Ellagic Acid Exerts Beneficial Effects on Hyperuricemia by Inhibiting Xanthine Oxidase and NLRP3 Inflammasome Activation

Abstract

Hyperuricemia is a metabolic disease caused by impaired uric acid (UA) metabolism. Ellagic acid (EA) is a natural small-molecule polyphenolic compound with known antioxidative and anti-inflammatory properties. Here, we evaluated the regulatory effects of EA on hyperuricemia and explored the underlying mechanisms. We found that EA is an effective xanthine oxidase (XOD) inhibitor (IC50 = 165.6 μmol/L) and superoxide anion scavenger (IC50 = 27.66 μmol/L). EA (5 and 10 μmol/L) treatment significantly and dose-dependently reduced UA levels in L-O2 cells; meanwhile, intraperitoneal EA administration (50 and 100 mg/kg) also significantly reduced serum XOD activity and UA levels in hyperuricemic mice and markedly improved their liver and kidney histopathology. EA treatment significantly reduced the degree of foot edema and inhibited the expression of NLPR3 pathway-related proteins in foot tissue of monosodium urate (MSU)-treated mice. The anti-inflammatory effect was also observed in lipopolysaccharide-stimulated RAW-264.7 cells. Furthermore, EA significantly inhibited the expressions of XOD and NLRP3 pathway-related proteins (TLR4, p-p65, caspase-1, TNF-α, and IL-18) in vitro and in vivo. Our results indicated that EA exerts ameliorative effects in experimental hyperuricemia and foot edema via regulating the NLRP3 signaling pathway and represents a promising therapeutic option for the management of hyperuricemia.

The Genus Alternanthera: Phytochemical and Ethnopharmacological Perspectives

“…Methanolic extract was able to inhibit xanthine oxidase enzyme with an IC50 of 557.77 μg/ml ( Chong and Loh, 2020 ). Phytomolecules like kaempferol ( Wang et al, 2015d ), quercetin ( Bindoli et al, 1985 ), stigmasterol ( Chiang and Chen, 2008 ), ellagic acid ( Sun et al, 2021 ), ferulic acid ( Nile et al, 2016 ), and chlorogenic acid ( Wang et al, 2009 ) may be responsible for the antigout potential of Alternanthera sessilis (L.) R.Br. ex DC.…”

Ellagic Acid Effect on the Components of Metabolic Syndrome, Insulin Sensitivity and Insulin Secretion: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

“…It has been reported an effect of EA upregulating endothelial nitric oxide synthase and restoring nitric oxide bioavailability [ 17 ]. Another study reported a direct effect of EA, reducing uric acid synthesis by inhibition of xanthine oxidase [ 46 ]. This inhibition reduces tissue injury, target-organ damage, and cardiovascular risks [ 46 ].…”

“…Another study reported a direct effect of EA, reducing uric acid synthesis by inhibition of xanthine oxidase [ 46 ]. This inhibition reduces tissue injury, target-organ damage, and cardiovascular risks [ 46 ]. An important related fact is that in a long-term cohort for mortality analysis, it was identified that uric acid > 5.1 mg/dL (303 µmol/L) in females, or >5.6 mg/dL (333 µmol/L) in males, can be a predictor of cardiovascular mortality with linear association between serum uric acid and increased risk of all-cause mortality and cardiovascular mortality [ 47 ].…”

Sinomenine Hydrochloride Can Ameliorate Benign Prostatic Hyperplasia by Lowering the 5α-Reductase 2 Level and Regulating the Balance between the Proliferation and Apoptosis of Cells

“…PG tissues were fixed in 10% formalin, embedded in paraffin, and sliced into sections of thickness 5 μm. Then, they were stained with hematoxylin and eosin (H&E) for general morphological evaluation under a light microscope (Olympus, Tokyo, Japan), as reported previously [ 30 ].…”