title: Protosappanin B protects PC12 cells against oxygen-glucose deprivation-induced neuronal death by maintaining mitochondrial homeostasis via induction of ubiquitin-dependent p53 protein degradation.
abstract: 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 homeostasis by up-regulation of mitochondrial membrane potential (MMP), inhibition of cytochrome 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-Bcl-2 complex and an enhancing translocation of Bcl-2 to mitochondrial outer membrane. Finally, we found the degradation of p53 protein was induced by PTB 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.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Ke-Wu
authors: KW
authors: Zeng
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Li-Xi
authors: LX
authors: Liao
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Ming-Bo
authors: MB
authors: Zhao
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing 100034, China.
authors: Fang-Jiao
authors: FJ
authors: Song
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing 100034, China.
authors: Qian
authors: Q
authors: Yu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors: Yong
authors: Y
authors: Jiang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: pengfeitu@vip.163.com.
authors: Peng-Fei
authors: PF
authors: Tu
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D005947:Glucose / Q000172:deficiency*; D006706:Homeostasis / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D035964:Oxocins / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D035964:Oxocins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C000603101:protosappanin B; D045304:Cytochromes c; D051736:Proto-Oncogene Proteins c-mdm2; D053148:Caspase 3; D053453:Caspase 9; D005947:Glucose; D010100:Oxygen
keywords: Mitochondrial dysfunction; Protosappanin B (PubChem CID: 102036-29-3); Ubiquition-dependent degradation; p53