Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2016-08-01T19:25:55Z No. of bitstreams: 2 Dissertação - Monallisa Alves Ferreira - 2016.pdf: 3140045 bytes, checksum: 7ed313979941a30be50154016e30d177 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2016-08-02T12:21:35Z (GMT) No. of bitstreams: 2 Dissertação - Monallisa Alves Ferreira - 2016.pdf: 3140045 bytes, checksum: 7ed313979941a30be50154016e30d177 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2016-08-02T12:21:35Z (GMT). No. of bitstreams: 2 Dissertação - Monallisa Alves Ferreira - 2016.pdf: 3140045 bytes, checksum: 7ed313979941a30be50154016e30d177 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2016-02-26 / Aim: The aim of this study was to evaluate the effect of dry green tea extract isolated and/or combined with metformin on diabetes type 2 risk factors in women with overweight. Methods: A double-blind, placebo-controlled, randomized trial which 120 obese women were randomly assigned in a double-blind manner to 1 of 4 groups: Control (n = 29; 1g of cellulose); Green tea (n = 32; 1g of dry green tea extract); Metformin (n = 28; 1g of metformin); Green tea + Metformin (n = 31; 1g of dry green tea extract + 1g of metformin). Anthropometric measurements, body composition, fasting blood samples were evaluated. Results: After 12 weeks, green tea had positive effect on glycemic control. In contrast, the metformin led to an increase of HbA1c concentration (0.048 ± 0.189%; p = 0.017). It also reduced body weight (-1.318 ± 0.366, p = 0.034) as well as decreased lean body mass (-1.249 ± 0.310; p = 0.009). Regarding the lipid parameters, green tea significantly reduced total cholesterol and LDL-c. Conclusion: The isolated action of green tea was superior to metformin on glycemic control and lipid profile. Therefore, green tea dry extract may be a better alternative to treat risk factors to DM2 in overweight women than metformin. / Objetivo: Avaliar o efeito do tratamento com o extrato seco de chá verde isolado e/ou combinado com a metformina sobre fatores de risco para o desenvolvimento do diabetes mellitus tipo 2 (DM2) em indivíduos com excesso de gordura corporal. Métodos: Ensaio clínico, randomizado controlado, duplo-cego com duração de 12 semanas, no qual 120 mulheres com excesso de gordura corporal foram distribuídas em um dos quatro grupos de intervenção: Controle (n = 29; 1g de celulose/dia); Chá Verde (n = 32; 1g de extrato de chá verde seco/dia); Metformina (n = 28; 1g de metformina/dia); Chá Verde + Metformina (n = 31; 1g de extrato de chá verde seco + 1 g de metformina/dia). Medidas antropométricas, de composição corporal, perfil lipídico, glicemia e insulinemia de jejum foram avaliadas. Resultados: Após 12 semanas de intervenção, o chá verde demonstrou efeito positivo em relação ao controle glicêmico. Em contrapartida, a metformina induziu o aumento de hemoglobina glicada (0.048 ± 0.189%; p = 0.017), a redução do peso corporal (-1,318 ± 0,366, p = 0,034) e da massa magra (-1,249 ± 0,310; p = 0,009). Somente o chá verde alterou o perfil lipídico reduzindo significativamente o colesterol total e LDL-c. Conclusão: O efeito isolado do chá verde foi superior ao da metformina no controle glicêmico e no perfil lipídico. Logo, o extrato seco de chá verde pode ser uma alternativa viável para minimizar o risco de desenvolvimento de DM2 em mulheres com excesso de gordura corporal.

