State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing, 100050, China; College of Public Health, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
J Ethnopharmacol. 2024 Jan 30;319(Pt 2):117254. doi: 10.1016/j.jep.2023.117254. Epub 2023 Sep 29.
Si Wei Jiang Huang Tang San (SWJHTS) is a traditional Tibetan medicine prescription for the treatment of urethritis, frequent urination, and urgency, composed of four traditional Chinese medicines: Curcumae longae rhizoma, Berberidis cortex, Tribuli fructus, and Phyllanthi fructus. However, whether SWJHTS exhibits hypoglycemic efficacy and its specific mechanism remain unclear.
In this study, we aimed to investigate the anti-diabetic effects of SWJHTS and elucidate the underlying mechanism.
HPLC-MS method was used to identify the key components of four kinds of traditional Chinese medicine (Curcumae longae rhizoma, Berberidis cortex., Tribuli fructus, and Phyllanthi fructus) which composed SWJHTS and determine their structure. Normal mice and 145 mg/kg STZ-induced type 1 diabetic mice were treated with three doses of SWJTHS by oral gavage. Body weight, 24h food and water intake, fasting blood glucose, glucose tolerance and other indicators were measured to evaluate the hypoglycemic effect of SWJHTS. OMIM, Genecards and other databases were used to collect targets of diabetes, and HPLC-MS results and TCMSP database information were used to collect drug component targets. Bioinformatics methods such as pathway enrichment analysis and molecular docking were used to predict the key targets of SWJHTS. The gene and protein expressions of HIF1α and ERK signaling pathways in HepG2 cells treated with SWJHTS were detected by RT-PCR and Western blot.
A total of 181 components were identified, including curcumin, palmatine, and berberine, etc. The in vivo studies showed that SWJHTS could significantly lower fasting blood glucose levels and improve the symptoms of polydipsia, polyphagia, and polyuria in diabetic mice. Furthermore, we identified HIF1α as the potential key target of SWJHTS against diabetes utilizing network pharmacology approach and in silico molecular docking. Subsequently, we experimentally confirmed that SWJHTS could suppress the high glucose-induced upregulation of HIF1α expression, which mediated the glucose consumption in HepG2 cells. The ERK signaling pathway was further found to be activated by the SWJHTS as the upstream of HIF1α.
SWJHTS can improve glucose metabolism by targeting the ERK/HIF1α signaling pathway; hence might be a prospective anti-diabetic drug for diabetic patients as traditional Tibetan medicine.
四味姜黄汤散（SWJHTS）是一种传统的藏药处方，用于治疗尿道炎、尿频和尿急，由四种中药组成：姜黄、黄柏、蒺藜和叶下珠。然而，SWJHTS 是否具有降血糖作用及其具体机制尚不清楚。
本研究旨在探讨 SWJHTS 的抗糖尿病作用，并阐明其潜在机制。
采用高效液相色谱-质谱联用（HPLC-MS）法鉴定 SWJHTS 中四种中药（姜黄、黄柏、蒺藜和叶下珠）的关键成分，并确定其结构。用 SWJTHS 经口灌胃给药正常小鼠和 145mg/kg STZ 诱导的 1 型糖尿病小鼠，测量体重、24h 食物和水摄入量、空腹血糖、葡萄糖耐量等指标，评价 SWJHTS 的降血糖作用。使用 OMIM、Genecards 等数据库收集糖尿病靶点，使用 HPLC-MS 结果和 TCMSP 数据库信息收集药物成分靶点。采用通路富集分析和分子对接等生物信息学方法预测 SWJHTS 的关键靶点。采用 RT-PCR 和 Western blot 检测 SWJHTS 处理 HepG2 细胞后 HIF1α 和 ERK 信号通路的基因和蛋白表达。
共鉴定出 181 种成分，包括姜黄素、巴马汀和小檗碱等。体内研究表明，SWJHTS 可显著降低糖尿病小鼠的空腹血糖水平，并改善其多饮、多食和多尿症状。此外，我们利用网络药理学方法和计算机分子对接技术，鉴定出 HIF1α 是 SWJHTS 治疗糖尿病的潜在关键靶点。随后，我们通过实验证实，SWJHTS 可抑制高糖诱导的 HepG2 细胞中 HIF1α 表达的上调，从而介导葡萄糖消耗。进一步发现，SWJHTS 通过激活 ERK 信号通路作为 HIF1α 的上游来调节 HIF1α 的表达。
SWJHTS 可通过靶向 ERK/HIF1α 信号通路改善葡萄糖代谢，可能成为治疗糖尿病患者的一种有前途的藏药。
