Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China.
Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, China.
Phytomedicine. 2023 Jul;115:154756. doi: 10.1016/j.phymed.2023.154756. Epub 2023 Mar 12.
The limited understanding of the pathological mechanisms of intracerebral hemorrhage (ICH) and the absence of successful therapies lead to poor prognoses for patients with ICH. Dihydromyricetin (DMY) has many physiological functions, such as regulating lipid and glucose metabolism and modulating tumorigenesis. Moreover, DMY has been proven to be an effective treatment of neuroprotection. However, no reports to date have been made regarding the impact of DMY on ICH.
This investigation aimed to identify the role of DMY on ICH in mice and the underlying mechanisms.
METHODS/RESULTS: This study demonstrated that DMY treatment effectively reduced hematoma size and cell apoptosis of brain tissue, and improved neurobehavioral outcomes in mice with ICH. Transcriptional and network pharmacological analyses revealed that lipocalin-2 (LCN2) was a potential target of DMY in ICH. After ICH, LCN2 mRNA and protein expression in brain tissue increased and DMY could inhibit the expression of LCN2. The rescue experiment with the implementation of LCN2 overexpression verified these observations. Furthermore, after DMY treatment, there was a significant decrease in cyclooxygenase 2 (COX2), phospho-extracellular regulated protein kinase (P-ERK), iron deposition, and the number of abnormal mitochondria, which were reversed by the overexpression of LCN2. Proteomics analysis suggests that SLC3A2 may be the downstream target of LCN2, promoting ferroptosis. Finally, LCN2 was shown to bind to SLC3A2 and regulate the downstream glutathione (GSH) synthesis and Glutathione Peroxidase 4 (GPX4) expression and glutathione (GSH) synthesis, as determined by molecular docking and co-immunoprecipitation analysis.
Our study confirmed for the first time that DMY might offer a favorable treatment for ICH through its action on LCN2. The possible mechanism for this could be that DMY reverses the inhibitory effect of LCN2 on the system Xc-, lessening ferroptosis in brain tissue. The findings of this study offer a greater understanding of how DMY affects ICH at a molecular level and could be conducive to developing therapeutic targets for ICH.
由于对脑出血（ICH）病理机制的了解有限，以及缺乏成功的治疗方法，ICH 患者的预后较差。二氢杨梅素（DMY）具有调节脂质和葡萄糖代谢以及调节肿瘤发生等多种生理功能。此外，已经证明 DMY 是一种有效的神经保护治疗方法。然而，迄今为止，尚无关于 DMY 对 ICH 影响的报道。
本研究旨在确定 DMY 对小鼠 ICH 的作用及其潜在机制。
方法/结果：本研究表明，DMY 治疗可有效减小血肿体积，减少脑组织细胞凋亡，改善 ICH 小鼠的神经行为学结局。转录组和网络药理学分析表明，脂联素（LCN2）是 DMY 在 ICH 中的潜在靶点。ICH 后，脑组织中 LCN2 mRNA 和蛋白表达增加，DMY 可抑制 LCN2 的表达。实施 LCN2 过表达的挽救实验验证了这些观察结果。此外，在用 DMY 治疗后，环氧化酶 2（COX2）、磷酸细胞外调节蛋白激酶（P-ERK）、铁沉积和异常线粒体数量显著减少，而过表达 LCN2 则逆转了这些变化。蛋白质组学分析表明，SLC3A2 可能是 LCN2 的下游靶点，促进铁死亡。最后，通过分子对接和共免疫沉淀分析表明，LCN2 与 SLC3A2 结合并调节下游谷胱甘肽（GSH）合成和谷胱甘肽过氧化物酶 4（GPX4）表达和谷胱甘肽（GSH）合成。
本研究首次证实，DMY 通过作用于 LCN2 可能为 ICH 提供有利的治疗方法。其可能的机制是 DMY 逆转 LCN2 对系统 Xc-的抑制作用，减轻脑组织中的铁死亡。本研究的发现提供了对 DMY 如何在分子水平上影响 ICH 的更深入了解，并可能有助于为 ICH 开发治疗靶点。
