Inappropriate activation of the Hh signaling pathway has been implicated in the development of several types of cancers including
prostate, lung, pancreas, breast, brain and skin. Present study identified the binding affinities of eight established inhibitors viz.,
Cyclopamine, Saridegib, Itraconazole, LDE-225, TAK-441, BMS-833923 (XL139), PF-04449913 and Vismodegib targeting SMO
receptor - a candidate protein involved in hedgehog pathway and sought to identify the best amongst the established inhibitors
through by molecular docking. Exelxis® BMS 833923 (XL 139) demonstrated superior binding affinity aided by MolDock scoring
docking algorithm. Further BMS 833923 (XL 139) was evaluated for pharmacophoric features which revealed appreciable ligand
receptor interactions.
In this investigation, combined effects of quercetin and atenolol in the regulation of isoproterenol (ISO)-induced cardiotoxicity have been evaluated in rats. While ISO administration increased the levels of serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (SGPT) as well as cardiac malondialdehyde (MDA); it reduced the activities of superoxide dismutase, catalase, glutathione peroxidase and the level of reduced glutathione. ISO-induced rats also exhibited ST-segment elevation and tachycardia. Oral administration of atenolol (6 mg/kg) and quercetin (5 mg/kg), along with ISO (5 mg/kg, subcutaneously) every day for 10 days markedly reduced the serum CK-MB, LDH and SGPT levels. Concomitantly the test drugs improved the status of antioxidative enzymes, decreased the cardiac MDA and nearly normalized the electrocardiogram. Electron paramagnetic resonance study also revealed a decrease in 5,5'-dimethyl-1-pyroline-N-oxide-hydroxyl radicals signal intensity when atenolol and quercetin were administered together to ISO-treated rats. In conclusion, the combined treatment of atenolol and quercetin appears to produce a better cardioprotective effect in ISO-induced animals as compared to their individual treatments, and possibly the beneficial actions are associated with the free radical scavenging action of quercetin.
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