Abstract

Our previous studies found that osthole markedly reduced blood glucose levels in both db/db and ob/ob mice. To improve the antidiabetic activity of osthole, a series of N-hydroxycinnamide derivatives of osthole were synthesized, and their hypoglycemia activities were examined in vitro and in vivo. Both N-hydroxycinnamide derivatives of osthole, OHC-4p and OHC-2m, had the greatest potential for activating AMPK and increasing glucose uptake by L6 skeletal muscle cells. In addition, OHC-4p and OHC-2m time- and dose-dependently increased phosphorylation levels of AMPK and p38 MAPK. The AMPK inhibitor, compound C, and the p38 MAPK inhibitor, SB203580, significantly reversed activation of AMPK and p38 MAPK, respectively, in OHC-4p- and OHC-2m-treated cells. Compound C and SB203580 also inhibited glucose uptake induced by OHC-4p and OHC-2m. Next, we found that OHC-4p and OHC-2m significantly increased glucose transporter 4 (GLUT4) translocation to plasma membranes and counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that activation of AMPK and p38 MAPK by OHC-4p and OHC-2m is associated with increased glucose uptake and GLUT4 translocation and subsequently led to amelioration of hyperglycemia. Therefore, OHC-4p and OHC-2m might have potential as antidiabetic agents for treating type 2 diabetes.

Original languageEnglish
Pages (from-to)4516-4529
Number of pages14
JournalMolecules
Volume20
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

Fingerprint

hyperglycemia
AMP-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
glucose
Hyperglycemia
Chemical activation
activation
Derivatives
Facilitative Glucose Transport Proteins
transporter
Medical problems
Hypoglycemic Agents
Glucose
inhibitors
mice
Cells
hypoglycemia
Phosphorylation
Experimental Diabetes Mellitus
muscle cells

Keywords

  • AMP-activated protein kinase (AMPK)
  • Glucose uptake
  • N-hydroxycinnamide
  • Osthole
  • p38 MAPK
  • Skeletal muscle
  • Streptozotocin

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

N-hydroxycinnamide derivatives of osthole ameliorate hyperglycemia through activation of AMPK and p38 MAPK. / Lee, Wei Hwa; Wu, Hsueh Hsia; Huang, Wei Jan; Li, Yi Ning; Lin, Ren-Jye; Lin, Shyr Yi; Liang, Yu Chih.

In: Molecules, Vol. 20, No. 3, 01.03.2015, p. 4516-4529.

Research output: Contribution to journalArticle

@article{b22047dc058e4d6d937f93b2c80e7d66,
title = "N-hydroxycinnamide derivatives of osthole ameliorate hyperglycemia through activation of AMPK and p38 MAPK",
abstract = "Our previous studies found that osthole markedly reduced blood glucose levels in both db/db and ob/ob mice. To improve the antidiabetic activity of osthole, a series of N-hydroxycinnamide derivatives of osthole were synthesized, and their hypoglycemia activities were examined in vitro and in vivo. Both N-hydroxycinnamide derivatives of osthole, OHC-4p and OHC-2m, had the greatest potential for activating AMPK and increasing glucose uptake by L6 skeletal muscle cells. In addition, OHC-4p and OHC-2m time- and dose-dependently increased phosphorylation levels of AMPK and p38 MAPK. The AMPK inhibitor, compound C, and the p38 MAPK inhibitor, SB203580, significantly reversed activation of AMPK and p38 MAPK, respectively, in OHC-4p- and OHC-2m-treated cells. Compound C and SB203580 also inhibited glucose uptake induced by OHC-4p and OHC-2m. Next, we found that OHC-4p and OHC-2m significantly increased glucose transporter 4 (GLUT4) translocation to plasma membranes and counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that activation of AMPK and p38 MAPK by OHC-4p and OHC-2m is associated with increased glucose uptake and GLUT4 translocation and subsequently led to amelioration of hyperglycemia. Therefore, OHC-4p and OHC-2m might have potential as antidiabetic agents for treating type 2 diabetes.",
keywords = "AMP-activated protein kinase (AMPK), Glucose uptake, N-hydroxycinnamide, Osthole, p38 MAPK, Skeletal muscle, Streptozotocin",
author = "Lee, {Wei Hwa} and Wu, {Hsueh Hsia} and Huang, {Wei Jan} and Li, {Yi Ning} and Ren-Jye Lin and Lin, {Shyr Yi} and Liang, {Yu Chih}",
year = "2015",
month = "3",
day = "1",
doi = "10.3390/molecules20034516",
language = "English",
volume = "20",
pages = "4516--4529",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "3",

