Isoorientin exerts a urate-lowering effect through inhibition of xanthine oxidase and regulation of the TLR4-NLRP3 inflammasome signaling pathway

• Published in: Journal of natural medicines Vol. 75; no. 1; pp. 129 - 141
• Main Authors: An, Meng-Fei, Wang, Ming-Yue, Shen, Chang, Sun, Ze-Rui, Zhao, Yun-Li, Wang, Xuan-Jun, Sheng, Jun
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 2021; Springer Nature B.V
• Subjects: Animal models; Animals; Biological activity; Biomedical and Life Sciences; Biomedicine; Caspase-1; Cathepsin B; Complementary & Alternative Medicine; Creatinine; Disease Models, Animal; Flavonoids; Humans; Hyperuricemia; Hyperuricemia - drug therapy; Hypoxanthine; Inflammasomes; Inflammasomes - drug effects; Interleukin 18; Luteolin - pharmacology; Luteolin - therapeutic use; Male; Medicinal Chemistry; Mice; NLR Family, Pyrin Domain-Containing 3 Protein - drug effects; Original Paper; Pharmacology/Toxicology; Pharmacy; Phytochemicals; Plant Sciences; Signal Transduction; TLR4 protein; Toll-like receptors; Urea; Uric acid; Uric Acid - chemistry; Xanthine oxidase; Xanthine Oxidase - antagonists & inhibitors; Xanthine oxidase; Hyperuricemia; Uric acid; NLRP3 inflammasome; Isoorientin
• ISSN: 1340-3443; 1861-0293
• DOI: 10.1007/s11418-020-01464-z

Isoorientin (ISO), a natural flavonoid compound, has been identified in several plants and its biological activity is determined and the study on lowering uric acid has not been reported. In view of the current status of treatment of hyperuricemia, we evaluated the hypouricemic effects of ISO in vivo and in vitro, and explored the underlying mechanisms. Yeast extract-induced hyperuricemia animal model as well as hypoxanthine and xanthine oxidase (XOD) co-induced high uric acid L-O2 cell model and enzymatic experiments in vitro were selected. The XOD activity and uric acid (UA) level were inhibited after the treatment of ISO in vitro and in vivo. Furthermore, serum creatinine (CRE) and blood urea nitrogen (BUN) levels were also significantly reduced and liver damage was recovered in pathological histology after the ISO administration in hyperuricemia animal model. The results of mechanism illustrated that protein expressions such as XOD, toll-like receptor 4 (TLR4), cathepsin B (CTSB), NLRP3, and its downstream caspase-1 as well as interleukin-18 (IL-18) were markedly downregulated by ISO intervention in vitro and in vivo. Our results suggest that ISO exerts a urate-lowering effect through inhibiting XOD activity and regulating TLR4-NLRP3 inflammasome signal pathway, thus representing a promising candidate therapeutic agent for hyperuricemia. Graphic abstract Both animal models and in vitro experiments suggested that ISO may effectively lower uric acid produce. The mechanism might be the inhibition of XOD activity and NLRP3 inflammasome of upregulation.