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叉头框蛋白A1（FOXA1）转录激活三叶因子1（TFF1）以减少6-羟基多巴胺（6-OHDA）诱导的多巴胺能神经元损伤。

FOXA1 transcription activates TFF1 to reduce 6-OHDA-induced dopaminergic neuron damage.

作者信息

Liang Tingting, Zhao Ping, Zhang Xiao, Han Xuedan, Hong Bo, Kong Lingsheng, Chang Huanxian, Liu Liyan

机构信息

Department of Neurology, The Affiliated Lianyungang Oriental Hospital of Xuzhou Medical University, Lianyungang, Jiangsu 222042, P.R. China.

出版信息

Exp Ther Med. 2022 Jun;23(6):372. doi: 10.3892/etm.2022.11299. Epub 2022 Apr 5.

DOI:10.3892/etm.2022.11299
PMID:35495601
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9019776/
Abstract

Forkhead box A1 (FOXA1) plays an important role in the central nervous system, and its loss can lead to the downregulation of tyrosine hydroxylase, which directly affects the synthesis of dopamine, thus leading to Parkinson's disease (PD). The present study aimed to explore the specific role of FOXA1 in PD. Blood samples from patients with PD were collected to determine the expression levels of FOXA1 using reverse transcription-quantitative PCR (RT-qPCR). In addition, mouse dopaminergic neuron MES23.5 cells were induced with 6-hydroxydopamine (6-OHDA) to construct an PD model in order to study the effect of FOXA1 overexpression on cell inflammation, oxidative stress and apoptosis with RT-qPCR, assay kits and TUNEL assays, respectively. Subsequently, the expression of FOXA1 was silenced to assess the effect on the downstream mechanism. The results revealed that the expression level of FOXA1 was downregulated in patients with PD, and FOXA1 overexpression attenuated 6-OHDA-induced inflammation, oxidative stress and apoptosis in MES23.5 cells. Furthermore, FOXA1 could bind to the trefoil factor 1 (TFF1) promoter, and the effects of FOXA1 overexpression on cells were reversed by TFF1 silencing, indicating that TFF1 mediated the mechanism of FOXA1 overexpression in MES23.5 cells. In conclusion, following FOXA1 transcription, TFF1 expression was activated, thereby relieving 6-OHDA-induced cell inflammation, oxidative stress and apoptosis. The present findings suggested that FOXA1 may serve as a target for the treatment of PD.

摘要

叉头框A1（FOXA1）在中枢神经系统中发挥着重要作用，其缺失会导致酪氨酸羟化酶表达下调，直接影响多巴胺的合成，进而引发帕金森病（PD）。本研究旨在探讨FOXA1在PD中的具体作用。收集PD患者的血液样本，采用逆转录定量PCR（RT-qPCR）测定FOXA1的表达水平。此外，用6-羟基多巴胺（6-OHDA）诱导小鼠多巴胺能神经元MES23.5细胞构建PD模型，分别通过RT-qPCR、检测试剂盒和TUNEL检测研究FOXA1过表达对细胞炎症、氧化应激和凋亡的影响。随后，沉默FOXA1的表达以评估其对下游机制的影响。结果显示，PD患者中FOXA1的表达水平下调，FOXA1过表达减轻了6-OHDA诱导的MES23.5细胞炎症、氧化应激和凋亡。此外，FOXA1可与三叶因子1（TFF1）启动子结合，TFF1沉默可逆转FOXA1过表达对细胞产生的影响，表明TFF1介导了FOXA1过表达在MES23.5细胞中的作用机制。总之，FOXA1转录后激活了TFF1的表达，从而减轻了6-OHDA诱导的细胞炎症、氧化应激和凋亡。本研究结果提示，FOXA1可能成为PD治疗的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/6737fd421a0b/etm-23-06-11299-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/2394841a65d4/etm-23-06-11299-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/169c31b58e6a/etm-23-06-11299-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/607fb5b50d98/etm-23-06-11299-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/88797bbc2750/etm-23-06-11299-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/6737fd421a0b/etm-23-06-11299-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/2394841a65d4/etm-23-06-11299-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/169c31b58e6a/etm-23-06-11299-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/607fb5b50d98/etm-23-06-11299-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/88797bbc2750/etm-23-06-11299-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5e62/9019776/6737fd421a0b/etm-23-06-11299-g04.jpg

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