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.

Subacute toxicological evaluation of AT‑533 and AT‑533 gel in Sprague‑Dawley rats

“…During the drug exposure period, some rats may have been uncomfortable, due to the stimulation of AT-533, and used their front paws to scratch the skin continuously in order to feel comfortable. As a result, continuous scratching caused skin damage and bleeding, leading to inflammation, as characterized by the abnormal increased numbers of WBC and NE (33). This phenomenon was concentration-dependent and rats in the 4 mg/kg AT-533 group were more severely affected than other medication-administration groups.…”

Dual Targeting EGFR and STAT3 With Erlotinib and Alantolactone Co-Loaded PLGA Nanoparticles for Pancreatic Cancer Treatment

“…MTT assay was performed according to the reported procedure ( Yao et al, 2020b ; Yao et al, 2020c ; Kv et al, 2020 ). The human pancreatic cancer cells were plated 5,000 cells per well in a 96-well plate and cultured in RPMI 1640 medium containing 10% heat-inactivated FBS for 12 h. The cells were then treated with various drug treatments for 24 h. Following that, the MTT solution was added and incubated at 37°C for 4 h. The formed formazan was dissolved in 100 µL DMSO, and the absorption was then determined by a microplate reader.…”

Ferroptosis and Its Potential Role in Metabolic Diseases: A Curse or Revitalization?

“…Although the phenotype and mechanism of ferroptosis developed in β cells have been pressed for in-depth exploration, some substances directed against ferroptosis have been found to ameliorate impairment of transplanted islet cells and treat diabetes. Bilirubin may protect the islet by raising GPX4, upregulating Nrf2/HO-1 and chelating iron to interdict ferroptosis (Yao et al, 2020). Cryptochlorogenic acid (CCA), the active constituent of the mulberry leaf, was reported to target some major regulators (system Xc-GPX4, Nrf2 and NCOA4) to inhibit ferroptosis in a concentration-dependent manner in a diabetic model (Zhou, 2020).…”