Medicinal Chemistry & Computer Aided Drug Designing

Biography

Biography: Bin Xu

Abstract

The incidence of type 1 diabetes (T1D) is increasing fast worldwide and currently there is no known cure for this disease. Past studies provided encouraging evidence that b-cells have the potential to regenerate primarily by proliferation of existing b-cells. Through performing a systematic screen of a natural products collection, we discovered that oleuropein, a natural compound typically found in olive leaf and fruit and olive oil, induces b-cell growth and potentiates glucose stimulated insulin secretion. Oleuropein is shown to stimulate INS1 b-cell proliferation following a 24 hour incubation period as determined by bromo-deoxyuridine (BrdU) DNA incorporation-based cell replication assay and tetrazolium MTT-based cell proliferation assay. The effect of oleuropein on β-cell growth is as potent as that of glucagon-like peptide, a known FDA-approved type 2diabetes drug. To determine the molecular mechanisms by which oleuropein induces b-cell growth and exerts its potential anti-diabetes effects, we have performed detailed signaling analyses. Our results show that oleuropein acutely (within the time-frame of 20 minutes of treatment) activated ERK1/2 in INS1 cells. Using pharmacological inhibitors, we found PD98059, a known MEK1/2 inhibitor, strongly diminished ERK phosphorylation induced by oleuropein. To further map pathways upstream of ERK-MEK, we applied a panel of inhibitors. We found small compound Sorafenib (BAY 43-9006), a kinase Raf inhibitor, significantly inhibits oleuropein-induced ERK phosphorylation. Treatments of PKA inhibitors KT5720 or H89, PI3K inhibitor LY294002, AMPK inhibitor compound C each had no significant effects. We conclude oleuropein promotes b-cell proliferation through ERK-MEK-Raf pathway.