RESUMO
A high incidence of intentional or accidental paraquat (PQ) ingestion is related to irreversible lung fibrosis and no effective therapy is currently available. Vitamin D has emerged with promising results as an immunomodulatory molecule when abrogating the inflammatory responses of lung diseases. Therefore, we have investigated the role of vitamin D treatments on PQ-induced lung fibrosis in male C57/BL6 mice. Lung fibrosis was induced by a single injection of PQ (10â¯mg/kg; i.p.). The control group received PQ vehicle. Seven days later, after the PQ injection or the vehicle injection, the mice received vitamin D (5⯵g/kg, i.p., once a day) or vehicle, for a further 7â¯days. Twenty-four hours after the last dose of vitamin D or the vehicle, the analysis were performed. The vitamin D treatments reduced the number of leukocytes in their BALF and they decreased the IL-6, IL-17, TGF-beta and MMP-9 levels and the abrogated collagenase deposits in their lung tissues. Conversely, the vitamin D treatments increased the resolvin D levels in their BALF. Moreover, their tracheal contractility was also significantly reduced by the vitamin D treatments. Altogether, the data that was obtained showed a promising use of vitamin D, in treating the lung fibrosis that had been induced by the PQ intoxications. This may improve its prognostic use for a non-invasive and low cost therapy.
Assuntos
Herbicidas/toxicidade , Inflamação/prevenção & controle , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Edema Pulmonar/prevenção & controle , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Lesão Pulmonar Aguda , Animais , Líquido da Lavagem Broncoalveolar/citologia , Colágeno/biossíntese , Citocinas/metabolismo , Inflamação/induzido quimicamente , Contagem de Leucócitos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacosRESUMO
Organic selenium and tellurium compounds are known for their broad-spectrum effects in a variety of experimental disease models. However, these compounds commonly display high toxicity and the molecular mechanisms underlying these deleterious effects have yet to be elucidated. Thus, the need for an animal model that is inexpensive, amenable to high-throughput analyses, and feasible for molecular studies is highly desirable to improve organochalcogen pharmacological and toxicological characterization. Herein, we use Caenorhabdtis elegans (C. elegans) as a model for the assessment of pharmacological and toxicological parameters following exposure to two 4-phenylchalcogenil-7-chloroquinolines derivatives (PSQ for selenium and PTQ for tellurium-containing compounds). While non-lethal concentrations (NLC) of PTQ and PSQ attenuated paraquat-induced effects on survival, lifespan and oxidative stress parameters, lethal concentrations (LC) of PTQ and PSQ alone are able to impair these parameters in C. elegans. We also demonstrate that DAF-16/FOXO and SKN-1/Nrf2 transcription factors underlie the mechanism of action of these compounds, as their targets sod-3, gst-4 and gcs-1 were modulated following exposures in a daf-16- and skn-1-dependent manner. Finally, in accordance with a disturbed thiol metabolism in both LC and NLC, we found higher sensitivity of trxr-1 worm mutants (lacking the selenoprotein thioredoxin reductase 1) when exposed to PSQ. Finally, our study suggests new targets for the investigation of organochalcogen pharmacological effects, reinforcing the use of C. elegans as a powerful platform for preclinical approaches.
