RESUMO
PURPOSE: No optimal, well designed and reproducible animal model for upper urothelial carcinogenesis exists. This study characterized the histopathological features on top of immunolocalization of alpha-dystroglycans (alpha-DG) and matrix metalloproteinase (MMP-9) and cell turn-over in the upper urinary tract using a novel experimental model. METHODS: Seventy-five female Fischer 344 rats were divided into three groups: the control group received a 0.30-ml dose of 0.9% physiological saline; the MNU group (chemical carcinogen N-methyl-N-nitrosourea) received 0.30 ml of MNU; and the MNU-citrate group received 0.30 ml of MNU plus sodium citrate, every one intravesically every other week for a total of 4 doses. After 15 weeks, bladder, ureters and renal pelvis were collected for morphological and molecular analysis. RESULTS: Associated management with MNU and sodium citrate was able to lead to 100% of both urinary bladder and upper urinary tract tumors, being the high-grade noninvasive papillary urothelial carcinoma the most frequent lesion. The upper urothelium showed reduced alpha-DG and increased MMP-9 and Ki-67 immunoreactivities in the MNU-citrate group in relation to the other groups. MNU group presented no upper urothelium tumor and 100% bladder tumor. CONCLUSIONS: This is a relevant evolution on experimental animal model for upper urinary tract carcinogenesis field. MMP-dependent disruption of the DG complex plays an important role in urothelial tumor carcinogenesis and showed the model applicability and significance. MNU-citrate model could contribute to a better understanding of human upper urothelial cancer development as well as to its local treatment strategies in a near future.
Assuntos
Modelos Animais de Doenças , Ratos Endogâmicos F344 , Neoplasias Urológicas/patologia , Urotélio/patologia , Alquilantes/toxicidade , Animais , Biópsia , Citratos/toxicidade , Feminino , Medula Renal/diagnóstico por imagem , Medula Renal/patologia , Metilnitrosoureia/toxicidade , Ratos , Citrato de Sódio , Ureter/diagnóstico por imagem , Ureter/patologia , Bexiga Urinária/diagnóstico por imagem , Bexiga Urinária/patologia , Urografia , Neoplasias Urológicas/induzido quimicamente , Neoplasias Urológicas/diagnóstico por imagem , Urotélio/diagnóstico por imagemRESUMO
While traces of manganese (Mn) take part in important and essential functions in biology, elevated exposures have been shown to cause significant toxicity. Chronic exposure to the metal leads to manganese neurotoxicity (or manganism), a brain disorder that resembles Parkinsonism. Toxic effect mechanisms of Mn is not understood, toxic concentrations of manganese are not well defined and blood manganese concentration at which neurotoxicity occurs has not been identified. There are reports indicating that the most abundant Mn-species in Mn carriers within blood is the Mn-citrate complex. Despite the well-documented information about the toxic effects of Mn, there are scarce reports concerning the effects of manganese compounds on both structure and functions of cell membranes, particularly those of human erythrocytes. With the aim to better understand the molecular mechanisms of the interaction of Mn with cell membranes, MnCl(2), and the Mn-citrate complex were incubated with intact erythrocytes, isolated unsealead human erythrocyte membranes (IUM), and molecular models of the erythrocyte membrane. These consisted in bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), phospholipid classes present in the outer and inner monolayers of the erythrocyte membrane, respectively. The capacity of the Mn compounds to perturb the bilayer structures of DMPC and DMPE was evaluated by X-ray diffraction, IUM were studied by fluorescence spectroscopy, and intact human erythrocytes were observed by scanning electron microscopy (SEM). In all these systems it was found that Mn(2+) exerted considerable higher structural perturbations than the Mn-citrate complex.
Assuntos
Citratos/toxicidade , Membrana Eritrocítica/química , Membrana Eritrocítica/efeitos dos fármacos , Manganês/toxicidade , Modelos Moleculares , Citratos/química , Dimiristoilfosfatidilcolina/química , Membrana Eritrocítica/ultraestrutura , Humanos , Manganês/química , Microscopia Eletrônica de Varredura , Fosfatidiletanolaminas/química , Difração de Raios XRESUMO
The effect of policosanol on circulating endothelial cells has been studied in different experimental models with endothelium damage. Oral administration of 25 mg kg-1 policosanol to Sprague-Dawley rats resulted in significant protection of the endothelial lining against the desquamating effect of citrate. Oral administration of 5 mg kg-1 policosanol to spontaneously hypertensive rats (SHR) resulted in a significant reduction of circulating endothelial cells compared with controls. Moreover, comparison between groups revealed a lower frequency of aortic lesions in policosanol-treated animals than in controls. On the other hand, administration of 5 mg kg-1 policosanol to rabbits with intimal hyperplasia induced by cuff placement in the carotid artery resulted in levels of circulating endothelial cells significantly lower than in controls. These results demonstrate the protective effect of policosanol in different experimental models and suggest its potential for endothelial protection.
Assuntos
Anticolesterolemiantes/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Álcoois Graxos/farmacologia , Animais , Aorta Torácica/patologia , Contagem de Células , Citratos/toxicidade , Hiperplasia/patologia , Masculino , Coelhos , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Citrato de SódioRESUMO
Rhodium II citrate was tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and inhibition of DNA synthesis by Ehrlich tumor, malignant adrenocortical cells (Y-1) and normal adrenocortical cells (AR-1). At ip doses up to 260 mg/kg, the compound had no toxic effects for up to 14 days. The same total dose given over 4 days significantly increased the survival rate of mice bearing Ehrlich ascites cells. Thymidine incorporation by Ehrlich tumor, Y-1 and AR-1 cells in vitro was inhibited 50% by 0.1 to 0.2 mM concentrations of the compound. We conclude that the increased survival of the tumor-bearing mice was due at least in part to the inhibition of DNA synthesis with a consequent reduction of cell division and tumor growth.
Assuntos
Carcinoma de Ehrlich/patologia , Citratos/farmacologia , DNA/biossíntese , Ródio/farmacologia , Animais , Carcinoma de Ehrlich/mortalidade , Citratos/toxicidade , Camundongos , Ródio/toxicidade , Timidina/metabolismoRESUMO
Rhodium II citrate was tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and inhibition of DNA synthesis by Ehrlich tumor, malignant adrenocortical cells (Y-1) and normal adrenocortical cells (AR-1)_. At ip doses up to 260 mg/Kg, the compound had no toxic effects for up to 14 days. The same total dose given over 4 days significantly increased the survial rat of mice bearing Ehrlich ascites cells. Thymidine incorporation by Ehrlkich tumor, Y-1 cells in vitro was inhibited 50% by a.1 to 0.2 mM concentrations of the compound. We conclude that the increase survival of the tumor-bearing mice was due at least in part to the inhibition of DNA synthesis with a consequet reduction of cell division and tumor growth