General anesthetics are both neuroprotective and neurotoxic with unclear mechanisms. General anesthetics may control cell survival via their effects on autophagy by activation of type 1 inositol triphosphate receptor (InsP3R-1). DT40 or SH-SY5Y cells with only or over 99% expression of InsP3R-1 were treated with isoflurane or propofol. Cell viability was determined by MTT reduction or LDH release assays. Apoptosis was determined by measuring Caspase-3 or by TUNEL assay. Autophagy activity was determined by measuring LC3 II and P62. We evaluated mitochondrial integrity using MitoTracker Green and cytosolic ATP levels. Fura2-AM was used to measure the concentrations of cytosolic calcium ([Ca2+]c). Propofol significantly increased peak and integrated calcium response (P < 0.001) in cells with InsP3R-1 but not in cells with triple knockout of InsP3R. Both propofol and isoflurane increased autophagy induction (P < 0.05) in an mTOR- and InsP3R- activity dependent manner. Short exposure to propofol adequately activated InsP3-1 to provide sufficient autophagy for cytoprotection, while prolonged exposure to propofol induced cell apoptosis via impairment of autophagy flux through over activation of InsP3-1. Propofol damaged mitochondria and decreased cytosolic ATP. The effects of general anesthetics on apoptosis and autophagy are closely integrated; both are caused by differential activation of the type 1 InsP3R.

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Angiogenesis plays a vital role in many physiological and pathological processes and several diseases are connected with its dysregulation. Asiatic acid (AA) has demonstrated anticancer properties and we suspect this might be attributable to an effect on angio-genesis. A modified derivative of AA, N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-L-proline methyl ester (AA-PMe), has improved efficacy over its parent compound, but its effect on blood vessel development remains unclear.MethodsIn this study, we investigated the antiangiogenic activity of AA and AA-PMe in zebrafish embryos and human umbilical vein endothelial cells (HUVECs). First of all, we treated HUVECs with increasing concentrations of AA-PMe or AA, with or without vascular endothelial growth factor (VEGF) present, and assessed cell viability, tube formation, and cell migration and invasion. Quantitative real-time polymerase chain reaction and Western blot analysis were later used to determine the role of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated signaling in AA-PMe inhibition of angiogenesis. We extended these studies to follow angiogenesis using Tg(fli:EGFP) transgenic zebrafish embryos. For these experiments, embryos were treated with varying concentrations of AA-PMe or AA from 24 to 72 hours postfertilization prior to morphological observation, angiogenesis assessment, and endogenous alkaline phosphatase assay. VEGFR2 expression in whole embryos following AA-PMe treatment was also determined.ResultsWe found AA-PMe decreased cell viability and inhibited migration and tube formation in a dose-dependent manner in HUVECs. Similarly, AA-PMe disrupted the formation of intersegmental vessels, the dorsal aorta, and the posterior cardinal vein in zebrafish embryos. Both in vitro and in vivo AA-PMe surpassed AA in its ability to block angiogenesis by suppressing VEGF-induced phosphorylation of VEGFR2 and disrupting downstream extracellular regulated protein kinase and AKT signaling.ConclusionFor the first time, this study reveals that AA-PMe acts as a potent VEGFR2 kinase inhibitor and exerts powerful antiangiogenic activity, suggesting it to be a promising therapeutic candidate for further research.

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0.5 mg/kg ketamine pretreatment showed significant protective effect on acute lung injury induced by HIR, which might be mediated by the NF-κB pathway.

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IntroductionEmergence delirium (ED) is a common adverse manifestation after general anaesthesia and may result in undesirable consequences. Its causes and mechanisms are diverse and complex, and it is still unavoidable in clinical work. There is a high incidence of ED after otorhinolaryngology surgery, which may result from the sudden loss of functional senses and discomfort of surgical organs. This study aims to test a non-invasive, non-drug treatment modality of nose clamping and mouth-breathing training before surgery to reduce ED.Methods and analysisThis prospective randomised controlled trial (RCT) will include 200 patients who undergo functional endoscopic sinus surgery (FESS) at Shanghai General Hospital, China. Study participants will be randomly assigned in two groups with a 1:1 ratio. The pretreatment group (P-group) will receive an intervention by nasal splint and mouth-breathing training before surgery, while the control group (C-group) will not receive any intervention; following which both groups will undergo FESS under general anaesthesia in accordance with the same anaesthesia scheme. After surgery, we will perform a single-blinded assessment of ED occurrence with stratification. IBM SPSS Statistics V.20 statistical software will be used for statistical analyses. A X2 test will be used to compare the two groups, and t-tests will determine the statistical significance of continuous variables.Ethics and disseminationThis RCT was designed in accordance with the principles of the Declaration of Helsinki and has been approved by the Ethics Committee of Shanghai General Hospital, ID: 2019KY039.We expect to release the original data in February 2022 on the ResMan original data sharing platform (IPD sharing platform) of the China clinical trial registry, which can be viewed at the following website:http://www.medresman.org.cn/pub/cn/proj/projectshow.aspx?proj=6293.Trial registration numberChiCTR1900024925