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Silencing of TXNIP Alleviated Oxidative Stress Injury by Regulating MAPK-Nrf2 Axis in Ischemic Stroke
1Department of Neurosurgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
Abstract:
Ischemic stroke is a life-threatening cerebrovascular thrombotic disease, oxidative stress is considered to be a critical factor to stroke pathophysiology. This study aimed to investigate the underlying molecular mechanism and propose the potential therapeutic strategy for ischemic stroke. Bioinformatics analysis based on a public microarray profile (GSE 61616) of ischemic stroke rats was performed as a pilot research. Oxidative stress was enriched as a significantly gene ontology item, and thioredoxin-interacting protein (TXNIP) and MAPK signaling were identified as the hub gene and pathway, respectively. The experiments in middle cerebral artery occlusion rats demonstrated that ischemia induced the activation of oxidative stress. The expressions of TXNIP, p-p38, p-JNK, p-ERK were significantly increased while Nrf2 and HO-1 expressions were decreased after stroke. Rescue assays were conducted in primary cultured neurons to explore the accurate interrelations among these factors. The results indicated that MAPK specific inhibitor and siRNA-TXNIP significantly alleviated the oxidative stress injury induced by oxygen-glucose deprivation. In addition, knocking down of TXNIP inhibited the activation of MAPK pathway and promoted Nrf2 pathway. Taken together, these findings indicated that TXNIP aggravated the oxidative stress injury by regulating MAPK-Nrf2 axis in ischemic stroke. Silencing of TXNIP seems a promising therapeutic strategy to alleviate ischemic stroke.
Insights
Thioredoxin-interacting protein (TXNIP) aggravates oxidative stress in ischemic stroke by activating the MAPK pathway and inhibiting the Nrf2 pathway. Silencing TXNIP offers a potential therapeutic strategy for stroke treatment.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Ischemic stroke is a major cause of death and disability.
- Oxidative stress plays a critical role in the pathophysiology of ischemic stroke.
- Understanding the molecular mechanisms underlying stroke is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the molecular mechanisms of ischemic stroke.
- To identify potential therapeutic targets for ischemic stroke.
- To explore the role of thioredoxin-interacting protein (TXNIP) and MAPK signaling in ischemic stroke.
Main Methods:
- Bioinformatics analysis of public microarray data (GSE 61616).
- In vivo experiments using middle cerebral artery occlusion (MCAO) rat models.
- In vitro rescue assays in primary cultured neurons subjected to oxygen-glucose deprivation (OGD).
Main Results:
- Bioinformatics analysis identified TXNIP as a hub gene and MAPK signaling as a key pathway.
- Ischemia induced oxidative stress, increased TXNIP and MAPK pathway activation (p-p38, p-JNK, p-ERK), and decreased Nrf2 and HO-1 expression.
- Inhibition of TXNIP or MAPK signaling alleviated oxidative stress injury in vitro.
- Knockdown of TXNIP suppressed MAPK activation and promoted Nrf2 pathway activity.
Conclusions:
- TXNIP exacerbates oxidative stress injury in ischemic stroke by regulating the MAPK-Nrf2 axis.
- Targeting TXNIP, potentially through silencing, represents a promising therapeutic strategy for ischemic stroke.
