## 4 Discussion  
Peterostilbene, a natural compound in blueberries, is a potent derivative of the natural antioxidant resveratrol (25). Several lines of evidence show that PTE has beneficial effects for cancer prevention and therapy, improving insulin sensitivity, adjusting blood glycemia and lipid levels, and conquering cardiovascular diseases, inflammation diseases, and aging (26). Our recent study demonstrated that PTE has potent antiplatelet effects and suggested its possible therapeutic uses in thromboembolic disorders (27). In this current study, we examined the anti-inflammatory effects of PTE in LTA-stimulated RAW264.7 cells. PTE showed anti-inflammatory effects via inhibiting the production of NO and its related iNOS enzyme expression. It expressively inhibited the protein expression of IL-18  
Figure 5: PTE enhances antioxidant defense molecules. Cells were treated with 0.1% DMSO or PTE (20 and 40 \(\upmu\)M) for 30 min followed by LTA (5 \(\upmu\)g/mL) for 24 h. PTE increases HO-1 expression (**A**), catalase (CAT) activity (**B**) and glutathione (GSH) content (**C**) in LTA-induced RAW cells. The figures are representative examples of three independent experiments. \({}^{\#}\)\(p\) < 0.05 vs. LTA induced cells; \({}^{**}\)\(p\) < 0.01 vs. control cells (\(n\) = 4). and TNF-\(\alpha\). Additionally, it showed that PTE reserved LTA- induced inflammation chiefly by hindering the ERK-refereed NF-kB pathway. Nitric oxide (NO), a key cytotoxic agent, plays a role in the pathogenesis of numerous inflammatory diseases. The production of NO in activated macrophages via iNOS activation plays a major role in the pathology of several acute and chronic inflammatory conditions [28]. The activation of TNF-\(\alpha\), IL-6, and IL-1\(\beta\) is associated with modulating inflammation and tumor progression [29]. Natural plant-derived products have been reported to inhibit the expression of iNOS [30]. [PERSON] et al. [31] found that wogonin, a bioactive flavonoid, inhibits LTA-induced NO production and its gene expression in macrophages. In this study, PTE was found to significantly inhibit the production of NO in LTA-stimulated RAW 264.7 cells, without inducing cytotoxicity. The PTE's suppressive effect in LTA-induced NO production seems to involve the destruction of iNOS expression. Moreover, PTE expressively inhibited the LTA-induced production of TNF-\(\alpha\), and IL-1\(\beta\). This finding is consistent with a previous study showing that apigenin, a natural flavonoid compound, inhibited inflammatory diseases by inhibiting cytokines and TNF-\(\alpha\) expression [32]. NF-kB and MAPKs act as serious mediators of the release of inflammatory cytokines and control the expression of a variety of genes, such as TNF-\(\alpha\), IL-6, and iNOS [33]. Increasing evidence shows that the ERK signaling pathway contributes in regulating inflammatory events [34]. A study demonstrated that treatment with flavonoids, quercetin and lute-olin blocked LTA-induced phosphorylation of ERK1/2 [35]. In this study, we found PTE treatment expressively attenuated LTA-induced ERK activation in RAW 264.7 cells. The phosphorylation of ERK1/2 is reported to be associated with NF-\(\kappa\)B activation [36], and the phosphorylation of \(\mathrm{lxB}\alpha\) can be induced by ERK1/2-mediated \(\mathrm{lxB}\) kinase, activating the degradation of \(\mathrm{lxB}\alpha\) and subsequently induced nuclear translocation of NF-\(\kappa\)B [8]. LTA increased the phosphorylation of \(\mathrm{lxB}\) and p65 and its translocation from the cytoplasm to nuclei, as this distinctive transcription factor stimulates by LTA [8]. LTA binds with TLR2, which in turn activates NF-\(\kappa\)B by protein kinases, and subsequently translocated to nuclei from the cytoplasm [37]. An in vitro study in microglia cells had shown that curcumin suppressed LTA-induced nuclear translocation and activation of NF-\(\kappa\)B [38].