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1.
Chem Biol Interact ; 311: 108796, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31421116

RESUMO

Lambda-cyhalothrin (LCT) is a broad-spectrum pesticide widely used in agriculture throughout the world. This pesticide is considered a potential contaminant of surface and underground water as well as food, posing a risk to ecosystems and humans. In this sense, we decided to evaluate the activity of enzymes belonging to the purinergic system, which is linked with regulation of extracellular nucleotides and nucleosides, such as adenosine triphosphate (ATP) and adenosine (Ado) molecules involved in the regulation of inflammatory response. However, there are no data concerning the effects of LCT exposure on the purinergic system, where extracellular nucleotides act as signaling molecules. The aim of this study was to evaluate nucleotide hydrolysis by E-NTPDase (ecto-nucleoside triphosphate diphosphohydrolase), Ecto-NPP (ecto-nucleotide pyrophosphatase/phosphodiesterase), ecto-5'-nucleotidase and ecto-adenosine deaminase (E-ADA) in platelets and liver of adult rats on days 7, 30, 45 and 60 after daily gavage with 6.2 and 31.1 mg/kg bw of LCT. Gene expression patterns of NTPDases1-3 and 5'-nucleotidase were also determined in those tissues. In parallel, lambda-cyhalothrin metabolites [3-(2-chloro-3,3,3- trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic acid (CFMP), 4-hydroxyphenoxybenzoic acid (4-OH-3-PBA), and 3-phenoxybenzoic acid (3-PBA)] were measured in plasma. Results showed that exposure rats to LCT caused a significant increase in the assessed enzymes activities. Gene expression pattern of ectonucleotidases further revealed a significant increase in E-NTPDase1, E-NTPDase2, and E-NTPDase3 mRNA levels after LCT administration at all times. A dose-dependent increase in LCT metabolite levels was also observed but there no significant variations in levels from weeks to week, suggesting steady-steady equilibrium. Correlation analyses revealed that LCT metabolites in the liver and plasma were positively correlated with the adenine nucleotides hydrolyzing enzyme, E-ADA and E-NPP activities in platelets and liver of rats exposed to lambda-cyhalothin. Our results show that LCT and its metabolites may affect purinergic enzymatic cascade and cause alterations in energy metabolism.


Assuntos
Plaquetas/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nitrilos/farmacologia , Nucleotidases/genética , Nucleosídeos de Purina/metabolismo , Piretrinas/farmacologia , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Animais , Plaquetas/enzimologia , Plaquetas/metabolismo , Cromatografia Líquida de Alta Pressão , Hidrólise , Fígado/enzimologia , Fígado/metabolismo , Masculino , Espectrometria de Massas , Nitrilos/sangue , Nitrilos/metabolismo , Nucleotidases/metabolismo , Piretrinas/sangue , Piretrinas/metabolismo , Pirofosfatases/genética , Pirofosfatases/metabolismo , Ratos , Ratos Wistar
2.
Behav Brain Res ; 370: 111898, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-30978409

RESUMO

Exposure to insecticides has been associated with depression-like symptoms, especially among occupationally exposed populations, such as farmers. Although the neurotoxicity of pyrethroids such as bifenthrin (BF) is well established, it is still unclear whether exposure to BF may have deleterious effects on the hippocampus and thus behavior. We verified the hypothesis that repeated exposure to BF in a rat model elicits neurochemical and behavioral alterations, the latter of which reflects depression-related symptoms. Adult male Wistar rats (n = 12 per group) were orally administered with different doses of BF (0.6 or 2.1 mg/kg body weight (b.w.)) on a daily basis for 60 days; control rats received the vehicle (corn oil). Different biochemical changes were assessed in the hippocampus, a region of the brain regulating spatial memory; behavioral tests were also conducted. Our results revealed depressive-like behaviors that were expressed by increased despair behavior in the Forced-swimming test. Repeated exposure to BF also decreased acetylcholinesterase (AChE) activity in the hippocampus and butyrylcholinesterase (BuChE) activity in plasma. A significant reduction in the activities of hippocampal membrane-bound ATPases (Na+/K+-ATPase and Mg2+-ATPase) was also observed in BF-treated rats compared to controls. Furthermore, a significant decrease in mRNA expression and protein synthesis of both AChE and orphan nuclear receptor (Nurr-1), as well as in the expression of muscarinic-cholinergic receptor (M1 mAchR) and nicotinic-cholinergic receptor (nAchR2α) was observed in the hippocampus of treated rats compared to controls. Also, BF exposure induced apoptosis as assessed by hippocampal Casp-3 protein levels. Our findings suggest that repeated exposure to BF affects hippocampal signaling and Nurr-1/AChE, and this was accompanied by depression-like state in adult rats.

3.
Toxicol Lett ; 296: 132-138, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30120931

RESUMO

A controlled kinetic study was conducted in volunteers dermally exposed to the widely used lambda-cyhalothrin pyrethroid pesticide to document the time courses of relevant biomarkers of exposure, in order to better assess biomonitoring data in workers. Matador® EC120 formulation (120 g/l) was applied on 40 cm2 of the forearm at a 0.25 mg/kg dose of lambda-cyhalothrin and left without occlusion or washing for 6 h. The application site was then washed thoroughly with soap and water. The kinetic time courses of cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were determined in plasma and urine up to 84 h post-application. Results show that the fraction of lambda-cyhalothrin absorbed in the body was rapidly cleared following dermal contact. According to CFMP and 3-PBA plasma profiles, calculated mean apparent absorption half-lives (t1/2) were 3 and 7.3 h, respectively, and corresponding mean apparent elimination t1/2 were 11.2 and 7.6 h. These differences suggest some metabolism at the site-of-entry and storage of metabolites by the dermal route. Toxicokinetic parameters calculated from urinary profiles confirm the values of absorption and elimination rates. Metabolites were almost completely excreted over the 84-h period post-application and, on average, 0.12 and 0.08% of the applied lambda-cyhalothrin dose was recovered in the urine as CFMP and 3-PBA, respectively, indicating a low dermal absorption fraction of this pyrethroid. This study showed the potential use of CFMP and 3-PBA biomarkers for the assessment of dermal exposure to lambda-cyhalothrin pyrethroid.


Assuntos
Inseticidas/farmacocinética , Nitrilos/farmacocinética , Piretrinas/farmacocinética , Administração Cutânea , Adulto , Área Sob a Curva , Benzoatos/sangue , Benzoatos/urina , Biotransformação , Monitoramento Ambiental , Feminino , Meia-Vida , Humanos , Inseticidas/sangue , Inseticidas/toxicidade , Masculino , Nitrilos/sangue , Nitrilos/toxicidade , Piretrinas/sangue , Piretrinas/toxicidade , Absorção Cutânea , Adulto Jovem
4.
Neurochem Int ; 120: 121-133, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30102949

RESUMO

Exposure to synthetic pyrethroid (SPs) pesticides such as bifenthrin (BF) has been associated with adverse neurodevelopmental outcomes and cognitive impairments, but the underlying neurobiological mechanism is poorly understood so far. The present study has been designed to evaluate changes in behavior and in biomarkers of oxidative stress and neuroinflammation in the hippocampus of rats subchronically treated with BF. Rats exposed daily to BF at doses of 0.6 and 2.1 mg/kg b. w. for 60 days exhibited spatial and cognitive impairments as well as memory dysfunction after 60 days. This repeated BF treatment also significantly increased mRNA expression of pro-inflammatory cytokines tumor necrosis factor (TNF-α), interleukin (IL-1ß), (IL-6), nuclear factor erythroid-2 (Nrf2), cyclooxygenase-2 (COX-2), nuclear factor-kappaB pathway (NF-kappaB), and prostaglandin E2 (PGE2) in the hippocampus. It further resulted in a significant increase in protein levels of Nrf2, COX-2, microsomal prostaglandin synthase-1 (mPGES-1) and NF-kappaB. This was accompanied by oxidative/nitrosative stress in the hippocampus of treated rats, as shown by increased levels of malondialdehyde (MDA), protein carbonyls (PCO), and nitric oxide (NO), and reduced levels of enzymatic (catalase, superoxide dismutase, and glutathione peroxidase) and non-enzymatic (reduced glutathione) antioxidants. The data are in line with those obtained in organotypic hippocampal slice cultures (OHSCs) isolated from mouse brain and exposed to BF for 72 h, showing neuronal death only at the high dose of 20 µM when compared to controls. These findings suggest that exposure to BF induces neuronal damage, alters redox state, and causes neuroinflammation in the hippocampus, which might lead to cognitive and memory impairment.

