Ganoderic acid D protects human amnion mesenchymal stem cells against oxidative stress-induced senescence through PERK/NRF2 signaling pathway
Ganoderic acid D protects human amnion mesenchymal stem cells against oxidative stress-induced senescence through PERK/NRF2 signaling pathway
复制标题
灵芝酸D通过PERK/NRF2信号通路保护人羊膜间充质干细胞免受氧化应激诱导的衰老
DOI：
10.1155/2020/8291413
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发表时间：
2020
影响因子：
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通讯作者：
Xiao Jian-Hui
中科院分区：
文献类型：
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作者：
Xu Yan;Yuan Huan;Luo Yi;Zhao Yu-Jie;Xiao Jian-Hui
衰老是许多慢性病发生的重要危险因素。成体干细胞的衰老和衰竭被认为是生物体衰老的标志。本研究利用过氧化氢在体外建立人羊膜间充质干细胞（human amniotic mesenchymal stem cell，hAMSC）氧化应激模型。我们研究了灵芝酸D（GA-D），一种从灵芝中产生的天然三萜类化合物，对hAMSC衰老的影响。GA-D以剂量依赖性方式显著抑制β-半乳糖苷酶（一种衰老相关标志物）的形成，剂量范围为0.1 μ M至10 μ M，而不会诱导细胞毒性副作用。此外，GA-D还能显著抑制衰老hAMSC中活性氧（ROS）的产生和p21、p16蛋白的表达，缓解细胞周期阻滞，增强端粒酶活性。此外，GA-D上调磷酸化蛋白激酶R-（PKR-）如内质网激酶（PERK）、过氧化物酶III（PRDX3）和核因子-红细胞2相关因子（NRF 2）的表达，并促进衰老细胞中NRF 2的核内转移。PERK抑制剂GSK2656157和/或NRF2抑制剂ML385抑制由GA-D激活的PERK/NRF2信号传导。它们诱导ROS和β-半乳糖苷酶阳性细胞产生反弹，并减弱分化能力。这些发现表明，GA-D通过激活PERK/NRF2信号通路延缓hAMSC衰老，并且可能是发现抗衰老剂的有希望的候选者。
Aging is an important risk factor in the occurrence of many chronic diseases. Senescence and exhaustion of adult stem cells are considered as a hallmark of aging in organisms. In this study, a senescent human amniotic mesenchymal stem cell (hAMSC) model subjected to oxidative stress was establishedin vitrousing hydrogen peroxide. We investigated the effects of ganoderic acid D (GA‐D), a natural triterpenoid compound produced fromGanoderma lucidum, on hAMSC senescence. GA‐D significantly inhibitedβ‐galactosidase (a senescence‐associated marker) formation, in a dose‐dependent manner, with doses ranging from 0.1μM to 10μM, without inducing cytotoxic side‐effects. Furthermore, GA‐D markedly inhibited the generation of reactive oxygen species (ROS) and the expression of p21 and p16 proteins, relieved the cell cycle arrest, and enhanced telomerase activity in senescent hAMSCs. Furthermore, GA‐D upregulated the expression of phosphorylated protein kinase R‐ (PKR‐) like endoplasmic reticulum kinase (PERK), peroxidase III (PRDX3), and nuclear factor‐erythroid 2‐related factor (NRF2) and promoted intranuclear transfer of NRF2 in senescent cells. The PERK inhibitor GSK2656157 and/or the NRF2 inhibitor ML385 suppressed the PERK/NRF2 signaling, which was activated by GA‐D. They induced a rebound for the generation of ROS andβ‐galactosidase‐positive cells and attenuated the differentiation capacity. These findings suggest that GA‐D retards hAMSC senescence through activation of the PERK/NRF2 signaling pathway and may be a promising candidate for the discovery of antiaging agents.