title: A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells.
abstract: BACKGROUND
  Heme oxygenase-1 (HO-1) has potential anti-apoptotic properties. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2- ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)] was synthesized by joining danshensu and cysteine through an appropriate linker. This study investigated if the cytoprotective properties of DSC involved the induction of HO-1.
  
  
  METHODS
  We evaluated the cytoprotective effects of DSC on H2O2-induced cell damage, apoptosis, intracellular and mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm) loss, and apoptosis-related proteins expression and its underlying mechanisms.
  
  
  RESULTS
  DSC concentration-dependently attenuated cell death, lactate dehydrogenase release, intracellular and mitochondrial ROS production, and ΔΨm collapse, modulated apoptosis-related proteins (Bcl-2, Bax, caspase-3, p53, and cleaved PARP) expression, and inhibited phosphorylation of extracellular signal-regulated kinase 1/2 in SH-SY5Y cells induced by H2O2. In addition, DSC concentration-dependently induced HO-1 expression associated with nuclear translocation of nuclear factor-erythroid 2 related factor 2 (Nrf-2), while the effect of DSC was inhibited by a phosphoinositide 3-kinase (PI3K) inhibitor LY294002. Furthermore, the protective effect of DSC on H2O2-induced cell death was abolished by HO-1 inhibitor ZnPP, but was mimicked by carbon monoxide-releasing moiety CORM-3 or HO-1 by-product bilirubin. Finally, DSC inhibited H2O2-induced changes of Bcl-2, Bax, and caspase-3 expression, and all of these effects were reversed by HO-1 silencing.
  
  
  CONCLUSIONS
  Induction of HO-1 may be, at least in part, responsible for the anti-apoptotic property of DSC, an effect that involved the activation of PI3K/Akt/Nrf-2 axis.
  
  
  CONCLUSIONS
  DSC might have the potential for beneficial therapeutic interventions for neurodegenerative diseases.
authors: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors: Li-Long
authors: LL
authors: Pan
authors: Xin-Hua
authors: XH
authors: Liu
authors: Yao-Ling
authors: YL
authors: Jia
authors: Dan
authors: D
authors: Wu
authors: Qing-Hui
authors: QH
authors: Xiong
authors: Qi-Hai
authors: QH
authors: Gong
authors: Yang
authors: Y
authors: Wang
authors: Yi-Zhun
authors: YZ
authors: Zhu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007773:Lactates / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010648:Phenylacetates / Q000494:pharmacology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C581653:4-(2-acetoxy-3-((R)-3-(benzylthio)-1-methoxy-1-oxopropan-2- ylamino)-3-oxopropyl)-1,2-phenylene diacetate; D004365:Drugs, Chinese Herbal; D007773:Lactates; D010648:Phenylacetates; D017382:Reactive Oxygen Species; C035055:3,4-dihydroxyphenyllactic acid; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases