Percorrer por autor "Oliveira, P. A."
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- Age influence in BBN induced urothelial lesions in ICR male micePublication . Vasconcelos-Nóbrega, C.; Mega, C.; Arantes, R.; Talhada, D.; Teixeira-Guedes, C.; Faustino-Rocha, A.; Vala, Helena; Oliveira, P. A.
- Bioética e experimentação animalPublication . Nóbrega, Carmen; Oliveira, P. A.; Mesquita, João; Santos, C.; Arantes, R.; Themudo, D.; Esteves, Fernando; Cruz, Rita; Mega, Cristina; Vala, Helena- Introdução: O contributo da experimentação animal para a ciência é inegável. Dificilmente os meios médicos e profiláticos teriam atingido o presente estado de evolução sem a sua contribuição. O objectivo deste trabalho é a apresentação do conceito de experimentação animal, como uma prática válida e eticamente correta, desde que devidamente planeada e executada. - Estado da Arte: O recurso a animais vivos em investigação, tem desempenhado um papel importante no avanço científico, particularmente na área da saúde. Este facto dá origem a um dilema ético: se por um lado a maior parte dos animais utilizados são seres sencientes, por outro lado, a investigação pode ser de vital importância para a prevenção, cura ou melhoria significativa de doenças em humanos. Não sendo um tema consensual, é geralmente alvo de intenso debate. Opositores a qualquer tipo de investigação com recurso a animais, afirmam que a experimentação animal é cruel e desnecessária porque os animais não existem para serem usados segundo o nosso critério. No entanto, a generalidade da sociedade aceita que os animais possam ser utilizados em experimentação mas não a qualquer preço. Nos últimos anos, têm ocorrido progressos na criação de alternativas à experimentação animal, nomeadamente as culturas celulares, de tecidos e órgãos, fazendo com que, em certas situações, os animais possam já ser substituídos por alternativas eticamente mais aceitáveis, não podem, contudo, ser inteiramente eliminados da investigação. - Novas perspetivas/diretrizes Uma investigação ética e cientificamente válida com aplicabilidade na saúde humana, exige a seleção de modelos adequados para a acção estudada e o cumprimento do princípio dos 3Rs: Replace; Reduce; Refine. A estes, deve juntar-se ainda o R da responsabilidade, que deve prevalecer desde o delineamento da experimentação e acompanhar o decurso dos trabalhos experimentais. - Implicações teóricas e práticas Pesando os prós e contras, os benefícios da experimentação animal pesam mais no que se refere ao impacto na melhoria da saúde humana. Se esta prática fosse abandonada, certamente existiriam severas consequências a nível da investigação e da saúde pública.
- Carcinogénese Experimental da Bexiga em MurganhosPublication . Nóbrega, Carmen; Vala, Helena; Mesquita, João; Santos, C.; Themudo, D.; Oliveira, P. A.; Esteves, Fernando; Cruz, Rita; Mega, Cristina; Arantes, R.; PA., OliveiraIntrodução: A oncologia experimental é uma ciência em crescente evolução, que tem permitido estudar os mecanismos biopatológicos associados ao crescimento, invasão e metastização dos tumores, bem como a investigação de novas moléculas, eventuais novos agentes profilácticos, terapêuticos ou paliativos. O objetivo deste trabalho consiste na apresentação de um projeto de investigação em que se promoveu a carcinogénese experimental da bexiga em murganhos, para a posterior realização testes farmacológicos. Estado da Arte: O cancro da bexiga é o 7º tumor mais comum no homem e o 2º do trato urogenital, encontrando-se descrita predisposição sexual para o sexo masculino (4:1). Histologicamente, a maioria dos tumores de bexiga são superficiais, sendo o carcinoma invasivo menos frequente. No entanto, este último assume grande importância clínica, dado o difícil tratamento, a elevada possibilidade de metastização e o prognóstico reservado. São vários os modelos animais que podem ser utilizados no estudo dos tumores bexiga. O modelo animal para o carcinoma invasivo da bexiga consiste na indução pela administração na água de bebida da N-butil-N-(4-hidroxibutil)nitrosamina (BBN) a murganhos. Métodos: Foram utilizados murganhos macho da estirpe ICR, divididos em dois grupos: grupo controlo e experimental, que foi submetido à acção da BBN (0,05%), durante 12 semanas. Os animais foram distribuídos por gaiolas adequadas em tamanho, com água à disposição, alimentação ad libitum e enriquecimento ambiental. Todos os animais foram sacrificados no final do trabalho experimental e submetidos a necrópsia. Resultados: A incidência de tumores induzidos pela BBN, em roedores, atingiu os 100%. Foram também observadas outras lesões, nomeadamente metaplasia epidermoide, hiperplasia simples, hiperplasia nodular, displasia e hiperplasia papilar. Conclusões: As lesões quimicamente induzidas em roedores pela BBN assemelharam-se grandemente às observadas em humanos, facto que permitiu caraterizar este como um bom modelo para o estudo das neoplasias da bexiga.
