Abstract: We previously reported that a novel marine compound, xyloketal B, has strong antioxidative actions in different models of cardiovascular diseases. Induction of heme oxygenase-1 (HO-1), an important endogenous antioxidant enzyme, has been considered as a potential therapeutic strategy for cardiovascular diseases. We here investigated whether xyloketal B exhibits its antioxidant activity through induction of HO-1. In human umbilical vein endothelial cells (HUVECs), xyloketal B significantly induced HO-1 gene expression and translocation of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) in a concentration- and time-dependent manner. The protection of xyloketal B against angiotensin II-induced apoptosis and reactive oxygen species (ROS) production could be abrogated by the HO-1 specific inhibitor, tin protoporphyrin-IX (SnPP). Consistently, the suppressive effects of xyloketal B on NADPH oxidase activity could be reversed by SnPP in zebrafish embryos. In addition, xyloketal B induced Akt and Erk1/2 phosphorylation in a concentration- and time-dependent manner. Furthermore, PI3K inhibitor LY294002 and Erk1/2 inhibitor U0126 suppressed the induction of HO-1 and translocation of Nrf-2 by xyloketal B, whereas P38 inhibitor SB203580 did not. In conclusion, xyloketal B can induce HO-1 expression via PI3K/Akt/Nrf-2 pathways, and the induction of HO-1 is mainly responsible for the antioxidant and antiapoptotic actions of xyloketal B.
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Li, Z.-X.; Chen, J.-W.; Yuan, F.; Huang, Y.-Y.; Zhao, L.-Y.; Li, J.; Su, H.-X.; Liu, J.; Pang, J.-Y.; Lin, Y.-C.; Lu, X.-L.; Pei, Z.; Wang, G.-L.; Guan, Y.-Y. Xyloketal B Exhibits Its Antioxidant Activity through Induction of HO-1 in Vascular Endothelial Cells and Zebrafish. Mar. Drugs 2013, 11, 504-522.
Li Z-X, Chen J-W, Yuan F, Huang Y-Y, Zhao L-Y, Li J, Su H-X, Liu J, Pang J-Y, Lin Y-C, Lu X-L, Pei Z, Wang G-L, Guan Y-Y. Xyloketal B Exhibits Its Antioxidant Activity through Induction of HO-1 in Vascular Endothelial Cells and Zebrafish. Marine Drugs. 2013; 11(2):504-522.
Li, Zhen-Xing; Chen, Jian-Wen; Yuan, Feng; Huang, Yun-Ying; Zhao, Li-Yan; Li, Jie; Su, Huan-Xing; Liu, Jie; Pang, Ji-Yan; Lin, Yong-Cheng; Lu, Xi-Lin; Pei, Zhong; Wang, Guan-Lei; Guan, Yong-Yuan. 2013. "Xyloketal B Exhibits Its Antioxidant Activity through Induction of HO-1 in Vascular Endothelial Cells and Zebrafish." Mar. Drugs 11, no. 2: 504-522.