The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade

Abstract

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.

Stachydrine protects eNOS uncoupling and ameliorates endothelial dysfunction induced by homocysteine

“…Nuclear factor erythroid 2–related factor 2 (Nrf2) transcriptionally controls the gene expression of many cytoprotective enzymes, such as heme oxygenase-1 (HO-1) (Swamy et al, 2016 ) and NAD(P)H:quinone reductase (NQO1) (Rohrer et al, 2014 ). Particularly, it was shown that Nrf2 regulated-GTPCH1/BH4 axis ameliorated skin injury (Xue et al, 2017 ). To test whether Nrf2 is involved in the effects of STA on the induction of expressions of GTPCH1 and DHFR, BAECs were treated with STA (10 μM) for different time periods and the Nrf2 levels were detected by using western blotting.…”

Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis

“…The concept of NRF2-directed topical radioprotection and prevention of radiation-induced dermatitis has remained largely unexplored [ 1 , [33] , [34] , [35] , [36] , [37] , [48] , [49] , [50] ]. Herein, we have elucidated the critical role that NRF2 plays in mitigating IR-induced damage and tested the efficacy of topical application of bixin to negate the effects of RT in non-tumor tissue, specifically radiation-induced dermatitis.…”

Fabrication of smart polymeric nanovectors to amplify intracellular oxidative stress for chemodynamic therapy

“…图 3 Lapa负载的聚前药两亲分子(PEG-b-PTCPT)胶束组装体用于CT和CDT协同治疗 [51] (网络版彩图) 除单独使用外, ION还可以与其他ROS产生剂协 同作用. Gao等 [59] 同时将Lapa和ION负载到pH敏感的 [58] (网络版彩图) Figure 4 Schematic illustration of the fabrication of hybrid iron oxide nanoparticles by tethering hydrophobic (p1) and hydrophilic (p2) polymers onto the surface. After cell internalization into endolysosomes, the hybrid nanoparticles release ferrous ions within acidic organelles, which catalyzes the generation of 1 O 2 through the Russell mechanism and induces cell death [58] (color online).…”