Introduction Myocardial infarction is coronary artery-related heart disease, and the leading cause of mortality globally. Circular RNAs (circRNAs) are a new type of regulatory RNAs and participate in multiple pathological cardiac progression. Methods However, the function of circFoxo3 in MI-induced myocardial injury remains obscure. Results Significantly, we identified that circFoxo3 was downregulated in the MI rat model and the overexpression of circFoxo3 ameliorated MI-induced cardiac dysfunction and attenuated MI-induced autophagy in rat model. Meanwhile, the overexpression of circFoxo3 repressed oxygen–glucose deprivation (OGD)-induced autophagy, apoptosis, inflammation, and injury of cardiomyocyte in vitro. Mechanically, we identified that the expression of KAT7 was reduced by circFoxo3 overexpression in cardiomyocytes. Meanwhile, the expression of HMGB1 was repressed by the depletion of KAT7 in cardiomyocytes. The enrichment of histone H3 lysine 14 acetylation (H3K14ac) and RNA polymerase II (RNA pol II) on HMGB1 promoter was inhibited by the knockdown of KAT7. Moreover, the overexpression of circFoxo3 suppressed HMGB1 expression and KAT7 overexpression rescued the expression of HMGB1 in cardiomyocytes. The enrichment of KAT7, H3K14ac, and RNA poly II on HMGB1 promoter was decreased by circFoxo3 overexpression, while the overexpression of KAT7 could reverse the effect. The overexpression of KAT7 or HMGB1 could reverse circFoxo3-attenuated cardiomyocyte injury and autophagy in vitro. Thus, we conclude that circular RNA circFoxo3 relieved myocardial ischemia/reperfusion injury by suppressing autophagy via inhibiting HMGB1 by repressing KAT7 in MI. Discussion Our finding provides new insight into the mechanism by which circFoxo3 regulates MI-related cardiac dysfunction by targeting KAT7/HMGB1 axis.

The present study aimed to investigate the protective effects of sacubitril/valsartan (lcZ696) on ventricular remodeling in myocardial infarction (Mi) and the effects of the inflammasome-mediated inflammatory response. First, a rat model was established. Animals were then treated with lcZ696 so that the histopathological changes associated with ventricular remodeling could be investigated. The serum levels of the inflammatory factors IL-18 and IL-1β were also determined by ELISA. Immunofluorescence was used to investigate the ratio of pyroptosis following MI modelling. Western blotting and reverse transcription-quantitative Pcr were used to detect the relative expression levels of proteins and mrnas in the transforming growth factor β-activated kinase-1 (TaK1)/JnK pathway and those associated with the nlr pyrin family domain containing 3 (nlrP3) inflammasome, respectively. The present study also investigated the regulatory mechanisms and associations between the TaK1 and JnK pathways, nod-, leucine-rich repeat-and the NLRP3 inflammasome, in H9C2 cells and myocardial cells from the rat model of MI. LCZ696 improved MI-induced myocardial fibrosis, rescued myocardial injury and suppressed the release of inflammatory factors. With regards to myocardial cell damage, pyroptosis in cardiomyocytes was observed. The in vitro experiments demonstrated that the overexpression of TaK1 promoted lysis of the n-terminal of GSdMd, thereby activating the NLRP3 inflammasome and promoting the conversion of pro-il-1β and pro-IL-18 into mature IL-1β and IL-18, respectively. In contrast, the silencing of TAK1 inhibited the expression levels of the NLRP3 inflammasome. in summary, lcZ696 reduced the expression levels of the NLRP3 inflammasome, suppressed inflammatory responses, improved the ventricular remodeling and exhibited protective effects in the Mi heart by inhibiting the TaK1/JnK signaling pathway.

BackgroundHypoadiponectinemia is a high risk factor for type 2 diabetes and cardiovascular disease. Although adiponectin is a protective molecule in cardiovascular diseases, it is hampered due to short plasma half-life and high cost of production. This study aimed to investigate whether AdipoRon, a small-molecule adiponectin receptor agonist, alleviated saturated free fatty acids such as palmitic acid (PA)-induced cardiomyocyte injury by suppressing Nlrp3 inflammasome activation.MethodsCell viability was used with MTT assay. Cell apoptosis and mitochondria membrane potential were detected by flow cytometry. We also detected the ROS production and colocolization of inflammasome protein with fluorescence and immunofluorescence microscopic analysis, respectively. Then, IL-1β was detected by Elisa assay and other protein expression was analyzed by Western blot.ResultsOur observations demonstrated PA dose-dependently promoted the cell injury, and such high lipotoxicity induced impairment of cardiomyocytes was significantly attenuated by AdipoRon treatment. Moreover, PA markedly activated the first phase of Nlrp3 inflammasome (NF-ƙb) signaling. Notably, the stimulation of PA enhanced ROS production as regulators of Nlrp3 inflammasome activation. In addition, treatment with PA increased the Nlrp3 inflammasome protein expression and complex formation, while AdipoRon abolished it. Lastly, the suppressive effect of AdipoRon to PA-induced cell injury and Nlrp3 inflammasome activation was significantly reversed by Nlrp3 siRNA and pan-caspase inhibitor (z-vad-fmk).ConclusionTaken together, these data suggested that AdipoRon suppressed PA-induced myocardial cell injury by suppressing Nlrp3 inflammasome activation. Thus, AdipoRon might possess potent protective effect in lipotoxicity injury such as obesity leading to cardiac disease.

Curcumin has a variety of anticancer properties, but low bioavailability prevents its use in chemotherapeutic applications. To address this problem, we tested the efficacy of the synthetic curcumin analog B14 in breast cancer cells and explored the mechanism by which B14 inhibits proliferation and metastasis of breast cancer cells. We used the breast cancer cell line MCF‐7, MDA‐MB‐231 to study the anticancer effects of B14 and assessed cell viability, cell migration and invasion, cell cycle, and apoptosis, in addition, the antitumor effect of B14 in vivo was examined in mice bearing MDA‐MB‐231 cells. We found that, as the concentration of B14 increased, cell viability decreased in a dose‐dependent manner. Compound B14 exerted the best antitumor activity and selectivity for MCF‐7 and MDA‐M‐231 cells (IC50 = 8.84 μmol/L and 8.33 μmol/L, respectively), while its IC50 value for MCF‐10A breast epithelial cells was 34.96 μmol/L. B14 has been shown to be a multi‐targeted drug that alters the expression of cyclin D1, cyclin E1, and cyclin‐dependent kinase 2 (CDK2), and ultimately induces G1 phase cell cycle arrest. At the same time, B14 activates the mitochondrial apoptosis pathway in breast cancer cells. Furthermore, B14 was more effective than curcumin in inhibiting cell migration, invasion, and colony formation. In tumor‐bearing mice, analog B14 significantly reduced tumor growth and inhibited cell proliferation and angiogenesis. The pharmacokinetic test found that B14 was more stable than curcumin in vivo. Our data reveal the therapeutic potential of the curcumin analog B14 and the underlying mechanisms to fight breast cancer cells.