人参皂苷化合物K通过调节ASK1-MKK7-JNK信号通路抑制铁变态反应,从而缓解大脑衰老。

IF 6.7 1区 医学 Q1 CHEMISTRY, MEDICINAL
Phytomedicine Pub Date : 2024-12-01 Epub Date: 2024-11-10 DOI:10.1016/j.phymed.2024.156239
Xiaojun Yan, Xue Bai, Guanghui Sun, Zhiguang Duan, Rongzhan Fu, Wen Zeng, Chenhui Zhu, Daidi Fan
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引用次数: 0

摘要

背景:大脑老化是导致神经退行性疾病发生和发展的主要因素。治疗这些疾病的传统方法往往受到严重副作用的限制,而且在阻止疾病进展方面缺乏疗效。目的:本研究旨在阐明人参皂苷化合物 K(CK)影响大脑衰老的分子机制,尤其关注其在调节氧化应激和相关信号通路中的作用:我们采用双半乳糖(D-gal)诱导的PC-12衰老细胞模型和小鼠脑衰老模型来探讨CK在脑衰老中的抗氧化特性。研究采用免疫荧光和免疫印迹技术评估了 CK 对与脑衰老相关的线粒体功能障碍的影响。利用转录组分析和 Western 印迹技术研究了 CK 影响脑衰老的潜在分子机制。此外,还通过分子对接、微尺度热泳和小干扰 RNA 转染等方法验证了 CK 对细胞凋亡信号调节激酶 1(ASK1)的调节作用:我们的研究结果表明,CK 能有效缓解与大脑衰老相关的认知能力下降。CK 能减少衰老细胞的数量,减轻神经元损伤,并增强过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶等关键抗氧化酶的活性。此外,CK 还能恢复线粒体功能,上调溶质运载家族 7 成员 11 和谷胱甘肽过氧化物酶 4 的表达,从而抑制铁变态反应。此外,CK 还以 ASK1 为靶标,抑制 MAPK 激酶 7 (MKK7) 和 c-Jun N 端激酶 (JNK) 的过度磷酸化。这种抑制促进了核因子红细胞2相关因子2(Nrf2)的核积累,有效减少了与脑衰老相关的铁变态反应和氧化损伤:总之,我们的研究表明,CK能通过抑制ASK1-MKK7-JNK信号通路、增强Nrf2核表达和抑制铁变态反应,有效延缓大脑衰老。这些发现突出表明,CK 是一种有望延缓大脑衰老和缓解神经退行性疾病的治疗药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ginsenoside compound K alleviates brain aging by inhibiting ferroptosis through modulation of the ASK1-MKK7-JNK signaling pathway.

Background: Aging of the brain is a major contributor to the onset and progression of neurodegenerative diseases. Conventional treatments for these diseases are often limited by significant side effects and a lack of efficacy in halting disease progression. Ginsenoside compound K (CK), a bioactive secondary metabolite derived from ginseng, has shown promise because of its potent antioxidant properties.

Purpose: This study aimed to elucidate the molecular mechanisms underlying the impact of CK on brain senescence, with a particular focus on its role in modulating oxidative stress and related signaling pathways.

Methods: We employed a d-galactose (D-gal)-induced PC-12 senescent cell model and a mouse brain aging model to explore the antioxidant properties of CK in the context of brain aging. The effects of CK on mitochondrial dysfunction associated with brain aging were assessed using immunofluorescence and western blotting techniques. The potential molecular mechanisms by CK influences brain aging were investigated using transcriptomic analysis and western blotting. Additionally, CK's regulatory effect on apoptosis signal-regulating kinase 1 (ASK1) was validated by molecular docking, microscale thermophoresis, and small interfering RNA transfection.

Results: Our findings demonstrate that CK effectively alleviates cognitive decline associated with brain aging. CK reduces the number of senescent cells, alleviates neuronal damage, and enhances the activity of key antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase. Additionally, CK restores mitochondrial function and upregulated the expression of solute carrier family 7 member 11 and glutathione peroxidase 4, thereby inhibiting ferroptosis. Furthermore, CK targets ASK1 and suppresses the hyperphosphorylation of MAPK kinase 7 (MKK7) and c-Jun N-terminal kinase (JNK). This suppression promotes the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), effectively reducing ferroptosis and oxidative damage linked to brain aging.

Conclusion: In summary, our research demonstrates that CK effectively delays brain aging by inhibiting the ASK1-MKK7-JNK signaling pathway, enhancing nuclear Nrf2 expression, and suppressing the ferroptosis response. These findings highlight CK as a promising therapeutic agent for slowing brain aging and alleviating neurodegenerative diseases.

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来源期刊
Phytomedicine
Phytomedicine 医学-药学
CiteScore
10.30
自引率
5.10%
发文量
670
审稿时长
91 days
期刊介绍: Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.
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