P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy

open access articleDuchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP–P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target

CONTRIBUTION A L'ETUDE DES MECANISMES DE REGULATION DE LA BIOSYNTHESE DES NEUROSTEROIDES (EFFETS DES ENDOZEPINES ET DU GABA)

ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Fabrication of Ge-ZnS multilayered optical filters for mid-infrared applications

International audienceGermanium/Zinc Sulphide (Ge/ZnS) single and multilayers are deposited by ion assisted electron beam deposition on Silicon substrates for applications in the 2-15 µm wavelength region. Refractive indices of Ge and ZnS thin films are extracted from measured reflectance and transmittance spectra. Several types of mid-infrared filters (high-, anti-reflection coatings and dichroic filters) with a number of layers ranging from 3 to 29 are then designed and deposited. The optical responses of fabricated mid-infrared filters show a good agreement between experimental spectra and simulation in the case of high- and anti-reflection coatings in the long-wave infrared but also for dichroic filters with a low transmittance in the mid-wave infrared and broadband bandpass in the long-wave infrared

Study of vertical multilayer structures based on Germanium and Zinc Sulphide films for mid-Infrared applications

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E-beam deposition of Germanium and Zinc Sulphide thin films and multilayered structures for mid-infrared applications

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Variable Optical Attenuator based on thermally tuned Mach-Zehnder Interferometer within a twin core fiber

International audienceA variable optical attenuator (VOA) based on a tunable Mach-Zehnder interferometer has been produced based on a twin core fiber design. Two achromatic 3 dB-couplers have been manufactured utilizing the fused-stretched technique between both cores of the fiber, in order to obtain a Mach-Zehnder interferometer. A metallic thin layer deposit on one arm of the interferometer allows thermal tuning of the Mach-Zehnder interferometer, which obtains the desired attenuation at the component output. We obtained a −0.5 to −24 dB attenuation-range VOA with an achromatic response from 1535 to 1560 nm

Optimization of bandpass optical filters based on TiO2 nanolayers

International audienceThe design and realization of high-quality bandpass optical filters are often very difficult tasks due to the strong correlation of the optical index of dielectric thin films to their final thickness, as observed in many industrial deposition processes. We report on the optimization of complex optical filters in the visible and NIR spectral ranges as realized by ion beam-assisted electron beam deposition of silica and titanium oxide multilayers. We show that this process always leads to amorphous films prior to thermal annealing. On the contrary, the optical dispersion of TiO2 nanolayers is highly dependent on their thickness, while this dependence vanishes for layers thicker than 100 nm. We demonstrate that accounting for this nonlinear dependence of the optical index is both very important and necessary in order to obtain high-quality optical filters

Effects of peripherally administered urotensin II and arginine vasotocin on the QT interval of the electrocardiogram in trout

International audienceThe QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In fish as in human, the QT interval is positively correlated with the RR interval of the ECG, a measure of the cardiac cycle length. Urotensin II (UII) is a neuropeptide that has been highly conserved from fish to human, and UII and its receptor (UT) are expressed in cardiovascular tissues including the heart. Although UII exerts potent cardiovascular actions, its possible effects on the QT interval have never been investigated. The goal of the present study was to provide insight into the potential effect of UII on the QT interval in an established in vivo trout model. To this end, the effects of UII on dorsal aortic blood pressure (PDA), RR, QT intervals and corrected QT (QTc) for RR interval, were investigated after intra-arterial (IA) injection of 5, 50 and 100 pmol UII. The effects of UII were compared to those of two structurally UII-related peptides (URPs), URP1 and URP2, and to those of arginine vasotocin (AVT), homolog of the mammalian arginine vasopressin. IA injection of vehicle or 5 pmol UII had no effect on the various parameters. At the 50-pmol dose, UII evoked its usual increase in PDA with a peak value observed 15 min after the injection (+22% from baseline, P<0.001). This hypertensive effect of UII was accompanied by a significant increase in the RR interval (+18%, P<0.001), i.e. a bradycardia, and these effects remained constant until the end of the recording. The highest dose of UII evoked similar hypertensive and bradycardic effects. Of interest, the QT interval did not change during the bradycardic action of UII (50 and 100 pmol) but the QTc interval significantly decreased. In trout pre-treated with urantide, a peptidic antagonist of UT, the hypertensive and bradycardic actions of 50 pmol UII were reduced 3-fold and no change occurred in the QT and QTc intervals. In trout pre-treated with blockers of the autonomic nervous system, the hypertensive effect of UII was maintained but no change appeared in RR, QT and QTc intervals. IA injections of 50 pmol URPs were without action on the preceding parameters. IA administration of 50 pmol AVT provoked quite similar increase in PDA, and elevation of the RR interval to those evoked by IA injection of UII but, in contrast to UII, AVT injection induced a highly significant and sustained prolongation of the QT interval compared to baseline (+7%, P<0.001) without change in QTc. Our results are indicative of a lack of QT interval change during UII-evoked bradycardia but not after AVT-induced bradycardia and suggest for the first time that some compensatory mechanism specific for the UII peptide is working to stabilize the QT interval. Further research is needed to elucidate the mechanism involved in this action of UII. The potential for UII to prevent detrimental prolongation of cardiac ventricular repolarization might be questioned

