KMID : 0043320170400121403
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Archives of Pharmacal Research 2017 Volume.40 No. 12 p.1403 ~ p.1413
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¥á-Methyl artoflavanocoumarin from Juniperus chinensis exerts anti-diabetic effects by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant HepG2 cells
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Jung Hee-Jin
Seong Su-Hui Ali Md Yousof Min Byung-Sun Jung Hyun-Ah Choi Jae-Sue
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Abstract
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Diabetes mellitus is one of the greatest global health issues and much research effort continues to be directed toward identifying novel therapeutic agents. Insulin resistance is a challenging integrally related topic and molecules capable of overcoming it are of considerable therapeutic interest in the context of type 2 diabetes mellitus (T2DM). Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling transduction and is regarded a novel therapeutic target in T2DM. Here, we investigated the inhibitory effect of ¥á-methyl artoflavanocoumarin (MAFC), a natural flavanocoumarin isolated from Juniperus chinensis, on PTP1B in insulin-resistant HepG2 cells. MAFC was found to potently inhibit PTP1B with an IC50 of 25.27 ¡¾ 0.14 ¥ìM, and a kinetics study revealed MAFC is a mixed type PTP1B inhibitor with a Ki value of 13.84 ¥ìM. Molecular docking simulations demonstrated MAFC can bind to catalytic and allosteric sites of PTP1B. Furthermore, MAFC significantly increased glucose uptake and decreased the expression of PTP1B in insulin-resistant HepG2 cells, down-regulated the phosphorylation of insulin receptor substrate (IRS)-1 (Ser307), and dose-dependently enhanced the protein levels of IRS-1, phosphorylated phosphoinositide 3-kinase (PI3K), Akt, and ERK1. These results suggest that MAFC from J. chinensis has therapeutic potential in T2DM by inhibiting PTP1B and activating insulin signaling pathways.
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KEYWORD
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Juniperus chinensis, Protein tyrosine phosphatase 1B, ¥á-Methyl artoflavanocoumarin, Antidiabetic, Glucose uptake, Molecular docking
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