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Hyperuricemia characterized by high serum levels of uric acid (UA, >6.8 mg/dL) is regarded as a common chronic metabolic disease. When used as a food supplement, naringenin might have various pharmacological activities, including antioxidant, free-radical-scavenging, and inflammation-suppressing activities. However, the effects of naringenin on hyperuricemia and renal inflammation and the underlying mechanisms remain to be elucidated. Here, we comprehensively examined the effects of naringenin on hyperuricemia and the attenuation of renal impairment. Mice were injected with 250 mg/kg of potassium oxonate (PO) and given 5% fructose water to induce hyperuricemia. The pharmacological effects of naringenin (10 and 50 mg/kg) and benzbromarone (positive control group, 20 mg/kg) on hyperuricemic mice were evaluated in vivo. The disordered expression of urate transporters in HK-2 cells was stimulated by 8 mg/dL UA, which was used to determine the mechanisms underlying the effects of naringenin in vitro. Naringenin markedly reduced the serum UA level in a dose-dependent manner and improved renal dysfunction. Moreover, the increased elimination of UA in urine showed that the effects of naringenin were associated with the regulation of renal excretion. Further examination indicated that naringenin reduced the expression of GLUT9 by inhibiting the PI3K/AKT signaling pathway and reinforced the expression of ABCG2 by increasing the abundance of PDZK1 in vivo and in vitro. Furthermore, sirius red staining and western blotting indicated that naringenin plays a protective role in renal injury by suppressing increases in the levels of proinflammatory cytokines, including IL-6 and TNF-α, which contribute to the inhibition of the TLR4/NF-κB signaling pathway in vivo and in vitro. Naringenin supplementation might be a potential therapeutic strategy to ameliorate hyperuricemia by promoting UA excretion in the kidney and attenuating the inflammatory response by decreasing the release of inflammatory cytokines. This study shows that naringenin could be used as a functional food or dietary supplement for hyperuricemia prevention and treatment.

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Metabolism-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide, and the use of traditional Chinese medicines (TCMs) to treat this disease has attracted increasing attention. The Qing Gan San (QGS) formula comprises Polygonatum sibiricum, the peel of Citrus reticulata Blanco, the leaves of Morus alba L, Cichorium intybus, Glycyrrhiza uralensis Fisch, and Cirsium setosum. The present study aimed to uncover the anti-hyperlipidaemic effects, hepatic fat accumulation-lowering effects and mechanisms of QGS in high-fat diet-induced MAFLD rats. QGS significantly reduced the levels of total cholesterol and triglycerides in both serum and liver tissue and partially protected hepatic function. Additionally, QGS significantly ameliorated hepatic lipid accumulation with histopathology observation, as demonstrated by H&E and oil red O staining. RNA sequencing was used to further investigate the key genes involved in the development and treatment of MAFLD. Hierarchical clustering analysis showed that the gene expression profiles in rats with MAFLD were reversed to normal after QGS treatment. QGS had 222 potential therapeutic targets associated with MAFLD. Enrichment analysis among these targets revealed that QGS affected biological functions/pathways such as the regulation of lipid metabolic processes (GO: 0019216) and the non-alcoholic fatty liver disease pathway (hsa04932), and identified Srebp-1 as a key regulator in the synthesis of cholesterol and triglycerides. Subsequently, both immunofluorescence and Western blot analyses demonstrated that QGS suppressed the transfer of Srebp-1 to the nucleus from the cytoplasm, suggesting that the activation of Srebp-1 was inhibited. Our study reveals the effects and mechanisms of QGS in the treatment of MAFLD and provides insights and prospects to further explore the pathogenesis of MAFLD and TCM therapies.

Hyperuricemia is the result of increased production and/or underexcretion of uric acid. Hyperuricemia has been epidemiologically associated with multiple comorbidities, including metabolic syndrome, gout with long-term systemic inflammation, chronic kidney disease, urolithiasis, cardiovascular disease, hypertension, rheumatoid arthritis, dyslipidemia, diabetes/insulin resistance and increased oxidative stress. Dysregulation of xanthine oxidoreductase (XOD), the enzyme that catalyzes uric acid biosynthesis primarily in the liver, and urate transporters that reabsorb urate in the renal proximal tubules (URAT1, GLUT9, OAT4 and OAT10) and secrete urate (ABCG2, OAT1, OAT3, NPT1, and NPT4) in the renal tubules and intestine, is a major cause of hyperuricemia, along with variations in the genes encoding these proteins. The first-line therapeutic drugs used to lower serum uric acid levels include XOD inhibitors that limit uric acid biosynthesis and uricosurics that decrease urate reabsorption in the renal proximal tubules and increase urate excretion into the urine and intestine via urate transporters. However, long-term use of high doses of these drugs induces acute kidney disease, chronic kidney disease and liver toxicity. Therefore, there is an urgent need for new nephroprotective drugs with improved safety profiles and tolerance. The current systematic review summarizes the characteristics of major urate transporters, the mechanisms underlying the pathogenesis of hyperuricemia, and the regulation of uric acid biosynthesis and transport. Most importantly, this review highlights the potential mechanisms of action of some naturally occurring bioactive compounds with antihyperuricemic and nephroprotective potential isolated from various medicinal plants.