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The Bauhinia ungulata, also known by its common name "pata de vaca", is one of the species used in Brazil for medicinal purposes, and is commonly used for the treatment of diabetes. In this study, the authors studied the interaction between the chemical constituents which are present in the essential oil of Bauhinia ungulata (EOBU), collected in Boa Vista-RR, Legal Amazon, and their effects on the enzyme acetylcholinesterase (AChE) in the essential oil. The analysis that we perform includes proton magnetic resonance ( 1H NMR), enzymatic inhibition, molecular docking, in silico toxicity prediction, enrichment analysis, and target prediction for biological interactions. According to the tests performed on the essential oil, it obtained 100% inhibition of the enzyme AChE. During 1H NMR experiments, it was found that α- Bisabolol, one of the main components, had a significant alteration in its chemical shift. A molecular docking analysis confirmed that this compound binds to the AChE enzyme, which confirms the 1H NMR analysis. The results of this work showed that the major component of EOBU acted as a possible inhibitor of AChE enzyme in vitro and in silico assays. These results show that EOBU could be potentially applied in Alzheimer's disease treatment.
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Acetilcolinesterase , Bauhinia , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Óleos Voláteis , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/química , Bauhinia/química , Brasil , Acetilcolinesterase/metabolismo , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Simulação por Computador , Sesquiterpenos/farmacologia , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/químicaRESUMO
One prominent aspect of Parkinson's disease (PD) is the presence of elevated levels of free radicals, including reactive oxygen species (ROS). Syagrus coronata (S. coronata), a palm tree, exhibits antioxidant activity attributed to its phytochemical composition, containing fatty acids, polyphenols, and flavonoids. The aim of this investigation was to examine the potential neuroprotective effects of S. coronata fixed oil against rotenone-induced toxicity using Drosophila melanogaster. Young Drosophila specimens (3-4 d old) were exposed to a diet supplemented with rotenone (50 µM) for 7 d with and without the inclusion of S. coronata fixed oil (0.2 mg/g diet). Data demonstrated that rotenone exposure resulted in significant locomotor impairment and increased mortality rates in flies. Further, rotenone administration reduced total thiol levels but elevated lipid peroxidation, iron (Fe) levels, and nitric oxide (NO) levels while decreasing the reduced capacity of mitochondria. Concomitant administration of S. coronata exhibited a protective effect against rotenone, as evidenced by a return to control levels of Fe, NO, and total thiols, lowered lipid peroxidation levels, reversed locomotor impairment, and enhanced % cell viability. Molecular docking of the oil lipidic components with antioxidant enzymes showed strong binding affinity to superoxide dismutase (SOD) and glutathione peroxidase (GPX1) enzymes. Overall, treatment with S. coronata fixed oil was found to prevent rotenone-induced movement disorders and oxidative stress in Drosophila melanogaster.
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Transtornos dos Movimentos , Rotenona , Animais , Drosophila melanogaster , Simulação de Acoplamento Molecular , Estresse Oxidativo , Antioxidantes/farmacologia , Óxido Nítrico/metabolismoRESUMO
INTRODUCTION: Bee venom has therapeutics and pharmacological properties. Further toxicological studies on animal models are necessary due to the severe allergic reactions caused by this product. METHOD: Here, Caenorhabditis elegans was used as an in vivo toxicity model, while breast cancer cells were used to evaluate the pharmacological benefits. The bee venom utilized in this research was collected from Apis mellifera species found in Northeast Brazil. The cytotoxicity caused by bee venom was measured by MTT assay on MDA-MB-231 and J774 A.1 cells during 24 - 72 hours of exposure. C. elegans at the L4 larval stage were exposed for three hours to M9 buffer or bee venom. Survival, behavioral parameters, reproduction, DAF-16 transcription factor translocation, the expression of superoxide dismutase (SOD), and metabolomics were analyzed. Bee venom suppressed the growth of MDA-MB-231 cancer cells and exhibited cytotoxic effects on macrophages. Also, decreased C. elegans survival impacted its behaviors by decreasing C. elegans feeding behavior, movement, and reproduction. RESULTS: Bee venom did not increase the expression of SOD-3, but it enhanced DAF-16 translocation from the cytoplasm to the nucleus. C. elegans metabolites differed after bee venom exposure, primarily related to aminoacyl- tRNA biosynthesis, glycine, serine and threonine metabolism, and sphingolipid and purine metabolic pathways. Our findings indicate that exposure to bee venom resulted in harmful effects on the cells and animal models examined. CONCLUSION: Thus, due to its potential toxic effect and induction of allergic reactions, using bee venom as a therapeutic approach has been limited. The development of controlled-release drug strategies to improve this natural product's efficacy and safety should be intensified.
