@article{Dinis-Oliveira20071017,
title = {Full survival of paraquat-exposed rats after treatment with sodium salicylate},
author = {R J Dinis-Oliveira and C Sousa and F Remião and J A Duarte and A S Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33847611966&doi=10.1016%2fj.freeradbiomed.2006.12.031&partnerID=40&md5=899e3c5c6723776b930e5f6357b47493},
doi = {10.1016/j.freeradbiomed.2006.12.031},
year = {2007},
date = {2007-01-01},
volume = {42},
number = {7},
pages = {1017-1028},
abstract = {Over the past decades, there have been numerous fatalities resulting from accidental or voluntary ingestion of the widely used herbicide paraquat dichloride (methyl viologen; PQ). Considering that the main target organ for PQ toxicity is the lung and involves the production of reactive oxygen and nitrogen species, inflammation, disseminated intravascular coagulation, and activation of transcriptional regulatory mechanisms, it may be hypothesized that an antidote against PQ poisonings should counteract all these effects. For this purpose, sodium salicylate (NaSAL) may constitute an adequate therapeutic drug, due to its ability to modulate inflammatory signaling systems and to prevent oxidative stress. To test this hypothesis, NaSAL (200 mg/kg ip) was injected in rats 2 h after exposure to a toxic dose of PQ (25 mg/kg, ip). NaSAL treatment caused a significant reduction in PQ-induced oxidative stress, platelet activation, and nuclear factor (NF)-κB activation in lung. In addition, histopathological lesions induced by PQ in lung were strongly attenuated and the oxidant-induced increases of glutathione peroxidase and catalase expression became absent. These effects were associated with a full survival of the PQ-treated rats (extended for more than 30 days) in comparison with 100% of mortality by Day 6 in animals exposed only to PQ, suggesting that NaSAL constitutes an important and valuable therapeutic drug to be used against PQ-induced toxicity. Indeed, NaSAL constitutes the first compound with such degree of success (100% survival). © 2007 Elsevier Inc. All rights reserved.},
note = {cited By 67},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira200748,
title = {Sodium salicylate prevents paraquat-induced apoptosis in the rat lung},
author = {R J Dinis-Oliveira and C Sousa and F Remião and J A Duarte and R Ferreira and A Sánchez Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-34249903639&doi=10.1016%2fj.freeradbiomed.2007.03.014&partnerID=40&md5=028508bd0e1da3f70d7e69de247f343d},
doi = {10.1016/j.freeradbiomed.2007.03.014},
year = {2007},
date = {2007-01-01},
volume = {43},
number = {1},
pages = {48-61},
abstract = {The nonselective contact herbicide, paraquat (PQ), is a strong pneumotoxicant, especially due to its accumulation in the lung through a polyamine uptake system and to its capacity to induce redox cycling, leading to oxidative stress-related damage. In the present study, we aimed to investigate the occurrence of apoptotic events in the lungs of male Wistar rats, 24, 48, and 96 h after PQ exposure (25 mg/kg ip) as well as the putative healing effects provided by sodium salicylate [(NaSAL), 200 mg/kg ip] when administered 2 h after PQ. PQ exposure resulted in marked lung apoptosis, in a time-dependent manner, characterized by the "ladder-like" pattern of DNA observed through electrophoresis and by the presence of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells (TPC) as revealed by immunohistochemistry. The two main caspase cascades (the extrinsic receptor-mediated and the intrinsic mitochondria-mediated) and the expressions of p53 and activator protein-1 (AP-1) were also evaluated, to obtain an insight into apoptotic cellular signaling. PQ-exposed rats suffered a time-dependent increase of caspase-3 and caspase-8 and a decrease of caspase-1 activities in lungs compared to the control group. A marked mitochondrial dysfunction evidenced by cytochrome c (Cyt c) release was also observed as a consequence of PQ exposure. In addition, fluorescence electrophoretic mobility shift assay (fEMSA) revealed a transcriptional induction of the p53 and AP-1 transcription factors in a time-dependent manner as a consequence of PQ exposure. NaSAL treatment resulted in the remission of the observed apoptotic signaling and consequently of lung apoptosis. Taken together, the present results showed that PQ activates several events involved in the apoptotic pathways, which might contribute to its lung toxicodynamics. NaSAL, a recently implemented antidote for PQ intoxications, proved to protect lungs from PQ-induced apoptosis. © 2007 Elsevier Inc. All rights reserved.},
note = {cited By 42},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira200748b,
