GPER1介导Prunetin在尿毒症脑病中的海马治疗作用:RUNX2轴、TLR4级联、坏死坏死和线粒体功能障碍的调节

IF 3.6 3区 医学 Q2 CHEMISTRY, MEDICINAL
Ahmed B. Hamed, Iten M. Fawzy, Dalaal M. Abdallah, Yasmin S. Abulfadl, Kawkab A. Ahmed, Hanan S. El-Abhar
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引用次数: 0

摘要

肾缺血/再氧化引发尿毒症性脑病(UE),最终导致认知和神经紊乱。尽管具有神经保护功能,雌激素受体G蛋白偶联雌激素受体1 (GPER1)在UE中的海马反应仍未明确,同时RUNX2的预期参与也未明确。在硅虚拟筛选表明,prunetin (PRU)可能激活GPER1,抑制RUNX2。为了在体内验证这些发现,雄性Sprague Dawley大鼠被分为五组:安慰剂手术(PS)、PRU治疗的PS、未治疗的UE、PRU治疗的UE和PRU前用G-15(一种选择性GPER1阻滞剂)预处理的UE。从生化角度看,PRU显著恢复了UE损伤的海马结构和行为功能,降低了血清IS水平,并补充了GPER1表达。此外,它还能抑制p-AKT、p-GSK3β、RUNX2、TLR4和NF-κB,同时通过沉默坏死信号(TICAM1/RIPK1/RIPK3/MLKL)和恢复caspase-8来提高细胞存活率。PRU还通过下调PGAM5和p-DRP-1来抵消线粒体功能障碍。至关重要的是,这些有益作用被G-15抵消,证实了活化的GPER1在介导PRU治疗作用中的作用。总的来说,pru诱导GPER1协调神经完整性信号UE/AKT/GSK-3β/RUNX2,炎症轴UE/TLR-4/NF-κB,坏死坏死通路(TICAM1/RIPK1/RIPK3/MLKL),通过抑制PGAM5/DRP-1信号来预防线粒体功能障碍。这些发现强调了PRU通过激活GPER1治疗ue相关海马损伤的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

GPER1 Mediates Hippocampal Therapeutic Effect of Prunetin in Uremic Encephalopathy: Modulation of the RUNX2 Axis, TLR4 Cascade, Necroptosis, and Mitochondrial Dysfunction

GPER1 Mediates Hippocampal Therapeutic Effect of Prunetin in Uremic Encephalopathy: Modulation of the RUNX2 Axis, TLR4 Cascade, Necroptosis, and Mitochondrial Dysfunction

Renal ischemia/reoxygenation triggers uremic encephalopathy (UE), culminating in cognitive and neural derangements. Despite its neuroprotective functions, the hippocampal repercussion of the estrogen receptor G protein-coupled estrogen receptor 1 (GPER1) in UE remains uncharted, alongside the prospective involvement of RUNX2. In Silico virtual screening suggested that prunetin (PRU) may activate GPER1 and inhibit RUNX2. To validate these findings in vivo, male Sprague Dawley rats were allocated into five groups: placebo-surgery (PS), PRU-treated PS, untreated UE, PRU-treated UE, and UE pretreated with G-15 (a selective GPER1 blocker) before PRU. Biochemically, PRU significantly restored hippocampal structure and behavioral functions impaired by UE, reduced serum IS levels, and replenished GPER1 expression. Additionally, it suppressed p-AKT, p-GSK3β, RUNX2, TLR4, and NF-κB, while enhancing cell survival by silencing the necroptotic signal (TICAM1/RIPK1/RIPK3/MLKL) and restoring caspase-8. PRU also counteracted mitochondrial dysfunction by downregulating PGAM5 and p-DRP-1. Crucially, these beneficial effects were nullified by G-15, confirming the role of activated GPER1 in mediating PRU's therapeutic effects. Collectively, PRU-induced GPER1 orchestrated neural integrity signal UE/AKT/GSK-3β/RUNX2, inflammatory axis UE/TLR-4/NF-κB, necroptosis pathway (TICAM1/RIPK1/RIPK3/MLKL), preventing mitochondrial dysfunction by suppressing the PGAM5/DRP-1 cue. These findings highlight the therapeutic potential of PRU in treating UE-related hippocampal damage through GPER1 activation.

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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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