The Protective Effect And Mechanism Of Thymoquinone On Doxorubicin-induced Cardiotoxicity

Object:This study aim to explore whether thymoquinone(TQ)attenuates doxorubicin(DOX)-induced cardiotoxicity and to elucidate its possible molecular mechanism.Methods:1.Forty-eight male 10-week-old C57BL/6j mice were randomly divided into 4groups of 12 mice each.CON group: corn oil was intragastrically administered once a day for 14 days;DOX group:corn oil was intragastrically administered once a day for14 days,and a single dose of DOX(20 mg/Kg)intraperitoneal injection was given on the 7th day;TQ10 group: TQ(10 mg/Kg)was intragastrically administered once a day for 14 days,and a single dose of DOX(20 mg/Kg)intraperitoneal injection was given on the 7th day;TQ20 group: TQ(20mg/Kg)was intragastrically administered once a day for 14 days,and a single dose of DOX(20 mg/Kg)intraperitoneally injection was given on the 7th day.2.Evaluate blood pressure,heart rate,ECG parameters and echocardiographic parameters of mice in each group.3.HE staining was used to observe the pathological changes of cardiomyocytes in each group of mice.4.The changes of mitochondrial structure in cardiomyocytes of mice in each group were observed by transmission electron microscope.5.Western blot was used to detect the expression levels of Nrf2,HO-1,GPX4 and FTH1 in myocardial tissue of mice in each group.6.The expression levels of NQO1,COX-2 and NOX4 in each group were detected by immunohistochemistry.7.The iron content of myocardial tissue of mice in each group was evaluated.8.The contents of GSH and MDA in myocardial tissue of mice in each group were detected,and their T-AOC was evaluated.Results:1.TQ ameliorated DOX-induced hypotension,bradycardia and systolic dysfunction in mice.2.TQ ameliorated DOX-induced cardiomyocyte injury and mitochondrial damage in mice.3.TQ up-regulated the expression levels of Nrf2,HO-1,and increased the expression levels of ferroptosis-related proteins GPX4 and FTH1.4.TQ increased the expression levels of NQO1 and decreased the expression levels of COX-2 and NOX4.5.TQ reduced iron content in mice myocardial tissue.6.TQ increased myocardial tissue GSH levels,decreased lipid peroxide malondialdehyde levels,and enhanced its total antioxidant capacity.Conclusion:1.TQ can alleviate DOX-induced cardiotoxicity.2.TQ may alleviate DOX-induced cardiotoxicity by reducing ferroptosis in cardiomyocytes by activating the Nrf2/HO-1 signaling pathway.3.TQ can reduce the oxidative stress of cardiomyocytes in mice.