Orientador: Rosangela Goncalves Peccinini / Resumo: A tuberculose é uma doença infectocontagiosa provocada pelo Mycobacterium tuberculosis que apesar de reconhecida a muitos anos, ainda tem ocorrência frequente na sociedade, assim como os casos de resistência aos medicamentos, que tem apresentado aumento significativo nos últimos anos. Na busca de novas estratégias para o tratamento, pesquisadores da Unifesp-Diadema desenvolveram novos compostos com potencial atividade antimicobacteriana, denominados pirazinoato de metila (I), pirazinoato de etila (II), pirazinoato de butila (III) e 2-(pirazina-2-carboniloxi)etill pirazina-2-carboxilato (IV), derivados do ácido pirazinóico, principal metabólito da pirazinamida. Ensaios in vitro como a avalição de propriedades físico-químicas e ensaios que avaliam a absorção, distribuição, metabolismo e excreção (ADME), auxiliam na predição das características farmacocinéticas em um estágio inicial do desenvolvimento, permitindo a seleção dos melhores candidatos a novos fármacos. O presente estudo teve como objetivo a realização de screening físico-químico (determinação do coeficiente de partição e da estabilidade química nos pHs de 1,2; 7,4 e 8,8) e ensaios de ADME (cálculo da permeabilidade aparente em monocamada de células Caco-2, a avaliação da estabilidade metabólica em microssoma de ratos e de humanos e avaliação da estabilidade em plasma de rato). Os compostos apresentaram logP de valor negativo, indicando hidrofilicidade e foi observada estabilidade frente os três pHs avaliados. A perme... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis which, although recognized for many years, still occurs frequently in society, as well as cases of drug resistance, which has shown a significant increase in recent years. In the search for new treatment strategies, researchers at Unifesp-Diadema have developed new compounds with potential antimycobacterial activity called methyl pyrazinoate (I), ethyl pyrazinoate (II), butyl pyrazinoate (III) and 2- (pyrazine-2 -carbonyloxy) ethyl] pyrazine-2-carboxylate (IV), derivatives of pyrazinoic acid, pyrazinamide's main metabolite. In vitro assays such as the evaluation of physicochemical properties and assays that evaluate absorption, distribution, metabolism and excretion (ADME), aid in the prediction of pharmacokinetic characteristics at an early stage of development, allowing the selection of the best candidates for new drugs. The objective of the present study was the physical-chemical screening (determination of partition coefficient and chemical stability at pHs of 1.2, 7.4 and 8.8) and ADME tests (calculation of the apparent permeability in monolayer of Caco-2 cells, evaluation of metabolic stability in rat and human microsomes and evaluation of stability in rat plasma). The compounds presented logP negative value, indicating hydrophilicity and stability was observed the three pHs evaluated. The apparent permeability calculated for compounds I, II, III and IV resulted in values of 4.66 x10-6; 4.14 x10-... (Complete abstract click electronic access below) / Mestre

Accumulation of triglyceride (TG) in enterocytes of the small intestine follows two specific absorption pathways: the monoacylglycerol acyltransferase pathway (MGAT) and glycerol acyltransferase pathway (GPAT), the latter (GPAT) is usually found in the small intestine. In this study, we investigated the effects of Lactobacillus rhamnosus MRS6AN, an isolate from “amabere amaruranu” a Kenyan traditional cultured milk, on triglyceride accumulation and expression of GPAT3, I-FABP, MTP and NPC1L1 in Caco-2 cell enterocyte model. Intracellular triglyceride level (TG) of Caco2 cells was significantly reduced by live L. rhamnosus (LB) compared with other bacterial products. MTP expression in Caco2 cells was minimally reduced in live L. rhamnosus (LB) treated Caco2 cells. However, the expression level GPAT3, I-FABP and NPC1L1 was reduced in Caco2 cells treated with live bacteria. Data from this study suggests that Lactobacillus rhamnosus MRS6AN may reduce lipid uptake and accumulation perhaps via modulation of GPAT3 pathway.

