title: Pharmacological activation of Nrf2 pathway improves pancreatic islet isolation and transplantation.
abstract: Oxidative stress is a major cause of islet damage and loss during the islet isolation process. The Nrf2 pathway plays a critical role in protecting the cells against oxidative stress. The aim of this study was to investigate the effect of an Nrf2 activator (dh404) on islet isolation and transplantation in a rodent model. Islet isolation was conducted using Nrf2-deficient and wild-type mice and vehicle-treated and Nrf2 activator (dh404)-treated rats. Islet yield, viability, and Nrf2 pathway activity were determined. An in vivo islet potency test was done. Islet yield and viability in Nrf2-deficient mice was significantly lower compared to wild-type (p < 0.05) mice. Furthermore, administration of dh404 to normal Sprague-Dawley rats enhanced nuclear translocation of Nrf2 and elevated HO-1 expression in the pancreas. Islet yield and viability in dh404-treated rats was significantly higher compared to the vehicle-treated group (p < 0.05). The diabetes cure rate in nude mice with chemically induced diabetes was significantly greater in those transplanted with islets from the dh404-treated group (6/9) than vehicle-treated rats (2/9, p < 0.05). The Nrf2 pathway plays a significant role in protecting islets against stress caused by the isolation process. Pharmacological activation of the Nrf2 pathway significantly increased HO-1 expression, improved islet yield, viability, and function after transplantation.
authors.affiliation: Department of Surgery, University of California, Irvine, CA, USA.
authors.forename: Shiri
authors.initials: S
authors.lastname: Li
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Masuda
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hajighasemi-Ossareh
authors.forename: Lourdes
authors.initials: L
authors.lastname: Robles
authors.forename: Aimee
authors.initials: A
authors.lastname: Le
authors.forename: Kelly
authors.initials: K
authors.lastname: Vo
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.forename: Clarence E
authors.initials: CE
authors.lastname: Foster
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stamos
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ichii
mesh_terms: D000818:Animals; D002470:Cell Survival; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000628:therapy*; D007515:Islets of Langerhans / Q000187:drug effects; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C547749:dh404 compound; D013311:Streptozocin; D009828:Oleanolic Acid