Assuntos
Antioxidantes/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Calcogênios/farmacologia , Compostos Organometálicos/farmacologia , Compostos Organosselênicos/farmacologia , Quinolinas/farmacologia , Telúrio/farmacologia , Animais , Antioxidantes/síntese química , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Calcogênios/síntese química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Longevidade/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Compostos Organometálicos/síntese química , Compostos Organosselênicos/síntese química , Oxidantes/antagonistas & inibidores , Oxidantes/toxicidade , Estresse Oxidativo , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Quinolinas/síntese química , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Microorganisms produce siderophores to facilitate iron uptake and even though this trait has been extensively studied, there is growing evidence suggesting that siderophores may have other physiological roles aside from iron acquisition. In support of this notion, we previously linked the archetypal siderophore enterobactin with oxidative stress alleviation. To further characterize this association, we studied the sensitivity of Escherichia coli strains lacking different components of the enterobactin system to the classical oxidative stressors hydrogen peroxide and paraquat. We observed that strains impaired in enterobactin production, uptake and hydrolysis were more susceptible to the oxidative damage caused by both compounds than the wild-type strain. In addition, meanwhile iron supplementation had little impact on the sensitivity, the reducing agent ascorbic acid alleviated the oxidative stress and therefore significantly decreased the sensitivity to the stressors. This indicated that the enterobactin-mediated protection is independent of its ability to scavenge iron. Furthermore, enterobactin supplementation conferred resistance to the entE mutant but did not have any protective effect on the fepG and fes mutants. Thus, we inferred that only after enterobactin is hydrolysed by Fes in the cell cytoplasm and iron is released, the free hydroxyl groups are available for radical stabilization. This hypothesis was validated testing the ability of enterobactin to scavenge radicals in vitro. Given the strong connection between enterobactin and oxidative stress, we studied the transcription of the entE gene and the concomitant production of the siderophore in response to such kind of stress. Interestingly, we observed that meanwhile iron represses the expression and production of the siderophore, hydrogen peroxide and paraquat favour these events even if iron is present. Our results support the involvement of enterobactin as part of the oxidative stress response and highlight the existence of a novel regulation mechanism for enterobactin biosynthesis.
Assuntos
Enterobactina/biossíntese , Escherichia coli/genética , Regulação da Expressão Gênica , Sideróforos/biossíntese , Estresse Fisiológico/genética , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Cloretos/farmacologia , Enterobactina/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Compostos Férricos/farmacologia , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Hidrólise , Ferro/metabolismo , Ligases/genética , Ligases/metabolismo , Mutação , Oxidantes/antagonistas & inibidores , Oxidantes/farmacologia , Oxirredução , Estresse Oxidativo , Paraquat/antagonistas & inibidores , Paraquat/farmacologia , Sideróforos/genética , Transcrição GênicaRESUMO
We investigated the effect of melatonin (MEL) in the activities of cytosolic superoxide dismutase (SOD) and catalase as well as in the levels of H2O2 and mitochondrial malondialdehyde (MDA) in paraquat-intoxicated Drosophila melanogaster. Paraquat (40 mM) was administrated for 36 h. Three groups of flies intoxicated with paraquat were used: PQ (exposed during 36h to paraquat), PQ-MEL (exposed during 36h to paraquat and then treated with MEL [0.43 mM] for 12 days) and PQ-Control (maintained in standard corn meal for 12 days). Two additional groups without pre-intoxication with PQ were added: Control (maintained in standard corn meal) and MEL (treated with MEL for 12 days). Immediately after PQ intoxication the concentration of MDA (17.240 ± 0.554 nmoles MDA/mg protein) and H2O2 (3.313 ± 0.086 nmol hydrogen peroxide/mg protein) and the activities of SOD and catalase (419.667 ± 0.731 and 0.216 ± 0.009 Units/mg of protein, respectively) in the PQ group were significantly increased with respect to Control. After 12 days of intoxication with PQ, the PQ-Control flies showed increases in H2O2 (4.336 ± 0.108) and MDA levels (8.620 ± 0.156), and in the activities of SOD and catalase (692.570 ± 0.433 and 0.327 ± 0.003, respectively) as compared to PQ-MEL (p<0.001). Treatment with MEL extended the life span of the groups PQ-MEL and MEL when compared to their corresponding controls. Motor activity decreased significantly in PQ-Control and PQ-MEL flies, suggesting that the damage caused by PQ affected the nervous system of flies. Our findings showed that oxidative damage caused by paraquat was observed even after 12 days and that melatonin mitigates this damage.