5.
J Neuroinflammation ; 15(1): 159, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29793499

RESUMO

BACKGROUND: Pyrethroids, such as bifenthrin (BF), are among the most widely used class of insecticides that pose serious risks to human and wildlife health. Pyrethroids are proposed to affect astrocytic functions and to cause neuron injury in the central nervous system (CNS). Microglia are key cells involved in innate immune responses in the CNS, and microglia activation has been linked to inflammation and neurotoxicity. However, little information is known about the effects of BF-induced toxicity in primary microglial cells as well as in organotypic hippocampal slice cultures (OHSCs). METHODS: Oxidative stress and inflammatory responses induced by BF were evaluated in primary microglial cells and OHSCs incubated with different concentrations of BF (1-20 µM) for 4 and 24 h. mRNA and protein synthesis of cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), nuclear erythroid-2 like factor-2 (Nrf-2), and microsomal prostaglandin synthase-1 (mPGES-1) was also studied by qPCR and Western blot. Cell viability was analyzed by MTT-tetrazolio (MTT) and lactate dehydrogenase (LDH) assays. Neurotoxicity in OHSCs was analyzed by propidium iodide (PI) staining and confocal microscopy. RESULTS: Exposure of microglial cells to BF for 24 h resulted in a dose-dependent reduction in the number of viable cells. At sub-cytotoxic concentrations, BF increased reactive oxygen species (ROS), TNF-alpha synthesis, and prostaglandin E2 (PGE2) production, at both 4- and 24-h time points, respectively. Furthermore, BF incubation decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and increased lipid peroxidation, protein oxidation, and H2O2 formation. In addition, BF significantly induced protein synthesis and mRNA expression of oxidative and inflammatory mediators after 4 and 24 h, including Nrf-2, COX-2, mPGES-1, and nuclear factor kappaB (NF-kappaB). A 24-h exposure of OHSCs to BF also increased neuronal death compared to untreated controls. Furthermore, depletion of microglia from OHSCs potently enhanced neuronal death induced by BF. CONCLUSIONS: Overall, BF exhibited cytotoxic effects in primary microglial cells, accompanied by the induction of various inflammatory and oxidative stress markers including the Nrf-2/COX-2/mPGES-1/NF-kappaB pathways. Moreover, the study provided evidence that BF induced neuronal death in OHSCs and suggests that microglia exert a protective function against BF toxicity.

6.
Toxicol Lett ; 294: 73-86, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29775722

RESUMO

Bifenthrin (BF) is a synthetic pyrethroid pesticide widely used in several countries to manage insect pests on diverse agricultural crops. Growing evidence indicates that BF exposure is associated with an increased risk of developing neurodegenerative disorders. However, the mechanisms by which BF induces neurological and anxiety alterations in the frontal cortex and striatum are not well known. The present in vivo study was carried out to determine whether reactive oxygen species (ROS)-mediated oxidative stress (OS) and neuroinflammation are involved in such alterations. Thirty-six Wistar rats were thus randomly divided into three groups and were orally administered with BF (0.6 and 2.1 mg/kg body weight, respectively) or the vehicle (corn oil), on a daily basis for 60 days. Results revealed that BF exposure in rats enhanced anxiety-like behavior after 60 days of treatment, as assessed with the elevated plus-maze test by decreases in the percentage of time spent in open arms and frequency of entries into these arms. BF-treated rats also exhibited increased oxidation of lipids and carbonylated proteins in the frontal cortex and striatum, and decreased glutathione levels and antioxidant enzyme activities including superoxide dismutase, catalase and glutathione peroxidase. Treatment with BF also increased protein synthesis and mRNA expression of the inflammatory mediators cyclooxygenase-2 (COX-2), microsomal prostaglandin synthase-1 (mPGES-1) and nuclear factor-kappaBp65 (NF-kBp65), as well as the production of tumor necrosis factor-α (TNF-α) and ROS. Moreover, BF exposure significantly decreased protein synthesis and mRNA expression of nuclear factor erythroid-2 (Nrf2) and acetylcholinesterase (AChE), as well as gene expression of muscarinic-cholinergic receptors (mAchR) and choline acetyltransferase (ChAT) in the frontal cortex and striatum. These data suggest that BF induced neurological alterations in the frontal cortex and striatum of rats, and that this may be associated with neuroinflammation and oxidative stress via the activation of Nrf2/NF-kBp65 pathways, which might promote anxiety-like behavior.


Assuntos
Ansiedade/etiologia , Inseticidas/toxicidade , Neurite (Inflamação)/induzido quimicamente , Síndromes Neurotóxicas/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Piretrinas/toxicidade , Tremor/etiologia , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/imunologia , Neurônios Colinérgicos/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/imunologia , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/imunologia , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inseticidas/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/metabolismo , Neurite (Inflamação)/fisiopatologia , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/metabolismo , Piretrinas/administração & dosagem , Distribuição Aleatória , Ratos Wistar
7.
Biomed Res Int ; 2018: 6251546, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29568760

RESUMO

Natural plant extracts contain a variety of phenolic compounds which are assigned various biological activities. Our work aims to make a quantitative and qualitative characterization of the Zest (ZL) and the Flesh (FL) of lemon (Citrus limon), to valorize the pharmacological uses of lemon, by evaluating in vitro activities (DPPH, free radical scavenging and reducing power). The antibacterial, antifungal, and antiproliferative activities were sought in the ability of Citrus limon extracts to protect DNA and protein. We found that the ZL contains high amounts of phenolics responsible for the important antioxidant properties of the extract. However, the FL is richer in flavonoids than the ZL. The FL extract was also found to be more effective than the ZL in protecting plasmid DNA against the strand breakage induced by hydroxyl radicals. We also concluded that the FL extract exhibited potent antibacterial activity unlike ZL. Analysis by LC/MS-MS identified 6 compounds (Caffeoyl N-Tryptophan, Hydroxycinnamoyl-Oglucoside acid, Vicenin 2, Eriocitrin, Kaempferol-3-O- rutinoside, and Quercetin-3-rutinoside). These preliminary results showed that Citrus limon has antibacterial and antioxidant activity in vitro. It would be interesting to conduct further studies to evaluate the in vivo potential in an animal model.


