Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 751, Issue -, Pages 13-23Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2015.01.039
Keywords
Mitochondrial dysfunction; p53; Ubiquition-dependent degradation
Categories
Funding
- National Key Technology R & D Program New Drug Innovation of China [2012ZX09301002-002-002]
- Natural Science Foundation of China [81303253, 30873072]
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Protosappanin B (PTB) is a bioactive dibenzoxocin derivative isolated from Caesalpinia sappan L. Here, we investigated the neuroprotective effects and the potential mechanisms of PTB on oxygen-glucose deprivation (OGD)-injured PC12 cells. Results showed that PTB significantly increased cell viability, inhibited cell apoptosis and up-regulated the expression of growth-associated protein 43 (a marker of neural outgrowth). Moreover, our study revealed that PTB effectively maintained mitochondrial home-ostasis by up-regulation of mitochondrial membrane potential (MMP), inhibition of cytochrom c release from mitochondria and inactivation of mitochondrial caspase-9/3 apoptosis pathway. Further study showed that PTB significantly promoted cytoplasmic component degradation of p53 protein, a key negative regulator for mitochondrial function, resulting in a release of Bcl-2 from p53-Bc1-2 complex and an enhancing translocation of Bc1-2 to mitochondrial outer membrane. Finally, we found the degradation of p53 protein was induced by FIB via activation of a MDM2-dependent ubiquitination process. Taken together, our findings provided a new viewpoint of neuronal protection strategy for anoxia and ischemic injury with natural small molecular dibenzoxocin derivative by activating ubiquitin-dependent p53 protein degradation as well as increasing mitochondrial function. (C) 2015 Elsevier B.V. All rights reserved.
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