Insulino-mimetic and anti-diabetic effects of zinc

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Role of receptor and non-receptor protein tyrosine kinases in vasoactive peptide-induced signaling

L'endothéline-1 (ET-1) et l'angiotensine II (Ang II) jouent un rôle important dans le maintien de la pression artérielle et l'homéostasie vasculaire. Une activité accrue de ces peptides vasoactifs est présumée contribuer au développement de pathologies vasculaires, telles que l'hypertension, l'athérosclérose, l'hypertrophie et la resténose. Ceci est causé par une activation excessive de plusieurs voies de signalisation hypertrophiques et prolifératives, qui incluent des membres de la famille des Mitogen Activated Protein Kinases (MAPK), ainsi que la famille phosphatidylinositol 3-kinase (PI3-K) / protéine kinase B (PKB). Bien que l'activation de ces voies de signalisation soit bien élucidée, les éléments en amont responsables de l'activation des MAPK et de la PKB, induite par l'ET-1 et Ang II, demeurent mal compris. Durant les dernières années, le concept de la transactivation de récepteurs et/ou non-récepteurs protéines tyrosine kinases (PTK) dans le déclenchement des événements de signalisation induits par les peptides vasoactifs a gagné beaucoup de reconnaissance. Nous avons récemment démontré que la PTK Insulin-like Growth Factor type-1 Receptor (IGF-1R) joue un rôle dans la transduction des signaux induits par l‟H2O2, menant à la phosphorylation de la PKB. Étant donné que les peptides vasoactifs génèrent des espèces réactives d'oxygène, telles que l‟H2O2 lors de leur signalisation, nous avons examiné le rôle de d‟IGF-1R dans la phosphorylation de la PKB et les réponses hypertrophiques dans les cellules muscle lisse vasculaires (CMLV) induites par l'ET-1 et Ang II. AG-1024, un inhibiteur spécifique de l'IGF-1R, a atténué la phosphorylation de la PKB induite à la fois par l'ET-1 et Ang II. Le traitement des CMLVs avec l‟ET-1 et Ang II a également induit une phosphorylation des résidus tyrosine dans les sites d'autophosphorylation d'IGF-1R, celle-ci a été bloquée par l‟AG-1024. En outre, l‟ET-1 et l‟Ang II on tous les deux provoqué la phosphorylation de c-Src, une PTK non-récepteur, bloqué par PP-2, inhibiteur spécifique de la famille Src. La PP-2 a également inhibé la phosphorylation de PKB et d‟IGF-1R induite par l‟ET-1 et l‟Ang II. De plus, la synthèse de protéines ainsi que d‟ADN, marqueurs de la prolifération cellulaire et de l'hypertrophie, ont également été atténuée par l‟AG-1024 et le PP-2. Bien que ce travail démontre le rôle de c-Src dans la phosphorylation PKB induite par l'ET-1 et Ang II, son rôle dans l'activation des MAPK induit par l'ET-1 dans les CMLVs reste controversé. Par conséquent, nous avons examiné l'implication de c-Src dans l'activation de ERK 1/2, JNK et p38MAPK, par l'ET-1 et Ang II, ainsi que leur capacité à régulariser l'expression du facteur de transcription Early growth transcription factor-1 « Egr-1 ». ET-1 et Ang II ont induit la phosphorylation de ERK 1/2, JNK et p38 MAPK, et ont amplifié l'expression d'Egr-1 dans les CMLVs. Cette augmentation de la phosphorylation des MAPK a été diminuée par la PP-2, qui a aussi atténué l'expression d'Egr-1 induite par l'ET-1 et l'Ang II. Une preuve supplémentaire du rôle de c-Src dans ce processus a été obtenue en utilisant des fibroblastes embryonnaires de souris déficientes en c-Src (Src -/- MEF). L'expression d'Egr-1, ainsi que l'activation des trois MAPKs par l'ET-1 ont été atténuées dans les cellules Src -/- par rapport au MEF exprimant des taux normaux Src. En résumé, ces