## 3 Keep1-Nrf2-ARE Signaling System
The FAK-dependent signaling pathway helps tumor progression and consequent metastasis by causing cell migration, invasion, transition, and angiogenesis [79; 80]. In addition, the antioxidative action of Nrf2 and its associated detoxifying enzymes is dependent on the inhibition of the NF-kB signaling pathway [81]. Therefore, the capacity of ZB to combat colorectal cancer might be indirectly related to the Nrf2 signaling pathway. The suppression of NF-kB activity by ZB was also observed in AGS gastric cancer cells; the vascular endothelial growth factor (VEGF) expression was also downregulated [82]. A recent review gathered the accumulated evidence supporting the role of ZB in the amelioration of cancer in various cancer cells [83]. Here, ZB showed significant cytotoxicity against Raji (Epstein-Barr virus), promylocytic leukemia HL-60, CCL-240, murine lymphoid neoplasm P-388D1, CCL-46, liver cancer HepG2, breast cancer MCF-7, MDA-MB231, lung cancer A549, ovarian cancer Caov-3, cervix cancer HeLa, etc., cells. In HEK 293 cells, ZB exhibited cytoprotective action by enhancing the protein levels of Nrf2 and ARE-dependent transcriptional activity, which in turn increased the expression of NQO1 and HO-1 [84]. In THP-1 cell-derived macrophages, ZB mediated anti-inflammatory action by abrogating the induction of NF-kB p65 and toll-like receptor 2/4 (TLR-2/4) [85]. ZB prevented ultraviolet (UV)-induced photoaging and skin carcinogenesis by increasing the nuclear translocation of Nrf2 and enhancing the ARE luciferase activity, whereby the Nrf2/ ARE signaling pathway was accompanied by HO-1 and \(\gamma\) glutamate cysteine ligase catalytic subunit (\(\gamma\)-GCLC) gene induction [86]. Protection of skin keratinocytes and fibroblasts requires the action of Nrf2 signaling against UVA-induced oxidative insult [87; 88]. Nrf2 safeguards cells from oxidative injury by means of its target genes, such as HO-1, and suppresses cellular malignant transformation [89]. ZB-induced Nrf2 transcriptional activation was mediated by upregulated expression of p38 MAPK, PI3K/protein kinase B (AKT), and PKC signaling pathways [86]. According to another study, ZB upregulated the expressions of antioxidant enzymes HO-1 and \(\gamma\)-GCLC via increased nuclear accumulation of Nrf2, and decreased cytosolic Keap1 content by means of the ERK, JNK, PI3K/AKT, PKC, and AMP-activated protein kinase (AMPK) signaling pathways [90]. The chemical adduction, oxidation or glutathione of single or several important cysteine residues in Keap1 disturbs the association between Keap1 and Nrf2, making it possible for Nrf2 nuclear translocation to activate cytoprotective genes [86; 91]. In response to oxidant injuries, Nrf2 binds to cis-acting AREs in the promoter site of phase II antioxidant encoding genes, leading to the expression of their respective proteins [90]. Acute lung injury was ameliorated by ZB as well, whereby it abolished lipopolysaccharide-induced lipid peroxidation and promoted the activation of antioxidant defense system [92]. Here, nuclear expression of Nrf2 was markedly enhanced, and therefore the expressions of HO-1, catalase (CAT), SOD and Gpx were upregulated. Mechanistically, inhibition of two specific signaling pathways namely TLR4/NF-kB/cyclooxygenase-2 (COX-2) and p38 MAPK/JNK-kB/NF-kB by ZR were implicated in the amelioration of acute lung injury [93; 94]. Moreover, ZB markedly enhanced the expressions of antioxidant enzymes SOD, Gpx, and GSH and suppressed the production of malondialdehydehyde (MDA). Finally, it induced an anti-skin carcinogenic effect in female mice, wherein Nrf2 and its downstream target gene HO-1 were upregulated after topical administration of ZB on the dorsal skin of mice [95]. Figure 5 presents the mechanism of Nrf2 activation by ZB.