title = {Sodium salicylate prevents paraquat-induced apoptosis in the rat lung},
author = {R J Dinis-Oliveira and C Sousa and F Remião and J A Duarte and R Ferreira and A Sánchez Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-34249903639&doi=10.1016%2fj.freeradbiomed.2007.03.014&partnerID=40&md5=028508bd0e1da3f70d7e69de247f343d},
doi = {10.1016/j.freeradbiomed.2007.03.014},
year = {2007},
date = {2007-01-01},
journal = {Free Radical Biology and Medicine},
volume = {43},
number = {1},
pages = {48-61},
abstract = {The nonselective contact herbicide, paraquat (PQ), is a strong pneumotoxicant, especially due to its accumulation in the lung through a polyamine uptake system and to its capacity to induce redox cycling, leading to oxidative stress-related damage. In the present study, we aimed to investigate the occurrence of apoptotic events in the lungs of male Wistar rats, 24, 48, and 96 h after PQ exposure (25 mg/kg ip) as well as the putative healing effects provided by sodium salicylate [(NaSAL), 200 mg/kg ip] when administered 2 h after PQ. PQ exposure resulted in marked lung apoptosis, in a time-dependent manner, characterized by the "ladder-like" pattern of DNA observed through electrophoresis and by the presence of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells (TPC) as revealed by immunohistochemistry. The two main caspase cascades (the extrinsic receptor-mediated and the intrinsic mitochondria-mediated) and the expressions of p53 and activator protein-1 (AP-1) were also evaluated, to obtain an insight into apoptotic cellular signaling. PQ-exposed rats suffered a time-dependent increase of caspase-3 and caspase-8 and a decrease of caspase-1 activities in lungs compared to the control group. A marked mitochondrial dysfunction evidenced by cytochrome c (Cyt c) release was also observed as a consequence of PQ exposure. In addition, fluorescence electrophoretic mobility shift assay (fEMSA) revealed a transcriptional induction of the p53 and AP-1 transcription factors in a time-dependent manner as a consequence of PQ exposure. NaSAL treatment resulted in the remission of the observed apoptotic signaling and consequently of lung apoptosis. Taken together, the present results showed that PQ activates several events involved in the apoptotic pathways, which might contribute to its lung toxicodynamics. NaSAL, a recently implemented antidote for PQ intoxications, proved to protect lungs from PQ-induced apoptosis. © 2007 Elsevier Inc. All rights reserved.},
note = {cited By 45},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira20061110b,
title = {Paraquat exposure as an etiological factor of Parkinson's disease},
author = {R J Dinis-Oliveira and F Remião and H Carmo and J A Duarte and A S Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33751520926&doi=10.1016%2fj.neuro.2006.05.012&partnerID=40&md5=491de9369a299ade3fd6f2c5d7ae2e47},
doi = {10.1016/j.neuro.2006.05.012},
year = {2006},
date = {2006-01-01},
journal = {NeuroToxicology},
volume = {27},
number = {6},
pages = {1110-1122},
abstract = {Parkinson's disease (PD) is a multifactorial chronic progressive neurodegenerative disease influenced by age, and by genetic and environmental factors. The role of genetic predisposition in PD has been increasingly acknowledged and a number of relevant genes have been identified (e.g., genes encoding α-synuclein, parkin, and dardarin), while the search for environmental factors that influence the pathogenesis of PD has only recently begun to escalate. In recent years, the investigation on paraquat (PQ) toxicity has suggested that this herbicide might be an environmental factor contributing to this neurodegenerative disorder. Although the biochemical mechanism through which PQ causes neurodegeneration in PD is not yet fully understood, PQ-induced lipid peroxidation and consequent cell death of dopaminergic neurons can be responsible for the onset of the Parkinsonian syndrome, thus indicating that this herbicide may induce PD or influence its natural course. PQ has also been recently considered as an eligible candidate for inducing the Parkinsonian syndrome in laboratory animals, and can therefore constitute an alternative tool in suitable animal models for the study of PD. In the present review, the recent evidences linking PQ exposure with PD development are discussed, with the aim of encouraging new perspectives and further investigation on the involvement of environmental agents in PD. © 2006 Elsevier Inc. All rights reserved.},
note = {cited By 209},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira20061213b,
title = {P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity},