Made available in DSpace on 2017-07-10T18:08:00Z (GMT). No. of bitstreams: 1 Jonas Laurentino de Souza.pdf: 1900199 bytes, checksum: 3994bd57ce92b5d78685371435d4291e (MD5) Previous issue date: 2012-02-24 / The oral administration of drugs for systemic effects is the most common way used in medical treatment. Among these, drugs as tablets are the most used. The granulation is a process that seeks to improve the transportation of powder in the compacting machine by the agglomeration of particles. The fluidized bed drying added to "spray dryer" technique is commonly used to form granules that reaches the required characteristics of a uniform grain, with strict control of final humidity of the granules and relatively short process when compared to other techniques for drugs production. Metformin is a drug displayed as hydrochloride and orally administered as coated tablets. It is indicated for the treatment of type 2 Diabetes mellitus. In order to improve productivity in an industrial fluidized bed used in the granulation and drying of Metformin, it is necessary to evaluate the effects of operation conditions used in the process, as particulate material and in the production process. For that purpose, it was performed the study of fluiddynamic granulation and drying of Metformin in fluidized bed in order to investigate the minimum fluidization velocity for the process of this drug. The influence of temperature and speed of drying air in processing time of the formula, and the average particle size were also evaluated. The experiments were elaborated based on the Evolutionary Operation Theory, proposed by Box (1957). It performed the shaping at drying stage. With these experiments was possible to reduce to zero the reworks of batches caused by the formation of preferential channels, which could occur deposition polymer solution on the particulate material. It was also possible to reduce the average processing time in 8 minutes, adding greater productivity and savings for the company where the work was developed. The results achieved, besides the gain in productivity, guide to where efforts should be directed to continue improving productivity, providing a practical methodology for applying the technique that can be applied in the production of other drugs that use the granulation process in fluidized bed. / A administração de fármacos para efeitos sistêmicos por via oral é a forma mais comum dentre os medicamentos. Dentre estes, os medicamentos na forma de comprimidos são os mais empregados. A granulação é um processo que visa melhorar o transporte do pó na máquina compressora por meio da aglomeração de partículas. A secagem em leito fluidizado acoplado à técnica de spray dryer é a técnica comumente empregada para a formação de grânulos que atendam as características necessárias de granulometria uniforme, com controle rigoroso da umidade final do granulado e tempo relativamente curto de processo quando comparado a outras técnicas para produção de medicamentos. A metformina é um fármaco, apresentado na forma de cloridrato, e administrado como comprimidos revestidos por via oral. É indicado no tratamento de diabetes, mais especificamente diabetes mellitus tipo 2. Com o objetivo de aprimorar a produtividade em um leito fluidizado industrial utilizado na granulação e secagem de metformina, faz-se necessário avaliar os efeitos das condições operacionais utilizadas no processo referentes a qualidade material particulado e o processo de produção propriamente dito. Para tanto, realizou-se o estudo fluidodinâmico da granulação e secagem de metformina em leito fluidizado investigando assim a velocidade mínima de fluidização para o processamento deste fármaco. A influência da temperatura e da velocidade do ar de secagem no tempo de processamento da fórmula e no tamanho médio da partícula também foram avaliados. Os experimentos foram elaborados a partir da teoria da Operação Evolutiva, proposta por Box (1957). A modelagem da etapa de secagem também foi realizada. Por meio dos experimentos realizados conseguiu-se reduzir a zero os reprocessos de bateladas por formação de canais preferenciais, onde poderia ocorrer deposição de solução polimérica sobre o material particulado. Foi possível também reduzir o tempo médio de processamento em 8 minutos, agregando maior produtividade e economia para a empresa na qual este trabalho foi desenvolvido. Os resultados obtidos mostram que houve ganhos em relação a produtividade, e norteiam para onde os esforços devem ser direcionados para continuidade do melhoramento de produtividade, fornecendo uma metodologia prática para aplicação da técnica que poderá ser aplicada na produção de outros fármacos que utilizam o processo de granulação por via úmida em leito fluidizado.