Investigamos el efecto de la melatonina (MEL) en la actividad de la superóxido dismutasa citosólica (SOD) y la catalasa, así como en las concentraciones del H2O2 y del malondialdehido mitocondrial (MDA) en la toxicidad inducida por paraquat (PQ) en Drosophila melanogaster. El paraquat (40 mM) fue administrado durante 36h. Tres grupos de moscas se utilizaron después de la intoxicación con paraquat: PQ (expuestas a paraquat durante 36 h), PQ-MEL (expuestas durante 36 horas a PQ y luego tratadas con MEL [0,43 mM] por 12 días) y PQ-Control (mantenidas en medio estándar por 12 días). Se incluyeron dos grupos adicionales sin pre-intoxicación con PQ: Control (mantenido en medio estándar) y MEL (tratado con MEL por 12 días). Inmediatamente después de la intoxicación con PQ, las concentraciones de MDA (17,240 ± 0,554 nmol de MDA/mg de proteína), H2O2 (3,313 ± 0,086 nmol de H2O2/mg de proteína) y las actividades de la SOD y catalasa (419,667 ± 0,731 y 0,216 ± 0,009 unidades/mg de proteína, respectivamente) se incrementaron significativamente con respecto al Control. Doce días después de la intoxicación con PQ, las moscas PQ-Control mostraron un aumento en la concentración de H2O2 (4,336 ± 0,108), de los niveles de MDA (8,620 ± 0,156) y en las actividades de la SOD y la catalasa (692,570 ± 0,433 y 0,327 ± 0,003, respectivamente) en comparación con el grupo PQ-MEL (p<0,001). El tratamiento con MEL extendió el tiempo de vida de los grupos PQ-MEL y MEL en comparación con sus correspondientes controles. La actividad motora disminuyó significativamente en las moscas de los grupos PQ-Control y PQ-MEL, lo que sugiere que el PQ afectó el sistema nervioso de las moscas. Nuestros hallazgos demostraron que el daño oxidativo causado por paraquat en las moscas fue observado aún después de 12 días de intoxicadas y que la melatonina logró mitigar este daño.
Assuntos
Animais , Masculino , Antioxidantes/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Herbicidas/antagonistas & inibidores , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Catalase/análise , Avaliação Pré-Clínica de Medicamentos , Proteínas de Drosophila/análise , Drosophila melanogaster/fisiologia , Herbicidas/toxicidade , Peróxido de Hidrogênio/análise , Peroxidação de Lipídeos/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Malondialdeído/análise , Mitocôndrias/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Paraquat/toxicidadeRESUMO
We investigated the effect of melatonin (MEL) in the activities of cytosolic superoxide dismutase (SOD) and catalase as well as in the levels of H2O2 and mitochondrial malondialdehyde (MDA) in paraquat-intoxicated Drosophila melanogaster. Paraquat (40 mM) was administrated for 36 h. Three groups of flies intoxicated with paraquat were used: PQ (exposed during 36h to paraquat), PQ-MEL (exposed during 36h to paraquat and then treated with MEL [0.43 mM] for 12 days) and PQ-Control (maintained in standard corn meal for 12 days). Two additional groups without pre-intoxication with PQ were added: Control (maintained in standard corn meal) and MEL (treated with MEL for 12 days). Immediately after PQ intoxication the concentration of MDA (17.240 +/- 0.554 nmoles MDA/mg protein) and H2O2 (3.313 +/- 0.086 nmol hydrogen peroxide/mg protein) and the activities of SOD and catalase (419.667 + 0.731 and 0.216 +/- 0.009 Units/mg of protein, respectively) in the PQ group were significantly increased with respect to Control. After 12 days of intoxication with PQ, the PQ-Control flies showed in- creases in H2O2 (4.336 +/- 0.108) and MDA levels (8.620 +/- 0.156), and in the activities of SOD and catalase (692.570 +/- 0.433 and 0.327 +/- 0.003, respectively) as compared to PQ-MEL (p<0.001). Treatment with MEL extended the life span of the groups PQ-MEL and MEL when compared to their corresponding controls. Motor activity decreased significantly in PQ-Control and PQ-MEL flies, suggesting that the damage caused by PQ affected the nervous system of flies. Our findings showed that oxidative damage caused by paraquat was observed even after 12 days and that melatonin mitigates this damage.
