PMID- 29177868 OWN - NLM STAT- MEDLINE DCOM- 20180723 LR - 20180723 IS - 1976-3786 (Electronic) IS - 0253-6269 (Linking) VI - 40 IP - 12 DP - 2017 Dec TI - alpha-Methyl artoflavanocoumarin from Juniperus chinensis exerts anti-diabetic effects by inhibiting PTP1B and activating the PI3K/Akt signaling pathway in insulin-resistant HepG2 cells. PG - 1403-1413 LID - 10.1007/s12272-017-0992-0 [doi] AB - 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 alpha-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 IC(50) of 25.27 +/- 0.14 microM, and a kinetics study revealed MAFC is a mixed type PTP1B inhibitor with a K (i) value of 13.84 microM. 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. FAU - Jung, Hee Jin AU - Jung HJ AD - Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea. FAU - Seong, Su Hui AU - Seong SH AD - Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea. FAU - Ali, Md Yousof AU - Ali MY AD - Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea. FAU - Min, Byung-Sun AU - Min BS AD - College of Pharmacy, Catholic University of Daegu, Gyeongsan, 38430, Republic of Korea. FAU - Jung, Hyun Ah AU - Jung HA AD - Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju, 54896, Republic of Korea. jungha@jbnu.ac.kr. FAU - Choi, Jae Sue AU - Choi JS AD - Department of Food and Life Science, Pukyong National University, Busan, 48513, Republic of Korea. choijs@pknu.ac.kr. LA - eng PT - Journal Article DEP - 20171124 PL - Korea (South) TA - Arch Pharm Res JT - Archives of pharmacal research JID - 8000036 RN - 0 (Coumarins) RN - 0 (Enzyme Inhibitors) RN - 0 (Flavones) RN - 0 (Hypoglycemic Agents) RN - 0 (Plant Extracts) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.1.3.48 (PTPN1 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1) SB - IM MH - Cell Survival/drug effects MH - Coumarins/chemistry/isolation & purification/*pharmacology MH - Diabetes Mellitus, Type 2/*drug therapy MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/chemistry/isolation & purification/*pharmacology MH - Flavones/chemistry/isolation & purification/*pharmacology MH - Hep G2 Cells MH - Humans MH - Hypoglycemic Agents/chemistry/isolation & purification/pharmacology MH - Insulin Resistance MH - Juniperus/*chemistry MH - Molecular Docking Simulation MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Plant Extracts/chemistry/isolation & purification/pharmacology MH - Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists & inhibitors/metabolism MH - Proto-Oncogene Proteins c-akt/*agonists/metabolism MH - Signal Transduction/drug effects MH - Structure-Activity Relationship OTO - NOTNLM OT - Antidiabetic OT - Glucose uptake OT - Juniperus chinensis OT - Molecular docking OT - Protein tyrosine phosphatase 1B OT - alpha-Methyl artoflavanocoumarin EDAT- 2017/11/28 06:00 MHDA- 2018/07/24 06:00 CRDT- 2017/11/28 06:00 PHST- 2017/07/16 00:00 [received] PHST- 2017/11/19 00:00 [accepted] PHST- 2017/11/28 06:00 [pubmed] PHST- 2018/07/24 06:00 [medline] PHST- 2017/11/28 06:00 [entrez] AID - 10.1007/s12272-017-0992-0 [pii] AID - 10.1007/s12272-017-0992-0 [doi] PST - ppublish SO - Arch Pharm Res. 2017 Dec;40(12):1403-1413. doi: 10.1007/s12272-017-0992-0. Epub 2017 Nov 24.