INTRODUÇÃO: A metformina tem sido amplamente utilizada no tratamento da síndrome dos ovários policísticos (SOP), porém poucos estudos comparam a metformina e a dieta associada a exercícios físicos. O objetivo deste estudo é comparar parâmetros clínicos e laboratoriais de mulheres com SOP em uso de metformina ou através de dieta e exercícios físicos. MÉTODOS: Foram avaliadas 30 mulheres com SOP, com idades entre 18 a 34 anos, as quais foram divididas em dois grupos: grupo A- tratamento com metformina 1.800mg/dia e grupo B- dieta hipocalórica associada a exercícios físicos. Avaliações clínica e laboratorial foram feitas antes dos tratamentos e a cada três meses, por período de seis meses. RESULTADOS: Não houve diferença significativa entre os tratamentos quanto à regularização do ciclo menstrual (p=0,711), acne (p=0,271), hirsutismo (p=0,146) e índice de massa corpórea (IMC) p=0,328; assim como nas dosagens laboratoriais de LH (p=0,147), FSH (p=0,891), testosterona total (p=0,226) e livre(p=0,455), androstenediona (p=0,066), 17alfa-hidroxiprogesterona (p=0,914), SHBG (p=0,791), colesterol total (p=0,692) e frações, triglicérides (0,291) e nos índices de avaliação de resistência insulínica HOMA-R (p=0,111) e relação glicemia/insulina (p=0,976). Os dois tratamentos apresentaram melhora do ciclo menstrual (76%) e do IMC (p<0,001). A diminuição da circunferência abdominal foi maior no grupo B (p=0,006). CONCLUSÕES: Comparando os dois tratamentos não houve diferença nos parâmetros clínicos e laboratoriais avaliados. Ambos foram eficazes na redução do peso corpóreo e na regularização do ciclo menstrual. / Metformin has been widly used in treatment of polycystic ovary syndrome (PCOS) but only few studies compare metformin with diet and exercises. The aim of this study is to compare clinical and laboratorial parameters of women with PCOS using metformin or under diet and exercises. Methods: Thirty women with PCOS were evaluated with ages between 18- 34 years old, who were divided in two groups: group A- treatment with metformin 1.800mg/day and group B- hypocaloric diet and exercises. Clinical and laboratorial evaluations were done before treatment and each three months during a period of six months. RESULTS: There were no significant differences between treatments for menstrual disturbances (p=0,711), acne (p=0,271), hirsutism (p=0,146) and body mass index (BMI), p=0,328; in laboratorial parameters there were no significant differences for LH (p=0,147); FSH (p=0,891), total testosterone (p=0,226), free testosterone (p=0,455), androstenedione (p=0,066), 17alfa-hidroxiprogesterone (p=0,914), SHBG (p=0,791), total cholesterol (p=0,692) and fractions and indexes for evaluation of insulin resitence HOMA-IR (p=0,111) and glycemia and insulin ratio (p=0,976). Both treatments improved menstrual disturbances (76%) and BMI (p<0,001). The abdominal circunference decreasing was greater in group B (p<0,006). CONCLUSIONS: Comparing both treatments there were no differences in clinical and laboratorial parameters evaluated. Both were efficient in improving body mass index and menstrual disturbances.

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La metformine, un médicament couramment utilisé pour le traitement du diabète de type II, fut récemment identifiée comme un composé ayant des propriétés anticancéreuses très intéressantes, notamment pour le cancer du pancréas. Toutefois, malgré les nombreuses expériences in vitro et sur des modèles murins qui ont confirmé cet effet, les essais cliniques sur les humains sont restés infructueux. Un des facteurs mis en cause pour expliquer ces résultats est la grande hydrophilie de la metformine, qui diminue sa biodisponibilité et limite son transport au travers des membranes cellulaires. Nous nous sommes donc intéressés à la synthèse de sels de biguanidium amphiphiles inspirés de la metformine qui se partitionnent plus facilement dans les bicouches phospholipidiques et qui possèdent de meilleures activités anticancéreuses. Pour ce faire, nous avons tout d’abord étudié la perturbation des membranes par de simples alkylbiguanidium. Nous avons démontré que ces composés peuvent transporter des ions H+/OH- et dépolariser les membranes bactériennes, ce qui leur confère des propriétés antibactériennes et antifongiques. Afin de limiter l’hémolyse associée à ces composés, des sels de biguanidium substitués par le groupement phényléthynylbenzyle ont par la suite été synthétisés. La structure de ceux-ci leur permet de mieux se partitionner dans les membranes et s’accumuler dans les mitochondries, tout en diminuant la toxicité associée à une perturbation membranaire trop forte. Leur activité sur les cellules cancéreuses du pancréas est ainsi beaucoup plus importante que celle de la metformine, de même que leur capacité à inhiber la croissance de xénogreffes chez les souris. Ces résultats nous ont ensuite amené vers la synthèse d’une petite librairie de sels de biguanidium et l’étude de leurs activités anticancéreuses et antibactériennes. Les modifications structurales et les changements de contre-ion apportés à cette librairie ont permis d’obtenir des composés encore plus efficaces et surtout beaucoup plus sélectifs envers les cellules saines, ouvrant ainsi la porte à une nouvelle classe de médicaments anticancéreux à base de sels de biguanidium. / Metformin, a common drug used for the treatment of type II diabetes, has recently been linked to interesting anticancer properties, notably on pancreatic cancer. Although there have been many experiments in vitro and on murine models that have confirmed this effect, human clinical trials featuring metformin have been unsuccessful. One of the reasons brought forward to explain these