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. 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.
authors.affiliation: Department of Pathology, Shuang Ho Hospital, Taipei Medical University, 291 Zhongzheng Rd., New Taipei City 23561, Taiwan. whlpath97616@shh.org.tw.
authors.forename: Wei-Hwa
authors.initials: WH
authors.lastname: Lee
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan. wuhh@tmu.edu.tw.
authors.forename: Hsueh-Hsia
authors.initials: HH
authors.lastname: Wu
authors.affiliation: Graduate Institute of Pharmacognosy Science, College of Pharmacy, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan. wjhuang@tmu.edu.tw.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan. m120097071@tmu.edu.tw.
authors.forename: Yi-Ning
authors.initials: YN
authors.lastname: Li
authors.affiliation: Department of Primary Care Medicine, Taipei Medical University Hospital, 252 Wuxing St., Taipei 11031, Taiwan. linrenjye@tmu.edu.tw.|Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan. linrenjye@tmu.edu.tw.
authors.forename: Ren-Jye
authors.initials: RJ
authors.lastname: Lin
authors.affiliation: Department of Primary Care Medicine, Taipei Medical University Hospital, 252 Wuxing St., Taipei 11031, Taiwan. sylin@tmu.edu.tw.|Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan. sylin@tmu.edu.tw.
authors.forename: Shyr-Yi
authors.initials: SY
authors.lastname: Lin
authors.affiliation: School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, 250 Wuxing St., Taipei 11031, Taiwan. ycliang@tmu.edu.tw.|Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, 252 Wuxing St., Taipei 11031, Taiwan. ycliang@tmu.edu.tw.
authors.forename: Yu-Chih
authors.initials: YC
authors.lastname: Liang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D003373:Coumaric Acids / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D003374:Coumarins / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D051381:Rats; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D003373:Coumaric Acids; D003374:Coumarins; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; C000603055:OHC-2m compound; C000603054:OHC-4p compound; D013311:Streptozocin; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C046627:osthol