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Nous avons récemment observé que la stimulation des cellules pancréatiques par le glucose et d'autres substrats mitochondriaux s'accompagne d'une protection contre de faibles concentrations d'H202 exogène (15µM). L'objectif de mon mémoire est d'étudier plus en détails ces effets protecteurs dans des amas de cellules d'îlots pancréatiques de rat, et d'en identifier le mécanisme. La concentration en H202 a été mesurée en conditions dynamiques dans des cellules à l'aide de la sonde roGFP2-0rp1 ciblée dans le cytosol ou la matrice mitochondriale : à différentes concentrations de glucose (0.5, 5, 10 et 30) en présence et en absence d'H202 avec ou sans nutriments (Leucine + Glutamine ou l'acide alpha-kétoisocaproique). Nous observons qu'en présence de ces nutriments, principalement l'acide alpha-kétoisocaproique, l'état d'oxydation de la sonde est plus bas au niveau cytosolique et mitochondrial en présence d'H202 exogène,ainsi qu'au niveau mitochondrial en son absence, montrant un effet protecteur de ces nutriments contre l'H202 endogène et exogène. Ensuite, nous avons inhibé la glucose-6-phosphate-déshydrog énase avec le trans-dehydroepiandrosterone pour tester le rôle du NADPH cytosolique dans les défenses antioxydantes. Nous avons aussi commencé à tester l'effet d'une surexpression des peroxirédoxines 5 dans les cellules. Pour la suite de mon mémoire,je vais compléter ces expériences et tester dans quelle mesure l'effet protecteur des nutriments contre l'H202 se traduit en une amélioration de la fonction sécrétoire et de la survie des cellules.

Oxidative Stress --- Pancreatic Stellate Cells

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La fibrose hépatique est une conséquence commune d’atteinte hépatique chronique ayant plusieurs origines (hépatite virale, consommation excessive d’alcool, maladie héréditaire) et est caractérisée par un dépôt excessif de matrice extracellulaire dans l’espace interstitiel du parenchyme hépatique. Elle représente un phénomène cicatriciel et dynamique qui est le résultat d’un déséquilibre d’une balance comprenant d’un côté les différents facteurs profibrotiques, et de l’autre côté, les différents mécanismes antifibrotiques. Des études précédentes nous prouvent que les cellules stellaires hépatiques représentent la composante profibrotique majeure de cette réponse cicatricielle au sein du parenchyme hépatique. La sénescence réplicative est une caractéristique normale de toutes cellules humaines. En effet, elle fait référence à la capacité proliférative limitée des cellules une fois qu’elles arrivent en fin de croissance. Des études traitant la sénescence réplicative des cellules stellaires hépatiques humaines activées ont non seulement montré que ces dernières subissaient un switch phénotypique lors de leur vieillissement en culture, mais aussi qu’il y avait une diminution de l’expression des gènes impliqués dans la prolifération et la production de matrice extracellulaire. D’autres études ont également montré que la progression de la fibrose est restreinte par une machinerie de sénescence intacte au sein des cellules stellaires hépatiques Les buts de cette étude sont, dans un premier temps, d’observer les différences d’expressions géniques et protéiques entre des cellules stellaires jeunes et des cellules stellaires sénescentes dans le mécanisme de fibrose hépatique et ainsi, de voir si l’âge altère la réponse fibrotique. Si oui, nous essayerons d’en déterminer les mécanismes. Puis, de comparer la réponse fibrotique chez des animaux naïfs et des animaux ayant subi des épisodes de fibrose précédents pour voir s’il y a modification la réponse fibrogénique chez des sujets qui ont été soumis à des stimuli profibrotiques au préalable

Liver Cirrhosis --- Cell Aging --- Hepatic Stellate Cells --- Fibrosis

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Pancreatic Cancer has been and still is one of the deadliest types of human malignancies. The annual mortality rates almost equal incidence rates making this disease virtually universally fatal. The 5-year survival of patients with pancreatic cancer is a dismal 5% or less. Therapeutic strategies are extremely limited with gemcitabine extending the survival by a disappointing few weeks. The failure of several randomized clinical trials in the past decade investigating the therapeutic efficacy of different mono- and combination therapies reflects our limited knowledge of pancreatic cancer biology. In addition, biomarkers for early detection are sorely missing. Several pancreatic cancer risk factors have been identified. Unfortunately, the underlying mechanisms linking these risk factors to cancer development are poorly understood. Well known possible and probable risk factors for the development of pancreatic cancer are age, smoking, chronic pancreatitis, obesity, and type-2 diabetes mellitus. Age is certainly of the most important risk factors as most cases of pancreatic cancer occur in the elderly population. Smoking ten cigarettes a day increases the risk by 2.6 times and smoking a pack per day increases it by 5 folds. Chronic pancreatitis increases the risk of pancreatic cancer by up to 13 times. Patients with hereditary forms of chronic pancreatitis have an even higher risk. Obesity, a growing global health problem, increases the risk of pancreatic cancer by about 1.5 fold. Type-2 diabetes mellitus is also associated with an increased risk of pancreatic cancer by at least two-fold. The more recent the onset of diabetes, the stronger the correlation with pancreatic cancer is. In addition, heavy alcohol drinking, a family history of the disease, male gender and African American ethnicity are other risk factors for pancreatic cancer. Pancreatic cancer is characterized by several genetic alterations including mutations in the Kras proto-oncogene and mutations in the tumor suppressor genes p53 and p16. While Kras mutations are currently thought as early events present in a certain percentage of pancreatic intraepithelial neoplasias (PanINs), known precursor lesions of pancreatic ductal adenocarcinomas, mutations in tumor suppressor genes, e.g. p53, seem to accumulate later during progression. In addition, several intracellular signaling pathways are amplified or enhanced, including the MAPK/ERK and PI3K/AKT signaling modules. Overall, these genetic alterations lead to enhanced and sustained proliferation, resistance to cell death, invasive and metastatic potential, and angiogenesis, all hallmarks of cancers. The scope of this Research Topic is to collect data and knowledge of how risk factors increase the risk of initiation/progression of pancreatic cancer. Of particular interest are potential underlying molecular mechanisms. Understanding the molecular mechanisms and driving signaling pathways will ultimately allow the development of targeted interventions to disrupt the risk factor-induced cancer development. This Research Topic is interested in a broad range of risk factors, including genetic and environmental, and welcomes original papers, mini and full reviews, and hypothesis papers. Manuscripts that address the effect of combination of risk factors on pancreatic cancer development and progression are of great interest as well.

