Thesis (doctoral)--Karolinska Institutet, Stockholm, 1988. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1988. / Extra t.p. with thesis statement inserted. Includes bibliographical references.

No description available.

Thesis (Ph. D.)--University of Adelaide, 1987. / Includes bibliographical references (leaves 196-251).

Thesis (DDSc) - University of Queensland, 2003. / Includes bibliography.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2005. / Vita. Appendix A: "C program listing." Includes bibliographical references (leaves 201-211).

No description available.

The nitrogen-containing bisphosphonates (NBPs) are the most widely used treatment for diseases involving excessive osteoclastic bone resorption, such as osteoporosis. The clinical efficacy of NBPs is due in large part to their affinity for bone mineral, but it has been suggested that lowering affinity may have benefits due to altered distribution and duration of action possibly allowing direct anti-tumour effects. In addition, the phosphonocarboxylate (PC) analogues inhibit prenylation more selectively through a different enzyme target, Rab geranylgeranyl transferase (RGGT), which may offer additional benefits by reducing side-effects associated with farnesyl diphosphate synthase (FPPS) inhibition. Using fluorescent analogues of PCs and NBPs demonstrated that mineral affinity not only affects initial bone-binding, but also influences desorption, reattachment and penetration at the bone surface, suggesting that lower affinity compounds have lower retention and increased access to other cell types, such as tumour cells. The work presented aimed to investigate the potential of low affinity analogues by characterising their intracellular potency for inhibiting their target enzymes. The results showed that modification to the phosphonate groups to produce phosphonoalkylphosphinate analogues reduced potency for inhibiting FPPS. By contrast, removal of one of the phosphonate groups to give a monophosphonate changed the target enzyme to RGGT. Modifications to the R1 side-chain (substituting with hydrogen or a halogen) of both NBPs and PCs were studied and showed contrasting results, modifications to the R1 side-chain of NBPs affect their ability to inhibit FPPS whereas the same modification to PCs is insignificant for inhibiting RGGT. This showed the distinction between the structural requirements for inhibition of RGGT and FPPS and furthers the understanding of the structure-activity relationships of both NBPs and PCs which could guide future drug design. Within this thesis the most potent inhibitor of RGGT to date, 3-IPEHPC, was characterised which in addition to having therapeutic potential may be used as tool to investigate the importance of Rab prenylation for cellular function.

Orientador: Carlos Rossa Junior / Banca: Karina Gonzales Silverio Ruiz / Banca: Marcia Pinto Alves Mayer / Banca: Alexandra Ivo de Medeiros / Banca: Luis Carlos Spolidorio / Resumo: As interações microrganismo-hospedeiro se iniciam pela detecção de padrões moleculares associados a microrganismos (MAMPs) por receptores semelhantes à Toll (TLR) e por proteínas com domínio de ligação à nucleotídeos e oligomerização (Nod) na resposta imune inata. No entanto, como a cavidade bucal saudável é continuamente colonizada por microrganismos não patogênicos que também apresentam MAMPs, deve haver um mecanismo endógeno de regulação negativa da resposta do hospedeiro para evitar uma resposta exagerada e desnecessária com consequências negativas ao hospedeiro. Os mecanismos associados à distinção de microrganismos comensais e patogênicos na mucosa bucal são ainda pouco compreendidos. As proteínas Nod foram inicialmente descritas como 'TLRs intracelulares' capazes de reconhecer MAMPs no citosol; no entanto, estudos in vitro indicam que Nod têm papel relevante na regulação da expressão de RANKL e OPG induzidas por antígenos microbianos, bem como na modulação da atividade de vias de sinalização intracelular associadas à expressão de citocinas diretamente relacionadas à regulação do turnover do tecido ósseo. Devido à escassez de informações sobre o papel das proteínas Nod na modulação das interações microrganismo-hospedeiro na mucosa oral e com base nestas informações, nossa hipótese é que as proteínas Nod tem um papel relevante na modulação da reação inflamatória e suas consequências, incluindo a reabsorção do osso alveolar. Para testar esta hipótese, os objetivos específicos propostos foram: avaliar em camundongos knockout para Nod1, Nod2 ou Rip2, através de microtomografia computadorizada e avaliações histológicas descritivas, estereométricas e imunohistoquímicas (TRAP), o papel das proteínas Nod na inflamação e reabsorção óssea associadas à doença periodontal experimental induzida por bactérias inativadas por calor... / Abstract: Recognition of pathogenic bacteria by the host is initially mediated by the innate immune response through detection of microbe-associated molecular pattern (MAMPs) by Toll-like receptors (TLR) and Nucleotide-oligomerization domain (Nod) proteins. Since the oral cavity, as well as other mucosal surfaces, is continuously colonized with non-pathogenic bacteria that also present MAMPs, there has to be an endogenous negative regulatory mechanism in place to prevent an overt host response with deleterious consequences. Specifically in the oral mucosa, it is not clear how the immune system is able to quickly distinguish between commensal and pathogenic bacteria and tailor the host response. Nod proteins were initially described as 'intracellular TLRs' that recognize MAMPs associated with bacteria invading the cytosol; however these proteins have been shown to modulate the activation of various signaling pathways involved in the expression of inflammatory genes, including p38 MAPK and NF-κB in concert with TLR stimulation. There is paucity of information on the in vivo role of Nod proteins in the modulation of host-microbe interactions in the oral mucosa. Based on this information, our hypothesis is that Nod proteins play an important role in the modulation of the inflammatory reaction associated with periodontal diseases and its consequences, including alveolar bone resorption. To test this hypothesis, we propose the following specific aims: Assess the role of Nod proteins in the inflammation and bone resorption in experimentally-induced periodontal disease Describe the influence of Nod proteins on the cytokine and signaling networks associated with periodontal disease. / Doutor

