Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China.
J Ethnopharmacol. 2023 Jun 28;310:116349. doi: 10.1016/j.jep.2023.116349. Epub 2023 Mar 15.
Kunxian capsule (KXC) is a new traditional Chinese medicine drug included in "The key science and technology achievements" in the Ninth Five Year Plan of China. KXC has been clinically used for more than 10 years in the treatment of lupus nephritis (LN). However, the underlying role and molecular mechanism of KXC in LN remain unclear.
This study aimed to explore the efficacy and potential mechanisms of KXC through pharmacological network, in vitro and in vivo studies.
Pharmacological network analysis of KXC treatment in LN was performed using data acquired from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP, https://old.tcmsp-e.com/tcmsp.php) and NCBI Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/database). HK-2 cells were chosen as an in vitro model of the tubular immune response by simulation with interferon γ (IFN-γ). MRL/lpr mice were used to explore the mechanism of KXC in vivo. Finally, the specific active molecules of KXC were further analyzed by molecular docking.
The pharmacological network analysis showed that STAT1 is a key factor in the effects of KXC. In vitro and in vivo experiments confirmed the therapeutic effect of KXC on LN renal function and tubular inflammation. The protective effect of KXC is mediated by STAT1 blockade, which further reduces T-cell infiltration and improves the renal microenvironment in LN. Two main components of KXC, Tripterygium hypoglaucum (H.Lév.) Hutch (Shanhaitang) and Epimedium brevicornu Maxim (Yinyanghuo) could block JAK1-STAT1 activation. Furthermore, we found 8 molecules that could bind to the ATP pocket of JAK1 with high affinities by performing docking analysis.
KXC inhibits renal damage and T-cell infiltration in LN by blocking the JAK1-STAT1 pathway.
昆仙胶囊（KXC）是中国“九五”计划中的“重点科技成果”之一，是一种新型的中药药物。KXC 已在临床上用于治疗狼疮性肾炎（LN）超过 10 年。然而，KXC 在 LN 中的作用机制尚不清楚。
本研究旨在通过药理网络、体外和体内研究探讨 KXC 的疗效及其潜在机制。
采用中药系统药理学数据库和分析平台（TCMSP，https://old.tcmsp-e.com/tcmsp.php）和 NCBI 基因表达综合数据库（GEO，https://www.ncbi.nlm.nih.gov/geo/database）获取的 KXC 治疗 LN 的相关数据进行 KXC 治疗 LN 的药理网络分析。选择 HK-2 细胞作为模拟干扰素γ（IFN-γ）的管状免疫反应的体外模型。采用 MRL/lpr 小鼠体内研究 KXC 的作用机制。最后，通过分子对接进一步分析 KXC 的活性分子。
药理网络分析表明，STAT1 是 KXC 作用的关键因素。体外和体内实验证实 KXC 对 LN 肾功能和管状炎症有治疗作用。KXC 的保护作用是通过阻断 STAT1 来介导的，进一步减少 T 细胞浸润，改善 LN 中的肾脏微环境。KXC 的两个主要成分雷公藤（H.Lév.）Hutch（Shanhaitang）和淫羊藿（Epimedium brevicornu Maxim（Yinyanghuo）可以阻断 JAK1-STAT1 激活。此外，通过对接分析，我们发现了 8 种可以与 JAK1 的 ATP 结合口袋高亲和力结合的分子。
KXC 通过阻断 JAK1-STAT1 通路抑制 LN 中的肾损伤和 T 细胞浸润。
