Thesis (M.S.)--University of Michigan, 1975.

Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 68-94).

Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisor: Daniel D. Carson, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (Ph.D.)--McMaster University, 2005. / Advisor: Colin A. Nurse. Includes bibliographical references (leaves 175-194). Also available online.

Thesis (Ph.D.)--University of Delaware, 2006. / Principal faculty advisor: Daniel D. Carson, Dept. of Biological Sciences. Includes bibliographical references.

Thesis (Ph. D.)--University of Idaho, 2005. / Also available online in PDF format. Abstract. "December 2005." Includes bibliographical references.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A mortalidade infantil afeta milhÃes de crianÃas em todo mundo e a desnutriÃÃo contribui com cerca de um terÃo dessa mortalidade. A vitamina A jà à utilizada no tratamento da desnutriÃÃo infantil. Contudo, poucos ou nenhum estudo fora realizado, ao nÃvel celular, para avaliar o impacto da suplementaÃÃo com a vitamina A em cÃlulas epiteliais intestinais com desnutriÃÃo proteica in vitro. Desse modo, objetivamos demonstrar os efeitos da desnutriÃÃo e do tratamento com retinoides nos processos de proliferaÃÃo, apoptose/necrose, ciclo celular e diferenciaÃÃo celular, assim como na ativaÃÃo das vias de sinalizaÃÃo em cÃlulas IEC-6 de rato com desnutriÃÃo proteica. Demonstramos que a desnutriÃÃo diminuiu a proliferaÃÃo celular nos tempos de 6, 12, 24 e 48 horas. Em adiÃÃo, nos tempos de 24 e 48 horas a suplementaÃÃo com palmitato de retinol intensificou esta reduÃÃo em comparaÃÃo ao grupo desnutrido. Contudo, a diminuiÃÃo da proliferaÃÃo nÃo estava relacionada à morte celular. Na verdade, o palmitato de retinol reduziu apoptose no tempo de 48 horas apÃs a induÃÃo de desnutriÃÃo. Adicionalmente, a desnutriÃÃo estimulou a quiescÃncia celular e a mesma foi intensificada pelo retinol identificada pelo aumento do percentual de cÃlulas na fase G0/G1 e diminuiÃÃo dos percentuais de cÃlulas nas fases S e G2/M, principalmente nos tempos entre 24 e 48 horas. Para verificar se a desnutriÃÃo, associada ou nÃo à suplementaÃÃo dos retinoides, estimulava a diferenciaÃÃo celular foi realizada a anÃlise da transcriÃÃo gÃnica dos marcadores especÃficos FABP e IAP no perÃodo de 42 horas. Os dois retinoides testados aumentaram em aproximadamente cinco vezes a expressÃo dos mRNAs de FABP e IAP. Visto que a diferenciaÃÃo fora estimulada, foram verificadas quais as vias de sinalizaÃÃo intracelular, acopladas à ativaÃÃo da proteÃna G, estavam ativadas. Os resultados deste trabalho demonstraram que a desnutriÃÃo proteica diminuiu a transcriÃÃo gÃnica de c-Jun, STAT3, MEF2C, e ATF2, mas aumentou a expressÃo dos mRNAs de GLI-3 e c-Fos em relaÃÃo ao grupo nutrido. Entretanto, os retinoides aumentaram a transcriÃÃo dos mRNAs de ELK-1, SRF, c-Jun, FOXO, STAT3, ATF2, GLI-3 e NF-κB em relaÃÃo com o grupo desnutrido. Deste modo, este trabalho mostrou que a desnutriÃÃo interferiu na proliferaÃÃo estimulando a quiescÃncia celular. PorÃm, o tratamento com os retinoides intensificou a quiescÃncia diminuindo a apoptose com estimulaÃÃo da diferenciaÃÃo celular associado com a ativaÃÃo das vias moleculares do ATF2, MAPK/ERK/JNK, IL-6, Hedgehog, PI3K/AKT e NF-κB. / Infant mortality affects millions of children around the world and malnutrition contributes about one third of this mortality. Vitamin A is already used in the treatment of childhood malnutrition. However, few or no study has been done, carried out at the cellular level, to assess the impact of vitamin A supplementation in intestinal epithelial cells under in vitro protein malnutrition. Thus, we aimed to demonstrate the effects of malnutrition and treatment with retinoids in the processes of proliferation, apoptosis/necrosis, cell cycle and cell differentiation as well as activation of signaling pathways in IEC-6 rat cells under protein malnutrition. We demonstrated that malnutrition decreased cell proliferation in periods of 6, 12, 24 and 48 hours. In addition, retinyl palmitate treatment intensified the decrease of cell proliferation when compared to the malnourished group in the periods of 24 and 48 hours after supplementation. However, the reduction in proliferation was not related to cell death. Indeed, retinyl palmitate reduced apoptosis in the period of 48 hours after induction of malnutrition. Additionally, malnutrition stimulated cell quiescence, and the same was enhanced by retinol, which was identified by the increase in the percentage of cells in G0/G1 phase and the reduction of the percentage of cells in S phase and G2/M, especially in periods of 24 and 48 hours. To check if malnutrition, with or without supplementation of retinoids, was stimulating cell differentiation, we evaluated the gene transcription of the specific markers FABP and IAP within 42 hours. Both retinoids tested increased approximately 5-fold the expression of FABP and IAP mRNAs. Knowing that differentiation had been stimulated, we decided to check which intracellular signaling pathways, coupled to the activation of G proteins, were activated. Our results demonstrated that protein malnutrition decreased gene transcription of c-Jun, STAT3, MEF2C and ATF2, but increased the expression of the GLI-3 and c-Fos mRNAs in relation to the nourish group. However, retinoids increased the transcription of ELK-1, SRF, c-Jun, FOXO, STAT3, ATF2, GLI-3, NF-kB in relation to the malnourished group. Thus, this study showed that cell malnutrition interfered with cell proliferation stimulating cell quiescence. However, retinoids treatment intensified cell quiescence, decreased IEC-6 apoptosis and stimulated cell differentiation associated with the activation of the molecular pathways of ATF2, MAPK/ERK/JNK, IL-6, Hedgehog, PI3K/AKT and NF-kB.

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published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy