Background: Sphingosine-1-phosphate (S1P), a bioactive lipid, is generally increased in human nonsmall cell lung cancer (NSCLC). Evidence has shown that the levels of enzymes in S1P metabolism were associated with clinical outcomes in patients with NSCLC. Nevertheless, the roles of mRNA expression of major enzymes (SPHK1, SPHK2 and SGPL1) in S1P metabolism for predicting outcomes in NSCLC patients have not been determined.Methods: "The Kaplan-Meier plotter" (the KM plotter) is an online database which contains gene expression and clinical data of 1,928 NSCLC patients. In this study, we analyzed the relationship between mRNA expression of major enzymes in S1P metabolism and overall survival (OS) in 1,926 NSCLC patients with the KM plotter. Further analyses stratified by smoking history, non-metastasis patents, clinical stages, negative surgical margin, chemotherapy and radiotherapy were also performed.Results: High SPHK1 mRNA expression [hazard ratio (HR) 1.47, 95% confident interval (CI): 1.28-1.68, P=2.6e-08] was significantly correlated to worse OS, but high SPHK2 (0.66, 95% CI: 0.59-0.75, P=1.9e-10) or SGPL1 (HR 0.64, 95% CI: 0.55-0.75, P=8.7e-09) mRNA expression was in favor of better OS in NSCLC patients. Conclusions:The mRNA expression of SPHK1, SPHK2, and SGPL1 is potential predictor of outcomes in NSCLC patients.
BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality that imposes a serious medical burden. Antiplatelet therapy is a potential strategy for preventing ARDS in patients with a high risk of developing this condition. A meta-analysis was performed to investigate whether antiplatelet therapy could reduce the incidence of newly developed ARDS and its associated mortality in high-risk patients.MethodsThe Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Medline, and the Web of Science were searched for published studies from inception to 26 October 2017. We included randomized clinical trials, cohort studies and case-control studies investigating antiplatelet therapy in adult patients presenting to the hospital or ICU with a high risk for ARDS. Baseline patient characteristics, interventions, controls and outcomes were extracted. Our primary outcome was the incidence of newly developed ARDS in high-risk patients. Secondary outcomes were hospital and ICU mortality. A random-effects or fixed-effects model was used for quantitative synthesis.ResultsWe identified nine eligible studies including 7660 high-risk patients who received antiplatelet therapy. Based on seven observational studies, antiplatelet therapy was associated with a decreased incidence of ARDS (odds ratio (OR) 0.68, 95% confidence interval (CI) 0.52–0.88; I2 = 68.4%, p = 0.004). In two randomized studies, no significant difference was found in newly developed ARDS between the antiplatelet groups and placebo groups (OR 1.32, 95% CI 0.72–2.42; I2 = 0.0%, p = 0.329). Antiplatelet therapy did not reduce hospital mortality in randomized studies (OR 1.15, 95% CI 0.58–2.27; I2 = 0.0%; p = 0.440) or observational studies (OR 0.80, 95% CI 0.62–1.03; I2 = 31.9%, p = 0.221).ConclusionsAntiplatelet therapy did not significantly decrease hospital mortality in high-risk patients. However, whether antiplatelet therapy is associated with a decreased incidence of ARDS in patients at a high risk of developing the condition remains unclear.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-1988-y) contains supplementary material, which is available to authorized users.
Background Sepsis is the overwhelming inflammatory response to infection, in which nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome plays a crucial role. Shingosine-1-phosphate is reported to evoke NLRP3 inflammasome activation. Sphingosine kinase 1 (SphK1) is the major kinase that catalyzes bioactive lipid shingosine-1–phosphate formation and its role in sepsis remains uncertain. The authors hypothesize that SphK1 elicits NLRP3 inflammasome activation and exacerbates sepsis. Methods Peripheral blood mononuclear cells were isolated from septic patients and healthy volunteers to measure messenger RNA (mRNA) expression. In mice, sepsis was induced by cecal ligation and puncture. Bone marrow–derived macrophages were prepared from C57BL/6J wild-type, Casp1−/−, Nlrp3−/− and SphK1−/− mice. PF-543 was used as the specific inhibitor of SphK1. Mortality, peripheral perfusion, lung Evan’s blue dye index, lung wet/dry ratio, lung injury score, lung myeloperoxidase activity, NLRP3 activation, and function of endothelial adherens junction were measured. Results SphK1 mRNA expression was higher in cells from septic patients versus healthy volunteers (septic patients vs. healthy volunteers: 50.9 ± 57.0 fold change vs. 1.2 ± 0.1 fold change, P < 0.0001) and was positively correlated with IL-1β mRNA expression in these cells (r = 0.537, P = 0.012) and negatively correlated with PaO2/Fio2 ratios (r = 0.516, P = 0.017). In mice that had undergone cecal ligation and puncture, the 5-day mortality was 30% in PF-543–treated group and 80% in control group (n = 10 per group, P = 