Made available in DSpace on 2018-08-02T00:02:55Z (GMT). No. of bitstreams: 1 tese_10444_Flávio Lopes Francisco Bittencourt.pdf: 4150669 bytes, checksum: 3a0e0fe3ddb584b9889cf304cb62e145 (MD5) Previous issue date: 2016-12-16 / A mineração desempenha um importante papel no cenário econômico nacional, com a presença de inúmeras reservas. Porém, o ferro, da forma como é extraído dessas jazidas, não é propício para utilização direta na indústria, devendo passar por atividades de beneficiamento como a aglomeração de finos e formação de pelotas. O processamento térmico das pelotas de minério é largamente utilizado, pois além de proporcionar reaproveitamento dos finos de minério, concede às pelotas propriedades físicas e metalúrgicas necessárias às operações em alto-forno. Para que essas transformações ocorram é utilizado o processo de combustão de gases, com intuito de fornecer calor e produtos de combustão com potencial redutor para transformar as pelotas. O problema encontra-se na complexidade dos processos térmicos existentes em fornos e combustores industriais, que associada à falta de controle comumente observada nas plantas, acaba resultando em gastos excessivos de combustível. No presente trabalho foram realizadas simulações computacionais utilizando o software de simulação ANSYS FLUENT para modelar um combustor presente em uma planta industrial cujo combustível utilizado é o Gás Liquefeito de Petróleo (GLP). Foram analisadas características da chama como perfil de temperatura, comprimento de chama, taxa de formação de produtos e velocidade de chama turbulenta. Duas geometrias para o combustor foram estudadas: uma considerando seção de saída livre e uma com a presença de estricção. Os resultados mostraram que a redução abrupta do diâmetro de saída influencia diretamente na formação da chama, tornando-a mais fina e estreita devido a ação de vórtices na entrada e na saída do combustor. Foi possível determinar a espessura da zona de reação química para as duas situações, caracterizando-a como uma região estreita, como era esperado. A velocidade turbulenta de chama foi determinada para as duas geometrias, notando-se diferenças para os casos.

Orientador: Celso Aparecido Bertran / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-05T16:03:35Z (GMT). No. of bitstreams: 1 CarinhanaJunior_Dermeval_D.pdf: 1993187 bytes, checksum: 8551883498a0459ecaf6e225dd799789 (MD5) Previous issue date: 2006 / Doutorado / Físico-Química / Doutor em Quimica

Les cellules béta pancréatiques synthétisent et sécrètent l’insuline, unique hormone hypoglycémiante de l’organisme. Ces cellules jouent un rôle central dans l’apparition du diabète, préserver leurs masses fonctionnelles est donc essentiel. Le récepteur GLP-1, appartenant à la classe B de la super famille des récepteurs couplés aux protéines G (RCPGs), est considéré comme une cible thérapeutique majeure dans le traitement du diabète de type 2. Via son récepteur, le GLP-1 potentialise la sécrétion d’insuline en réponse au glucose et favorise la survie des cellules beta. Les glucocorticoïdes sont des hormones du stress impliquées dans la régulation énergétique, largement utilisés en thérapeutique pour leur propriétés anti-inflammatoire, immunosuppresseur et antiallergique. Néanmoins, les glucocorticoïdes administrés en chronique sont diabétogènes en exerçant notamment des effets délétères sur les cellules beta. Nous avons caractérisé l’impact d’une exposition prolongée des cellules beta à un glucocorticoïde de synthèse (la dexaméthasone) sur les actions biologiques du glucose et du GLP-1.Nous montrons qu’une exposition prolongée des cellules beta à la dexaméthasone exerce des effets délétères en inhibant la sécrétion d’insuline en réponse au glucose et l’activation des kinases de survie ERK1/2 (Extracellular Regulated Kinases 1/2). A l’inverse, nous démontrons que l’exposition prolongée des cellules bêta à la dexaméthasone favorise le maintien du récepteur GLP-1 à la membrane plasmique, augmente le couplage du récepteur à la protéine Galpha s, ce qui se traduit par une production de second messager (AMPc) intracellulaire doublée. Malgré une diminution des effets du glucose, la sécrétion d’insuline et l’activation des kinases ERK1/2 en réponse au GLP-1 ne sont pas affectées. Cette étude révèle qu’une exposition chronique des cellules beta aux glucocorticoïdes 1) régule le trafficking du récepteur GLP-1 et favorise son maintien à la surface cellulaire, 2) hypersensibilise la signalisation du récepteur GLP-1 dépendante de la protéine Gαs , et 3) pourrait impacter les effets thérapeutiques des molécules ciblant l’activation du récepteur GLP-1. / Pancreatic beta cells synthesize and secrete insulin, the only hypoglycemic hormone in the body. These cells play a central role in the onset of diabetes. To protect the functional beta-cell mass is