## 4 Discussion
Interestingly, PSGE promoted 15-PGDH expression, which in turn impaired PGE\({}_{2}\) synthesis (Figure 2D,H). However, previous studies reported that the regulatory effects of SG and PSG on PGE\({}_{2}\) production are dependent on COX-2 downregulation, which remains controversial [35,36]. Other studies have shown that thiazolinedines pioglitazone and rosigiltazone inhibited PGE\({}_{2}\) production in A427 and A549 lung cancer cells by the catabolic 15-PGDH rather than the synthetic COX-2/mPGES-1 [37]. Further study is needed to fully understand how 15-PGDH expression, altered by PSGE, leads to PGE\({}_{2}\) inhibition without significant change in COX-2 expression. Additionally, the ability of PSGE to increase 15-PGDH may offer therapeutic benefits without resulting in cardiotoxicity known in selective COX-2 inhibitors. PSGE also demonstrated anti-inflammatory effects by decreasing IL-6 and TNF-\(\alpha\) release (Figure 3A,B). NF-\(\kappa\)B is a transcription factor that plays a central role in regulating a large array of genes during immune response and inflammation [38]. NF-\(\kappa\)B activity is tightly regulated by \(\kappa\)B\(\alpha\) binding in the cytoplasm. Inflammatory stimuli induce \(\kappa\)B\(\alpha\) phosphorylation and degradation result in NF-\(\kappa\)B nuclear translocation [39]. Our data demonstrated that PSGE inhibition on IL-6 and TNF-\(\alpha\) levels involved the prevention of NF-\(\kappa\)B release from an inactive complex due to dephosphorylation of \(\kappa\)B\(\alpha\) (Figure 3A-F). Studies have suggested that HO-1 acts on \(\kappa\)B phosphorylation and inhibits activation of NF-\(\kappa\)B dependent gene expression [40, 41, 42]. PSGE treatment increased HO-1 expression, which correlated with decreased \(\kappa\)B\(\alpha\) phosphorylation (Figure 3E,F). These data support the idea that the anti-inflammatory effect of PSGE is mediated by NF-\(\kappa\)B regulation via HO-1. The NF-\(\kappa\)B and NRF2 pathways play an integral role to maintain redox balance and inflammatory homeostasis upon disruption by cellular stressors. The NRF2 activation is negatively regulated by KEAP1, which promotes ubiquitination and degradation of NRF2. Under stress, KEAP1 is modified and allows NRF2 to translocate to the nucleus where the transcription levels of antioxidant enzymes such as HO-1, NQO1, and TRX1 are activated. The KEAP1/NRF2 signaling pathway negatively regulates the NF-\(\kappa\)B-induced cytokine expression by inhibiting intracellular ROS levels [23,43]. Many recent studies provide compelling evidence for the antioxidant and anti-inflammatory role of HO-1 [44]. Our data showed that PSGE pretreatment prevented LPS stimulated increase in ROS production. This was achieved through NRF2 dissociation from KEAP1, leading to nuclear translocation and accumulation of NRF2 (Figure 4A-F). Furthermore, considerable enrichment of nuclear NFR2 facilitated antioxidant enzyme upregulation and provided robust protection against oxidative stress. We used SnPPIX to confirm whether the antioxidant effect of PSGE against LPS triggered ROS generation was obtained by enhancement of HO-1. HO-1 inhibition restored intracellular ROS levels suppressed by PSGE (Figure 4G-J). Previous studies on LPS-induced experimental models have shown that SG components such as bacialin,apigetrin, and baicalin alleviate elevated inflammatory cytokines by NF-\(\kappa\)B regulation and oxidative damage by HO-1 induction [45; 46; 47]. Here, we identified that HO-1 may play dual roles in anti-inflammatory and anti-oxidative effects of PSGE mediated by crosstalk between NF-\(\kappa\)B and the KEAP1/NRF2 signaling pathway.