- Effect of chronic therapy with chaethomellic acid A on renal fibrosis in 5/6 nephrectomized rats: A preliminary studyPublication . Nogueira, A.; Vala, Helena; Nóbrega, C.; Pires, C. A.; Colaço, B.; Oliveira, P. A.; Pires, M. J.Objective: The high prevalence of chronic kidney disease underscores the failure to provide therapies to effectively halt, prevent, and/or reverse renal fibrosis. Thus, the aim of this study was to evaluate the effect of chronic treatment with chaethomellic acid A (CA) on renal fibrosis associated to 5/6 nephrectomy. Methods: Male Wistar rats were subjected to 5/6 nephrectomy (RMR) or sham-operated (SO). One week after surgery, rats were placed in four experimental groups: RMR: rats without treatment (n=13); RMR+CA: rats treated with CA (n=13); SO: rats without treatment (n=13); SO+CA: rats treated with CA (n=13). CA was intraperitoneally administered in a dose of 0.23 µg/Kg three times a week for six months. Renal samples were scored for the following lesions: glomerulosclerosis, interstitial fibrosis, arteriolosclerosis and interstitial inflammation. Results: Animals from the SO and SO+CA groups presented no kidney histological changes. Glomerulosclerosis, interstitial fibrosis and arteriolosclerosis scores were significantly lower (p< 0.001) in RMR+CA group when compared with RMR group. There were no significantly differences in interstitial inflammation score between RMR+CA and RMR groups. Conclusions: This preliminary data suggests that pharmacological inhibition of Ras (small GTPase proteins) activation may be a future strategy in the prevention of renal fibrosis.
- Effects of histamine on the development of MNU-induced mammary tumoursPublication . Faustino-Rocha AI, A. I.; Gama, A.; Oliveira, P. A.; Vala, Helena; Ferreira, R.; Ginja, M.Objective: Breast cancer is frequently diagnosed worldwide. Histamine acts as mediator in several cancers. Ketotifen is a mast cells stabilizer drug that inhibits their degranulation. This work aimed to evaluate the effects of histamine on the development of MNU-induced mammary tumors. Methods: Procedures followed the European Directive 2010/63/EU. Twenty animals were equally divided into two experimental groups: ketotifen and control. At seven weeks of age, all animals received an intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Animals from ketotifen group received ketotifen in drinking water (1mg/Kg; 7days/week; for 18 weeks). At the sacrifice, mammary tumors were fixed and histologically evaluated. Results: During the protocol one ketotifen-treated animal died. At the end, eight animals from ketotifen group developed 19 mammary tumors (2.4 tumors per animal), while six animals from control group developed 21 mammary tumors (3.5 tumors per animal). Animals from control group developed one benign lesion and 20 non-invasive carcinoma; all lesions from ketotifen-treated animals were malignant, however they did not develop any comedo carcinoma that was the lesion of the highest grade of malignancy found in this work. Conclusion: Inhibition of histamine release by ketotifen seems to reduce the number and malignancy of MNU-induced mammary tumors.
