Xie Wang, Hong Chen, Xiaoyan Zhang, Nan Shao, Ze Chang, Daojun Xie, Juan Zhang
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摘要

威尔逊氏病(WD)是一种以铜代谢异常为特征的遗传性疾病,会引发一系列神经症状和认知障碍。新近的研究强调,铁凋亡(FPT)是一种独特的程序性细胞死亡,可能与各种认知功能障碍有关。然而,FPT 与威尔逊氏病(WDCI)认知障碍之间的联系在很大程度上仍然是个谜。在我们的研究中,我们采用了一种多方面的方法,结合反向网络药理学、数据挖掘和分子对接技术,探索通过 FPT 相关通路治疗 WDCI 的潜力。这一深入分析揭示了一系列蛋白质,包括 P38[式中:见正文]、GSK3[式中:见正文]、P53、GPX4 和 PTGS2,它们是治疗 WDCI 的关键靶点。值得注意的是,薯蓣皂苷(DG)已被确定为这一治疗框架的前瞻性核心成分。在WD铜负荷大鼠模型中,使用莫里斯水迷宫(MWM)、Y迷宫、苏木精和伊红染色、透射电子显微镜(TEM)和免疫荧光(IF)检测进行的评估表明,DG能显著促进认知功能的恢复,减少海马神经元的结构损伤,并保护线粒体的完整性。此外,Western blot(WB)和定量反转录 PCR(qRT-PCR)分析表明,DG 能显著提高动物和细胞模型中 P38[式中:见正文]、GSK3[式中:见正文]、P53、GPX4 和 PTGS2 等蛋白质和 mRNA 的表达水平。此外,DG 还能有效逆转氧化应激标记物的表达失调,包括[式中:见正文]、丙二醛(MDA)、超氧化物歧化酶(SOD)和活性氧(ROS)。本研究阐明了 DG 通过激活 P38[方见正文]介导的 FPT 通路对海马神经元的神经保护作用,突出了其作为传统中药中一种强效单体的功效,并阐明了其在 WDCI 临床治疗中的潜在作用。
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Therapeutic Targets and Natural Product Screening for Cognitive Impairments Associated with Ferroptosis in Wilson's Disease.

Wilson's disease (WD) is a hereditary condition marked by abnormalities in copper metabolism, which precipitate a spectrum of neurological symptoms and cognitive impairments. Emerging research has highlighted ferroptosis (FPT) as a distinct type of programmed cell death, potentially linked to various cognitive dysfunctions. Nevertheless, the connection between FPT and cognitive impairment in Wilson's disease (WDCI) remains largely enigmatic. In our study, we utilized a multifaceted approach, combining reverse network pharmacology, data mining, and molecular docking techniques to explore the potential for treating WDCI via FPT-related pathways. This thorough analysis revealed a series of proteins, including P38[Formula: see text], GSK3[Formula: see text], P53, GPX4, and PTGS2, as pivotal targets for WDCI treatment. Notably, Diosgenin (DG) has been identified as a prospective core component in this therapeutic framework. In the WD copper-loaded rat model, evaluations using the Morris water maze (MWM), Y maze, hematoxylin and eosin staining, transmission electron microscopy (TEM), and immunofluorescence (IF) detection showed that DG significantly enhanced cognitive function recovery, reduced structural damage to hippocampal neurons, and protected mitochondrial integrity. In addition, Western blot (WB) and quantitative reverse transcription PCR (qRT-PCR) analysis showed that DG significantly upregulated the expression levels of proteins and mRNA such as P38[Formula: see text], GSK3[Formula: see text], P53, GPX4, and PTGS2 in animal and cell models. Furthermore, DG effectively reversed the dysregulated expression of oxidative stress markers, including [Formula: see text], malondialdehyde (MDA), superoxide dismutase (SOD), and reactive oxygen species (ROS). This study elucidates the neuroprotective effect of DG on hippocampal neurons by activating the P38[Formula: see text]-mediated FPT pathway, highlighting its efficacy as a potent monomer in traditional Chinese medicine and illuminating its potential role in the clinical treatment of WDCI.

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