Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, People's Republic of China.
University of Chinese Academy of Sciences, Beijing, People's Republic of China.
Arch Pharm (Weinheim). 2024 Oct;357(10):e2400383. doi: 10.1002/ardp.202400383. Epub 2024 Jul 19.
Glucagon-like peptide-1 (GLP-1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors in treating diabetes and obesity. To discover new GLP-1 secretagogues from natural sources, alpigalangols A-Q (1-17), 17 new labdane diterpenoids including four unusual nor-labdane and N-containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP-1 promotive effects in NCl-H716 cells, of which compounds 3, 4, 12, and 14-17 were revealed with high promoting rates of 246.0%-413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3β, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K-Akt pathway was involved in the GLP-1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP-1 promoting effects, representing a new type of antidiabetic candidates from natural sources.
胰高血糖素样肽-1 (GLP-1) 分泌激动剂是克服 GLP-1 类似物和二肽基肽酶-4 (DPP-4) 抑制剂在治疗糖尿病和肥胖症中的缺陷的令人着迷的药物疗法。为了从天然来源中发现新的 GLP-1 分泌激动剂，从 Alpinia galanga 的果实中分离得到了 alpigalangols A-Q（1-17），17 种新的裂环二萜类化合物，包括 4 种不寻常的降冰片烷和含氮化合物。大多数分离物在 NCl-H716 细胞中均显示出促进 GLP-1 的作用，其中化合物 3、4、12 和 14-17 在 50μM 时表现出 246.0%-413.8%的高促进率。机制研究表明，最有效的化合物 12 上调了 Gcg 和 Pcsk1 的 mRNA 表达，以及 PKA、CREB 和 GSK3β 的蛋白磷酸化，但对 GPBAR 和 GPR119 受体无活性。网络药理学分析表明，PI3K-Akt 通路参与了 12 对 GLP-1 的刺激，这与 AKT1、CASP3、PPARG 和 ICAM1 蛋白高度相关。本研究表明，A. galanga 富含具有 GLP-1 促进作用的多种裂环二萜类化合物，代表了一种新型的天然来源抗糖尿病候选物。