- Expression of estrogen receptors-α and β in chemically-induced mammary tumoursPublication . Faustino-Rocha, A. I.; Gama, A.; Oliveira, P. A.; Alvarado, A.; Vala, Helena; Ferreira, R.; Ginja, M.Objective: Estrogen receptors (ERs)-α and β are important for stimulating the growth and differentiation of human mammary tumours, respectively. This work aimed to evaluate the expression of ERs-α and β in rat chemically-induced mammary tumours. Methods: Procedures followed the European legislation (2010/63/EU). Fifteen seven-week-old female Sprague-Dawley rats received an intraperitoneal injection of N-methyl-N-nitrosourea (MNU) (50mg/Kg). At sacrifice, mammary tumours were fixed and histologically evaluated. Sections were incubated with ER-α and β primary antibodies and the percentage of immunopositive cells was determined. Results: During the experimental protocol four animals died, all survived animals developed mammary tumours: 30 benign, 2 preneoplastic and 39 malignant lesions. All histological patterns expressed ERs-α and β. The mean expression of ER-α (55.14% ± 13.26) was lower than the expression of ER-β (70.06% ± 18.51) (p<0.05). The expression of both receptors was not statistically different among lesions, however it was higher in preneoplastic lesions, followed by malignant and benign ones (p>0.05). Conclusion: All MNU-induced mammary tumours in rats expressed ERs-α and β, being a good model of ER-positive human mammary tumours. Once the expression of ER-β was higher, tumours’ differentiation was stimulated and its proliferation was inhibited.
- Meloxicam inhibits the progression of mice urothelial lesions chemically inducedPublication . R Arantes-Rodrigues, A Colaço, PA Oliveira; Videira-Henriques, A.; Ribeiro, C.; Vasconcelos-Nóbrega, C.; Pinto-Leite, R.; Vala, Helena; Lopes, C.; Colaço, A.; Oliveira, P. A.Meloxicam, an anti-inflammatory drug, is a cyclooxygenase-2 inhibitor that has been used in cancer research. The goal of this work was to evaluate the effects of meloxicam on mouse urothelial lesions chemically induced. During 12 weeks, ICR male mice received N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in drinking water, after meloxicam was administered by intraperitoneal route (20 mg/kg), 5 days a week, during 6 consecutively weeks. At the end of treatment, mice only exposed to BBN and mice exposed to BBN and treated with meloxicam, were sacrificed and their urinary bladders were collected. Urinary bladders from control groups revealed no changes. The incidence of urothelial lesions on mice exposed to BBN and not treated was: simple hyperplasia 80%, nodular hyperplasia 40%, dysplasia 90%, carcinoma in situ 10%, papillary neoplasms of low malignant potential 10%, low-grade papillary tumour 20%, high-grade papillary tumour 30% and invasive carcinoma 20%. On the other hand mice treated with meloxicam showed: simple hyperplasia 77.8%, nodular hyperplasia 44.4% and dysplasia100%. According to our results in mice treated with meloxicam we just observed preneoplastic lesions, in mice not treated with meloxicam we identified all the spectrum of urothelial neoplastic lesions. It appears that meloxicam prevented the progression of urothelial lesions.
- Mice: An Animal Model for Bladder CancerPublication . Vasconcelos-Nóbrega, C.; Arantes-Rodrigues, R.; Colaço, A.; Santos, L.; Vala, Helena; Palomino, L. F.; Lopes, C.; Oliveira, P. A.Background: Bladder cancer is a common malignancy and an important cause of morbidity and mortality in western world. Animal models are the centre of experimental researches aiming to elucidate our knowledge about carcinogenesis, its treatment and prevention. Mice have a lower urinary tract comparable to humans. Methods: 22 ICR male mice were randomized into two groups (I and II). Group I was the negative control drinking tap water, and group II received N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water during twelve weeks. Euthanasia was executed one week after BBN exposition. Results: All animals from Group I exhibited normal urothelium. In Group II, 100% of animals exhibited histological changes. 62.79% were preneoplastic lesions (simple hyperplasia, nodular hyperplasia, dysplasia) and 37.21% were neoplastic lesions (carcinoma in situ, invasive carcinoma, epidermoid metaplasia). Conclusions: Experimental urinary bladder tumours are useful models for the study of urinary bladder carcinogenesis and for the evaluation of new therapeutic strategies. In mice, chemically induced bladder cancer is nearly always of the invasive type and the incidence of spontaneous tumours is very rare. The similarity between human’s and mice’s bladder cancer allows the investigation of several aspects that can’t be studied under clinical conditions, such as pharmacokinetics and toxicity.
