Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p.44-49

Thesis (Ph. D.)--University of Texas at Austin, 1998. / Vita. Includes bibliographical references (leaves 96-105). Available also in a digital version from Dissertation Abstracts.

Thesis (M.Med.Sc.)--University of Hong Kong, 2004. / Also available in print.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliography.

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 120-130).

Orientador: José Predrazzoli Júnior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T14:31:33Z (GMT). No. of bitstreams: 1 Nakamitsu_PatriciaFernandesZanotti_M.pdf: 13932642 bytes, checksum: 5c0fce47b8f53f69fc7e1bb4ae8609e6 (MD5) Previous issue date: 2014 / Resumo: A expansão do tecido adiposo durante a obesidade é dependente de proliferação e maturação de adipócitos, formação de novos vasos sanguíneos, e remodelamento da matriz, e é acompanhada por infiltração de macrófagos e modificações significativas na produção de adipocinas. Estas alterações contribuem para o estabelecimento da inflamação crônica sistêmica de baixo grau. Os agentes imunossupressores são capazes de modular a atividade do sistema imunológico e que podem controlar a resposta inflamatória associada ao tecido adiposo durante a obesidade. Neste trabalho, foi investigada a ação de um fármaco, a talidomida, que possui atividade anti-inflamatória, pró apoptótica, antiproliferativa e antiangiogênica, nas alterações do tecido adiposo induzidas por dieta hiperlipídica. Em camundongos obesos, a administração de talidomida (100 mg/kg/ por 10 dias) reduz a adiposidade, o tamanho dos adipócitos, a ativação da JNK, a produção de TNF-? e leptina, e a infiltração de macrófagos. Em paralelo, aumenta a produção de IL-1ra. A redução da adiposidade parece estar relacionada com a atividade antiangiogênica da talidomida através da inibição de VEGF e TIMP e, a indução de apoptose. In vitro, observou-se inibição de TNF- ? e MCP-1 liberadas por células 3T3-L1 induzida por LPS. Os nossos resultados sugerem que o desenvolvimento de fármacos que são capazes de modular o estado inflamatório e adicionalmente controlar a expansão do tecido adiposo pode ser uma abordagem interessante no tratamento da obesidade / Abstract: Adipose tissue expansion during obesity is dependent on adipocyte proliferation and maturation, angiogenesis and matrix remodeling, and it is followed by a significant macrophage infiltration and adipokine production alterations. These alterations contribute to the establishment of a chronic low grade systemic inflammation. Immunosuppressant agents are able to modify the immune system activity and they can control the inflammatory response associated to adipose tissue during obesity. We investigated the action of a drug, thalidomide, which contains anti-inflammatory, pro-apoptotic, anti-proliferative and anti-angiogenic activities, on adipose tissue alterations induced by a high-fat diet. In obese mice, thalidomide administration (100 mg.kg-10 days) induces a reduction in adiposity, adipocyte size, JNK activation, TNF-? and leptin production, and macrophage infiltration. Aditionally, increases IL-1ra production. Adiposity reduction seems to be related to thalidomide anti-angiogenic activity through VEGF and TIMP inhibition and, apoptosis induction. In vitro, it was observed an inhibition of basal TNF-? and LPS-induced MCP-1 released by 3T3-L1. Our results suggested that the development of drugs that can modulate the inflammatory status and additionally control the expansion of adipose tissue could be an interesting approach in the management of obesity / Mestrado / Farmacologia / Mestra em Farmacologia

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Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination. / Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs. / FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes. / Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.