**2.8 Quercetin**

Quercetin is bioactive flavonoids that can be found in fruits and vegetables including onion, kale, apple, many berries, citrus fruits and tea [73]. Anti-cancer, anti-inflammatory, antioxidant, anti-diabetes, anti-atherosclerosis and anti-viral effects have been reported in different in vitro studies for quercetin [74]. Several studies have focused on quercetin and miRNAs modulation for therapeutic approaches. miR-200b-3p was up-regulated in pancreatic cancer cells when treated with quercetin, resulting in inhibition of self-renewal and decrease of proliferation through Notch1 signaling pathway [75]. Quercetin significantly inhibited breast cancer cell proliferation and invasion via up-regulated miR-146a expression and targeting EGFR [76]. Quercetin inhibited cell viability, migration and invasion by up-regulated miR-16 and targeting HOXA10 in oral cancer cells [77]. In addition, quercetin decreased oral cancer cell viability and increased cell apoptosis via miR-22/WNT1/β-catenin pathway [78].

Recently, quercetin modulated 34 miRNAs expression (5 upregulated and 29 downregulated) and novel miR-97, miR-298, miR-2218, miR-1502, and miR-2117 were identified in pheochromocytoma of the rat adrenal medulla that responded for protective effect against oxidative stress through PI3K-AKT signaling pathway [79]. Treatment of quercetin inhibited proliferation of endometriosis through up-regulated miR-503-5p, miR-1283, miR-3714 and miR-6867-5p by targeting CCND1 [80]. TGFβ1 is a fibrosis inducer and quercetin significantly down-regulated miR-21 and TGFβ1 and up-regulated miR-122 in liver fibrosis [81]. Protection of cardiomyocyte against hypoxia caused insults of quercetin has been reported by up-regulation of miR-199 mediated sirt1 expression and AMPK phosphorylation [82].

### **2.9 Silymarin**

Silymarin is a flavonolignans extracted from the milk thistle *Silybum marianum* (L.) gaernt and recent studies have demonstrated the anti-cancer, anti-inflammatory, vascularization inhibitory, antioxidant, hepatoprotective, cardioprotective and antimetastasis activities of silymarin [83]. Several miRNAs have been implicated in the invasive potential of cancer cells. Tumor suppressor miRNA, miR-203, was up-regulated and class 1 HDAC proteins and ZEB1 were repressed with silymarin treatment, resulted in inhibition of non-small cell lung cancer migration [84]. Silibinin, the major active constituent of silymarin extract, induced apoptosis and ERβ expression, inhibited cell proliferation, and reduced pro-inflammatory cytokines expression including IL-17 and

TNF-α, through ERβ binding and down-regulated miR-155 in rheumatoid arthritis [85]. miR-122 is liver-specific miRNA and was down-regulation upon silymarin treatment in rat model for hepatoprotective and radio protective effects via increased superoxide dismutase (SOD), glutathione (GSH) and reduced lipid peroxidation (MDA) [86]. It has been reported the hepatoprotective activity of silymarin on thioacetamide-induced liver damage by restored miR-122, miR-192, and miR-194 expression levels [87].
