Potential Benefits of Nrf2/Keap1 Targeting in Pancreatic Islet Cell Transplantation

Abstract

Permanent pancreatic islet cell destruction occurs in type 1 diabetes mellitus (T1DM) through the infiltration of inflammatory cells and cytokines. Loss of β-cell integrity secondary to oxidation leads to an inability to appropriately synthesize and secrete insulin. Allogenic islet cell transplantation (ICT) has risen as a therapeutic option to mitigate problematic hypoglycemia. Nevertheless, during the process of transplantation, islet cells are exposed to oxidatively caustic conditions that severely decrease the islet cell yield. Islet cells are at a baseline disadvantage to sustain themselves during times of metabolic stress as they lack a robust anti-oxidant defense system, glycogen stores, and vascularity. The Nrf2/Keap1 system is a master regulator of antioxidant genes that has garnered attention as pharmacologic activators have shown a protective response and a low side effect profile. Herein, we present the most recently studied Nrf2/Keap1 activators in pancreas for application in ICT: Dh404, dimethyl fumarate (DMF), and epigallocatechin gallate (EGCG). Furthermore, we discuss that Nrf2/Keap1 is a potential target to ameliorate oxidative stress at every step of the Edmonton Protocol.

Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications

“…The beneficial effects of MMF were correlated to the enhancement of Nrf2 nuclear translocation, and the upregulation of antioxidant enzymes including HO-1, CAT, SOD-1, and GPX-1 [ 274 ]. DMF has been demonstrated to be an activator of Nrf2 [ 275 , 276 ] and can also act as a selectively repressor for the TNF-mediated nuclear translocation of activated NF-κB [ 277 ] that plays important roles for the pathogenesis of DR.…”

Keap1/Nrf2 Signaling Pathway

“…Therefore, investigations of the protective effects of Keap1/Nrf2 signaling that focus on specific tissues or organs are of great interest. Such studies have traditionally focused on tissues with detoxification functions such as the liver [ 6 , 7 ] but have also expanded to diverse tissues, including the kidney [ 8 , 9 ], skin [ 10 ], lung [ 11 ], colon [ 12 ], heart [ 13 ], nervous system [ 14 ], adipose tissue [ 15 ], pancreas [ 16 ] and thyroid [ 17 , 18 ], as evidenced by the respective tissue/organ-specific studies that are outlined below and comprise the majority of studies in the present Special Issue. Lastly, research on Nrf2 has expanded to encompass not only basic but also translational and clinical studies.…”

“…Therefore, methods to improve the viability of islet cells for transplantation are actively pursued. Jarrin Lopez et al review the results of recent studies that employed dimethyl fumarate or the Nrf2-activating phytochemical epigallocatechin gallate for ICT, and they discuss Keap1/Nrf2 signaling as a potential target to ameliorate oxidative stress at every step of the standard ICT protocol [ 16 ].…”

Antioxidant Therapy in Pancreatitis

“…When TPIAT was first implemented to treat CP several decades ago, the outcomes were variable owing to the lack of standards for islet isolation. Nonetheless, continued research on islet isolation techniques since then has steadily improved the possibility of collecting high-quality islets from the resected pancreas [ 118 , 119 , 120 , 121 ].…”