Celastrol protected the MPTP-injected mice Parkinson's disease model via redox regulation of CDC37

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-07-09 DOI:10.1016/j.phymed.2025.157067

Wanfen Liao , Aiwen Dong , Fatima Hafeez , Qinyong Ye , En Huang

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引用次数: 0

Abstract

Background

Celastrol (CEL), a bioactive compound isolated from Tripterygium Wilfordii Hook. F, exerts neuroprotective effects through anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms in several neurodegenerative diseases, including Parkinson's disease (PD). CEL covalently binds to the thiol group of cysteine residues in cell division cycle 37 (CDC37), leading to redox-dependent modulation of CDC37 function. However, whether CEL redox regulates CDC37 and CEL-CDC37 interaction plays a role in pathogenesis of PD is still not be investigated yet. This study aids to demonstrate the role of CEL redox regulation of CDC37 in an MPTP-induced mouse model of PD.

Methods

Lentiviral vectors were used to overexpress or knock down CDC37 in MPTP-injected mice. CEL was administered to assess its effect on CDC37 redox status and related molecular pathways.

Results

CDC37 overexpression alleviated MPTP-induced motor deficits and dopaminergic neuron loss, whereas CDC37 knockdown exacerbated these impairments. Overexpression of CDC37 also suppressed activation of the NF-κB pathway and reduced phosphorylation of α-synuclein at serine 129 (p-S129-syn). MPTP insult decreased the reduced (active) form of CDC37 due to oxidative stress. CEL treatment restored CDC37 redox status, improved locomotor performance, preserved dopaminergic neurons, and inhibited both NF-κB activation and p-S129-synuclein levels. These effects were mediated by CEL's redox regulation of CDC37, which prevented its overoxidation, disrupted the Hsp90/CDC37 complex, and suppressed downstream pro-inflammatory and pro-pathogenic signaling.

Conclusion

Our study suggests that CEL restores the protective role of CDC37 in the MPTP-injected Parkinson's disease (PD) mouse model via redox regulation of CDC37, which prevents over-oxidation of CDC37 under high oxidative stress, and disrupts the Hsp90/CDC37 complex and subsequently blocks NF-κB pathway activation and p-S129-synuclein production. This study might provide a promising strategy for PD and further understanding of the therapeutic mechanism of CEL application.

Abstract Image

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Celastrol通过氧化还原调控CDC37对mptp注射小鼠帕金森病模型的保护作用

雷公藤红素（celastrol， CEL）是从雷公藤中分离得到的活性化合物。F，通过抗氧化、抗炎和抗凋亡机制在包括帕金森病（PD）在内的几种神经退行性疾病中发挥神经保护作用。CEL共价结合细胞分裂周期37 （CDC37）中半胱氨酸残基的巯基，导致CDC37功能的氧化还原依赖性调节。然而，CEL氧化还原是否调控CDC37，以及CEL-CDC37相互作用是否在PD发病机制中发挥作用尚不清楚。本研究有助于证明CEL氧化还原调控CDC37在mptp诱导的PD小鼠模型中的作用。方法采用慢病毒载体对注射mptp的小鼠进行过表达或敲低CDC37。给予CEL以评估其对CDC37氧化还原状态和相关分子途径的影响。结果scdc37过表达可减轻mptp诱导的运动障碍和多巴胺能神经元损失，而CDC37敲低可加重这些损伤。CDC37的过表达也抑制了NF-κB通路的激活，降低了α-synuclein丝氨酸129 （p-S129-syn）的磷酸化。MPTP损伤降低了氧化应激引起的CDC37的还原（活性）形式。CEL治疗恢复了CDC37氧化还原状态，改善了运动表现，保存了多巴胺能神经元，抑制了NF-κB活化和p-S129-synuclein水平。这些作用是通过CEL对CDC37的氧化还原调控介导的，从而阻止了CDC37的过度氧化，破坏了Hsp90/CDC37复合物，并抑制了下游的促炎和促致病信号。结论本研究提示，CEL通过对CDC37的氧化还原调控，恢复了mptp注射帕金森病（PD）小鼠模型中CDC37的保护作用，从而阻止了高氧化应激下CDC37的过度氧化，破坏了Hsp90/CDC37复合物，进而阻断了NF-κB通路的激活和p-S129-synuclein的产生。本研究可能为帕金森病的治疗提供一个有希望的策略，并进一步了解CEL的治疗机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.