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

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  • Yu Jie
    Department of Pharmaceutical Sciences, Southwest University
  • Jiang Zhuyun
    Department of Pharmaceutical Sciences, Southwest University
  • Ning Ling
    Department of Pharmaceutical Sciences, Southwest University
  • Zhao Zhilong
    Institute of Laboratory Animals, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital
  • Yang Na
    Institute of Laboratory Animals, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital
  • Chen Lu
    Department of Pharmaceutical Sciences, Southwest University
  • Ma Hui
    Department of Pharmaceutical Sciences, Southwest University
  • Li Li
    Department of Pharmaceutical Sciences, Southwest University
  • Fu Ya
    Department of Chemistry and Chemical Engineering, Chongqing University of Science & Technology
  • Zhu Huifeng
    Department of Pharmaceutical Sciences, Southwest University
  • Qi Hongyi
    Department of Pharmaceutical Sciences, Southwest University

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

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Heat-shock protein 70 (HSP70) is known to function as a protective molecular chaperone that is massively induced in response to misfolded proteins following cerebral ischemia. The objective of this study was to characterize HSP70 induction by Z-ligustilide and explore its potential role in protection against cerebral ischemia–reperfusion injury. Our results demonstrated that the intranasal administration of Z-ligustilide reduced infarct volume and improved neurological function in a rat stroke model. Meanwhile, Z-ligustilide enhanced the cell viability of PC12 cells insulted by oxygen–glucose deprivation-reoxygenation (OGD-Reoxy) and decreased apoptotic and necrotic cell death. Importantly, Z-ligustilide induced HSP70 expression both in vitro and in vivo. Although heat-shock factor 1 (HSF1) nuclear translocation was promoted by Z-ligustilide, HSP70-based heat-shock element (HSE)-binding luciferase activity was not activated, and HSP70 expression responsive to Z-ligustilide was not attenuated by HSE decoy oligonucleotides. However, Z-ligustilide significantly activated the phosphorylation of mitogen-activated protein kinases (MAPKs). Further inhibition of MAPK activity by specific inhibitors attenuated HSP70 induction by Z-ligustilide. Meanwhile, downregulation of HSP70 using KNK437, an HSP70 synthesis inhibitor, or small hairpin RNA (shRNA) significantly attenuated the protection of Z-ligustilide against OGD-Reoxy-induced injury. Moreover, the application of specific inhibitors of MAPKs also achieved similar results. Finally, Z-ligustilide alleviated the accumulation of ubiquitinated proteins induced by OGD-Reoxy, which was inhibited by HSP70-shRNA. Taken together, our results demonstrated that Z-ligustilide may induce protective HSP70 expression via the activation of the MAPK pathway, but not canonical HSF1 transcription. HSP70 plays a key role in the protection of Z-ligustilide against OGD-Reoxy-induced injury.

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