données suggèrent que l'IGF-1R et c-Src PTK jouent un rôle essentiel dans la régulation de la phosphorylation de PKB et des MAPK dans l‟expression d'Egr-1, ainsi que dans les réponses hypertrophiques et prolifératives induites par l'ET-1 et Ang II dans les CMLVs.Endothelin-1 (ET-1) and angiotensin II (Ang II) play important roles in maintaining blood pressure and vascular homeostasis, and a heightened activity of these vasoactive peptides is thought to contribute to the development of vascular pathologies, such as hypertension, atherosclerosis, hypertrophy and restenosis. This is caused by an excessive activation of several growth and proliferative signaling pathways, which include members of the mitogen-activated protein kinase (MAPK) family, as well as the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway. While the activation of these signaling pathways is well elucidated, the upstream elements responsible for ET-1 and Ang II-induced MAPK and PI3-K/PKB activation remain poorly understood. During the last several years, the concept of transactivation of receptor and/or non-receptor protein tyrosine kinases (PTK) in triggering vasoactive peptide-induced signaling events has gained much recognition. We have recently demonstrated that insulin-like growth factor-1 receptor (IGF-1R) plays a role in tranducing the effect of H2O2, leading to PKB phosphorylation. Since vasoactive peptides elicit their responses through generation of reactive oxygen species, including H2O2, we investigated whether IGF-1R transactivation plays a similar role in ET-1 and Ang II-induced PKB phosphorylation and hypertrophic responses in VSMC. AG-1024, a specific inhibitor of IGF-1R, attenuated both ET-1 and Ang II-induced PKB phosphorylation in a dose-dependent manner. ET-1 and Ang II treatment also induced the phosphorylation of tyrosine residues in the autophosphorylation sites of IGF-1R, which was blocked by AG-1024. In addition, both ET-1 and Ang II evoked tyrosine phosphorylation of c-Src, a non-receptor PTK, and pharmacological inhibition of c-Src PTK activity by PP-2, a specific inhibitor of Src-family tyrosine kinase, significantly reduced PKB phosphorylation as well as tyrosine phosphorylation of IGF-1R induced by the two vasoactive peptides. Furthermore, protein and DNA synthesis, markers of cell growth and proliferation, enhanced by ET-1 and Ang II were also attenuated by AG-1024 and PP-2. While this work demonstrates the role of c-Src in ET-1 and Ang II-induced PKB phosphorylation, its role in ET-1-induced MAPK signaling and regulation of transcription factors, such as early growth response factor-1 (Egr-1), which was recently shown to be expressed in atherosclerotic plaque, remains controversial in VSMC. Therefore, we have also investigated the involvement of c-Src in ET-1 and Ang II-induced ERK 1/2, JNK and p38mapk activation, as well as Egr-1 regulation. ET-1 and Ang II-induced the phosphorylation of ERK 1/2, JNK and p38mapk, and enhanced the expression of Egr-1 in aortic VSMC. This increased phosphorylation was decreased by PP-2. Further proof for the role of c-Src in this process was obtained by using mouse embryonic fibroblasts (MEF) deficient in c-Src (Src -/- MEF). ET-1-induced Egr-1 expression, as well as MAPK activation, were found to be downregulated in Src -/- MEF, as compared to MEF expressing normal Src levels. In summary, these data demonstrate that IGF-1R and c-Src PTK play a critical role in mediating both PKB and MAPK phosphorylation and Egr-1 expression, as well as hypertrophic and proliferative responses induced by ET-1 and Ang II in VSMC