0.028). Compared with controls, PF-543–treated mice demonstrated improved peripheral perfusion and alleviated extravascular Evan’s blue dye effusion (control vs. PF-543: 25.5 ± 3.2 ng/g vs. 18.2 ± 1.4 ng/g, P < 0.001), lower lung wet/dry ratio (control vs. PF-543: 8.0 ± 0.2 vs. 7.1 ± 0.4, P < 0.0001), descending lung injury score, and weaker lung myeloperoxidase activity. Inhibition of SphK1 suppressed caspase-1 maturation and interleukin-1β release through repressing NLRP3 inflammasome activation, and subsequently stabilized vascular endothelial cadherin through suppressing interleukin-1β–evoked Src-mediated phosphorylation of vascular endothelial cadherin. Conclusions SphK1 plays a crucial role in NLRP3 inflammasome activation and contributes to lung injury and mortality in mice polymicrobial sepsis. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
Background: Coronavirus disease 2019 has caused more than 2 million deaths worldwide.Viral sepsis has been proposed as a description for severe COVID-19, and numerous therapies have been on trials based upon this hypothesis. However, whether the clinical characteristics of severe COVID-19 are similar to those of bacterial sepsis has not been elucidated. Methods:We retrospectively compared the clinical data of non-surviving COVID-19 patients who were admitted to a 30-bed intensive care unit (ICU) in Wuhan Infectious Diseases Hospital (Wuhan, China) from 22
In this work, the corrosion behavior of 30CrMnSiNi2A in a simulated marine environment was studied. The electrochemical behavior was studied by changing the temperature and pH of the solution environment. Detailed information about the rust layer was obtained by scanning electron microscopy, energy-dispersive spectroscopy, and X-ray diffraction. The stress corrosion cracking (SCC) behavior of the steel in artificial seawater was studied through a slow strain rate tensile test (SSRT). The experimental results showed that the corrosion products were mainly composed of α-FeOOH, γ-FeOOH, and Fe3O4, while the content of Fe3O4 in the rust layer formed in the salt spray environment was much higher. The steel in the salt spray test showed a much higher corrosion rate than that observed when it underwent a full-immersion test. The decrease in the pH value mainly accelerated the cathodic reaction, and the temperature simultaneously promoted anodic dissolution and cathodic reductions. The decrease in the elongation during SCC test was minimal, while the index for the reduction-in-area showed a slight SCC susceptibility in the seawater environment, suggesting that anodic dissolution is the dominant mechanism of SCC degradation.
BackgroundInhibition of sphingosine kinase 1 (SphK1), which catalyzes bioactive lipid sphingosine-1–phosphate (S1P), attenuates NLRP3 inflammasome activation. S1P exerts most of its function by binding to S1P receptors (S1PR1-5). The roles of S1P receptors in NLRP3 inflammasome activation remain unclear.Materials and methodsThe mRNA expressions of S1PRs in bone marrow-derived macrophages (BMDMs) were measured by real-time quantitative polymerase chain reaction (qPCR) assays. BMDMs were primed with LPS and stimulated with NLRP3 activators, including ATP, nigericin, and imiquimod. Interleukin-1β (IL-1β) in the cell culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA). Intracellular potassium was labeled with a potassium indicator and was measured by confocal microscopy. Protein expression in whole-cell or plasma membrane fraction was measured by Western blot. Cecal ligation and puncture (CLP) was induced in C57BL/6J mice. Mortality, lung wet/dry ratio, NLRP3 activation, and bacterial loads were measured.ResultsMacrophages expressed all five S1PRs in the resting state. The mRNA expression of S1PR3 was upregulated after lipopolysaccharide (LPS) stimulation. Inhibition of S1PR3 suppressed NLRP3 and pro-IL-1β in macrophages primed with LPS. Inhibition of S1PR3 attenuated ATP-induced NLRP3 inflammasome activation, enhanced nigericin-induced NLRP3 activation, and did not affect imiquimod-induced NLRP3 inflammasome activation. In addition, inhibition of S1PR3 suppressed ATP-induced intracellular potassium efflux. Inhibition of S1PR3 did not affect the mRNA or protein expression of TWIK2 in LPS-primed BMDMs. ATP stimulation induced TWIK2 expression in the plasma membrane of LPS-primed BMDMs, and inhibition of S1PR3 impeded the membrane expression of TWIK2 induced by ATP. Compared with CLP mice treated with vehicle, CLP mice treated with the S1PR3 antagonist, TY52156, had aggravated pulmonary edema, increased bacterial loads in the lung, liver, spleen, and blood, and a higher seven-day mortality rate.ConclusionsInhibition of S1PR3 suppresses the expression of NLRP3 and pro-IL-1β during LPS priming, and attenuates ATP-induced NLRP3 inflammasome activation by impeding membrane trafficking of TWIK2 and potassium efflux. Although inhibition of S1PR3 decreases IL-1β maturation in the lungs, it leads to higher bacterial loads and mortality in CLP mice.
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