Atractylenolide III alleviates inflammation in cerebral ischemia/reperfusion injury by modulating the PI3K/Akt/NF-κB signaling pathway.

IF 5.4 2区医学 Q1 CHEMISTRY, MEDICINAL

Journal of ethnopharmacology Pub Date : 2025-09-24 DOI:10.1016/j.jep.2025.120644

Mingjiang Mao, Chenhuan Shentu, Xueao Chen, Qingling Meng, Ziyu Jiao, Yikai Zhang, Na Zhu, Liping Zhou, Yangsheng Wu, Shijie Dai, Xiaofeng Yuan

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引用次数: 0

Abstract

Ethnopharmacological relevance: Atractylodes macrocephala, traditionally recorded in classical formulas such as 'Banxia Baizhu Tianma Tang' and 'Xiaoxuming Tang', has been used in traditional medicine for conditions described as 'fēng tán zǔ luò xíng' and 'bì zǔ jīng luò xíng', which are considered related to cerebrovascular disorders. Atractylenolide Ⅲ (ATL Ⅲ), a typical sesquiterpene lactone derived from A. macrocephala, has been reported to exert neuroprotective effects through antioxidant and anti-inflammatory activities. Nevertheless, its specific role and underlying mechanisms in cerebral ischemia reperfusion injury (CIRI) remain to be clarified.

Aim of the study: The present study was designed to test the hypothesis that ATL Ⅲ ameliorates CIRI primarily by suppressing inflammation through the PI3K/Akt/NF-κB signaling pathway, which was evaluated in both middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) models.

Materials and methods: In this study, models of MCAO and OGD/R were established to explore its effect of ATL Ⅲ on CIRI. Thereafter, the therapeutic mechanism of ATL Ⅲ via transcriptomics, molecular docking, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, immunofluorescence, Western blot analysis.

Results: ATL Ⅲ treatment significantly reduced infarct volume, neurological deficits, and pro-inflammatory cytokine release, while preserving blood-brain barrier (BBB) integrity in MCAO mice. In OGD/R-exposed PC12 cells, ATL Ⅲ attenuated oxidative stress, inhibited apoptosis, and decreased inflammatory mediator production. Transcriptomic analysis revealed several significantly enriched pathways following ATL Ⅲ treatment, among which the PI3K/Akt/NF-κB signaling pathway was prominent and therefore guided our mechanistic focus. Molecular docking supported the binding of ATL Ⅲ to key pathway proteins, and inhibition of PI3K with LY294002 attenuated the protective effects of ATL Ⅲ, confirming the central role of this pathway.

Conclusion: ATL Ⅲ may inhibit inflammation in CIRI, potentially through regulation of the PI3K/Akt/NF-κB signaling pathway, highlighting its promise as a candidate compound for further preclinical investigation in ischemic stroke.

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白术内酯III通过调节PI3K/Akt/NF-κB信号通路减轻脑缺血/再灌注损伤的炎症反应

民族药理学相关性：白术，传统上记录在“半夏白术天麻汤”和“小醒醒汤”等经典方剂中，已被用于传统医学中描述为“fēng tán z´luò xíng”和“bì z´jj´ng luò xíng”的病症，被认为与脑血管疾病有关。苍术内酯Ⅲ（ATLⅢ）是一种典型的倍半萜内酯类化合物，具有抗氧化和抗炎作用，具有神经保护作用。然而，其在脑缺血再灌注损伤（CIRI）中的具体作用及其机制尚不清楚。研究目的：本研究旨在验证ATLⅢ主要通过PI3K/Akt/NF-κB信号通路抑制炎症来改善CIRI的假设，并在大脑中动脉闭塞（MCAO）和氧-葡萄糖剥夺/再氧化（OGD/R）模型中进行了评估。材料与方法：本研究通过建立MCAO和OGD/R模型，探讨ATLⅢ对CIRI的影响。随后，通过转录组学、分子对接、酶联免疫吸附试验（ELISA）、免疫组织化学、免疫荧光、western blot分析ATL的治疗机制Ⅲ。结果：ATLⅢ治疗显著减少了MCAO小鼠的梗死面积、神经功能缺损和促炎细胞因子释放，同时保持了血脑屏障（BBB）的完整性。在OGD/ r暴露的PC12细胞中，ATLⅢ减轻氧化应激，抑制细胞凋亡，减少炎症介质的产生。转录组学分析显示，ATLⅢ治疗后，多条通路显著富集，其中PI3K/Akt/NF-κB信号通路突出，因此指导了我们的机制重点。分子对接支持ATLⅢ与关键通路蛋白结合，LY294002抑制PI3K减弱ATLⅢ的保护作用，证实了该通路的核心作用。结论：ATLⅢ可能通过调控PI3K/Akt/NF-κB信号通路抑制CIRI炎症，这凸显了ATL作为进一步缺血性卒中临床前研究的候选化合物的前景。

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

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.