essential. The GLP-1 receptor, which belongs to the class B of the G protein-coupled receptor (GPCR) family, is a major therapeutic target in type 2 diabetes. Through its receptor, GLP-1 potentiates glucose-induced insulin secretion and improves the survival of pancreatic beta cells. Glucocorticoids are stress hormones implied in energetic metabolism and are widely used in therapeutics for their anti-inflammatory, immunosupressive and anti-allergic properties. Neverless, on chronic administration, glucocorticoids can induce metabolic syndrome especially due beta cell functional mass impairement. Here, we characterized the impact of a prolonged exposure of pancreatic beta cells to a synthetic glucocorticoid (dexamethasone) on biological actions of glucose and GLP-1.We show that a chronic exposure of beta cells to dexamethasone exerted deleterious effects on glucose-induced insulin secretion and ERK1/2 (Extracelllular Regulated Kinases 1/2) activation. In contrast, we observed that the glucocorticoid treatment increased GLP-1 receptor expression at the plasma membrane and improved the Galpha s protein coupling leading to an enhancement of cAMP production (2 fold increase). Despite the negative impact on glucose effects, glucocorticoids did not impair neither GLP-1-induced insulin secretion nor ERK1/2 activation. This study reveals that a glucocorticoid chronic exposure 1) regulates GLP-1 receptor trafficking and increases its expression to the plasma membrane, 2) causes supersensitization of Gαs-associated signaling, and 3) could impact on therapeutic effects of GLP-1 receptor-based drugs.

Background: Stem cells are a promising therapy for regeneration following myocardial infarction (MI). Another therapy currently under investigation for MI is glucagon-like peptide-1 (GLP-1), a natural incretin hormone that has cardio-protective properties, although a short half-life in vivo. GLP-1 CellBeads are a novel therapy, combining stem cells and GLP-1. Human mesenchymal stem cells (MSCs) were immortalised, engineered to secrete a fusion protein of GLP-1 and encapsulated in alginate. We have previously demonstrated that GLP-1 CellBeads significantly reduce infarct size and improve ejection fraction post-MI, but the underlying mechanisms are unclear. The therapy was assessed in an in vivo pig MI model and an in vitro cardiomyocyte ischaemia model. Methods: GLP-1 CellBeads were delivered to coronary artery branches in pigs, creating micro-infarcts, as determined by echocardiography. Cell-free beads (Beads) and CellBeads containing hMSCs without GLP-1 (Beads-MSC) were delivered as controls (n=3-5/group). Pigs were sacrificed one and four weeks post-MI. Tissue was analysed for: apoptosis, collagen, cardiomyocyte cross sectional area and myofibroblasts. The localised response around the beads was also measured using immunohistochemistry. Atomic force microscopy (AFM) was used to examine the ultra-structure of the collagen scar. The expression profiles of genes involved in collagen remodelling were measured using qRT-PCR. Viability of MSCs was measured using GFP-tagging and confirmed using qRT-PCR. To examine effects on apoptosis in vitro, human adult cardiomyocytes underwent ischaemia for 1 hour before incubation with: media conditioned with MSCs or MSC+GLP-1, GLP-1, Exendin-4 or media. Apoptosis and viability were measured at 24 and 48 hours respectively. Results: In the in vivo pig model, significant increases in apoptosis were observed in the infarct of all groups one week post-MI, with no differences between treatments. Despite decreased numbers of myofibroblasts, significantly more collagen was observed in MSC treated groups, with increased collagen fibril periodicity and a more organised collagen scar. The altered scar structure was reflected in differences in gene expression between groups, with an accelerated healing response in the MSC groups. However, significantly fewer myofibroblasts were observed in the MSC treated groups. Viability of MSCs was confirmed up to four weeks post-infusion, with GLP-1 secretion confirmed up to one week. In the in vitro ischaemia model, MSC+GLP-1 conditioned media significantly reduced cardiomyocyte apoptosis 24 hours post-ischaemia, compared to media alone. All agonists (GLP-1, MSC media and MSC+GLP-1 media) significantly improved viability compared to media alone 48 hours post-ischaemia. Conclusions GLP-1 CellBeads have a beneficial effect on healing following MI by significantly decreasing infarct size and improving ejection fraction post-MI. these benefits are associated with decreased cardiomyocyte apoptosis and altered collagen scar formation. The CellBeads act as local hubs for regeneration and are viable up to one month post-infusion. The effects observed are due to a combination of the GLP-1 and paracrine factors released from the hMSCs.

