Expression subcellular localization transcriptional activity

Expression, subcellular localization, transcriptional activity and protein stability of Foxo are regulated by proteins such as STAT3, PKB, JNK and AMPK (Sun et al., 2017; Zhang et al., 2011). STAT3 is a member of the signal transducer and activator of transcription (STAT) protein family that plays critical roles in cell apoptosis and cell growth (Kong et al., 2016aa,b). STAT3 has been reported to promote up-regulation of Foxo and cell survival in T-lymphocytes (Oh et al., 2011). Here, we demonstrate that JEV infection in Neuro-2a cells reduce the Foxo expression, at least in part, by decreasing STAT3 expression (Fig. 4).
Introduction Stress is an adaptive and coordinated response to an internal or external challenge that is perceived as unpleasant or threatening to homeostasis, wellbeing or survival of an individual. The physiological stress response comprises the rapid activation of the sympatho-adrenal axis and the release of catecholamines from the adrenal medulla and the delayed activation of the hypothalamic–pituitary–adrenal (HPA) axis and the release of glucocorticoids, corticosterone (CORT) in rodents and cortisol in humans from the adrenal cortex (Lucassen et al., 2014). All these aim to use energy resources more efficiently by shifting attention on the most urgent and important elements to prepare individuals to be able to cope with stress while less urgent vegetative functions, such as digestion and absorption, are temporarily suppressed (Joels et al., 2012). Exposure to strong and long-term physical and psychological stress leads to the hyperactivity of the HPA axis and elevated glucocorticoid levels (Dettmer et al., 2012). Glucocorticoid receptors (GR) are expressed in many ghrelin receptor structures, particularly in the hippocampus. This makes the hippocampus vulnerable to elevated glucocorticoid levels as seen in a stress response (de Kloet et al., 2005, Swaab et al., 2005, Lucassen et al., 2010). Previous studies show that stress induces atrophy and loss of neurons in the adult hippocampus (Watanabe et al., 1992, Stein-Behrens et al., 1994, McEwen, 1999). Negative correlations were observed between glucocorticoid levels and hippocampal size and cognitive function (Lupien et al., 1998). In depressed adolescent patients, smaller hippocampal volumes were observed compared to healthy controls (MacMaster and Kusumakar, 2004). Administration of a GR agonist induces apoptosis in the dentate gyrus and CA3 pyramidal cell layers (Sousa et al., 1999, Almeida et al., 2000). Hippocampal damage could result from the hypersecretion of glucocorticoids amounting to neuronal death or the failure of adult neurogenesis in the dentate gyrus (Tae et al., 2011). We hypothesized that high corticosteroid levels as seen in stress and depressed patients might cause hippocampal volume reduction, hippocampal damage and impaired cognitive function by inducing apoptosis of hippocampal neurons. Oxytocin (OT), a neuropeptide produced mainly in the paraventricular and the supraoptic nuclei of the hypothalamus, is essential in parturition and lactation (Swanson and Sawchenko, 1983). In the brain, OT plays an important role in regulation of emotional, parental, affiliative and sexual behaviors. Previous studies showed that OT mediates antistress and antidepressant-like effects in mice and rats (Uvnas-Moberg and Petersson, 2005, Matsuzaki et al., 2012). Plasma OT levels increase during stress responses and decrease stress in humans (Taylor et al., 2006). In addition, centrally administered OT inhibited stress-induced CORT release in rats (Windle et al., 1997). OT receptors (OTRs) are strongly expressed in mouse hippocampus and amygdala (Tomizawa et al., 2003, Freeman and Young, 2016). OT maintains hippocampal synaptic plasticity and memory during stress (Lee et al., 2015). OT also stimulates adult neurogenesis in rats subjected to glucocorticoid administration or cold water swim stress (Leuner et al., 2012). OT may exert anti-stress effects by protecting hippocampal neurons from the damaging effects of glucocorticoids. In the present study, we demonstrated that OT inhibits CORT-induced apoptosis in primary hippocampal neurons.