## 3 Keep1-Nrf2-ARE Signaling System
### Ursolic Acid (UA)  
Ursolic acid (**8**) is a naturally occurring pentacyclic triterpenoid acid found in apple peels, cranberries, blueberries, etc., which possesses a wide range of biological activities including antioxidant, antitumor and anti-inflammatory effects [185; 186; 187].  
A low dose of UA effectively induced HO-1 expression in acute myeloid leukemia kasumi-1 cells [188]. However, the expression of HO-1 suppression increased the sensitization of Kasumi-1 cells to UA, which in turn mediated more efficient apoptosis. An important chemopre mechanism of UA observed in human mammary epithelial and hepatocellular carcinoma cells involved the inhibition of COX-2 [189; 190]. Another study supported the same notion that UA effectively promoted apoptosis in gastric cancer cells by suppressing the expression of pro-inflammatory mediator COX-2 [191]. In LNCaP and PC-3 prostate cancer cells, UA enhanced the expression of SET domain-containing lysine methyltransferase 7 (Setd7), which in turn upregulated Nrf2/ARE signaling [192]. As a result, the Nrf2 downstream enzymes NQO1 and glutathione S-transferase theta 2 (GSTT2) were enhanced, and oxidative insult was attenuated. However, a recent finding demonstrated the Nrf2 inhibitory role of UA in treating breast cancer [193]. In MDA-MB-231 breast cancer cells, UA suppressed the expression of Nrf2, NQO1 and SOD1 and increased the expression of Keep1. The anti-migration and anti-invasive effects of UA in MDA-MB-231 human breast cancer cells were triggered by the downregulation of JNK, AKT, and NF-\(\kappa\)B expressions [194]. UA and cisplatin combination sensitized HepG2/DDP cells to cisplatin by following an Nrf2 inhibitory mechanism, as well [195]. This combinatorial therapy worked against HepG2/DDP cells by inducing ROS generation, cell cycle arrest, and apoptosis. Moreover, UA induced apoptosis in SNG-II and HEC108 endometrial adenocarcinoma cells by inhibiting AKT/PI3K and MAPK signaling [61]. Apoptosis was also induced by UA in HCT116 and HT29 colorectal cancer cells via inhibition of JAK2/STAT3 phosphorylation [196]. UA nanoparticles ameliorated cervical cancer by enhancing the expressions of p53 and caspases and abrogating the anti-apoptosis-related signals [197].  
It improved CCl\({}_{4}\)-induced fibrosis by modulating the Nrf2/ARE antioxidant signaling by elevating the expression of HO-1, NQO1, GST and downregulating the levels of inflammatory cytokines like TNF-\(\alpha\), prostaglandin, and iNOS [198]. One study correlated the link between upregulated phase II antioxidant enzymes and downregulated inflammatory cytokines expression with chemoprevention in an in vivo rat model [199]. Again, some reviews have summarized the essential role of activated Nrf2/ARE antioxidative signaling and anti-inflammatory action in the chemopretive role of UA [200,201]. UA helped to actively prevent skin carcinogenesis by upregulating the expression of Nrf2-dependent antioxidant enzymes such as HO-1, NQO1 and UDP-glucuronrosyltransferase 1A1 [202]. A quite similar effect was obtained for UA against skin cancer, implicating the epigenetic activation of Nrf2 [203]. It demonstrated a cytoprotective effect in lung cells by upregulating the expression of Nrf2 and its target genes NQO1 and GST [204]. Non-melanoma skin cancer was improved by UA treatment, whereby Nrf2 and NQO1 expression was upregulated [205]. Additionally, the expressions of inflammatory cytokines IL-8 and NF-\(\kappa\)B were suppressed.