Bakgrund: Typ-2 diabetes är en sjukdom som kännetecknas av nedsatt insulinkänslighet (insulinresistens) samtidigt minskar betacellsfunktionen gradvis med fördröjt och otillräckligt insulinsvar på stimuli. Produktionen av insulin i bukspottkörteln räcker inte för kroppens behov. Insulinet håller blodsockerhalten på en jämn nivå och vid brist på insulin blir blodsockerhalten i cellerna för hög. Riskfaktorer är exempelvis livsstilsfaktorer som kost, låg fysisk aktivitet, rökning och stress. Övervikt, hög ålder, hypertoni, dyslipidemi och nedsatt glukostolerans ökar också risken för diabetes. Metabola syndromet ger en ökad risk för sjukdom i kärlen och hjärtat. En vanlig dödsorsak hos diabetiker är  makrovaskulära komplikationer och det gäller framför allt kardiovaskulära komplikationer. Förekomsten är 2–4 gånger högre än hos patienter som inte har diabetes. Typ-2 diabetes behandlas först med kostintervention och ökad fysisk aktivitet eller med antidiabeteka läkemedel. Glukagonlik peptid 1(GLP-1) analoger är en ny läkemedelsgrupp. Behandling med GLP-1 analoger minskar risken för hjärt-kärlsjukdomar exempelvis arterioskleros och hjärtinfarkt genom att reducera flera riskfaktorer som fetma och diabetes.                                                                            Syfte: Examensarbetes syfte var att enligt kliniska studier undersöka om GLP-1 analoger är en säker och effektiv behandling av hjärtsjukdomar hos patienter med typ-2 diabetes.  Metod: Det här arbetet baserat på en undersökning i PubMed databas med sökorden” GLP-1 diabetes type-2 with cardiovascular risk” och därefter valdes fem artiklar som hade mål som var relevanta för arbetet. Resultat: Liraglutid visade en viktminsknings effekt  och förbättring  av HBA1c. Analysen i studien visade signifikant postprandial minskning av triglycerider, och  fastande och postprandiala apoCIII-koncentrationer minskade vilket kan vara kopplat  till minskad glykemi. Patienter som fick dulaglutid  hade en signifikant lägre värden på Body Mass Index, BMI, Pulsvågshastighet PWV, totalt serumkolesterol, LDL-kolesterol diastoliskt blodtryck. Resultat visade att Exenatid hade bättre effekt än  sitagliptin och insulin glargin för att uppnå de sammansatta målen såsom lågdensitetslipoprotein <2,59 mmol/L och systoliskt blodtryck <130 mm Hg. Resultatet visade en konsekvent minskning av kardiokomplikationer utan tecken på signifikant relation till blodtrycks-mätning eller stadium av hypertoni. Slutsats: GLP-1 analoger har visat hjärtskyddande effekt vid behandling av typ-2 diabetiker genom förbättring av flera faktorer som minskar den kardiovaskulära risken. Faktorer som viktminskning, prevalens av hypoglykemi, hypertoni och dyslipidemi spelar avgörande roll för att minska risk för hjärt-kärlsjukdom hos typ-2 diabetiker.

Glycemic control in patients with type 2 diabetes (T2D) can be achieved through potentiation of the signalling by glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both incretin hormones have been traditionally characterized to be secreted by distinct enteroendocrine cells within the gut in response to nutrients. Signalling through the incretin receptors stimulates islet hormone release by potentiating glucose-stimulated insulin secretion from the β-cell and decreasing glucagon secretion from the α-cell. However, the bioactivity of GLP-1 and GIP is controlled by post-translational, N-terminal cleavage by the widely expressed serine protease dipeptidyl peptidase 4 (DPP4). As such, DPP4 inhibitors (DPP4i) have been successfully used to treat millions of patients with T2D. DPP4i target the catalytic active site of DPP4 and prevent the cleavage of the incretin hormones, thus prolonging their action. Recently, studies in genetically modified mice have demonstrated that GLP-1 is not solely an intestinally-derived peptide hormone and proposed that islet-derived GLP-1 is required for proper glucose homeostasis. Therefore, with the current study, we sought to assess whether β-cell-derived DPP4 is an important target for the regulation of glycemia. Treatment of Glp1r/Gipr^(β-cell-/-) mice with the DPP4 inhibitor sitagliptin demonstrated that β-cell incretin receptor signaling is required to mediate the beneficial effects of this class of drugs on glucose homeostasis. Additionally, Dpp4^(-/-) mice exhibited a significant reduction in hepatic glucose production during hyperinsulinemic-euglycemic clamps. Dpp4 mRNA, DPP4 protein and activity are present in isolated mouse islets, further supporting the islet as an important potential site of DPP4i action. In this study, we show that both DPP4i-treated wildtype islets and islets isolated from Dpp4^(β-cell-/-) mice exhibit increased glucose-stimulated insulin secretion (GSIS) during perifusion after a high-fat diet feeding. Genetic elimination of Dpp4 from islet β-cells also improved oral glucose tolerance and insulin sensitivity in female mice, but had no effects on circulating DPP4 or incretin levels. Finally, eliminating Dpp4 from β-cells or the whole pancreas did not improve whole-body glucose tolerance, response to DPP4i, insulin tolerance, or body weight in male mice fed chow or a high-fat diet. Therefore, we provide evidence for islet-derived DPP4 to have a role in local hormone responses to glucose; however, its role in systemic glucose metabolism is shown to be sex-dependent.

