Thesis (Ph. D.)--Michigan State University. Dept. of Neuroscience, 2008. / Cindy Jordan, graduate advisor--From acknowledgments. Title from PDF t.p. (viewed Aug. 20, 2009). Includes bibliographical references (p. 139-155). Also issued in print.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 52-61).

Proefschrift Universiteit Maastricht. / Met lit. opg. - Met een samenvatting in het Nederlands.

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Thesis (Master's Degree (Medical Technology)-- Cape Technikon, Cape Town, 1997 / There is, at present, no recognised diagnostic biochemical marker of Alzheimer's Disease (AD). Recently, Gunnerson and Haley, (1992), reported that the presence of glutamine synthetase (GS) in cerebrospinal fluid (CSF) samples showed a 97% correlation with patients diagnosed as having AD. GS was detected by photolabelling with [y32P]2-azido-ATP or [y32P]8azido- ATP and visualisation following sodium dodecyl sulphate polyacrylamide gel electrophoresis (SOS-PAGE) and autoradiography. This study set out to reproduce Gunnerson and Haley's methodology for labelling sheep GS in CSF using [y32P]8-azidoATP, to develop this assay or possibly another, using a fluorescent probe of ATP binding sites, into a robust procedure suitable for a routine diagnostic laboratory, and finally to assess whether the presence of GS in CSF is indeed a marker of AD.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / The Systemic Inflammatory Response Syndrome (SIRS) is characterized by an excessive release of inflammatory mediators as a systemic inflammatory response to a serious clinical injuries. The use of glutamine in nutraceutical doses has been studied as a strategy in tissue protection and preservative of tissue metabolic function in stressful situations, helping to improve the immune response of patients. The effects of enteral glutamine supplementation in nutraceutical doses on the inflammatory markers, of glycolytic metabolism, of immune system and of oxidative stress were studied in adult and elderly patients with SIRS in a prospective, clinical, randomized, controlled, double-blind crossover study. Thirty six moderately severe patients admitted to the Intensive Care Unit were selected according to pre-defined criteria, diagnosis of SIRS and the APACHE II score (>10<20), distributed into two groups and submitted to the supplementation with 1 litre of enteral nutrition with addition of 30g of L-glutamine or calcium caseinate or 1 litre of enteral nutrition with addition of 30g of calcium caseinate or L-glutamine for two days, pause for one day only with diet, followed by four days of supplementation. Blood samples were collected before (T0) and after (T1) each supplementation. For evaluation blood parameters (hematocrit, leukocytes, lymphocytes, monocytes, prealbumin, blood urea nitrogen, creatinine, glucose, lactate, C-peptide and insulin), IL-1, IL-6, IL-10 and TNF&#945; were also assayed. Glutathione, TBARS, and glutamine and glutamate amino acids were measured. Six patients died during the study. Thirty patients finished the study, 16 men (53%) and 14 (47%) women, median age 74.4 years (30-92 years) in moderately severe state of health (APACHE II 13.1 - range 10-19). All patients developed SIRS and were given enteral nutrition supplemented with L-glutamine or calcium caseinate, 1464kcal/day (range 792-1914kcal/day). The use of L-glutamine in nutraceutical dose of 30g/day showed no changes in blood parameters. All laboratory parameters remained within normal values except the blood urea [Calcium Caseinate T1=47.0mg/dL (range 34.0-69.0 mg/dL) versus Glutamine T1=50.0mg/dL (36.75-75.0mg/dL); p=0.030]. Creatinine concentrations were not statistically different. There was no statistically significant difference in assessment of inflammatory parameters (IL-1, IL-6, IL-10 E TNF&#945;). Leukocytes count decreased significantly in both groups [Calcium Caseinate T0=13.650 1/mm3 (10.148-18.250 1/mm3) versus T1=11.500 1/mm3 (8.050-29.100 1/mm3); p=0,019] and [Glutamine T0=12.850 1/mm3 (11.155-15.550 1/mm3) versus T1=11.000 1/mm3 (9.200-16.325 1/mm3); p=0.046]. There was increase statistically significant difference in lymphocytes count between groups [Calcium Caseinate T1=1085 1/mm3 (range 805-1363 1/mm3) versus Glutamine T1=1916 1/mm3 (1301-2517 l/mm3); p<0.0001] and Calcium Caseinate group decreases [T0=1288 1/mm3 (range 834-2209 1/mm3) versus T1=1085 1/mm3 (range 805-1363 