School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, 510006, Guangzhou, P.R. China.
The Second Clinical College of Guangzhou University of Chinese Medicine, 510120, Guangzhou, P.R. China.
Eur J Pharmacol. 2021 Dec 5;912:174592. doi: 10.1016/j.ejphar.2021.174592. Epub 2021 Oct 23.
Phellodendri Chinensis Cortex (PC) is a traditional medicinal material used to treat gout and hyperuricemia (HUA) in China. Berberine (BBR), the main component of PC, possesses anti-hyperuricemic and anti-gout effects. However, BBR exhibits low bioavailability due to its extensive metabolism and limited absorption. Thus, the metabolites of BBR are believed to be the potential active forms responsible for its in vivo biological activities. Berberrubine (BRB), one of the major metabolites of BBR, exhibits appreciable biological activities even superior to BBR. In this work, the anti-hyperuricemic efficacy of BRB was investigated in HUA model mice induced by co-administration with intraperitoneal potassium oxonate (PO) and oral hypoxanthine (HX) for 7 days. Results showed that administration with BRB (6.25, 12.5, and 25.0 mg/kg) significantly decreased the serum levels of uric acid (UA) by 49.70%, 75.35%, and 75.96% respectively, when compared to the HUA group. In addition, BRB sharply decreased the levels of blood urea nitrogen (BUN) (by 19.62%, 28.98%, and 38.72%, respectively) and serum creatinine (CRE) (by 16.19%, 25.07%, and 52.08%, respectively) and reversed the PO/HX-induced renal histopathological damage dose-dependently. Additionally, BRB lowered the hepatic XOD activity, downregulated the expressions of glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1), upregulated expressions of organic anion transporter 1/3 (OAT1/3) and ATP-binding cassette transporter subfamily G member 2 (ABCG2) at both protein and mRNA levels, and suppressed the activation of the JAK2/STAT3 signaling pathway. In addition, BRB significantly decreased the levels of inflammatory mediators (IL-1β, IL-6, and TNF-α). In conclusion, our study indicated that BRB exerted anti-hyperuricemic effect, at least in part, via regulating the urate transporter expressions and suppressing the JAK2/STAT3 signaling pathway. BRB was believed to be promising for further development into a potential therapeutic agent for HUA treatment.
黄柏是中国传统的药用材料，用于治疗痛风和高尿酸血症（HUA）。黄柏中的主要成分小檗碱（BBR）具有降尿酸和抗痛风作用。然而，由于其广泛的代谢和有限的吸收，BBR 的生物利用度较低。因此，人们认为 BBR 的代谢物是其体内生物活性的潜在活性形式。小檗红碱（BRB）是 BBR 的主要代谢物之一，具有显著的生物活性，甚至优于 BBR。在这项工作中，研究了 BRB 在腹腔注射氧嗪酸钾（PO）和口服次黄嘌呤（HX）联合诱导的 HUA 模型小鼠中的降尿酸作用。结果表明，与 HUA 组相比，BRB（6.25、12.5 和 25.0mg/kg）给药分别显著降低血清尿酸（UA）水平 49.70%、75.35%和 75.96%。此外，BRB 还显著降低了血尿素氮（BUN）（分别降低 19.62%、28.98%和 38.72%）和血清肌酐（CRE）（分别降低 16.19%、25.07%和 52.08%）水平，并呈剂量依赖性逆转 PO/HX 诱导的肾组织病理学损伤。此外，BRB 降低了肝 XOD 活性，下调了葡萄糖转运蛋白 9（GLUT9）和尿酸转运蛋白 1（URAT1）的表达，上调了有机阴离子转运蛋白 1/3（OAT1/3）和三磷酸腺苷结合盒转运体家族 G 成员 2（ABCG2）的表达，同时抑制了 JAK2/STAT3 信号通路的激活。此外，BRB 显著降低了炎症介质（IL-1β、IL-6 和 TNF-α）的水平。综上所述，本研究表明 BRB 通过调节尿酸转运蛋白的表达和抑制 JAK2/STAT3 信号通路发挥降尿酸作用，有望进一步开发成为治疗 HUA 的潜在药物。
