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Bilirubin Protects Transplanted Islets by Targeting Ferroptosis.

ABSTRACT: Islet transplantation is an attractive treatment for type 1 diabetic patients. However, transplanted islets suffered from considerable cell death due to inflammatory reactions and oxidative stress. Ferroptosis is a programmed death characterized by iron-dependent lipid peroxidation, which has been implicated in the islet loss and dysfunction. Our previous studies showed that bilirubin displayed protection effect for islets by inhibiting early inflammation and oxidative stress. However, whether bilirubin protects islets by targeting ferroptosis has not yet been elucidated. Here, the isolated islet was exposed to ferroptosis-inducing agents with or without bilirubin. Islet viability, insulin secretion, and oxidative stress levels were assessed. Subsequently, the pretreated islets were transplanted into the subrenal site of streptozotocin-induced diabetic mice. Bilirubin could significantly attenuate ferroptosis in isolated islets, along with reduced oxidative stress, elevated GPX4 expression and upregulation of Nrf2/HO-1. Experimental data also confirmed that bilirubin could chelate iron. In vivo graft study demonstrated that euglycemia was achieved in diabetic mice receiving bilirubin-pretreated islets within 24 hours, while the control islets required at least 7 days. Bilirubin could improve islet viability and function through inhibiting ferroptosis, which could be of clinic interest to apply bilirubin into the islet transplantation system.

SUBMITTER: Yao Q

PROVIDER: S-EPMC7308534 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Bilirubin Protects Transplanted Islets by Targeting Ferroptosis.

Yao Qing Q Sun Rui R Bao Shihui S Chen Ruijie R Kou Longfa L

Frontiers in pharmacology 20200616

Islet transplantation is an attractive treatment for type 1 diabetic patients. However, transplanted islets suffered from considerable cell death due to inflammatory reactions and oxidative stress. Ferroptosis is a programmed death characterized by iron-dependent lipid peroxidation, which has been implicated in the islet loss and dysfunction. Our previous studies showed that bilirubin displayed protection effect for islets by inhibiting early inflammation and oxidative stress. However, whether b ...[more]

PMID: 32612533

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Project description:ObjectiveBecause of reduced antioxidant defenses, beta-cells are especially vulnerable to free radical and inflammatory damage. Commonly used antirejection drugs are excellent at inhibiting the adaptive immune response; however, most are harmful to islets and do not protect well from reactive oxygen species and inflammation resulting from islet isolation and ischemia-reperfusion injury. The aim of this study was to determine whether redox modulation, using the catalytic antioxidant (CA), FBC-007, can improve in vivo islet function post-transplant.Research design and methodsThe abilities of redox modulation to preserve islet function were analyzed using three models of ischemia-reperfusion injury: 1) streptozotocin (STZ) treatment of human islets, 2) STZ-induced murine model of diabetes, and 3) models of syngeneic, allogeneic, and xenogeneic transplantation.ResultsIncubating human islets with catalytic antioxidant during STZ treatment protects from STZ-induced islet damage, and systemic delivery of catalytic antioxidant ablates STZ-induced diabetes in mice. Islets treated with catalytic antioxidant before syngeneic, suboptimal syngeneic, or xenogeneic transplant exhibited superior function compared with untreated controls. Diabetic murine recipients of catalytic antioxidant-treated allogeneic islets exhibited improved glycemic control post-transplant and demonstrated a delay in allograft rejection. Treating recipients systemically with catalytic antioxidant further extended the delay in allograft rejection.ConclusionsPretreating donor islets with catalytic antioxidant protects from antigen-independent ischemia-reperfusion injury in multiple transplant settings. Treating systemically with catalytic antioxidant protects islets from antigen-independent ischemia-reperfusion injury and hinders the antigen-dependent alloimmune response. These results suggest that the addition of a redox modulation strategy would be a beneficial clinical approach for islet preservation in syngeneic, allogeneic, and xenogeneic transplantation.

Dataset Information

Bilirubin Protects Transplanted Islets by Targeting Ferroptosis.

Publications

Bilirubin Protects Transplanted Islets by Targeting Ferroptosis.

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