The challenge to verify ceramide's role of apoptosis induction in human cardiomyocytes - a pilot study

<p>Abstract</p> <p>Background</p> <p>Cardioplegia and reperfusion of the myocardium may be associated with cardiomyocyte apoptosis and subsequent myocardial injury. In order to establish a pharmacological strategy for the prevention of these events, this study aimed to verify the reliability of our human cardiac model and to evaluate the pro-apoptotic properties of the sphingolipid second messenger ceramide and the anti-apoptotic properties of the acid sphingomyelinase inhibitor amitryptiline during simulated cardioplegia and reperfusion ex vivo.</p> <p>Methods</p> <p>Cardiac biopsies were retrieved from the right auricle of patients undergoing elective CABG before induction of cardiopulmonary bypass. Biopsies were exposed to <it>ex vivo </it>conditions of varying periods of cp/rep (30/10, 60/20, 120/40 min). Groups: I (untreated control, n = 10), II (treated control cp/rep, n = 10), III (cp/rep + ceramide, n = 10), IV (cp/rep + amitryptiline, n = 10) and V (cp/rep + ceramide + amitryptiline, n = 10). For detection of apoptosis anti-activated-caspase-3 and PARP-1 cleavage immunostaining were employed.</p> <p>Results</p> <p>In group I the percentage of apoptotic cardiomyocytes was significantly (p < 0.05) low if compared to group II revealing a time-dependent increase. In group III ceramid increased and in group IV amitryptiline inhibited apoptosis significantly (p < 0.05). In contrast in group V, under the influence of ceramide and amitryptiline the induction of apoptosis was partially suppressed.</p> <p>Conclusion</p> <p>Ceramid induces and amitryptiline suppresses apoptosis significantly in our ex vivo setting. This finding warrants further studies aiming to evaluate potential beneficial effects of selective inhibition of apoptosis inducing mediators on the suppression of ischemia/reperfusion injury in clinical settings.</p

How curvature-generating proteins build scaffolds on membrane nanotubes

International audienceBin/Amphiphysin/Rvs (BAR) domain proteins control the curvature of lipid membranes in endocytosis, trafficking, cell motility, the formation of complex subcellular structures, and many other cellular phenomena. They form 3D assemblies that act as molecular scaffolds to reshape the membrane and alter its mechanical properties. It is unknown, however, how a protein scaffold forms and how BAR domains interact in these assemblies at protein densities relevant for a cell. In this work, we use various experimental, theoretical, and simulation approaches to explore how BAR proteins organize to form a scaffold on a membrane nanotube. By combining quantitative microscopy with analytical modeling, we demonstrate that a highly curving BAR protein endophilin nucleates its scaffolds at the ends of a membrane tube, contrary to a weaker curving protein centaurin, which binds evenly along the tube's length. Our work implies that the nature of local protein-membrane interactions can affect the specific localization of proteins on membrane-remodeling sites. Furthermore, we show that amphipathic helices are dispensable in forming protein scaffolds. Finally, we explore a possible molecular structure of a BAR-domain scaffold using coarse-grained molecular dynamics simulations. Together with fluorescence microscopy, the simulations show that proteins need only to cover 30-40% of a tube's surface to form a rigid assembly. Our work provides mechanical and structural insights into the way BAR proteins may sculpt the membrane as a high-order cooperative assembly in important biological processes

Acute Aortic Syndromes from Diagnosis to Treatment—A Comprehensive Review

This work aims to provide a comprehensive description of the characteristics of a group of acute aortic diseases that are all potentially life-threatening and are collectively referred to as acute aortic syndromes (AASs). There have been recent developments in the care and diagnostic plan for AAS. A substantial clinical index of suspicion is required to identify AASs before irreversible fatal consequences arise because of their indefinite symptoms and physical indicators. A methodical approach to the diagnosis of AAS is addressed. Timely and suitable therapy should be started immediately after diagnosis. Improving clinical outcomes requires centralising patients with AAS in high-volume centres with high-volume surgeons. Consequently, the management of these patients benefits from the increased use of aortic centres, multidisciplinary teams and an “aorta code”. Each acute aortic entity requires a different patient treatment strategy; these are outlined below. Finally, numerous preventive strategies for AAS are discussed. The keys to good results are early diagnosis, understanding the natural history of these disorders and, where necessary, prompt surgical intervention. It is important to keep in mind that chest pain does not necessarily correspond with coronary heart disease and to be alert to the possible existence of aortic diseases because once antiplatelet drugs are administered, a blocked coagulation system can complicate aortic surgery and affect prognosis. The management of AAS in “aortic centres” improves long-term outcomes and decreases mortality rates.ISSN:2077-038

Acute Aortic Syndromes from Diagnosis to Treatment—A Comprehensive Review

This work aims to provide a comprehensive description of the characteristics of a group of acute aortic diseases that are all potentially life-threatening and are collectively referred to as acute aortic syndromes (AASs). There have been recent developments in the care and diagnostic plan for AAS. A substantial clinical index of suspicion is required to identify AASs before irreversible fatal consequences arise because of their indefinite symptoms and physical indicators. A methodical approach to the diagnosis of AAS is addressed. Timely and suitable therapy should be started immediately after diagnosis. Improving clinical outcomes requires centralising patients with AAS in high-volume centres with high-volume surgeons. Consequently, the management of these patients benefits from the increased use of aortic centres, multidisciplinary teams and an “aorta code”. Each acute aortic entity requires a different patient treatment strategy; these are outlined below. Finally, numerous preventive strategies for AAS are discussed. The keys to good results are early diagnosis, understanding the natural history of these disorders and, where necessary, prompt surgical intervention. It is important to keep in mind that chest pain does not necessarily correspond with coronary heart disease and to be alert to the possible existence of aortic diseases because once antiplatelet drugs are administered, a blocked coagulation system can complicate aortic surgery and affect prognosis. The management of AAS in “aortic centres” improves long-term outcomes and decreases mortality rates