Beta-D-glucoside protects against advanced glycation end products (AGEs)-mediated diabetic responses by suppressing ERK and inducing PPAR gamma DNA binding.
Accumulation of advanced glycation end products (AGEs), due to excessive amounts of 3- or 4-carbon sugars derived from glucose; cause multiple consequences in diabetic patients and older persons. The transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), is down regulated in the diabetic condition. Drugs targeting PPARγ were developed for diabetes therapy. We found that AGE inhibited PPARγ activity in different cell types induced by PPARγ activators, like troglitazone, rosiglitazone, oleamide, and anandamide. AGE induced translocation of PPARγ from nucleus to cytoplasm, increased on activation of ERK in cells. Antioxidants that inhibit AGE-induced NF-κB activation by preventing ROI generation were unable to protect AGE-mediated decrease in PPARγ activity. Only mangiferin, a β-D-glucoside, prevented AGE-mediated decrease in PPARγ activity and inhibited phosphorylation of ERK and cytoplasmic translocation of PPARγ. Mangiferin interacts with PPARγ and enhanced its DNA binding activity as predicted by in silico and shown by in vitro DNA-binding activity. Overall, the data suggest that (i) mangiferin inhibited AGE-induced ERK activation thereby inhibited PPARγ phosphorylation and cytoplasmic translocation; (ii) mangiferin interacts with PPARγ and enhances its DNA-binding ability. With these dual effects, mangiferin can be a likely candidate for developing therapeutic drug against diabetes.
Laboratory of Immunology, Centre for DNA Fingerprinting & Diagnostics, Nampally, Hyderabad 500001, India.
Sidhartha K
SK
Mahali
Sunil K
SK
Manna
D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D017931:DNA Primers; D048909:Diabetes Complications / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005960:Glucosides / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D005960:Glucosides; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases