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.

Sacubitril valsartan (lcz696) has been demonstrated as a substitute for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for the treatment of heart failure. This research is aimed at examining the effects of lcz696 and its target molecules on myocardial infarction (MI). A rat model of MI was induced by left anterior descending artery ligation and treated with lcz696. Lcz696 treatment significantly reduced cardiac injury and heart failure, restored the left ventricular fractional shortening and ejection fraction, and reduced oxidative stress and inflammatory responses in rat myocardium. By analyzing the heart failure-related GSE47495 dataset and performing gene ontology (GO) functional enrichment analysis, we obtained histone lysine methyltransferase SUV39H1 and secreted phosphoprotein 1 (SPP1) as two molecules implicated in the oxidative stress and inflammation processes. An elevation of SUV39H1 whereas a decline of SPP1 were detected in cardiac tissues after lcz696 treatment. Enrichments of SUV39H1 and H3K9me3 at the SPP1 promoter were identified by chromatin immunoprecipitation assay. SUV39H1 catalyzed H3K9me3 modification to suppress the expression of SPP1. Preconditioning of SUV39H1 silencing blocked the protective roles of lcz696, but SPP1 silencing alleviated the myocardial injury. In conclusion, this study demonstrates that lcz696 enhances cardiac function and alleviates MI in rats through a SUV39H1/SPP1 axis.

Background. The perioperative management of pancreaticoduodenectomy is complicated, and the significant morbidity and mortality may be influenced by the method of intraoperative fluid management. Whether intraoperative restrictive fluid therapy can affect the outcomes of pancreaticoduodenectomy or not is controversial. Methods. PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov were searched for prospective and retrospective studies comparing restrictive and liberal intraoperative fluids in patients undergoing pancreaticoduodenectomy. Following study identification, a systematic review and meta-analysis were performed. Results. Fourteen studies, including six prospective trials and eight retrospective studies, involving 2,596 patients, were included. Intraoperative restrictive fluid regimens had no effect on the mortality compared to liberal fluid regimens in the overall cohort (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 0.82–2.35, p = 0.773 ). Liberal fluid regimens could increase the risk of pulmonary adverse events (OR: 1.66; 95% CI: 1.10–2.50, p = 0.131 ) and prolong the length of hospital stay (SMD -0.10; 95% CI -0.19– -0.01, p = 0.375 ). There were no significant differences in the incidence of pancreatic fistulas. Conclusions. Restrictive fluid regimens have a slight effect on the outcomes of pancreaticoduodenectomy. The clinical relevance of this finding needs to be interpreted. The existing evidence may not be adequate; therefore, further studies are warranted.