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Orientador: Paulo Noronha Lisboa-Filho / Banca: Silvania Lanfredi Nobre / Banca: Diogo Paschoalini Volanti / Banca: Marcia Tsuyama Escote / Banca: Fabio Coral Fonseca / Resumo: Este trabalho teve como objetivo otimizar rotas de síntese de diferentes métodos de materiais cerâmicos monofásicos e estudar propriedades cristalográficas e magnéticas de manganitas destes materiais. Foram utilizados os métodos da reação no estado sólido, método da reação de combustão e o método hidrotérmico. Após otimização, foram sintetizadas pelo método da reação de combustão amostras com composição nominal Bi1-xMxMn2O5, onde (M= Eu, Er e x = 0,10). Para obter as fases desejadas, os materiais sintetizados pelo método da combustão foram tratados termicamente a diferentes temperaturas de 600°C, 700°C e 800°C para amostras de composição BiMn2O5, e a 900°C para as amostras com substituições de Eu e Er. Já, as amostras obtidas pelo método da reação no estado sólido foram tratadas a 700, 750 e 800°C por 24 horas em cada temperatura. Para o estudo da das fases cristalográficas formadas nos materiais foi utilizada a difração de raios X, seguida do refinamento estrutural pelo método de Rietveld. Os métodos de síntese, por combustão com ureia e de reação no estado sólido, permitiram obter amostras monofásicas para o material com composição nominal BiMn2O5, que apresentaram estrutura perovisquita do tipo mulita e grupo espacial Pbam, a reação de combustão com ureia permitiu também obter amostras monofásicas para a composição nominal Bi1-xMxMn2O5, na qual (M = Eu e x = 0,10), onde foi observada a formação de um material monofásico com a mesma estrutura e grupo espacial do BiMn2O5 (IC... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The objective of this work is to optimize different methods of routes for synthesis of monophasic ceramic materials, and to study the crystallographic as well as its manganites magnetic properties. The reaction methods to be analyzed were the solid state reaction method, the combustion reaction method and the hidrotermic method. After optimization, the samples with nominal composition of Bi1-xMxMn2O5 (M= Eu, Er e x = 0.10) were synthesized using the combustion reaction method. With the aim of obtaining the desired phases, the synthesized materials using the combustion reaction method were then treated thermally at 600,700 and 800ºC for the samples presenting composition BiMn2O5, and 900ºC for the samples containing substitutions Eu and Er. The samples obtained by the solid state reaction method were treated at 700, 750 and 800ºC for 24 hours for each temperature. The X-ray diffraction using the Rietveld method for structural refining was used to study the crystallographic phases formed in the studied materials. The synthesis methods for combustion with urea as well as solid state allowed to obtain monophasic samples for the materials with nominal composition of BiMn2O5-. They presented perovskite-like mullite-type structure with special group Pbam. The combustion reaction method with urea also allowed to obtain manophasic samples with nominal composition Bi1-xMxMn2O5, (M=Eu e x = 0.10), where it was possible to observe the formation of a monophasic materials with the same structure and space group of BiMn2O5 (ICSD-026806). This result suggests the substitution of the Bi3+ site for Eu3+ cations for the nominal compositions with x - 0.1. The scanning electron microscopy indicated that the materials synthesized for combustion with urea presented a good particle distribution in the order of 300nm, while the materials synthesized for solid state allowed to obtain samples in the order of 1 um... (Complete abstract electronic access below) / Doutor

Typescript (Photocopy) / Addendum inserted. / Bibliography: leaves 202-216. / vii, 216 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1989

