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基于CCL2/CCR2轴探讨桃红四物汤治疗缺血性脑卒中的机制

Exploration of the mechanism of Taohong Siwu Decoction for the treatment of ischemic stroke based on CCL2/CCR2 axis.

作者信息

Li Jingjing, Zhang Lijuan, Xue Sujun, Yu Chao, Li Yumeng, Li Shuangping, Ye Qingping, Duan Xianchun, Peng Daiyin

机构信息

Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.

School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.

出版信息

Front Pharmacol. 2024 Aug 29;15:1428572. doi: 10.3389/fphar.2024.1428572. eCollection 2024.

DOI:10.3389/fphar.2024.1428572
PMID:39268469
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11390630/
Abstract

BACKGROUND AND AIMS

Taohong Siwu Decoction (THSWD) is a traditional Chinese herbal prescription that is effective for ischemic stroke, Whether THSWD regulates the CCL2/CCR2 axis and thus reduces the inflammatory response induced by ischemic stroke is not known. The aim of this study was to elucidate the mechanism of action of THSWD in the treatment of ischemic stroke using bioinformatics combined with and experiments.

METHODS

R language was used to analyze middle cerebral artery occlusion/reperfusion (MCAO/R) rat transcriptome data and to identify differential gene expression following THSWD treatment. Gene set enrichment analysis (GSEA) was used to analyze the gene set enrichment pathway of MCAO/R rats treated with THSWD. PPI networks screened key targets. The Human Brain Microvascular Endothelial Cells (HBMEC) Oxygen Glucose Deprivation/Reoxygenation (OGD/R) model and SD rat models of MCAO/R were established. FITC-dextran, immunofluorescence, flow cytometry, ELISA, immunohistochemistry, Western blotting, and RT-qPCR were performed to identify potential treatment targets.

RESULTS

A total of 515 differentially expressed genes of THSWD in MCAO/R rats were screened and 92 differentially expressed genes of THSWD potentially involved in stroke intervention were identified, including Cd68, Ccl2, and other key genes. , THSWD reversed the increase in permeability of HBMEC cells and M1/M2 polarization of macrophages induced by CCL2/CCR2 axis agonists. , THSWD improved nerve function injury and blood-brain barrier injury in MCAO/R rats. Further, THSWD inhibited the infiltration and polarization of macrophages, reduced the expression of IL-6, TNF-α, and MMP-9, and increased the expression of IL-4, while reducing the gene and protein expression of CCL2 and CCR2.

CONCLUSION

THSWD may play a protective role in ischemic stroke by inhibiting the CCL2/CCR2 axis, reducing the infiltration of macrophages, and promoting the polarization of M2 macrophages, thereby reducing inflammatory damage, and protecting injury to the blood-brain barrier.

摘要

背景与目的

桃红四物汤（THSWD）是一种对缺血性中风有效的传统中药方剂，其是否通过调节CCL2/CCR2轴从而减轻缺血性中风诱导的炎症反应尚不清楚。本研究旨在运用生物信息学结合体内和体外实验阐明THSWD治疗缺血性中风的作用机制。

方法

使用R语言分析大脑中动脉闭塞/再灌注（MCAO/R）大鼠转录组数据，以鉴定THSWD治疗后的差异基因表达。基因集富集分析（GSEA）用于分析THSWD处理的MCAO/R大鼠的基因集富集途径。蛋白质-蛋白质相互作用（PPI）网络筛选关键靶点。建立人脑微血管内皮细胞（HBMEC）氧糖剥夺/复氧（OGD/R）模型和MCAO/R的SD大鼠模型。进行异硫氰酸荧光素-葡聚糖（FITC-dextran）、免疫荧光、流式细胞术、酶联免疫吸附测定（ELISA）、免疫组织化学、蛋白质免疫印迹法（Western blotting）和逆转录定量聚合酶链反应（RT-qPCR）以鉴定潜在的治疗靶点。

结果

共筛选出MCAO/R大鼠中THSWD的515个差异表达基因，并鉴定出92个THSWD潜在参与中风干预的差异表达基因，包括Cd68、Ccl2等关键基因。体外实验表明，THSWD逆转了CCL2/CCR2轴激动剂诱导的HBMEC细胞通透性增加和巨噬细胞M1/M2极化。体内实验表明，THSWD改善了MCAO/R大鼠的神经功能损伤和血脑屏障损伤。此外，THSWD抑制巨噬细胞的浸润和极化，降低白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）和基质金属蛋白酶-9（MMP-9）的表达，并增加白细胞介素-4（IL-4）的表达，同时降低CCL2和CCR2的基因和蛋白表达。

结论

THSWD可能通过抑制CCL2/CCR2轴、减少巨噬细胞浸润和促进M2巨噬细胞极化，从而减轻炎症损伤，保护血脑屏障损伤，在缺血性中风中发挥保护作用。

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