Structure-activity relationships on cynnamoyl derivatives as inhibitors of p300 Histone acetyltransferase

Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors. Our cinnamoyl derivative, RC 56, was identified as active and selective p300 inhibitor, proving to be a good hit candidate to investigate the structure-activity relationship towards p300. Herein we describe the design, synthesis and biological evaluation of new HATi structurally related to our hit, investigating, moreover, the interactions between p300 and the best-emerged hits by means of induced fit docking and molecular dynamics simulations, gaining insight on the peculiar chemical features that influenced their activity toward the targeted enzyme

Réduction de la Consommation Electrique du Contrôle-Commande des Machines Automatisées

This thesis presents an analysis of energy consumption of control systems of automated machines. The main objective is to reduce energy consumption of control part. In this document, we present notions related with control systems and we develop methods and an energy consumption simulator which is an analysis tool of energy consumption. Thus, we make an analysis according 3 axes: energy consumption of each control part, consumption of control systems according to choice of components and consumption according to operating modes. The results show that energy consumption of control systems is often low compared toCette thèse présente une analyse de la consommation d'énergie des systèmes de contrôlecommande électriques des machines automatisées en vue de réduire leur consommation d'énergie. Il est notamment présenté les notions associées aux systèmes de contrôle-commande et il est développé des méthodes et un simulateur de consommation d'énergie destiné à l'analyse de la consommation d'énergie. A partir de ceci, il est réalisé une analyse selon 3 axes : consommation des composants de contrôlecommande pris individuellement, consommation des systèmes de contrôle-commande selon le type de machine et l'assemblage des composants et enfin, consommation dans le temps selon les modes de marche. Ces travaux mettent en évidence que la consommation des systèmes de contrôle-commande est souvent faible comparée à celle des actionneurs, mais qu'il est tout de même possible de réduire d'un facteur 2 la consommation d'énergie

Réduction de la Consommation Electrique du Contrôle-Commande des Machines Automatisées

This thesis presents an analysis of energy consumption of control systems of automated machines. The main objective is to reduce energy consumption of control part. In this document, we present notions related with control systems and we develop methods and an energy consumption simulator which is an analysis tool of energy consumption. Thus, we make an analysis according 3 axes: energy consumption of each control part, consumption of control systems according to choice of components and consumption according to operating modes. The results show that energy consumption of control systems is often low compared toCette thèse présente une analyse de la consommation d'énergie des systèmes de contrôlecommande électriques des machines automatisées en vue de réduire leur consommation d'énergie. Il est notamment présenté les notions associées aux systèmes de contrôle-commande et il est développé des méthodes et un simulateur de consommation d'énergie destiné à l'analyse de la consommation d'énergie. A partir de ceci, il est réalisé une analyse selon 3 axes : consommation des composants de contrôlecommande pris individuellement, consommation des systèmes de contrôle-commande selon le type de machine et l'assemblage des composants et enfin, consommation dans le temps selon les modes de marche. Ces travaux mettent en évidence que la consommation des systèmes de contrôle-commande est souvent faible comparée à celle des actionneurs, mais qu'il est tout de même possible de réduire d'un facteur 2 la consommation d'énergie

Détermination des effets mitochondriaux de la curcumine et de quelques dérivés (proposition d'un mécanisme d'action impliquant le pore de transition de perméabilité)

