European journal of pharmacology
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Excessive sympathetic activity is associated with heart failure and ventricular arrhythmias, which regulated by enhanced cardiac sympathetic afferent reflex, which can be blunted by resiniferatoxin, a selective receptor agonist of transient vanilloid potential 1 (TRPV1) + primary sensory afferents. The present study is aimed to determine whether intrathecal resiniferatoxin application affect cardiac sympathetic tone and electrophysiology, furtherly create a new effective strategy to prevent lethal arrhythmias in chronic heart failure. Four weeks after coronary artery occlusion to induce heart failure in rats, RTX (2μg/10 μl) or vehicle was injected intrathecally into the T2/T3 interspace. ⋯ Electrophysiological studies revealed that resiniferatoxin administration intrathecally significantly reversed the prolongation of action potential duration (APD) and APD alternan, reduced the inducibilities of ventricular arrhythmias. Moreover, the over-activated calcium handling related protein CaMKII and RyR2 in heart failure was reversed by resiniferatoxin administration. In conclusion, these results firstly demonstrate that central chemo-ablation of the TRPV1+ afferents in spinal cord prevent heart from ventricular arrhythmias in heart failure via selectively blunting cardiac sympathetic afferent projection into spinal cord, which suggest a novel promising therapeutic method for anti-arrhythmia in heart failure.
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Increasing costs, much time consumption and high risk of failure associated with the process of de novo development of new anticancer drugs have prompted the pharmaceutical industry to seek alternative strategies that may facilitate and accelerate the whole process. In particular, the repurposing strategy, known also as repositioning or reprofiling strategy, is a potential source of new treatment options for cancer patients with high unmet medical needs. ⋯ In this review article we discuss the advantages of the repurposing strategy, and provide an overview of a number of promising candidates, such as artesunate, aspirin, cimetidine, doxycycline, ivermectin, metformin, rapamycin (sirolimus), and thalidomide, that have the potential to be repurposed as anticancer drugs both in cancer prevention and therapy. In addition, we highlight some of the studies regarding the signalling pathways and molecular targets altered by these drugs, and describe the biological mechanisms underlying their anticancer effects.