An integrated study of Shenling Baizhu San against hyperuricemia: Efficacy evaluation, core target identification and active component discovery

Shenling Baizhu San (SLBZ) is a famous Traditional Chinese Medicine (TCM) formula that strengthens the spleen for replenishing qi, removing dampness, and inducing diuresis to relieve diarrhea. Combining the TCM interpretation that dampness is a vital pathogenesis factor in hyperuricemia occurrence and development, SLBZ has excellent potential against hyperuricemia from the perspective of TCM theories.This study aimed to investigate the efficacy of SLBZ against hyperuricemia and its possible mechanism with emphasis on the active components and the core targets.In the present study, we employed meta-analysis and a hyperuricemia quail model to evaluate the uric acid-lowering effect of SLBZ. Bodyweight, serum uric acid, and excreta uric acid levels in quails were assessed. Subsequently, we analyzed the potential active components and core targets of SLBZ against hyperuricemia by network pharmacology and calculated their interaction using molecular docking. Furthermore, the hyperuricemia rats treated with interfering agents of core targets were established to determine the central role of selected targets in hyperuricemia progression. Besides, we isolated and characterized the primary renal tubular epithelial cells of quails to verify the active components and core targets of SLBZ against hyperuricemia. Western blotting was used to observe the expression of core targets treated with active components under the stimulation of interfering agents.Data from meta-analysis and animal experiments showed that SLBZ could work effectively against hyperuricemia. Hyperuricemia quails treated with SLBZ displayed significantly reduced serum uric acid levels accompanied by increased excretion of uric acid. According to network pharmacology and molecular docking results, 34 potential active components and the core target peroxisome proliferator-activated receptor gamma (PPARγ) for SLBZ against hyperuricemia were identified. The decreased serum uric acid levels in hyperuricemia rats treated with rosiglitazone, an agonist of PPARγ, confirms the essential role of PPARγ in the pathological process of hyperuricemia. Moreover, we first successfully isolated and characterized the primary renal tubular epithelial cells of quails and observed enhanced phosphorylation of PPARγ at Ser273 in cells handled with high-level uric acid. Whereas, the enhanced expression of p-PPARγ Ser273 could be down-regulated by luteolin and naringenin, two active components of SLBZ against hyperuricemia.In summary, SLBZ is a promising anti-hyperuricemia agent, and luteolin and naringenin are the active components for SLBZ against hyperuricemia by down-regulating phosphorylation of PPARγ at Ser273.