Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs?

The management of premature birth still remains unsatisfactory. Since the relative lack of efficiency and/or safety of current tocolytic agents have been highlighted, it is necessary to develop new uterorelaxant drugs deprived of important maternal and foetal side effects. Our work reported in this review focuses on a potential new target for tocolytic drugs, the β3-adrenoceptor (ADRB3). This third type of ADRB is shown to be present and functional in human myometrium. We demonstrated that ADRB3 agonists are able to inhibit in-vitro spontaneous contractions of myometrial strips, via a cyclic AMP-mediated pathway. Furthermore, we established that ADRB3 is the predominant subtype over the ADRB2 in human myometrium and that its expression is increased in near-term myometrium, compared to non-pregnant myometrium. Finally, we reported that contrary to ADRB2, the human myometrial ADRB3 is resistant to long-term agonist-induced desensitisation. These compelling data confirm the clinical potential interest of ADRB3 agonists in the pharmacological management of preterm labour

Optimization of vacuum coating conditions to improve oil retention in trout feed

This work describes a process approach to study the oil leakage phenomenon in feeds for large Trout. Using a pilot vacuum coater, four experimental coating parameters were studied (stirring speed, pressure, filling rate, and time needed to restore atmospheric pressure) through an experimental design. The properties measured on the coated pellets were the oil leakage rate and three other important usage properties, i.e. durability, hardness, and floatability. The coating conditions had a significant influence on oil leakage rate, varying at 40 °C from 2.7 % to 1.2 % depending on the coating conditions used. Finally, the vacuum level was the most effective factor in reducing leakage. Indeed, a progressive reduction in oil leakage rate was observed as the pressure inside the coater was reduced during coating

Biphasic effect of extracellular ATP on human and rat airways is due to multiple P2 purinoceptor activation

BACKGROUND: Extracellular ATP may modulate airway responsiveness. Studies on ATP-induced contraction and [Ca(2+)](i )signalling in airway smooth muscle are rather controversial and discrepancies exist regarding both ATP effects and signalling pathways. We compared the effect of extracellular ATP on rat trachea and extrapulmonary bronchi (EPB) and both human and rat intrapulmonary bronchi (IPB), and investigated the implicated signalling pathways. METHODS: Isometric contraction was measured on rat trachea, EPB and IPB isolated rings and human IPB isolated rings. [Ca(2+)](i )was monitored fluorimetrically using indo 1 in freshly isolated and cultured tracheal myocytes. Statistical comparisons were done with ANOVA or Student's t tests for quantitative variables and χ(2 )tests for qualitative variables. Results were considered significant at P < 0.05. RESULTS: In rat airways, extracellular ATP (10(-6)–10(-3 )M) induced an epithelium-independent and concentration-dependent contraction, which amplitude increased from trachea to IPB. The response was transient and returned to baseline within minutes. Similar responses were obtained with the non-hydrolysable ATP analogous ATP-γ-S. Successive stimulations at 15 min-intervals decreased the contractile response. In human IPB, the contraction was similar to that of rat IPB but the time needed for the return to baseline was longer. In isolated myocytes, ATP induced a concentration-dependent [Ca(2+)](i )response. The contractile response was not reduced by thapsigargin and RB2, a P2Y receptor inhibitor, except in rat and human IPB. By contrast, removal of external Ca(2+), external Na(+ )and treatment with D600 decreased the ATP-induced response. The contraction induced by α-β-methylene ATP, a P2X agonist, was similar to that induced by ATP, except in IPB where it was lower. Indomethacin and H-89, a PKA inhibitor, delayed the return to baseline in extrapulmonary airways. CONCLUSION: Extracellular ATP induces a transient contractile response in human and rat airways, mainly due to P2X receptors and extracellular Ca(2+ )influx in addition with, in IPB, P2Y receptors stimulation and Ca(2+ )release from intracellular Ca(2+ )stores. Extracellular Ca(2+ )influx occurs through L-type voltage-dependent channels activated by external Na(+ )entrance through P2X receptors. The transience of the response cannot be attributed to ATP degradation but to purinoceptor desensitization and, in extrapulmonary airways, prostaglandin-dependent PKA activation

