[show abstract][hide abstract] ABSTRACT: Nitric oxide is a small messenger molecule utilized by nature in cell signalling and the non-specific immune response. At present, nitric oxide releasing prodrugs cannot be efficiently targeted towards a specific body compartment, which restricts their therapeutic applications. To address this limitation, we have designed two photolabile nitric oxide releasing prodrugs, tert-butyl S-nitrosothiol and tert-dodecane S-nitrosothiol, which are based on the S-nitrosothiol functionality. By modulating the prodrugs' hydrophobicity, we postulated that we could increase their stability within the cell by preventing their interaction with hydrophilic thiols and metal ions; processes that are known to inactivate this prodrug class. Our data demonstrate that these prodrugs have improved nitric oxide release kinetics compared to currently available S-nitrosothiols, as they are highly stable in vitro in the absence of irradiation (t(1/2) > 3 h), while their rate of decomposition can be regulated by controlling the intensity or duration of the photostimulus. Nitric oxide release can readily be achieved using non-laser based light sources, which enabled us to characterize photoactivation as a trigger mechanism for nitric oxide release in A549 lung carcinoma cells. Here we confirmed that irradiation induced highly significant increases in cytotoxicity within a therapeutic drug range (1-100 μm), and the utility of this photoactivation switch opens up avenues for exploring the applications of these prodrugs for chemical biology studies and chemotherapy.
Chemical Biology & Drug Design 05/2012; 80(3):471-8. · 2.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Transition metal ions have been implicated in atherosclerosis. The goal of this study was to investigate whether metal ion levels were higher in people with diabetes, in view of their increased risk of aggravated atherosclerosis.
Absolute concentrations of iron, copper, zinc and calcium, and products of protein and lipid oxidation were quantified in atherosclerotic lesions from subjects with (T2DM, n=27), without Type 2 diabetes (nonDM, n=22), or hyperglycaemia (HG, n=17). Iron (P<0.05), zinc (P<0.01) and calcium (P=0.01) were lower in T2DM compared to nonDM subjects. Copper levels were comparable. A strong correlation (r=0.618; P<0.001) between EPR-detectable and total iron in nonDM patients was not seen in T2DM. X-ray fluorescence microscopy revealed "hot spots" of iron in both T2DM and nonDM. Calcium and zinc co-localised and levels correlated strongly. F(2)-isoprostanes (P<0.05) and di-Tyr/Tyr ratio (P<0.025), oxidative damage markers were decreased in T2DM compared to nonDM, or HG.
Advanced atherosclerotic lesions from T2DM subjects unexpectedly contained lower levels of transition metal ions, and protein and lipid oxidation products, compared to nonDM and HG. These data do not support the hypothesis that elevated metal ion levels may be a major causative factor in the aggravated atherosclerosis observed in T2DM patients.