Assuntos
Citrus/química , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/farmacologia , Fenóis/química , Fenóis/farmacologia , Tunísia
8.
Environ Sci Pollut Res Int ; 24(24): 19714-19722, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28685329

RESUMO

Pyrethrinoïds are synthetic pesticides widely used in agriculture and farms to protect crops from weeds, insects, fungi, and molds. Increased and uncontrolled use of these pollutants can have harmful effects on human health via consumption of contaminated food products. In the present study, deltamethrin (DLT = 3.72 mg/kg) and Bifenthrin (BF = 2.6 mg/kg) were used during a long-term exposition in the rats to assess their effect on mitochondrial integrity and function in different brain areas (hippocampus, striatum, cortex, and cerebellum). The results of this study have shown that chronic treatment of rats by both DLT and BF, on their own or in a mixture, has induced a significant increase in mitochondrial MDA, but when quercetin (Que) was co-administered with pesticides, this enhancement has been prevented in the almost of treated rats compared to solvent and control groups. In hippocampus area, GSH has significantly increased in all treated rats, except for BF and DLT-Que.-treated groups. In striatum, GSH has been depleted in the BF and DLT-treated groups compared to control and solvent groups; in contrast, when Que. was associated with pesticides, the rate of this tripeptide has been maintained at normal levels. In the cortex and cerebellum, GSH has been depleted significantly in all treated animals but has increased in DLT-Que. and mixture-Que.-treated groups in the cerebral cortex, at the same time; it has been maintained at normal levels in BF-Que.-treated groups in the cerebellum compared to control and solvent rats. On the other side, the results of this study have shown a loss of catalase (CAT) and glutathione S-transferase (GST) activities in all brain regions of pesticide-treated rats, but such a fall in enzymatic activities has been prevented by Que. when it was co-administered to rats with pesticides at the dose of 5 mg/kg, except in the cerebellum. In addition, this study has shown mitochondria's swelling in almost all the brain areas with exception of the cerebellum, providing information about a loss of mitochondrial membrane integrity in brain neurons of rats exposed to pyrethrinoïds. Furthermore, preventive administration of Que., in association with pesticides (5 mg/kg) or their mixture (10 mg/kg), has prevented mitochondria swelling in almost all of the analyzed brain tissues.


Assuntos
Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/toxicidade , Piretrinas/toxicidade , Quercetina/farmacologia , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Dilatação Mitocondrial/efeitos dos fármacos , Oxirredução , Ratos Wistar , Fatores de Tempo
9.
Toxicol Lett ; 276: 115-121, 2017 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-28539253

RESUMO

Lambda-cyhalothrin is a pyrethroid pesticide largely used in agriculture. Exposure assessment can be performed by measuring key urinary metabolites. For a proper use of biomonitoring data, it is however important to gain information on the toxicokinetics of these key biomarkers of exposure. A human volunteer study was performed to document the plasma and urinary time courses of major lambda-cyhalothrin metabolites. Seven volunteers ingested 0.025mgkg-1 body weight of lambda-cyhalothrin. Blood samples were withdrawn prior to dosing and at fixed time periods over the 72 h-period following ingestion and complete urine voids were collected pre-exposure and at pre-established intervals over 84h post-dosing. The cis-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylic acid (CFMP) and 3-phenoxybenzoic acid (3-PBA) metabolites were quantified in these samples. Plasma concentrations of CFMP and 3-PBA increased rapidly after ingestion, with average peak values at 3.1 and 4.0h post-dosing, respectively; subsequent elimination phase showed a rapid decay with a mean half-life (t½) of ≈5.3 and 6.4h for CFMP and 3-PBA, respectively. Urinary rate time courses displayed a profile similar to the plasma concentration-time curves with corresponding mean t½ of ≈4.2 and 5.9h. In the 84-h period post-treatment, on average 21% of lambda-cyhalothrin dose were excreted in urine as CFMP as compared to 30% as 3-PBA. Overall, CFMP and 3-PBA metabolites were confirmed to be major metabolites of lambda-cyhalothrin and exhibited similar kinetics with short half-lives; they thus both appear as useful biomarkers of exposure to lambda-cyhalothrin in humans.