Iron plays a crucial role in various essential functions within the human body, participating in processes vital for overall health and well-being. To address iron deficiency, a wide array of iron supplements are commonly employed. However, it is important to recognize that certain types of iron supplements can have adverse effects on the body, including the induction of oxidative stress and inflammation. Therefore, extensive research is imperative to investigate the inflammatory potential of different sources of iron supplements in order to ensure their safety and effectiveness. In the pursuit of evaluating the inflammatory effects of various iron supplements, researchers frequently employ the Caco2 cell model. In this study, the focus was placed on examining the pro-inflammatory potential of different iron supplements by measuring the levels of a specific inflammatory biomarker, the cytokine IL-6, in the Caco2 cells. To mimic the physiological conditions, the supplements were subjected to a simulated gastrointestinal digestion protocol, ensuring that the Caco2 cells were exposed to digested forms of the supplement after which the levels of IL-6 were determined using ELISA. Surprisingly, the results of the study unveiled intriguing findings. Specifically, the two iron supplements derived from bovine sources exhibited no significant effect on IL-6 levels, indicating a lack of pro-inflammatory activity. However, it was the iron supplement derived from Spirulina, a marine-originated source that captured attention. This particular supplement showcased the ability to decrease the levels of IL-6, suggesting a potentially anti-inflammatory effect on intestinal cells. / <p>Utbytesstudent</p>

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On étudie les effets des nanoparticules (d'argent et de silice) manufacturées sur les métabolismes oxydatifs et inflammatoire. La première partie étudie la toxicité in vivo de l'ingestion de nanoparticules d'argent, pendant 11 semaines, sur un modèle animal - rat Sprague Dawley. Nous y avons mis en évidence l'action toxique des nanoparticules d'argent notamment une hausse de la production d'anion superoxyde par les NADPH oxydases hépatiques et cardiaques, des dyslipidémies, une cytolyse hépatique, une augmentation de cytokines pro-inflammatoires et une tendance à la baisse de l'activité d'enzymes antioxydantes. Ceci nous a conduit à aborder l'étude in vitro, sur des modèles cellulaires intestinaux (Caco-2) et cutanés (HaCaT). Au cours de cette étude, des nanoparticules de silice, fonctionnalisées ou non avec des antioxydants, ont été incubées pendant 24 H en présence des cellules. Nous montrons que la modification de la surface des nanoparticules réduit considérablement leur toxicité en limitant la production d'espèces radicalaires et la mortalité cellulaire. D’autre part, le couplage avec un antioxydant permet d’augmenter la stimulation de voie de signalisation du facteur Nrf2. Cette voie est impliquée dans la protection de l’organisme contre les troubles liés aux espèces radicalaires. En somme, ce travail met en avant les potentialités de la vectorisation d’antioxydants avec des nanoparticules à des fins thérapeutiques. / The purpose of this study is to explore the effects of nanoparticles (silver and silica) manufactured on oxidative and inflammatory metabolism. In the first part of this work, we explored the in vivo toxicity from ingestion of silver nanoparticles, for 11 weeks, in an animal model - Sprague Dawley rat. This enabled us to demonstrate the toxic properties of silver nanoparticles including superoxide anion production by hepatic and cardiac NADPH oxidases, dyslipidemia, hepatic cytolysis, an increase in proinflammatory cytokines and a downward trend the activity of antioxidant enzymes. This led us to address the in vitro study on intestinal cell models (Caco-2) and cutaneous (HaCaT). During this study, silica nanoparticles, functionalized or not with anti-oxidants, were incubated for 24 hours in the presence of the cells. We show that the modification of the surface of the nanoparticles significantly reduces their toxicity limiting the production of free radical species and cell death. Furthermore, the coupling with an anti-oxidant increases the stimulation of Nrf2 factor that involves the protection of the body against disorders associated with radical species. In summary, this work highlights the potential of vectorization of antioxidants with nanoparticles for therapeutic purposes.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.