Trehalose promotes the survival of random-pattern skin flaps by TFEB mediated autophagy enhancement
Trehalose promotes the survival of random-pattern skin flaps by TFEB mediated autophagy enhancement
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海藻糖通过 TFEB 介导的自噬增强促进随机图案皮瓣的存活
DOI：
10.1038/s41419-019-1704-0
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发表时间：
2019
影响因子：
9
通讯作者：
Kailiang Zhou
中科院分区：
文献类型：
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作者：
Hongqiang Wu;Huanwen Chen;Zhilong Zheng;Jiafeng Li;Jian Ding;Zihuai Huang;Chang Jia;Zitong Shen;Guodong Bao;Lingyun Wu;Abdullah Al Mamun;Huazi Xu;Weiyang Gao;Kailiang Zhou
随意型皮瓣是重建手术中常用和有价值的工具，然而，术后随意型皮瓣坏死仍然是一个主要和常见的并发症。以前的研究表明，激活自噬，降解细胞内废物的主要途径，可能会提高皮瓣的存活率。在这项研究中，我们研究了海藻糖，一种新的和有效的自噬激活剂，是否提高随机皮瓣的活力。我们的研究结果表明，海藻糖显着提高活力，增加血流量，并减少组织水肿。此外，我们发现海藻糖导致血管生成增加，细胞凋亡减少，氧化应激减少。使用免疫组化和蛋白质印迹，我们证明了海藻糖增强自噬，并且使用3 MA抑制自噬增强显著减弱了海藻糖治疗的上述益处。从机制上讲，我们表明海藻糖的自噬增强是由TFEB的激活和核转位介导的，这可能是由于Akt的抑制和AMPK-SKP 2-CARM 1信号通路的激活。总之，我们的研究结果表明，海藻糖是一种有效的药物，能够通过增强自噬和随后促进血管生成，减少氧化应激和抑制细胞死亡，显著增加随机模式皮瓣的存活率。
Random-pattern skin flaps are commonly used and valuable tools in reconstructive surgery, however, post-operative random skin flap necrosis remains a major and common complication. Previous studies have suggested that activating autophagy, a major pathway for degradation of intracellular waste, may improve flap survival. In this study, we investigated whether trehalose, a novel and potent autophagy activator, improves random skin flap viability. Our results demonstrated that trehalose significantly improves viability, augments blood flow, and decreases tissue edema. Furthermore, we found that trehalose leads to increased angiogenesis, decreased apoptosis, and reduced oxidative stress. Using immunohistochestry and western blot, we demonstrated that trehalose augments autophagy, and that inhibition of autophagy augmentation using 3MA significantly blunted the aforementioned benefits of trehalose therapy. Mechanistically, we showed that trehalose’s autophagy augmentation is mediated by activation and nuclear translocation of TFEB, which may be due to inhibition of Akt and activation of the AMPK-SKP2-CARM1 signaling pathway. Altogether, our results established that trehalose is a potent agent capable for significantly increasing random-pattern skin flap survival by augmenting autophagy and subsequently promoting angiogenesis, reducing oxidative stress, and inhibiting cell death.