Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3K/Akt/mTOR-dependent manner.

Doxorubicin (DOX) is one of the most effective anti-neoplastic drugs although its clinical use is limited by the severe cardiotoxicity. Apoptosis and defective autophagy are believed to contribute to DOX-induced cardiotoxicity. Here we explored the effect of curcumin (Cur) on DOX-induced cardiac injury and the mechanism involved with a focus on oxidative stress, autophagy and pyroptosis. Kunming mice were challenged with DOX (3 mg·kg-1, i.p. every other day) with cohorts of mice receiving Cur at 50, 100, 200 and 400 mg·kg-1 via gavage daily. Serum levels of cardiac enzymes, such as aspartate amino transferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), and heart homogenate oxidative stress markers, such as superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Echocardiographic and cardiac contraction were examined. Apoptosis, pyroptosis, autophagy and Akt/mTOR-signalling proteins were detected using western blot or electron microscopy. Cardiac contractile properties were assessed including peak shortening, maximal velocity of shortening/relengthening (± dL/dt), time-to-PS, and time-to-90% relengthening (TR90). Superoxide levels were evaluated using DHE staining. GFP-LC3 was conducted to measure autophagosomes. Our study showed that Cur protected against cardiotoxicity manifested by a significant decrease in serum myocardial enzymes and improvement of anti-oxidative capacity. Cur inhibited autophagy and offered overt benefit for cardiomyocyte survive against DOX-induced toxicity. Cur attenuated DOX-induced cardiomyocyte pyroptosis as evidenced by NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and interleukin-18 levels. DOX impaired cardiac function (reduced fractional shortening, ejection fraction, increased plasma cTnI level and TR90, decreased PS and ± dL/dt), the effects of which were overtly reconciled by 100 mg·kg-1 but not 50 mg·kg-1 Cur. H9c2 cells exposure to DOX displayed increased intracellular reactive oxygen species (ROS) and autophagy, the effects of which were nullified by Cur. Autophagy activator rapamycin cancelled off Cur-induced protective effects. Our finding suggested that Cur rescued against DOX-induced cardiac injury probably through regulation of autophagy and pyroptosis in a mTOR-dependent manner.

Yu W ，Qin X ，Zhang Y ，Qiu P ，Wang L ，Zha W ，Ren J ... -  《-》

Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14-3-3γ.

He H ，Luo Y ，Qiao Y ，Zhang Z ，Yin D ，Yao J ，You J ，He M ... -  《-》

Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction.

Doxorubicin (DOX) is an effective broad-spectrum antitumor drug, but its clinical application is limited due to the side effects of cardiac damage. Astragaloside IV (AS-IV) is a significant active component of Astragalus membranaceus that exerts cardioprotective effects through various pathways. However, whether AS-IV exerts protective effects against DOX-induced myocardial injury by regulating the pyroptosis is still unknown and is investigated in this study. The myocardial injury model was constructed by intraperitoneal injection of DOX, and AS-IV was administered via oral gavage to explore its specific protective mechanism. Cardiac function and cardiac injury indicators, including lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and brain natriuretic peptide (BNP), and histopathology of the cardiomyocytes were assessed 4 weeks post DOX challenge. Serum levels of IL-1β, IL-18, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) and the expression of pyroptosis and signaling proteins were also determined. Cardiac dysfunction was observed after the DOX challenge, as evidenced by reduced ejection fraction, increased myocardial fibrosis, and increased BNP, LDH, cTnI, and CK-MB levels (p < 0.05, N = 3-10). AS-IV attenuated DOX-induced myocardial injury. The mitochondrial morphology and structure were also significantly damaged after DOX treatment, and these changes were restored after AS-IV treatment. DOX induced an increase in the serum levels of IL-1β, IL-18, SOD, MDA and GSH as well as an increase in the expression of pyroptosis-related proteins (p < 0.05, N = 3-6). Besides, AS-IV depressed myocardial inflammatory-related pyroptosis via activation of the expressions of nuclear factor E2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) (p < 0.05, N = 3). Our results showed that AS-IV had a significant protective effect against DOX-induced myocardial injury, which may be associated with the activation of Nrf-2/HO-1 to inhibit pyroptosis.

Chen X ，Tian C ，Zhang Z ，Qin Y ，Meng R ，Dai X ，Zhong Y ，Wei X ，Zhang J ，Shen C ... -  《-》

Resolvin E1 protects against doxorubicin-induced cardiotoxicity by inhibiting oxidative stress, autophagy and apoptosis by targeting AKT/mTOR signaling.

Doxorubicin (DOX)-induced cardiotoxicity impairs the quality of life of cancer patients during or after DOX treatment, and it is imperative to explore a novel strategy to address this problem. Resolvin E1 (RvE1) is derived from eicosapentaenoic acid (EPA), which has been reported to exert beneficial effects on DOX-induced oxidative stress in cardiomyocytes. This study was designed to investigate whether RvE1 protects against DOX-induced cardiotoxicity, and the underlying mechanism was explored. DOX (20 mg/kg, one injection, i.p.) was used to induce DOX-induced cardiotoxicity in C57BL/6 mice. At 5 days after DOX administration, the effect of RvE1 was assessed by measuring cardiac function, oxidative stress, autophagy and apoptosis in cardiac tissue. We used an AKT inhibitor and rapamycin to investigate the underlying mechanisms. Our results showed that RvE1 inhibited the DOX-induced decrease in body weight and heart weight, the reduction in left ventricular ejection fraction and fractional shortening, and the increase in lactate dehydrogenase, creatine kinase myocardial bound and cardiomyocyte vacuolization. Compared to the control group, the DOX group exhibited increased oxidative stress, autophagy and apoptosis in cardiac tissue, which were alleviated by treatment with RvE1. The AKT/mTOR signaling pathways were responsible for RvE1-mediated regulation of DOX-induced oxidative stress, autophagy and myocardial apoptosis. In conclusion, RvE1 protected against DOX-induced cardiotoxicity via the regulation of AKT/mTOR signaling.

Zhang J ，Wang M ，Ding W ，Zhao M ，Ye J ，Xu Y ，Wang Z ，Ye D ，Li D ，Liu J ，Wan J ... -  《-》

Mitochonic acid 5 rescues cardiomyocytes from doxorubicin-induced toxicity via repressing the TNF-α/NF-κB/NLRP3-mediated pyroptosis.

Zha W ，Zhao Q ，Xiao Y ，Gan Y ，Wei J ，Yu M ，Xu Y ，Xu Q ，Wu S ，Yu W ... -  《-》