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

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2024-11-04 DOI:10.1186/s10020-024-00951-3

Han Wu, Jianping Wu, Jianzhuo Jiang, Zeyu Qian, Shuang Yang, Yanze Sun, Hongxia Cui, Shengwen Li, Peng Zhang, Zhiqiang Zhou

{"title":"Compound 7 regulates microglia polarization and attenuates radiation-induced myelopathy via the Nrf2 signaling pathway in vivo and in vitro studies.","authors":"Han Wu, Jianping Wu, Jianzhuo Jiang, Zeyu Qian, Shuang Yang, Yanze Sun, Hongxia Cui, Shengwen Li, Peng Zhang, Zhiqiang Zhou","doi":"10.1186/s10020-024-00951-3","DOIUrl":null,"url":null,"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.","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536861/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s10020-024-00951-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

在体内和体外研究中，化合物 7 通过 Nrf2 信号通路调节小胶质细胞的极化并减轻辐射诱导的骨髓病变。

背景：放疗引起的脊髓病（RM）是放疗的一个重要并发症，其发病机制尚未完全明了，也缺乏有效的治疗方法。化合物 7（C7）是一种新发现的 Keap1-Nrf2 相互作用的强效选择性抑制剂。本研究旨在探讨C7在体外和体内对RM的保护作用及其机制：方法：采用Western印迹、定量实时聚合酶链式反应（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对辐射诱导的原代大鼠小胶质细胞和BV2细胞以及RM大鼠模型的保护作用及其机制：结果：本研究发现，C7 可抑制体外辐照诱导的促炎细胞因子和氧化应激的产生。此外，数据还显示，辐射使大鼠的运动功能恶化，而 C7 能显著改善 RM 大鼠的组织学和功能恢复。C7可激活Nrf2信号传导，促进小胶质细胞从M1表型向M2表型转化：结论：C7能在体外和体内通过增强Nrf2信号传导和促进M2表型小胶质细胞极化来改善RM。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.