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 ... -  《-》

Carnosic acid protects against doxorubicin-induced cardiotoxicity through enhancing the Nrf2/HO-1 pathway.

Hu S ，Liu B ，Yang M ，Mao S ，Ju H ，Liu Z ，Huang M ，Wu G ... -  《-》

MCC950 attenuates doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis.

MCC950, an NLRP3 inflammasome inhibitor, displays multiple pharmacological properties. However, the protective potential and underlying mechanism of MCC950 against doxorubicin (DOX)-induced myocardial injury has not been well investigated yet. Herein, DOX-induced myocardial injury in mice and in H9c2 myocardial cells was investigated, and the protective effects and underlying mechanism of MCC950 were fully explored. The results showed that MCC950 co-treatment significantly improved myocardial function, inhibited inflammatory and myocardial fibrosis, and attenuated cardiomyocyte pyroptosis in DOX-treated mice. Mechanismly, MCC950 had the potential to inhibit DOX-induced the cleavage of NLRP3, ASC, Caspase-1, IL-18, IL-1β and GSDMD in vivo. Moreover, MCC950 co-treatment in vivo suppressed DOX-induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis through the same molecular mechanism. Taken together, our findings validated that MCC950, an NLRP3 inflammasome inhibitor, has the potential to attenuate doxorubicin-induced myocardial injury in vivo and in vitro by inhibiting NLRP3-mediated pyroptosis.

Zhang L ，Jiang YH ，Fan C ，Zhang Q ，Jiang YH ，Li Y ，Xue YT ... -  《-》

Exogenous 8-hydroxydeoxyguanosine attenuates doxorubicin-induced cardiotoxicity by decreasing pyroptosis in H9c2 cardiomyocytes.

Doxorubicin (DOX), which is widely used in cancer treatment, can induce cardiomyopathy. One of the main mechanisms whereby DOX induces cardiotoxicity involves pyroptosis through the NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD). Increased NAPDH oxidase (NOX) and oxidative stress trigger pyroptosis. Exogenous 8-hydroxydeoxyguanosine (8-OHdG) decreases reactive oxygen species (ROS) production by inactivating NOX. Here, we examined whether 8-OHdG treatment can attenuate DOX-induced pyroptosis in H9c2 cardiomyocytes. Exposure to DOX increased the peroxidative glutathione redox status and NOX1/2/4, toll-like receptor (TLR)2/4, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, while an additional 8-OHdG treatment attenuated these effects. Furthermore, DOX induced higher expression of NLRP3 inflammasome components, including NLRP3, apoptosis-associated speck-like protein containing a c-terminal caspase recruitment domain (ASC), and pro-caspase-1. Moreover, it increased caspase-1 activity, a marker of pyroptosis, and interleukin (IL)-1β expression. All these effects were attenuated by 8-OHdG treatment. In addition, the expression of the cardiotoxicity markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was increased by DOX, whereas the increase of ANP and BNP induced by DOX treatment was reversed by 8-OHdG. In conclusion, exogenous 8-OHdG attenuated DOX-induced pyroptosis by decreasing the expression of NOX1/2/3, TLR2/4, and NF-κB. Thus, 8-OHdG may attenuate DOX-induced cardiotoxicity through the inhibition of pyroptosis.

Hwang S ，Kim SH ，Yoo KH ，Chung MH ，Lee JW ，Son KH ... -  《-》

Astragaloside IV Alleviates Doxorubicin-Induced Cardiotoxicity by Inhibiting Cardiomyocyte Pyroptosis through the SIRT1/NLRP3 Pathway.

Tian W ，Zhang P ，Yang L ，Song P ，Zhao J ，Wang H ，Zhao Y ，Cao L ... -  《-》