Header menu link for other important links
X
Amarogentin, a secoiridoid glycoside, activates AMP- activated protein kinase (AMPK)to exert beneficial vasculo-metabolic effects
Uma Rani Potunuru, Priya, K. Vishnu, Mosur Kumaraswamy Nagarajan Sai Varsha, Mehta, Nikunj, Shivam Chandel, , Raman, Thiagarajan, Ramar, Manikandan, ,
Published in Elsevier B.V.
2019
PMID: 31125678
Volume: 1863
   
Issue: 8
Pages: 1270 - 1282
Abstract
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. © 2019 Elsevier B.V.
About the journal
JournalData powered by TypesetBiochimica et Biophysica Acta - General Subjects
PublisherData powered by TypesetElsevier B.V.
ISSN03044165
Open AccessNo
Concepts (47)
  •  related image
    ACETYL COENZYME A CARBOXYLASE
  •  related image
    Alanine aminotransferase
  •  related image
    AMAROGENTIN
  •  related image
    Aspartate aminotransferase
  •  related image
    Cholesterol
  •  related image
    Collagen
  •  related image
    Creatinine
  •  related image
    Endothelial nitric oxide synthase
  •  related image
    HIGH DENSITY LIPOPROTEIN
  •  related image
    HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE
  •  related image
    LOW DENSITY LIPOPROTEIN
  •  related image
    Triacylglycerol
  •  related image
    Urea
  •  related image
    VERY LOW DENSITY LIPOPROTEIN
  •  related image
    Animal cell
  •  related image
    Animal experiment
  •  related image
    Animal model
  •  related image
    Animal tissue
  •  related image
    Aorta
  •  related image
    Article
  •  related image
    Controlled study
  •  related image
    Crystal structure
  •  related image
    Drug binding
  •  related image
    Drug effect
  •  related image
    EC50
  •  related image
    Endothelium cell
  •  related image
    Enzyme activation
  •  related image
    Enzyme phosphorylation
  •  related image
    Flow cytometry
  •  related image
    GENTIANA LUTEA
  •  related image
    Glucose transport
  •  related image
    HUH-7 CELL LINE
  •  related image
    Human
  •  related image
    Human cell
  •  related image
    IMMUNOBLOTTING
  •  related image
    In vitro study
  •  related image
    Isothermal titration calorimetry
  •  related image
    L6 CELL LINE
  •  related image
    LIPID STORAGE
  •  related image
    Liver function
  •  related image
    Male
  •  related image
    Molecular docking
  •  related image
    Mouse
  •  related image
    Nonhuman
  •  related image
    Priority journal
  •  related image
    Rat
  •  related image
    STREPTOZOTOCIN-INDUCED DIABETES MELLITUS