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.

Background: Heart failure is primarily characterized by damage to the structure and function of the heart. Ferroptosis represents a form of programmed cell death, and studies indicate that it constitutes one of the primary mechanisms underlying cardiomyocyte death in heart failure. Calycosin, a natural compound derived from astragalus, exhibits various pharmacological properties, including anti-ferroptosis, antioxidant effects, and cardiovascular protection. Nonetheless, the specific role of Calycosin in the treatment of ferroptosis in heart failure remains poorly understood.Objective: This study aims to elucidate the regulatory effect of Calycosin on ferroptosis and its influence on the treatment mechanisms of heart failure through in vivo and in vitro experiments.Methods: A rat model of heart failure was induced using doxorubicin, and the cardiac function was evaluated through cardiac ultrasound examination and NT-Pro BNP detection. Myocardial injury was assessed using H&E staining and Masson staining. The extent of mitochondrial damage was evaluated through transmission electron microscopy. Concurrently, the level of ferroptosis was analyzed by measuring ferroptosis markers, including MDA, ferrous ions, the GSH/GSSG ratio, and GPX4 activity. Subsequently, the molecular mechanism by which Calycosin exerts its therapeutic effects in heart failure was investigated through immunofluorescence and Western blotting. Finally, H9c2 cardiomyocytes were treated with doxorubicin to simulate myocardial injury, and the mechanism by which Calycosin mediates its effects in the treatment of heart failure was further verified through Nrf2 gene silencing.Results: Calycosin significantly improves cardiac function in rats, reduces serum NT-Pro BNP levels, and alleviates myocardial cell damage. Additionally, it significantly decreases the levels of ferroptosis in myocardial tissue, as confirmed through transmission electron microscopy and the assessment of ferroptosis markers, including MDA, ferrous ions, GSH, and GPX4 activity. At the molecular level, Calycosin exerts its effects by activating the Nrf2/SLC7A11/GPX4 signaling pathway, evidenced by the upregulation of Nrf2, SLC7A11, GPX4, GSS, and GCL protein expression. This process substantially enhances the antioxidant capacity of rat myocardial tissue and effectively suppresses ferroptosis in myocardial cells. The results obtained from both in vivo and in vitro experiments are consistent. Notably, when Nrf2 is silenced, the protective effect of Calycosin on the myocardium is markedly diminished.Conclusion: Calycosin effectively treats doxorubicin-induced cardiac injury, and its therapeutic effect is likely closely associated with the activation of the Nrf2/SLC7A11/GPX4 signaling pathway and the inhibition of ferroptosis in myocardial cells. Consequently, Calycosin, as a promising compound against doxorubicin-induced cardiotoxicity, warrants further investigation.

Calycosin (CAL) is the main active component present in Astragalus and reportedly possesses diverse pharmacological properties. However, the cardioprotective effect and underlying mechanism of CAL against doxorubicin‐ (DOX‐) induced cardiotoxicity need to be comprehensively examined. Herein, we aimed to investigate whether the cardioprotective effects of CAL are related to its antipyroptotic effect. A cardiatoxicity model was established by stimulating H9c2 cells and C57BL/6J mice using DOX. In vitro, CAL increased H9c2 cell viability and decreased DOX‐induced pyroptosis via NLRP3, caspase‐1, and gasdermin D signaling pathways in a dose‐dependent manner. In vivo, CAL‐DOX cotreatment effectively suppressed DOX‐induced cytotoxicity as well as inflammatory and cardiomyocyte pyroptosis via the same molecular mechanism. Next, we used nigericin (Nig) and NLRP3 forced overexpression to determine whether CAL imparts antipyroptotic effects by inhibiting the NLRP3 inflammasome in vitro. Furthermore, CAL suppressed DOX‐induced mitochondrial oxidative stress injury in H9c2 cells by decreasing the generation of reactive oxygen species and increasing mitochondrial membrane potential and adenosine triphosphate. Likewise, CAL attenuated the DOX‐induced increase in malondialdehyde content and decreased superoxide dismutase and glutathione peroxidase activities in H9c2 cells. In vivo, CAL afforded a protective effect against DOX‐induced cardiac injury by improving myocardial function, inhibiting brain natriuretic peptide, and improving the changes of the histological morphology of DOX‐treated mice. Collectively, our findings confirmed that CAL alleviates DOX‐induced cardiotoxicity and pyroptosis by inhibiting NLRP3 inflammasome activation in vivo and in vitro.

