6-Hydroxygenistein Ameliorates High Altitude Brain Injury via Activating PI3K/AKT Signaling Pathway Based on Transcriptomic Analysis and Experimental Validation.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-09-23 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S526988

Yu Xin, Gege Wang, Chenyu Yang, Huiping Ma, Linlin Jing

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引用次数: 0

Abstract

Purpose: Our Prior research has shown that 6-hydroxygenistein (6-OHG) alleviates hypobaric hypoxia induced brain injury (HHBI) achieved by its powerful antioxidant, anti-inflammatory, and anti-apoptotic capabilities, but its mechanism still requires additional investigation. The objective of this study was to uncover the protective mechanism of 6-OHG against HHBI based on transcriptomics analysis and experimental validation.

Methods: The gene levels in brain tissue obtained from previous study were accessed via the RNA-Seq technique. DESeq2 R package was used to identify the differentially expressed genes (DEGs). Functional enrichment analysis and molecular docking were investigated utilizing the clusterProfiler R package and Autodock Vina software, respectively. In experimental validation stage, histological analysis was performed using Hematoxylin-Eosin (HE) staining. Oxidative stress, inflammatory, and apoptotic indexes in brain tissue were measured using commercial kits. Western blot was applied for detecting related protein expression.

Results: The RNA-Seq analysis revealed 905 differentially expressed genes (DEGs) between the Con and Mod groups, with 239 upregulated and 666 downregulated. Between the 6-OHG and Mod groups, there were 192 DEGs, including 98 upregulated and 94 downregulated genes. Go and KEGG function analyses highlighted the PI3K/AKT signaling pathway as a crucial regulatory mechanism. Western blot analysis showed that HH exposure caused a decrease in the ratios of p-PI3K/PI3K and p-AKT/AKT in the mouse brain, but this effect was reversed by 6-OHG treatment, indicating that 6-OHG activates the PI3K/AKT signaling pathway. Furthermore, LY294002, a selective PI3K inhibitor, effectively blocked this activation and also abolished the protective effects of 6-OHG on histopathological damage, as well as its antioxidant, anti-inflammatory, and anti-apoptotic activities in HHBI mice.

Conclusion: 6-OHG mitigates HHBI by activating the PI3K/AKT signaling pathway, suggesting its potential therapeutic application for HHBI treatment.

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基于转录组学分析和实验验证的6-羟基染料木素通过激活PI3K/AKT信号通路改善高原脑损伤

目的：我们已有研究表明6-羟基染料木素（6-OHG）通过其强大的抗氧化、抗炎和抗凋亡能力减轻了低氧缺氧所致的脑损伤（HHBI），但其机制仍有待进一步研究。本研究旨在通过转录组学分析和实验验证，揭示6-OHG对HHBI的保护机制。方法：利用RNA-Seq技术获取前人研究中获得的脑组织基因水平。采用DESeq2 R包鉴定差异表达基因（DEGs）。分别利用clusterProfiler R软件包和Autodock Vina软件进行功能富集分析和分子对接。在实验验证阶段，采用苏木精-伊红（HE）染色进行组织学分析。使用商业试剂盒测量脑组织氧化应激、炎症和凋亡指标。Western blot检测相关蛋白表达。结果：RNA-Seq分析显示，Con组和Mod组有905个差异表达基因（DEGs），其中239个表达上调，666个表达下调。6-OHG组和Mod组共192个基因，其中98个基因上调，94个基因下调。Go和KEGG功能分析强调PI3K/AKT信号通路是一个重要的调控机制。Western blot分析显示，HH暴露导致小鼠大脑中p-PI3K/PI3K和p-AKT/AKT比值降低，但6-OHG处理逆转了这一作用，表明6-OHG激活了PI3K/AKT信号通路。此外，选择性PI3K抑制剂LY294002有效阻断了这一激活，也消除了6-OHG对HHBI小鼠组织病理损伤的保护作用，以及其抗氧化、抗炎和抗凋亡活性。结论：6-OHG通过激活PI3K/AKT信号通路减轻HHBI，提示其在HHBI治疗中的潜在应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.