title: Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish.
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.
authors: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
authors: Zhen-Xing
authors: ZX
authors: Li
authors: Jian-Wen
authors: JW
authors: Chen
authors: Feng
authors: F
authors: Yuan
authors: Yun-Ying
authors: YY
authors: Huang
authors: Li-Yan
authors: LY
authors: Zhao
authors: Jie
authors: J
authors: Li
authors: Huan-Xing
authors: HX
authors: Su
authors: Jie
authors: J
authors: Liu
authors: Ji-Yan
authors: JY
authors: Pang
authors: Yong-Cheng
authors: YC
authors: Lin
authors: Xi-Lin
authors: XL
authors: Lu
authors: Zhong
authors: Z
authors: Pei
authors: Guan-Lei
authors: GL
authors: Wang
authors: Yong-Yuan
authors: YY
authors: Guan
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011714:Pyrans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011714:Pyrans; C515343:xyloketal B; D051547:Heme Oxygenase-1