## 3 Keep1-Nrf2-ARE Signaling System
### Fucoxanthin (FX)  
Fucoxanthin (**13**) is the most abundant marine carotenoid extracted from seaweeds and microalgae [52].  
FX exhibited anti-inflammatory and antioxidant effects in RAW 264.7 cells by activating the Nrf2, which was induced by activated PI3K/AKT signaling [292]. In addition, expressions of inflammatory markers including IL-6, IL-1\(\beta\), and TNF-\(\alpha\) were suppressed by FX. It demonstrated chemoresistant activity in HepG2-C8 human hepatocarcinoma cells by upregulating the mRNA and protein levels of Nrf2, ARE luciferase activity, NQO1, HO-1, and SOD [293]. The same study demonstrated another potential mechanism of FX in preventing oxidative stress and cancer, whereby epigenetic changes to Nrf2 DNA methylation occurred, altering the gene expressions without changing the DNA composition. In contrast, a study reported that the Nrf2/ARE-mediated antioxidant action of FX was partially mediated by its pro-oxidant activity [294]. Here, FX-treated mouse hepatic BNL CL2 cells demonstrated a marked rise in cellular ROS generation. In the same study, FX enhanced the binding of Nrf2 with ARE, upregulated the mRNA and protein expression of HO-1, NQO1 and phosphorylation of ERK and p38. However, in HepG2 liver cancer cells, FX caused suppression of antioxidant enzymes SOD1, SOD2, CAT and downregulation of AKT1, ERK1/2, and JNK signaling in order to mediate its anticancer effect [295]. Here, generation of ROS by FX increased oxidative stress, which helped to destroy the liver cancer cells by means of an apoptotic mechanism. It exerted cytoprotective activity against H\({}_{2}\)O\({}_{2}\)-mediated oxidative insult in L02 hepatic cells by PI3K-regulated increases in Nrf2, HO-1 and NQO1 expressions [296]. The effects of a combined therapy of FX and rosmarinic acid were evaluated on cell viability, apoptosis induction, inflammosome regulation, and anti-oxidative response activation in UVB-irradiated HaCaT keratinocytes [297]. This combination (1:1) demonstrated improved antioxidant and anti-inflammatory profiles, with FX facilitating Nrf2 nuclear translocation and ARE-mediated activation of its detoxifying enzymes [297]. Furthermore, this combination suppressed the inflammatory response by downregulating the NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like Protein (ASC), and IL-1\(\beta\) expression. Again, in human keratinocytes, FX substantially facilitated Nrf2 activation and its binding to AREs, which in turn increased the mRNA and protein levels of GSH, GCLC and glutathione synthetase (GSS) [298]. This upregulated Nrf2 activity was accompanied by increased PI3K/AKT signaling. FX enhanced the sensitivity of cisplatin to HepG2 hepatoma cells by downregulating the NF-kB expression [299]. Here, the phosphorylation of ERK, p38 and PI3K/AKT signaling was attenuated by FX.  
The oxidative stress suppressing effect of FX was also evident in a study in which FX treatment in experimental rats enhanced the mRNA expression of Nrf2 and NQO1 [300]. Moreover, expressions of CAT and Gpx were also increased in FX-treated rats. Alcohol-mediated oxidative injury and inflammation were ameliorated by FX through activation of Nrf2 and suppression of TLR4-induced NF-\(\kappa\)B signaling [301]. Promotion of Nrf2 and SOD and suppression of TNF-\(\alpha\) action were implicated in ameliorating pathogen-associated molecular pattern-induced inflammation by FX [302]. A recent review reported that signaling pathways like PI3K/AKT/Nrf2, ERK, AMPK/AKT/cAMP response element binding protein (CREB)/peroxisome proliferatorator-activated receptor-gamma coactivator-1\(\alpha\) (PGC-1\(\alpha\)), and Nrf2-autophagy were involved in FX-induced anti-inflammatory response [303]. Figure 9 presents the mechanism of Nrf2-ARE activation by FX.