期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 137, 期 10, 页码 2059-2068出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2017.05.019
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资金
- National Natural Science Foundation of China [81522039, 81274150, 81573080, 31400720]
- Key Scientific Development Program of China [2016YFC0904702]
- Suzhou Administration of Science Technology [SYS201416]
- Suzhou Key Medical Center [SZZX201506]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
Radiation-induced skin injury is a common side effect of radiotherapy and can limit the duration and dose of radiotherapy. Most early work focused on elimination of reactive oxygen species (ROS) after radiation; however, less is known about the mechanisms underlying amplification of ROS and consequent skin injury by radiation. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synthases. Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and production of highly oxidative radicals. In this study, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling and augmented radiation-induced ROS. Overexpression of GTP cyclohydrolase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased radiation-induced ROS. GCH1 also protected skin cells and rat skins against radiation-induced damage. We found that GCH1 was regulated by NF-E2-related factor 2, a key mediator of the cellular antioxidant response. Importantly, we identified GCH1 as a key effector for NF-E2-related factor 2-mediated protection against radiation-induced skin injury by inhibiting ROS production. Taken together, the findings of this study illustrate the key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage.
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