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- ItemAcesso aberto (Open Access)Antineoplastic drugs in environmentally relevant concentrations cause endocrine disruption and testicular dysfunction in experimental conditions(Elsevier, 2023-04-07) Medeiros, Paloma da Cunha de [UNIFESP]; Perobelli, Juliana Elaine [UNIFESP]; Nascimento, Cinthia Castro do [UNIFESP]; https://lattes.cnpq.br/9844283096155413; http://lattes.cnpq.br/2047233951021632; Universidade Federal de São Paulo (UNIFESP)5-fluorouracil (5-FU) and methotrexate (MTX) are among the most widely consumed antineoplastic drugs worldwide. These drugs are known as emerging pollutants, once after consumption are excreted by feces and/or urine in a mixture of compounds and metabolites, entering the aquatic environment due to low efficiency in drug removal by effluent treatment plants. Considering that these substances may interact with the DNA, causing metabolic and morphological changes, leading to cell death, the present study aimed to investigate the potential impact of a long-term exposure to these antineoplastic drugs in environmentally relevant concentrations, on testicular morphophysiology of rats. Male Wistar rats (70 days old) were distributed into 4 groups (n = 10 / group): control, received only vehicle; MTX, received methotrexate at 10ng/L in drinking water; 5-FU received 5-fluorouracil at 10ng/L in drinking water; and MTX+ 5FU, received the combination of MTX and 5-FU at 10ng/L each. The treatment period was from postnatal day (PND)70 to PND160, when the animals were euthanized for evaluation of testicular toxicity and changes in endocrine signaling. In these experimental conditions, both drugs acted as endocrine disruptors causing cytotoxic effects in the testes of exposed rats, altering the structural pattern of seminiferous tubules and leading to oxidative stress even at environmental concentrations.
- ItemAcesso aberto (Open Access)Acute Lung Injury in Cholinergic-Deficient Mice Supports Anti-Inflammatory Role of α7 Nicotinic Acetylcholine Receptor(Nicola Scichilone, 2021-07) Pinheiro, Nathalia Montouro [UNIFESP]; Banzato, Rosana; Tibério, Iolanda de Fátima Lopes Calvo; Prado, Marco Antônio Máximo; Prado, Vania Ferreira; Hamouda, Ayman; Prado, Carla Máximo [UNIFESP]; http://lattes.cnpq.br/8960401765088965Abstract: (1) Background: The lung cholinergic pathway is important for controlling pulmonary inflammation in acute lung injury, a condition that is characterized by a sudden onset and intense inflammation. This study investigated changes in the expression levels of nicotinic and muscarinic acetylcholine receptors (nAChR and mAChR) in the lung during acute lung injury. (2) Methods: acute lung injury (ALI) was induced in wild-type and cholinergic-deficient (VAChT-KDHOM) mice using intratracheal lipopolysaccharide (LPS) instillation with or without concurrent treatment with nicotinic ligands. Bronchoalveolar lavage fluid was collected to evaluate markers of inflammation, and then the lung was removed and processed for isolation of membrane fraction and determination of acetylcholine receptors level using radioligand binding assays. (3) Results: LPS-induced increase in lung inflammatory markers (e.g., neutrophils and IL-1β) was significantly higher in VAChT-KDHOM than wild-type mice. In contrast, LPS treatment resulted in a significant increase in lung’s α7 nicotinic receptor level in wild-type, but not in VAChT-KDHOM mice. However, treatment with PNU 282987, a selective α7 nicotinic receptor agonist, restored VAChT-KDHOM mice’s ability to increase α7 nicotinic receptor levels in response to LPS-induced acute lung injury and reduced lung inflammation. LPS also increased muscarinic receptors level in VAChT-KDHOM mice, and PNU 282987 treatment reduced this response. (4) Conclusions: Our data indicate that the anti-inflammatory effects of the lung cholinergic system involve an increase in the level of α7 nicotinic receptors. Pharmacological agents that increase the expression or the function of lung α7 nicotinic receptors have potential clinical uses for treating acute lung injury.
- ItemAcesso aberto (Open Access)Effects of VAChT reduction and α7nAChR stimulation by PNU-282987 in lung inflammation in a model of chronic allergic airway inflammation(Elsevier, 2020-09-05) Pinheiro, Nathalia Montouro; Miranda, Cláudia Jeane Claudino de Pontes; Santana, Fernanda Paula Roncon [UNIFESP]; Bittencourt-Mernak, Marcia Isabel [UNIFESP]; Arantes-Costas, Fernanda Magalhães; Olivo, Clarice Rosa; Perini, Adenir; Festa, Sergio [UNIFESP]; Caperuto, Luciana Chagas [UNIFESP]; Tiberio, Iolanda de Fátima Lopes Calvo; Prado, Marco Antônio Máximo; Martins, Milton de Arruda; Prado, Vânia Ferreira; Prado, Carla Máximo [UNIFESP]; http://lattes.cnpq.br/8960401765088965; Universidade Federal de São Paulo (UNIFESP)The cholinergic anti-inflammatory pathway has been shown to regulate lung inflammation and cytokine release in acute models of inflammation, mainly via α7 nicotinic receptor (α7nAChR). We aimed to evaluate the role of endogenous acetylcholine in chronic allergic airway inflammation in mice and the effects of therapeutic nAChR stimulation in this model. We first evaluated lung inflammation and remodeling on knock-down mice with 65% of vesicular acetylcholine transport (VAChT) gene reduction (KDVAChT) and wild-type(WT) controls that were subcutaneously sensitized and then inhaled with ovalbumin(OVA). We then evaluated the effects of PNU-282987(0.5-to-2mg/kg),(α7nAChR agonist) treatment in BALB/c male mice intraperitoneal sensitized and then inhaled with OVA. Another OVA-sensitized-group was treated with PNU-282987 plus Methyllycaconitine (MLA,1 mg/kg, α7nAChR antagonist) to confirm that the effects observed by PNU were due to α7nAChR. We showed that KDVAChT-OVA mice exhibit exacerbated airway inflammation when compared to WT-OVA mice. In BALB/c, PNU-282987 treatment reduced the number of eosinophils in the blood, BAL fluid, and around airways, and also decreased pulmonary levels of IL-4,IL-13,IL-17, and IgE in the serum of OVA-exposed mice. MLA pre-treatment abolished all the effects of PNU-282987. Additionally, we showed that PNU-282987 inhibited STAT3-phosphorylation and reduced SOCS3 expression in the lung. These data indicate that endogenous cholinergic tone is important to control allergic airway inflammation in a murine model. Moreover, α7nAChR is involved in the control of eosinophilic inflammation and airway remodeling, possibly via inhibition of STAT3/SOCS3 pathways. Together these data suggest that cholinergic anti-inflammatory system mainly α7nAChR should be further considered as a therapeutic target in asthma.
