A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells
A novel compound derived from danshensu inhibits apoptosis via upregulation of heme oxygenase-1 expression in SH-SY5Y cells
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一种源自丹参素的新型化合物通过上调 SH-SY5Y 细胞中血红素加氧酶-1 的表达来抑制细胞凋亡
DOI：
10.1016/j.bbagen.2013.01.008
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发表时间：
2013-04-01
影响因子：
3
通讯作者：
Zhu, Yi-Zhun
中科院分区：
文献类型：
--
作者：
Pan, Li-Long;Liu, Xin-Hua;Zhu, Yi-Zhun
背景：血红素氧合酶-1（HO-1）具有潜在的抗凋亡作用。以丹参素和半胱氨酸为原料，通过适当的连接基团连接，合成了新型化合物[4-（2-乙酰氧基-3-（（R）-3-苄硫基）-1-甲氧基-1-氧代丙-2-基氨基）-3-氧代丙基）-1，2-苯二乙酸酯（DSC）]。方法：观察DSC对H2 O2诱导的细胞损伤、细胞凋亡、细胞内和线粒体活性氧（ROS）产生、线粒体膜电位（MMPs）、线粒体膜电位（MMPs）等的保护作用（Delta Psi（m））损失和凋亡相关蛋白的表达及其潜在机制。DSC浓度依赖性地减弱细胞死亡、乳酸脱氢酶释放、细胞内和线粒体ROS产生以及Δ Psi（m）崩溃，调节凋亡相关蛋白（Bcl-2、Bax、caspase-3、p53和裂解PARP）表达，并抑制H2 O2诱导的SH-SY 5 Y细胞胞外信号调节激酶1/2磷酸化。此外，DSC浓度依赖性地诱导HO-1的表达与核因子-甲状腺素2相关因子2（Nrf-2）的核转位，而DSC的作用被抑制的磷酸肌醇3-激酶（PI 3 K）抑制剂LY 294002。此外，DSC对H2 O2诱导的细胞死亡的保护作用被HO-1抑制剂ZnPP消除，但被一氧化碳释放部分CORM-3或HO-1副产物胆红素模仿。DSC抑制H2 O2诱导的Bcl-2、Bax和caspase-3表达的变化，并且所有这些作用都被HO-1沉默逆转。结论：HO-1的诱导可能是DSC抗凋亡的部分原因，DSC的抗凋亡作用涉及PI 3 K/Akt/Nrf-2轴的激活。DSC可能具有对神经退行性疾病进行有益的治疗干预的潜力。(C)2013年由Elsevier B. V.出版
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 (Delta Psi(m)) 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 Delta Psi(m) collapse, modulated apoptosis-related proteins (Bcl-2, Bax, caspase-3, p53, and cleaved PARP) expression, and inhibited phosphotylation 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-elythroid 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.General significance: DSC might have the potential for beneficial therapeutic interventions for neurodegenerative diseases. (C) 2013 Published by Elsevier B.V.