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Antineoplásicos , Venenos de Abelha , Caenorhabditis elegans , Animais , Humanos , Venenos de Abelha/farmacologia , Venenos de Abelha/química , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Relação Dose-Resposta a Droga , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Relação Estrutura-Atividade , Feminino , Estrutura MolecularRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, the first being Alzheimer's disease. Patients with PD have a loss of dopaminergic neurons in the substantia nigra of the basal ganglia, which controls voluntary movements, causing a motor impairment as a result of dopaminergic signaling impairment. Studies have shown that mutations in several genes, such as SNCA, PARK2, PINK1, DJ-1, ATP13A2, and LRRK2, and the exposure to neurotoxic agents can potentially increase the chances of PD development. The nematode Caenorhabditis elegans (C. elegans) plays an important role in studying the risk factors, such as genetic factors, aging, exposure to chemicals, disease progression, and drug treatments for PD. C. elegans has a conserved neurotransmission system during evolution; it produces dopamine, through the eight dopaminergic neurons; it can be used to study the effect of neurotoxins and also has strains that express human α-synuclein. Furthermore, the human PD-related genes, LRK-1, PINK-1, PDR-1, DJR-1.1, and CATP-6, are present and functional in this model. Therefore, this review focuses on highlighting and discussing the use of C. elegans an in vivo model in PD-related studies. Here, we identified that nematodes exposed to the neurotoxins, such as 6-OHDA, MPTP, paraquat, and rotenone, had a progressive loss of dopaminergic neurons, dopamine deficits, and decreased survival rate. Several studies have reported that expression of human LRRK2 (G2019S) caused neurodegeneration and pink-1, pdr-1, and djr-1.1 deletion caused several effects PD-related in C. elegans, including mitochondrial dysfunctions. Of note, the deletion of catp-6 in nematodes caused behavioral dysfunction, mitochondrial damage, and reduced survival. In addition, nematodes expressing α-synuclein had neurodegeneration and dopamine-dependent deficits. Therefore, C. elegans can be considered an accurate animal model of PD that can be used to elucidate to assess the underlying mechanisms implicated in PD to find novel therapeutic targets.
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Proteínas de Caenorhabditis elegans , Doenças Neurodegenerativas , Doença de Parkinson , Animais , Humanos , Doença de Parkinson/genética , alfa-Sinucleína/genética , Caenorhabditis elegans , Neurotoxinas , Dopamina , Adenosina Trifosfatases , Proteínas de Caenorhabditis elegans/genéticaRESUMO
Bauhinia ungulata is an antioxidant medicinal plant that has been manipuled in Brazil to lower glycemic index as well is for alternative treatment for diabetes. Therefore, the present hearch has aimed to investigates the antioxidant effects of the essential oil of Bauhinia ungulata L. (EOBU) collected in Amazon region better specified in Boa Vista, Roraima, Brazil, located in the Amazon region. Gas chromatography had been used to characterize the components, and antioxidant assays such as DPPH, TAC, reducing power, Fe2+ chelation, and total phenols had also been performed. The major constituents had molecularly anchored with the human catalase (CAT) enzyme, and maltol has showed as a positive control. Among the 25 revealed components, the main ones have been α-bisabolol (27.2 %), ß-Caryophyllene (12.5 %) and Epi-γ-eudesmol (13.6 %). The EOBU has comproved a TAC value of 618.79â mg of ascorbic acid equivalent, free radical scavenging capacity (DPPH) around 53.7 % and 65.27 %, Fe2+ chelation capacity of 161±6 and 126.7±39.6, for 0.1â mg.mL-1 and 0.5â mg.mL-1 , respectively. The power around the EOBU has appeared percentages equals to 28.66 %, 44.6 %, and 77.03 % in the concentrations tested. As well as, 96.5 % of total phenols. The compounds α-bisabolol (-5.7±0.4â Kcal.mol-1 ) and ß-caryophyllene (-6.1±0.5â Kcal.mol-1 ) have showed good interaction with CAT compared to Maltol (-4.4±0.4â Kcal.mol-1 ). The present work has demonstrated that EOBU functions as a potent antioxidant, capable of scavenging free radicals and reducing oxidative stress damage.
