Du Jiana, Wang Na, Yu Dehong, He Pei, Gao Yu, Tu Yanbei, Li Yanfang
School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu 212013, China.
Phytomedicine. 2024 Feb;124:155305. doi: 10.1016/j.phymed.2023.155305. Epub 2023 Dec 19.
Hyperuricemia (HUA) is a metabolic disease characterized by a high level of uric acid (UA). The extensive historical application of traditional Chinese medicine (TCM) offers a range of herbs and prescriptions used for the treatment of HUA-related disorders. However, the core herbs in the prescriptions and their mechanisms have not been sufficiently explained.
Our current investigation aimed to estimate the anti-HUA effect and mechanisms of Paeonia veitchii Lynch, an herb with high use frequency identified from data mining of TCM prescriptions.
Prescriptions for HUA/gout treatment were statistically analyzed through a data mining approach to determine the common nature and use frequency of their composition herbs. The chemical constituents of Paeonia veitchii extract (PVE) were analyzed by UPLC-QTOF-MS/MS, while its UA-lowering effect was further evaluated in adenosine-induced liver cells and potassium oxonate (PO) and hypoxanthine (HX)-induced HUA mice.
A total of 225 prescriptions involving 246 herbs were sorted out. The properties, flavors and meridians of the appearing herbs were mainly cold, bitter and liver, respectively, while their efficacy was primarily concentrated on clearing heat and dispelling wind. Further usage frequency analysis yielded the top 20 most commonly used herbs, in which PVE presented significant inhibitory activity (IC = 131.33 µg/ml) against xanthine oxidase (XOD), and its constituents showed strong binding with XOD in a molecular docking study and further were experimentally validated through XOD enzymatic inhibition and surface plasmon resonance (SPR). PVE (50 to 200 μg/ml) dose-dependently decreased UA levels by inhibiting XOD expression and activity in BRL 3A liver cells. In HUA mice, oral administration of PVE exhibited a significant UA-lowering effect, which was attributed to the reduction of UA production by inhibiting XOD activity and expression, as well as the enhancement of UA excretion by regulating renal urate transporters (URAT1, GLUT9, OAT1 and ABCG2). Noticeably, all doses of PVE treatment did not cause any liver injury, and displayed a renal protective effect.
Our results first comprehensively clarified the therapeutic effect and mechanisms of PVE against HUA through suppressing UA production and promoting UA excretion with hepatic and renal protection, suggesting that PVE could be a promising UA-lowering candidate with a desirable safety profile for the treatment of HUA and prevention of gout.
高尿酸血症（HUA）是一种以尿酸（UA）水平升高为特征的代谢性疾病。中药（TCM）有着广泛的历史应用，提供了一系列用于治疗与HUA相关病症的草药和方剂。然而，方剂中的核心草药及其作用机制尚未得到充分阐释。
我们当前的研究旨在评估川赤芍（Paeonia veitchii Lynch）的抗HUA作用及其机制，川赤芍是一种从中药方剂数据挖掘中识别出的高频使用草药。
通过数据挖掘方法对治疗HUA/痛风的方剂进行统计分析，以确定其组成草药的共性和使用频率。采用超高效液相色谱-四极杆飞行时间串联质谱（UPLC-QTOF-MS/MS）分析川赤芍提取物（PVE）的化学成分，同时在腺苷诱导的肝细胞以及氧嗪酸钾（PO）和次黄嘌呤（HX）诱导的HUA小鼠中进一步评估其降低UA的作用。
共整理出涉及246味草药的225首方剂。出现的草药的性味和归经主要分别为寒、苦和肝，其功效主要集中在清热祛风。进一步的使用频率分析得出了最常用的前20味草药，其中PVE对黄嘌呤氧化酶（XOD）呈现出显著的抑制活性（IC = 131.33 μg/ml），并且在分子对接研究中其成分显示出与XOD有强烈的结合，进一步通过XOD酶抑制和表面等离子体共振（SPR）进行了实验验证。PVE（50至200 μg/ml）通过抑制BRL 3A肝细胞中XOD的表达和活性，剂量依赖性地降低UA水平。在HUA小鼠中，口服PVE表现出显著的降低UA的作用，这归因于通过抑制XOD活性和表达减少了UA的产生，以及通过调节肾尿酸转运蛋白（URAT1、GLUT9、OAT1和ABCG2）增强了UA的排泄。值得注意的是，所有剂量的PVE治疗均未引起任何肝损伤，并且显示出肾脏保护作用。
我们的结果首次全面阐明了PVE通过抑制UA产生和促进UA排泄并具有肝肾保护作用来对抗HUA的治疗效果和机制，表明PVE可能是一种有前景的降低UA的候选药物，在治疗HUA和预防痛风方面具有良好的安全性。
