The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on hepatic pyruvate carboxylase (PC) gene expression were investigated in C57BL/6J Ah[superscipt b/b male mice. A dose-dependent reduction of PC levels and activity occurred in animals given a single intraperitoneal dose of TCDD in a corn oil carrier. The dose ranged from 1 to 75 ug/kg body weight and the analysis performed 8 days postinjection. At the maximum TCDD level investigated, a 10-fold reduction in PC activity occurred. At doses beyond those required to initiate a reduction in PC, a lactate dehydrogenase isozyme patterns shift is observed. This is accompanied by increases in blood lactic acid levels. Northern blot analysis on RNA extracts from hepatic tissues indicated that at 8 days post TCDD treatment, a dose-dependent reduction of hepatic mRNA levels occurs. The aryl hydrocarbon receptor (AhR) is believed to mediate all responses to TCDD. Liganded AhR and the aryl hydrocarbon receptor nuclear translocator (ARNT) protein form a heterodimeric transcription factor which interacts with dioxin response elements (DREs). These are found in enhancer/promoter regions of many genes that respond transcriptionally to TCDD exposure. Cloning and sequencing a region approximately 1.4 kb upstream of the PC translational start site revealed an untranslated leader sequence of 124 nucleotides starting with adenosine. Primary structural analysis of the upstream region revealed an 1nr element in place of a TATA element. Additional transcription factor elements were identified including: Spl, GCF, UBP-1, GRE, CREB, NF-1, HNF-4, TFII-I and E-boxes; DRE elements were notably lacking. A tandem series of 10 evenly spaced E-boxes, which bind ARNT homodimers, are each juxtaposed to a TFII-I element, possibly forming composite elements. Tertiary structure analysis revealed the positioning of nine composite elements displayed as a trio of phased elements. Transient transfections into Hepa lc1c7 cells, using a luciferase reporter gene under the transcriptional control of the PC upstream region, unlike the animal studies, produced an induction in activity in the presence of 10 nM TCDD. Co-transfections with an ARNT encoding plasmid reduced induction indicating overexpression of ARNT protein partially overrides the TCDD-induced increase in activity. These results in relationship to whole animal experiments are discussed. / Graduation date: 1997

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 164-173). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 164-173). Also available on the Internet.

Thesis (M.Sc.) - Carleton University, 2007. / Includes bibliographical references (p. 182-200). Also available in electronic format on the Internet.

Thesis (Ph. D.)--Illinois State University, 1993. / Title from title page screen, viewed March 7, 2006. Dissertation Committee: Herman E. Brockman (chair), Alan J. Katz, Brian J. Wilkinson, David F. Weber, Radheshyam K. Jayaswal. Includes bibliographical references (leaves 162-177) and abstract. Also available in print.

Thesis (Ph. D.)--Illinois State University, 1993. / Title from title page screen, viewed March 10, 2006. Dissertation Committee: Alan J. Katz (chair), Herman E. Brockman, David F. Weber, Brian J. Wilkinson, Marjorie A. Jones. Includes bibliographical references (leaves 146-159) and abstract. Also available in print.