Assuntos
Bauhinia , Sesquiterpenos Monocíclicos , Óleos Voláteis , Sesquiterpenos Policíclicos , Humanos , Antioxidantes/farmacologia , Antioxidantes/química , Óleos Voláteis/farmacologia , Óleos Voláteis/química , Fenóis/química , Extratos Vegetais/químicaRESUMO
Nanotechnology-based strategies have played a pivotal role in innovative products in different technological fields, including medicine, agriculture, and engineering. The redesign of the nanometric scale has improved drug targeting and delivery, diagnosis, water treatment, and analytical methods. Although efficiency brings benefits, toxicity in organisms and the environment is a concern, particularly in light of global climate change and plastic disposal in the environment. Therefore, to measure such effects, alternative models enable the assessment of impacts on both functional properties and toxicity. Caenorhabditis elegans is a nematode model that poses valuable advantages such as transparency, sensibility in responding to exogenous compounds, fast response to perturbations besides the possibility to replicate human disease through transgenics. Herein, we discuss the applications of C. elegans to nanomaterial safety and efficacy evaluations from one health perspective. We also highlight the directions for developing appropriate techniques to safely adopt magnetic and organic nanoparticles, and carbon nanosystems. A description was given of the specifics of targeting and treatment, especially for health purposes. Finally, we discuss C. elegans potential for studying the impacts caused by nanopesticides and nanoplastics as emerging contaminants, pointing out gaps in environmental studies related to toxicity, analytical methods, and future directions.
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Magnetic nanoparticles (NPs) are suitable candidates for various medical and biological applications, despite some concerns that they may have negative impacts on human health. In this study, the toxicity effects of magnetic NPs consisting of α"-Fe16N2 captured and bioaccumulated by the nematode Caenorhabditis elegans (C. elegans) in the early larval stage are evaluated. The choice of α"-Fe16N2 NPs is based on their good structural stability when stored in saline solution and high magnetic performance. The uptake and bioaccumulation of α"-Fe16N2 NPs in intestinal cells of C. elegans was evidenced by transmission electron microscopy. After exposure to NPs up to 40 mg mL-1, C. elegans larval development, survival, feeding behavior, defecation cycles, movement and reproduction were monitored. C. elegans survival and other monitored behavioral evolutions do not show significant changes, except for a slight statistical reduction in the reproductive profile. Therefore, the present results are promising and very encouraging for investigations of applications of α"-Fe16N2 NPs in the biomedical area.
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Nanopartículas de Magnetita , Nanopartículas , Animais , Caenorhabditis elegans , Humanos , Ferro/toxicidade , Nanopartículas de Magnetita/toxicidade , Nanopartículas/toxicidade , Reprodução , Solução SalinaRESUMO
Pachira aquatica is a species used for medicinal and food purposes and has numerous phytochemicals that may have systemic toxic effects and damage to genetic material. This study aimed to evaluate acute and short-term oral toxicity, as well as genotoxic and clastogenic effects of oil extracted from P. aquatica (PASO) seeds in rats and Drosophila melanogaster. The results obtained with biochemical and hematological analyses did not show significant changes in any evaluated parameters when compared with reference values for the species used in the study. Data from the histopathological analysis corroborated results found in this study. These findings indicate low acute and short-term toxicity following oral PASO exposure in rats under the experimental conditions tested. Tests performed in rats showed that PASO did not present significant genotoxic or clastogenic effects on the cells analyzed with the three doses tested. Treatment with PASO in the offspring of HB crossing, which showed high cytochrome P450 levels, did not exhibit genotoxic activity, as demonstrated by the SMART test. These results suggest that products from the hepatic oil metabolism did not show genotoxicity under the conditions tested. Together, the results indicate that, under the experimental conditions tested, PASO is safe for repeated intake. As PASO exhibited low potential to cause harmful effects on living organisms, our study encourages further research aimed at assessing its pharmacological activity, since it is a widely consumed plant.
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Bombacaceae , Malvaceae , Animais , Drosophila melanogaster , Mutagênicos/química , Extratos Vegetais/farmacologia , Ratos , Sementes , Testes de Toxicidade AgudaRESUMO
Organochlorine pesticides (OCPs) are widely used around the world as insecticides, herbicides, fungicides, nematicides, and rodenticides. Despite banned in Brazil, the usage remains occurring in many countries. The persistence and extreme mobility of OCPs contribute to the contamination of the environment and the human body. The OCPs bioaccumulation in adipose tissue triggers the excretion into human milk during breastfeeding. Hence, the present study determined eighteen OCPs residues in the breast milk of mothers from the Western Region of Bahia State, Brazil. Nine different residue species were found, including beta-Hexachlorocyclohexane (9.24 ± 0.00 ng g-1 fat), delta- Hexachlorocyclohexane (22.15 ± 10.48 ng g-1 fat), Heptachlor (58.08 ± 74.13 ng g-1 fat), Aldrin (142.65 ± 50.65 ng g-1 fat), Dieldrin (774.62 ± 472.68 ng g-1 fat), Endosulfan I (408.44 ± 245.51 ng g-1 fat), Dichloro-diphenyl-dichloro-ethylene (29.17 ± 22.42 ng g-1 fat), Dichloro-diphenyl-trichloro-ethane (28.87 ± 0.00 ng g-1 fat) and Methoxychlor (1699.67 ± 797.43 ng g-1 fat). The Methoxychlor presence in all samples may reveal a recent exposure, while Dieldrin and Endosulfan I analyses can point to distant past exposure.
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Contaminação de Alimentos/análise , Hidrocarbonetos Clorados/análise , Leite Humano/química , Resíduos de Praguicidas/análise , Adolescente , Adulto , Brasil , Exposição Ambiental , Monitoramento Ambiental , Feminino , Humanos , Lactente , Medição de Risco , Adulto JovemRESUMO
BACKGROUND: Diabetes mellitus is one of the most common todays public health problems. According to a survey by the World Health Organization, this metabolic disorder has reached global epidemic proportions, with a worldwide prevalence of 8.5% in the adult population. OBJECTIVES: The present study aimed to investigate the hypoglycemic effect of aqueous extract of Mangifera indica (EAMI) leaves in streptozotocin-induced diabetic rats. METHODS: Sixty male rats were divided into 2 groups: Normoglycemic and Diabetic. Each group was subdivided into negative control, glibenclamide 3 or 10 mg/kg, EAMI 125, 250, 500, and 1000 mg/kg. Intraperitoneal injection of streptozotocin 100 mg/kg was used to DM induction. The hypoglycemic response was assessed acutely after two and four weeks of treatment. After a 6-hour fasting period, the fasting blood glucose of animals was verified, and 2.5 g/kg glucose solution was orally administered. The insulin tolerance test and plasma insulin levels assessment were performed in the morning after fasting of 12 to 14 hours. RESULTS AND CONCLUSION: The chemical analysis of EAMI showed high levels of phenolic compounds. There was no significant difference in fasting blood glucose between normoglycemic and diabetic groups, and that EAMI did not have an acute effect on diabetes. After two and four weeks of treatment, the extract significantly reduced blood glucose levels, exceeding glibenclamide effects. EAMI was effective in maintaining the long-term hypoglycemic effect, as well as, significantly increased the sensitivity of diabetic animals to insulin and the plasma insulin level.