Assuntos
Antioxidantes/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Herbicidas/antagonistas & inibidores , Melatonina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Animais , Catalase/análise , Proteínas de Drosophila/análise , Drosophila melanogaster/fisiologia , Avaliação Pré-Clínica de Medicamentos , Herbicidas/toxicidade , Peróxido de Hidrogênio/análise , Peroxidação de Lipídeos/efeitos dos fármacos , Longevidade/efeitos dos fármacos , Masculino , Malondialdeído/análise , Mitocôndrias/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Paraquat/toxicidadeRESUMO
This study aimed to investigate the beneficial effect of diphenyl diselenide (PhSe)2 on paraquat (PQ) induced alterations in rats liver. Adult male Wistar rats received (PhSe)2 at 10 mg kg(-1), by oral administration (p.o.), during five consecutive days. Twenty-four hours after the last (PhSe)2 dose, rats received PQ at 15 mg kg(-1), in a single intraperitoneally injection (i.p.). Seventy-two hours after PQ exposure, animals were sacrificed by decapitation for blood and liver samples obtainment. Histological alterations induced by PQ exposure, such as inflammatory cells infiltration and edema, were prevented by (PhSe)2 administration. Moreover, (PhSe)2 prevented hepatic lipid peroxidation (LPO) induced by PQ and was effective in reducing the myeloperoxidase (MPO) activity in liver, which was enhanced by PQ exposure. (PhSe)2 also was effective in protecting against the reduction in ascorbic acid and non-protein thiols (NPSH) levels induced by PQ. The inhibition of glutathione S-transferase (GST) activity, in rats exposed to PQ, was normalized by (PhSe)2 pre-treatment, whereas the inhibition of catalase (CAT) activity was not prevented by (PhSe)2. The serum alkaline phosphatase (ALP) inhibition, induced by PQ administration, was also prevented by (PhSe)2 pre-treatment. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were not modified by PQ and/or (PhSe)2 administration. Therefore, (PhSe)2 pre-treatment was effective in protecting against the hepatic alterations induced by PQ in rats. This protective effect can involve the antioxidant and anti-inflammatory properties of (PhSe)2.
Assuntos
Derivados de Benzeno/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Herbicidas/antagonistas & inibidores , Herbicidas/toxicidade , Compostos Organosselênicos/farmacologia , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Animais , Ácido Ascórbico/metabolismo , Catalase/metabolismo , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/patologia , Testes de Função Hepática , Masculino , Peroxidase/metabolismo , Ratos , Ratos Wistar , Compostos de Sulfidrila/metabolismoRESUMO
Psychollatine is a monoterpene indole alkaloid produced and accumulated by Psychotria umbellata Vell. (Rubiaceae) leaves in relatively high amounts (approximately 3% of the dry weight). The alkaloid has been shown to display opioid-like analgesic, anxiolytic, antidepressive and antipsychotic activities in rodents. In vitro assays suggested a protective role for this molecule in plant oxidative stress responses. This work reports antioxidant properties of psychollatine and the crude foliar extract from P. umbellata in strains of Saccharomyces cerevisiae proficient and deficient in antioxidant defenses exposed to H2O2 and paraquat. The antimutagenic activity of P. umbellata and its main alkaloid were assayed in S. cerevisiae N123 strain in presence of H2O2. Moreover, the antioxidant capacity of these substances on the hydroxyl radical (OH.) was investigated, using the hypoxanthine/xanthine oxidase assay. Psychollatine and the crude foliar extract of P. umbellata showed protective effect against oxidative stress in yeast, acting both as antioxidant and antimutagenic agents.
Assuntos
Antimutagênicos/farmacologia , Antioxidantes/farmacologia , Glicosídeos/farmacologia , Alcaloides Indólicos/farmacologia , Psychotria/química , Divisão Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Meios de Cultura , Herbicidas/antagonistas & inibidores , Herbicidas/toxicidade , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/toxicidade , Oxidantes/toxicidade , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Extratos Vegetais/farmacologia , Folhas de Planta/química , Espécies Reativas de Oxigênio/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Xantina Oxidase/metabolismoRESUMO
The efficacy of melatonin, glutathione, serotonin, minocycline, lipoic acid and ascorbic acid in counteracting the toxicity of paraquat in Drosophila melanogaster was examined. Male Oregon wild strain flies were fed for 5 days with control food or food containing the test substance. They were transferred in groups of five to vials containing only filter paper soaked with 20 mM paraquat in 5% sucrose solution. Survival was determined 24 and 48 h later. All the substances assayed increased the survival of D. melanogaster. At equimolar concentrations (0.43 mM) melatonin was more effective than serotonin, lipoic acid and ascorbic acid. However, lower concentrations of glutathione (0.22 mM) and minocycline (0.05 mM) were as efficient as melatonin. The highest survival rate (38.6%) after 48 h of paraquat treatment was found with 2.15 mM of lipoic acid. No synergistic effect of melatonin with glutathione, serotonin, minocycline, lipoic acid and ascorbic acid was detected.
Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Glutationa/farmacologia , Herbicidas/antagonistas & inibidores , Herbicidas/toxicidade , Melatonina/farmacologia , Minociclina/farmacologia , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Serotonina/farmacologia , Ácido Tióctico/farmacologia , Animais , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Drosophila melanogaster , Resistência a Medicamentos , Glutationa/metabolismo , Masculino , Melatonina/metabolismo , Minociclina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Serotonina/metabolismo , Taxa de Sobrevida , Ácido Tióctico/metabolismoRESUMO
Antioxidant effects of extracts from Croton cajucara BENTH. leaves was investigated in different in vitro and in vivo models. Extracts showed inhibitory radical scavenging activity against the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) (75%, 43% and 25% of the standard trolox at 1, 10 and 100 mg/ml, respectively; IC50 218 mg/ml). Percentage survival of Saccharomyces cerevisiae cells treated with 10 mM paraquat increased by 21% and 55%, when 1 mg/ml and 10 mg/ml concentrations of the extract, respectively, were added. The cytosolic concentration of TBARS increased in animals treated with paraquat (+283%), while values did not significantly differ from the controls in rats additionally receiving the leaf extract. Paraquat administration also induced a significant increase in hydroperoxide-initiated chemiluminiscence (+76%), that was partially prevented by the leaf extract (+31%). Liver SOD activity was a 158% higher in animals receiving paraquat as compared to the controls. This effect was abolished by administration of the leaf extract. Paraquat administration did not significantly modify the activity of GPx or catalase. Croton cajucara extract increased GPx and catalase activities in paraquat treated-animals by 342% and 70%, respectively. Our results confirm that Croton cajucara leaf extract present radical scavenging activity and reduce oxidative stress induced by paraquat, suggesting the beneficial use as a potential source of antioxidant agents of natural origin.
Assuntos
Croton/química , Sequestradores de Radicais Livres/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Paraquat/antagonistas & inibidores , Paraquat/toxicidade , Animais , Compostos de Bifenilo , Sequestradores de Radicais Livres/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Medições Luminescentes , Masculino , Oxidantes/metabolismo , Picratos/metabolismo , Extratos Vegetais/química , Folhas de Planta/química , Ratos , Ratos Wistar , Saccharomyces cerevisiae/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
La neurotoxina 1-metil-4-fenil-1,2,3,6-tetrahidropiridina (MPTP) produce toxicidad de las neuronas dopaminérgicas de la vía nigroestriatal, como en la enfermedad de Parkinson idiopática. El mecanismo de daño celular causado por esta toxina se desconoce, sin embargo, se han propuesto una serie de hipótesis: el daño a la mitocondria y la fuerza oxidativa. El 1-metil-4-fenilpiridino (MPP+), el mayor metabolito activo de la MPTP es captado por la mitocondria, en donde se acumula e inhibe la oxidación de sustratos unidos al NADH de la mitocondria causando una disminución del ATP. Esto sugiere que la toxicidad del MPP+ puede atribuirse a la inhibición de las funciones de la mitocondria. Sin embargo, esta disminución ha sido observada durante pocas horas. Esto sugiere un segundo mecanismo de daño a las neuronas que pueda explicar los efectos a largo plazo del MPP+. La MPTP genera la formación de radicales libres del oxígeno así como también reduce las defensas antioxidantes endógenas y el glutatión para combatir los radicales libres. La toxicidad de la MPTP es disminuida por una variedad de antioxidantes y por el ácido ascórbico que pueden reducir los cambios bioquímicos producidos por el tratamiento con la MPTP. Esos resultados sugieren que la fuerza oxidativa puede producir daño a las neuronas después de la administración de la MPTP.