Effects of zilpaterol hydrochloride and zinc methionine on growth performance and carcass characteristics of beef bulls

Sixty beef bulls with a body weight (BW) of 314.79 16.2 kg were used to evaluate the effects of zilpaterol hydrochloride (ZH) and zinc methionine (ZM) on growth performance and carcass characteristics. The experimental design was a randomized complete block, with a factorial 22 arrangement of treatments (ZH: 0 and 0.15 mg kg 1 BW; ZM: 0 and 80 mg kg 1 dry matter). The ZH increased (PB0.05) the final BW, average daily gain, feed conversion, carcass yield and longissimus dorsi area. Bulls fed ZH plus ZM had less (PB0.01) backfat thickness and intramuscular fat (IMF) compared with those fed ZH or ZM alone. The ZH increased (PB0.02) the meat crude protein content and cooking loss. It is therefore concluded that ZH increases growth performance, carcass yield, longissimus dorsi area, and meat crude protein. The interaction of ZM and ZH did not present additional advantages. The reason for the reduction in backfat thickness and IMF by ZH plus ZM is unclear, and implies that our knowledge of b-agonistic adrenergic substances and their interactions with minerals is incomplete

Trace elements in glucometabolic disorders: an update

Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed

Validation and Factoring of Prime Numbers

63 σ.Η παρούσα διπλωματική εργασία πραγματεύεται τη μελέτη αλγορίθμων πιστοποίησης και παραγοντοποίησης πρώτων αριθμών. Ξεκινώντας, το πρώτο κεφάλαιο περιλαμβάνει βασικά θεωρήματα και στοιχεία από τη θεωρία αριθμών όπως το Θεώρημα του Lucas, οι γραμμικές ισοδυναμίες, οι ισοδυναμίες δευτέρου βαθμού, τα τετραγωνικά υπόλοιπα και οι πρωταρχικές ρίζες. Εν συνεχεία, στο δεύτερο κεφάλαιο γίνεται παρουσίαση των βασικών αλγόριθμων που χρησιμοποιούνται για την πιστοποίηση πρώτων. Γίνεται αναφορά στο κόσκινο του Ερατοσθένη και στο κριτήριο του Fermat. Επίσης, αναλύονται τα κριτήρια Miller - Rabin και Solovay-Strassen. Το τρίτο κεφάλαιο αφορά την παραγοντοποίηση ακεραίων. Παρατίθενται συνοπτικά η μέθοδος των διαδοχικών διαιρέσεων, η μέθοδος του Fermat και η μέθοδος του Euler, ενώ αναπτύσσονται ο αλγόριθμος p-1 του John Pollard (1974) και ο αλγόριθμος Pollard Rho.This thesis deals with the study of certification and factorization algorithms of prime numbers. The first chapter includes basic theorems from the theory of numbers such as theorem Lucas, linear equations, the equivalence quadratic, the quadratic residues and primary roots. Subsequently, in the second chapter we present the basic algorithms used for certification first. The sieve of Eratosthenes is mentioned as well as and the criterion of Fermat. Also the criteria Miller - Rabin and Solovay-Strassen are included. The third chapter covers the integer factorization. Initially, the method of successive divisions is mentioned, Fermat's method and the method of Euler. Finally the thesis is concluded with the analysis of the p-1 algorithm of John Pollard (1974) and the algorithm Pollard Rho.Χρήστος Ν. Βαρδάτσικο

IGF-1 induces expression of zinc-finger protein 143 in colon cancer cells through phosphatidylinositide 3-kinase and reactive oxygen species

Expression of zinc-finger protein 143 (ZNF143), a human homolog of the Xenopus transcriptional activator protein Staf, is induced by various DNA-damaging agents including etoposide, doxorubicin, and γ-irradiation. ZNF143 binds to cisplatin-modified DNA, and its levels are increased in cancer cells that are resistant to anticancer drugs, including cisplatin, suggesting that it plays a role in carcinogenesis and cancer cell survival. However, the mechanism of ZNF143 induction in cancer cells remains unclear. Both insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) have been reported to be overexpressed in cancer cells and to be related to anticancer drug resistance, but the identity of the relevant signaling mediators is still being investigated. In the present study, we observed that IGF-1 was able to induce ZNF143 expression in HCT116 human colon cancer cells and that wortmannin, an inhibitor of phosphatidylinositide 3-kinase (PI3-kinase), inhibited this induction, as did diphenyleneiodonium (DPI), an NADPH oxidase inhibitor, and monodansylcardavarine (MDC), a receptor internalization inhibitor. Treatment with MDC decreased the IGF-1-stimulated generation of reactive oxygen species. Taken together, these data suggest that IGF-1 induces ZNF143 expression in cancer cells via PI3-kinase and reactive oxygen species generation during receptor internalization