Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor β (TNF-β) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.
BackgroundPathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.MethodsThe anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.
To discuss the optimal interval time between genetic algorithm-based ultrasound imaging-guided percutaneous drainage surgery (PTGD) and laparoscopic cholecystectomy (LC), 64 cholecystitis patients were selected as the research objects and evenly divided into experimental group (intelligent algorithm was adopted to recognize patients’ ultrasonic images) and control group (professional doctors carried out diagnosis). 92 acute cholecystitis patients undergoing PTGD were divided into three groups. 30 out of the 92 patients received LC within 2 months and were defined as the early group. 32 were performed with LC within 2 to 4 months and were defined as the metaphase group. 28 underwent LC over 4 months and were defined as the late-stage group. The average operation time, the transition from LC to laparotomy, the average postoperative hospital stay, and the incidence of complications of the three groups were compared. The results revealed that the comparison of the diagnostic accuracy and comprehensive effectiveness between experimental group and control group demonstrated that the differences were statistically significant ( P < 0.05 ). When the optimal interval of implementing LC after PTGD was realized, the corresponding values of the early group were 88.5 minutes, 16.67%, 8.13 days, and 13.75%. Those of the metaphase group were 49.91 minutes, 3.13%, 4.97 days, and 9.52%. Those of the late stage group were 68.78 minutes, 10.71%, 7.09 days, and 11.96%. To sum up, the diagnostic accuracy and comprehensive effectiveness of intelligent algorithm were higher than those of conventional ultrasound, and the optimal interval time of implementing LC after PTGD was 2 to 4 months.
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