La mitochondrie joue un rôle clé dans la production des radicaux libres oxygénés (RLO) et dans le processus apoptotique. La première partie de ce travail a consisté à étudier les effets mitochondriaux de la curcumine et a révélé qu'elle réduisait les productions de RLO et induisait l'ouverture du pore de transition de perméabilité (PTP). Pour comprendre son mécanisme d'action, notre travail a, ensuite, consisté à tester les effets mitochondriaux de 22 dérivés de la curcumine obtenus par substitution de certaines fonctions chimiques. Cette étude révéla que la curcumine et certains dérivés induisaient l'ouverture du PTP en réduisant l'ion Fe entraînant la production du radical H0 qui oxyde certaines protéines membranaires au niveau de leurs fonctions thiols. D'autre part, cette propriété semble conférée par le groupe phénol associé au groupe méthoxy en ortho. Enfin, cette étude a mis en évidence des molécules fortement anti-oxydantes et d'autres potentiellement anti-cancéreuses.Mitochondria play an important role in free radical oxygen species (ROS) generation and in apoptotic process. The first part of tins work was the study of the mitochondrial effects of curcumin: it decreased ROS productions and induced permeability transition pore (PTP) opening. To understand its mechanism of action, we study, in the second part of this work, the mitochondrial effects of 22 curcumin-derivatives obtained after chemical substitutions. We showed that curcuniin and some derivatives iriduced Fe reduction leading to H0 generation. Then, tins radical promoted membrane thiol groups oxidation leading to PTP opening. The cheniical functions that are needed to promote PTP opening were the hydroxy and the methoxy groups located at the phenolic cycle. Furthermore, this study indicated that some curcumin-derivatives, like curcumin, could constitute a pool of antitumoral compounds whereas other compounds could be protective agents during oxidant stress.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Analysis and savings of energy consumed by production cell control

International audienc

Phenylephrine postconditioning increases myocardial injury: Are alpha-1 sympathomimetic agonist cardioprotective?

Objective: We studied effects of phenylephrine (PHE) on postischemic functional recovery and myocardial injury in an ischemia-reperfusion (I-R) experimental model. Materials and Methods: Rat hearts were Langendorff-perfused and subjected to 30 min zero-flow ischemia (I) and 60 min reperfusion (R). During R PHE was added at doses of 1 μM (n = 10) and 50 μM (n = 12). Hearts (n = 14) subjected to 30 and 60 min of I-R served as controls. Contractile function was assessed by left ventricular developed pressure (LVDP) and the rate of increase and decrease of LVDP; apoptosis by fluorescent imaging targeting activated caspase-3, while myocardial injury by lactate dehydrogenase (LDH) released during R. Activation of kinases was measured at 5, 15, and 60 min of R using western blotting. Results: PHE did not improve postischemic contractile function. PHE increased LDH release (IU/g); 102 ± 10.4 (Mean ± standard error of mean) control versus 148 ± 14.8 PHE (1), and 145.3 ± 11 PHE (50) hearts, (P < 0.05). PHE markedly increased apoptosis. Molecular analysis showed no effect of PHE on the activation of proapoptotic c-Jun N-terminal kinase signaling; a differential pattern of p38 mitogen activated protein kinase (MAPK) activation was found depending on the PHE dose used. With 1 μM PHE, p-p38/total-p38 MAPK levels at R were markedly increased, indicating its detrimental effect. With PHE 50 μM, no further changes in p38 MAPK were seen. Activation of Akt kinase was decreased implying involvement of different mechanisms in this response. Conclusions: PHE administration during reperfusion does not improve postischemic recovery due to exacerbation of myocardial necrosis and apoptosis. This finding may be of clinical and therapeutic relevance

Predictive functional control of an expansion valve for minimizing the superheat of an evaporator

International audienceIn a previous paper, a Predictive Functional Control (PFC) method was proposed to control the evaporator superheat with an electronic expansion valve. it has been shown that superheat may be more accurately controlled by PFC than the conventional Proportional-Integral-Derivative (PID) control. In this paper, the proposed methodology is extended to regulate the condensing pressure. In order to study the influence of this control method on the Coefficient of Performance (COP), experiments are conducted on a refrigerating machine by changing the cooling capacity from 120 to 30 kW. As PFC improves disturbance rejection compared to a PID control, it is possible to reduce the Superheat Setting Value and to prevent any unevaporated refrigerant liquid from reaching the compressor. As a consequence the use of PFC leads to an increase of COP which depends on operating conditions

Economies d'énergie grâce au contrôle par commandes avancées sur groupes de production d'eau glacée à compresseurs à pistons

National audienc