Made available in DSpace on 2014-06-11T19:33:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-03-12Bitstream added on 2014-06-13T20:05:23Z : No. of bitstreams: 1 bastos_as_dr_arafo.pdf: 971405 bytes, checksum: a74b6a8b306a24bb6ac6bb99a6d39a6f (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O presente estudo teve por objetivo avaliar os níveis locais e sistêmicos de peroxidação lipídica (LPO) e sua correlação com o perfil de marcadores inflamatórios, locais e sistêmicos em com Diabetes mellitus (DM) tipo 2, dislipidemia e periodontite crônica, comparando-os a indivíduos sem diabetes. Além disso, buscou-se propor um método validado para avaliar o malondiadeído (MDA) no fluido sulcular gengival de sítios saudáveis e doentes. A amostra foi constituída de 120 pacientes com doença periodontal crônica divididos em 4 grupos: Grupo1 (DM descompensado); Grupo2 (DM compensado); Grupo3 (sem diabetes com dislipidemia); Grupo 4 (sistemicamente saudável). Toda a amostra foi submetida a exame periodontal completo, exame físico e avaliação laboratorial para verificação da glicemia de jejum, hemoglobina glicada (HbA1c), insulina, proteína C-reativa e perfil lipídico. O exame periodontal consistiu na avaliação do índice de placa visível, do índice de sangramento marginal, da posição da margem gengival, da profundidade de sondagem, do sangramento à sondagem e do nível clínico de inserção. Para todos os grupos foram coletadas amostras de fluido sulcular gengival (FSG) (4 sítios sem periodontite e 4 sítios com periodontite) e de sangue para obtenção do plasma sanguíneo. Os níveis de peroxidação lipídica representados pelo MDA, avaliado por HPLC, e pelo LDL oxidado (LDLox), avaliado por ELISA, foram quantificados no fluido sulcular gengival e no plasma. Foram avaliadas ainda as citocinas (IL)-1, -2, - 4, -5, -6, -7, -8, -10, -12, -13 e fator de necrose tumoral α (TNF-α) no FSG e no plasma. Foi possível determinar e validar o método de avaliação no fluido sulcular gengival, com alta precisão, sendo que os coeficientes... / The aim of this study is to evaluate the levels of the lipid peroxidation and its correlation with systemic and local inflammatory markers profile in patients with type 2 diabetes mellitus (DM2) dyslipidemia and chronic periodontitis compared to systemically healthy patients. We also aimed to quantify a specific product of the lipid peroxidation process, malondialdehyde (MDA), in gingival crevicular fluid and to describe the validation of this method in this matrix using HPLC. The study sample comprised 120 patients divided into four groups with 30 patients in each group: group 1- diabetes with poor metabolic control with dyslipidemia, group 2- diabetes with good metabolic control, group 3- without diabetes with dyslipidemia and group 4- systemically healthy. All the subjects will go through a complete periodontal examination and physical and laboratory evaluation in order to verify fasting plasma glucose, glycated hemoglobin (HbA1c), lipid profile, insulin and high sensitivity C-reactive protein. Periodontal examination will consist of visible plaque index, gingival bleeding index, bleeding on probing, probing depth (PD) and clinical attachment levels (CAL). Plasma and samples of gingival crevicular fluid (GCF) will be collected in 4 sites without periodontal disease and 4 sites with periodontal disease. The lipid peroxidation levels, evaluated by oxidized LDL (ox LDL) and MDA were measured in GCF and in plasma. Inflammatory cytokines, (IL)-1, -2, -4, -5, -6, -7, -8, -10, -12, -13 and tumor necrosis factor-alpha α (TNF-α) were also evaluated in plasma and GCF. It was possible to validate a HPLC-based method to identify and quantify the MDA in GCF with sensitivity, precision, and accuracy even in small concentrations as observed in healthy... (Complete abstract click electronic access below)

In this thesis, I have explored the role of three genes related to p53, namely p21, MDM2 and MDMX, in regulating ferroptosis, a form of non-apoptotic cell death. Ferroptosis, an iron-dependent mechanism that leads to cell death due to lipid peroxidation, has a large potential to be used as a cancer therapy. My results indicate that p21, the effector of p53-mediated cell cycle arrest, can suppress ferroptosis possibly through its interaction with CDKs. Further, that MDM2 and MDMX, the negative regulators of p53, can act as pro-ferroptosis agents and that this role is independent of p53. Using various approaches to alter their activity, I found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. They were found to alter the cellular lipid profile to prevent the cells from mounting an adequate defense against lipid peroxidation. For example, inhibition of MDM2 or MDMX lead to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q₁₀, an endogenous lipophilic antioxidant. Moreover, I found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis. My findings also suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Further, that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers. Therefore, I believe that this thesis project has successfully identified several new regulators of ferroptosis and this knowledge can aid better design of therapies centered around ferroptosis.

