Pretreatment with Bilirubin Protects Islet against Oxidative Injury During Isolation and Purification

Zhu, Hui; Gao, Yang; Guo, Hong-Yi; Kong, Qingbo; Ma, Yun‐Bao; Wang, J.Z.; Pan, Shangha; Jiang, Hongchi; Dai, Wenjie

doi:10.1016/j.transproceed.2010.12.058

Cited by 16 publications

(11 citation statements)

References 21 publications

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“…These data were in agreement with previously reported data from Zhu, who found that a low concentration (20 mM) of bilirubin did not affect the insulin secretion function of insulinoma INS-1 cells [35]. In addition, pretreatment with bilirubin improved islet function against oxidative injury by reducing lipid peroxidation during the isolation and purification processes [34]. Collectively, these data indicated that the optimal concentration (40 mM) of bilirubin did not damage the insulin secretion function of islet cells.…”

Section: Potential Toxicity Of Brnpssupporting

confidence: 92%

PEGylated bilirubin nanoparticle as an anti-oxidative and anti-inflammatory demulcent in pancreatic islet xenotransplantation

et al. 2017

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Section: Potential Toxicity Of Brnpssupporting

confidence: 92%

PEGylated bilirubin nanoparticle as an anti-oxidative and anti-inflammatory demulcent in pancreatic islet xenotransplantation

et al. 2017

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“…Various pathological processes disrupt this balance by increasing ROS or decreasing the level of available antioxidants. Oxidative stress contributes to loss of islet mass and function and may trigger cell death via apoptosis and necrosis (18,19). Armann et al (20) determined that ROS production in islets was associated with the percentage of cells undergoing apoptosis and islet functional potency in vivo.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of TLR4 protects rat islets against lipopolysaccharide-induced dysfunction

Wang

Fan

et al. 2016

Molecular Medicine Reports

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Oxidative stress leads to dysfunction in pancreatic cells, causing a reduction in insulin secretion following exposure to glucose. Toll-like receptor 4 (TLR4) may be activated by exposure to lipopolysaccharide (LPS) stress. TLR4 may mediate the initiation of inflammatory and immune defense responses; however, the importance of the LPS/TLR4 interaction in apoptosis induced by oxidative stress in pancreatic β cells remains to be elucidated. The present study aimed to investigate the importance of TLR4 during LPS‑induced oxidative stress, apoptosis and dysfunction of insulin secretion in isolated islets of rats. LPS‑induced stimulation of TLR4 increased the production of reactive oxygen species and promoted apoptosis by upregulating the expression levels of caspase‑3, poly ADP ribose polymerase and altering the expression ratio of B‑cell lymphoma‑2 (Bcl‑2)/Bcl‑2 associated X protein. Additionally, the insulin secretion of islets cells was reduced. Anti‑TLR4 antibody and a knockdown of TLR4 by TLR4‑short hairpin RNA were used to inhibit TLR4 activity, which may reverse LPS‑induced events. The present study determined that in islets exposed to LPS oxidative stress, dysfunction may be partly mediated via the TLR4 pathway. Inhibition of TLR4 may prevent dysfunction of rat islets due to oxidative stress. The present study revealed that targeting the LPS/TLR4 signaling pathway and antioxidant therapy may be a novel treatment for the severely septic patients with hyperglycemia stress.

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“…Bilirubin has been established as a powerful endogenous cytoprotectant, mediating improved outcomes in several models of health and disease including ischemia reperfusion injury, endothelial damage, and myocardial infarction, as well as solid organ transplantation via significant antioxidant activity and immunomodulatory effects 7 , 12 – 16 , 25 – 27 . However, our study is the first to evaluate the feasibility of using a synthetic, significantly simplified, bilirubin analog, which could provide a safe, sterile, easily mass-produced drug for use in islet cell transplantation while avoiding the shortcomings of bilirubin procured from an animal source.…”

Section: Discussionmentioning

confidence: 99%

“…Bilirubin has been shown to be an important mediator of cytoprotection via powerful endogenous antioxidant activity and anti-inflammatory effects 7 , 11 – 13 . Bilirubin has not only been shown to provide potent cytoprotection of transplanted islets via induction of HO-1 and significant scavenging of free oxygen and nitrogen radicals, but it has also been shown to suppress the innate immune system resulting in improved donor tolerance to islet grafts 14 – 16 .…”

Section: Introductionmentioning

confidence: 99%

In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation

et al. 2020

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Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application. In the current study, we synthesized two bilirubin analogs that can be produced without the use of animal-derived products. Antioxidant activity for the analogs was measured using the ferric-reducing-ability-of-plasma (FRAP) and 2,2V-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. Dose-dependent cytotoxicity and cytoprotective effects were then demonstrated in isolated rat islets. Compound 1 showed similar antioxidant activity to natural bilirubin. Dose-dependent cytotoxicity was seen following treatment with Compound 1 and natural bilirubin at doses >40 μM, resulting in significantly increased cell death when compared to control islets ( P < 0.05) or islets treated with doses ≤20 μM ( P < 0.05). Following hypoxic challenge, islet cell death was reduced in islets treated with Compound 1 at 10 μM (17.27% ± 0.26%) compared to natural bilirubin at 10 μM (51.36% ± 0.71%; P < 0.0001) or 20 μM (59.02% ± 0.83%; P < 0.0001) and control islets (36.51% ± 0.44%; P < 0.0001). Compound 1 was found to have promising antioxidant and cytoprotective effects, limiting islet cell death in a model of islet transplantation hypoxic stress. Compound 1 may serve as a synthetic drug lead for clinical islet transplantation and further evaluation of this molecule and its analogs is warranted.

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Pretreatment with Bilirubin Protects Islet against Oxidative Injury During Isolation and Purification

Cited by 16 publications

References 21 publications

PEGylated bilirubin nanoparticle as an anti-oxidative and anti-inflammatory demulcent in pancreatic islet xenotransplantation

PEGylated bilirubin nanoparticle as an anti-oxidative and anti-inflammatory demulcent in pancreatic islet xenotransplantation

Inhibition of TLR4 protects rat islets against lipopolysaccharide-induced dysfunction

In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation

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