## 3 Keep1-Nrf2-ARE Signaling System
### Aistaxanthin (AX)  
Aistaxanthin (**12**) is a xanthophyll carotenoid compound belonging to the broad chemical class of terpenoids. It is widely found in marine species like algae, yeast, salmon, trout, krill, shrimp and crayfish [51]. AX possesses a wide range of anti-inflammatory and antioxidant activities, with 550-fold more potency than vitamin E [266, 267]. AX has been reported to possess anti-inflammatory and antioxidant activities, whereby it enhanced Nrf2 activity and reduced mRNA expression of IL-6 and IL-1B by suppressing NF-\(\kappa\)B p65 nuclear expression [268]. A recent review reported that the antioxidant capacity of AX was highly dependent on the modulation of several signaling pathway proteins, including Nrf2, PI3K/AKT, JAK/STAT-3, NF-\(\kappa\)B, MAPKs and PPARy [269]. This same group of signaling pathways were implicated in other reviews summarizing the protective effect of AX against various cancers [270, 271]. AX upregulated the nuclear expression of Nrf2, which inhibited the proliferation and progression of K562 human leukemia cells [272]. In contrast, it reduced LPS-induced inflammation and oxidative stress by inhibiting the activation of Nrf2 in U937 human myeloid leukemia cells [273]. The previous two reports suggested that AX possessed both an activating and an inhibitory role for Nrf2 in the management of human leukemia. The Nrf2 inhibitory role of AX might be associated with the administration of high doses in test animals [274]. In LNCaPP prostate cancer cells, AX epigenetically produced an ameliorative effect by mediating upregulated mRNA and protein expression of Nrf2, NQO1 and _GSTP1_[275]. In hepatocellular carcinoma cells, AX induced anti-tumor action through marked suppression of NF-\(\kappa\)B p65 and Wnt/\(\beta\)-catenin, and negative activation of PI3K/AKT and ERK signaling [276]. Mechanistically, the inhibition of oral cancer by AX also took place by a quite similar mechanism [277]. AX was found to be effective against human colon cancer, whereby it induced apoptosis by suppressing the phosphorylation of AKT and enhancing the phosphorylation of p38, JNK, and ERK1/2 [278]. In HUVECs, AX caused Nrf2 nuclear translocation and enhanced the mRNA levels of HO-1, NQO1 and Gpx [279, 280]. Mechanistically, in this case, AX mediated ERK phosphorylation and activated ARE-driven luciferase activity to exert its antioxidant effect. In addition, activation of PTEN/AKT signaling was also reported in the Nrf2 driven antioxidant activity of AX in HUVECs. Low concentrations of AX with polyunsaturated fatty acids synergistically resulted in a marked decrease in oxidative stress by upregulating Nrf2/ARE signaling [281]. In SKOV3 ovarian cancer cells, AX in combination with human serum albumin produced a better anticancer effect and overcame drug resistance by suppressing the NF-\(\kappa\)B and activating p53 and MAPKs signaling [282]. In myeloid-derived suppressor cells (MDSCs), AX induced Nrf2 and its antioxidant enzyme expressions, thus causing maturation of MDSCs and regulating the immunosuppressive tumor environment in mice [283]. Notably, MDSCs are immature myeloid cells that are aggregated in stress conditions like tumor. Inflammatory pathway proteins NF-\(\kappa\)B and COX-2 were effectively downregulated by AX in ameliorating esophageal cancer [284]. AX improved cyclophosphamide-mediated oxidative stress, DNA damage and hepatocarcinogenesis in rats via induction of Nrf2 and phase-II enzymes NQO-1 and HO-1 [285]. Here, it markedly downregulated the p53 and p38 expressions. In lying hens, it ameliorated oxidative stress by upregulating Nrf2, SOD1, SOD2 and Gpx4 [286]. It showed anti-colon cancer activity in vivo by abrogating the NF-\(\kappa\)B, COX-2 and increasing the AKT and ERK-2 expressions [287]. The chemopreventive potential of AX was found to be prominent in hamster buccal pouch carcinoma, where it suppressed JAK2/STAT3 signaling, particularly the phosphorylation and consequent nuclear translocation of STAT3 [288].