Blood type --- Genetic mutations --- src --- Pancreatitis --- stellate cells --- Inflammation --- KRAS --- Pancreatic Cancer --- diabetes --- Risk factors

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Myofibroblasts (MFB) are found in most tissues of the body. They have the matrix-producing functions of fibroblasts and contractile properties that are known from smooth muscle cells. Fundamental work of the last decades has shed remarkable light on their origin, biological functions and role in disease. During hepatic injury, they fulfill manifold functions in connective tissue remodeling and wound healing, but overshooting activity of MFB on the other side induces fibrosis and cirrhosis. The present e-book "Liver myofibroblasts" contains 9 articles providing comprehensive information on "hot topics" of MFB. In our opening editorial we provide a short overview of the origin of MFB and their relevance in extracellular matrix formation which is the hallmark of hepatic fibrosis. Thereafter, leading experts in the field share their current perspectives on special topics of (i) MFB in development and disease, ii) their role in hepatic fibrogenesis, and (iii) promising therapies and targets that are suitable to interfere with hepatic fibrosis.

Xanthohumol --- Hepatic Stellate Cells --- therapy --- Portal myofibroblasts --- Cytoglobin --- miRNA --- Myofibroblasts --- Autophagy --- Matrix stiffness --- NADPH Oxidase --- Xanthohumol --- Hepatic Stellate Cells --- therapy --- Portal myofibroblasts --- Cytoglobin --- miRNA --- Myofibroblasts --- Autophagy --- Matrix stiffness --- NADPH Oxidase

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Pancreatic diseases include intractable ones including acute and chronic pancreatitis, and pancreatic cancer. In recent years, great advances have been made in the field of pancreatology, including the pathogenesis, diagnostic modalities, and development of novel therapeutic interventions. It has been established that pancreatic stellate cells play a pivotal role in the development of pancreatic fibrosis in chronic pancreatitis as well as in pancreatic cancer known as desmoplastic reaction. Although it might be still controversial, accumulating evidence has shown that interaction between pancreatic stellate cells-cancer cells contribute to the progression of pancreatic cancer through the increased proliferation and migration, and production of cytokines and extracellular matrix components. In addition, pancreatic stellate cells lead to the resistance to chemotherapy and radiation therapy. Pancreatic stellate cells attract the researchers as a novel therapeutic target of pancreatic cancer. Genetic studies have shown that mutations in the trypsin-related genes such as cationic trypsinogen (PRSS1) gene and the serine protease inhibitor, Kazal type 1 (SPINK1) gene are associated with pancreatitis. In general, each of these factors appears to limit trypsin activation or enhance inactivation, and is believed to increase intrapancreatic trypsin activity and predispose to pancreatitis when the gene is mutated. These results have supported a concept that pancreatic protease/anti-protease plays pivotal roles in the pathogenesis of pancreatitis. In addition, genetic studies focusing on phenotypic variances would provide us with important information how genetic variants would affect the phenotypic variances. Autophagy is an intracellular bulk degradation system in which cytoplasmic components are directed to the lysosome/vacuole by a membrane-mediated process. Recent studies have highlighted a role of autophagy in acute pancreatitis. Using a conditional knockout mouse that lacks the autophagy-related (Atg) gene Atg5 in the pancreatic acinar cells, autophagy exerts a detrimental effect in pancreatic acinar cells by activation of trypsinogen to trypsin. A theory in which autophagy accelerates trypsinogen activation by lysosomal hydrolases under acidic conditions, thus triggering acute pancreatitis in its early stage. The epithelial-mesenchymal transition is a developmental process that allows a polarized epithelial cell to undergo multiple biochemical changes that enable it to assume a mesenchymal phenotype. The phenotype associated with epithelial-mesenchymal transition includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of extracellular matrix components. In addition to its role in development, tissue regeneration, and fibrosis, epithelial-mesenchymal transition is now considered as a critical process in cancer progression. Induction of epithelial-mesenchymal transition in cancer cells results in the acquisition of invasive and metastatic properties. Epithelial-mesenchymal transition could be an important mechanism in the progression of pancreatic cancer and its poor prognosis. Autoimmune pancreatitis is a unique form of pancreatitis in which autoimmune mechanisms are suspected to be involved in the pathogenesis. There is accumulating study to deal with this new disease concept. In addition to these topics, we have selected several topics in pancreatology, focusing on recent studies increasingly deepening our knowledge in both basic and clinical researches.

Trypsin --- Epithelial-Mesenchymal Transition --- Fibrosis --- Pancreatitis --- autoimmune pancreatitis --- Pancreatic Cancer --- Pancreatic Stellate Cells --- Cystic Fibrosis Transmembrane Conductance Regulator