was carried out. Further, blood glucose levels were determined in an attempt to correlate alloxan-induced hyperglycemia with changes in thiol status. Results showed that mice exhibited a significant inhibition of hepatic and renal δ-ALA-D activity in addition to a significant decrease in total sulfhydryl groups of same tissues in both acute and sub-acute alloxan administrations. Moreover, alloxan-induced inhibition of δ-ALA-D activity was partly suppressed when enzymatic assay was performed in the presence of dithiothreitol, suggesting that inhibitory effect of alloxan on δ-ALA-D activity is, at least partially, related to the oxidation of the enzyme's essential thiol groups. Blood δ-ALA-D activity was significantly inhibited only 24h after alloxan administration; however, at this time, a hyperglycemic status was not observed in animals. In contrast, a significant increase in blood glucose levels was observed seven days after alloxan administration. Despite of alterations in biochemical parameters, histological tissue examination of alloxan-treated mice revealed typical renal and hepatic parenchyma. Therefore, these results showed that acute toxic effects of alloxan are related, at least partially, to depletion of sulfhydryl groups, and do not closely relate to the development of hyperglycemia in mice.
Assuntos
Aloxano/farmacologia , Inibidores Enzimáticos/farmacologia , Hiperglicemia/enzimologia , Sintase do Porfobilinogênio/antagonistas & inibidores , Aloxano/química , Animais , Glicemia/análise , Ativação Enzimática , Inibidores Enzimáticos/química , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Hiperglicemia/patologia , Rim/efeitos dos fármacos , Rim/enzimologia , Rim/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Estrutura Molecular , Sintase do Porfobilinogênio/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
(S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate, a new telluroamino acid derivative, showed remarkable glutathione peroxidase (GPx)-like activity, attesting to its antioxidant potential. However, the stability and toxicity of this compound has not yet been investigated. The present study was designed to investigate the pharmacological/toxicological properties of this compound in vitro and in vivo. In vitro, this telluroamino acid derivative significantly blocked spontaneous and Fe(II)-induced TBARS formation in rat brain homogenates, demonstrating high antioxidant activity. In addition, it exhibited GPx-like and thiol oxidase activities. However, when subcutaneously administered to mice, (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate indicated genotoxic and mutagenic effect in adult male mice. Considering the differential effects of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate in vitro and in vivo, additional experiments are needed to elucidate the mechanism(s) by which this compound displays its antioxidant/toxicological effects.