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

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. B...

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Autores principales: Lee, Wei-Hwa, Wu, Hsueh-Hsia, Huang, Wei-Jan, Li, Yi-Ning, Lin, Ren-Jye, Lin, Shyr-Yi, Liang, Yu-Chih
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272315/
https://www.ncbi.nlm.nih.gov/pubmed/25768846
http://dx.doi.org/10.3390/molecules20034516
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author Lee, Wei-Hwa
Wu, Hsueh-Hsia
Huang, Wei-Jan
Li, Yi-Ning
Lin, Ren-Jye
Lin, Shyr-Yi
Liang, Yu-Chih
author_facet Lee, Wei-Hwa
Wu, Hsueh-Hsia
Huang, Wei-Jan
Li, Yi-Ning
Lin, Ren-Jye
Lin, Shyr-Yi
Liang, Yu-Chih
author_sort Lee, Wei-Hwa
collection PubMed
description 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.
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spelling pubmed-62723152018-12-31 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 Molecules Article 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. MDPI 2015-03-11 /pmc/articles/PMC6272315/ /pubmed/25768846 http://dx.doi.org/10.3390/molecules20034516 Text en © 2015 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Wei-Hwa
Wu, Hsueh-Hsia
Huang, Wei-Jan
Li, Yi-Ning
Lin, Ren-Jye
Lin, Shyr-Yi
Liang, Yu-Chih
N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK
title N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK
title_full N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK
title_fullStr N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK
title_full_unstemmed N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK
title_short N-Hydroxycinnamide Derivatives of Osthole Ameliorate Hyperglycemia through Activation of AMPK and p38 MAPK
title_sort n-hydroxycinnamide derivatives of osthole ameliorate hyperglycemia through activation of ampk and p38 mapk
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272315/
https://www.ncbi.nlm.nih.gov/pubmed/25768846
http://dx.doi.org/10.3390/molecules20034516
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