Assuntos
Inseticidas/administração & dosagem , Inseticidas/farmacocinética , Nitrilos/administração & dosagem , Nitrilos/farmacocinética , Piretrinas/administração & dosagem , Piretrinas/farmacocinética , Administração Oral , Biomarcadores/sangue , Biomarcadores/urina , Biotransformação , Meia-Vida , Humanos , Inseticidas/sangue , Inseticidas/urina , Taxa de Depuração Metabólica , Nitrilos/urina , Piretrinas/urina , Eliminação Renal
10.
Biomed Pharmacother ; 89: 185-193, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28226292

RESUMO

The phenolic constituents of the aqueous-ethanolic extract of two Tunisian Ficus carica leaves cultivars and their hypoglycaemic, hypolipidaemic and antioxidative activities in alloxan-induced diabetic rats were investigated. Our results demonstrated that the treatment with the leaves extracts of F. carica improved lipid profile and reduced blood glucose level as well as thiobarbituric acid-reactive substances content. The antioxidant enzymes activity in the liver and heart tissues of diabetic rats was increased after the treatment. These antihyperglycaemic, antihyperlipidaemic and antioxidant effects of both leaf extracts could be associated with their in vitro scavenging ability and their phenolic composition. The HPLC-DAD-QTOF-MS analysis of both extracts revealed the presence of dihydroxybenzoic acid, dipentoside, rutin, psoralen, methoxypsoralen and oxypeudacin hydrate as relatively the most abundant compounds. These results showed indicated the capacity of the leaves extracts of F. carica to ameliorate hyperglycaemia, hyperlipidaemia and antioxidant status in diabetic rats.


Assuntos
Ficus/química , Fenóis/química , Extratos Vegetais/química , Folhas de Planta/química , Animais , Antioxidantes/química , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Frutas/química , Alimento Funcional , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Lipídeos/sangue , Masculino , Espectrometria de Massas/métodos , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
11.
J Complement Integr Med ; 14(1)2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28195545

RESUMO

Background Berberis vulgaris L. (BV), commonly known as "Aghriss" in Moroccan pharmacopoeia, is used to cure liver disorders and other diseases. The present study aimed to investigate the protective effect of BV aqueous extract against lead-induced toxicity in mice liver. Methods Sixty IOPS mice were divided into six groups and were treated as follows: group 1 (normal control) received double distilled water; group 2 (toxic control) received lead acetate (5 mg/kg body weight/day) in double distilled water for 40 days; groups 3-6 received BV aqueous extract at doses of 25, 50, 100 and 150 mg/kg body weight , respectively, once daily for 30 days from 11 day after beginning of lead acetate exposure to the end of the experiment. Results Toxic control group showed a significant alteration of serum alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), total cholesterol (TC), total bilirubin (TB), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH). Histological assessment of lead-intoxicated mice liver revealed alterations in hepatocytes and focal necrosis. BV treatment significantly prevented lead accumulation, increased ALT, AST, TC, and TB, inhibited lipid peroxidation and protein carbonyls(PCO) formation. Additionally, BV extract normalized the antioxidant enzymes (CAT, SOD and GPx), GSH and architecture of liver tissues. Conclusions BV aqueous extract exerts significant hepatoprotective effects against lead-induced oxidative stress and liver dysfunction. The BV effect may be mediated through the enhancement of antioxidant status, lead-chelating abilities and free radicals quenching.


Assuntos
Antioxidantes/uso terapêutico , Berberis , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Chumbo/efeitos adversos , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fitoterapia , Alanina Transaminase/sangue , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Catalase/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colesterol/sangue , Glutationa/sangue , Glutationa Peroxidase/sangue , Chumbo/sangue , Chumbo/toxicidade , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Carbonilação Proteica/efeitos dos fármacos , Superóxido Dismutase/sangue
12.
Environ Sci Pollut Res Int ; 24(6): 5841-5856, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28058584

RESUMO

Lambda-cyhalothrin (LTC) [α-cyano-3-phenoxybenzyl-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclo-propanecarboxylate] is a synthetic type II pyrethroid insecticide commonly used in residential and agricultural areas. The potential hepatotoxicity of pyrethroids remains unclear and could easily be assessed by measuring common clinical indicators of liver disease. To understand more about the potential risks for humans associated with LTC exposure, male adult rats were orally exposed to 6.2 and 31.1 mg/kg bw of LTC for 7, 30, 45, and 60 days. Histopathological changes and alterations of main parameters related to oxidative stress and inflammatory responses in the liver were evaluated. Further, lambda-cyhalothrin metabolites [3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropane carboxylic acid (CFMP), 4-hydroxyphenoxybenzoic acid (4-OH-3-PBA), and 3-phenoxybenzoic acid (3-PBA)] in the liver tissues were identified and quantified by ultra-high-performance liquid chromatography coupled to quadripole time-of-flight mass spectrometry (UHPLC-MS-Q-ToF). Results revealed that LTC exposure significantly increased markers of hepatic oxidative stress in a time-dependent and dose-dependent manner, and this was associated with an accumulation of CFMP and 3-PBA in the liver tissues. In addition, the levels of tumor necrosis factor-α (TNF-α) and interleukin (IL-6 and IL-1ß) gene expressions were significantly increased in the liver of exposed rats compared to controls. Correlation analyses revealed that CFMP and 3-PBA metabolite levels in the liver tissues were significantly correlated with the indexes of oxidative stress, redox status, and inflammatory markers in rats exposed to lambda-cyhalothin. Overall, this study provided novel evidence that hepatic damage is likely due to increased oxidative stress and inflammation under the condition of acute and subchronic exposure to lambda-cyhalothrin and that LTC metabolites (CFMP and 3-PBA) could be used as potential biomarker in human biomonitoring studies.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Inseticidas/toxicidade , Nitrilos/toxicidade , Estresse Oxidativo , Piretrinas/toxicidade , Animais , Benzoatos , Monitoramento Ambiental , Expressão Gênica , Hepatopatias , Masculino , Ratos , Fator de Necrose Tumoral alfa
13.
Biomed Pharmacother ; 84: 1088-1098, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27780137

