## 3 Keep1-Nrf2-ARE Signaling System
### Oleanolic Acid (OA)  
Oleanolic acid (**7**) is a pentacyclic triterpenoid compound naturally existing in olive leaves, juibube, ginseng, etc., either as a free acid or as an aglycone precursor [46; 159]. It has been demonstrated to possess a wide array of pharmacological potentials, including hep-astoprotective, anti-inflammatory, anti-viral, anti-hyperlipidemic, anti-hyperglycemic, and anti-tumor activities [159]. OA is an active suppressor of cellular inflammatory pathways and an established enhancer of phase II antioxidant enzymes [46]. It has been reported to improve malignant glioma, leukemia, liver, lung, breast, colon, bladder, gallbladder, prostate, and pancreatic cancer [160; 161; 162; 163; 164; 165; 166; 167; 168]. OA, a known Nrf2 activator, reportedly upregulated the expression of Nrf2 and its target antioxidant enzymes, including NQO1, HO-1, GCLC, and GCLM, to exert cytoprotective effect in hepatocytes [169]. In A549 lung cancer cells, OA and unsolic acid activated the Nrf2/ARE signaling [170]. In addition, this combination enhanced the p62 expression in A549 cells. Conjugation of diclofenac with OA derivatives exhibited enhanced chemopre-ventive activity [171]. In immortalized normal THLE-2 hepatocyte cells, the OA conjugates activated Nrf2 and enhanced SOD-1 and NQO1 expression. However, in HepG2 hepatoma cells, the opposite effect was obtained, with the apoptotic pathway being induced due to increased ROS generation. In both THLE-2 and HepG2 cells, the expressions of NF-\(\kappa\)B and COX-2 were suppressed. A quite similar effect was observed when OA derivatives were conjugated with indomethacin [172]. Here, the Nrf2-ARE pathway was inhibited in HepG2 cells, but not in THLE-2 hepatocytes. In another report, OA oxime derivatives provided chemopre response by activating Nrf2 in human hepatoma cells [173]. This study also showed that the conjugation of OA oximes with aspirin caused increased Nrf2 expression in normal THLE-2 cells, whereas the opposite effect was observed in HepG2 cells. Moreover, activation of AMPK signaling was observed in the OA-mediated anticancer effect in PC3 prostate and MCF-7 breast cancer cells [174]. OA improved tBHP-mediated oxidative insult via an Nrf2-dependent increase in antioxidant enzymes GSH, CAT, and peroxidizedoxins (PRX1) in which the activated signaling of JNK and ERK were involved [175]. A review reported that OA and its derivatives influenced a wide range of signaling pathways including NF-\(\kappa\)B, AKT, STAT3, mTOR, caspases, intercellular adhesion molecule 1 (ICAM-1), VEGF, and poly (ADP-ribose) polymerase (PARP) in different tumor cells [176]. VEGFR-2 activation was abolished by OA in HU-VECs in another study [177]. OA ameliorated DMBA-induced liver carcinogenesis through modulating the antioxidant level, causing apoptosis and autophagy [178]. Here, downregulation of VEGF, proliferating cell nuclear antigen (PCNA), NF-\(\kappa\)B, TNF-\(\alpha\) and COX-2 expression and upregulation of caspase-3, Bcl-2 and Beclin-1 expression were observed. Synergistic action of grafted chitosan and OA improved liver injury by enhancing the hepatic antioxidant capacity [179]. Here, the Nrf2/Keap1 pathway played the key role in enhancing the hepatic antioxidant capacity, while hepatic inflammation was tackled by the downregulation of NF-\(\kappa\)B signaling. OA ameliorated hepatotoxicityoxicity and provided cytoprotection against oxidative stress via Nrf2 nuclear accumulation and enhancing its target enzymes, including NQO1, GLC, GCLC and HO-1 [180]. A recent review described the role of OA in hepatoprotection, wherein activation of the Nrf2/ARE pathway was reported [181]. Here, the activated Nrf2 upregulated the expressions of GSH, NQO1 and HO-1. One study suggested that the anti-tumor potential of OA involved the generation of cellular apoptotic signals, whereby ERK-mediated Nrf2 upregulation actively suppressed ROS generation in oncogenic cells [182].