Cyclosporin A-mediated translocation of HuR improves MTX-induced cognitive impairment in a mouse model via NCOA4-mediated ferritinophagy.
Cyclosporin A-mediated translocation of HuR improves MTX-induced cognitive impairment in a mouse model via NCOA4-mediated ferritinophagy.
复制标题
DOI：
10.18632/aging.205195
复制
发表时间：
2023-11-09
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
化疗引起的认知障碍（CICI）是一个需要神经科学和肿瘤学的关键解决方案的主题。然而，其潜在的作用机制仍不明确。本研究的目的是探讨HuR在甲氨蝶呤（MTX）诱导的认知障碍期间环孢素A （CsA）的神经保护中的重要作用。在体外和体内，通过一系列hu抗原R （HuR）的获得和损失实验，检测环孢素A （CsA）介导的HuR易位通过ncoa4介导的铁蛋白自噬改善mtx诱导的认知障碍的能力。结果表明，CsA可减轻mtx诱导的小鼠认知功能障碍。MTX的存在促进了HuR从细胞质向细胞核的穿梭，而与MTX组相比，CsA处理增加了细胞质HuR表达水平和铁蛋白噬噬相关蛋白（如NCOA4和LC3II）的水平。然而，应用HuR抑制剂KH-3，逆转了CsA对海马和体外铁蛋白噬噬相关蛋白表达的影响。此外，CsA治疗通过改变小鼠海马Iba-1表达和降低TNF-α和IL-1β水平来减弱小胶质细胞的活化。此外，KH-3中和了CsA对体内和体外Iba-1和HuR表达的影响。综上所述，CsA在CICI中具有神经保护作用。其潜在机制可能与HuR易位有关。在CICI过程中，通过ncoa4介导的铁蛋白噬噬，介导HuR易位可减轻CICI小鼠的神经炎症和神经元凋亡，从而减轻CICI小鼠的认知功能障碍。
Chemotherapy-induced cognitive impairment (CICI) is a subject that requires critical solutions in neuroscience and oncology. However, its potential mechanism of action remains ambiguous. The aim of this study was to investigate the vital role of HuR in the neuroprotection of cyclosporin A (CsA) during methotrexate (MTX)-induced cognitive impairment. A series of Hu-antigen R (HuR) gain and loss experiments were used to examine cyclosporin A (CsA)-mediated translocation of HuR’s ability to improve MTX-induced cognitive impairment through NCOA4-mediated ferritinophagy in vitro and in vivo. Obtained results show that the administration of CsA alleviated MTX-induced cognitive impairment in mice. The presence of MTX promoted the shuttling of HuR from the cytoplasm to the nucleus, whereas treatment with CsA increased cytoplasmic HuR expression levels and the levels of ferritinophagy-related proteins, such as NCOA4 and LC3II, compared to the MTX group. However, applying KH-3, an inhibitor of HuR, reversed CsA’s impact on the expression of ferritinophagy-related proteins in the hippocampus and in vitro. Also, treatment with CsA attenuated microglial activation by altering Iba-1 expression and decreased TNF-α and IL-1β levels in mice hippocampi. Moreover, KH-3 neutralized CsA’s effects on the expression of both Iba-1 and HuR in vivo and in vitro. In summary, CsA was confirmed to have a neuroprotective role in CICI. Its possible underlying mechanisms may be involved in the translocation of HuR. Mediating the translocation of HuR during CICI could mitigate neruoinflammation and neuronal apoptosis via NCOA4-mediated ferritinophagy and, thus, alleviate cognitive impairment in mice with CICI.
影响因子：
6.8
作者：
Huai, Ying;Chen, Zhihao;Deng, Xiaoni;Wang, Xue;Mao, Wenjing;Miao, Zhiping;Li, Yu;Li, Hui;Lin, Xiao;Qian, Airong
通讯作者：
Qian, Airong