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Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Extratos Vegetais/uso terapêutico , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Hipoglicemiantes/química , Insulina/sangue , Masculino , Mangifera/química , Extratos Vegetais/química , Ratos WistarRESUMO
Major depressive disorder (MDD), also known as unipolar depression, is one of the leading causes of disability and disease worldwide. The signs and symptoms are low selfesteem, anhedonia, feeling of worthlessness, sense of rejection and guilt, suicidal thoughts, among others. This review focuses on studies with molecular-based approaches involving MDD to obtain an integrated, more detailed and comprehensive view of the brain changes produced by this disorder and its treatment and how the Central Nervous System (CNS) produces neuroplasticity to orchestrate adaptive defensive behaviors. This article integrates affective neuroscience, psychopharmacology, neuroanatomy and molecular biology data. In addition, there are two problems with current MDD treatments, namely: 1) Low rates of responsiveness to antidepressants and too slow onset of therapeutic effect; 2) Increased stress vulnerability and autonomy, which reduces the responses of currently available treatments. In the present review, we encourage the prospection of new bioactive agents for the development of treatments with post-transduction mechanisms, neurogenesis and pharmacogenetics inducers that bring greater benefits, with reduced risks and maximized access to patients, stimulating the field of research on mood disorders in order to use the potential of preclinical studies. For this purpose, improved animal models that incorporate the molecular and anatomical tools currently available can be applied. Besides, we encourage the study of drugs that do not present "classical application" as antidepressants, (e.g., the dissociative anesthetic ketamine and dextromethorphan) and drugs that have dual action mechanisms since they represent potential targets for novel drug development more useful for the treatment of MDD.
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Depressão/terapia , Neurobiologia , Animais , Depressão/metabolismo , Depressão/patologia , Depressão/fisiopatologia , HumanosRESUMO
Ilex paraguariensis is a well-known plant that is widely consumed in South America, primarily as a drink called mate. Mate is described to have stimulant and medicinal properties. Considering the potential anti-lipid effects of I. paraguariensis infusion, we used an extract of this plant as a possible modulator of fat storage to control lipid metabolism in worms. Herein, the I. paraguariensis-dependent modulation of fat metabolism in Caenorhabditis elegans was investigated. C. elegans were treated with I. paraguariensis aqueous extract (1 mg/ml) from L1 larvae stage until adulthood, to simulate the primary form of consumption. Expression of adipocyte triglyceride lipase 1 (ATGL-1) and heat shock protein 16.2, lipid accumulation through C1-BODIPY-C12 (BODIPY) lipid staining, behavioral parameters, body length, total body energy expenditure and overall survival were analyzed. Total body energy expenditure was determined by the oxygen consumption rate in N2, nuclear hormone receptor knockout, nhr-49(nr2041), and adenosine receptor knockout, ador-1(ox489) strains. Ilex paraguariensis extract increased ATGL-1 expression 20.06% and decreased intestinal BODIPY fat staining 63.36%, compared with the respective control group, without affecting bacterial growth and energetic balance, while nhr-49(nr2041) and ador-1(ox489) strains blocked the worm fat loss. In addition, I. paraguariensis increased the oxygen consumption in N2 worms, but not in mutant strains, increased N2 worm survival following juglone exposure, and did not alter hsp-16.2 expression. We demonstrate for the first time that I. paraguariensis can decrease fat storage and increase body energy expenditure in worms. These effects depend on the purinergic system (ADOR-1) and NHR-49 pathways. Ilex paraguariensis upregulated the expression of ATGL-1 to modulate fat metabolism. Furthermore, our data corroborates with other studies that demonstrate that C. elegans is a useful tool for studies of fat metabolism and energy consumption.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Ilex paraguariensis , Metabolismo dos Lipídeos/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Purinérgicos P1/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Cromatografia Líquida de Alta Pressão , Metabolismo Energético/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Lipase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacosRESUMO
Manganese (Mn) is an essential trace element for physiological functions since it acts as an enzymatic co-factor. Nevertheless, overexposure to Mn has been associated with a pathologic condition called manganism. Furthermore, Mn has been reported to affect lipid metabolism by mechanisms which have yet to be established. Herein, we used the nematode Caenorhabditis elegans to examine Mn's effects on the dopaminergic (DAergic) system and determine which transcription factors that regulate with lipid metabolism are affected by it. Worms were exposed to Mn for four hours in the presence of bacteria and in a liquid medium (85â¯mM NaCl). Mn increased fat storage as evidenced both by Oil Red O accumulation and triglyceride levels. In addition, metabolic activity was reduced as a reflection of decreased oxygen consumption caused by Mn. Mn also affected feeding behavior as evidenced by decreased pharyngeal pumping rate. DAergic neurons viability were not altered by Mn, however the dopamine levels were significantly reduced following Mn exposure. Furthermore, the expression of sbp-1 transcription factor and let-363 protein kinase responsible for lipid accumulation control was increased and decreased, respectively, by Mn. Altogether, our data suggest that Mn increases the fat storage in C. elegans, secondary to DAergic system alterations, under the control of SBP-1 and LET-363 proteins.
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Proteínas de Caenorhabditis elegans/biossíntese , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Manganês/toxicidade , Fatores de Transcrição/biossíntese , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Metabolismo dos Lipídeos/fisiologia , Fatores de Transcrição/genéticaRESUMO
AIMS: Vitellogenesis is the yolk production process which provides the essential nutrients for the developing embryos. Yolk is a lipoprotein particle that presents lipids and lipid-binding proteins, referred to as vitellogenins (VIT). The Caenorhabditis elegans nematode has six genes encoding VIT lipoproteins. Several pathways are known to regulate vitellogenesis, including the DAF-16 transcription factor. Some reports have shown that heavy metals, such as manganese (Mn), impair brood size in C. elegans; however the mechanisms associated with this effect have yet to be identified. Our aim was to evaluate Mn's effects on C. elegans reproduction and better understand the pathways related to these effects. MAIN METHODS: Young adult larval stage worms were treated for 4h with Mn in 85mM NaCl and Escherichia coli OP50 medium. KEY FINDINGS: Mn reduced egg-production and egg-laying during the first 24h after the treatment, although the total number of progenies were indistinguishable from the control group levels. This delay may have occurred due to DAF-16 activation, which was noted only after the treatment and was not apparent 24h later. Moreover, the expression, protein levels and green fluorescent protein (GFP) fluorescence associated with VIT were decreased soon after Mn treatment and recovered after 24h. SIGNIFICANCE: Combined, these data suggest that the delay in egg-production is likely regulated by DAF-16 and followed by the inhibition of VIT transport activity. Further studies are needed to clarify the mechanisms associated with Mn-induced DAF-16 activation.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Manganês/toxicidade , Vitelogeninas/metabolismo , Animais , Caenorhabditis elegans/genética , Óvulo/efeitos dos fármacos , Vitelogeninas/deficiênciaRESUMO
Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.