1/mm3); p=0.0324] and Glutamine group increases [T0=954 1/mm3 (range 785-1442 1/mm3) versus T1=1916 1/mm3 (range 1301-2517 l/mm3); p<0.0001]. Blood concentration of TBARS decreased significantly in both groups [Calcium Caseinate T0=20.56&#61549;mol MDA/ml (range 13.64-20.56&#61549;mol MDA/ml); p=0.001] and [Glutamine T0=17.67 &#61549;mol MDA/ml (range 8.11-34.98 &#61549;mol MDA/ml) versus T1=16.52 &#61549;mol MDA/ml (range 5.41-21.86 &#61549;mol MDA/ml); p=0.020]. The blood concentrations of Gluthatione showed a statistically significant reduction in caseinate group (T0=486.0&#61549;mol/ml (range 486.0Â165.8&#61549;mol/ml versus T1=451.0Â167.4&#61549;mol/ml; p=0.047) and no statistically significant difference in the glutamine group, nor between groups. However, there were no differences between groups. Glutamine and glutamate were not statistically different. Enteral nutrition supplemented with glutamine in nutraceutical doses of 30g/day increase lymphocyte count, helps to reduce lipid peroxidation and maintains the antioxidant glutathione capacity, interfering beneficially modulating the inflammatory response and stress, but present no effect upon cytokines concentrations or glycolytic parameters. / A SÃndrome da Resposta InflamatÃria SistÃmica (SRIS) caracteriza-se por uma liberaÃÃo excessiva de mediadores inflamatÃrios a uma sÃrie de situaÃÃes clÃnicas graves. A utilizaÃÃo da glutamina em doses nutracÃuticas tem sido estudada como uma estratÃgia de proteÃÃo tecidual e metabÃlica em situaÃÃes de estresse, melhorando a resposta imune de pacientes. Os efeitos da nutriÃÃo enteral suplementada com 30g/dia de glutamina sobre os marcadores inflamatÃrios, do metabolismo glicolÃtico, da funÃÃo imune e do estresse oxidativo foram estudados em pacientes adultos e idosos com SRIS. Foi realizado estudo clÃnico prospectivo, randomizado, controlado, duplo-cego, cruzado. Trinta e seis pacientes internados em Unidade de Terapia Intensiva foram selecionados pelos critÃrios do estudo, diagnÃstico da SRIS e score APACHE II (>10<20), distribuÃdos em dois grupos e submetidos à suplementaÃÃo com 1 litro de dieta enteral suplementada com 30g de L-glutamina ou caseinato de cÃlcio ou 1 litro de dieta enteral suplementada com 30g de caseinato de cÃlcio ou L-glutamina por dois dias, intervalo de um dia somente com dieta, perfazendo quatro dias de dieta com suplementaÃÃo. Amostras de sangue foram coletadas antes (T0) e apÃs (T1) cada suplementaÃÃo. Foram realizadas anÃlises do hematÃcrito, leucÃcitos, linfÃcitos, monÃcitos, prÃ-albumina, urÃia, creatinina, glicose, lactato, peptÃdeo-C e insulina, das IL-1, IL-6, IL-10, TNF&#945;, glutationa, TBARS e dos aminoÃcidos glutamina e glutamato. Seis pacientes foram a Ãbito durante o estudo e trinta pacientes concluÃram o estudo, sendo 16(53%) homens e 14(47%) mulheres, mediana de idade 74,4 anos (30-92 anos), moderadamente graves, mediana de APACHE II 13,1 (10-19) e mediana de ingestÃo calÃrica de 1464kcal/dia (792-1914kcal/dia). O uso L-glutamina em dose nutracÃutica de 30g/dia nÃo mostrou alteraÃÃes nos parÃmetros hematolÃgicos. Houve aumento da urÃia [Caseinato T1=47,000mg/dL (34,000-69,000mg/dL) versus Glutamina T1=50,000mg/dL (36,750-75,000mg/dL); p=0,030] na comparaÃÃo intergrupos, mas nÃo houve diferenÃa estatisticamente significante de creatinina em nenhum dos grupos. NÃo houve alteraÃÃo estatisticamente significante nos parÃmetros inflamatÃrios (IL-1, IL-6, IL-10 e TNF&#945;). A contagem de leucÃcitos diminuiu significantemente em ambos os grupos [Caseinato T0=13.650 1/mm3 (10.148-18.250 1/mm3) versus T1=11.500 1/mm3 (8.050-29.100 1/mm3); p=0,019] e [Glutamina T0=12.850 1/mm3 (11.155-15.550 1/mm3) versus T1=11.000 1/mm3 (9.200-16.325 1/mm3); p=0,046]. Houve aumento estatisticamente significante na contagem de linfÃcitos na comparaÃÃo intergrupos [Caseinato T1=1.085 1/mm3 (805-1.363 1/mm3) versus Glutamina T1=1.916 1/mm3 (1.301-2.517 l/mm3); p<0,0001], uma diminuiÃÃo estatisticamente significante no grupo Caseinato [T0=1.288 1/mm3 (834-2.209 1/mm3) versus T1=1.085 1/mm3 (805-1.363 1/mm3); p=0,0324] e aumento no grupo Glutamina [T0=954 1/mm3 (785-1.442 1/mm3) versus T1=1.916 1/mm3 (1.301-2.517 l/mm3); p<0,0001]. Observou-se reduÃÃo estatisticamente significante na dosagem do TBARS na comparaÃÃo intragrupos [Caseinato T0=20,56&#61549;mol MDA/ml (13,64-20,56&#61549;mol MDA/ml) versus T1=15,08 &#61549;mol MDA/ml (13,64-20,56 &#61549;mol MDA/ml); p=0,001] e [Glutamina T0=17,67 &#61549;mol MDA/ml (8,11-34,98 &#61549;mol MDA/ml) versus T1=16,52 &#61549;mol MDA/ml (5,41-21,86 &#61549;mol MDA/ml); p=0,020], mas nÃo houve diferenÃas intergrupos. A concentraÃÃo sanguÃnea de glutationa apresentou uma reduÃÃo estatisticamente significante no grupo Caseinato (T0=486,00&#61549;mol/mlÂ165,80&#61549;mol/ml) versus T1=451,00Â167,40&#61549;mol/ml; p=0,047) e nÃo houve diferenÃa no grupo Glutamina, tampouco entre os grupos. Glutamina e glutamato nÃo demonstraram diferenÃas estatisticamente significantes. Conclui-se que a nutriÃÃo enteral suplementada com glutamina em dose nutracÃutica de 30g/dia em pacientes moderadamente graves promove um aumento dos linfÃcitos, contribui para reduzir a peroxidaÃÃo lipÃdica e mantÃm a capacidade antioxidante da glutationa, interferindo de forma benÃfica na modulaÃÃo da resposta inflamatÃria e do estresse, mas nÃo apresenta nenhum efeito sobre a concentraÃÃo de citocinas ou parÃmetros glicolÃticos.

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Orientador: Patrícia de Oliveira Prada / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas / Made available in DSpace on 2018-08-26T21:26:16Z (GMT). No. of bitstreams: 1 Abboud_KahlileYoussef_M.pdf: 2486444 bytes, checksum: c7ecb857ad37f6bfbb7dd2e09bd6bfed (MD5) Previous issue date: 2014 / Resumo: A obesidade tornou-se um dos maiores problemas de saúde publica no mundo. Nas ultimas décadas, estudos têm demonstrado que a obesidade produz um estado de inflamação crônica subclínica e resistência à insulina em vários tecidos. Indivíduos obesos podem apresentar elevados níveis séricos de LPS e esta condição está associada à resistência à insulina e ao aumento na expressão de citocinas pró-inflamatórias e consequentemente na inflamação subclínica associada à obesidade. Neste contexto, a ação da glutamina tem despertado interesse por melhorar a resistência à insulina em tecidos periféricos através redução da expressão de marcadores inflamatórios nestes tecidos. Entretanto, ainda não foi bem elucidado se a suplementação oral de glutamina pode intervir nestas condições. Portanto, o objetivo do presente estudo foi de investigar se a suplementação oral com glutamina influencia o estado nutricional de indivíduos sobrepeso e obesos e também os níveis de LPS e citocinas pró-inflamatórias. No nosso estudo, a suplementação com glutamina não demonstrou reduzir significativamente os níveis séricos de LPS, no entanto, houve redução da citocina próinflamatória TNF-'alfa', dos níveis séricos de insulina de jejum, bem como da circunferência da cintura. Assim, a suplementação com GLN em indivíduos com sobrepeso e obesos pode ser benéfica para reduzir a adiposidade e melhorar a inflamação subclínica associada ao aumento do peso corpóreo. A suplementação com GLN em indivíduos com sobrepeso e obesos também melhora o quadro de resistência à insulina. Neste sentido, sua suplementação, pelo menos em curto prazo, pode ser recomendada para a melhora do metabolismo energético / Abstract: Obesity has become a major public health problem. In the last decades studies shown that it can induce low-grade chronic inflammation and insulin resistance in tissues. Obese individuals can have elevated lipopolissacharides (LPS) serum levels and this condition is associated to insulin resistance and the increased inflammatory cytokine expression. In this context, Glutamine actions has been studied for its role in insulin resistance in peripheral tissues decreasing of inflammatory markers expression. Although, it's still not clear if oral glutamine supplementation can change these conditions. Therefore, the aim of this study is to investigate whether oral glutamine supplementation can influence in the nutritional state of overweight and obese individuals and also in LPS serum levels and proinflammatory citokines In our study, glutamine doesn¿t demonstrate to significantly reduce LPS serum levels, although TNF-'alfa', fasting insulin and waist circumference was decreased after supplementation. Finally, supplementation with glutamine in overweight and obese individuals can show benefits reducing adiposity and improve low-grade chronic inflammation. It can also improve insulin resistance. Is this sense, GLN supplementation can be recommended in short term to improve energy metabolism / Mestrado / Nutrição / Mestra em Ciências da Nutrição e do Esporte e Metabolismo

