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1 Medicine; Division of Endocrinology, University of Colorado at Denver and health Sciences Center, P.O Box 6511, Aurora, Colorado, 80045, United States; Research Services, Denver VA Medical Center, 1055 Clermont Street, Denver, Colorado, 80220, United States
2 Molecular Genetics, Ochsner Med Foundation, 1516 Jefferson Hwy, New Orleans, Louisiana, 70121-2484, United States
* To whom correspondence should be addressed. E-mail: subbiah.pugazhenthi{at}uchsc.edu.
Curcumin, a component of turmeric, is to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, is reported to have cytoprotective effects in pancreatic 
cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response elements (ARE) sites-containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of Nrf2, the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of PI3-kinase and Akt. Real time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase (GCLM) which is needed for the synthesis of glutathione and NAD(P)H:quinone oxidoreductase (NQO1), which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in cells under conditions of stress as seen in diabetes.
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