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Vitis vinifera is used in traditional medicine for diarrhea, hepatitis and stomachaches. The objective of this study was to investigate the anti-oxidant, anti-inflammatory, analgesic and antipyretic properties of the hydroalcoholic leaf extract of Vitis vinifera (EVV) on experimental models to provide scientific basis for its use. MATERIALS AND METHODS: The EVV was chemically characterized by LC-MS/MS analyses. The in vitro antioxidant activities of the EVV extract were measured using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay and Ferric reducing antioxidant power assay (FRAP). Analgesic activity using acetic acid induced writhing and formalin test in mice, anti-inflammatory activity using carrageenan induced paw oedema and acetic acid-induced vascular permeability in mice, and antipyretic activity using Brewer's yeast induced pyrexia in rats were evaluated at 100mg/kg, 200mg/kg, and 400mg/kg doses of the extract. RESULTS: The extract (EVV) was found to contain resveratrol, quercetin, catechin, flavone, flavonols, anthocyanin, gallic acid and epicatechin. EVV produced significant dose-response anti-inflammatory activity against carrageenan-induced paw edema. EVV at dosages of 100, 200 and 400mg/kgbw significantly reduced carrageenan-induced paw edema by 34.48% (P<0.05), 36.20% (P<0.05), and 41.37% (P<0.05) at 5h after carrageenan injection, respectively. Also EVV extract reduces significantly acetic acid-induced vascular permeability in mice dose dependently. EVV (100, 200 and 400mg/kgbw) produced significant dose-response analgesic activity in the formalin test. However, the low percentage inhibition (50%) suggests that it is not a centrally acting analgesic. Extract at dosages of 100, 200 and 400mg/kg bw, p.o. significantly reduced acetic acid-induced writhing by 48.15% (p<0.05), 57.97% (p<0.05), and 68.09% (p<0.05), respectively. The extract also caused marked dose-dependent inhibition of formalin-induced pain in the second phase (p<0.05). Statistical significant reduction in rectal temperatures was observed in standard group at 21 and 23h, and in 200mg/kg and 400mg/kg doses of the extract at 23h (p<0.05) compared with the 19h. CONCLUSIONS: The results obtained indicated potential analgesic, anti-inflammatory and antipyretic effects of them hydroalcoholic leaf extract of V. vinifera observed at doses tested which support the claim for the traditional use of the plant in the treatment of various inflammatory and pain diseases.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Antipiréticos/farmacologia , Cromatografia Líquida , Edema/prevenção & controle , Febre/prevenção & controle , Dor/prevenção & controle , Extratos Vegetais/farmacologia , Folhas de Planta , Espectrometria de Massas em Tandem , Ácido Acético , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Antipiréticos/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Compostos de Bifenilo/química , Regulação da Temperatura Corporal/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Carragenina , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/fisiopatologia , Etanol/química , Ferricianetos/química , Febre/induzido quimicamente , Febre/fisiopatologia , Formaldeído , Camundongos , Estrutura Molecular , Dor/induzido quimicamente , Dor/fisiopatologia , Fitoterapia , Picratos/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Plantas Medicinais , Saccharomyces cerevisiae , Solventes/química , Vitis/química
15.
Environ Sci Pollut Res Int ; 23(19): 19030-40, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27240828

