Orientador: Valéria Helena Alves Cagnon Quitete / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T04:47:08Z (GMT). No. of bitstreams: 1 Kido_LarissaAkemi_M.pdf: 14026607 bytes, checksum: 4b5dcdcd04b3cf312f7b62cb4cf2ac2b (MD5) Previous issue date: 2013 / Resumo: A senescência está associada a mudanças significativas no ambiente hormonal, sendo fator causador de alterações morfofuncionais na próstata. Os diferentes processos biológicos que ocorrem na próstata são regulados por polipeptídeos, dentre esses os fatores de crescimento do endotélio vascular (VEGF) e Endostatina, relacionados à angiogênese. Além disso, inibidores da enzima 5_ redutase-II, como a finasterida, tem papel importante no combate às doenças prostáticas. Assim, os principais objetivos desse estudo foram avaliar os efeitos estruturais e moleculares das terapias antiangiogênicas e da finasterida sobre a próstata ventral de camundongos durante a senescência. Noventa camundongos machos FVB de 18 e 52 semanas de idade foram divididos nos seguintes grupos: Jovem (JV) e Senil (SEN), os quais receberam injeções de Solução Fisiológica 0,9% (5 mL/Kg/dia s.c.); Finasterida (FIN): injeções de Finasterida (20 mg/Kg, s.c.); SU5416 (SU): SU5416 (6 mg/Kg, i.p.); TNP-470 (TNP): injeções de TNP-470 (15 mg/Kg, s.c.), e SU5416 + TNP-470 (SU+TNP): os mesmos tratamentos dos grupos SU e TNP. Após 21 dias de tratamento, amostras do lobo ventral da próstata foram coletadas e submetidas às análises morfológicas, imunohistoquímicas e Western Blotting. Os resultados demonstraram alterações moleculares e estruturais no microambiente prostático durante a senescência, como atrofia presença de células inflamatórias, e lesões proliferativas, as quais foram interrompidas e ou bloqueadas através dos tratamentos com as drogas antiangiogênicas e pela finasterida. Os resultados moleculares revelaram no grupo senil a diminuição das reatividades para AR e Endostatina, e aumento para ER-_, ER-_ e VEGF, quando comparados aos camundongos jovens. Os camundongos dos grupos tratados com finasterida, SU5416 e SU5416+TNP-470, quando comparados aos do grupo senil, demonstraram de forma geral diminuição das reatividades de VEGF e ER-_ e aumento de ER-_. Já o tratamento com TNP-470 foi marcado principalmente pela redução da reatividade e dos níveis protéicos de AR e ER-_, quando comparado aos grupos jovem e senil. Desta maneira, conclui-se que a senescência favoreceu a ocorrência de alterações estruturais e/ ou funcionais que sugerem o aparecimento de lesões malignas, em virtude do desequilíbrio na sinalização entre epitélio e estroma. O tratamento com finasterida, SU5416 e SU5416+TNP- 470 mostraram-se mais ativos na regulação dos processos proliferativos através da via estrogênica / Abstract: Senescence is associated with significant changes in the hormonal environment and is a cause of morphological and functional changes in the prostate. The different biological processes that occur in the prostate are influenced by different factors such as vascular endothelial growth factor (VEGF) and Endostatin, related to angiogenesis. Also, 5_-reductase inhibitors, such as finasteride, play an important role in treatment of prostatic diseases. Thus, the aims of this study were to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of mice during senescence. Ninety 52 and 18 week old male FVB mice, were divided into groups: Young (YNG) and Senile (SEN) groups, which received 0.9% saline (5 mL/kg/day sc) injections; Finasteride (FIN) group: Finasteride (20 mg/kg, sc); SU5416 (SU) group: SU5416 (6 mg/kg, ip) injections; TNP-470 (TNP) group: TNP-470 (15 mg/kg, sc) injections and SU5416+TNP-470 (SU+TNP470) group: The same treatment as the SU and TNP-470 groups. After 21 days of treatment, samples of the ventral lobe of the prostate were collected and analyzed for morphological, immunohistochemical and Western Blotting analyses. The results demonstrated structural and molecular changes in the prostatic microenvironment during senescence, such as atrophy, inflammatory cells, and proliferative lesions, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. The molecular results revealed decreased reactivity for AR and Endostatin, and an increase for ER-_, ER-_ and VEGF in the senile group, when compared to young mice. The mice in the groups treated with finasteride, SU5416 and SU5416 + TNP-470, when compared to the senile group, showed in general decreased VEGF and ER-_ reactivities and increased ER-_ reactivity. The treatment with TNP-470 however, was marked mainly by reduced AR and ER-_ reactivity and protein levels, when compared to young and senile groups. Thus, it can be concluded that senescence contributed to the occurrence of structural and/or molecular alterations that suggest the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. Treatments with finasteride, SU5416 and SU5416+TNP-470, were active in the regulation of proliferative processes by means of the estrogen pathways / Mestrado / Anatomia / Mestra em Biologia Celular e Estrutural

No / Red deer stags produce an androgen-dependent mane of long hairs only in the breeding season; in the non-breeding season, when circulating androgen levels are low, the neck hair resembles the rest of the coat. This study was designed to determine whether androgen receptors are present in deer follicles throughout the year or only in the mane (neck) follicles when circulating testosterone levels are high in the breeding season. Although androgens regulate much human hair growth the mechanisms are not well understood; they are believed to act on the hair follicle epithelium via the mesenchyme-derived dermal papilla. The location of androgen receptors in the follicle was investigated by immunohistochemistry and androgen binding was measured biochemically in cultured dermal papilla cells derived from mane and flank follicles during the breeding season and from neck follicles during the non-breeding season. Immunohistochemistry of frozen skin sections using a polyclonal antibody to the androgen receptor localised nuclear staining only in the dermal papilla cells of mane follicles. Saturation analysis assays of 14 primary dermal papilla cell lines using [(3)H]-mibolerone demonstrated high-affinity, low-capacity androgen receptors were present only in mane (breeding season neck) cells; competition studies with other steroids confirmed the specificity of the receptors. Androgen receptors were not detectable in cells from either the breeding season flank nor the non-breeding season neck follicles. The unusual biological model offered by red deer of androgen-dependent hair being produced on the neck in the breeding, but not the non-breeding season, has allowed confirmation that androgen receptors are required in follicle dermal papilla cells for an androgen response; this concurs with previous human studies. In addition, the absence of receptors in the non-breeding season follicles demonstrates that receptors are not expressed unless the follicle is responding to androgens. Androgen receptors may be induced in mane follicles by seasonal changes in circulating hormone(s).