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Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.
Allostery is a phenomenon observed in many proteins where binding of a macromolecular partner or a small-molecule ligand at one location leads to specific perturbations at a site not in direct contact with the region where the binding occurs. The list of proteins under allosteric regulation includes AGC protein kinases. AGC kinases have a conserved allosteric site, the phosphoinositide-dependent protein kinase 1 (PDK1)-interacting fragment (PIF) pocket, which regulates protein ATP-binding, activity, and interaction with substrates. In this study, we identify small molecules that bind to the ATP-binding site and affect the PIF pocket of AGC kinase family members, PDK1 and Aurora kinase. We describe the mechanistic details and show that although PDK1 and Aurora kinase inhibitors bind to the conserved ATP-binding site, they differentially modulate physiological interactions at the PIF-pocket site. Our work outlines a strategy for developing bidirectional small-molecule allosteric modulators of protein kinases and other signaling proteins.
Aims: We sought to describe perfusion dyssynchrony analysis specifically to exploit the high temporal resolution of stress perfusion CMR. This novel approach detects differences in the temporal distribution of the wash-in of contrast agent across the left ventricular wall.
Methods and results: Ninety-eight patients with suspected coronary artery disease (CAD) were retrospectively identified. All patients had undergone perfusion CMR at 3T and invasive angiography with fractional flow reserve (FFR) of lesions visually judged >50% stenosis. Stress images were analysed using four different perfusion dyssynchrony indices: the variance and coefficient of variation of the time to maximum signal upslope (V-TTMU and C-TTMU) and the variance and coefficient of variation of the time to peak myocardial signal enhancement (V-TTP and C-TTP). Patients were classified according to the number of vessels with haemodynamically significant CAD indicated by FFR <0.8. All indices of perfusion dyssynchrony were capable of identifying the presence of significant CAD. C-TTP >10% identified CAD with sensitivity 0.889, specificity 0.857 (P < 0.0001). All indices correlated with the number of diseased vessels. C-TTP >12% identified multi-vessel disease with sensitivity 0.806, specificity 0.657 (P < 0.0001). C-TTP was also the dyssynchrony index with the best inter- and intra-observer reproducibility. Perfusion dyssynchrony indices showed weak correlation with other invasive and non-invasive measurements of the severity of ischaemia, including FFR, visual ischaemic burden, and MPR.
Conclusion: These findings suggest that perfusion dyssynchrony analysis is a robust novel approach to the analysis of first-pass perfusion and has the potential to add complementary information to aid assessment of CAD.