Yes / The level of glutamine (Gln) deamidation in bone collagen provides information on the diagenetic history of bone but, in order to accurately assess the extent of Gln deamidation, it is important to minimise the conditions that may induce deamidation during the sample preparation. Here we report the results of a preliminary investigation of the variability in glutamine deamidation levels in an archaeological bone due to: a) sampling location within a bone; b) localised diagenesis; and c) sample preparation methods. We then investigate the effects of pre-treatment on three bone samples: one modern, one Medieval and one Pleistocene. The treatment of bone with acidic solutions was found to both induce deamidation and break down the collagen fibril structure. This is particularly evident in the Pleistocene material (~80,000 years BP) considered in this study. We show that ethylenediaminetetraacetic acid (EDTA), when used as an alternative to hydrochloric acid (HCl) demineralisation, induces minimal levels of deamidation and maintains the collagen fibril structure. Areas of bone exhibiting localised degradation are shown to be correlated with an increase in the levels of Gln deamidation. This indicates that the extent of Gln deamidation could provide a marker for diagenesis but that sampling is important, and that, whenever possible, subsamples should be taken from areas of the bone that are visually representative of the bone as a whole. Although validation of our observations will require analysis of a larger sample set, deamidation measurements could be a valuable screening tool to evaluate the suitability of bone for further destructive collagen analyses such as isotopic or DNA analysis, as well as assessing the overall preservation of bone material at a site. The measure of bone preservation may be useful to help conservators identify bones that may require special long-term storage conditions. / NERC (NE/J500197/1), Yorkshire Forward - Northern Way Initiative, Science City York, Gordon and Betty Moore Foundation, Leverhulme Trust

Drosophila melanogaster is a valuable model for studying various aspects of human cancer, including proliferative capacity, invasiveness and metabolic adaptation typical of tumour cells to support cell growth. One of the major players in this process is Myc, which can promote tumorigenesis by triggering a metabolic reprogramming that allows cells to produce macromolecules, by modulating glycolytic flux, glutaminolysis, lipidogenesis, and autophagy. The process by which hyperproliferative cells undergo metabolic reprogramming to sustain growth can be recapitulated in the epithelial cells from Drosophila imaginal discs, where different levels of Myc induce cell competition. This process is a mechanism for selection of cells expressing higher level of Myc that acquire a super-competitor condition, with the ability to non-autonomously kill the neighbouring slow-growing cells. The direct connection between Myc, glutamine metabolism and autophagy and their role in competitive events between cancerous cells and wild type cells have not been clearly explained; therefore, the main purpose of this project is to determine a plausible link between Myc and autophagy, by examining the dependency of Myc-induced autophagy on glutaminase and major regulators of autophagy, such as TOR, Atg1, Atg5 and ammonia, a by-product of glutamine catabolism, by dissecting these mechanisms both in normal epithelial clones and hyperproliferating RasV12 -expressing cells. Our results show that Myc promotes the transcription of glutamine-related genes and the production of ammonia, and that glutaminase is necessary for Myc-induced autophagy in epithelial cells of clones of the wing imaginal discs, with a mechanism independent from TOR and Atg1. Conversely, the effect of Myc on autophagy induction is mediated by Atg5. We then investigated the contribute of Myc in autophagy in RasV12-transformed cells, that upregulate Myc to sustain growth and hyperproliferation. Intriguingly, our data report that autophagy is increased non-autonomously in neighbouring wild type cells, and that this non-autonomous RasV12-driven autophagic flux depends on Myc activity. Moreover, downregulation of glutaminase in RasV12-expressing cells significantly reduces non-autonomous autophagy. Collectively, our results give new insights on how glutamine metabolism can contribute to Myc-induced autophagy and how this enhances cancerous cell fitness.