Atherosclerosis, a chronic comprehensive cardiovascular disease, is characterized by the lipid infiltration, formation of foam cells derived from macrophages and inflammation in the vessel wall. Substantial evidence confirms that the activity of autophagic bodies plays a pivot role in regulating cell deaths, but the mechanisms of autophagy to regulate the pyroptosis of macrophages in atherosclerosis remain unclear. In our study, we explored that ox-LDL decreased the cell viability and destroyed the integrity of cell membrane, resulting in the pyroptosis of THP-1 derived macrophages in a dose-dependent manner. Western blotting, qRT-PCR and ELISA also showed that chloroquine (CQ) could up-regulate the expression of p62 through impairing autophagy and induce the pyroptosis of macrophages treated by ox-LDL, as evidenced by the decrease of cell viability and membrane integrity, and the increase of pro-caspase-1, GSDMD, and proinflammatory factors IL-1β and IL-18. Further researches demonstrated that Nrf2, a nuclear factor activated by p62, was linked to macrophage pyroptosis. Overactivating or suppressing Nrf2/ARE signaling would correspondingly aggravate or alleviate pyroptosis, in which the level of p62 was regulated by Nrf2 feedback. Then, bioinformatic analysis verified that there was a close interaction between p62, Nrf2/ARE signaling proteins and pyroptosis-related proteins. Taken together, our results show that blocking autophagy promotes the pyroptosis of ox-LDL-treated macrophages via the p62/Nrf2/ARE axis, providing a novel therapeutic target for atherosclerosis.

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ObjectiveSimulation training of endotracheal intubation (ETI) has proven to be an effective training tool. We used an adjustable airway mannequin that allows the achievement of various difficulty levels of laryngoscopy to train inexperienced medical students. The purpose of this study was to evaluate the effect of training using this novel airway mannequin on ETI success rates of medical students.MethodsThis was a randomised non-blinded trial conducted at the Steinberg Centre for Simulation and Interactive Learning. Twenty recruited medical students were randomly allocated to two different training groups. During training, the mixed training group was asked to perform successful intubations in three levels of difficulty; the standard training group was asked to perform the same number of successful intubations in one level of difficulty. After training, all participants were asked to perform intubations using both the adjustable airway mannequin and a standard mannequin. Success rates and airway surface area visualised were compared between the two groups.ResultsStudents in the mixed training group had a significantly higher success rate both in the adjustable airway mannequin (p=0.01) and in the standard mannequin (p=0.02). Students in the mixed group had 51%, 59% and 47% significantly more visual area surface than students in the standard group during standard and difficult setup of the adjustable airway mannequin and the standard airway mannequin, respectively.ConclusionsThe use of an adjustable airway mannequin to train medical students leads to superior ETI success rates and better glottis visualisation.

Age and inflammation are powerful drivers of cardiovascular disease. With the growing recognition that traditional cardiovascular risk factors are not fully accurate predictors of cardiovascular disease, recent studies have revealed the prevalence of positive selection of somatic cell mutations in hematopoietic stem cells in the elderly population, which can cause clonal hematopoiesis. Interestingly, clonal hematopoiesis is not only associated with cancer and death, but also closely related to the risk of increased cardiovascular disease due to mutations in TET2, DNMT3A, ASXL1, and JAK2. However, the mechanism of the interaction of clonal hematopoiesis and cardiovascular disease is only partially understood. In mice, somatic mutations have led to significantly increased expression of inflammatory genes in innate immune cells, which may explain the relationship between mutations and cardiovascular disease. Here, we further discuss the association between inflammatory signaling, clonal hematopoiesis, and cardiovascular disease,and using two hypotheses to propose a feedback loop between inflammatory signaling and clonal hematopoiesis for getting insight into the pathogenesis of cardiovascular diseases in depth. Therapies targeting mutant clones or increased inflammatory mediators may be useful for ameliorating the risk of cardiovascular disease.

There is now overwhelming experimental and clinical evidence that atherosclerosis is a chronic inflammatory disease and characterized by lipid deposition in blood vessels. Pyroptosis, an inflammatory form of cell death by certain inflammasomes, has been shown to be associated with the development of AS in recent years. However, the relationship between lipid deposition in foam cells and cell pyroptosis has not been clarified. Here, we demonstrate that with increasing ox-LDL concentration, the expression of pyroptosis associated protein GSDMD, NLRP3 inflammasome gradually increased, intracellular LDH and mature IL-1β release increased, and the proportion of double positive cells with Hoechst/PI staining increased. Interestingly, the expression of NF-κB signal activation marker protein p-NF-κB and p-IκB increased with the increase of ox-LDL concentration. Ox-LDL-induced pyroptosis can be abolished by NF-κB phosphorylation inhibitor, BAY11-7082. Additionally, BAY11-7082 could also significantly up-regulate the protein expression of ABCA1 and eliminate the inhibitory effect of ox-LDL on the expression of ABCA1.Moreover, siABCA1 was transfected into THP-1-derived macrophages under ox-LDL treatment. Compared with the control group, the expression of GSDMD and NLRP3 inflammasome, the release of mature IL-1β and LDH increased, and the proportion of Hoechst/PI staining double-positive cells increased with blocked cholesterol efflux. Finally, cells treated with VX-765, a pyroptosis inhibitor, showed increased cholesterol efflux and cell foaming in THP-1-derived macrophages,which suggest that cell pyroptosis may be a "double-edged sword" in the development of AS. In conclusion,our findings demonstrate for the first time that the NF-κB/ABCA1 pathway is involved in ox-LDL induced pyroptosis by cholesterol efflux blocked activation of NLRP3 inflammasomes in THP-1-derived macrophages, providing a new therapeutic avenue for the prevention and treatment of AS.

The Vision Health Research Network (VHRN) is a provincial scientific organization that aims to improve the ocular health of patients across Quebec by supporting local research endeavors in vision health. The VHRN Student Committee, composed of 288 trainees with diverse backgrounds, has demonstrated its commitment to the scholarly development of its members by providing leadership opportunities, creating networking events, increasing visibility of researchers-in-training and encouraging professional advancement through educational workshops and funding programs. In this article, we review the contributions of the VHRN Student Committee and discuss its future projects.

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