Simvastatin attenuates abdominal aortic aneurysm formation favoured by lack of Nrf2 transcriptional activity

Surgical intervention is currently the only option for an abdominal aortic aneurysm (AAA), preventing its rupture and sudden death of a patient. Therefore, it is crucial to determine the pathogenic mechanisms of this disease for the development of effective pharmacological therapies. Oxidative stress is said to be one of the pivotal factors in the pathogenesis of AAAs. Thus, we aimed to evaluate the significance of nuclear factor erythroid 2-related factor 2 (Nrf2) transcriptional activity in the development of AAA and to verify if simvastatin, administered as pre- and cotreatment, may counteract this structural malformation. Experiments were performed on mice with inhibited transcriptional activity of Nrf2 (tKO) and wild-type (WT) counterparts. We used a model of angiotensin II- (AngII-) induced AAA, combined with a fat-enriched diet. Mice were administered with AngII or saline for up to 28 days via osmotic minipumps. Simvastatin administration was started 7 days before the osmotic pump placement and then continued until the end of the experiment. We found that Nrf2 inactivation increased the risk of development and rupture of AAA. Importantly, these effects were reversed by simvastatin in tKO mice, but not in WT. The abrupt blood pressure rise induced by AngII was mitigated in simvastatin-treated animals regardless of the genotype. Simvastatin-affected parameters that differed between the healthy structure of the aorta and aneurysmal tissue included immune cell infiltration of the aortic wall, VCAM1 mRNA and protein level, extracellular matrix degradation, TGF-β1 mRNA level, and ERK phosphorylation, but neither oxidative stress nor the level of Angiotensin II Type 1 Receptor (AT1R). Taken together, the inhibition of Nrf2 transcriptional activity facilitates AAA formation in mice, which can be prevented by simvastatin. It suggests that statin treatment of patients with hypercholesterolemia might have not only a beneficial effect in terms of controlling atherosclerosis but also potential AAA prevention

Endothelial glycocalyx shields the interaction of SARS-CoV-2 spike protein with ACE2 receptors

Endothelial cells (ECs) play a crucial role in the development and propagation of the severe COVID-19 stage as well as multiorgan dysfunction. It remains, however, controversial whether COVID-19-induced endothelial injury is caused directly by the infection of ECs with SARS-CoV-2 or via indirect mechanisms. One of the major concerns is raised by the contradictory data supporting or denying the presence of ACE2, the SARS-CoV-2 binding receptor, on the EC surface. Here, we show that primary human pulmonary artery ECs possess ACE2 capable of interaction with the viral Spike protein (S-protein) and demonstrate the crucial role of the endothelial glycocalyx in the regulation of the S-protein binding to ACE2 on ECs. Using force spectroscopy method, we directly measured ACE2- and glycocalyx-dependent adhesive forces between S-protein and ECs and characterized the nanomechanical parameters of the cells exposed to S-protein. We revealed that the intact glycocalyx strongly binds S-protein but screens its interaction with ACE2. Reduction of glycocalyx layer exposes ACE2 receptors and promotes their interaction with S-protein. These results indicate that the susceptibility of ECs to COVID-19 infection may depend on the glycocalyx condition

Risk of transmission of blood-derived pathogens by transfusion in Poland

Blood transfusion in Poland is the safest in history. High virological level of safety has been achieved mainly by improving not only the qualification of donors and methods used for donor screening, but also applying leukoreduction, pathogen reduction technology and grace period for serum.In this article, we discuss the improvement of the epidemic situation among blood donors for hepatitis B virus (HBV) and hepatitis C virus (HCV) and the increasing trend for HIV. Preliminary results of residual risk calculation for these pathogens are presented.Hepatitis E virus (HEV) and Babesia microti were considered as new factors potentially relevant for the safety of blood transfusion in our country. Due to evidence of West Nile virus (WNV) circulation in the ecosystem in Poland, it is also necessary to monitor the infections with this pathogen.In this article, it was emphasized that the reporting of all possible complications associated with transfusion and meticulous implementation of the look-back procedure play a key role for monitoring the risk of transmission of infectious agents by blood. It is especially important in view of the increasing epidemiological problems associated with emerging infectious agents

