Cyclo-(Phe-Tyr) as a novel cyclic dipeptide compound alleviates ischemic/reperfusion brain injury via JUNB/JNK/NF-κB and SOX5/PI3K/AKT pathways
Cyclo-(Phe-Tyr) as a novel cyclic dipeptide compound alleviates ischemic/reperfusion brain injury via JUNB/JNK/NF-κB and SOX5/PI3K/AKT pathways
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DOI：
10.1016/j.phrs.2022.106230
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发表时间：
2022-05-06
影响因子：
9.3
通讯作者：
Wang, Shumei
中科院分区：
文献类型：
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作者：
Liang, Jiayin;Zhang, Yutong;Wang, Shumei
缺血/再灌注（IR）可引起细胞凋亡、氧化应激和炎症等不良反应，但现有的治疗策略有限。此外，小胶质细胞的调节在再灌注后的脑损伤中起着重要作用。因此，迫切需要寻找新的有效的调节小胶质细胞的药物来治疗IR脑损伤。环肽化合物 cyclo-(Phe-Tyr) (Sparganin C, SC) 是从 Spargana Rhizoma 中分离出来的化合物。然而，SC对中枢神经系统的保护作用尚不清楚。为了阐明SC对IR引起的脑损伤的保护作用和机制，我们使用大鼠大脑中动脉闭塞再灌注（MCAO/R）模型，发现SC显着减小了脑梗塞的面积，改善了神经功能评分，并阻止了炎症和氧化因子的释放。使用 RNA-Seq 和代谢组学关联分析，SC 被证明通过 JUNB 和 SOX5 相关途径具有保护作用。代谢组学分析揭示了二十八种差异表达的生物标志物。此外，利用LC/MS检测脑组织中的SC含量，发现SC具有血脑屏障穿透性。为了研究其机制，我们建立了体外 BV2 细胞氧葡萄糖剥夺/再灌注 (OGD/R) 模型，并使用 siRNA 和抑制剂。 SC 的保护作用依赖于 JUNB 和 SOX5 抑制小胶质细胞炎症和凋亡。我们的研究结果首次揭示了 SC 通过减少炎症和细胞凋亡来对抗 IR 损伤，同时作为缺血性中风的潜在治疗先导化合物。
Ischemic/reperfusion (IR) can cause adverse reactions including apoptosis, oxidative stress, and inflammation, but the existing therapeutic strategies have been limited. Moreover, the regulation of microglia plays an important role in brain injury after reperfusion. Hence, it is imperative to find new and effective drugs for modulating microglia to treat IR brain injury. Cyclic peptide compound cyclo-(Phe-Tyr) (Sparganin C, SC) is a compound isolated from Spargana Rhizoma. However, the protective effects of SC on the central nervous system are rather unclear. In an attempt to elucidate the protective effects and mechanism of SC on cerebral damage induced by the IR, we used a middle cerebral artery occlusion reperfusion (MCAO/R) model in rats and discovered that SC significantly decreased the size of cerebral infarcts, improved neurological scores, and blocked inflammatory and oxidative factor release. Using RNA-Seq and metabolomics association analyses, SC was shown to have a protective impact through the JUNB and SOX5-related pathways. Metabolomic analysis revealed twenty-eight differentially expressed biomarkers. In addition, the detection of SC content in brain tissue using LC/MS revealed that SC had blood-brain barrier penetration. To investigate the mechanism, we established an in vitro BV2 cell oxygen-glucose deprivation/reperfusion (OGD/R) model and used siRNA as well as an inhibitor. The protective effects of SC were dependent on the JUNB and SOX5 to inhibit inflammation and apoptosis in microglia. Our findings revealed for the first that SC against IR injury by reducing inflammation and apoptosis while simultaneously acting as potential therapeutic lead compound for ischemic stroke.