Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Angoroside C: A potent AMPK activator in the aqueous extract of Scrophularia ningpoensis, alleviates metabolic syndrome in db/db mice.
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Li Xiaohan, Zhang Yue, Yu Chunxiao, Guo Xu, Fu Xiangxiang, Chen Shiqi, Gao Yanguo, Zhang Yu, Xiang Qin, Lu Wei, Zhang Yonghong, Wang Qibin, Chen Li, Zheng Tao
Аннотация
BACKGROUND: Scrophularia ningpoensis Hemsl. (SN) is a traditional herbal medicine used for treating diabetes mellitus (DM). Previous studies indicated that the aqueous extract of SN (AESN) improves type 2 DM (T2DM) by activating AMP-activated protein kinase (AMPK), but the active components were unclear.
PURPOSE: This study aimed to identify the compound in AESN responsible for AMPK activation and to verify its therapeutic effects on T2DM.
METHODS: Rats were administered AESN intragastrically. The absorbed compounds in serum samples were analyzed using LC-MS/MS and subjected to molecular docking with AMPK. The compound with the highest docking score was further verified using SPR, CETSA, and TR-FRET to confirm its effects on AMPK activation. Primary mouse hepatocytes were used to examine the effects of angoroside C (ANC) on AMPK activity, Akt/GSK3β signaling, NLRP3 inflammasome activation, and lipid accumulation. An AMPK inhibitor was used to determine whether the effects were AMPK-dependent. In type 2 diabetic db/db mice, various dosages of ANC were administered intragastrically to observe its therapeutic effects.
RESULTS: Among the 17 absorbed prototype compounds, ANC exhibited the strongest binding ability to AMPK. SPR, CETSA, and TR-FRET assays confirmed that ANC binds to and activates AMPK. In hepatocytes, ANC activated the Akt/GSK3β signaling, suppressed NLRP3 inflammasome activation, and inhibited lipid accumulation in an AMPK-dependent manner. In db/db mice, ANC intervention improved glucose and lipid metabolic disorders, insulin resistance, and histopathological abnormalities in a dose-dependent manner, while activating AMPK and alleviating lipid metabolic disorders and metabolic inflammatory responses.
CONCLUSION: ANC can treat T2DM by directly binding to and activating AMPK.
PURPOSE: This study aimed to identify the compound in AESN responsible for AMPK activation and to verify its therapeutic effects on T2DM.
METHODS: Rats were administered AESN intragastrically. The absorbed compounds in serum samples were analyzed using LC-MS/MS and subjected to molecular docking with AMPK. The compound with the highest docking score was further verified using SPR, CETSA, and TR-FRET to confirm its effects on AMPK activation. Primary mouse hepatocytes were used to examine the effects of angoroside C (ANC) on AMPK activity, Akt/GSK3β signaling, NLRP3 inflammasome activation, and lipid accumulation. An AMPK inhibitor was used to determine whether the effects were AMPK-dependent. In type 2 diabetic db/db mice, various dosages of ANC were administered intragastrically to observe its therapeutic effects.
RESULTS: Among the 17 absorbed prototype compounds, ANC exhibited the strongest binding ability to AMPK. SPR, CETSA, and TR-FRET assays confirmed that ANC binds to and activates AMPK. In hepatocytes, ANC activated the Akt/GSK3β signaling, suppressed NLRP3 inflammasome activation, and inhibited lipid accumulation in an AMPK-dependent manner. In db/db mice, ANC intervention improved glucose and lipid metabolic disorders, insulin resistance, and histopathological abnormalities in a dose-dependent manner, while activating AMPK and alleviating lipid metabolic disorders and metabolic inflammatory responses.
CONCLUSION: ANC can treat T2DM by directly binding to and activating AMPK.