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La question posée durant mon mémoire de master trouve son origine dans le travail de thèse de doctorat d'Anne-Christine Hick réalisé dans le laboratoire d'accueil. En étudiant, in vitro et in vivo, l'organogenèse de la thyroïde chez la souris, elle a montré que l'organisation tridimensionnelle des thyrocytes en follicules clos et entourés de vaisseaux sanguins, organisation essentielle à la fonction endocrine de la thyroïde, dépend d'une prod uction forte et soutenue de VEG FA par les progéniteurs des thyrocytes au cours du développement embryonnaire.Le but de mon travail a été de découvrir par quel mécanisme les progéniteurs des thyrocytes sécrètent tant de VEGFA, messager essentiel et déclencheur pour Je recrutement des cellules endothéliales et la formation des unités angio-folliculaires. Nous avons d'abord détecté par hybridation in situ la présence de VEGFA dans l'ébauche de la thyroïde dès E.12.5, bien avant la formation des unités angio-folliculaires . Nous avons ensuite testé l'implication du facteur de transcription HIFla, un régulateur positif puissant de la transcription de VEGFA, dans ce processus. Dans un premier temps, une combinaison de techniques standard a démontré la transcription et la traduction de HIFla dans les progéniteurs des thyrocytes. Dans un deuxième temps, en stabilisant HIFla dans des cultures d'ébauches de thyroïdes, nous avons observé une stimulation dose- et temps-dépendante de la transcription du gène Vegfa. Cet effet, détecté dès 14h de culture, s'accompagne d'une réponse angiogénique mise en évidence par augmentation de l'expression de marqueurs endothéliaux et de la densité des cellules endothéliales autour des lobes thyroïdiens. En outre, la stabilisation de HIFla dans les explants thyroïdiens entraine une stimulation de l'expression de quatre autres de ses gènes-cibles. Parmi ceux-ci, deux codent pour des régulateurs connus de la dégradation de HIFla, et assurent ainsi une boucle de rétrocontrôle négative.Ces résultats indiquent que l'ébauche thyroïdienne est équipée pour contrôler l'activité du facteur de transcription HIFla et que la stabilisation de ce dernier en culture stimule l'angiogenèse via l'expression de VEGFA. Ces données suggèrent donc que HIFla est un bon candidat pour initier la formation des unités angio-folliculaires in vivo. The question we addressed in this work finds its origin in the PhD thesis of Anne­ Christine Hick in the hast laboratory. Studying mouse thyroid organogenesis, using in vitro and in vivo approaches, she found that the 3D organisation of thyrocytes into closed follicles surrounded by blood vessels, essential for the endocrine function of the thyroid, depends on a strong and long-lasting prod uction of VEGFa by thyrocytes progenitors during embryonic development.The aim of my work was to elucidate the mechanism by which thyrocytes progenitors produce so much VEGFa, an essential and triggeri ng signal for the recruitment of endothelial cells and the formation of angio-folliculars units. We first demonstrated by in situ hybridization that Vefga expression was found in the thyroid primordium at E.12,5, well before the formation of the angio-folliculars units. We then assessed the implication of the transcription factor HIFla, a major and powerful positive regulator of Vegfa gene transcription in various biological systems. Usfog a combination of standard techniques; we detected the presence of HIFla in thyrocytes progenitors, at the mRNA and protein levels. Stabilization of HIFla in an ex vivo culture system of the thyroid primordium, led to a time- and dose-dependent stimulation of Vegfa transcription. This stimulation, detected as early as 14 hours of culture, is followed by an angiogenic response as evidenced by an increased expression of angiogenic-marker and of the endothelial cell density around the developing thyroid lobes. Furthermore, HIFla stabilization led to a stimulation of four other well-known HIFla target genes, among which two coding for proteins involved in HIFla degradation and thereby ensuring a negative feedback loop.These results indicate that developi ng thyroid primordium is equipped to control HIFla transcription factor activity, and that HIFla stabilisation in thyroid culture stimulates angiogenesis via the expression of VEGFA.These data suggest that HIFla is a good candidate to initiate the formation of angio-folliculars unit in vivo.