author = {R J Dinis-Oliveira and F Remião and J A Duarte and R Ferreira and A Sánchez Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33749065926&doi=10.1016%2fj.freeradbiomed.2006.06.012&partnerID=40&md5=e0a20f0598de468e27f81c94ef6d6449},
doi = {10.1016/j.freeradbiomed.2006.06.012},
year = {2006},
date = {2006-01-01},
journal = {Free Radical Biology and Medicine},
volume = {41},
number = {8},
pages = {1213-1224},
abstract = {The widespread use of the nonselective contact herbicide paraquat (PQ) has been the cause of thousands of deaths from both accidental and voluntary ingestion. The main target organ for PQ toxicity is the lung. No antidote or effective treatment to decrease PQ accumulation in the lung or to disrupt its toxicity has yet been developed. The present study describes a procedure that leads to a remarkable decrease in PQ accumulation in the lung, together with an increase in its fecal excretion and a subsequent decrease in several biochemical and histopathological biomarkers of toxicity. The administration of dexamethasone (100 mg/kg ip) to Wistar rats, 2 h after PQ intoxication (25 mg/kg ip), decreased the lung PQ accumulation to about 40% of the group exposed to only PQ and led to an improvement in tissue healing in just 24 h as a result of the induction of de novo synthesis of P-glycoprotein (P-gp). The involvement of P-gp in these effects was confirmed by Western blot analysis and by the use of a competitive inhibitor of this transporter, verapamil (10 mg/kg ip), which, given 1 h before dexamethasone, blocked its protective effects, causing instead an increase in lung PQ concentration and an aggravation of toxicity. In conclusion, the induction of P-gp, leading to a decrease in lung levels of PQ and the consequent prevention of toxicity, seems to be a new and promising treatment for PQ poisonings that should be further clinically tested. © 2006 Elsevier Inc. All rights reserved.},
note = {cited By 67},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira200673b,
title = {Single high dose dexamethasone treatment decreases the pathological score and increases the survival rate of paraquat-intoxicated rats},
author = {R J Dinis-Oliveira and J A Duarte and F Remião and A Sánchez-Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33748740652&doi=10.1016%2fj.tox.2006.07.025&partnerID=40&md5=8e08ed3f9a7f9a83a6904f6e3e0241a9},
doi = {10.1016/j.tox.2006.07.025},
year = {2006},
date = {2006-01-01},
journal = {Toxicology},
volume = {227},
number = {1-2},
pages = {73-85},
abstract = {Dexamethasone (DEX), a synthetic corticosteroid, has been successfully used in clinical practice during paraquat (PQ) poisonings due to its anti-inflammatory activity, although, as recently observed, its effects related to de novo synthesis of P-glycoprotein (P-gp), may also strongly contribute for its healing effects. The main purpose of this study was to evaluate the effects of a single high dose DEX administration, which induces de novo synthesis of P-gp, in the histological and biochemical parameters in lung, liver, kidney and spleen of acute PQ-intoxicated rats. Four groups of rats were constituted: (i) control group, (ii) DEX group (100 mg/kg i.p.), (iii) PQ group (25 mg/kg i.p.) and (iv) PQ + DEX group (DEX injected 2 h after PQ). The obtained results showed that DEX ameliorated the biochemical and histological lung and liver alterations induced by PQ in Wistar rats at the end of 24 hours. This was evidenced by a significant reduction in lipid peroxidation (LPO) and carbonyl groups content, as well as by normalization of the myeloperoxidase (MPO) activities. Moreover, DEX prevented the increase of relative lung weight. On the other hand, these improvements were not observed in kidney and spleen of DEX treated rats. Conversely, an increase of LPO and carbonyl groups content and aggravation of histological damages were observed in the latter tissues. In addition, MPO activity increased in the spleen of PQ + DEX group and urinary N-acetyl-β-d-glucosaminidase activity, a biomarker of renal tubular proximal damage, also augmented in this group. Nevertheless, it is legitimate to hypothesize that the apparent protection of high dosage DEX treatment awards to the lungs of the PQ-intoxicated animals outweighs the increased damage to their spleens and kidneys, because a higher survival rate was observed, indicating that DEX treatment may constitute an important and valuable therapeutic drug to be used against PQ-induced toxicity. © 2006 Elsevier Ireland Ltd. All rights reserved.},
note = {cited By 82},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira2006724b,
title = {Kinetics of paraquat in the isolated rat lung: Influence of sodium depletion},
author = {R J Dinis-Oliveira and M J D J Valle and M L Bastos and F Carvalho and A Sánchez Navarro},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33746909463&doi=10.1080%2f00498250600790331&partnerID=40&md5=71ed4acd3ba50aac382a4c33f8ccf6bd},