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / The bisphosphonate tiludronic acid (TIL) presents anti-resorptive and anti-inflammatory properties and it has not been evaluated in the association periodontitis-diabetes mellitus (DM) to date. The purpose of this study was to evaluate the effects of local administration of TIL on experimental periodontitis (EP) in rats with streptozotocin (STZ)-induced DM. On day 1, thirty two rats received STZ injection. The animals were divided into groups (n=8): DM/C (Control), DM/EP, DM/EP/TIL1 and DM/EP/TIL3. In groups EP, a ligature was placed around the cervical area of mandibular first molars at day 8. In groups DM/EP/TIL1 and DM/EP/TIL3, TIL solutions of 1 and 3 mg/kg body weight, respectively, were injected into the buccal gingival margin of mandibular first molars every other day. Animals were euthanized at day 18. Histomorphometric analyses were performed. Data were statistically analyzed (p<0.05). Group DM/EP/TIL3 presented reduced alveolar bone loss and attachment loss when compared with group DM/EP (p<0.05). Within the limits of this study, it can be concluded that i) the local administration of TIL solutions presented a protective effect on tissue destruction in EP in diabetic rats and ii) the dosage of TIL may influence its effects. / O bisfosfonato Ãcido tiludrÃnico (TIL) apresenta propriedades antirreabsortivas e anti-inflamatÃrias e ainda nÃo foi estudado na associaÃÃo periodontite-diabetes mellitus (DM). O objetivo deste estudo foi avaliar os efeitos da administraÃÃo local do TIL na periodontite experimental (PE) em ratos com DM induzido por streptozotocina (STZ). No 1 dia, trinta e dois ratos receberam injeÃÃo de STZ. Os animais foram divididos nos grupos (n = 8): DM/C (Controle), DM/PE, DM/PE/TIL1 e DM/PE/TIL3. Nos grupos PE, uma ligadura foi colocada na Ãrea cervical dos primeiros molares inferiores no 8 dia. Nos grupos DM/PE/TIL1 e DM/PE/TIL3, soluÃÃes de TIL (1 e 3 mg/kg de peso corporal, respectivamente) foram injetadas na margem gengival vestibular dos primeiros molares inferiores em dias alternados. Os animais foram submetidos à eutanÃsia no 18 dia. AnÃlises histomorfomÃtricas foram realizadas. Os dados foram estatisticamente analisados (p<0,05). O grupo DM/PE/TIL3 apresentou perda Ãssea alveolar e perda de inserÃÃo reduzidas quando comparado com o grupo DM/PE (p<0,05). Dentro dos limites deste estudo, pode-se concluir que i) a administraÃÃo local de soluÃÃes de TIL apresentou um efeito protetor na destruiÃÃo tecidual na PE em ratos diabÃticos e ii) a dosagem de TIL pode influenciar seus efeitos.