益智仁倍半萜类化合物通过 Ca2+/CaMKII 和 PKA 途径以及多酶抑制具有 GLP-1 刺激作用,Journal of Agricultural and Food Chemistry

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益智仁倍半萜类化合物通过 Ca2+/CaMKII 和 PKA 途径以及多酶抑制具有 GLP-1 刺激作用
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-10-23 , DOI: 10.1021/acs.jafc.3c06093
Can Cui _{1,

2} , Sheng-Li Wu ₂ , Ji-Jun Chen _{2,

3} , Pianchou Gongpan ₂ , Min Guan ₄ , Chang-An Geng ₂

Affiliation

从益智仁的果实中分离得到六种新的倍半萜类化合物( 1-6 )、一对对映体( 7a和7b )和六种已知的倍半萜类化合物( 8-13 )。通过大量的光谱数据和 ECD 计算阐明了新化合物的结构。7a和7b的立体化学为首次报道。所有化合物均在 NCI-H716 细胞中显示出显着的 GLP-1 刺激作用，在 50 μM 时促进比例范围为 90.4% 至 668.9%。机制研究表明，化合物6主要通过调节胰高血糖素原的转录和剪切过程刺激GLP-1分泌，而化合物13通过上调prkaca水平发挥作用。有趣的是， 6和13的GLP-1刺激作用均与Ca ²⁺ /CaMKII和PKA途径密切相关，但与TGR5和GPR119受体无关。此外，大多数化合物在浓度为 100 和 200 μM 时对 α-葡萄糖苷酶和 PTP1B 表现出抑制活性，而对 GPa 没有活性。化合物3、9、11和13可以抑制α-葡萄糖苷酶，IC 50值为_{190.0、204.0、181.8}和159.6 μM，相当于阿卡波糖(IC 50 ₌ 212.0 μM)。本研究表明，益生菌含有多种倍半萜类化合物，具有多种活性。

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Sesquiterpenoids from Alpinia oxyphylla with GLP-1 Stimulative Effects through Ca2+/CaMKII and PKA Pathways and Multiple-Enzyme Inhibition

Six new sesquiterpenoids (1–6), a pair of enantiomers (7a and 7b), and six known ones (8–13) were isolated from the fruits of Alpinia oxyphylla. The structures of the new compounds were elucidated by extensive spectroscopic data and ECD calculations. The stereochemistry of 7a and 7b was reported for the first time. All compounds showed significant GLP-1 stimulation in NCI-H716 cells with promoting ratios ranging from 90.4 to 668.9% at 50 μM. Mechanism study indicated that compound 6 stimulated GLP-1 secretion mainly by regulating the transcription and the shearing process of proglucagon, while compound 13 exerted its effects through up-regulating prkaca levels. Interestingly, the GLP-1 stimulative effects of 6 and 13 were both closely related with Ca²⁺/CaMKII and PKA pathways but irrelevant to TGR5 and GPR119 receptors. Moreover, most compounds exhibited inhibitory activity against α-glucosidase and PTP1B at concentrations of 100 and 200 μM, while showing no activity against GPa. Compounds 3, 9, 11, and 13 could suppress α-glucosidase with IC₅₀ values of 190.0, 204.0, 181.8, and 159.6 μM, equivalent to acarbose (IC₅₀ = 212.0 μM). This study manifests that A. oxyphylla contains diverse sesquiterpenoids with multiple activities.

更新日期：2023-10-23

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