High lipid : low dextrose (HL:LD) parenteral admixture (PA) is high in polyunsaturated fatty acids (PUFA) that are sensitive to peroxidation. This study evaluated the antioxidative effect of vitamin E in both HL:LD PA and in obese cats given HL:LD PA. Natural d-α-tocopherol (Vital E-300) was added to HL:LD PA at seven concentrations (8, 12, 16, 24, 32, 48, or 64 IU/g of lipid). PA were exposed to fluorescent light for 24 hours at room temperature. Hydroperoxides were measured at baseline and 24 hours hang time. Significantly lower hydroperoxide concentrations were found with > 24 IU/g of lipid at baseline (P < 0.01). A higher d-α-tocopherol concentration was required (> 48 IU/g lipid) to lower hydroperoxides at 24 hours (P < 0.0001). HL:LD PA with 40 IU/g lipid/day d-α-tocopherol was delivered intravenously to obese cats (PA Toc⁺) over 48 hours. Control cats (PA Toc⁻) received HL:LD PA without a d-α-tocopherol supplementation. Oxidative status of cats was evaluated at baseline and 24, 48, and 96 hours. Cats in both groups exhibited an increase in MDA concentration (time effect; P < 0.0001). WBC-tGSH and WBC-GPx did not change in either group of cats. RBC-tGSH and RBC-GPx changed over time (time effects; P = 0.0005; P = 0.0016, respectively) with the PA Toc⁺ cats exhibiting a higher RBC-tGSH concentration (treatment x time interaction; P = 0.012). Serum α- and γ-tocopherol concentrations increased in PA Toc⁺ cats (treatment effect; P < 0.0001). These findings suggest that d-α-tocopherol significantly alters oxidative status in vivo. / Master of Science

Lipid peroxidation is believed to play a key role in the onset and progression of degenerative disease. Interestingly, although cholesterol is the most abundant lipid in the human body, our understanding of its autoxidation and subsequent decomposition is relatively limited. In fact, until recently, cholesterol-7-hydroperoxide was accepted as the only primary product of cholesterol autoxidation in organic solution, however, our group exhibited that the 4-, 5-, and 6-hydroperoxides are also formed. Although this work facilitated thorough investigation of the complexities of both H-atom abstraction and addition in cholesterol autoxidation in organic solution, it did not account for the dynamic environment of a cell membrane. Herein, we report on the product distribution of these primary autoxidation products in lipid bilayers and how antioxidant supplementation, H-bonding interactions, and concentration of polyunsaturated fatty acid (PUFA) substrate influence both the product distribution and efficiency of autoxidation. Indeed, not only does H-bonding of the 3β-OH of cholesterol appear to shut-down C4 H-atom abstraction, the absence of kinetic chol-5α-OOH product is likely due to the poor potency of α- tocopherol (α-TOH), also as a result of H-bonding with phosphate head group of lipid membrane phospholipids. Therefore, within a lipid membrane the 7-hydroperoxide products predominate, consistent with literature precedent, however the factors involved are more complex than previously understood. Moreover, with the authentic cholesterol hydroperoxides in hand, we sought to determine if the different regioisomers exhibit different cytotoxicity. Glutathione peroxidases (GPXs) are cytoprotective enzymes that reduce harmful hydroperoxides to benign alcohols in vivo. Using RSL3, a small-molecule inhibitor for GPX4, we were able to sensitize mammalian cells to ferroptotic cell death via administration of our exogenously prepared chol-OOHs. Surprisingly, we found that the toxicities of each of 7α-OOH, 6β-OOH and 5α-OOH were only marginally augmented by RSL3 treatment, suggesting that they do not substantially sensitize cells to ferroptosis, perhaps because their decomposition to lipid peroxidation chain-initiating species (i.e. alkoxyl radicals) is not particularly efficient. Instead their cytotoxicities may derive from other mechanisms, such as the induction of apoptosis. This inspired our investigation of the fate of lipid hydroperoxides in vivo, namely the secondary products of the predominant 7-hydroperoxide species. Acid-catalyzed Hock fragmentation, known for the industrial synthesis of phenol and acetone from cumene or implication in the generation of 4-hydroxynonenal (4-HNE), of 5α- and 6β-OOH has been shown by our group to produce highly electrophilic secosterol species; we sought to investigate the same decomposition mechanism for 7α-OOH in light of our investigations in the lipid membrane. Interestingly, we found that Hock fragmentation of 7α-OOH does not exhibit products resulting from the anticipated O-vinyl oxocarbenium intermediate, rather, the mechanism appears to funnel through an α-epoxy carbenium to produce unprecedented A-ring cleavage and epoxide products. Herein, we describe our thorough analysis of this chol-7α-OOH Hock fragmentation and attempts to investigate the presence of these products in biological samples, similar to previous analyses of similar products in atherosclerotic plaque extracts. The products isolated and characterized through this work have provided new mechanistic insight with regards to the primary and secondary oxidation products of cholesterol in vivo; through further development of these findings, we hope to provide a better understanding of the implications of cholesterol oxidation in the pathogenesis of atherosclerosis.