Acute myocardial infarction (AMI) and the myocardial ischemia-reperfusion injury (MI/RI) that typically ensues represent a significant global health burden, accounting for a considerable number of deaths and disabilities. In the context of AMI, percutaneous coronary intervention (PCI) is the preferred treatment option for reducing acute ischemic damage to the heart. Despite the modernity of PCI therapy, pathological damage to cardiomyocytes due to MI/RI remains an important target for intervention that affects the long-term prognosis of patients. In recent years, mitochondrial dysfunction during AMI has been increasingly recognized as a critical factor in cardiomyocyte death. Damaged mitochondria play an active role in the formation of an inflammatory environment by triggering key signaling pathways, including those mediated by cyclic GMP-AMP synthase, NOD-like receptors and Toll-like receptors. This review emphasizes the dual role of mitochondria as both contributors to and regulators of inflammation. The aim is to explore the complex mechanisms of mitochondrial dysfunction in AMI and its profound impact on immune dysregulation. Specific interventions including mitochondrial-targeted antioxidants, membrane-stabilizing peptides, and mitochondrial transplantation therapies have demonstrated efficacy in preclinical AMI models.

Heart failure is the final destination of most cardiovascular diseases, and its complex molecular mechanisms remain largely uncertain. This study aimed to systematically investigate the underlying molecular mechanisms and diagnostic and therapeutic targets of heart failure using bioinformatics. We obtained 8 healthy samples and 8 heart failure samples from GSE8331 and GSE76701. After removing the batch effect, we performed a differential analysis on it and obtained 185 differentially expressed ID. The results of enrichment analysis showed that the molecular mechanisms of heart failure were mostly related to immune, inflammation, and metabolism-related pathways. Immune cell infiltration analysis showed that the degree of infiltration of Tgd cells and Neurons was significantly enriched in heart failure samples, whereas pDCs and NKTs were in healthy tissue samples. We obtained Hub genes including EGR1, EGR2, FOS and FOSB by PPI network analysis. We established a 4-gene diagnostic model with Hub gene, and validated it in GSE21610 and GSE57338, and evaluated the discriminative ability of Hub gene by ROC curve. The 4-gene diagnostic model has an AUC value of 0.775 in GSE21610 and 0.877 in GSE57338. In conclusion, we explored the underlying molecular mechanisms of heart failure and the immune cell infiltration environment of failing myocardium by performing bioinformatic analysis of the GEO dataset. In addition, we identified EGR1, EGR2, FOS and FOSB as potential diagnostic biomarkers and therapeutic targets for heart failure. More importantly, a diagnostic model of heart failure based on these 4 genes was developed, which leads to a new understanding of the pathogenesis of heart failure and may be an interesting target for future in-depth research.

B. anthracis edema toxin (ET) and lethal toxin (LT) are each composed of protective antigen (PA), necessary for toxin uptake by host cells, and their respective toxic moieties, edema factor (EF) and lethal factor (LF). Although both toxins likely contribute to shock during infection, their mechanisms are unclear. To test whether ET and LT produce arterial relaxation, their effects on phenylephrine (PE)-stimulated contraction in a Sprague-Dawley rat aortic ring model were measured. Rings were prepared and connected to pressure transducers. Their viability was confirmed, and peak contraction with 60 mM KCl was determined. Compared with PA pretreatment (control, 60 min), ET pretreatment at concentrations similar to those noted in vivo decreased the mean (±SE) maximum contractile force (MCF; percent peak contraction) in rings generated during stimulation with increasing PE concentrations (96.2 ± 7.0 vs. 57.3 ± 9.1) and increased the estimated PE concentration producing half the MCF (EC₅₀; 10⁻⁷M, 1.1 ± 0.3 vs. 3.7 ± 0.8, P ≤ 0.002). ET inhibition with PA-directed monoclonal antibodies, selective EF inhibition with adefovir, or removal of the ring endothelium inhibited the effects of ET on MCF and EC₅₀( P ≤ 0.02). Consistent with its adenyl cyclase activity, ET increased tissue cAMP in endothelium-intact but not endothelium-denuded rings ( P < 0.0001 and 0.25, respectively). LT pretreatment, even in high concentrations, did not significantly decrease MCF or increase EC₅₀(all P > 0.05). In rings precontracted with PE compared with posttreatment with PA (90 min), ET posttreatment produced progressive reductions in contractile force and increases in relaxation in endothelium-intact rings ( P < 0.0001) but not endothelium-denuded rings ( P = 0.51). Thus, ET may contribute to shock by producing arterial relaxation.