No abstract

Background: By associated with inflammation intraplaque, Trimethylamine N-oxide (TMAO) increase the risk of atherosclerotic plaque rupture and has been identified as the independent predictor of cardiovascular events. However, the underlying mechanism is yet unclarity. Accumulating studies have established the critical role of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome in mediating intraplaque inflammation and plaque progression. Here, we discussed the role of NLRP3 inflammasome in aggravating ox-LDL-induced macrophage inflammation response to TMAO and its potential mechanism. Results: Our results showed that TMAO enhanced ox-LDL-induced inflammation in THP-1cells. Adding to TMAO remarkably upregulated the expression or mRNA level of NLRP3, Cysteinyl aspartate specific proteinase 1(caspase-1) p20 and Apoptosis associated speck-like protein containing CARD(ASC) and enhanced the activity of caspase-1. An NLRP3 inhibitor (MCC950) reversed the promoting effect of NLRP3 inflammasome activation by TMAO and subsequently macrophage inflammation. Significantly, TMAO also boosted the activation of endoplasmic reticulum stress (ERS) and nuclear factor-kappa B (NF-kB) pathway in ox-LDL-induced cells, manifested as the increasing expression of p-NF-κB, Bip and phosphorylated protein kinase R-like ER kinase (p-PERK). Activation of the NLRP3 inflammasome by TMAO was reversed by the ERS inhibitor 4-PBA or the NF-κB phosphorylation inhibitor JSH-23. Meanwhile, 4-PBA further inhibited the NF-κB phosphorylation and alleviated the NLRP3 inflammasome activation. Conclusions: We concluded that TMAO exacerbates ox-LDL-induced NLRP3 inflammasomes activation and subsequently interleukin (IL)-18 and IL-1b release in THP-1 macrophages, which partly regulated by the activating of the PERK/NF-κB signaling pathway.

In order to investigate the structural stress dependence on the load conditions and material parameters, reduce and optimize the design variables, an orthogonal numerical test method is presented. First of all, the oxygen decompressor stress sensitivities to pressure, inertia force, elastic modulus and Poisson's Ratio are analyzed based on the method. The results show that besides the effects of the pressure and the inertial force controlled by environmental load conditions, the effect of the elastic modulus on the stress is greatest; Then, the elastic modulus of the spring cavity, shell and screw are optimized by the optimization, and the optimal combination of elastic modulus for minimum stress is obtained. The conclusion shows that: the method used in this paper has a small amount of calculation, and can meet the requirement of the engineering design.

No abstract

Macrophages inflammation from variety of risk factors is critical in the rupture of atherosclerotic(AS) plaques. Trimethylamine oxide (TMAO), a dietary metabolite that depends on Gut microbiota, exerts strongly pro-inflammatory effects on Atherosclerosis. Nowadays, mounting research showed that NLRP3 inflammasome activation is essential for the pathogenesis of AS. The present study was to investigate the effect of TMAO on ox-LDL-induced NLRP3 inflammasomes activation of THP-1 cells, and to explore the potential mechanism. Used Cell Counting Kit-8 assay, LDH assay to evaluate the changes of macrophage activity under TMAO and ox-LDL, respectively, to clarify the appropriate dosage. Proteins related to NLRP3 inflammasomes, NF-kb and ERS were determined via Western Blot. Inflammatory cytokine secretion was then examined via ELISA. PCR detected gene levels of inflammatory markers, and caspase-1 activity assay was utilized to detect intracellular caspase-1 activity. The results showed that TMAO could activate NLRP3 inflammasome in ox-LDL-induced THP-1 macrophages and accelerate inflammatory factor release. In addition, TMAO can further activate the expression of ERS-related proteins( including BiP、p-PERK) and NF-KB pathway. NLRP3 inhibitor MCC950, NF-kb inhibitor JSH-23, and ER stress inhibitor 4-PBA reversed TMAO's promoting effect in ox-LDL-induced macrophage. Given these data, we conclude that TMAO promotes NLRP3 inflammasomes activation via the ERS/NF-kb pathway in ox-LDL induced THP-1 macrophages. Reducing the TMAO levels may be a viable approach to prevent atherosclerosis plaque development.