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Molecules 2015, 20(3), 4516-4529; doi:10.3390/molecules20034516

N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK

1
Department of Pathology, Shuang Ho Hospital, Taipei Medical University, 291 Zhongzheng Rd., New Taipei City 23561, Taiwan
2
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan
3
Graduate Institute of Pharmacognosy Science, College of Pharmacy, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan
4
Department of Primary Care Medicine, Taipei Medical University Hospital, 252 Wuxing St., Taipei 11031, Taiwan
5
Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan
6
Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, 252 Wuxing St., Taipei 11031, Taiwan
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 20 January 2015 / Revised: 4 March 2015 / Accepted: 5 March 2015 / Published: 11 March 2015
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [5106 KB, uploaded 11 March 2015]   |  

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. 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. View Full-Text
Keywords: osthole; N-hydroxycinnamide; AMP-activated protein kinase (AMPK); p38 MAPK; glucose uptake; skeletal muscle; streptozotocin osthole; N-hydroxycinnamide; AMP-activated protein kinase (AMPK); p38 MAPK; glucose uptake; skeletal muscle; streptozotocin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lee, W.-H.; Wu, H.-H.; Huang, W.-J.; Li, Y.-N.; Lin, R.-J.; Lin, S.-Y.; Liang, Y.-C. N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK. Molecules 2015, 20, 4516-4529.

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