六神丸通过调控高尿酸血症大鼠尿酸转运蛋白促进肠道尿酸排泄。
Six Nostrum Promotes Intestinal Urate Underexcretion via Regulations of Urate Transporter Proteins in Hyperuricemic Rats.
机构信息
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China.
College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
出版信息
Comb Chem High Throughput Screen. 2023;26(4):848-861. doi: 10.2174/1386207325666220830141531.
BACKGROUND
Dendrobium officinalis Six nostrum (DOS) can be prepared by adding Dendrobium officinalis into Simiao Wan in accordance with the Traditional Chinese Medicine (TCM) theory and other previous findings. Our previous study has shown that DOS treatment can lead to a marked decrease in Serum UA (SUA) levels. The purpose of this study was to explore the effects of DOS on intestinal UA excretion in hyperuricemia and its underlying mechanisms.
METHODS
DOS was administered intragastrically to hyperuricemic rats induced by oral administration of HX and PO for 7 weeks. The SUA level, fecal UA and XOD activity were detected. The expressions of UA transporters (ABCG2, GLUT9, and PDZK1), CNT2, and tight junction proteins (ZO- 1 and claudin-1) in the intestine were assayed by IHC staining. The serum LPS and DAO levels were detected by ELISA kits. The intestinal histological changes were assessed using H&E staining.
RESULTS
DOS treatment decreased the SUA level while markedly increasing the fecal UA level by 28.85%35.72%. Moreover, DOS effectively up-regulated the expression of ABCG2 and PDZK1 and down-regulated the expression of GLUT9 in the intestine. DOS markedly decreased the serum LPS level by 21.4%32.1% and DAO activity by 12.3%~19.7%, which in turn ameliorated the intestinal pathology. As a result, it could protect intestinal barrier function, as indicated by the increase of villus height (V), the reduction of the crypt depth (C), and the elevation of the V/C ratio. It also increased the expression of ZO-1 and claudin-1. In addition, DOS significantly down-regulated the expression of CNT2, which reduced purine nucleoside transportation from the intestine into the blood, and inhibited XOD activity, leading to a decrease in UA production.
CONCLUSION
DOS exerted anti-hyperuricemic effects via regulation of intestinal urate transporters and could protect intestinal barrier function by restoring the expressions of ZO-1 and claudin-1.
背景
根据中医理论和以往的研究发现，铁皮石斛可加入四妙丸中制成六神丸（DOS）。我们之前的研究表明，DOS 治疗可显著降低血尿酸（SUA）水平。本研究旨在探讨 DOS 对高尿酸血症肠道 UA 排泄的影响及其机制。
方法
通过给予 HX 和 PO 口服诱导高尿酸血症大鼠，连续灌胃 7 周给予 DOS。检测 SUA 水平、粪便 UA 和 XOD 活性。采用免疫组化染色检测 UA 转运体（ABCG2、GLUT9 和 PDZK1）、CNT2 和紧密连接蛋白（ZO-1 和 Claudin-1）在肠道中的表达。采用 ELISA 试剂盒检测血清 LPS 和DAO 水平。采用 H&E 染色评估肠道组织学变化。
结果
DOS 治疗可降低 SUA 水平，同时使粪便 UA 水平升高 28.85%35.72%。此外，DOS 可有效上调肠道中 ABCG2 和 PDZK1 的表达，下调 GLUT9 的表达。DOS 可使血清 LPS 水平降低 21.4%32.1%，DAO 活性降低 12.3%~19.7%，从而改善肠道病理。结果表明，DOS 可保护肠道屏障功能，增加绒毛高度（V），降低隐窝深度（C），提高 V/C 比值；同时增加 ZO-1 和 Claudin-1 的表达。此外，DOS 可显著下调 CNT2 的表达，减少嘌呤核苷从肠道向血液中的转运，抑制 XOD 活性，从而减少 UA 的产生。
结论
DOS 通过调节肠道尿酸转运体发挥抗高尿酸血症作用，并通过恢复 ZO-1 和 Claudin-1 的表达来保护肠道屏障功能。
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