- ItemAcesso aberto (Open Access)Biseugenol Exhibited Anti-Inflammatory and Anti-Asthmatic Effects in an Asthma Mouse Model of Mixed-Granulocytic Asthma(Prof. Dr. R. Daniel Little, 2020-11-18) Ponci, Vitor [UNIFESP]; Silva, Rafael Cossi da [UNIFESP]; Santana, Fernanda Paula Roncon [UNIFESP]; Grecco, Simone dos Santos [UNIFESP]; Fortunato, Célia Regina Martinez; Oliveira, Maria Aparecida de; Tavares-de-Lima, Wothan; Olivo, Clarice Rosa; Tibério, Iolanda de Fátima Lopes Calvo; Gomes, Kaio de Souza; Prado, Carla Máximo [UNIFESP]; Lago, Joao Henrique Ghilardi; http://lattes.cnpq.br/1740478426977844In the present work, the anti-inflammatory and antiasthmatic potential of biseugenol, isolated as the main component from n-hexane extract from leaves of Nectandra leucantha and chemically prepared using oxidative coupling from eugenol, was evaluated in an experimental model of mixed-granulocytic asthma. Initially, in silico studies of biseugenol showed good predictions for drug-likeness, with adherence to Lipinski’s rules of five (RO5), good Absorption, Distribution, Metabolism and Excretion (ADME) properties and no alerts for Pan-Assay Interference Compounds (PAINS), indicating adequate adherence to perform in vivo assays. Biseugenol (20 mg·kg−1) was thus administered intraperitoneally (four days of treatment) and resulted in a significant reduction in both eosinophils and neutrophils of bronchoalveolar lavage fluid in ovalbumin-sensitized mice with no statistical difference from dexamethasone (5 mg·kg−1). As for lung function parameters, biseugenol (20 mg·kg−1) significantly reduced airway and tissue damping in comparison to ovalbumin group, with similar efficacy to positive control dexamethasone. Airway hyperresponsiveness to intravenous methacholine was reduced with biseugenol but was inferior to dexamethasone in higher doses. In conclusion, biseugenol displayed antiasthmatic effects, as observed through the reduction of inflammation and airway hyperresponsiveness, with similar effects to dexamethasone, on mixed-granulocytic ovalbumin-sensitized mice
- ItemAcesso aberto (Open Access)Fatores relacionados à eficiência da propulsão em cadeira de rodas manual de usuários com paraplegia devido à lesão medular(Cad. Bras. Ter. Ocup, 2020-04-04) Curi, Haidar Tafner [UNIFESP]; Lima, Jaqueline de; Ferretti, Eliana Chaves [UNIFESP]; http://lattes.cnpq.br/7869059238387906Introdução Indivíduos com paraplegia devido à lesão medular (LM) realizam propulsão de cadeira de rodas manual (CRM), a fim de promover mobilidade funcional para realização das atividades cotidianas. No entanto, a ineficiência da propulsão causada pela inadequada configuração da CRM, assim como dores e lesões nos membros superiores (MMSS), pode resultar na diminuição da mobilidade do usuário. Objetivo Por meio da metodologia da revisão integrativa, buscou-se identificar e avaliar fatores relacionados à eficiência da propulsão em CRM de usuários com paraplegia devido à LM. Método Foram selecionados estudos indexados na PubMed, LILACS e SciELO sobre a biomecânica da propulsão de usuários de CRM com paraplegia devido à LM, entre os anos de 2008 e 2018. Resultados Dentre os 10 estudos incluídos na revisão, dois foram classificados como nível III-2 e oito como nível IV de evidência. Foram identificados como fatores relacionados à eficiência da propulsão: os momentos não propulsivos; a velocidade dos MMSS na fase de recuperação; a posição da mão no período de liberação; o tamanho do encosto; a manutenção do peso corporal; o nível de atividade diária e a força de adutores de ombro; a intensidade da propulsão; a orientação dos MMSS; e o tempo de LM. Conclusão As evidências sobre ciclo e padrões de propulsão, configurações de CRM, características do usuário e dores e lesões nos MMSS demonstraram ser fatores relacionados à eficiência da propulsão em CRM de usuários com paraplegia devido à LM