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      L-Cysteine Provides Neuroprotection of Hypoxia-Ischemia Injury in Neonatal Mice via a PI3K/Akt-Dependent Mechanism

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          Abstract

          Background

          Previous work within our laboratory has revealed that hydrogen sulfide (H 2S) can serve as neuroprotectant against brain damage caused by hypoxia-ischemia (HI) exposure in neonatal mice. After HI insult, activation of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway has been shown to be implicated in neuro-restoration processes. The goal of the current study was to determine whether the neuroprotective effects of H 2S were mediated by the PI3K/Akt signaling pathway.

          Methods

          The mouse HI model was built at postnatal day 7 (P7), and the effects of L-Cysteine treatment on acute brain damage (72 h post-HI) and long-term neurological responses (28 days post-HI) were evaluated. Nissl staining and Transmission electron microscopy were used to evaluate the neuronal loss and apoptosis. Immunofluorescence imaging and dihydroethidium staining were utilized to determine glial cell activation and ROS content, respectively.

          Results

          Quantitative results revealed that L-Cysteine treatment significantly prevented the acute effects of HI on apoptosis, glial cell activation and oxidative injury as well as the long-term effects upon memory impairment in neonatal mice. This protective effect of L-Cysteine was found to be associated with the phosphorylation of Akt and phosphatase and a tensin homolog deletion on chromosome 10 (PTEN). Following treatment with the PI3K inhibitor, LY294002, the neuroprotective effects of L-Cysteine were attenuated.

          Conclusion

          PTEN/PI3K/Akt signaling was involved in mediating the neuroprotective effects of exogenous H 2S against HI exposure in neonatal mice.

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          Most cited references 30

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          Neonatal brain injury.

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            PI 3-kinase, Akt and cell survival.

            Phosphoinositide 3-OH kinase (PI 3-kinase) provides cells with a survival signal that allows them to withstand apoptotic stimuli. Many tumour cells display elevated levels of PI 3-kinase products as a result of deletion of the phosphatase PTEN, activation of Ras or expression of autocrine growth factors. As a result they are relatively resistant to apoptosis. The mechanisms for PI 3-kinase survival signalling are becoming clear. The principal mediator is Akt, a PI 3-kinase activated protein kinase. Akt has direct effects on the apoptosis machinery, for example targeting the pro-apoptotic Bcl-2 related protein, BAD. It also affects the transcriptional response to apoptotic stimuli, for example by acting on Forkhead factors and also influence the activity of the p53 family. In addition, novel connections between the metabolic effects of Akt and its control of survival have recently been made.
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              TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.

               D Li,  Ying Sun (1997)
              It has long been postulated that protein tyrosine phosphatases may act as tumor suppressors because of their ability to counteract the oncogenic actions of protein tyrosine kinases. Here we report the cloning and characterization of a novel human protein tyrosine phosphatase, TEP1. TEP1 contains the protein tyrosine phosphatase signature motif, and we show that it possesses an intrinsic protein tyrosine phosphatase activity. TEP1 also shares extensive homology with tensin, a cytoskeletal protein localized to focal adhesions, and with auxilin, a protein involved in synaptic vesicle transport. Immunofluorescence studies show that TEP1 is a cytoplasmic protein. The abundance of TEP1 transcription is altered in many transformed cells. In the transforming growth factor beta-sensitive cells, TEP1 expression is rapidly down-regulated by transforming growth factor beta, a cytokine shown to be involved in regulating cell adhesion and cell motility. We have also mapped the gene encoding TEP1 to chromosome 10q23, a locus that is frequently deleted in a variety of human cancers. TEP1 protein is identical to the protein encoded by the candidate tumor suppressor gene PTEN/MMAC1. Our functional studies of the TEP1 protein suggest that its tumor suppressor function may associate with its intrinsic protein tyrosine phosphatase activity and its cytoplasmic localization.
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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
                11 February 2021
                2021
                : 15
                : 517-529
                Affiliations
                [1 ]Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University , Jinan, Shandong, People’s Republic of China
                [2 ]Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University , Jinan, Shandong, People’s Republic of China
                [3 ]Department of Neurosurgery Surgery, Qingdao Municipal Hospital , Shandong Province, People’s Republic of China
                [4 ]Department of Medical Psychology and Ethics, School of Basic Medicine Sciences, Cheeloo College of Medicine, Shandong University , Jinan, Shandong, People’s Republic of China
                Author notes
                Correspondence: Dexiang Liu Department of Medical Psychology and Ethics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University , Jinan, Shandong, 250012, People’s Republic of China Email liudexiang@sdu.edu.cn
                Zhen Wang Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University , 44 Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China Email wangzhen@sdu.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                293025
                10.2147/DDDT.S293025
                7886094
                © 2021 Li 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: 8, References: 30, Pages: 13
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                akt, h2s, hypoxia-ischemia, neuroinflammation

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