Central and Peripheral Effects of Urotensin II and Urotensin II-Related Peptides on Cardiac Baroreflex Sensitivity in Trout

International audienceThe baroreflex response is an essential component of the cardiovascular regulation that buffers abrupt changes in blood pressure to maintain homeostasis. Urotensin II (UII) and its receptor UT are present in the brain and in peripheral cardiovascular tissues of fish and mammals. Intracerebroventricular (ICV) injection of UII in these vertebrates provokes hypertension and tachycardia, suggesting that the cardio-inhibitory baroreflex response is impaired. Since nothing is known about the effect of UII on the cardiac baroreflex sensitivity (BRS), we decided to clarify the changes in spontaneous BRS using a cross spectral analysis technique of systolic blood pressure (SBP) and R-R interval variabilities after ICV and intra-arterial (IA) injections of trout UII in the unanesthetized trout. We contrasted the effects of UII with those observed for the UII-related peptides (URP), URP1 and URP2. Compared with vehicle-injected trout, ICV injection of UII (5-500 pmol) produced a gradual increase in SBP, a decrease in the R-R interval (reflecting a tachycardia) associated with a dose-dependent reduction of the BRS. The threshold dose for a significant effect on these parameters was 50 pmol (BRS; -55%; 1450 ± 165 ms/kPa vs. 3240 ± 300 ms/kPa; P < 0.05). Only the 500-pmol dose of URP2 caused a significant increase in SBP without changing significantly the R-R interval but reduced the BRS. IA injection of UII (5-500 pmol) caused a dose-dependent elevation of SBP. Contrasting with the ICV effects of UII, the R-R interval increased (reflecting a bradycardia) up to the 50-pmol dose while the BRS remained unchanged (50 pmol; 2530 ± 270 ms/kPa vs. 2600 ± 180 ms/kPa; P < 0.05). Nonetheless, the highest dose of UII reduced the BRS as did the highest dose of URP1. In conclusion, the contrasting effect of low picomolar doses of UII after central and peripheral injection on the BRS suggests that only the central urotensinergic system is involved in the attenuation of the BRS. The limited and quite divergent effects of URP1 and URP2 on the BRS, indicate that the action of UII is specific for this peptide. Further studies are required to elucidate the site(s) and mechanisms of action of UII on the baroreflex pathways. Whether such effects of central UII on the BRS exist in mammals including humans warrants further investigations

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function.

International audienceUrotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. Subsequently, UII was characterized in tetrapods including humans. Phylogenetic studies and synteny analysis indicate that UII and its paralogous peptide urotensin II-related peptide (URP) belong to the somatostatin/cortistatin superfamily. In mammals, the UII and URP genes are primarily expressed in cholinergic neurons of the brainstem and spinal cord. UII and URP mRNAs are also present in various organs notably in the cardiovascular, renal, and endocrine systems. UII and URP activate a common G protein-coupled receptor, called UT, that exhibits relatively high sequence identity with somatostatin, opioid, and galanin receptors. The UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including the retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle. Structure-activity relationship studies and NMR conformational analysis have led to the rational design of a number of peptidic and nonpeptidic UT agonists and antagonists. Consistent with the wide distribution of UT, UII has now been shown to exert a large array of biologic activities, in particular in the CNS, the cardiovascular system, and the kidney. Here, we review the current knowledge concerning the pleiotropic actions of UII and discusses the possible use of antagonists for future therapeutic applications