Amarogentin, a secoiridoid glycoside, activates AMP- activated protein kinase (AMPK) to exert beneficial vasculo-metabolic effects
| Autor: | Nikunj Mehta, Madhulika Dixit, Uma Rani Potunuru, K. Vishnu Priya, Manikandan Ramar, M.K.N. Sai Varsha, Shivam Chandel, Narayanan Manoj, M. Michael Gromiha, Thiagarajan Raman |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Biophysics Pharmacology AMP-Activated Protein Kinases Calorimetry Biochemistry Diabetes Mellitus Experimental 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine AMP-activated protein kinase Human Umbilical Vein Endothelial Cells Oil Red O Animals Humans Iridoids Protein kinase A Molecular Biology biology Chemistry Kinase Tumor Necrosis Factor-alpha AMPK Amarogentin Atherosclerosis Lipids Rats Endothelial stem cell Enzyme Activation Mice Inbred C57BL Molecular Docking Simulation 030104 developmental biology Glucose 030220 oncology & carcinogenesis biology.protein Liver function Endothelium Vascular Signal Transduction |
| Zdroj: | Biochimica et biophysica acta. General subjects. 1863(8) |
| ISSN: | 1872-8006 |
| Popis: | Introduction AMP-activated protein kinase (AMPK) is a drug target for treatment of metabolic and cardiovascular complications. Extracts of Gentianaceace plants exhibit anti-diabetic and anti-atherosclerotic effects, however, whether their phyto-constitutents activate AMPK remains to be determined. Methods Molecular docking of Gentiana lutea constituents was performed with crystal structure of human α2β1γ1 trimeric AMPK (PDB ID: 4CFE ). Binding of Amarogentin (AG) to α2 subunit was confirmed through isothermal titration calorimetry (ITC) and in vitro kinase assays were performed. L6 myotube, HUH7 and endothelial cell cultures were employed to validate in silico and in vitro observations. Lipid lowering and anti-atherosclerotic effects were confirmed in streptozotocin induced diabetic mice via biochemical measurements and through heamatoxylin and eosin, Masson's trichrome and Oil Red O staining. Results AG interacts with the α2 subunit of AMPK and activates the trimeric kinase with an EC50 value of 277 pM. In cell culture experiments, AG induced phosphorylation of AMPK as well as its downstream targets, acetyl-coA-carboxylase (ACC) and endothelial nitric oxide synthase (eNOS). Additionally, it enhanced glucose uptake in myotubes and blocked TNF-α induced endothelial inflammation. Oral supplementation of AG significantly attenuated diabetes-mediated neointimal thickening, and collagen and lipid deposition in the aorta. It also improved circulating levels of lipids and liver function in diabetic mice. Conclusion In conclusion, AG exerts beneficial vasculo-metabolic effects by activating AMPK. General significance Amarogentin, a naturally occurring secoiridoid glycoside, is a promising lead for design and synthesis of novel drugs for treatment and management of dyslipidemia and cardiovascular diseases. |
| Databáze: | OpenAIRE |
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