- A N-Butil-N-(4-Hidroxibutil)Nitrosamina como Agente Carcinogénico da Bexiga.Publication . Vasconcelos-Nóbrega, C.; Vala, Helena; Colaço, A.; Oliveira, P. A.A N-butil-N-(4-hidroxibutil)nitrosamina, também conhecida como BBN, é um agente carcinogénico muito utilizado em investigação oncológica para promover o desenvolvimento de neoplasias de bexiga em animais de laboratório. A BBN é metabolicamente activada em N-butil-N-(3-carboxipropil)nitrosamina BCPN), metabolito que é conduzido até à bexiga através da urina. Quando atinge o órgão alvo, liga-se ao DNA urotelial, promovendo a carcinogénese. A forma mais comum de administrar a BBN é através da água de bebida, em concentrações que variam entre 0,01-0,05%. A incidência de tumores induzidos pela BBN, em roedores, é de cerca de 100%, com um tempo de desenvolvimento consistente e previsível, exibindo características morfológicas homogéneas. Os tumores quimicamente induzidos em roedores pela BBN assemelham-se grandemente aos tumores vesicais observados em humanos, fazendo com que sejam considerados bons modelos para o estudo das neoplasias da bexiga, bem como para a descoberta e desenvolvimento de novos fármacos terapêuticos e preventivos.
- New therapeutic approaches on chronic kidney diseasePublication . Nogueira, A.; Vala, Helena; Nóbrega, Carmen; Pires, C. A.; Colaço, B.; Oliveira, P. A.; Pires, M. J.Introduction: chronic kidney disease is a serious public health problem that affects millions of patients worldwide. So, the main research goals in the CKD patients are the research of new therapeutic approaches capable of slowing down the progression to end-stage renal disease. Objective: the aim of this work, was to evaluate the effects of chronic administration of chaetomellic acid A (CAA), which selectively blocks H-Ras farnesylation, on kidney chronic lesions in 5/6 nephrectomized Wistar rats, an animal model of chronic renal disease. Material and methods: sixty male Wistar rats (Rattus norvergicus) were housed under controlled conditions. After seven weeks of acclimatization, rats (weighing 359 to 402 g) were sham-operated (SO) or submitted to 5/6 nephrectomy (RMR). One week after surgery surviving animals (n=53) were distributed into four groups: SO: SO rats receiving no treatment (n=13); SO+CAA: SO rats receiving CAA treatment (n=13); RMR: RMR rats receiving no treatment (n=14); RMR+CAA: RMR rats receiving CAA treatment (n=13). CAA was intraperitoneally administered (0.23 µg/Kg) three times a week for six months. Six months after the surgical procedure, in the left kidney of each animal was evaluated the mean cortical and medullary echogenicity by two-dimensional ultrasonography. Then, the kidneys were removed, fixed in 10% neutral-buffered formalin and processed for routine histopathological diagnosis and chronic lesions were evaluated, by Hematoxylin-Eosin, reticulin and Masson trichrome methods, for severity. All experimental procedures followed the European (European Directive 2010/63/EU) and National (Decree-Law 113/2013) legislation on the protection of the animals used for scientific purposes. Results: the kidneys of the RMR animals treated with CAA showed a significantly decrease in the medullary echogenicity (p<0.05) compared with the RMR rats that received no treatment. Glomerulosclerosis and arteriolosclerosis scores were significantly lower (p<0.001) in the RMR+CAA group when compared with the RMR group. There were no significant differences in interstitial fibrosis, interstitial inflammation and tubular dilatation scores between the RMR+CAA and RMR groups.Conclusion: this data suggests that pharmacological inhibition of H-Ras proteins activation may be a future strategy in the prevention of end-stage renal disease.