results is the high hydrophilicity of metformin, which limits its bioavailability and transport through cellular membranes. For this reason, we have been interested in the synthesis of amphiphilic biguanidium salts inspired from metformin that can partition more easily in phospholipid membranes and thus have better anticancer properties. We first studied the membrane perturbation properties of simple alkylbiguanidium salts and showed that these compounds can transport H+/OH- ions and depolarize bacterial membranes, which in turn gives them antibacterial and antifungal properties. To limit the hemolytic activity associated with these compounds, biguanidium salts substituted by the phenylethynylbenzyl moiety were then synthesised. Their structure allows them to partition more easily in membranes and accumulate in mitochondria, while lowering the toxicity associated with high membrane perturbation. For those reasons, their activity on pancreatic cancer cells is much higher than metformin, as is their inhibition of xenograft growth in mice. These results encouraged us to synthesise a small library of biguanidium salts and study their anticancer activity. The structural modifications and counter-anion variations brought to this library have improved the efficiency of these compounds as well as their selectivity towards healthy cells, thus opening the door to a new class of anticancer drugs based on biguanidium salts.

Le cancer du pancréas est la quatrième cause de décès par cancer au Canada. Avec des mutations activatrices de KRas présentes dans près de 90% des lésions bénignes et tumeurs, ce cancer arbore une activation de la voie MAPK très tôt dans son développement. Or, peu de littérature existe sur les étapes clés de la progression et sur le rôle précis de cette signalisation dans le passage des lésions bénignes (PanIN) au stade avancé (PDAC). Depuis plusieurs années, notre laboratoire s’intéresse aux kinases ERK1/2, actives en aval de Ras, des acteurs centraux du programme de sénescence cellulaire, soit un programme antitumoral intrinsèque aux cellules. L’hypothèse centrale des présents travaux est donc que les mutations de KRas acquises dès le stade PanIN induisent une sénescence qui agit comme barrière à la progression tumorale, et que l’atténuation du signal de ERK est impliquée dans le contournement de ce mécanisme. La première partie de cette thèse montrera donc les avancées que nous avons faites sur la caractérisation de la progression entre le stade bénin et le stade avancé, de laquelle l’acquisition d’un caractère souche, la transition épithélio-mésenchymateuse et le développement d’une dépendance mitochondriale semblent être des déterminants. Ensuite, nous présenterons nos découvertes sur le rôle des kinases ERK1/2, de la sénescence cellulaire et du stress nucléolaire dans une nouvelle approche visant à restaurer un mécanisme de suppression tumorale inspiré des lésions bénignes et impliquant une altération de la biogenèse ribosomique. Finalement, pour bonifier cette nouvelle stratégie, nous présenterons les résultats d’un criblage CRISPR-Cas9 génome-entier nous ayant permis d’identifier les composantes d’une stratégie « one-two punch » basée sur l’induction de sénescence dans les cellules PDAC combinée à l’inhibition de la Glutathion peroxydase 4 (GPX4), de façon à promouvoir une sénolyse efficace dans ce contexte. Dans leur ensemble, les travaux présentés dans cette thèse montrent un avancement significatif dans la compréhension de la biologie des cancers pancréatiques en identifiant à la fois des vulnérabilités intrinsèques et inductibles afin de générer de nouvelles idées thérapeutiques pour ce cancer hautement fatal. / Pancreatic cancer is the fourth leading cause of death by cancer in Canada. With frequent activating mutations in KRas in up to 90% of benign lesions and tumors, this cancer possesses an early activation of the MAPK pathway. However, key events of its progression from the PanIN stage to the PDAC stage and the precise role of MAPK signaling in it are still poorly understood. For many years, our laboratory has taken interest in the ERK1/2 signaling pathway, activated downstream of oncogenic Ras and a key mediator of cellular senescence. Cellular senescence is considered an intrinsic antitumor mechanism due to its ability to stably halt the cell cycle. The central hypothesis of this work is then that KRas mutations that are acquired at the PanIN stage induce cellular senescence which acts as a barrier against tumor development. Still, this powerful mechanism can be circumvented as cells tend to attenuate the ERK1/2 signaling to promote progression and acquisition of more aggressive features. Thus, the first part of this thesis will present our most recent advances in characterizing the progression events between PanIN and PDAC stages, during which stem cell features acquisition, epithelial-mesenchymal transition and mitochondrial dependency seem to occur. Next, we will present our discoveries regarding the implication of ERK1/2 kinases, cellular senescence and nucleolar stress in a new approach to restore a tumor suppression mechanism inspired by the PanIN stage and based on ribosome biogenesis alteration. Finally, to potentiate this strategy, we will show the results of a genome-wide CRISPR-Cas9 screen that identified the components of a “one-two punch” approach to induce cellular senescence in PDAC cells and to efficiently eliminate them by GPX4 inhibitors-mediated senolysis. Globally, the work presented in this thesis show significant progress in the field of pancreatic cancer, identifying previously unknown vulnerabilities of those cancer cells and paving the way for the development of new therapeutic combinations.

