Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells.
Ganoderic acid D prevents oxidative stress-induced senescence by targeting 14-3-3ε to activate CaM/CaMKII/NRF2 signaling pathway in mesenchymal stem cells.
复制标题
灵芝酸D通过靶向14-3-3ε激活间充质干细胞中的CaM/CaMKII/NRF 2信号通路来防止氧化应激诱导的衰老。
DOI：
10.1111/acel.13686
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发表时间：
2022-09
期刊：
影响因子：
7.8
通讯作者：
Xiao, Jian-Hui
中科院分区：
文献类型：
--
作者：
Yuan, Huan;Xu, Yan;Luo, Yi;Zhang, Jia-Rong;Zhu, Xin-Xin;Xiao, Jian-Hui
关键词：
干细胞衰老是衰老的重要原因。延缓衰老可能是对抗衰老和年龄相关疾病的一种新方法。本研究提供了灵芝酸D（GA-D）对人羊膜间充质干细胞（hAMSC）衰老的保护作用的机制见解。GA-D是一种灵芝衍生的三萜类化合物，通过激活Ca 2+钙调蛋白（CaM）/CaM依赖性蛋白激酶II（CaMKII）/核红细胞2相关因子2（Nrf 2）轴，显著防止hAMSC衰老，14 - 3 - 3ε被确定为GA-D的靶点。hAMSC中的14 - 3 - 3ε编码基因（YWHAE）敲低逆转了CaM/CaMKII/Nrf 2信号的激活，从而减弱了GA-D的抗衰老作用，并增加了衰老相关β-半乳糖苷酶（SA-β-gal）、p16和p21的表达水平，包括活性氧（ROS）的产生，从而促进了细胞周期停滞并降低了分化潜力。YWHAE过表达维持或略微增强了GA‐D抗衰老作用。GA-D通过显著增加总抗氧化能力以及超氧化物歧化酶和谷胱甘肽过氧化物酶活性，并减少丙二醛、晚期糖基化终产物和晚期糖基化终产物受体的形成，防止d-半乳糖引起的小鼠衰老。与GA-D抗hAMSC衰老的保护机制一致，GA-D通过调节14 - 3 - 3ε和CaM/CaMK II/Nrf 2轴，延缓该体内衰老模型中骨髓间充质干细胞的衰老，减少SA-β-gal和ROS的产生，减轻细胞周期阻滞，提高细胞活力和分化。因此，GA-D通过靶向14 - 3 - 3ε激活CaM/CaMKII/Nrf 2信号通路来延缓hAMSC衰老。此外，体内GA-D抗衰老作用可能涉及通过相同的信号轴调节干细胞衰老。GA-D通过调节14 - 3 - 3e激活CaM/CaMKII/Nrf 2通路来防止MSC衰老; GA-D通过增强抗氧化防御来防止d-gal-致衰老小鼠的衰老，并延缓d-gal-致衰老小鼠的BMSC衰老; GA-D可能是一种潜在的抗衰老剂。
Stem cell senescence is an important cause of aging. Delaying senescence may present a novel way to combat aging and age‐associated diseases. This study provided a mechanistic insight into the protective effect of ganoderic acid D (GA‐D) against human amniotic mesenchymal stem cell (hAMSCs) senescence. GA‐D, a Ganoderma lucidum‐derived triterpenoid, markedly prevented hAMSCs senescence via activating the Ca2+ calmodulin (CaM)/CaM‐dependent protein kinase II (CaMKII)/nuclear erythroid 2‐related factor 2 (Nrf2) axis, and 14‐3‐3ε was identified as a target of GA‐D. 14‐3‐3ε‐encoding gene (YWHAE) knockdown in hAMSCs reversed the activation of the CaM/CaMKII/Nrf2 signals to attenuate the GA‐D anti‐aging effect and increase senescence‐associated β‐galactosidase (SA‐β‐gal), p16 and p21 expression levels, including reactive oxygen species (ROS) production, thereby promoting cell cycle arrest and decreasing differentiation potential. YWHAE overexpression maintained or slightly enhanced the GA‐D anti‐aging effect. GA‐D prevented d‐galactose‐caused aging in mice by significantly increasing the total antioxidant capacity, as well as superoxide dismutase and glutathione peroxidase activity, and reducing the formation of malondialdehyde, advanced glycation end products, and receptor of advanced glycation end products. Consistent with the protective mechanism of GA‐D against hAMSCs senescence, GA‐D delayed the senescence of bone‐marrow mesenchymal stem cells in this aging model in vivo, reduced SA‐β‐gal and ROS production, alleviated cell cycle arrest, and enhanced cell viability and differentiation via regulating 14‐3‐3ε and CaM/CaMKII/Nrf2 axis. Therefore, GA‐D retards hAMSCs senescence by targeting 14‐3‐3ε to activate the CaM/CaMKII/Nrf2 signaling pathway. Furthermore, the in vivo GA‐D anti‐aging effect may involve the regulation of stem cell senescence via the same signal axis. GA‐D prevents MSC senescence via regulating 14‐3‐3e to activate the CaM/CaMKII/Nrf2 pathway; GA‐D prevents d‐gal‐caused aging in mice by enhancing antioxidative defense and retards the BMSCs senescence in d‐gal‐caused aging mice; GA‐D may be a potential anti‐aging agent.
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影响因子：
5.6
作者：
Dezfouli, Ali Bashiri;Salar-Amoli, Jamileh;Hassan, Jalal
通讯作者：
Hassan, Jalal
影响因子：
4.6
作者：
Camoni, Lorenzo;Visconti, Sabina;Aducci, Patrizia
通讯作者：
Aducci, Patrizia
影响因子：
2.2
作者：
Ferrer, TJ;Webb, JW;Cone, JB
通讯作者：
Cone, JB
影响因子：
4
作者：
Baddoo, M;Hill, K;Phinney, DG
通讯作者：
Phinney, DG
DOI：
10.1073/pnas.1813205115
发表时间：
2018-11-06
影响因子：
11.1
作者：
Díaz-Moreno M;Armenteros T;Gradari S;Hortigüela R;García-Corzo L;Fontán-Lozano Á;Trejo JL;Mira H
通讯作者：
Mira H