Activation of Nrf2 by MIND4-17 protects osteoblasts from hydrogen peroxide-induced oxidative stress

Shiguang Guo; Hao-Dong Fei; Feng Ji; Feng-Li Chen; Yue Xie; Shou-Guo Wang

doi:10.18632/oncotarget.22360

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Research Papers:

Activation of Nrf2 by MIND4-17 protects osteoblasts from hydrogen peroxide-induced oxidative stress

Shiguang Guo, Hao-Dong Fei, Feng Ji _, Feng-Li Chen, Yue Xie and Shou-Guo Wang

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Oncotarget. 2017; 8:105662-105672. https://doi.org/10.18632/oncotarget.22360

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Abstract

Shiguang Guo1,*, Hao-Dong Fei2,*, Feng Ji2, Feng-Li Chen3, Yue Xie2 and Shou-Guo Wang2

1Department of Intensive Care Unit, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

2Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

3Clinical Laboratory, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China

*Co-first authors

Correspondence to:

Feng Ji, email: [email protected]

Shou-Guo Wang, email: [email protected]

Keywords: osteoblasts; oxidative stress; Nrf2; MIND4-17; Keap

Received: August 23, 2017 Accepted: October 14, 2017 Published: November 10, 2017

ABSTRACT

MIND4-17 is a recently developed NF-E2-related factor 2 (Nrf2) activator, which uniquely causes Nrf2 disassociation from Keap1. Here, we showed that pretreatment with MIND4-17 significantly inhibited hydrogen peroxide (H₂O₂)-induced viability reduction of primary osteoblasts and OB-6 osteoblastic cells. Meanwhile, MIND4-17 inhibited both apoptotic and non-apoptotic osteoblast cell death by H₂O₂. MIND4-17 treatment induced Keap1-Nrf2 disassociation, causing Nrf2 stabilization, accumulation and nuclear translocation in osteoblasts, leading to transcription of several Nrf2-dependent genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), γ-glutamylcysteine synthetase modifier subunit (GCLM) and catalytic subunit (GCLC). Additionally, MIND4-17 largely attenuated H₂O₂-reactive oxygen species (ROS) production, lipid peroxidation and DNA damages. Nrf2 knockdown by targeted short hairpin RNA (shRNA) exacerbated H₂O₂-induced cytotoxicity in OB-6 osteoblastic cells, and nullified MIND4-17-mediated cytoprotection against H₂O₂. Meanwhile, Keap1 shRNA took over MIND4-17’s actions and protected OB-6 cells from H₂O₂. Together, MIND4-17 activates Nrf2 signaling and protects osteoblasts from H₂O₂.

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Research Papers:

Activation of Nrf2 by MIND4-17 protects osteoblasts from hydrogen peroxide-induced oxidative stress

Abstract