Orientador: Edson Luis Maistro / Resumo: Os anti-inflamatórios não esteroides (NSAIDs) estão entre os medicamentos mais amplamente utilizados no mundo inteiro. Isso se deve à medicina curativa implantada principalmente no ocidente. Com frequência os NSAIDs são usados para aliviar queixas musculoesqueléticas, artrite, bursite, dor de dentes, dismenorreia, dor de estados pós-parto e na dor de metástases de câncer no osso, sendo todas essas enfermidades associadas ao aumento da síntese de prostaglandinas. Os efeitos farmacológicos dos NSAIDs são devidos à inibição da ciclooxigenase (COX) e a subsequente diminuição da síntese de prostaglandinas (PGs), levando a uma diminuição da inflamação, dor e febre. Essa diminuição de PGs leva a uma larga escala de efeitos colaterais que são associados à NSAIDs, incluindo complicações gastrointestinais (CGI), problemas cardiovasculares, toxicidade renal, hipertensão e retenção de líquidos. Devido a essas características dos NSAIDs, justificam-se estudos envolvendo a utilização de outros meios para a entrega oral de fármacos anti-inflamatórios. Uma opção muito pesquisada, que vem crescendo de maneira significativa é o uso de nanopartículas, com potencial para constituir uma nova geração de "sistemas de entrega de drogas". Nanopartículas apresentam uma série de características, tais como: detectar, monitorar e tratar doenças; proteger o fármaco de ácidos estomacais e enzimas do trato gastrointestinal; e proteger o estômago e intestino do próprio fármaco. A indometacina é um poderoso a... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, in fulfilment of the requirements for the degree of Master of Science. Johannesburg, 2015. / RBBP6 is an E3 Ubiquitin ligase protein with a U-box motif. It interacts with p53 and Rb and is linked to several cellular functions. SNAMA is the Drosophila RBBP6 homolog, but is less characterized than its vertebrate counterparts. Gene expression studies on Drosophila have a potential to advance the knowledge on molecular mechanism underlying genotoxic stress. Previous studies have shown that SNAMA plays a critical role as an apoptosis suppressor and possibly in responses to genotoxic stress. The molecular basis for this is, however, unknown. Initially, two isoforms were identified by bioinformatics and one (Snama A) experimentally as well. Here, we confirm experimentally the existence of the second isoform (Snama B). We also show that these are differentially expressed during development and when the organism undergoes genotoxic stress. Total RNA samples were used to demonstrate gene expression by using Reverse Transcriptase Polymerase Chain Reaction. Using samples collected at different stages of development and from adult flies treated with the DNA damaging agent, irinotecan, it is shown that these isoforms are differentially expressed throughout development and upon genotoxic stress. This knowledge may help to understand the functional role SNAMA plays in normal physiology and in response to genotoxic stress. Furthermore, the results show that SNAMA is involved in a potentially beneficial intervention whereby the glycolytic pathway is bypassed by the addition of methyl pyruvate.

Insects have evolved various physiological responses to cope with stressors such as pathogens, toxins and environmental factors. It is known that the responses resulting from infection or DNA damage share some of the same pathways. Exposure of Drosophila melanogaster and the dung beetle Euoniticellus intermedius to stress led to changes in the expression of proteins involved in metabolism, development, protein degradation, mRNA processing and stress responses. Stress responses in D. melanogaster are well characterised. However, the role played by Drosophila p53 (Dmp53) and a member of the retinoblastoma binding protein 6 (RBBP6) family, Snama, are unknown. Snama has been proposed to play a role in Dmp53 regulation. Following DNA damage we investigated the role of Dmp53 and Snama. Flies recovering from camptothecin treatment display a glycolytic flux, involving a metabolic shift, different to that observed in cancer cells. Camptothecin treatment leads to an increase in the mortality of both sexes. Furthermore, females show a specific decrease in fecundity which is due to an increase in Dmp53 dependent apoptosis in the ovaries and is accompanied by a depletion of Snama and an increase in Dmp53 transcripts. Expression data indicated that Dmp53 activity may be largely regulated at the protein level. Bypassing glycolysis through methyl pyruvate supplementation led to differential expression of Dmp53 and Snama and improved reproduction and embryonic development. These results highlight differences between the metabolic strategies used by cancerous and non-cancerous cells which may be exploited in future chemotherapies. While immune responses amongst insect orders are evolutionarily conserved, many remain uncharacterised. To investigate the immune system of an organism that lives in a microbe rich environment, E. intermedius was infected with the fungal pathogen Beauveria bassiana. This resulted in decreased lifespan and fecundity. Homologs of proteins involved in the immune response of insects were identified in E. intermedius, including a member of the Toll family of proteins, an insect defensin (present in the hemolymph) as well as a homolog of the serine protease Persephone. These results show that immune signalling pathways are conserved in this dung beetle.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2000. / Bibliography: leaves 114-122.