Expression and function of human hemokinin-1 in human and guinea pig airways

<p>Abstract</p> <p>Background</p> <p>Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the <it>TAC4 </it>gene. <it>TAC4 </it>and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study.</p> <p>Methods</p> <p>RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages.</p> <p>Results</p> <p>In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK₁-and NK₂-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK₂-receptors, which blockade unmasked a NK₁-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK₁-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages.</p> <p>Conclusions</p> <p>We demonstrate endogenous expression of <it>TAC4 </it>in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.</p

Rôle des protéases et de leurs récepteurs dans les maladies inflammatoires chroniques des voies aériennes

Plusieurs protéases participent à la physiopathologie des maladies inflammatoires chroniques des bronches. Des cystéine-protéases des allergènes acariens augmentent la perméabilité para-cellulaire de l'épithélium des voies aériennes de rat. La modulation de la production macrophagique de MMP-9 et de son inhibiteur TIMP-1 par le tabac pourrait participer à la survenue d'un emphysème ou d'un remodelage bronchique. Les récepteurs activés par les protéases (PARs) sont impliqués dans l'inflammation et la réactivité bronchique. Le PAR-2 épithélial est surexprimé dans l'asthme, le PAR-1 macrophagique chez les fumeurs. La cathepsine G des neutrophiles pourrait protéger contre les effets de l'activation du PAR-1 monocytaire. Chez l'homme, le PAR-2 augmente la réactivité à l'histamine chez les non-fumeurs et la réduit chez les fumeurs, suggérant un équilibre entre les effets constricteurs du PAR-2 musculaire lisse et les effets protecteurs de prostanoïdes induits par les PAR-2 épithéliaux.Several proteases are involved in the pathophysiology of chronic inflammatory airway diseases. House dust mite cysteine-proteases increase the para-cellular epithelial permeability of rat airways. The modulation of macrophage release of MMP-9 and its inhibitor TIMP-1 by cigarette smoke could predispose to emphysema or bronchial remodelling. Protease-activated receptors play a role in bronchial inflammation and responsiveness. Epithelial PAR-2 is over-expressed in asthma, macrophage PAR-1 in smokers. Neutrophil cathepsin G may protect against monocyte PAR-1-related bronchoconstriction and inflammation. In human, PAR-2 increases bronchial reactivity to histamine in non-smokers and decreases it in smokers, suggesting a balance between constricting effects of smooth muscle PAR-2 and protecting effects of prostanoids released after activation of epithelial PAR-2.PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Le récepteur b3-adrénergique du muscle lisse utérin humain (une cible potentielle d'agents tocolytiques)

PARIS-BIUP (751062107) / SudocSudocFranceF

Résolution d'équations aux dérivées partielles par la méthode d'Adomian et application de nouvelles méthodes pour l'optimisation globale de fonctions multivariables

La thèse aborde deux méthodes : la méthode d'Adomian pour la résolution des équations aux dérivées partielles (E.D.P.) et la méthode Alienor pour la résolution des problèmes de contrôle. Dans la première partie, nous proposons trois méthodes permettant d'adapter la méthode d'Adomian aux E.D.P. en tenant compte de toutes les conditions (initiales et au bord). La deuxième partie aborde la méthode réductrice Alienor qui permet la résolution des problèmes d'optionisation globale. Nous avons proposé une nouvelle transformation réductrice et un nouvel opérateur qui préserve l'optionisation (O.P.O.). Ainsi, nous avons pu obtenir le minimum global de fonctions à plus de mille variables en instant très court. En guise d'application nous avons traité dans la troisième partie un problème de pharmacologie modélisant le transport d'un médicament anticancéreux administré dans le cerveau. Nous avons combiné la méthode d'Adomian et la méthode Alienor afin de déterminer la concentration optimale de médicament à administrer pour obtenir un résultat précis.In our thesis we are dealing with solving differential partial equation (P.D.E.) and optimal control, using the Adomian decomposition method and the Alienor method. The Adomian method is very effecient to solve ordinary differential equations, its application to partial differential equations still faces some difficulties. Three methods are proposed to avoid these difficulties. The second part of our thesis is devoted to the reducing Alienor method which is used to solve global optimization problems. We have proposed a new reducing transformation and a new operator that preserves the optimization (O.P.O.) and allows getting easily the global minimum of functions of one single variable....PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF