Induction of Heme Oxygenase-1 by Plant Extract KIOM-79 via Akt Pathway and NF-E2 Related Factor 2 in Pancreatic β-Cells

Abstract

The objective of the present study was to determine the mechanism by which KIOM-79 induced heme oxygenase-1 (HO-1) in rat pancreatic β-cells (RINm5F). A mixture of plant extracts (KIOM-79) was obtained from Magnolia officinalis, Pueraria lobata, Glycyrrhiza uralensis, and Euphorbia pekinensis. HO-1, an antioxidant phase 2 enzyme, was previously reported to possess cytoprotective properties in pancreatic β-cells. KIOM-79 induced heme oxygenase-1 (HO-1) expression at the mRNA and protein levels, leading to increased HO-1 activity. The transcription factor, NF-E2 related factor 2 (Nrf2), regulates the antioxidant response element (ARE) of the phase 2 detoxifying and antioxidant enzymes, resulting in modulation of HO-1 expression. KIOM-79 increased nuclear translocation, ARE binding, and transcriptional activity of Nrf2. Furthermore, KIOM-79 also elicited activation of Akt (protein kinase B) and LY294004 (inhibitor of Akt)-suppressed KIOM-79-induced activation of Nrf2, which subsequently decreased HO-1 protein levels. Taken together, these data suggest that KIOM-79 augments the cellular antioxidant defense capacity through induction of HO-1 via the Akt-Nrf2-ARE signaling pathway, thereby protecting cells from streptozotocin-induced oxidative stress.