}

TY - JOUR

T1 - N-hydroxycinnamide derivatives of osthole ameliorate hyperglycemia through activation of AMPK and p38 MAPK

AU - Lee, Wei Hwa

AU - Wu, Hsueh Hsia

AU - Huang, Wei Jan

AU - Li, Yi Ning

AU - Lin, Ren-Jye

AU - Lin, Shyr Yi

AU - Liang, Yu Chih

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Our previous studies found that osthole markedly reduced blood glucose levels in both db/db and ob/ob mice. To improve the antidiabetic activity of osthole, a series of N-hydroxycinnamide derivatives of osthole were synthesized, and their hypoglycemia activities were examined in vitro and in vivo. Both N-hydroxycinnamide derivatives of osthole, OHC-4p and OHC-2m, had the greatest potential for activating AMPK and increasing glucose uptake by L6 skeletal muscle cells. In addition, OHC-4p and OHC-2m time- and dose-dependently increased phosphorylation levels of AMPK and p38 MAPK. The AMPK inhibitor, compound C, and the p38 MAPK inhibitor, SB203580, significantly reversed activation of AMPK and p38 MAPK, respectively, in OHC-4p- and OHC-2m-treated cells. Compound C and SB203580 also inhibited glucose uptake induced by OHC-4p and OHC-2m. Next, we found that OHC-4p and OHC-2m significantly increased glucose transporter 4 (GLUT4) translocation to plasma membranes and counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that activation of AMPK and p38 MAPK by OHC-4p and OHC-2m is associated with increased glucose uptake and GLUT4 translocation and subsequently led to amelioration of hyperglycemia. Therefore, OHC-4p and OHC-2m might have potential as antidiabetic agents for treating type 2 diabetes.

AB - Our previous studies found that osthole markedly reduced blood glucose levels in both db/db and ob/ob mice. To improve the antidiabetic activity of osthole, a series of N-hydroxycinnamide derivatives of osthole were synthesized, and their hypoglycemia activities were examined in vitro and in vivo. Both N-hydroxycinnamide derivatives of osthole, OHC-4p and OHC-2m, had the greatest potential for activating AMPK and increasing glucose uptake by L6 skeletal muscle cells. In addition, OHC-4p and OHC-2m time- and dose-dependently increased phosphorylation levels of AMPK and p38 MAPK. The AMPK inhibitor, compound C, and the p38 MAPK inhibitor, SB203580, significantly reversed activation of AMPK and p38 MAPK, respectively, in OHC-4p- and OHC-2m-treated cells. Compound C and SB203580 also inhibited glucose uptake induced by OHC-4p and OHC-2m. Next, we found that OHC-4p and OHC-2m significantly increased glucose transporter 4 (GLUT4) translocation to plasma membranes and counteracted hyperglycemia in mice with streptozotocin-induced diabetes. These results suggest that activation of AMPK and p38 MAPK by OHC-4p and OHC-2m is associated with increased glucose uptake and GLUT4 translocation and subsequently led to amelioration of hyperglycemia. Therefore, OHC-4p and OHC-2m might have potential as antidiabetic agents for treating type 2 diabetes.

KW - AMP-activated protein kinase (AMPK)

KW - Glucose uptake

KW - N-hydroxycinnamide

KW - Osthole

KW - p38 MAPK

KW - Skeletal muscle

KW - Streptozotocin

UR - http://www.scopus.com/inward/record.url?scp=84928809968&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928809968&partnerID=8YFLogxK

U2 - 10.3390/molecules20034516

DO - 10.3390/molecules20034516

M3 - Article

C2 - 25768846

AN - SCOPUS:84928809968

VL - 20

SP - 4516

EP - 4529

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 3

ER -