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Type 2 diabetes (T2D) is one of the fasting growing chronic diseases, caused by insulin resistance and pancreatic β-cell dysfunction. While over thirty medications were approved to treat T2D in the United States, less than one in four patients treated with anti-diabetic drugs achieved the glycemic target. Thus, identifying more effective anti-diabetic drugs is still needed for improving glycemic control in T2D patients. Incretins are gut hormones that possess potent insulinotropic action, which have drawn considerable attention in research and developing treatment strategy for T2D. Specifically, glucagon like peptide 1 (GLP-1), the most important incretin that is secreted from enteroendocrine L-cells in response to food ingestion, plays a vital role in maintaining glycemic homeostasis via potentiating glucose stimulated insulin secretion (GSIS) and promoting pancreatic β-cell proliferation and survival. Therefore, targeting L-cells to induce GLP-1 secretion would be an alternative strategy for treating T2D. The goal of this research was to identify low-cost and safe naturally occurring agents as a primary or adjuvant treatment for T2D. Here, I found that a small molecule, elenolic acid (EA), which was generated in our lab but is also present in mature olive and extra virgin olive oil, dose-dependently stimulated GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts. EA induced a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling. Consistently, inhibition of (PLC) ablated EA-stimulated increase of [Ca2+]i and GLP-1 secretion in L-cells. In addition, EA-triggered GLP-1 secretion from L-cells was blocked by YM-254890, a Gαq inhibitor. Consistent with our in vitro study, a single dose of EA acutely stimulated GLP-1 secretion in mice, accompanied with an improved oral glucose tolerance. Chronic administration of EA restored the impaired glucose and lipid homeostasis in DIO mice, which may be partially due to promoting GLP-1 secretion and reduced hepatic gluconeogenesis. In addition, EA suppressed appetite, reduced food intake and gastric emptying rate, as well as promoted weight loss in obese mice, demonstrating that it is also an anti-obesity agent. Further, EA treatment reduced lipid absorption, and promoted hepatic fatty acid oxidation, and reversed abnormal plasma lipid profiles in DIO mice. Consistently, EA exerted potent anti-diabetic action in db/db mice, and its blood glucose-lowering effect is comparable with that of liraglutide in blood glycemic control but is better than that of metformin in this overt diabetic model. Collectively, I have identified for the first time, as to the best of our knowledge, that EA could be a dual-action compound that exerts anti-diabetic effects via activation of the GLP-1 mediated metabolic pathway and suppression of hepatic gluconeogenesis, leading to effective control on food intake, body weight gain, and glycemia in T2D mice. / Doctor of Philosophy / Type 2 diabetes (T2D) is one of the fasting growing chronic diseases, which results from insulin resistance and pancreatic β-cell dysfunction. Even though there have been over thirty drugs approved to treat T2D in the United States, less than 25% of patients treated with anti-diabetic drugs achieved the glycemic target. Thus, more effective anti-diabetic drugs are still needed for improving glycemic control in patients with T2D. Incretins are a group of gut hormones and responsible for over 50% postprandial insulin secretion in humans, which have drawn considerable attention in research and developing a treatment strategy for T2D. Specifically, glucagon-like peptide 1 (GLP-1), the most important incretin that is secreted from enteroendocrine L-cells in response to food ingestion, plays a vital role in controlling blood glucose via potentiating glucose-stimulated insulin secretion (GSIS) and promoting pancreatic β-cell proliferation and survival. Therefore, targeting L-cells to induce GLP-1 secretion would be an alternative strategy for treating T2D. The goal of this research was to identify low-cost and safe naturally occurring agents as a primary or adjuvant treatment for T2D. Here, I found that a small molecule, elenolic acid (EA), which was synthesized in our lab but is also present in mature olive and extra virgin olive oil, dose-dependently stimulated GLP-1 secretion in mouse clonal L-cells and isolated mouse ileum crypts (containing L-cells). Further experiments showed that EA induced a rapid increase in intracellular [Ca2+]i and the production