Co-administration of angiotensin II and simvastatin triggers kidney injury upon heme oxygenase-1 deficiency

Kidneys are pivotal organ in iron redistribution and can be severely damaged in the course of hemolysis. In our previous studies, we observed that induction of hypertension with angiotensin II (Ang II) combined with simvastatin administration results in a high mortality rate or the appearance of signs of kidney failure in heme oxygenase-1 knockout (HO-1 KO) mice. Here, we aimed to address the mechanisms underlying this effect, focusing on heme and iron metabolism. We show that HO-1 deficiency leads to iron accumulation in the renal cortex. Higher mortality of Ang II and simvastatin-treated HO-1 KO mice coincides with increased iron accumulation and the upregulation of mucin-1 in the proximal convoluted tubules. In vitro studies showed that mucin-1 hampers heme- and iron-related oxidative stress through the sialic acid residues. In parallel, knock-down of HO-1 induces the glutathione pathway in an NRF2-depedent manner, which likely protects against heme-induced toxicity. To sum up, we showed that heme degradation during heme overload is not solely dependent on HO-1 enzymatic activity, but can be modulated by the glutathione pathway. We also identified mucin-1 as a novel redox regulator. The results suggest that hypertensive patients with less active HMOX1 alleles may be at higher risk of kidney injury after statin treatment

Casein kinase 2 activity is a host restriction factor for AAV transduction

So far, the mechanisms that impede AAV transduction, especially in the human heart, are poorly understood, hampering the introduction of new, effective gene therapy strategies. Therefore, the aim of this study was to identify and overcome the main cellular barriers to successful transduction in the heart, using iPSC-derived cardiomyocytes (iPSC-CMs), cardiac fibroblasts (iPSC-CFs), and primary endothelial cells (HAECs) to model vector-host interactions. Through phosphoproteome analysis we established that casein kinase 2 (CK2) signalling is one of the most significantly affected pathways upon AAV exposure. Transient inhibition of CK2 activity substantially enhanced the transduction rate of AAV2, AAV6 and AAV9 in all tested cell types. In particular, CK2 inhibition improved the trafficking of AAVs through the cytoplasm, impaired DNA-damage response through destabilisation of Mre11 and altered the RNA processing pathways, which were also highly responsive to AAV transduction. Also, it augmented transgene expression in already transduced iPSC-CFs, which retain AAV genomes in a functional, but probably silent form. In summary, presented study provides new insights into the current understanding of the host-AAV vector interaction, identifying CK2 activity as a key barrier to efficient transduction and transgene expression, what may translate to improvement the outcome of AAV-based therapies in the future

Diagnostyka molekularna SARS-CoV-2

Zakażenia nowym koronawirusem — SARS-CoV-2 — stały się w ostatnich miesiącachgłównym problemem epidemiologicznym oraz klinicznym na świecie, w tym Polsce w zakresiechorób zakaźnych. Niniejszy artykuł powstał na podstawie wystąpienia zaprezentowanegow trakcie webinaru zatytułowanego „Hematologia i transfuzjologia a COVID-19”, który odbyłsię w maju 2020 roku. Praca ma na celu przybliżenie procedury diagnostyki zakażenia nowymkoronawirusem. Zwrócono w niej uwagę na krytyczne dla jakości wykonywanych badańaspekty fazy przedanalitycznej oraz analitycznej, na które ma wpływ zarówno osoba zlecająca,jak i personel wykonujący badanie. Na podstawie aktualnego piśmiennictwa przedstawionotakże dalsze kierunki doskonalenia diagnostyki molekularnej SARS-CoV-2