In conclusion our results show

In conclusion, our results show that P7C3 enhances endogenous neurogenesis by upregulating the generation of endogenous neuroblasts and neural stem/progenitor cells by increasing the expression of neuroprotective proteins (Bcl-2, ki67, DCX, adam11, adamts20, and β-tub3) by activation of the cAMP/PKA-dependent and/or Akt/GSK-3-associated β-catenin upregulation/activation through positive allosteric stimulation of GLP-1R (Fig. 9). This report provides novel findings related to the therapeutic action and underlying molecular mechanisms of P7C3 in protecting against ischemic BAY 87-2243 injury in mice. As a potent brain protective agent with strong endogenous neurogenesis enhancing capacities, the beneficial effects of P7C3 in the treatment of acute ischemic stroke in humans are well worth further investigation.
Conflict of interest
Introduction Yuet Wai Kan and colleagues first described NF-E2 p45-related factor 2 (Nrf2, encoded by NFE2L2) when they identified it as the third human cap'n'collar (CNC) basic-region leucine zipper (bZIP) transcription factor to be cloned [1]. Shortly thereafter, Masayuki Yamamoto and colleagues reported an orthologous cDNA from chicken encoding a transcription factor that they called erythroid cell-derived protein with CNC homology (ECH) [2]. The protein is now designated Nrf2, rather than ECH. In mammalian species, Nrf2 regulates the expression of approximately 250 genes, each of which contains an antioxidant response element (ARE, 5′-TGACNNNGC-3′) sequence in its promoter region(s) 3, 4. Nrf2 is a short-lived transcription factor, but upon exposure to oxidative stressors it is stabilized, rapidly accumulates, and increases transactivation of ARE-driven genes [5]. The instability of Nrf2 protein is largely controlled by Kelch-like ECH-associated protein 1 (Keap1), a redox-sensitive substrate adaptor for the cullin-3 (Cul3)-based ubiquitin ligase CRLKeap1∗6, ∗7, and a prevailing view is that alleviation of the repression exerted by Keap1 on Nrf2 is entirely responsible for induction of ARE-driven genes by oxidative stressors. It is however much less widely appreciated that Nrf2 is also negatively regulated by glycogen synthase kinase-3 (GSK-3), and it has been proposed that inhibition of GSK-3 contributes to induction of ARE-driven genes [8∗]. Critically, in this case, GSK-3 is active under normal homeostatic/basal conditions and it phosphorylates a destruction motif in Nrf2 that is recognized by β-transducin repeat-containing protein (β-TrCP) [9∗∗], a F-box-containing protein that acts as a substrate adaptor/receptor within the Skp1−Cul1−F-box (SCF) ubiquitin ligase SCFβ-TrCP∗10, ∗11. Through this joint enterprise between GSK-3 and β-TrCP, it is envisaged that inhibition of GSK-3 activity, ostensibly upon cell stimulation by insulin, growth factors or amino acids [12], diminishes ubiquitylation of Nrf2 by SCFβ-TrCP, thereby allowing the transcription factor to accumulate and transactivate ARE-driven genes. In this ‘opinion’ article, we describe the dual regulation of Nrf2 by Keap1 and by the combined actions of GSK-3 and β-TrCP. In particular, we highlight the putative role played by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in triggering Keap1-independent activation of Nrf2. One distinct possibility is that loss of the phosphatidylinositol (3,4,5)-trisphosphate (PIP3) 3-phosphatase activity of PTEN, stimulated by certain inducing agents, results in an increase in the levels of PIP3 that is produced by phosphoinositide 3-kinase (PI3K). As a consequence of increased PIP3 levels, 3-phosphoinositide-dependent protein kinase-1 (PDK1) activity is augmented, which then stimulates protein kinase B (PKB)/Akt signaling [13]. In turn, the increase in PKB/Akt activity (ultimately resulting from PTEN inhibition) leads to phosphorylation of an N-terminal Ser residue in GSK-3 that causes loss of its kinase activity, and thus an increase in the abundance of Nrf2 and induction of ARE-driven genes. Through its ability to increase PDK1 activity, via production of PIP3, PI3K may also repress GSK-3 activity by stimulating p70 ribosomal S6 kinase (p70S6K), p90 ribosomal S6 kinase (p90RSK) and certain protein kinase C (PKC) isoforms 14, 15, 16, and the possible regulation of Nrf2 by these pathways that lie downstream of PI3K is also discussed briefly.