Dalian Medical University

About: Dalian Medical University is a education organization based out in Dalian, China. It is known for research contribution in the topics: Cancer & Apoptosis. The organization has 15623 authors who have published 9993 publications receiving 164145 citations.

Statins Attenuate Activation of the NLRP3 Inflammasome by Oxidized LDL or TNFα in Vascular Endothelial Cells through a PXR-Dependent Mechanism.

Abstract: Excessive activation of the NLRP3 inflammasome is implicated in cardiovascular diseases. Statins exert an anti-inflammatory effect independent of their cholesterol-lowering effect. This study investigated the potential role of statins in the activation of the NLRP3 inflammasome in endothelial cells (ECs). Western blotting and quantitative reverse-transcription polymerase chain reaction showed that oxidized low-density lipoprotein (ox-LDL) or tumor necrosis factor α (TNFα) activated the NLRP3 inflammasome in ECs. Simvastatin or mevastatin significantly suppressed the effects of ox-LDL or TNFα Promoter reporter assays and small interfering RNA knockdown revealed that statins inhibit ox-LDL-mediated NLRP3 inflammasome activation via the pregnane X receptor (PXR). In addition, PXR agonists (rifampicin and SR12813) or overexpression of a constitutively active PXR markedly suppressed the NLRP3 inflammasome activation. Conversely, PXR knockdown abrogated the suppressive effect of rifampicin on NLRP3 inflammasome activation. Knockdown of lectin-like ox-LDL receptor or overexpression of IκBα-attenuated ox-LDL- or TNFα-triggered activation of the NLRP3 inflammasome. Chromatin immunoprecipitation assays indicated that mevastatin inhibited nuclear factor-κB binding to the promoter regions of the human NLRP3 gene. Collectively, these results demonstrate that the statin activation of PXR inhibits the activation of NLRP3 inflammasome in response to atherogenic stimuli such as ox-LDL and TNFα in ECs, providing a new mechanism for the cardiovascular benefit of statins.

Chloride channel inhibition by a red wine extract and a synthetic small molecule prevents rotaviral secretory diarrhoea in neonatal mice

Abstract: Background Rotavirus is the most common cause of severe secretory diarrhoea in infants and young children globally. The rotaviral enterotoxin, NSP4, has been proposed to stimulate calcium-activated chloride channels (CaCC) on the apical plasma membrane of intestinal epithelial cells. We previously identified red wine and small molecule CaCC inhibitors. Objective To investigate the efficacy of a red wine extract and a synthetic small molecule, CaCC inh -A01, in inhibiting intestinal CaCCs and rotaviral diarrhoea. Design Inhibition of CaCC-dependent current was measured in T84 cells and mouse ileum. The effectiveness of an orally administered wine extract and CaCC inh -A01 in inhibiting diarrhoea in vivo was determined in a neonatal mouse model of rotaviral infection. Results Screening of ∼150 red wines revealed a Cabernet Sauvignon that inhibited CaCC current in T84 cells with IC 50 at a ∼1:200 dilution, and higher concentrations producing 100% inhibition. A >1 kdalton wine extract prepared by dialysis, which retained full inhibition activity, blocked CaCC current in T84 cells and mouse intestine. In rotavirus-inoculated mice, oral administration of the wine extract prevented diarrhoea by inhibition of intestinal fluid secretion without affecting rotaviral infection. The wine extract did not inhibit the cystic fibrosis chloride channel (CFTR) in cell cultures, nor did it prevent watery stools in neonatal mice administered cholera toxin, which activates CFTR-dependent fluid secretion. CaCC inh -A01 also inhibited rotaviral diarrhoea. Conclusions Our results support a pathogenic role for enterocyte CaCCs in rotaviral diarrhoea and demonstrate the antidiarrhoeal action of CaCC inhibition by an alcohol-free, red wine extract and by a synthetic small molecule.

Integrin CD11b mediates α-synuclein-induced activation of NADPH oxidase through a Rho-dependent pathway.

Abstract: The activation of microglial NADPH oxidase (NOX2) induced by α-synuclein has been implicated in Parkinson's disease (PD) and other synucleinopathies. However, how α-synuclein activates NOX2 remains unclear. Previous study revealed that both toll-like receptor 2 (TLR2) and integrin play important roles in α-synuclein-induced microglial activation. In this study, we found that blocking CD11b, the α chain of integrin αMβ2, but not TLR2 attenuated α-synuclein-induced NOX2 activation in microglia. The involvement of CD11b in α-synuclein-induced activation of NOX2 was further confirmed in CD11b-/- microglia by showing reduced membrane translocation of NOX2 cytosolic subunit p47phox and superoxide production. Mechanistically, α-synuclein bound to CD11b and subsequently activated Rho signaling pathway. α-Synuclein induced activation of RhoA and downstream ROCK but not Rac1 in a CD11b-dependent manner. Moreover, siRNA-mediated knockdown of RhoA impeded NOX2 activation in response to α-synuclein. Furthermore, we found that inhibition of NOX2 failed to interfere with the activation of RhoA signaling and interactions between α-synuclein and CD11b, further confirming that NOX2 was the downstream target of CD11b. Finally, we found that genetic deletion of CD11b abrogated α-synuclein-induced NOX2 activatoin in vivo. Taken together, our results indicated that integrin CD11b mediates α-synuclein-induced NOX2 activation through a RhoA-dependent pathway, providing not only a novel mechanistic insight but also a new potential therapeutic target for synucleinopathies.