Targeting Energy Protection as a Novel Strategy to Disclose Di’ao Xinxuekang against the Cardiotoxicity Caused by Doxorubicin

Abstract

Doxorubicin (DOX) can induce myocardial energy metabolism disorder and further worsen heart failure. “Energy protection” is proposed as a new cardiac protection strategy. Previous studies have found that Di’ao Xinxuekang (DXXK) can improve doxorubicin-induced cardiotoxicity in mice by inhibiting ferroptosis. However, there are very few studies associating DXXK and energy protection. This study aims to explore the “energy protection” effect of DXXK on cardiotoxicity induced by DOX. A DOX-induced cardiotoxicity model established in rats and H9c2 cells are used to analyze the therapeutic effects of DXXK on serum indexes, cardiac function indexes and cardiac histopathology. The metabonomic methods were used to explore the potential mechanism of DXXK in treating DOX-induced cardiotoxicity. In addition, we also observed the mitochondrial- and autophagy-related indicators of myocardial cells and the mRNA expression level of the core target regulating energy-metabolism-related pathways. Our results indicated that DXXK can improve cardiac function, reduce myocardial enzymes and alleviate the histological damage of heart tissue caused by DOX. In addition, DXXK can improve mitochondrial damage induced by DOX and inhibit excessive autophagy. Metabonomics analysis showed that DOX can significantly affects the pathways related to energy metabolism of myocardial cells, which are involved in the therapeutic mechanism of DXXK. In conclusion, DXXK can treat DOX-induced cardiotoxicity through the AMPK-mediated energy protection pathway.

Influence of doxorubicin on the extracellular matrix of the liver of rats under conditions of chronic alcoholic hepatitis

“…An increase in the concentration of the heparin-heparan fraction of glycosaminoglycans in the liver when doxorubicin is administered can be considered as an adaptive response to doxorubicin-induced oxidative damage to hepatocytes (Pantea et al, 2023). An increased concentration of the heparin-heparan fraction of glycosaminoglycans can activate hepatocyte proliferation through the midkine-associated cascade, which acquires the ability to activate due to the reduction of AMPK expression by doxorubicin (Ou et al, 2020;Wang et al, 2023). Presumably, this is the same mechanism that ensures an increase in the concentration of the heparinheparan fraction in the group of animals administered doxorubicin against the background of chronic alcohol intoxication in relation to the group of rats with chronic alcoholic hepatitis.…”

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis

“…Myocardial enzymes including CK-MB, LDH, AST, and ALT levels were measured using the BS-360S automatic serum biochemical analyzer (Mindray, Shenzhen, China) [24]. The heart tissue was added to a homogenizer machine with a corresponding volume of cold PBS (1:9, w/v).…”

Cardiomyocyte Damage: Ferroptosis Relation to Ischemia-Reperfusion Injury and Future Treatment Options

“…The risk of cardiotoxicity increases with the dose and duration of treatment, and patients who receive anthracyclines are typically monitored for signs of cardiotoxicity. For example, to prevent cardiomyopathy, a cumulative dose of 450–550 mg/m 2 body surface area of doxorubicin (DOX) is recommended [ 21 , 25 , 28 ]. Although the exact mechanism causing doxorubicin-induced cardiomyopathy is unknown, new evidence points to iron–related damage.…”

“…NRF2 is a basic leucine zipper (bZIP) protein that may regulate the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation, according to preliminary research. Similarly, britanin upregulates GPX4 expression via same pathway, and the knockdown of NRF2 blocks the protective effects of britanin against IRI-induced damage in H9C2 cells [ 28 , 53 ].…”