Extracellular histones induce inflammation and senescence of vascular smooth muscle cells by activating the AMPK/FOXO4 signaling pathway.

BACKGROUND: Sepsis is an abnormal immune-inflammatory response that is mainly caused by infection. It can lead to life-threatening organ dysfunction and death. Severely damaged tissue cells will release intracellular histones into the circulation as damage-related molecular patterns (DAMPs) to accelerate the systemic immune response. Although various histone-related cytotoxicity mechanisms have been explored, those that affect extracellular histones involved in vascular smooth muscle cell (VSMC) dysfunction are yet to be determined. METHODS: Mouse aortic vascular smooth muscle cells (VSMCs) were stimulated with different concentrations of histones, and cell viability was detected by CCK-8 assay. Cellular senescence was assessed by SA ß-gal staining. C57BL/6 mice were treated with histones with or without BML-275 treatment. RT-qPCR was performed to determine the expression of inflammatory cytokines. Western blotting was used to analyze the expression of NLRP3, ASC and caspase-1 inflammasome proteins. The interaction of NLRP3 and ASC was detected by CoIP and immunofluorescence staining. RESULTS: In this study, we found that extracellular histones induced senescence and inflammatory response in a dose-dependent manner in cultured VSMCs. Histone treatment significantly promoted apoptosis-associated speck-like protein containing CARD (ASC) as well as NACHT, LRR and PYD domains-containing protein 3 (NLRP3) interaction of inflammasomes in VSMCs. Forkhead box protein O4 (FOXO4), which is a downstream effector molecule of extracellular histones, was found to be involved in histone-regulated VSMC inflammatory response and senescence. Furthermore, the 5'-AMP-activated protein kinase (AMPK) signaling pathway was confirmed to mediate extracellular histone-induced FOXO4 expression, and blocking this signaling pathway with an inhibitor can suppress vascular inflammation induced by extracellular histones in vivo and in vitro. CONCLUSION: Extracellular histones induce inflammation and senescence in VSMCs, and blocking the AMPK/FOXO4 pathway is a potential target for the treatment of histonemediated organ injury.

Downregulation of SENP1 suppresses LPS-induced macrophage inflammation by elevating Sp3 SUMOylation and disturbing Sp3-NF-κB interaction.

Macrophages participate in all stages of sepsis and affect immune homeostasis and inflammatory processes. Small ubiquitin-like modifier (SUMO) protease SENP1 plays an important role in cellular inflammation by regulating proteins in SUMOylation. However, the roles and related mechanisms of SENP1 in macrophage inflammation during sepsis are largely unknown. In the present study, SENP1 expression was significantly promoted in lipopolysaccharide (LPS)-induced RAW 264.7 cells; furthermore, the knock down of SENP1 reduced the expression of inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Momordin Ic (MC), a new type of SENP1 inhibitor, reduces LPS-induced cellular inflammation by depressing SENP1 expression. Moreover, the effect of SENP1 on LPS-induced inflammatory response was dependent on SENP1-Sp3 interaction and the promotion of Sp3 expression via Sp3 deSUMOylation. Furthermore, MC-depressed Sp3 expression disturbed Sp3-nuclear factor (NF)-κB interaction and then alleviated LPS-induced cellular inflammation. These results suggest that SENP1 promotes LPS-induced macrophage inflammation by promoting Sp3 expression via deSUMOylation and Sp3-NF-κB interaction in sepsis.

Prognostic value of ICU-acquired hypernatremia in patients with neurological dysfunction.

Many studies have indicated that hypernatremia is associated with increased mortality. In this study, we aimed to explore the relationship between intensive care unit (ICU)-acquired hypernatremia and the prognosis of critically neurological patients.Based on serum sodium level in the ICU, 450 patients were divided into 3 groups: 222 had normal serum sodium, 142 had mild hypernatremia, and 86 had severe hypernatremia. Kaplan-Meier and multivariable binary logistic regression analyses were performed to evaluate the prognostic value of hypernatremia in critically neurological patients. Receiver operating characteristic (ROC) curve was constructed for serum sodium levels to determine their roles in predicting ICU mortality.Hypernatremia was significantly related with age, Glasgow Coma Scale (GCS) score, serum sodium, APACHE II score, and serum creatinine. Moreover, the different treatment outcome including mechanical ventilation, the days of stayed in ICU, and Glasgow Outcome Scale score had correlation with serum sodium levels. Old ages, GCS score, therapeutic intervention scoring system (TISS) score, APACHE II score, serum sodium peak, and so on were all associated with the mortality. In addition, hypernatremia was an independent prognostic factor for critically neurological patients by logistic regression analysis (odds ratio = 1.192, 95% confidence interval = 1.135-1.252, P = 0.000). Moreover, we got the sensitivity of 79.4% and specificity of 74.5% in the ROC analysis between peak serum sodium and the mortality. The area under the ROC curve was 0.844, and the optimal cutoff value was 147.55.Our results showed that ICU-acquired hypernatremia may be a potential prognosis marker for critically neurological patients.

[Influence of different treatment patterns on cost-effectiveness in treatment of acute myocardial infarction].

OBJECTIVE: To investigate the influences of different treatment patterns on the cost-effectiveness in treating acute myocardial infarction (AMI). METHODS: Data about referral of AMI patients who called for help because of chest pain to the nearby hospitals from October 2003 to December 2005 were collected from the Guangzhou 120 Call Center. All these patients were followed up 6 months after discharge to survey the cost during hospitalization, major treatment, prognosis (death, re-infarction, stroke etc. ), and secondary prevention for coronary heart disease. We used SF-36 scale was used to quantify the health status. RESULTS: 101 AMI patients referred to grade 2 A hospitals (Group A) and 137 patients referred to grade 3 A hospitals (Group B) were successfully followed up. The cost during hospitalization of Group B was (33965 +/- 963) yuan RMB, significantly higher than that of Group A (18943 +/- 893) yuan, P = 0.021). 11 patients of Group B died, and 5 patients suffered from stroke with the mortality and stroke rate both significantly lower than those of Group A (18/101 and 12/101, P = 0.022, P = 0.015). There was no significant difference in the re-infarction rate between the 2 groups. The scores in physical function, general health status, vitality, social function, role-emotional, mental health of Group B were all significantly higher than those of Group A (all P < 0.05) , however, there were not significant differences in body pain and role-physical between these 2 groups. The smoking cessation rate, specialist outpatient department follow-up rate, statins use rate of Group B were significantly higher than those of Group A (P = 0.017, P = 0.016, P = 0.038). CONCLUSION: The 120-grade 3 A hospital CCU pattern is more cost-effective in treatment of AMI.