Browsing by Author "Parada, B."
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- Pancreatic lesions and metabolic aggravation are prevented by low doses of sitagliptin in a rat model of type 2 diabetesPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Teixeira de Lemos, E.; Reis, F.Introduction: The management of type 2 diabetes is designed to reduce disease-related complications and improve long-term outcomes. Inhibition of dipeptidyl peptidase-4 (DPP-4) activity by sitagliptin has been shown to improve glycaemic control in patients with type 2 diabetes Mellitus (T2DM) by prolonging the actions of incretin hormones, but the real impact of low-dose sitagliptin treatment on cardiometabolic risk factors and pancreatic lesions is almost unknown. This study aimed to evaluate the effects of low doses of sitagliptin on cardiovascular risk factors and histological pancreas parameters in Zucker Diabetic Fatty rats (ZDF (fa/fa)) an animal model of T2DM. Materials and Methods: Twenty weeks old diabetic obese (fa/fa) ZDF male rats were treated with vehicle or sitagliptin (10 mg/kg BW/day) during 6 weeks (n=8 each). The following parameters were assessed: glycaemia, HbA1c, insulin, lipidic profile; blood pressure. Specimens for pancreatic histopathology were stained with haematoxylin-eosin and periodic-acid-Shiff, examined by light microscopy. Endocrine and exocrine pancreas was evaluated semiquantitatively concerning inflammatory infiltrate, fibrosis, vacuolization and congestion, and scored from 0 (absent) to 3 (severe and extensive damage). Results: Sitagliptin in diabetic obese ZDF rats promoted a positive effect on dysglycaemia, dyslipidaemia and prevented the increase of blood pressure. Endocrine and exocrine pancreas presented a reduction/amelioration of fibrosis severity, inflammatory infiltrate, intra-islet vacuolation, and congestion vs the vehicle-treated diabetic rats. Conclusion: Simultaneous improvement of a sustainable glycaemic profile and of pancreatic histopathological lesions supports the favorable cardiovascular risk profile and may prove beneficial in decreasing long-term complications of T2DM.
- Progression of renal disease in the Zucker Diabetic Fatty rat, an experimental model of Type2 DiabetesPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Teixeira de Lemos, E.
- Renal structure modification in an animal model of type 2 diabetes with aging: focus on hydronephrosisPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Teixeira de Lemos, E.; Reis, F.Background and aims: The Zucker Diabetic Fatty (ZDF-fa/fa) rat is one of the most used models for the study of type 2 diabetes (T2DM). Characterization of renal morphology in this model may provide useful insights into the mechanism of diabetic nephropathy progression. The purpose of the present study was to determine renal morphology, identify and characterize renal dysfunction complications such as hydronephrosis, in Zucker Diabetic fatty (ZDF) rat through T2DM evolution. Material and Methods: Male diabetic obese ZDF (fa/fa) rats were sacrificed at 8, 20 and 26 weeks of age and compared with their lean counterparts ZDF (+/+) with de same age. Biochemistry in serum for metabolic assessment was also performed. Kidney slices stained with hematoxylin-eosin and periodic acid-Schiff were evaluated. A semiquantitative rating was assigned for hydronephrosis and scored from 0 (normal) to 3 (severe), based on conformational aspects of the papilla and calyx and cortex compression. Results: A striking progression in the severity of hydronephrosis was observed. All end-disease state rats, 26 weeks of age, showed hydronephrosis, which was more severe in the diabetic rats (scoring: 2, 3) when compared to lean controls (scoring 1). No significant cortical atrophy was found. These abnormalities accompanied aggravation in diabetic desmetabolism. Conclusions: The present study indicates that ZDF rats present nephropathy with hydronephrosis. Lesions are age-related and aggravated by diabetic desmetabolism but don’t hinder morphological evaluation. Therefore the ZDF rat might represent a useful model for the preclinical study of therapeutic interventions in diabetic nephropathy.
