Korean J Transplant.  2022 Nov;36(Supple 1):S374. 10.4285/ATW2022.F-5148.

The free radical scavenger NecroX-7 ameliorates tacrolimusinduced pancreatic β cell dysfunction

• Jang HJ
• Youn SJ
• Oh MY

• KMID: 2535230
• DOI: http://doi.org/10.4285/ATW2022.F-5148

Abstract

Background
Tacrolimus (FK506) induces pancreatic beta cell dysfunction, causing new-onset diabetes mellitus after transplan-tation. Cyclopentylamino carboxymethylthiazolylindole (NecroX-7) is a class of indole-derived, cell-permeable, antioxidant mole-cules that exhibit cytoprotective effects in cells acting as a scavenger of reactive oxygen species (ROS). In this study, we aimed to investigate the therapeutic potential of NecroX-7, a novel clinical-grade necrosis inhibitor that specifically targets mitochondri-al ROS, in tacrolimus-induced pancreatic beta cell dysfunction.
Methods
INS-1 cells were incubated with FK506 with or without NecroX-7 and harvested at 24-hour intervals. Cells were as-sessed for viability, adenosine triphosphate (ATP), apoptosis, cell insulin secretion and content. Western blotting and RT-PCR analyses evaluated protein or gene expression of MDA, HO-1, c-Jun N-terminal kinases (c-Jun), Bcl-2, Bax, caspase-3, interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and high mobility group box 1 protein (HMGB-1) expres-sion were assessed in INS-1 cells.
Results
NecroX-7 increased remarkably cell viability, ATP and insulin secretion. Cotreatment with NecroX-7 significantly increased expression of HO-1 and Bcl-2. Pancreatic beta cell line showed that FK506 treatment increased apoptosis, while co-treatment with NecroX-7 effectively attenuated these alterations. NecroX-7 could significantly reduce the levels of c-Jun, BAX, caspase-3, IL-6, IL-1β, TNF-α, HMGB1, and TLR-4 in INS-1 cells.
Conclusions
NecroX-7 could ameliorate FK506-induced—pancreas beta cell injury through the antioxidant and anti-inflammatory pathway. These findings suggest that NecroX-7 has beneficial effects in tacrolimus-induced diabetes mellitus.