of inositol trisphosphate (IP3) in L-cells, indicating that EA activates phospholipase C (PLC)-mediated signaling, as IP3 is a direct product of PLC. Consistently, inhibition of PLC ablated EA-stimulated increase of [Ca2+]i and GLP-1 secretion in L-cells. In addition, EA-triggered GLP-1 secretion from L-cells was blocked by YM-254890, a Gαq inhibitor. In line with the in vitro study, a single dose of EA acutely elevated plasma GLP-1 concentration in mice, accompanied by improved oral glucose tolerance. Chronic administration of EA restored the impaired glucose and lipid homeostasis in diet-induced obese (DIO) mice, which may be partially due to promoting GLP-1 secretion and reduced hepatic gluconeogenesis. In addition, EA suppressed appetite, reduced food intake, and gastric emptying rate, as well as promoted weight loss in the DIO mice, demonstrating that it is also an anti-obesity agent. Further, EA treatment reduced lipid absorption and promoted hepatic fatty acid oxidation, as well as reversed abnormal plasma lipid profiles in the DIO mice. Consistently, EA exerted potent anti-diabetic action in predisposed diabetic mice (db/db), and its blood glucose-lowering effect is comparable with that of liraglutide, a commercial GLP-1 receptor agonist, in blood glycemic control but is better than that of metformin, a widely used first-line anti-diabetic drug, in this overt diabetic model. Collectively, I have identified for the first time, as to the best of our knowledge, that EA could be a dual-action compound that exerts anti-diabetic effects via activation of the GLP-1 mediated metabolic pathway and suppression of hepatic gluconeogenesis, leading to effective control on food intake, body weight gain, and glycemia in T2D mice.

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by hyperglycemia, insulin resistance, and the dysfunction of β-cells. While there are several therapies for T2D, there is no effective treatment that can reverse the functional decline of pancreatic β cells in T2D patients. Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by human intestinal L cells, which can stimulate the proliferation and differentiation of β cells and promote glucose-stimulated insulin secretion (GSIS), thereby playing a critical role in maintaining glycemic homeostasis. Recently, GLP-1-based medications have been developed for treating T2D. However, most of the GLP-1-based drugs are expensive and have significant adverse effects. Therefore, development of safer and more convenient agents that can mimic the physiologically fed state to promote endogenous GLP-1 secretory function of intestinal L-cells to improve glucose homeostasis holds great potential for the prevention and treatment of T2D. This project aimed to examine whether natural compound genipin promotes intestinal GLP-1 secretion and exerts anti-diabetic effects. I found that genipin rapidly increased GLP-1 secretion from intestinal L-cells, with 10 and 100 μM concentration inducing significant incretin hormone release. L-cells exposed to genipin displayed a rapid increase in intracellular [Ca²⁺]i and the activity of phospholipase C (PLC). Inhibition of PLC ablated genipin-stimulated Ca²⁺] increase and GLP-1 secretion, suggesting that genipin-induced GLP-1 release from the cells depends on the PLC/Ca²⁺ pathway. In vivo, genipin reduced the non-fasting and fasting blood glucose levels, improved insulin resistance, and protected again high fat diet-induced liver damage. All together, these data indicate that genipin is a naturally occurring anti-diabetic agent, which could be a pharmaceutical lead for developing anti-diabetic drugs. / M.S. / More than 34 million Americans are suffering from diabetes, with over 90% of these cases being type 2 diabetes (T2D). Loss of β-cell mass and function is central to the deterioration of glycemic control over time in T2D. Therefore, preservation or improvement of β-cell mass and its insulin secretory function could prevent and treat T2D. While there are several pharmaceutical therapies for T2D, no effective treatment is available for reversing functional decline of pancreatic β-cells in T2D patients. It has been well recognized that glucagon-like peptide-1 (GLP-1), which is an incretin hormone secreted from intestinal L-cells, plays a critical role in maintaining glycemic homeostasis via potentiating glucose-stimulated insulin secretion and promoting β-cell proliferation. This present work is to determine whether natural compound genipin promotes intestinal GLP-1 secretion and thus exerts anti-diabetic effect.