الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
The anthracyclines, mainly doxorubicin (DOX), are among the most widely used chemotherapeutics for management of various types of malignancies, however their associated cumulative and dose-dependent cardiovascular injury has been a major concern for clinical oncologists and cardiologists as it limits its clinical use. Emerging evidences have confirmed that pyroptosis plays a crucial role in cardiovascular diseases and DOX-induced cardiovascular injury by causing a variety of cell death and inflammatory reactions. Thus, there is a growing necessity to develop preventive strategies and effective therapies against anthracycline-induced cardiovascular injury. The current study aimed to investigate the potential cardiovascular protective impacts of diacerein (DIA), nifuroxazide (NIFU), and lactoferrin (LACT) against DOX-induced cardiovascular injury; targeting pyroptotic signaling pathways. Furthermore, the underlying mechanisms of these possible effects of investigated drugs were explored in this study, targeting multiple pathological pathways; conducting in vivo and in vitro assays.In the present study, the experimental model of DOX-induced cardiovascular injury was established in rats by I.P. injection of a total cumulative dose of DOX (21 mg/kg) administered in divided way; (3.5 mg/kg) twice weekly for 3 weeks. DIA (10, 30 and 100 mg/kg), NIFU (10 and 30 mg/kg) and LACT (30, 100 and 300 mg/kg) were administered orally once daily for 3 weeks starting 1 week after the first DOX injection. At the end of the experiment, ECG recording was performed, blood samples were collected from retro-orbital puncture and sera were separated for biochemical assessment of iron content and cardiac injury biomarkers. The hearts were isolated for histopathological and immunohistochemical examination, and cardiac homogenate preparation, evaluation of the oxidative status, estimation of NLRP3/GSDMD-mediated pyroptotic signaling using western blotting and ELISA assays. Furthermore, aortas were isolated and used for the assessment of vascular injury. Moreover, rat neonatal cardiomyocytes primary culture was used to study impact of investigated drugs on DOX-induced cardiotoxicity in vitro.The results can be summarized as follows:•The current study suggests that DIA, NIFU, and LACT might have the potential to protect against DOX-induced cardiovascular injury with downregulation of NLRP3/GSDMD/IL-1β-mediated pyroptotic signaling. •Owing to their observed antioxidant, anti-inflammatory, and antipyroptotic activities; modulating ROS/TXNIP/NLRP3 and ROS/NF-κB/NLRP3 inflammasome pathways and their downstream signaling, including caspase-1, cleaved GSDMD-N, and IL-1β,these drugs are presumed to be repurposed for future clinical use to minimize DOX-associated cardiovascular injury.