Hypoxia-Inducible Factor-Proline Dioxygenases --- Thyroid Gland

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Insulin-secreting pancreatic β-cells play an important role in blood glucose homeostasis. Theirs function, survival and gene expression are markedly altered by prolonged exposure to high glucose concentrations. We previously showed that the mRNA levels of a large number of pancreatic islet genes increase between 5 and 30mM glucose (G5-G30), with z predominant effect between G10 and G30. The genes, which could be implicated in β-cell glucotoxicity, include most glycolytic enzymes and other genes typically induced by the transcription factor Hypoxia Inducible Factor 1 (HIF-1), such as adrenomedullin and ORP-150.
To test the role of HIF-1 in the alterations of the β-cell phenotype by high glucose concentrations, I compared the effects of hypoxia (1% O2 for 6-18h), CoCl2 (a pharmacological activator of HIF-1) and increasing glucose concentrations on the expression of gene mRNA levels (RT-PCR) in cultured rat islets. The result show that G30, CoCl2 and hypoxia similarly induce islet gen mRNA levels of various HIF-1 target genes. In contrast, other genes with a similar expression profile in response to glucose were not induced by CoCl2 nor hypoxia (VDUP-1, aldolase B). To test the role of HIF-1 (α et β) in these changes in islet gene expression, I measured the protein levels of the transcription factor and its nuclear translocation in INS-1 cells treated with CoCl2 or high glucose concentrations Les cellules β pancréatiques sécrètent l’insuline qui joue un rôle important dans l’homéostasie glucidique. L’exposition prolongée à des concentrations élevées de glucose altère la fonction, la survie et l’expression de gènes dans ces cellules. Notre laboratoire a mis en évidence un groupe de gènes dont l’expression (ARNm) augmente entre 5 et 30 mM de glucose (G5-G30) avec un effet prédominant entre G10 et G30. Ces gènes pourraient être impliqués dans ces phénomènes de la glucotoxicité. Parmi ces gènes, on retrouve des nombreux enzymes de la glycolyse et d’autres cibles du facteur de transcription Hypoxia Inductible Factor-1 (HIF-1), tels l’adrénomédulline et ORP-150.
Afin d’étudier le rôle de HIF-1 dans l’altération du phénotype des cellules β par les concentrations élevées de glucose, j’ai comparé l’effet de l’hypoxie (1% O2 pendant 6-18h), du CoCl2 (activateur pharmacologique d’HIF-1) et de concentrations croissantes de glucose sur l’expression de gènes cible de HIF-1 (PCR en temps réel) dans des îlots de rat cultivés. Les résultats montrent que l’expression de ces gènes est augmentée de façon comparable après culture en présence de G30, de 10-30 µM de CoCl2 ou en condition hypoxique par rapport aux îlots contrôles cultivés en G5. Par contre, d’autres gènes qui présentent le même profil d’expression en réponse au glucose mais qui ne sont pas cibles d’HIF-1 (VDUP-1n aldolase B) ne sont pas induits par le CoCL2 ni par l’hypoxie.
Afin de déterminer le rôle du facteur de transcription HIF-1 (α et β) dans ces modifications d’expression, j’ai étudié l’expression protéique de ce facteur ainsi que sa translocation nucléaire dans des cellules insulino-sécrétrices INS-1 stimulées par le CoCl2 ou des concentrations élevées de glucose

Gene Expression --- Glycolysis --- Islets of Langerhans --- Rats --- Insulin --- Diabetes Mellitus --- Hypoxia-Inducible Factor-1 --- Multigene Family

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This book will cover topics related to the preparation and use of heterogeneous catalytic systems for the transformation of renewable sources, as well as of materials deriving from agro-industrial wastes and by-products. At the same time, the ever-increasing importance of bioproducts, due to the acceptance and request of consumers, makes the upgrade of biomass into chemicals and materials not only an environmental issue, but also an economical advantage.

isoselenourea --- malignant --- chemotherapeutics --- epigenetics --- antitumor activity --- methylseleninic acid --- mTOR inhibitors --- tumor heterogeneity --- hypoxia --- ER stress --- melanoma --- EMT --- lipid peroxidation --- immune evasion --- hypoxia-inducible factors (HIFs) --- selenium-binding protein 1 --- glutathione --- DNA damage --- hSP56 --- apoptosis --- tocopherol --- anticancer --- viability --- SELENBP1 --- selenium --- clear-cell renal cell carcinoma microRNAs --- SBP1 --- entosis --- PD-L1 --- miRNA --- cancer stem cells --- cell plasticity --- disease --- clear cell renal cell carcinoma --- HIF --- head and neck cancer --- selenium species --- VEGF --- STAT3 --- hypoxia-inducible factor --- methylselenocysteine --- anticancer agent --- Se-containing nanoparticles --- DNA damage and repair --- radiation --- seleno-l-methionine --- cancer --- tumor microenvironment --- methylselenoesters

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MicroRNAs (miRs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression and have important roles in almost all biological pathways. Deregulated miR expression has been detected in numerous cancers, where miRs act as both oncogene and tumor suppressors. Due to their important roles in tumorigenesis, miRs have been investigated as prognostic and diagnostic biomarkers and as useful targets for therapeutic intervention. From a therapeutic point of view, two modalities can serve to rectify gene networks in cancer cells. For oncomiRs, a rational means is downregulation through antagomirs. Moreover, observations of the pathological reductions in tumor-suppressive miRs have inspired the concept of “miR replacement therapy” to enhance the amount of these miRs, thereby restoring them to normal levels. However, the clinical applicability of miR-based therapies is severely limited by the lack of effective delivery systems. Therefore, to understand the role of this new class of regulators, we need to identify the mRNA targets regulated by individual miRs as well as to develop specific, efficient, and safe delivery systems for therapeutic miRs.

