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      Anti-microRNA-132 causes sevoflurane-induced neuronal apoptosis via the PI3K/AKT/FOXO3a pathway

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          Abstract

          In the present study, the mechanisms underlying the protective effects of microRNA-132 (miRNA-132) on sevoflurane-induced neuronal apoptosis were investigated. Reverse transcription-quantitative polymerase chain reaction and gene microarray hybridization were used to analyze alterations in microRNA levels. Cell viability, apoptosis and caspase-3/9 activity were measured using MTT, flow cytometry and caspase-3/9 activity kits. Immunofluorescence staining and western blot analysis were used to measure protein expression of phosphoinositide 3-kinase (PI3K) and phosphorylated (p-)AKT, forkhead box O3a (FOXO3a). In sevoflurane-induced rats, the expression of miRNA-132 was downregulated, compared with that in negative control rats. The downregulation of miRNA-132 increased neuronal apoptosis and the upregulation of miRNA-132 inhibited neuronal apoptosis in the sevoflurane-induced in vitro model. The downregulation of miRNA-132 suppressed the protein expression of PI3K and p-AKT, and suppressed the protein expression of FOXO3a in the sevoflurane-induced in vitro model. The PI3K inhibitor increased the effects of anti-miRNA-132 on neuronal apoptosis through the AKT/FOXO3a pathway in the sevoflurane-induced in vitro model. The promotion of FOXO3a inhibited the effects of anti-miRNA-132 on neuronal apoptosis through the AKT/FOXO3a pathway in the sevoflurane-induced in vitro model. These data suggested that miRNA-132 caused sevoflurane-induced neuronal apoptosis via suppression of the PI3K/AKT/FOXO3a pathway.

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          Most cited references 20

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          Inhibition of Autophagy via Activation of PI3K/Akt Pathway Contributes to the Protection of Ginsenoside Rb1 against Neuronal Death Caused by Ischemic Insults

          Lethal autophagy is a pathway leading to neuronal death caused by transient global ischemia. In this study, we examined the effect of Ginsenoside Rb1 (GRb1) on ischemia/reperfusion-induced autophagic neuronal death and investigated the role of PI3K/Akt. Ischemic neuronal death in vitro was induced by using oxygen glucose deprivation (OGD) in SH-SY5Y cells, and transient global ischemia was produced by using two vessels occlusion in rats. Cellular viability of SH-SY5Y cells was assessed by MTT assay, and CA1 neuronal death was evaluated by Hematoxylin-eosin staining. Autophagic vacuoles were detected by using both fluorescent microscopy in combination with acridine orange (AO) and Monodansylcadaverine (MDC) staining and transmission electronic microscopy. Protein levels of LC3II, Beclin1, total Akt and phosphor-Akt at Ser473 were examined by western blotting analysis. GRb1 inhibited both OGD and transient ischemia-induced neuronal death and mitigated OGD-induced autophagic vacuoles in SH-SY5Y cells. By contrast, PI3K inhibitor LY294002 counteracted the protection of GRb1 against neuronal death caused by either OGD or transient ischemia. LY294002 not only mitigated the up-regulated protein level of phosphor Akt at Ser473 caused by GRb1, but also reversed the inhibitory effect of GRb1 on OGD and transient ischemia-induced elevation in protein levels of LC3II and Beclin1.
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            PI3K/AKT Signaling Pathway Is Essential for Survival of Induced Pluripotent Stem Cells

            Apoptosis is a highly conserved biochemical mechanism which is tightly controlled in cells. It contributes to maintenance of tissue homeostasis and normally eliminates highly proliferative cells with malignant properties. Induced pluripotent stem cells (iPSCs) have recently been described with significant functional and morphological similarities to embryonic stem cells. Human iPSCs are of great hope for regenerative medicine due to their broad potential to differentiate into specialized cell types in culture. They may be useful for exploring disease mechanisms and may provide the basis for future cell-based replacement therapies. However, there is only poor insight into iPSCs cell signaling as the regulation of apoptosis. In this study, we focused our attention on the apoptotic response of Alzheimer fibroblast-derived iPSCs and two other Alzheimer free iPSCs to five biologically relevant kinase inhibitors as well as to the death ligand TRAIL. To our knowledge, we are the first to report that the relatively high basal apoptotic rate of iPSCs is strongly suppressed by the pancaspase inhibitor QVD-Oph, thus underlining the dependency on proapoptotic caspase cascades. Furthermore, wortmannin, an inhibitor of phosphoinositid-3 kinase / Akt signaling (PI3K-AKT), dramatically and rapidly induced apoptosis in iPSCs. In contrast, parental fibroblasts as well as iPSC-derived neuronal cells were not responsive. The resulting condensation and fragmentation of DNA and decrease of the membrane potential are typical features of apoptosis. Comparable effects were observed with an AKT inhibitor (MK-2206). Wortmannin resulted in disappearance of phosphorylated AKT and activation of the main effector caspase-3 in iPSCs. These results clearly demonstrate for the first time that PI3K-AKT represents a highly essential survival signaling pathway in iPSCs. The findings provide improved understanding on the underlying mechanisms of apoptosis regulation in iPSCs.
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              Dicer and microRNAs protect adult dopamine neurons

              MicroRNAs (miRs) are important post-transcriptional regulators of gene expression implicated in neuronal development, differentiation, aging and neurodegenerative diseases, including Parkinson’s disease (PD). Several miRs have been linked to PD-associated genes, apoptosis and stress response pathways, suggesting that deregulation of miRs may contribute to the development of the neurodegenerative phenotype. Here, we investigate the cell-autonomous role of miR processing RNAse Dicer in the functional maintenance of adult dopamine (DA) neurons. We demonstrate a reduction of Dicer in the ventral midbrain and altered miR expression profiles in laser-microdissected DA neurons of aged mice. Using a mouse line expressing tamoxifen-inducible CreERT2 recombinase under control of the DA transporter promoter, we show that a tissue-specific conditional ablation of Dicer in DA neurons of adult mice led to decreased levels of striatal DA and its metabolites without a reduction in neuronal body numbers in hemizygous mice (DicerHET) and to progressive loss of DA neurons with severe locomotor deficits in nullizygous mice (DicerCKO). Moreover, we show that pharmacological stimulation of miR biosynthesis promoted survival of cultured DA neurons and reduced their vulnerability to thapsigargin-induced endoplasmic reticulum stress. Our data demonstrate that Dicer is crucial for maintenance of adult DA neurons, whereas a stimulation of miR production can promote neuronal survival, which may have direct implications for PD treatment.
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                Author and article information

                Journal
                Int J Mol Med
                Int. J. Mol. Med
                IJMM
                International Journal of Molecular Medicine
                D.A. Spandidos
                1107-3756
                1791-244X
                December 2018
                25 September 2018
                25 September 2018
                : 42
                : 6
                : 3238-3246
                Affiliations
                [1 ]Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012
                [2 ]Department of Anesthesiology, The People's Hospital of Chiping, Chiping, Shandong 252100, P.R. China
                Author notes
                Correspondence to: Ms. Bo Yang, Department of Anesthesiology, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, Shandong 250012, P.R. China, E-mail: bpy94861763@ 123456126.com
                [*]

                Contributed equally

                Article
                ijmm-42-06-3238
                10.3892/ijmm.2018.3895
                6202078
                30272258
                Copyright: © Dong et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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