# Litholytic Activities of Natural Bioactive Compounds and Their Mechanism Insights
## 3 Litholytic Activity of Flavonoids and Stilbenes
### In Vivo Investigations
#### 3.2.5 Quercetin  
Quercetin (Figure 1) is widely tested for its pharmacological effects in vivo [28; 29; 30]. However, few studies investigated its effects on nephrolithiasis animal models. The activity of quercetin was first studied by [PERSON] et al. [20]. In fact, they observed that the oral administration of quercetin at 10 mg/kg in lithiasis rats for 4 weeks reduced both MDA production and the number of crystals in kidneys, and significantly increased catalase and superoxide dismutase activity. The number of CaOx crystals in the quercetin group was significantly lower than in sodium oxalate group (2.5 \(\pm\) 1.7 vs. 4.3 \(\pm\) 1.8, respectively). In 2014, the prophylactic effect of the same molecule combined with hyperoside (QH ratio 1:1) was investigated at 20 mg/kg/day in urolithiasis rats. After 21 days, they found that the treatment by gastric intubation increased significantly the superoxide dismutase and catalase levels and decreased significantly the number of crystals deposits [19]. The authors suggested three mechanisms of action involved in QH against nephrolithiasis, including the inhibition of crystal formation by increasing urine pH, the anti-apoptotic effect, and the antioxidative effects. However, the exact mechanism of this bioactive compound remains unknown. After one year, the effect of quercetin in rats fed with a potassium-oxalate (KOx)-rich diet was studied by [PERSON] et al. [23]. At 10 mg/kg/day, the urinary pH of quercetin-treated rats showed the same pH value as the control (6.92 \(\pm\) 0.12 vs. 7.26 \(\pm\) 0.12 mL/day, respectively) while urinary volume was enhanced (8.6 \(\pm\) 0.89 vs. 5.2 \(\pm\) 0.66 mL/day, respectively). In addition, uric acid and phosphate concentrations were significantly reduced in rats treated with quercetin compared to lithiasis rats (0.75 \(\pm\) 0.09 vs. 1.20 \(\pm\) 0.10 mg/day and 6.52 \(\pm\) 0.35 vs. 6.80 \(\pm\) 0.38 mg/day). In addition, histopathological analysis revealed that this bioactive compound protected KOx-induced interstitial inflammation and high CaOx crystal deposition in lithiasis rats. Furthermore, [PERSON] et al. [23] analyzed the gene expression of OPN, angiotensin-converting enzyme (ACE), and renin using real-time PCR with GADPH as a reference gene, and revealed that quercetin significantly reduced the expression of OPN, ACE, and renin compared to lithiasis rats while the expression of SOD and GPx mRNA was increased. The authors suggested that this protective activity was mediated by antioxidant activity. The high diffusion ability into the membranes and chelating action of the catechol group explain the activity of the free radicals of quercetin. After three years, [PERSON] et al. [24] evaluated the effect of quercetin, isolated from _Aerva lanta_ L. (Belagavi Dist, Karnataka), at 2 mg/kg/day orally for 28 days on calculi formed by EG (0.75%) in rats. The results showed a significant reduction in biochemical parameter levels in urinary samples (calcium, phosphate, and oxalate), and serum parameters (creatinine and BUN) in rats treated with quercetin, while the level of magnesium (the main kidney stone inhibitor) increased [24]. The latter prevents oxalate supersaturation by inhibitingtheir absorption. From these findings, the authors suggested that quercetin possessed an important anti-lithiasis effect due to the inhibition of the activity of oxalate oxidase enzyme. In hyperoxaluria in rats developed by [PERSON] et al. [9], oral administration of EG (0.75%) and ammonium chloride (2%), apigenin (isolated from Celery, _Apium gravelens_ L.) at 1.2, 2.4, and 4.8 mg/kg reduced calcium levels in the kidney (306.25, 297.89, and 187.66 ppm, respectively vs. normal control 187.00 ppm) and significantly improved the calcium level in urine (310.80, 520.82, and 544.61 ppm, respectively) [9]. According to the findings of this work, the authors suggested that apigenin acts as rutin by lowering NO, which inactivates cGMP and controls the increase in intracellular calcium levels.