- Serum and renal tissue markers of nephropathy in rats under immunosuppressive therapy: cyclosporine vs sirolimusPublication . Sereno, J.; Parada, B.; Rodrigues-Santos, P.; Lopes, P.; Carvalho, E.; Vala, Helena; Teixeira-Lemos, E.; Alves, R.; Figueiredo, A.; Mota, A.; Teixeira, F.; Reis, F.Cyclosporin (CsA) has been progressively replaced by other drugs with putatively fever side effects, including nephrotoxicity and hypertension. Sirolimus (SRL) is one of the main options for management of kidney transplant patients in the post-CsA era. It shows identical efficacy with apparently less cardiorenal side effects than CsA. However, doubts remain concerning the mechanisms of putative renoprotection by SRL as well as the best serum and/or tissue markers for nephropathy, as assessed in this study employing CsA- and SRL-treated rats. Three groups (n = 6) were treated orally during a 6-week protocol: control (vehicle); CsA (5 mg/kg body weight per day Sandimmun Neoral); SRL (1 mg/kg body weight per day Rapamune). Blood pressure and heart rate were assessed with a "tail cuff". Renal dysfunction and morphology were characterized using serum creatinine and blood urea nitrogen (BUN) levels as well as hematoxylin and eosin and periodic acid Schiff staining, respectively. We examined serum concentrations of interleukin (IL)-2, IL-1β, high-sensitivity C-reactive protein, tumor necrosis factor TNF-α, and vascular endothelial growth factor and kidney mRNA expression of interleukin-1β (IL-1β), tumor protein 53 (TP53), mammalian target of rapamycin (mTOR) and proliferating cell nuclear antigen (PCNA), as well as markers of lipid peroxidation in the kidney and serum. Both CsA and SRL induced significant increases in systolic and diastolic blood pressure, but only CsA caused tachycardia. CsA-treated rats also displayed increased serum creatinine and BUN levels, accompanied by mild renal lesions, which were almost absent among SRL-treated rats, which presented hyperlipidemic and hyperglycemic profiles. CsA-induced nephrotoxicity was accompanied by kidney overexpression of inflammatory and proliferative mRNA markers (IL-1β, mTOR and PCNA), which were absent among SRL group. In conclusion, the antiproliferative and antifibrotic character of SRL may explain its less nephrotoxic profile. Renal over expression of mTOR in the CsA-treated group, associated with renal dysfunction and structural damage, reinforces the potential beneft of SRL as a strategy to reduce CsA-evoked nephrotoxicity.
- Sirolimus ameliorates cyclosporin-induced nephrotoxicity in a rat model – focus on renal lesions, oxidative stress, inflammation, proliferation and angiogenesisPublication . Sereno, José; Romão, A. M.; Teixeira, M.; Parada, B.; Mega, C.; Vala, Helena; Lemos, E. T.; Teixeira, F.; Reis, F.
- Sitagliptin delays progression of renal lesions in a rodent model of type 2 diabetesPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Lemos, E. T.
- Sitagliptin delays progression of renal lesions in a rodent model of type 2 diabetesPublication . Cristina, M.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Teixeira de Lemos, E.
- Sitagliptin treatment delays the progression of pancreatic and renal lesions and reduces tissular oxidative stress in a type 2 diabetes animal modelPublication . Mega, C.; Vala, Helena; Oliveira, J.; Fernandes, R.; Mascarenhas-Melo, F.; Parada, B.; Pinto, R.; Teixeira, F.; Reis, F.; Lemos, E. T.
- Utilização de parâmetros quantitativos e semi-quantitativos para avaliação dos Ilhéus de Langerhans num modelo animal de Diabetes Mellitus tipo 2.Publication . Mega, C.; Vala, Helena; Teixeira de Lemos, E.; Fernandes, R.; Garrido, P.; Sereno, J.; Parada, B.; Melo, F.; Teixeira, F.; Reis, F.Introduction: Type 2 diabetes mellitus 2 (T2DM) results, amongst others, from insulin resistance and reduction of ß-cell secretion, produced by functional changes and cellular mass reduction. Aim: Chronological morphologic characterization of the endocrine pancreas in an animal model of T2DM, the Zucker Diabetic Fatty (ZDF) rats to elucidate the underlying mechanisms of disease evolution. Material and methods: The pancreas of diabetic, obese rats (ZDF Gmi fa/fa) and their littermates (ZDF Gmi +/+) were compared at 8, 20, 26 weeks of age. After routine stain haematoxylin-eosin. Quantitative and semi-quantitative parameters were applied for evaluation of morphological changes in the islets of Langerhans. Quantitative parameters included counting islet numbers and islet size measurement. Semi-quantitive parameters consisted in the evaluation of islet conformation and perimeter regularity. The inflammatory lesions, vascular congestion and β-cell vacuolization were also classified in a scale from 0 to III. Results: Obese, diabetic ZDF (fa/fa) rats presented, with increasing age, a reduction in islet numbers, progressive deformation of insular architecture, fibrosis and vascular congestion, connected with inflammatory changes and joined by a decrease in insular cellular mass. Conclusion: The coincidence of the progressive histopathologic changes with the metabolic profile obtained in our previous studies shows a decrease in the capacity of the endocrine pancreas to compensate insulin resistance and ß-cell dysfunction. These two conjunct facts make the ZDF fa/fa, rat an appropriate model for a variety of T2DM studies.