doi = {10.1080/00498250600790331},
year = {2006},
date = {2006-01-01},
journal = {Xenobiotica},
volume = {36},
number = {8},
pages = {724-737},
abstract = {Paraquat accumulates in the lung through a characteristic polyamine uptake system. It has been previously shown that paraquat uptake can be significantly prevented if extracellular sodium (Na + ) is reduced, although the available data correspond to experiments performed using tissue slices or incubated cells. This type of in vitro study fails to give information on the actual behaviour occurring in vivo since the anatomy and physiology of the studied tissue is disrupted. Accordingly, the aim of the present study was to explore the usefulness of the isolated rat lung model when applied to characterize the kinetic behaviour of paraquat in this tissue after bolus injection under standard experimental conditions as well as to evaluate the influence of iso-osmotic replacement of Na + by lithium (Li + ) in the perfusion medium. The obtained results show that the present isolated rat lung model is useful for the analysis of paraquat toxicokinetics, which is reported herein for the first time. It was also observed that Na + depletion in the perfusion medium leads to a decreased uptake of paraquat in the isolated rat lung, although it seems that this condition does not contribute to improve the elimination of paraquat once the herbicide reaches the extravascular structures of the tissue, since the paraquat tissue wash-out phase is similar under both experimental conditions assayed. © 2006 Informa UK Ltd.},
note = {cited By 22},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira2006537b,
title = {Acute paraquat poisoning: Report of a survival case following intake of a potential lethal dose},
author = {R J Dinis-Oliveira and A Sarmento and P Reis and A Amaro and F Remião and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33746658144&doi=10.1097%2f01.pec.0000223179.07633.8a&partnerID=40&md5=115a2dbc87fd8ff71e70fb285aaa662e},
doi = {10.1097/01.pec.0000223179.07633.8a},
year = {2006},
date = {2006-01-01},
journal = {Pediatric Emergency Care},
volume = {22},
number = {7},
pages = {537-540},
abstract = {When properly used, paraquat (PQ) is a widely used bipyridil herbicide with a good safety record. Most cases of PQ poisoning result from intentional ingestion, with death resulting from hypoxemia secondary to lung fibrosis in moderate to severe poisonings. With high ingestion volumes (>50 mL of a 20% wt/vol formulation), death results from multiple organ failure and cardiovascular collapse within 1 week after intoxication. The present report describes a successful clinical case regarding the intoxication of a 15-year-old girl by a presumed lethal dose of PQ. The adolescent ingested approximately 50 mL of a commercialized concentrate (20% wt/vol of dichloride salt) formulation of PQ. High serum and urinary levels of PQ confirmed the bad prognosis. However, the therapeutic protocol followed in the present clinical case led to a positive outcome. Besides the measures for decreasing PQ absorption and increasing its elimination, other protective procedures were applied in aiming to reduce the production of reactive oxygen species (ROS), to scavenge ROS, to repair ROS-induced lesions, and to reduce inflammation. The status-of-the-art concerning the biochemical and toxicological aspects of PQ poisoning and the pharmacologic basis of the respective treatment is also presented. Copyright © 2006 by Lippincott Williams & Wilkins.},
note = {cited By 34},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Porto200641b,
title = {The role of foetal red blood cells in protecting cultured lymphocytes against diepoxybutane-induced chromosome breaks},
author = {B Porto and R J D Oliveira and C Sousa and J Gaspar and J Rueff and F Carvalho and I Malheiro},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33644871566&doi=10.1016%2fj.mrgentox.2005.10.012&partnerID=40&md5=1d8b0a565af8f7aa66c971dcba7e6e9b},
doi = {10.1016/j.mrgentox.2005.10.012},
year = {2006},
date = {2006-01-01},
journal = {Mutation Research - Genetic Toxicology and Environmental Mutagenesis},
volume = {603},
number = {1},
pages = {41-47},
