Curcumin pretreatment protects against hypoxia/reoxgenation injury via improvement of mitochondrial function, destabilization of HIF-1α and activation of Epac1-Akt pathway in rat bone marrow mesenchymal stem cells
Curcumin pretreatment protects against hypoxia/reoxgenation injury via improvement of mitochondrial function, destabilization of HIF-1α and activation of Epac1-Akt pathway in rat bone marrow mesenchymal stem cells
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DOI：
10.1016/j.biopha.2018.11.005
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发表时间：
2019-01-01
影响因子：
7.5
通讯作者：
Hu, Dahai
中科院分区：
文献类型：
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作者：
Wang, Xujie;Zhang, Yijie;Hu, Dahai
骨髓间充质干细胞（BMSCs）具有良好的治疗效果，被认为是组织损伤治疗的理想药物。然而，由于严重的重新定位条件（特征为长时间缺氧和氧化应激），移植后存活的细胞很少，导致基于BMSC的细胞治疗的益处受到阻碍。姜黄素是一种天然的膳食产品，由于其丰富的药理作用而引起人们的广泛关注。在这里，我们报告了姜黄素预处理对骨髓基质细胞对缺氧和复氧（H/R）触发的损伤的保护作用，这模拟了体内缺血/再灌注。姜黄素预处理可显著抑制缺氧/复氧诱导的细胞活力下降、细胞核浓缩、LDH漏出以及caspase-3活性升高。此外，姜黄素预处理可通过促进三磷酸腺苷的产生、抑制活性氧的积累和线粒体膜电位的下降来预防H/R诱导的线粒体功能障碍。此外，姜黄素预处理显著诱导HIF-1 α不稳定，Epac 1和Akt激活，Erk 1/2和p38失活。Epacl抑制剂ESI-09可明显抑制姜黄素诱导的p-Akt表达的增加，但对p-Erk 1/2和p-p38表达无明显影响，并可解除姜黄素对BMSCs存活的保护作用，使细胞周期阻滞于G 0/G1期。这些结果表明，姜黄素预处理可使BMSCs在缺氧/复氧损伤后存活，其机制可能与其保护线粒体功能、降低HIF-1 α的稳定性和激活Epac 1-Akt信号通路有关。因此，本研究提供了姜黄素的更多药理学方面，并表明用姜黄素预处理BMSC可以作为促进组织修复治疗中细胞治疗的有吸引力的方法。
Bone marrow mesenchymal stem cells (BMSCs) possess promising therapeutic effects and have been considered as a highly desirable agent for tissue injury treatment. However, little survived cells after transplanting due to severe relocated conditions (characterized by prolonged hypoxia and oxidative stress) lead to hampered benefits of BMSCs-based cell therapy. Curcumin, a natural dietary product, has attracted increasing attention owing to its profound pharmacologic properties. Here, we report the protective effects of curcumin pretreatment in BMSCs against hypoxia and reoxygenation (H/R) triggered injury, which mimick ischemia/reperfusion in vivo. We found that curcumin pretreatment remarkably inhibited H/R-induced cell viability loss, cell nuclei condensation, LDH leakage, as well as caspase-3 activity increase in BMSCs. Furthermore, curcumin pretreatment prevented H/R-induced mitochondrial dysfunction through expediting adenosine triphosphate production and suppressing reactive oxygen species accumulation and mitochondrial membrane potential decline. In addition, curcumin pretreatment notably induced HIF-1 alpha destabilization, Epac1 and Akt activation, and Erk1/2 and p38 deactivation. However, Epacl inhibitor ESI-09 obviously restrained the increase of p-Akt induced by curcumin, but not p-Erk1/2 or p-p38, and abrogated the protective effect of curcumin on BMSCs' survival and arrested cell cycle in G0/G1 phase. Taken together, these results demonstrated that curcumin pretreatment conferred BMSCs the ability to survive from H/R injury, which might attribute to its protection on mitochondrial function, destabilization of HIF-1 alpha and activation of Epac1-Akt signaling pathway. Thus, this study provides more pharmacologic aspects of curcumin, and suggests that pre-conditioning of BMSCs with curcumin could serve as an attractive approach for facilitating cell therapy in tissue repair treatment.