A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Long-term monitoring of a large deep-seated landslide (La Clapiere, South-East French Alps): initial study

International audienceThe large-scale deformation of high mountain slopes finds its origin in many phenomena (inherent parameters, external stresses) with very different time constants (instantaneous to geological scale). Gravitational effect, tectonic forces and water infiltration are generally the principal causes of slope instability. However, it can be very difficult to distinguish which cause is dominant and which are their respective effects. To gain a better understanding of the complex processes taking place during the evolution of an unstable slope and separate the causes responsible of the landslide dynamic, an observational study based on geodetic, meteorological, seismological and electrical data has been performed on the La Clapière rockslide (Southern French Alps). This deep-seated landslide (DSL) is known for many years as one of the largest and fastest rock slide in Europe (60 million m3 of highly weathered metamorphic material, moving at 1 to 3 m year−1). The set-up of the “Observatoire Multidisciplinaire des Instabilités de Versants” (OMIV, http://omiv.osug.fr) in 2011 has allowed the production and availability of an important and original data set over several years of accurate monitoring. Thus, for the first time, the long-term study of geodetic data permitted us to highlight acceleration phases in the general movement of the landslide that affect its dynamic. These modifications are associated with variations of the velocity by a factor 3 to 6. The characterization of the origin of these variations was possible due to the comparison with meteorological, electrical and seismological data. Based on these various signals, we were able to establish correlations and contributions of meteorological water infiltration in the dynamic evolution of the La Clapière slope. We determine several response times to the meteorological stress for seismic endogenous events (mainly rockfalls), the resistivity of the ground (quasi-instantaneous) and the kinematics of the slope (from 2 weeks to 2.5 months). Moreover, our results strongly suggest the existence of rainfall threshold of 3.5 ± 1 mm day−1 from which the number of seismic endogenous events is highly increased