abstract = {Diepoxybutane (DEB) is an established mutagen that induces chromosome damage following in vitro treatment of peripheral blood lymphocytes. It is widely used to identify patients with Fanconi Anemia (FA), a clinical situation that is characterized, besides the hypersensitivity to DEB, by an elevated foetal haemoglobin (HbF) content in the peripheral blood. In a previous study, we showed that red blood cells (RBC) from normal individuals can protect cultured lymphocytes against chromosomal breaks induced by DEB and demonstrated the particular role of haemoglobin in the protective effect. In the present work, we studied the influence of RBC extracted from umbilical cord blood of neonates (F cells) on the frequency of DEB-induced chromosome breaks in lymphocyte cultures from normal individuals. Simultaneously, we determined individual GSTT1 and GSTM1 genotypes and the activity of Pi-class glutathione S-transferase (GSTP), catalase and superoxide dismutase (SOD) in adult and foetal RBC. Our results show that F cells, in comparison with adult RBC, elicit a better protection of cultured lymphocytes from normal individuals against chromosome breaks induced by DEB. Variability in the protective effect among RBC from different individuals was observed; we confirmed that the GSTT1 genotype modulates this inter-individual variability, but it is not sufficient to explain all of the protective effect of F cells. Our results suggest that the increased protective effect of F cells can be, at least in part, correlated with an increase in the activity of glutathione S-transferase, catalase and superoxide dismutase, in particular Cu/Zn SOD, in F cells compared with adult RBC. © 2005 Elsevier B.V. All rights reserved.},
note = {cited By 5},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Porto200641,
title = {The role of foetal red blood cells in protecting cultured lymphocytes against diepoxybutane-induced chromosome breaks},
author = {B Porto and R J D Oliveira and C Sousa and J Gaspar and J Rueff and F Carvalho and I Malheiro},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33644871566&doi=10.1016%2fj.mrgentox.2005.10.012&partnerID=40&md5=1d8b0a565af8f7aa66c971dcba7e6e9b},
doi = {10.1016/j.mrgentox.2005.10.012},
year = {2006},
date = {2006-01-01},
volume = {603},
number = {1},
pages = {41-47},
abstract = {Diepoxybutane (DEB) is an established mutagen that induces chromosome damage following in vitro treatment of peripheral blood lymphocytes. It is widely used to identify patients with Fanconi Anemia (FA), a clinical situation that is characterized, besides the hypersensitivity to DEB, by an elevated foetal haemoglobin (HbF) content in the peripheral blood. In a previous study, we showed that red blood cells (RBC) from normal individuals can protect cultured lymphocytes against chromosomal breaks induced by DEB and demonstrated the particular role of haemoglobin in the protective effect. In the present work, we studied the influence of RBC extracted from umbilical cord blood of neonates (F cells) on the frequency of DEB-induced chromosome breaks in lymphocyte cultures from normal individuals. Simultaneously, we determined individual GSTT1 and GSTM1 genotypes and the activity of Pi-class glutathione S-transferase (GSTP), catalase and superoxide dismutase (SOD) in adult and foetal RBC. Our results show that F cells, in comparison with adult RBC, elicit a better protection of cultured lymphocytes from normal individuals against chromosome breaks induced by DEB. Variability in the protective effect among RBC from different individuals was observed; we confirmed that the GSTT1 genotype modulates this inter-individual variability, but it is not sufficient to explain all of the protective effect of F cells. Our results suggest that the increased protective effect of F cells can be, at least in part, correlated with an increase in the activity of glutathione S-transferase, catalase and superoxide dismutase, in particular Cu/Zn SOD, in F cells compared with adult RBC. © 2005 Elsevier B.V. All rights reserved.},
note = {cited By 5},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira2006537,
title = {Acute paraquat poisoning: Report of a survival case following intake of a potential lethal dose},
author = {R J Dinis-Oliveira and A Sarmento and P Reis and A Amaro and F Remião and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33746658144&doi=10.1097%2f01.pec.0000223179.07633.8a&partnerID=40&md5=115a2dbc87fd8ff71e70fb285aaa662e},
doi = {10.1097/01.pec.0000223179.07633.8a},
year = {2006},
date = {2006-01-01},
volume = {22},
number = {7},
pages = {537-540},
