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化合物 7 通过体内和体外研究的 Nrf2 信号通路调节小胶质细胞极化并减轻放射性脊髓病。

Compound 7 regulates microglia polarization and attenuates radiation-induced myelopathy via the Nrf2 signaling pathway in vivo and in vitro studies.

机构信息

Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Department of Orthopedics, The Affiliated Yixing Hospital of Jiangsu University, Wuxi, China.

出版信息

Mol Med. 2024 Nov 4;30(1):198. doi: 10.1186/s10020-024-00951-3.

DOI:10.1186/s10020-024-00951-3
PMID:39497026
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11536861/
Abstract

BACKGROUND

Radiation-induced myelopathy (RM) is a significant complication of radiotherapy with its mechanisms still not fully understood and lacking effective treatments. Compound 7 (C7) is a newly identified, potent, and selective inhibitor of the Keap1-Nrf2 interaction. This study aimed to explore the protective effects and mechanisms of C7 on RM in vitro and in vivo.

METHODS

Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), reactive oxygen species (ROS) and mitochondrial polarization, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, genetic editing techniques, locomotor functions, and tissue staining were employed to explore the protective effects and underlying mechanisms of C7 in radiation-induced primary rat microglia and BV2 cells, as well as RM rat models.

RESULTS

In this study, we found that C7 inhibited the production of pro-inflammation cytokines and oxidative stress induced by irradiation in vitro. Further, the data revealed that radiation worsened the locomotor functions in rats, and C7 significantly improved histological and functional recovery in RM rats. Mechanically, C7 activated Nrf2 signaling and promoted the microglia transformation from M1 to M2 phenotype.

CONCLUSION

C7 could ameliorate RM by boosting Nrf2 signaling and promoting M2 phenotype microglia polarization in vitro and in vivo.

摘要

背景

放射性脊髓病（RM）是放疗的一种严重并发症，其发病机制尚不完全清楚，且缺乏有效的治疗方法。化合物 7（C7）是一种新发现的、强效且选择性的 Keap1-Nrf2 相互作用抑制剂。本研究旨在探讨 C7 对体外和体内 RM 的保护作用及其机制。

方法

采用 Western blot、实时定量聚合酶链反应（qRT-PCR）、活性氧（ROS）和线粒体极化、末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测、基因编辑技术、运动功能和组织染色等方法，探讨 C7 在放射性诱导的原代大鼠小胶质细胞和 BV2 细胞以及 RM 大鼠模型中的保护作用及其潜在机制。

结果

本研究发现，C7 可抑制体外照射诱导的促炎细胞因子和氧化应激的产生。此外，数据显示，辐射会使大鼠的运动功能恶化，而 C7 可显著改善 RM 大鼠的组织学和功能恢复。机制上，C7 可激活 Nrf2 信号通路，并促进小胶质细胞从 M1 向 M2 表型转化。

结论

C7 可通过激活 Nrf2 信号通路和促进 M2 表型小胶质细胞极化，改善体外和体内 RM。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/f2c70a3e90b2/10020_2024_951_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/99a3eb1658c7/10020_2024_951_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/f2c70a3e90b2/10020_2024_951_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/99a3eb1658c7/10020_2024_951_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/a0060ffe6d12/10020_2024_951_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/c05c69ca058d/10020_2024_951_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a92b/11536861/c892d1fc6b1c/10020_2024_951_Fig6_HTML.jpg
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