Protective effect of a novel clinical-grade small molecule necrosis inhibitor against oxidative stress and inflammation during islet transplantation
| Autor: | Bae Jun Oh, Seungyeon Ha, Jae Hyeon Kim, Han Sin Lee, Sang-Man Jin, Youngsang Kwon, Gyuri Kim, Hyunjin Kim |
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| Rok vydání: | 2020 |
| Předmět: |
Mitochondrial ROS
endocrine system Amyloid Necrosis endocrine system diseases Islets of Langerhans Transplantation Mice Transgenic 030230 surgery Pharmacology medicine.disease_cause Proinflammatory cytokine 03 medical and health sciences Islets of Langerhans Mice 0302 clinical medicine medicine Immunology and Allergy Animals Pharmacology (medical) Inflammation Transplantation geography Mice Inbred BALB C geography.geographical_feature_category business.industry Islet Islet Amyloid Polypeptide Oxidative Stress Diabetes Mellitus Type 2 Tumor necrosis factor alpha medicine.symptom business Oxidative stress Ex vivo |
| Zdroj: | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant SurgeonsREFERENCES. 21(4) |
| ISSN: | 1600-6143 |
| Popis: | Inhibition of mitochondrial reactive oxygen species (ROS) and subsequent damage-associated molecular patterns (DAMPs)-induced inflammatory responses could be a novel target in clinical islet transplantation. We investigated the protective effects of NecroX-7, a novel clinical-grade necrosis inhibitor that specifically targets mitochondrial ROS, against primary islet graft failure. Islets from heterozygote human islet amyloid polypeptide transgenic (hIAPP+/- ) mice and nonhuman primates (NHPs) were isolated or cultured with or without NecroX-7 in serum-deprived medium. Supplementation with NecroX-7 during hIAPP+/- mouse islet isolation markedly increased islet viability and adenosine triphosphate content, and attenuated ROS, transcription of c-Jun N-terminal kinases, high mobility group box 1, interleukin-1beta (IL-1 β ), IL-6, and tumor necrosis factor-alpha. Supplementation of NecroX-7 during serum-deprived culture also protected hIAPP+/- mouse and NHP islets against impaired viability, serum deprivation-induced ROS, proinflammatory response, and accumulation of toxic IAPP oligomer. Supplementation with NecroX-7 during isolation or serum-deprived culture of hIAPP+/- mouse and NHP islets also improved posttransplant glycemia in the recipient streptozotocin-induced diabetic hIAPP-/- mice and BALB/c-nu/nu mice, respectively. In conclusion, pretransplant administration of NecroX-7 during islet isolation and serum-deprived culture suppressed mitochondrial ROS injury, generation of DAMPs-induced proinflammatory responses, and accumulation of toxic IAPP oligomers ex vivo, and improved posttransplant glycemia in vivo. |
| Databáze: | OpenAIRE |
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