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      Sevoflurane post-conditioning alleviates neonatal rat hypoxic-ischemic cerebral injury via Ezh2-regulated autophagy

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          Abstract

          Background: When neonatal rats suffer hypoxic-ischemic brain injury (HIBI), autophagy is over-activated in the hippocampus, and inhibition of autophagy provides neuroprotection. The aim of this study was to investigate the possible roles of autophagy and Ezh2-regulated Pten/Akt/mTOR pathway in sevoflurane post-conditioning (SPC)-mediated neuroprotection against HIBI in neonatal rats.

          Methods: Seven-day-old Sprague–Dawley rats underwent left common artery ligation followed by 2 h hypoxia as described in the Rice–Vannucci model. The roles of autophagy and the Ezh2-regulated Pten/Akt/mTOR signaling pathway in the neuroprotection conferred by SPC were examined by left-side intracerebroventricular injection with the autophagy activator rapamycin and the Ezh2 inhibitor GSK126.

          Results: SPC was neuroprotective against HIBI through the inhibition of over-activated autophagy in the hippocampus as characterized by the rapamycin-induced reversal of neuronal density, neuronal morphology, cerebral morphology, and the expression of the autophagy markers, LC3B-II and Beclin1. SPC significantly increased the expression of Ezh2, H3K27me3, pAkt, and mTOR and decreased the expression of Pten induced by HI. The Ezh2 inhibitor, GSK126, significantly reversed the SPC-induced changes in expression of H3K27me3, Pten, pAkt, mTOR, LC3B-II, and Beclin1. Ezh2 inhibition also reversed SPC-mediated attenuation of neuronal loss and behavioral improvement in the Morris water maze.

          Conclusion: These results indicate that SPC inhibits excessive autophagy via the regulation of Pten/Akt/mTOR signaling by Ezh2 to confer neuroprotection against HIBI in neonatal rats.

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          Most cited references 39

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          Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network.

           Y Kabeya,  Y Ohsumi,  A Kihara (2001)
          Autophagy is an intracellular bulk protein degradation system. Beclin is known to be involved in this process; however, its role is unclear. In this study, we showed that Beclin was co-immunoprecipitated with phosphatidylinositol (PtdIns) 3-kinase, which is also required for autophagy, suggesting that Beclin is a component of the PtdIns 3-kinase complex. Quantitative analyses using a cross-linker showed that all Beclin forms a complex with PtdIns 3-kinase, whereas approximately 50% of PtdIns 3-kinase remains free from Beclin. Indirect immunofluorescence microscopy demonstrated that the majority of Beclin and PtdIns 3-kinase localize to the trans-Golgi network (TGN). Some PtdIns 3-kinase is also distributed in the late endosome. These results suggest that Beclin and PtdIns 3-kinase control autophagy as a complex at the TGN.
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            Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation.

            Recently, investigation of new neurons in memory formation has focused on a specific function-pattern separation. However, it has been difficult to reconcile the form of separation tested in behavioral tasks with how it is conceptualized according to computational and electrophysiology perspectives. Here, we propose a memory resolution hypothesis that considers the unique information contributions of broadly tuned young neurons and highly specific mature neurons and describe how the fidelity of memories can relate to spatial and contextual discrimination. See the related Perspective from Sahay, Wilson, and Hen, "Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb," in this issue of Neuron. Copyright © 2011 Elsevier Inc. All rights reserved.
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              EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-β-catenin signaling.

              It has been proposed that an aggressive secondary cancer stem cell population arises from a primary cancer stem cell population through acquisition of additional genetic mutations and drives cancer progression. Overexpression of Polycomb protein EZH2, essential in stem cell self-renewal, has been linked to breast cancer progression. However, critical mechanism linking increased EZH2 expression to BTIC (breast tumor initiating cell) regulation and cancer progression remains unclear. Here, we identify a mechanism in which EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in BTICs, which activates p-ERK-β-catenin signaling to promote BTIC expansion. We further reveal that AZD6244, a clinical trial drug that inhibits RAF1-ERK signaling, could prevent breast cancer progression by eliminating BTICs. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                15 May 2019
                2019
                : 13
                : 1691-1706
                Affiliations
                [1 ]Department of Anesthesiology, Shengjing Hospital, China Medical University , Shenyang 110004, People’s Republic of China
                Author notes
                Correspondence: Ping ZhaoDepartment of Anesthesiology, Shengjing Hospital, China Medical University , 36 Sanhao Street, Shenyang110004, People’s Republic of ChinaTel +861 894 025 8971Fax +86 242 326 9477Email zhaop_sj@ 123456163.com ; zhaop@ 123456sj-hospital.org
                Article
                197325
                10.2147/DDDT.S197325
                6528650
                © 2019 Xue et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, Tables: 2, References: 49, Pages: 16
                Categories
                Original Research

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