RESUMO

Persistent organic pollutants (POPs) are long-lived organic compounds that are considered one of the major risks to ecosystem and human health. Recently, great concerns are raised about POPs mixtures and its potential toxicity even in low doses of daily human exposure. The brain is mostly targeted by these lipophilic compounds because of its important contain in lipids. So, it would be quite interesting to study the effects of exposure to these mixtures and evaluate their combined toxicity on brain cells. The present study was designed to characterize the cognitive and locomotors deficits and brain areas redox status in rat model. An orally chronic exposure to a representative mixture of POPs composed of endosulfan (2.6 µg/kg), chlorpyrifos (5.2 µg/kg), naphthalene (0.023 µg/kg) and benzopyrane (0.002 µg/kg); the same mixture with concentration multiplied by 10 and 100 was also tested. Exposed rats have shown a disturbance of memory and a decrease in learning ability concluded by Morris water maze and the open field tests results and anxiolytic behaviour in the test of light/dark box compared to control. Concerning brain redox homeostasis, exposed rats have shown an increased malondialdehyde (MDA) amount and an alteration in glutathione (GSH) levels in both the brain mitochondria and cytosolic fractions of the cerebellum, striatum and hippocampus. These effects were accompanied by a decrease in levels of cytosolic glutathione S-transferase (GST) and a highly significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in both cytosolic and mitochondrial fractions. The current study suggests that environmental exposure to daily even low doses of POPs mixtures through diet induces oxidative stress status in the brain and especially in the mitochondria with important cognitive and locomotor behaviour variations in the rats.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Compostos Orgânicos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia , Catalase/metabolismo , Clorpirifos/toxicidade , Citosol/efeitos dos fármacos , Citosol/metabolismo , Exposição Ambiental/efeitos adversos , Feminino , Glutationa/metabolismo , Malondialdeído/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo
16.
Int J Biochem Cell Biol ; 77(Pt A): 15-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27210502

RESUMO

A previous report has shown that a chimera between a platinum complexing agent (1) and the cell penetrating peptide maurocalcin, synthesized with D-amino acids, (DMCa), termed Pt-1-DMCa, is a highly successful anticancer compound that works by targeting the intracellular redox system in glioblastoma (GBM) cells. However, the detailed cellular mechanism whereby the conjugate specifically kills tumor cells remains unclear. Herein, we show that Pt-1-DMCa induces apoptosis in Human U87 GBM cells through reactive oxygen species (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signalling pathway. First, we found that Pt-1-DMCa treatment of these cells induces inhibition of AKT and nuclear accumulation of FoxO3a thereby facilitating transcription of the target genes Bim and PTEN. Modulation of the AKT/FoxO3a/Bim signaling pathway by RNA interference confirms that these signaling events are critical for Pt-1-DMCa-induced apoptosis of U87 GBM cells. Furthermore, we reveal that FoxO3a-mediated up-regulation of PTEN exerts an additional inhibitory effect on the AKT survival pathway. Thus, our results demonstrate that the conjugate can induce ROS-dependent FoxO3a-mediated apoptosis in U87 cells through PTEN-mediated inhibition of the PI3K/AKT survival axis. Our results help elucidate the molecular mechanisms underlying Pt-1-DMCa-induced cell death in U87 GBM cells and support a theoretical basis for future applications of the MCa peptide.


Assuntos
Apoptose/efeitos dos fármacos , Proteína 11 Semelhante a Bcl-2/metabolismo , Proteína Forkhead Box O3/metabolismo , Glioblastoma/patologia , PTEN Fosfo-Hidrolase/metabolismo , Platina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Humanos , Platina/química , Venenos de Escorpião/química , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
17.
Chem Biol Interact ; 244: 195-203, 2016 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-26721195

RESUMO

Naringin (4',5,7-trihydroxyflavanone 7-rhamnoglucoside), a natural flavonoid, has pharmacological properties. In the present study, we investigated the anti-metastatic activity of naringin and its molecular mechanism(s) of action in human glioblastoma cells. Naringin exhibits inhibitory effects on the invasion and adhesion of U87 cells in a concentration-dependent manner by Matrigel Transwell and cell adhesion assays. Naringin also inhibited the migration of U87 cells in a concentration-dependent manner by wound-healing assay. Additional experiments showed that naringin treatment reduced the enzymatic activities and protein levels of matrix metalloproteinase (MMP)-2 and MMP-9 using a gelatin zymography assay and western blot analyses. Furthermore, naringin was able to reduce the protein phosphorylation of extracellular signal-regulated kinase ERK, p38 mitogen-activated protein kinase and c-Jun N-terminal kinase by western blotting. Collectively, our data showed that naringin attenuated the MAPK signaling pathways including ERK, JNK and p38 and resulted in the downregulation of the expression and enzymatic activities of MMP-2, MMP-9, contributing to the inhibition of metastasis in U87 cells. These findings proved that naringin may offer further application as an antimetastatic agent.


Assuntos
Flavanonas/farmacologia , Glioblastoma/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Inibidores de Metaloproteinases de Matriz/farmacologia , Metástase Neoplásica/prevenção & controle , Movimento Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glioblastoma/tratamento farmacológico , Glioblastoma/enzimologia , Glioblastoma/metabolismo , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Metástase Neoplásica/tratamento farmacológico , Proteínas Proto-Oncogênicas c-jun/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
18.
Chem Biol Interact ; 243: 1-9, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26612654

