DJ-1 regulating PI3K-Nrf2 signaling plays a significant role in bibenzyl compound 20C-mediated neuroprotection against rotenone-induced oxidative insult.

Oxidative stress is thought to be involved in the development of Parkinson's disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β (GSK3β) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future.

Zhang XL ，Yuan YH ，Shao QH ，Wang ZZ ，Zhu CG ，Shi JG ，Ma KL ，Yan X ，Chen NH ... -  《-》

20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway.

Huang JY ，Yuan YH ，Yan JQ ，Wang YN ，Chu SF ，Zhu CG ，Guo QL ，Shi JG ，Chen NH ... -  《-》

RNAi-mediated knockdown of DJ-1 leads to mitochondrial dysfunction via Akt/GSK-3ß and JNK signaling pathways in dopaminergic neuron-like cells.

Deletions or some mutations in the gene encoding the multifunctional protein, DJ-1, have been considered to be linked with autosomal recessive early onset Parkinson's disease (PD). Current emerging evidence suggests that DJ-1 is involved in the protection against oxidative stress-induced mitochondrial damage. However, the exact molecular mechanisms underlying this are not completely clear. The aim of this study was to investigate the effects of DJ-1 on the Akt pathway, nuclear factor erythroid 2-related factor (Nrf2), and c-Jun N-terminal kinase (JNK) with regard to modulating mitochondrial function. Here we showed that knockdown of DJ-1 resulted in mitochondrial dysfunction, including a decrease in active mitochondrial mass, complex I deficits, and inhibition of cellular adenosine 5'-triphosphate (ATP) content in the dopaminergic neuron-like cells PC12 and SH-SY5Y. Additionally, loss of DJ-1 impaired Akt signaling, and reduced nuclear translocation of Nrf2, thereby inhibiting activity of Nrf2-regulated downstream antioxidant enzymes such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. Moreover, DJ-1 knockdown also led to a significant increase in the mitochondrial reactive oxygen species, and then promoted the activation of JNK pathways. Furthermore, oxidative stress and mitochondrial dysfunction induced by knockdown of DJ-1 were blocked by a JNK inhibitor, which confirmed the important role of JNK activation in mitochondrial dysfunction. In conclusion, the present study indicates that DJ-1 knockdown leads to mitochondrial dysfunction in dopaminergic neuron-like cells, at least in part, through suppressing the Akt/GSK3β pathway and impairing the oxidative stress response, as well as through the subsequent increased JNK activation in dopaminergic neuron-like cells.

Zhang XL ，Wang ZZ ，Shao QH ，Zhang Z ，Li L ，Guo ZY ，Sun HM ，Zhang Y ，Chen NH ... -  《-》

Phytoestrogen β-Ecdysterone Protects PC12 Cells Against MPP+-Induced Neurotoxicity In Vitro: Involvement of PI3K-Nrf2-Regulated Pathway.

Epidemiological studies have strongly linked postmenopausal estrogens uptake with a reduced risk of developing Parkinson's disease (PD) in women. Estrogen replacement therapy may be beneficial in early PD. The aim of this study is to evaluate the hypothesis that the neuroprotective effects of phytoestrogen β-ecdysterone (β-Ecd) might mainly result from its antioxidant capability by the activation of the phosphoinositide-3-kinase (PI3K)-nuclear factor E2-related factor 2 (Nrf2)-regulated signaling pathway. We found that β-Ecd is able to protect MPP(+)-induced oxidative stress and apoptosis in PC12 cells in a concentration-dependent manner. β-Ecd increased the Akt kinase activity and the Akt signaling pathways, including glycogen synthase kinase 3-β inactivation, nuclear translocation of Nrf2, upregulation of HO-1 expression, but without affecting activity of both NF-κB and calpain. Enhancement of antioxidant response element (ARE) promoter-driven luciferase activity by β-Ecd correlated with the blockade of oxidative stress. Antioxidative effects of β-Ecd could be blocked by pharmacologic inhibition of the PI3K pathways with LY294002 or Nrf2 pathway with shRNA-mediated knockdown of Nrf2 but not by SP600125 (JNK inhibitor), SB203580 (p38-MAPK inhibitor), or PD98059 (ERK1/2 inhibitor). Together, our results indicate that the inducible effect of β-Ecd on HO-1 expression might be mediated, at least in part, by activating Akt kinase pathway and subsequent enhancement of Nrf2/ARE signaling pathway. In concert, these data suggest that β-Ecd may be a potential candidate for further preclinical study aimed at the treatment of PD.

Zou Y ，Wang R ，Guo H ，Dong M ... -  《-》

Nrf2-mediated neuroprotection by MANF against 6-OHDA-induced cell damage via PI3K/AKT/GSK3β pathway.

Oxidative stress and apoptosis are thought to be broadly involved in the pathogenesis of Parkinson's disease. We previously reported that Mesencephalic astrocyte-derived neurotrophic factor (MANF) possesses anti-oxidation and anti-apoptotic effects against 6-OHDA-induced neurotoxicity, but the specific molecular mechanism remains unclear. In this study, we showed that MANF up-regulates the expression of nuclear factor erythroid 2-related factor (Nrf2) and promotes its translocation into the nucleus. The anti-oxidation and anti-apoptotic effects of MANF could be partially blocked by inhibitor or shRNA-mediated knockdown of Nrf2. Furthermore, MANF activated phospoinositide-3-kinase (PI3K)/Akt signaling and suppressed glycogen synthase kinase (GSK3β) activation. PI3K inhibitor (LY49002) abolished effects of MANF on AKT phosphorylation, GSK3β inactivation, Nrf2 nuclear translocation and subsequently abrogated MANF-mediates cytoprotection. Collectively, our findings indicated that MANF-mediated protection against 6-OHDA-induced cytotoxicity by potentiating the Nrf2-related survival mechanism through the PI3K/Akt/GSK3β pathway.

Zhang J ，Tong W ，Sun H ，Jiang M ，Shen Y ，Liu Y ，Gu H ，Guo J ，Fang J ，Jin L ... -  《-》