Muitas espécies de animais vivenciam situações nas quais há uma profunda depressão metabólica, como na anóxia, na hipóxia e na hibernação. Durante a reoxigenação ou o despertar, ocorre aumento da produção de espécies reativas de oxigênio (ROS), que tendem a causar danos oxidativos. Diferentes enzimas antioxidantes protegem o organismo contra as ROS, porém não se sabe qual a real importância de cada uma delas durante a reoxigenação. A hibernação é uma das formas de hipometabolismo menos estudadas, fazendo com que haja questionamentos sobre como os hibernantes se protegem das ROS durante o despertar. A análise dos dados existentes é complexa devido à existência de variáveis não controladas, como o efeito do jejum associado à hibernação. Nesta tese, foram desenvolvidos dois projetos. Em um, investigou-se a importância da catalase num ciclo de anóxia e reoxigenação em caramujos pulmonados. No segundo, investigou-se o efeito da hibernação e da privação alimentar no intestino de lagartos teiús. Com base nos resultados, foi possível concluir que a catalase exerce um papel complementar contra os danos oxidativos causados pelas ROS e em conjunto com os demais componentes do sistema antioxidante. Porém, sua função não parece ser essencial, sendo em grande parte compensada pela atividade de glutationa peroxidase. Também foi possível concluir que a hibernação, estudada sem a interferência de drásticas quedas da temperatura, causa nítidas alterações no metabolismo de radicais livres no intestino de lagartos, com queda de atividades enzimáticas e de concentração de glutationa. A ausência de grandes danos oxidativos durante o despertar dos animais mostra que eles têm um sistema antioxidante eficiente. A privação alimentar resultou em respostas semelhantes as da hibernação, mas parece ter causado um certo grau de estresse oxidativo. Os resultados apresentados nesta tese respondem dois questionamentos no estudo do metabolismo de radicais livres em situações que envolvem flutuações na disponibilidade e no consumo de oxigênio. / Many species of animals experience situations in which occurs a profound metabolic depression, like anoxia, hypoxia and hibernation. During reoxygenation or arousal, there is an increase of the production of reactive oxygen species (ROS), which tend to cause oxidative damage. Different antioxidant enzymes protect the organims against the ROS, however the real importance of each one of them during reoxygenation is not known. Hibernation is one of the types of hypometabolism less studied, and questions about how the hibernators protect themselves from ROS during the arousal have not yet been answered. The analysis of the existent data is complex due to the existence of uncontrolled variables. In this thesis were carried out two studies in which were investigated: the importance of catalase in a cycle of anoxia and reoxygenation in pulmonate snails, and the effect of hibernation and of food deprivation in the intestine of tegu lizards. Considering the results, it was possible to conclude that catalase plays an complementary role against the damages caused by ROS and in association with the other components of the antioxidant system. However, its function seems to be non-essential, being greatly compensated by the glutathione peroxidase activity. It was also possible to conclude that hibernation, studied without the interference of drastic falls in temperature, causes clear alterations in free radicals metabolism in the lizards intestine, with a reduction in enzymes activities and in glutathione concentration. The absence of big oxidative damage during the arousal of the animals shows that they have an efficient antioxidant system. Food deprivation resulted in similar responses of those from hibernation, but seemed to cause some degree of oxidative stress. The results presented in this thesis answer two questions in the study of the free radical metabolism in situations that involve fluctuations in oxygen availability and consumption.

