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学科主题: 药学
题名:
Ofloxacin induces apoptosis via beta 1 integrin-EGFR-Rac1-Nox2 pathway in microencapsulated chondrocytes
作者: Sheng, Zhi-Guo1; Huang, Wei2; Liu, Yu-Xiang1; Yuan, Ye3; Zhu, Ben-Zhan1,4
关键词: Ofloxacin ; Reactive oxygen species ; Apoptosis ; beta 1 integrin ; Nox2
刊名: TOXICOLOGY AND APPLIED PHARMACOLOGY
发表日期: 2013-02-15
DOI: 10.1016/j.taap.2012.12.015
卷: 267, 期:1, 页:74-87
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Pharmacology & Pharmacy ; Toxicology
研究领域[WOS]: Pharmacology & Pharmacy ; Toxicology
关键词[WOS]: FLUOROQUINOLONE ANTIMICROBIAL AGENTS ; QUINOLONE-INDUCED ARTHROPATHY ; JUVENILE RABBIT CHONDROCYTES ; ARTICULAR CHONDROCYTES ; NADPH OXIDASES ; MAGNESIUM-DEFICIENCY ; GLOMERULAR INJURY ; HUMAN NEUTROPHILS ; OXIDATIVE STRESS ; TENDON CELLS
英文摘要:

Quinolones (QNs)-induced arthropathy is an important toxic side-effect in immature animals leading to the restriction of their therapeutic use in pediatrics. Ofloxacin, a typical QN, was found to induce the chondrocytes apoptosis in the early phase (12-48 h) of arthropathy in our previous study. However, the exact mechanism(s) is unclear. Microencapsulated juvenile rabbit joint chondrocytes, a three-dimensional culture system, is utilized to perform the present study. Ofloxacin, at a therapeutically relevant concentration (10 mu g/ml), disturbs the interaction between 131 integrin and activated intracellular signaling proteins at 12 h, which is inhibited when supplementing Mg2+. Intracellular reactive oxygen species (ROS) significantly increases in a time-dependent manner after exposure to ofloxacin for 12-48 h. Furthermore, ofloxacin markedly enhances the level of activated Rac1 and epidermal growth factor receptor (EGFR) phosphorylation, and its inhibition in turn reduces the ROS production, apoptosis and Rac1 activation. Silencing Nox2, Rac1 or supplementing Mg2+ inhibits ROS accumulation, apoptosis occurrence and EGFR phosphorylation induced by ofloxacin. However, depletion of Nox2, Rac1 and inhibition of EGFR do not affect ofloxacin-mediated loss of interaction between beta 1 integrin and activated intracellular signaling proteins. In addition, ofloxacin also induces Vay2 phosphorylation, which is markedly suppressed after inactivating EGFR or supplementing Mg2+. These results suggest that ofloxacin causes Nox2-mediated intracellular ROS production by disrupting the beta 1 integrin function and then activating the EGFR-Vav2-Rac1 pathway, finally resulting in apoptosis within 12-48 h exposure. The present study provides a novel insight regarding the potential role of Nox-driven ROS in QNs-induced arthropathy. (C) 2012 Elsevier Inc. All rights reserved.

语种: 英语
所属项目编号: 2008CB418106 ; 20925724 ; 20907070 ; 20877081 ; 20890112 ; 20921063 ; 21207139 ; 21237005 ; ES11497 ; RR01008 ; ES00210
项目资助者: Project 973 ; Hundred-Talent Project, CAS ; NSF China Outstanding Youth Award ; NSFC ; NIH
WOS记录号: WOS:000314626300008
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62066
Appears in Collections:北京大学药学院_化学生物学系_期刊论文

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作者单位: 1.Chinese Acad Sci, State Key Lab Environm Chem & Ecotoxicol, Ecoenvironm Sci Res Ctr, Beijing 100085, Peoples R China
2.Peking Univ, Dept Biol Chem, Sch Pharmaceut Sci, Hlth Sci Ctr, Beijing 1000191, Peoples R China
3.Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China
4.Oregon State Univ, Linus Panting Inst, Corvallis, OR 97331 USA

Recommended Citation:
Sheng, Zhi-Guo,Huang, Wei,Liu, Yu-Xiang,et al. Ofloxacin induces apoptosis via beta 1 integrin-EGFR-Rac1-Nox2 pathway in microencapsulated chondrocytes[J]. TOXICOLOGY AND APPLIED PHARMACOLOGY,2013,267(1):74-87.
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