Research & information: general --- Biology, life sciences --- Breast cancer --- Hypoxia inducible factor 1-alpha (HIF-1α) --- MicroRNA (miRNA) --- miR526b --- miR655 --- Oxidative stress --- Migration --- Cyclooxygenase-2 (COX-2) --- Prostaglandin E2 receptor 4 (EP4) --- PI3K/Akt --- adipokines --- endometrial cancer --- estrogens --- hyperinsulinemia --- insulin --- insulin resistance --- insulin signaling --- insulin-like growth factors --- microRNA --- miRNA --- ovarian cancer --- survival --- prognostic factor --- serum LDH --- blood biomarker --- circulating microRNA --- plasma --- immunotherapy --- immune checkpoint inhibitors --- metastatic melanoma --- hepatocellular carcinoma --- metastasis --- exosome --- bioinformatics analysis --- renal cancer --- RCC --- ccRCC --- meta-analysis --- miRNAs --- normal B-cell development --- B-CLL --- miRNA-transcription factor network --- regulation --- biomarker --- therapy --- prognosis --- diagnosis --- progression --- prediction --- smoking --- non-small cell lung cancer --- methylation --- miR-584-5p --- YKT6 --- snoRNA --- 2′-O-methylation --- pseudouridylation --- malignant melanoma --- cancer stem cell --- stemness --- head and neck squamous cell carcinoma --- colon cancer --- cancer stem cells --- microRNAs --- deformability --- PARP --- replication stress --- targeted therapy --- breast cancer --- circulating biomarkers --- medulloblastoma --- brain tumour --- subgroups --- stem cells --- n/a --- 2'-O-methylation

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Acute kidney injury (AKI) is still associated with high morbidity and mortality incidence rates, and also bears an elevated risk of chronic kidney disease in the sequel. Whereas the kidney has a remarkable capacity for regeneration after injury and may recover completely depending on the type of renal lesions, the options for clinical intervention are restricted to fluid management and extracorporeal kidney support. The development of novel therapies to prevent AKI, to improve renal regeneration capacity after AKI, and to preserve renal function—in both the short- and long-term—is urgently needed. This Special Issue includes papers investigating the pathological mechanisms of renal inflammation and AKI and diagnostics using new biomarkers. Furthermore, experimental in vitro and in vivo studies examining potential new approaches to attenuate kidney dysfunction are included, as well as review articles.

inflammation --- chronic kidney disease --- anemia --- anemia of inflammation --- ESA hyporesponsiveness --- renal tubular epithelial cells --- macrophages --- lipocalin-2 --- iron --- cilastatin --- hypoxia inducible factor-1-α --- ischemia-reperfusion injury --- acute kidney injury --- cyclophilin A --- fibrosis --- renal fibrosis --- tubular necrosis --- preeclampsia --- podocytes --- VEGF --- FSGS --- proteinuria --- endocan --- ESM-1 --- renal replacement therapy --- kidney transplantation --- biomarker --- diabetic nephropathy --- focal segmental glomerulosclerosis --- innate immunity --- membranous nephropathy --- minimal change diseases --- TLR --- NOX1 --- ML171 --- reactive oxygen species --- ERK --- T cells --- glomerulonephritis --- chemokines --- renal disease --- DJ-1 --- ND-13 --- renal inflammation --- oxidative stress --- UUO --- autophagy --- apoptosis --- trehalose --- simvastatin --- endotoxin --- tubular apoptosis --- cytochrome C --- Bcl-XL --- survivin --- hypercholesterolemia --- xanthine oxidase --- NF-κB pathway --- tertiary lymphoid organs --- B cells --- BAFF --- kidney fibrosis --- myofibroblast activation --- extracellular matrix --- Hippo pathway --- verteporfin --- IgAN --- CKD --- progression --- ACEI --- corticosteroids --- costimulation --- coinhibition --- kidney transplant --- SPR --- protein binding affinity --- adaptive immunity --- epithelial-to-mesenchymal transition --- E. cava extracts --- dieckol --- spontaneously hypertensive rats --- angiotensin II --- n/a