by Hui Yee Han, Ellen. / Thesis (M.Sc.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 68-71). / acknowledgements --- p.i / abstract --- p.ii / table of contents --- p.iii-vi / list of figures --- p.vii / LIST OF TABLES --- p.viii / chapter / Chapter chapter i : --- introduction --- p.1 / Chapter chapter ii : --- background knowledge --- p.2 -33 / Chapter 2.1 --- Definition of Free Radical --- p.2 / Chapter 2.2 --- Oxygen Derived Radicals and Their Generation In Vivo --- p.2 -9 / Chapter 2.2.1 --- Production of Singlet Oxygen --- p.4 / Chapter 2.2.2 --- Production of Superoxide Radical (O2-) and Hydrogen Peroxide (H2O2) --- p.4 -8 / Chapter I. --- Endogenous Production --- p.4-7 / Chapter II. --- Exogenous Production --- p.7-8 / Chapter 2.2.3 --- Generation of Hydroxy Radical (OH) through H2O2 and O2- --- p.8 -9 / Chapter 2.3 --- Free Radical Damage and Lipid Peroxidation --- p.9 -13 / Chapter 2.4 --- Lipid Peroxidation and Atherosclerosis --- p.13 -14 / Chapter 2.5 --- Antioxidant --- p.15-21 / Chapter 2.5.1 --- Primary Preventive Antioxidants --- p.15-17 / Chapter 2.5.2 --- Secondary Radical Scavenging Antioxidants --- p.18-21 / Chapter I. --- Lipid Soluble Radical-Scavenging Antioxidants --- p.18-19 / Chapter II. --- Water Soluble Radical-Scavenging Antioxidants --- p.20 -21 / Chapter 2.6 --- Measurement of Oxygen-Derived Radical in Vivo --- p.21 -26 / Chapter 2.7 --- Principle of the TRAP assay --- p.27-33 / Chapter 2.7.1 --- Oxygen Consumption Method --- p.29 -30 / Chapter 2.7.2 --- Chemiluminescence Method --- p.31-33 / Chapter chapter III： --- materials and methods --- p.34 -43 / Chapter 3.1 --- Instrumentation and Materials --- p.34 / Chapter 3.2 --- Method --- p.34-43 / Chapter 3.2.1 --- Establishment of Chemiluminescence Method for Determination of TRAP --- p.34 -36 / Chapter I. --- Preparation of Luminometer --- p.35 / Chapter II. --- Preparation of Sample before Analysis --- p.3 5 / Chapter III. --- Manual Operation of the Chemiluminescence Method --- p.35-36 / Chapter IV. --- Calculation of TRAP --- p.36 / Chapter 3.2.2 --- Evaluation of the Chemiluminescence Method --- p.37 -42 / Chapter I. --- Linearity --- p.37 / Chapter II. --- Recovery --- p.37-38 / Chapter III. --- Precision --- p.39 / Chapter IV. --- Interference Experiment --- p.39 -41 / Chapter V. --- Effect of Storage on TRAP --- p.42 / Chapter 3.2.3 --- "Determination of Analytical, Intraindividual and Interindividual Biological Variation of TRAP in A Group of Healthy Chinese" --- p.42-43 / Chapter CHAPTER IV: --- ANALYTICAL RESULTS --- p.44-56 / Chapter 4.1 --- Method Evaluation --- p.44-51 / Chapter 4.1.1 --- Linearity --- p.44 / Chapter 4.1.2 --- Recovery --- p.45 / Chapter 4.1.3 --- Within-Day and Between-Day Precision --- p.46-47 / Chapter 4.1.4 --- Interference --- p.47-48 / Chapter 4.1.5 --- Effect of Storage on TRAP --- p.48-51 / Chapter 4.2 --- "Analytical, Intraindividual and Interindividual Variation of TRAP in A Group of Healthy Chinese Population" --- p.52 -56 / Chapter 4.2.1 --- Difference in TRAP value obtained from the 22 subjects over time --- p.52 -54 / Chapter 4.2.2 --- The Effect of Genders on Trap --- p.55 / Chapter 4.2.3 --- "Determination of Analytical, Intraindividual and Interindividual Variation of TRAP in A Group of Healthy Chinese" --- p.55-56 / Chapter CHAPTER V: --- DISCUSSION --- p.57-67 / Chapter 5.1 --- Validation of the Method Performance --- p.57 / Chapter 5.2 --- Effect of Storage on TRAP --- p.57 / Chapter 5.3 --- Interference of Hemolysis and Lipemia on TRAP assay --- p.58-60 / Chapter 5.3.1 --- Effect of Hemolysis on TRAP --- p.58-59 / Chapter 5.3.2 --- Effect of Lipemia on TRAP --- p.59-60 / Chapter 5.4 --- Possible Sources of Variation in TRAP Over Time --- p.60 -63 / Chapter 5.5 --- Usefulness of the Variation Data of TRAP obtained from a Group of Healthy Chinese --- p.64 -67 / reference --- p.68 -71

Freshwater zooplankton crustacean Daphnia frequently face strong temperature fluctuations in its natural environment, which necessitates adaptive plastic responses. This study focuses on changes in lipid peroxidation and total oxidative capacity in Daphnia tissues in response to long-term and short-term temperature changes. Long-term acclimation to 28ºC helped Daphnia survive longer at lethally high temperatures. This difference, however, was not accompanied by changes in lipid peroxidation, indicating that it isn’t a good measure of damage or predictor of temperature tolerance. On the other hand, total oxidation capacity was lower 28ºC- than in 18ºC-acclimated Daphnia, suggesting that acclimation resulted in higher amounts of antioxidants in Daphnia tissues. Exposure to hypoxia, known to up-regulate antioxidant pathways in Daphnia, further elevated heat tolerance in 28ºC- acclimated individuals. Yet, manipulations of glutathione, an important antioxidant, while predictably affecting oxidative capacity, didn’t influence heat tolerance in Daphnia, suggesting that other antioxidants may play a significant role in it.