Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway

Huang Hui Chen, Tai Chi Wang, Yen Chen Lee, Pei Ting Shen, Jang-Yang Chang, Teng Kuang Yeh, Chih Hsiang Huang, Hsin Huei Chang, Shu Ying Cheng, Chin Yu Lin, Chuan Shih, Chiung Tong Chen, Wei Min Liu, Ching Hui Chen, Ching Chuan Kuo

研究成果: Article

19 引文 斯高帕斯(Scopus)

摘要

The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.

原文English
頁(從 - 到)1681-1692
頁數12
期刊Chemical Research in Toxicology
28
發行號9
DOIs
出版狀態Published - 2015 八月 14

    指紋

All Science Journal Classification (ASJC) codes

  • Toxicology

引用此

Chen, H. H., Wang, T. C., Lee, Y. C., Shen, P. T., Chang, J-Y., Yeh, T. K., Huang, C. H., Chang, H. H., Cheng, S. Y., Lin, C. Y., Shih, C., Chen, C. T., Liu, W. M., Chen, C. H., & Kuo, C. C. (2015). Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway. Chemical Research in Toxicology, 28(9), 1681-1692. https://doi.org/10.1021/acs.chemrestox.5b00085