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ChiCTR-OCC-15005789, Results.

Background Neuroinflammation-induced injury is intimately associated with poor prognosis in patients with cerebral venous sinus thrombosis (CVST). The cyclic GMP-AMP synthase–stimulator of interferon gene (cGAS–STING) axis is a cytoplasmic double-stranded DNA (dsDNA) sensing pathway has recently emerged as a crucial mediator of neuroinflammation in ischemic stroke. However, the role of the cGAS–STING pathway in modulating post-CVST inflammation and the underlying mechanisms involved remain unclear. Methods A CVST model was induced by ferric chloride in male C57BL/6J mice. The selective cGAS inhibitor RU.521, STING agonist 2′3′-cGAMP, and STING siRNA were delivered by intranasal administration or intraventricular injection. Post-CVST assessments included rotarod test, TUNEL staining, Fluoro-Jade C staining, dihydroethidium staining, western blotting, qPCR, immunofluorescence, immunohistochemistry, ELISA and flow cytometry. Results cGAS, STING, NLRP3 and GSDMD were significantly upregulated after CVST and mostly in the microglia of the mouse brain. CVST triggered the release of dsDNA into the cytoplasm and elicited an inflammatory response via activating the cGAS–STING axis. RU.521 decreased the levels of 2′3′-cGAMP, STING and downstream inflammatory cytokines, and suppressed the expressions of NLRP3 inflammasome and pyroptosis-pertinent components containing cleaved caspase-1, GSDMD, GSDMD-C, pro- and cleaved IL-1β, and cleaved IL-1β/pro-IL-1β. Besides, RU.521 treatment also reduced oxidative stress, lessened the numbers of microglia and neutrophils, and ameliorated neuronal apoptosis, degeneration along with neurological deficits post-CVST. 2′3'-cGAMP delivery enhanced the expressions of STING and related inflammatory mediators, NLRP3 inflammasome and pyroptosis-relevant proteins, whereas these alterations were significantly abrogated by the silencing of STING by siRNA. Conclusions Our data demonstrate that repression of the cGAS–STING pathway diminishes the neuroinflammatory burden of CVST and highlight this approach as a potential therapeutic tactic in CVST-mediated pathologies.

BackgroundEvidence is currently accumulating for the role of in ammation in cerebral venous thrombosis (CVT). Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/high-density lipoprotein ratio (MHR), and systematic immune-in ammation index (SII) are easily obtainable indicators of systemic in ammations. However, there were few studies on the relationship between them and CVT.Therefore, we aimed to evaluate the connection between the occurrence of CVT and the in ammatory markers described. MethodsThe samples from 150 participants (including 90 CVT and 60 controls) with similar baseline characteristics were collected in this retrospective study. The NLR, PLR, MHR, SII and le records were employed to compare CVT patients with the control group.

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The accumulation of plasma advanced oxidation protein products (AOPPs) has been linked with diverse disorders, including diabetes, chronic kidney disease, obesity, and metabolic syndrome. The aim of the present study was to evaluate the pathophysiological relevance of AOPPs in β-cell destruction and dysfunction. Exposure of cultured rat β-cells (INS-1) to AOPPs induced an increase in Bax expression, caspase-3 activity, and apoptosis as well as a decrease in Bcl-2 expression in a dose- and time-dependent manner. AOPP challenge rapidly increased the production of intracellular superoxide by activation of NADPH oxidases, demonstrated by p47 translocation and interaction with p22 and gp91, and this in turn led to apoptosis. AOPPs treatment resulted in β-cell apoptosis, AOPPs accumulation, and decreased insulin content in pancreas and plasma in unilateral nephrectomized rats. Chronic inhibition of NADPH oxidase by apocynin prevented β-cell apoptosis and ameliorated insulin deficiency in AOPP-challenged rats. This study demonstrates for the first time that accumulation of AOPPs promotes NADPH oxidase-dependent β-cell destruction and dysfunction by the Bcl-2/Bax-caspase apoptotic pathway. This finding may provide a mechanistic explanation for β-cell destruction and dysfunction in patients with diverse disorders.

Micro-dimples are among the basic microfeatures that have been applied to different products in various fields. The product performance and service life of textured surfaces are directly affected by size, location, and density. A modified microscale pattern transfer process without photolithography of substrates, through the use of movable dry-film mask electrochemical micromachining, has been proposed for the production of micro-dimples. This paper investigates the influence of electrochemical micromachining parameters, namely, applied voltage and machining time on the machining accuracy of micro-dimples produced using this technique. Experimental results indicate that the machining accuracy deteriorates with prolonged machining time and increasing applied voltage. It is found that to obtain high machining accuracy when machining micro-dimples of similar depth, a combination of higher current density with reduced machining time is recommended.