abstract = {When properly used, paraquat (PQ) is a widely used bipyridil herbicide with a good safety record. Most cases of PQ poisoning result from intentional ingestion, with death resulting from hypoxemia secondary to lung fibrosis in moderate to severe poisonings. With high ingestion volumes (>50 mL of a 20% wt/vol formulation), death results from multiple organ failure and cardiovascular collapse within 1 week after intoxication. The present report describes a successful clinical case regarding the intoxication of a 15-year-old girl by a presumed lethal dose of PQ. The adolescent ingested approximately 50 mL of a commercialized concentrate (20% wt/vol of dichloride salt) formulation of PQ. High serum and urinary levels of PQ confirmed the bad prognosis. However, the therapeutic protocol followed in the present clinical case led to a positive outcome. Besides the measures for decreasing PQ absorption and increasing its elimination, other protective procedures were applied in aiming to reduce the production of reactive oxygen species (ROS), to scavenge ROS, to repair ROS-induced lesions, and to reduce inflammation. The status-of-the-art concerning the biochemical and toxicological aspects of PQ poisoning and the pharmacologic basis of the respective treatment is also presented. Copyright © 2006 by Lippincott Williams & Wilkins.},
note = {cited By 30},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira2006724,
title = {Kinetics of paraquat in the isolated rat lung: Influence of sodium depletion},
author = {R J Dinis-Oliveira and M J D J Valle and M L Bastos and F Carvalho and A Sánchez Navarro},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33746909463&doi=10.1080%2f00498250600790331&partnerID=40&md5=71ed4acd3ba50aac382a4c33f8ccf6bd},
doi = {10.1080/00498250600790331},
year = {2006},
date = {2006-01-01},
volume = {36},
number = {8},
pages = {724-737},
abstract = {Paraquat accumulates in the lung through a characteristic polyamine uptake system. It has been previously shown that paraquat uptake can be significantly prevented if extracellular sodium (Na + ) is reduced, although the available data correspond to experiments performed using tissue slices or incubated cells. This type of in vitro study fails to give information on the actual behaviour occurring in vivo since the anatomy and physiology of the studied tissue is disrupted. Accordingly, the aim of the present study was to explore the usefulness of the isolated rat lung model when applied to characterize the kinetic behaviour of paraquat in this tissue after bolus injection under standard experimental conditions as well as to evaluate the influence of iso-osmotic replacement of Na + by lithium (Li + ) in the perfusion medium. The obtained results show that the present isolated rat lung model is useful for the analysis of paraquat toxicokinetics, which is reported herein for the first time. It was also observed that Na + depletion in the perfusion medium leads to a decreased uptake of paraquat in the isolated rat lung, although it seems that this condition does not contribute to improve the elimination of paraquat once the herbicide reaches the extravascular structures of the tissue, since the paraquat tissue wash-out phase is similar under both experimental conditions assayed. © 2006 Informa UK Ltd.},
note = {cited By 20},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira200673,
title = {Single high dose dexamethasone treatment decreases the pathological score and increases the survival rate of paraquat-intoxicated rats},
author = {R J Dinis-Oliveira and J A Duarte and F Remião and A Sánchez-Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33748740652&doi=10.1016%2fj.tox.2006.07.025&partnerID=40&md5=8e08ed3f9a7f9a83a6904f6e3e0241a9},
doi = {10.1016/j.tox.2006.07.025},
year = {2006},
date = {2006-01-01},
volume = {227},
number = {1-2},
pages = {73-85},
abstract = {Dexamethasone (DEX), a synthetic corticosteroid, has been successfully used in clinical practice during paraquat (PQ) poisonings due to its anti-inflammatory activity, although, as recently observed, its effects related to de novo synthesis of P-glycoprotein (P-gp), may also strongly contribute for its healing effects. The main purpose of this study was to evaluate the effects of a single high dose DEX administration, which induces de novo synthesis of P-gp, in the histological and biochemical parameters in lung, liver, kidney and spleen of acute PQ-intoxicated rats. Four groups of rats were constituted: (i) control group, (ii) DEX group (100 mg/kg i.p.), (iii) PQ group (25 mg/kg i.p.) and (iv) PQ + DEX group (DEX injected 2 h after PQ). The obtained results showed that DEX ameliorated the biochemical and histological lung and liver alterations induced by PQ in Wistar rats at the end of 24 hours. This was evidenced by a significant reduction in lipid peroxidation (LPO) and carbonyl groups content, as well as by normalization of the myeloperoxidase (MPO) activities. Moreover, DEX prevented the increase of relative lung weight. On the other hand, these improvements were not observed in kidney and spleen of DEX treated rats. Conversely, an increase of LPO and carbonyl groups content and aggravation of histological damages were observed in the latter tissues. In addition, MPO activity increased in the spleen of PQ + DEX group and urinary N-acetyl-β-d-glucosaminidase activity, a biomarker of renal tubular proximal damage, also augmented in this group. Nevertheless, it is legitimate to hypothesize that the apparent protection of high dosage DEX treatment awards to the lungs of the PQ-intoxicated animals outweighs the increased damage to their spleens and kidneys, because a higher survival rate was observed, indicating that DEX treatment may constitute an important and valuable therapeutic drug to be used against PQ-induced toxicity. © 2006 Elsevier Ireland Ltd. All rights reserved.},
