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Vialinin A Alleviates Oxidative Stress and Neuronal Injuries after Ischaemic Stroke by Accelerating Keap1 Degradation Through Inhibiting USP4-mediated Deubiquitination.

Qian Xia,Gaofeng Zhan,Hailong Bing, Chenxi Zhang, Jie Wang, Wangli Tian,Hongkai Lian,Xing Li,Qinjun Chu

Phytomedicine(2024)

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摘要
Background: Oxidative stress is known as a hallmark of cerebral ischaemia-reperfusion injury and it exacerbates the pathologic progression of ischaemic brain damage. Vialinin A, derived from a Chinese edible mushroom, possesses multiple pharmacological activities in cancer, Kawasaki disease, asthma and pathological scarring. Notably, vialinin A is an inhibitor of ubiquitin-specific peptidase 4 (USP4) that shows anti-inflammatory and antioxidative properties. However, the precise effect of vialinin A in ischaemic stroke, as well as its underlying mechanisms, remains largely unexplored. Purpose: The present research focuses on the impacts of vialinin A on oxidative stress and explores the underlying mechanisms involved while also examining its potentiality as a therapeutic candidate for ischaemic stroke. Methods: Mouse ischaemic stroke was conducted by MCAO surgery. Vialinin A was administered via lateral ventricular injection at a dose of 2 mg/kg after reperfusion. Subsequent experiments were meticulously conducted at the appropriate time points. Stroke outcomes were evaluated by TTC staining, neurological score, Nissl staining and behavioural analysis. Co-IP assays were operated to examine the protein-protein interactions. Immunoblot analysis, qRT-PCR, and luciferase reporter assays were conducted to further investigate its underlying mechanisms. Results: In this study, we initially showed that administration of vialinin A alleviated cerebral ischaemiareperfusion injury-induced neurological deficits and neuronal apoptosis. Furthermore, vialinin A, which is an antioxidant, reduced oxidative stress injury, promoted the activation of the Keap1-Nrf2-ARE signaling pathway and increased the protein degradation of Keap1. The substantial neuroprotective effects of vialinin A against ischaemic stroke were compromised by the overexpression of USP4. Mechanistically, vialinin A inhibited the deubiquitinating enzymatic activity of USP4, leading to enhanced ubiquitination of Keap1 and subsequently promoting its degradation. This cascade caused the activation of Nrf2-dependent antioxidant response, culminating in a reduction of neuronal apoptosis and the amelioration of neurological dysfunction following ischaemic stroke. Conclusions: This study demonstrates that inhibition of USP4 to activate Keap1-Nrf2-ARE signaling pathway may represent a mechanism by which vialinin A conferred protection against cerebral ischaemia-reperfusion injury and sheds light on its promising prospects as a therapeutic intervention for ischaemic stroke.
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关键词
Vialinin A,Ischaemic stroke,Oxidative stress,USP4,Keap1,Ubiquitination
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