Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury <i>via</i> Activation of the MAPK Pathway but Not of HSF1

Abstract

Key words Z-ligustilide; heat-shock protein 70; mitogen-activated protein kinase; oxygen-glucose deprivation-reoxygenation; heat-shock factor 1The World Health Organization (WHO) Global Infobase reports that stroke has become the second leading cause of mortality in the world, causing around 6000000 deaths annually. 1)However, there are currently relatively few treatment options available to minimize damage or death following a stroke. Protein aggregates containing ubiquitinated proteins are commonly present in neurodegenerative disorders and have been considered to cause neuronal degeneration. The previous study also showed that transient cerebral ischemia caused severe protein aggregation in hippocampal CA1 neurons which appeared at 4 h and progressively accumulated at 24 and 48 h. 2)Therefore, control of protein aggregation may represent an alternative treatment to neurological damage caused by ischemic stroke.Heat shock proteins (HSPs) are a group of phylogenetically and ubiquitous cytoprotective proteins found in all prokaryotic and eukaryotic cells, many of which are chaperone molecules that facilitate protein folding, trafficking and also prevent their aggregation and degradation.3) Heat shock protein 70 (HSP70) is a major inducible heat shock protein that basically functions as a molecular chaperone and plays an important role in preventing protein aggregation, degrading unstable and misfolded proteins and transporting proteins between cellular compartments.4) It's reported that over-expression of HSP70 via transgenes and viruses or systemic administration of HSP70 fusion proteins that allow it to cross the blood brain barrier protects the brain against ischemia, 5,6) suggesting that increasing HSP70 level or activity may be a potential therapeutic target for pharmacological intervention of ischemic diseases.Ligusticum chuanxiong is a commonly used Chinese herbal medicine with its empiric treatment of cardiovascular and cerebrovascular diseases.7) Z-Ligustilide as the major bioactive phthalide compound of Rhizoma chuanxiong was previously suggested for the prevention and treatment of ischemic stroke. 8,9) Our and others' studies showed that Z-ligustilide could protect ischemic injury both in vitro and in vivo via the induction of direct and indirect antioxidant response. 8,10,11) However, its effect on the heat shock response, a highly conserved and fundamental cytoprotective mechanism, under ischemic stress remains unexplored. Along this line, we characterized the effect of Z-ligustilide on HSP70 and explored the potential role of HSP70 in the protection of Z-ligustilide against oxygen-glucose deprivation and reoxygenation (OGDReoxy) induced injury in this study.

Z‐Ligustilide Exerted Hormetic Effect on Growth and Detoxification Enzymes of Spodoptera litura Larvae

“…Interestingly, our results clearly demonstrated that the resistance of S. litura larvae against pesticide CPF was remarkably enhanced by the pretreatment of low dose (0.1 mg·g −1 ) of Z-LIG. This result obtained from the level of plant and insect interaction may provide an explanation for our recent study, in which subtoxic dose of Z-LIG activated the cellular stress response mechanisms, such as Nrf2 and HSP70 mediated pathways, in rats, and enhanced the tolerance of the rats against ischemic injury [ 14 – 16 ].…”

“…As a result, a group of phthalide compounds isolated from the essential oil of Rhizoma Chuanxiong drew our special attention. Among them, Z-LIG exhibited potent neuroprotective effect against ischemic injury via the activation of cellular stress response mechanism Nrf2 and HSP70 pathways [ 14 – 16 ]. Meanwhile, the role that Z-LIG plays in L. chuanxiong is also very interesting to us.…”

“…These results indicate the possibility that detoxification enzymes can be adaptively induced in S. litura larvae as a prosurvival mechanism in response to low dose of Z-LIG, whereas they were directly inhibited under the insult of high dose of Z-LIG, which further confirms the hormetic role of Z-LIG. Our previous studies showed that low dose of Z-LIG induced transcription factor Nrf2-mediated detoxification enzymes and HSP70 pathways, which resulted in the tolerance against ischemic injury [ 14 – 16 ]. We are then curious about whether low dose of Z-LIG enhances the resistance of S. litura larvae as we already showed that low dose of Z-LIG induced the expression and/or activity of detoxification enzymes in Figures 4 and 5 .…”

“…Recently, we and other investigators found that Z-LIG is one of main components responsible for the neuroprotection of Rhizoma Chuanxiong against ischemic stroke [ 11 – 16 ]. In particular, our investigations demonstrated that pretreatment with Z-LIG remarkably enhanced the tolerance of neuron-like PC12 cells and rats against ischemic injury through activating the cellular stress response pathways Nrf2 and HSP70 [ 14 – 16 ]. Thus, it is possible that Z-LIG belongs to hormetic phytochemicals.…”

Role of MAPKs in HSP70’s Protection against Heat Stress-Induced Injury in Rat Small Intestine

“…It has been shown that cells respond to elevated temperature exposure by activation of p38 MAPK, ERK1/2, and JNK, as well as by increasing the production of HSPs such as HSP27, HSP40, and HSP70 [ 17 – 19 ]. Furthermore, recent studies reported that there was a correlation between protective HSP70 expression and activation of the MAPK pathway [ 20 , 21 ]. Previous results indicate that the ERK- or p38 MAPK-mediated induction of HSP70 might play a crucial role in inhibiting caspase-3 activation [ 20 , 22 , 23 ].…”