This journal requires that authors assign a level of evidence to

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.spinger.com/00266.”
“Background

and Purpose Ectonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), 2, 3 and 8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under selleck compound physiological conditions, and NTPDase1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPDase1 are required to modulate responses induced by nucleotides in a number of pathological situations such

as thrombosis, inflammation and cancer. Experimental Approach Here, we present the synthesis and enzymatic characterization of five 8-BuS-adenine nucleotide derivatives as potent and selective inhibitors of NTPDase1. Key Results The compounds 8-BuS-AMP, 8-BuS-ADP and 8-BuS-ATP inhibit recombinant human and mouse NTPDase1 by mixed type inhibition, predominantly competitive with Ki values <1M. In contrast to 8-BuS-ATP which could be hydrolyzed by other NTPDases, the other BuS derivatives selleck chemicals were resistant to hydrolysis by either NTPDase1, 2, 3 or 8. 8-BuS-AMP and 8-BuS-ADP were the most potent and selective inhibitors of NTPDase1 expressed in human umbilical vein endothelial cells as well as in situ in human and mouse tissues. As expected, as a result

of their inhibition of recombinant click here human NTPDase1, 8-BuS-AMP and 8-BuS-ADP impaired the ability of this enzyme to block platelet aggregation. Importantly, neither of these two inhibitors triggered platelet aggregation nor prevented ADP-induced platelet aggregation, in support of their inactivity towards P2Y1 and P2Y12 receptors. Conclusions and Implications The 8-BuS-AMP and 8-BuS-ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPDase1.”
“Advances in the optimization of in vitro-transcribed mRNA are bringing mRNA-mediated therapy closer to reality. In cultured cells, we recently achieved high levels of translation with high-performance liquid chromatography (HPLC)-purified, in vitro-transcribed mRNAs containing the modified nucleoside pseudouridine. Importantly, pseudouridine rendered the mRNA non-immunogenic. Here, using erythropoietin (EPO)-encoding mRNA complexed with TransIT-mRNA, we evaluated this new generation of mRNA in vivo. A single injection of 100 ng (0.005 mg/kg) mRNA elevated serum EPO levels in mice significantly by 6 hours and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10-100-fold lower levels of EPO lasting only 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits.

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