RESUMO

Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. Naringin, a natural flavonoid, plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the involvement of ROS overproduction and inflammation in cisplatin-induced nephrotoxicity in aged rats, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after treatment with naringin (20, 50 or 100 mg/kg body weight). Cisplatin resulted in an increase of renal markers, lipid peroxidation, protein and DNA oxidation, and ROS formation. Renal tumor necrosis factor-α (TNF-α) and nitrite levels were also elevated. Expressions of nuclear factor-kappa B (NF-κB), inductible nitric oxide synthase (iNOS), caspase-3 and p53 were up-regulated in renal tissues of Cis-treated rats compared with the normal control group. Histopathological changes were also observed in cisplatin group. Adminstration of naringin at different doses (25, 50 and 100 mg/kg) was able to protect against the deterioration in kidney function, abrogate the decline in antioxidant enzyme activities and suppressed the increase in TBARS, nitrite and TNF-α concentrations. Moreover, naringin inhibited NF-κB and iNOS pathways, caspase-3 and p53 activation and improved the histological changes induced by cisplatin. In conclusion, our studies suggest that oxidative stress and inflammation might play important roles in the development of cisplatin-induced nephrotoxicity and naringin might become an effective therapeutic strategy for this disease.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Cisplatino/efeitos adversos , Flavanonas/uso terapêutico , Nefropatias/induzido quimicamente , Rim/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefropatias/tratamento farmacológico , Nefropatias/imunologia , Nefropatias/patologia , NF-kappa B/análise , NF-kappa B/genética , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética
19.
J Asthma ; 53(3): 227-37, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26516659

RESUMO

OBJECTIVE: This study aims to determine the systemic oxidant-antioxidant status in Tunisian patients with asthma. METHODS: We evaluated the levels of malondialdehyde (MDA) as thiobarbituric acid complexes, total protein carbonyls (PCs) and advanced oxidation protein products (AOPP). The levels of total thiols, protein sulfhydryls, glutathione (GSH), together with hydrogen peroxide, ascorbic acid, iron and total antioxidant status (TAS) were colorimetrically estimated. Glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) activities were assessed in plasma and erythrocytes by spectrophotometry. We also determined the levels of nitric oxide (NO) and peroxynitrite in plasma from asthmatic patients and healthy controls. The volume of fractionated exhaled NO (FeNO) was evaluated by the Medisoft HypAir method. Estimation of DNA damage was determined using the comet assay. RESULTS: Asthmatic patients showed increased levels of MDA in comparison to healthy controls (p < 0.001), while no significant difference was found in protein carbonyls (p = 0.79) and AOPP (p = 0.98). Patients with asthma also had significantly lower levels of total thiols (355.9 ± 15.72 versus 667.9 ± 22.65, p < 0.001), protein sulfhydryls (333.99 ± 16.41 versus 591.95 ± 24.28, p < 0.001) and glutathione (p < 0.001). They also showed decreased GSH-Px activity (p < 0.001), whereas no significant differences in measurements of catalase and SOD enzyme activities were observed between the two groups (respectively, p = 0.06 and p = 0.55). In addition, ascorbic acid and nitric oxide levels were decreased in asthmatics in comparison to controls (p < 0.01). CONCLUSIONS: Our findings highlight that oxidative stress and defective anti-oxidative status are major alterations in Tunisian patients with asthma.


Assuntos
Asma/fisiopatologia , Adulto , Produtos da Oxidação Avançada de Proteínas/metabolismo , Ácido Ascórbico/metabolismo , Asma/sangue , Biomarcadores , Catalase/metabolismo , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Carbonilação Proteica/fisiologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Superóxido Dismutase/metabolismo , Tunísia
20.
Tumour Biol ; 37(3): 3831-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26474590

RESUMO

Gliomas are the most common and malignant primary brain tumors. They are associated with a poor prognosis despite the availability of multiple therapeutic options. Naringin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative and anti-cancer properties. However, there are no reports describing its effects on the invasion and migration of glioblastoma cell lines. Our results showed that the treatment of U251 glioma cell lines with different concentrations of naringin inhibited the invasion and migration of these cells. In addition, we revealed a decrease in the levels of matrix metalloproteinases (MMP-2) and (MMP-9) expression as well as proteinase activity in U251 glioma cells. In contrast, the expression of tissue inhibitor of metalloproteinases (TIMP-1) and (TIMP-2) was increased. Furthermore, naringin treatment decreased significantly the phosphorylated level of p38. Combined treatment with a p38 inhibitor (SB203580) resulted in the synergistic reduction of MMP-2 and MMP-9 expressions correlated with an increase of TIMP-1 and TIMP-2 expressions and the anti-invasive properties. However, p38 chemical activator (anisomycin) could block these effects produced by naringin, suggesting a direct downregulation of the p38 signaling pathway. These data suggest that naringin may have therapeutic potential for controlling invasiveness of malignant gliomas by inhibiting of p38 signal transduction pathways.


Assuntos
Movimento Celular/efeitos dos fármacos , Flavanonas/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Imidazóis/farmacologia , Immunoblotting , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Invasividade Neoplásica , Fosforilação/efeitos dos fármacos , Piridinas/farmacologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores
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