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.

Xyloketal B exerts antihypertensive effect in renovascular hypertensive rats via the NO-sGC-cGMP pathway and calcium signaling

“…eNOS activity is known to be regulated by various intracellular signals, resulting in phosphorylation of eNOS [30] , and eNOS phosphorylation by the upstream PI3K/Akt pathway is required for efficient NO production [31,32] . Xyl-B has been shown to promote NO release and eNOS bioactivity in HUVECs [8] , which was confirmed in the present study through detection of the conversion ratio of [ 3 H]L-arginine into [ 3 H]L-citrulline. Our recent study showed that Xyl-B could increase eNOS activity by regulating phosphorylation of Akt and eNOS at Ser 1177 and Thr 495 [10] .…”

“…Xyloketal B (Xyl-B), obtained from the South China Sea Coast, is one of a series of novel ketal compounds isolated from the mangrove fungus Xylaria sp (No 2508) [4,5] . In previous studies, multiple biomedical activities of Xyl-B have been demonstrated, including neuroprotective effects against toxicity [6] , antioxidant effects on endothelial cells [7] and zebrafish [8] , anti-glioma effects [9] and reduced atherosclerosis plaque formation in apolipoprotein E-deficient mice [10] . After exploring the underlying mechanisms, we have found that Xyl-B can directly scavenge DPPH free radicals, promote endothelial NO release [7] and increase eNOS phosphorylation at Ser-1177 in a concentration-and time-dependent manner [10] .…”

Effects of marine compound xyloketal B on neuroprotection and potential drug development

“…This evidence further supports that xyloketal B has an effect on multiple downstream targets and is likely to act through multiple mechanisms. Li and colleagues discovered that one of those mechanisms involved Akt and ERK 1/2 phosphorylation which induces HO-1, an antioxidant enzyme, in HUVECs and zebrafish [7]. They found that inhibition of HO-l removed the protective effect of xyloketal B against angiotensin-II-induced apoptosis leading to believe that HO-1 induction is a critical mediator of the antioxidative actions of xyloketal B.…”

“…They found that inhibition of HO-l removed the protective effect of xyloketal B against angiotensin-II-induced apoptosis leading to believe that HO-1 induction is a critical mediator of the antioxidative actions of xyloketal B. Secondary to HO-1 induction, activating the Akt and ERK 1/2 pathway affects a cascade of signaling proteins involved in cell proliferation, survival and metabolism suggesting a modulatory role for xyloketal B in these cellular processes [7].…”

“…Of these compounds, xyloketal B has shown: 1) to protect endothelial cells against oxidized low-density lipoprotein (oxLDL)-induced cell injury [6], 2) to provide antioxidant activity though heme oxygenase-1 (HO-1) in endothelial cells [7], 3) to reduce oxygen and glucose deprivation (OGD)-induced neuronal cell death in vitro in primary cortical cell culture [8], and for the first time 4) to reduce neonatal hypoxic-ischemic (HI) brain injury in vivo in mice [8]. Recent studies demonstrated that xyloketal B act by targeting free radicals [6,7,9,10], apoptotic proteins and mitochondrion proteins [6][7][8][9][10]. In addition, unpublished data from our lab revealed that xyloketal B was also an inhibitor of transient receptor potential melastatin 7 (TRPM7) which is a nonselective cation channel strongly implicated in neurodegenerative diseases.…”