Revealing the improvement of diabetes by Si Wei Jiang Huang Tang San through ERK/HIF1α signaling pathway via network pharmacology

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.