note = {cited By 74},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira20061213,
title = {P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity},
author = {R J Dinis-Oliveira and F Remião and J A Duarte and R Ferreira and A Sánchez Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33749065926&doi=10.1016%2fj.freeradbiomed.2006.06.012&partnerID=40&md5=e0a20f0598de468e27f81c94ef6d6449},
doi = {10.1016/j.freeradbiomed.2006.06.012},
year = {2006},
date = {2006-01-01},
volume = {41},
number = {8},
pages = {1213-1224},
abstract = {The widespread use of the nonselective contact herbicide paraquat (PQ) has been the cause of thousands of deaths from both accidental and voluntary ingestion. The main target organ for PQ toxicity is the lung. No antidote or effective treatment to decrease PQ accumulation in the lung or to disrupt its toxicity has yet been developed. The present study describes a procedure that leads to a remarkable decrease in PQ accumulation in the lung, together with an increase in its fecal excretion and a subsequent decrease in several biochemical and histopathological biomarkers of toxicity. The administration of dexamethasone (100 mg/kg ip) to Wistar rats, 2 h after PQ intoxication (25 mg/kg ip), decreased the lung PQ accumulation to about 40% of the group exposed to only PQ and led to an improvement in tissue healing in just 24 h as a result of the induction of de novo synthesis of P-glycoprotein (P-gp). The involvement of P-gp in these effects was confirmed by Western blot analysis and by the use of a competitive inhibitor of this transporter, verapamil (10 mg/kg ip), which, given 1 h before dexamethasone, blocked its protective effects, causing instead an increase in lung PQ concentration and an aggravation of toxicity. In conclusion, the induction of P-gp, leading to a decrease in lung levels of PQ and the consequent prevention of toxicity, seems to be a new and promising treatment for PQ poisonings that should be further clinically tested. © 2006 Elsevier Inc. All rights reserved.},
note = {cited By 61},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

@article{Dinis-Oliveira20061110,
title = {Paraquat exposure as an etiological factor of Parkinson's disease},
author = {R J Dinis-Oliveira and F Remião and H Carmo and J A Duarte and A S Navarro and M L Bastos and F Carvalho},
url = {https://www.scopus.com/inward/record.uri?eid=2-s2.0-33751520926&doi=10.1016%2fj.neuro.2006.05.012&partnerID=40&md5=491de9369a299ade3fd6f2c5d7ae2e47},
doi = {10.1016/j.neuro.2006.05.012},
year = {2006},
date = {2006-01-01},
volume = {27},
number = {6},
pages = {1110-1122},
abstract = {Parkinson's disease (PD) is a multifactorial chronic progressive neurodegenerative disease influenced by age, and by genetic and environmental factors. The role of genetic predisposition in PD has been increasingly acknowledged and a number of relevant genes have been identified (e.g., genes encoding α-synuclein, parkin, and dardarin), while the search for environmental factors that influence the pathogenesis of PD has only recently begun to escalate. In recent years, the investigation on paraquat (PQ) toxicity has suggested that this herbicide might be an environmental factor contributing to this neurodegenerative disorder. Although the biochemical mechanism through which PQ causes neurodegeneration in PD is not yet fully understood, PQ-induced lipid peroxidation and consequent cell death of dopaminergic neurons can be responsible for the onset of the Parkinsonian syndrome, thus indicating that this herbicide may induce PD or influence its natural course. PQ has also been recently considered as an eligible candidate for inducing the Parkinsonian syndrome in laboratory animals, and can therefore constitute an alternative tool in suitable animal models for the study of PD. In the present review, the recent evidences linking PQ exposure with PD development are discussed, with the aim of encouraging new perspectives and further investigation on the involvement of environmental agents in PD. © 2006 Elsevier Inc. All rights reserved.},
note = {cited By 193},
keywords = {},
pubstate = {published},
tppubtype = {article}
}