10 research outputs found

    The Liver-Selective Thyromimetic T-0681 Influences Reverse Cholesterol Transport and Atherosclerosis Development in Mice

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    Liver-selective thyromimetics have been reported to efficiently reduce plasma cholesterol through the hepatic induction of both, the low-density lipoprotein receptor (LDLr) and the high-density lipoprotein (HDL) receptor; the scavenger receptor class B type I (SR-BI). Here, we investigated the effect of the thyromimetic T-0681 on reverse cholesterol transport (RCT) and atherosclerosis, and studied the underlying mechanisms using different mouse models, including mice lacking LDLr, SR-BI, and apoE, as well as CETP transgenic mice.T-0681 treatment promoted bile acid production and biliary sterol secretion consistently in the majority of the studied mouse models, which was associated with a marked reduction of plasma cholesterol. Using an assay of macrophage RCT in mice, we found T-0681 to significantly increase fecal excretion of macrophage-derived neutral and acidic sterols. No positive effect on RCT was found in CETP transgenic mice, most likely due to the observed decrease in plasma CETP mass. Studies in SR-BI KO and LDLr KO mice suggested hepatic LDLr to be necessary for the action of T-0681 on lipid metabolism, as the compound did not have any influence on plasma cholesterol levels in mice lacking this receptor. Finally, prolonged treatment with T-0681 reduced the development of atherosclerosis by 60% in apoE KOs on Western type diet. In contrast, at an earlier time-point T-0681 slightly increased small fatty streak lesions, in part due to an impaired macrophage cholesterol efflux capacity, when compared to controls.The present results show that liver-selective thyromimetics can promote RCT and that such compounds may protect from atherosclerosis partly through induction of bile acid metabolism and biliary sterol secretion. On-going clinical trials will show whether selective thyromimetics do prevent atherosclerosis also in humans

    Template-free galvanic nanostructuring of gold electrodes for sensitive electrochemical biosensors

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    Gold nanostructuring of smooth gold disk-electrodes has been performed by electrodeposition. FE-SEM images indicate a strongly enlarged electrochemically active surface of the modified electrodes. This could be approved by the gold oxide reduction peak in cyclic voltammetry. The electrodes were also applied for sequence-specific DNA detection. For this, complementary single stranded capture probes were immobilized on the electrodes and consecutively hybridized with complementary and noncomplementary [OsO4(bipy)]-labeled DNA targets. We found that intermediate dehybridization steps did not decrease the sensitivity for the specific target. Moreover, the surface modification increased the voltammetric signal by an approx. factor of 9. Further, an enhanced linear calibration range was observed. The presented simple nanostructuring process holds great promise for many electrochemical sensor applications

    HDL-targeted therapies: progress, failures and future

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