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Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dopamina/metabolismo , Reserpina/toxicidade , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Defecação/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Óvulo/efeitos dos fármacos , Doença de Parkinson/fisiopatologiaRESUMO
Organic selenium compounds possess numerous biological properties, including antioxidant activity. Yet, the high toxicity of some of them, such as diphenyl diselenide (DPDS), is a limiting factor in their current usage. Accordingly, we tested four novel organic selenium compounds in the non-parasite nematode Caenorhabditis elegans and compared their efficacy to DPDS. The novel organic selenium compounds are ß-selenoamines (1-phenyl-3-(p-tolylselanyl)propan-2-amine (C1) and 1-(2-methoxyphenylselanyl)-3-phenylpropan-2-amine (C2) and analogs of DPDS (1,2-bis (2-methoxyphenyl) diselenide (C3) and 1,2-bisp-tolyldiselenide (C4). Synchronized worms at the L4 larval stage were exposed for one hour in M9 buffer to these compounds. Oxidative stress conditions were induced by juglone (200 µM) and heat shock (35 °C). Moreover, we evaluated Caenorhabditis elegans behavior, GST-4::GFP (glutathione S-transferase) expression and the activity of acetylcholinesterase (AChE). All tested compounds efficiently restored viability in juglone stressed worms. However, DPDS, C2, C3 and C4 significantly decreased the defecation cycle time. Juglone-induced GST-4::GFP expression was not attenuated in worms pretreated with the novel compounds, except with C2. Finally, AChE activity was reduced by DPDS, C2, C3 and C4. To our knowledge, this is study firstly showed the effects of C1, C2, C3 and C4 selenium-derived compounds in Caenorhabditis elegans. Low toxic effects were noted, except for reduction in the defecation cycle, which is likely associated with AChE inhibition. The juglone-induced stress (reduced viability) was fully reversed by compounds to control animal levels. C2 was also efficient in reducing the juglone-induced GST-4::GFP expression, suggesting the latter may mediate the stress induced by this compound. Future studies could be profitably directed at addressing additional molecular mechanisms that mediate the protective effects of these novel organic selenium compounds.
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Organochalcogens are promising pharmacological agents that possess significant biological activities. Nevertheless, because of the complexity of mammalian models, it has been difficult to determine the molecular pathways and specific proteins that are modulated in response to treatments with these compounds. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging and in vivo live analysis of toxicity. Abundant evidence points to oxidative stress in mediating manganese (Mn)-induced toxicity. In this study we challenged worms with Mn, and investigated the efficacy of inedited selenium- and tellurium-xylofuranosides in reversing and/or protecting the worms from Mn-induced toxicity. In addition, we investigated their putative mechanism of action. First, we determined the lethal dose 50% (LD50) and the effects of the xylofuranosides on various toxic parameters. This was followed by studies on the ability of xylofuranosides to afford protection against Mn-induced toxicity. Both Se- and Te-xylofuranosides increased the expression of superoxide dismutase (SOD-3). Furthermore, we observed that the xylofuranosides induced nuclear translocation of the transcription factor DAF-16/FOXO, which in the worm is known to regulate stress responsiveness, aging and metabolism. These findings suggest that xylofuranosides attenuate toxicity Mn-induced, by regulating the DAF-16/FOXO signaling pathway.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Manganês/toxicidade , Compostos de Selênio/farmacologia , Telúrio/farmacologia , Fatores de Transcrição/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Relação Dose-Resposta a Droga , Fatores de Transcrição Forkhead , Espécies Reativas de Oxigênio/metabolismoRESUMO
Atypical antipsychotics are associated with metabolic syndrome, primarily associated with weight gain. The effects of Ziprasidone, an atypical antipsychotic, on metabolic syndrome has yet to be evaluated. Here in, we evaluated lipid accumulation and behavioral changes in a new experimental model, the nematode Caenorhabditis elegans (C. elegans). Behavioral parameters in the worms were evaluated 24 h after Ziprasidone treatment. Subsequently, lipid accumulation was examined using Nile red, LipidTox green and BODIPY labeling. Ziprasidone at 40 µM for 24 h effectively decreased the fluorescence labeling of all markers in intestinal cells of C. elegans compared to control (0.16% dimethyl sulfoxide). Ziprasidone did not alter behaviors related to energetic balance, such as pharynx pumping, defecation cycles and movement. There was, however, a reduction in egg-production, egg-laying and body-length in nematodes exposed to Ziprasidone without any changes in the progression of larval stages. The serotoninergic pathway did not appear to modulate Ziprasidone's effects on Nile red fluorescence. Additionally, Ziprasidone did not alter lipid accumulation in daf-16 or crh-1 deletion mutants (orthologous of the transcription factors DAF-16 and CREB, respectively). These results suggest that Ziprasidone alters reproductive behavior, morphology and lipid reserves in the intestinal cells of C. elegans. Our results highlight that the DAF-16 and CREB transcription factors are essential for Ziprasidone-induced fat store reduction.
Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Piperazinas/farmacologia , Tiazóis/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Caenorhabditis elegans/metabolismo , Perfilação da Expressão Gênica , Metabolismo dos Lipídeos/efeitos dos fármacosRESUMO
Methamidophos is one of the most toxic organophosphorus (OP) compounds. It acts via phosphorylation of a serine residue in the active site of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), leading to enzyme inactivation. Different oximes have been developed to reverse this inhibition. Thus, our work aimed to test the protective or reactivation capability of pralidoxime and obidoxime, as well as two new oximes synthesised in our laboratory, on human and rat cholinesterases inhibited by methamidophos. In addition, we performed molecular docking studies in non-aged methamidophos-inhibited AChE to understand the mechanisms involved. Our results suggested that pralidoxime protected and reactivated methamidophos-inhibited rat brain AChE. Regarding human erythrocyte AChE, all oximes tested protected and reactivated the enzyme, with the best reactivation index observed at the concentration of 50 µM. Concerning BChE, butane-2,3-dionethiosemicarbazone oxime (oxime 1) was able to protect and reactivate the methamidophos-inhibited BChE by 45% at 50 µM, whereas 2(3-(phenylhydrazono)butan-2-one oxime (oxime 2) reactivated 28% of BChE activity at 100 µM. The two classical oximes failed to reactivate BChE. The molecular docking study demonstrated that pralidoxime appears to be better positioned in the active site to attack the O-P moiety of the inhibited enzyme, being near the oxyanion hole, whereas our new oximes were stably positioned in the active site in a manner similar to that of obidoxime. In conclusion, our work demonstrated that the newly synthesised oximes were able to reactivate not only human erythrocyte AChE but also human plasma BChE, which could represent an advantage in the treatment of OP compounds poisoning.
Assuntos
Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Inseticidas/toxicidade , Cloreto de Obidoxima/farmacologia , Compostos Organotiofosforados/toxicidade , Compostos de Pralidoxima/farmacologia , Acetilcolinesterase/sangue , Animais , Butirilcolinesterase/sangue , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Humanos , Masculino , Ratos , Ratos WistarRESUMO
Acetaminophen (APAP) hepatotoxicity has been related to several cases of hepatitis, cirrhosis, and hepatic transplant. As APAP hepatotoxicity is related to reactive oxygen species (ROS) formation and excessive oxidative stress, natural antioxidant compounds have been tested as an alternative therapy to diminish the hepatic dysfunction induced by APAP. Taraxacum officinale Weber (Family Asteraceae), commonly known as dandelion, is used for medicinal purposes because of its choleretic, diuretic, antioxidant, anti-inflammatory, and hepatoprotective properties. This study evaluated the hepatoprotective activity of T. officinale leaf extract against APAP-induced hepatotoxicity. T. officinale was able to decrease thiobarbituric acid-reactive substance levels induced by 200 mg/kg APAP (p.o.), as well as prevent the decrease in sulfhydryl levels caused by APAP treatment. Furthermore, histopathological alterations, as well as the increased levels of serum aspartate and alanine aminotransferases caused by APAP, were prevented by T. officinale (0.1 and 0.5 mg/mL). In addition, T. officinale extract also demonstrated antioxidant activity in vitro, as well as scavenger activity against 2,2-diphenyl-1-picrylhydrazyl and nitric oxide radicals. Our results clearly demonstrate the hepatoprotective effect of T. officinale against the toxicity induced by APAP. The possible mechanisms involved include its scavenger activities against ROS and reactive nitrogen species, which are attributed to the content of phenolic compounds in the extract.