Yinaoxin granule alleviates cerebral ischemia-reperfusion injury by ferroptosis inhibition through Nrf2 pathway activation

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL Phytomedicine Pub Date : 2025-02-11 DOI:10.1016/j.phymed.2025.156476

Jingyu Weng , Lang Liu , Shuming Li , Yuangui Yang , Rui Zhou , Zhen Zhang , Yanru Liu , Lin Chen , Zeyu Feng , Zhishu Tang , Hongbo Xu

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Abstract

Background

Lipid peroxide accumulation plays significant roles in cerebral ischemia-reperfusion injury (CIRI) through various mechanisms, including ferroptosis. Preserving the neuronal metabolic equilibrium and averting cell death during cerebral ischemia-reperfusion are pivotal for protecting brain function. Yinaoxin granule (YNX) is a widely used Chinese herbal preparations for treating cerebrovascular diseases, but pharmacological mechanism remains ambiguous..

Purpose

The aim in this study was to assess the effectiveness of YNX in treating CIRI and to investigate the underlying mechanisms.

Methods

The active ingredients of YNX were quantified using high-performance liquid chromatography. To explore the effects of YNX on CIRI and ferroptosis, both an in vitro oxygen-glucose deprivation and reperfusion model and a middle cerebral artery occlusion and reperfusion rat model were used. To assess the neuroprotective effects of YNX in the latter, neurological scores and cerebral blood flow were evaluated. Neuronal damage was determined through 2,3,5-triphenyltetrazolium chloride, Nissl, and H&E staining. Ferroptosis-related markers, including ferrous ion, glutathione, 4-hydroxynonenal, and malondialdehyde were also investigated. Furthermore, the gene expression and protein levels of solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4) and glutamate-cysteine ligase modulator (GCLM) were determined.

Results

YNX enhanced neurological scores and cerebral blood flow, reduced infarct volume, and rescued necrotic neurons in rats. Additionally, YNX mitigated lipid peroxidation and upregulated the SLC7A11, GCLM, and GPX4 levels. The absence of Nrf2 rendered neurons more susceptible to ischemia-reperfusion damage and abrogated the anti-ferroptotic neuroprotective effects of YNX.

Conclusion

YNX activates the Nrf2 pathway, resulting in the transcription of genes associated with antioxidants, including SLC7A11, GCLM, and GPX4. This suggests that YNX reduces lipid peroxidation and alleviates ferroptosis-induced CIRI.

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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.