No description available.

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting deleterious side effects in heart and skeletal muscle. As an increased percentage of patients live many years past their cancer treatments, addressing the long-term side effects of chemotherapy treatment becomes critical. In an attempt to prevent heart and skeletal muscle damage caused by DOX, two co-treatments, exercise (EX) or metformin (MET) were studied for their effectiveness in maintaining muscle function, mitochondrial respiration and iron regulation. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, the degree to which the toxic side effects are due to iron dysregulation is poorly understood. To address this gap in understanding, the changes in proteins involved with iron regulation following DOX treatment with or without EX or MET was examined in liver, heart, and skeletal muscle. To study the effects of EX or MET on DOX muscle toxicity and the effect of DOX on iron regulation, C2C12 myotube cell culture and a mouse model were used. Results from this research suggest that the some of the toxic effects of DOX treatment can be reduced with EX or MET treatments. EX is effective at preventing an impairment in muscle relaxation, promoting positive iron regulation changes in the liver and blunting DOX-induced changes in iron regulation in muscle. MET partially prevents loss of mitochondrial respiration and promotes positive changes in iron regulation in the liver. Additionally, study of DOX on iron regulation in liver, heart, and skeletal muscle suggests that DOX promotes iron dysregulation. However, the cellular response is protective against excessive iron dysregulation and increased oxidative stress. This cellular response is at least partially dependent on NF-κB activation.

The obesity epidemic is an important global health concern. Obesity is associated with a number of diseases including type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, and some cancers. Insulin resistance, a precursor to type 2 diabetes, is defined as an unresponsiveness of metabolic tissues to insulin, leading to long-term hyperglycemia and hyperinsulinemia. The fatty acid-induced model of insulin resistance indicates that an accumulation of lipid intermediates interferes with insulin signal transduction leading to insulin resistance. It is, therefore, important to examine means by which these lipid intermediates can be reduced to alleviate interferences in insulin signaling in the treatment of insulin resistance and type 2 diabetes. Exercise and metformin are two common interventions in patients with type 2 diabetes and obesity. They both commonly activate AMP-activated protein kinase (AMPK). AMPK contributes to a number of metabolic processes including increased glucose and fatty acid oxidation. However, the effects of AMPK activation on insulin sensitivity are currently not fully understood. This compilation of studies examined the insulin sensitizing effects of AMPK activation via metformin, exercise, and novel AMPK activator R419 in obese mice. In Chapter 2 we show that metformin increases AMPK phosphorylation of acetyl-CoA carboxylase (ACC) 1 Ser79 and ACC2 Ser212, resulting in increased fatty acid oxidation, decreased lipid content and improvements in hepatic insulin sensitivity. In Chapter 3 we show that exercise-induced improvements in insulin sensitivity occur independent of AMPK phosphorylation of ACC phosphorylation sites and independent of lipid content in the liver. Finally, in Chapter 4 we show that R419 improves skeletal muscle insulin sensitivity independent of AMPK and lipid content but improves exercise capacity via a skeletal muscle AMPK-dependent pathway in obese mice. These findings suggest that future studies examining the effects of AMPK activation in obesity will aid in our understanding of the mechanisms of insulin resistance and introduce methods of prevention and treatment of obesity and type 2 diabetes. / Thesis / Doctor of Philosophy (PhD)

No description available.