Neuroprotective Effect of Ghrelin Is Associated with Decreased Expression of Prostate Apoptosis Response-4

Hwang, Sun‐Young; Moon, Minho; Kim, Sehee; Hwang, Lakkyong; Ahn, Kyu Joong; Park, Seungjoon

doi:10.1507/endocrj.k09e-072

Cited by 47 publications

(46 citation statements)

References 45 publications

(44 reference statements)

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“…Ghrelin also has wide variety of physiological actions throughout the body, including effects on exocrine and endocrine pancreatic functions, carbohydrate metabolism, the cardiovascular system, gastric secretion, stomach motility 230:2 and sleep (Van der Lely et al 2004, Ghigo et al 2005, Kojima & Kangawa 2005. In the central nervous system (CNS), ghrelin shows various nonendocrine effects to control different brain functions, such as enhancement of learning and memory (Diano et al 2006), attenuation of anxiety and depression (Carlini et al 2004, Lutter et al 2008, modulation of reward and motivation (Naleid et al 2005, Abizaid et al 2006, Jiang et al 2006, and protection of neuronal cells (Chung et al 2007, Miao et al 2007, Jiang et al 2008, Hwang et al 2009, Moon et al 2009a, Lee et al 2010a.…”

Section: Introductionmentioning

confidence: 99%

Ghrelin regulates cell cycle-related gene expression in cultured hippocampal neural stem cells

Chung

Park

2016

Journal of Endocrinology

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We have previously demonstrated that ghrelin stimulates the cellular proliferation of cultured adult rat hippocampal neural stem cells (NSCs). However, little is known about the molecular mechanisms by which ghrelin regulates cell cycle progression. The purpose of this study was to investigate the potential effects of ghrelin on cell cycle regulatory molecules in cultured hippocampal NSCs. Ghrelin treatment increased proliferation assessed by CCK-8 proliferation assay. The expression levels of proliferating cell nuclear antigen and cell division control 2, well-known cell-proliferating markers, were also increased by ghrelin. Fluorescence-activated cell sorting analysis revealed that ghrelin promoted progression of cell cycle from G 0 /G 1 to S phase, whereas this progression was attenuated by the pretreatment with specific inhibitors of MEK/extracellular signalregulated kinase 1/2, phosphoinositide 3-kinase/Akt, mammalian target of rapamycin, and janus kinase 2/signal transducer and activator of transcription 3. Ghrelin-induced proliferative effect was associated with increased expression of E2F1 transcription factor in the nucleus, as determined by Western blotting and immunofluorescence. We also found that ghrelin caused an increase in protein levels of positive regulators of cell cycle, such as cyclin A and cyclin-dependent kinase (CDK) 2. Moreover, p27 KIP1 and p57 KIP2 protein levels were reduced when cell were exposed to ghrelin, suggesting downregulation of CDK inhibitors may contribute to proliferative effect of ghrelin. Our data suggest that ghrelin targets both cell cycle positive and negative regulators to stimulate proliferation of cultured hippocampal NSCs.

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Section: Introductionmentioning

confidence: 99%

Ghrelin regulates cell cycle-related gene expression in cultured hippocampal neural stem cells

Chung

Park

2016

Journal of Endocrinology

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“…Among the wide range of common biological functions, acylated and unacylated ghrelin exert a protective activity on several cell lines including cardiac and endothelial cells, pancreatic b cells, islets, and islet microendothelial cells, cortical neurons, vascular smooth muscle cells, and visceral adipocytes (Baldanzi et al 2002;Chung et al 2008;Favaro et al 2012;Granata et al 2007;Hwang et al 2009;Rodríguez et al 2012;Zhan et al 2008). Both peptides promote the differentiation of skeletal myoblasts, preadipocytes, and embryonic stem cells toward cardiomyocytes (Filigheddu et al 2007;Gao et al 2012Gao et al , 2013Giovambattista et al 2008;Miegueu et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Ghrelin Gene Products in Acute and Chronic Inflammation

Prodam,

Filigheddu

2014

Arch. Immunol. Ther. Exp.

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Ghrelin gene products-the peptides ghrelin, unacylated ghrelin, and obestatin-have several actions on the immune system, opening new perspectives within neuroendocrinology, metabolism and inflammation. The aim of this review is to summarize the available evidence regarding the less known role of these peptides in the machinery of inflammation and autoimmunity, outlining some of their most promising therapeutic applications.

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“…In addition, ghrelin exerts numerous peripheral effects including direct effects on exocrine and endocrine pancreatic functions, carbohydrate metabolism, the cardiovascular system, gastric secretion, stomach motility, and sleep ( Van der Lely et al 2004, Ghigo et al 2005, Kojima & Kangawa 2005. Numerous studies have indicated that ghrelin has multiple nonendocrine functions in the CNS to control neuronal function and consequently influence diverse brain functions, such as learning and memory (Diano et al 2006), anxiety and depression (Carlini et al 2004, Lutter et al 2008, reward and motivation (Naleid et al 2005, Abizaid et al 2006, Jiang et al 2006, and neuroprotection (Jiang et al 2006, Chung et al 2007, Miao et al 2007, Hwang et al 2009, Moon et al 2009a, Lee et al 2010a.…”

Section: Introductionmentioning

confidence: 99%

Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells

Chung

Kim

et al. 2013

Journal of Endocrinology

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Ghrelin, an endogenous ligand for the GH secretagogue receptor (GHS-R) receptor 1a (GHS-R1a), has been implicated in several physiologic processes involving the hippocampus. The aim of this study was to investigate the molecular mechanisms of ghrelin-stimulated neurogenesis using cultured adult rat hippocampal neural stem cells (NSCs). The expression of GHS-R1a was detected in hippocampal NSCs, as assessed by western blot analysis and immunocytochemistry. Ghrelin treatment increased the proliferation of cultured hippocampal NSCs assessed by BrdU incorporation. The exposure of cells to the receptor-specific antagonist D-Lys-3-GHRP-6 abolished the proliferative effect of ghrelin. By contrast, ghrelin showed no significant effect on cell differentiation. The expression of GHS-R1a was significantly increased by ghrelin treatment. The analysis of signaling pathways showed that ghrelin caused rapid activation of ERK1/2 and Akt, which were blocked by the GHS-R1a antagonist. In addition, ghrelin stimulated the phosphorylation of Akt downstream effectors, such as glycogen synthase kinase (GSK)-3b, mammalian target of rapamycin (mTOR), and p70 S6K. The activation of STAT3 was also caused by ghrelin treatment. Furthermore, pretreatment of cells with specific inhibitors of MEK/ERK1/2, phosphatidylinositol-3-kinase (PI3K)/Akt, mTOR, and Jak2/STAT3 attenuated ghrelin-induced cell proliferation. Taken together, our results support a role for ghrelin in adult hippocampal neurogenesis and suggest the involvement of the ERK1/2, PI3K/Akt, and STAT3 signaling pathways in the mediation of the actions of ghrelin on neurogenesis. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3b and activation of mTOR/p70 S6K contribute to the proliferative effect of ghrelin.

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Neuroprotective Effect of Ghrelin Is Associated with Decreased Expression of Prostate Apoptosis Response-4

Cited by 47 publications

References 45 publications

Ghrelin regulates cell cycle-related gene expression in cultured hippocampal neural stem cells

Ghrelin regulates cell cycle-related gene expression in cultured hippocampal neural stem cells

Ghrelin Gene Products in Acute and Chronic Inflammation

Multiple signaling pathways mediate ghrelin-induced proliferation of hippocampal neural stem cells

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