title: Potential roles of PI3K/Akt and Nrf2-Keap1 pathways in regulating hormesis of Z-ligustilide in PC12 cells against oxygen and glucose deprivation.
abstract: Many phytochemicals may ameliorate neurological disorders through a hormetic mechanism. The aim of this study was to characterize the hormetic role of Z-ligustilide in PC12 cells against oxygen glucose deprivation (OGD) induced cell death. We examined the interactions of Z-ligustilide with the pro-survival signals mediated by phosphatidylinositol 3-kinase (PI3K) and transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathways. We also investigated the effect of Z-ligustilide on the intracellular redox signaling system involving reactive oxygen species (ROS) and glutathione (GSH). Z-ligustilide not only triggered stress response by causing ROS formation and transient GSH depletion, but also activated survival-promoting signals via cross-talking of PI3K and Nrf2 pathways. A key finding was that Z-ligustilide preconditioning protected PC12 cells from OGD-induced injury either at a low concentration for a prolonged period of time or at a high concentration for a short period of time. Presumably, mild preconditioning stimulated moderate ROS production, but effectively activated hormetic signals and induced stress responsive genes. In contrast, higher concentrations of Z-ligustilide could be toxic over a prolonged period of time due to massive ROS production. These results suggest that the effect of Z-ligustilide may be regulated by a biphasic hormetic mechanism involving initial induction of oxidative stress and subsequent activation of stress response gene expression.
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, PR China.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Qi
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.forename: Jianhui
authors.initials: J
authors.lastname: Rong
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D005947:Glucose / Q000172:deficiency; D051547:Heme Oxygenase-1 / Q000378:metabolism; D059165:Hormesis / Q000502:physiology*; D000860:Hypoxia / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D011506:Proteins; D017382:Reactive Oxygen Species; C027820:ligustilide; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; D015107:4-Butyrolactone