Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions

Stančić, Ana; Saksida, Tamara; Markelić, Milica; Vučetić, Milica; Grigorov, Ilijana; Martinović, Vesna; Gajić, Dragica; Ivanovic, Andjelija; Veličković, Ksenija; Savic, Nevena; Otašević, Vesna

doi:10.1155/2022/3873420

Cited by 29 publications

(24 citation statements)

References 96 publications

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“…We have found that lipofuscin showed a similar pattern of changes as the iron content and that its formation could be related to ferroptosis in the diabetic liver, as its accumulation in diabetes was diminished by Fer-1. This is in line with our recently published data where we characterized the relationship between the lipofuscin accumulation and ferroptosis in β-cells under the diabetogenic conditions in vitro [ 18 ].…”

Section: Discussionsupporting

confidence: 92%

“…We have recently confirmed the implication of ferroptosis in diabetes etiology, as well. Namely, we have found that mimicking the diabetic environment in vitro induced β-cell death through ferroptosis [ 18 ]. Moreover, our in vivo pilot study showed that ferrostatin-1 (Fer-1), a commonly used ferroptosis inhibitor, improved islet morphology and functional status along with the decrease in accumulation of lipid peroxides.…”

Section: Introductionmentioning

confidence: 99%

“…Fer-1 is one of the most potent ferroptosis inhibitors that exhibits high efficacy as radical-trapping antioxidants, with a particularly high potency in phospholipid bilayer membranes when compared to other antioxidants [ 19 ]. Its metabolic actions in vivo were extensively evidenced, and it is a well-established pharmacological tool for verification of ferroptosis [ 11 , 12 , 18 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Involvement of Ferroptosis in Diabetes-Induced Liver Pathology

Stančić

Veličković

Markelić

et al. 2022

IJMS

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Cell death plays an important role in diabetes-induced liver dysfunction. Ferroptosis is a newly defined regulated cell death caused by iron-dependent lipid peroxidation. Our previous studies have shown that high glucose and streptozotocin (STZ) cause β-cell death through ferroptosis and that ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, improves β-cell viability, islet morphology, and function. This study was aimed to examine in vivo the involvement of ferroptosis in diabetes-related pathological changes in the liver. For this purpose, male C57BL/6 mice, in which diabetes was induced with STZ (40 mg/kg/5 consecutive days), were treated with Fer-1 (1 mg/kg, from day 1–21 day). It was found that in diabetic mice Fer-1 improved serum levels of ALT and triglycerides and decreased liver fibrosis, hepatocytes size, and binucleation. This improvement was due to the Fer-1-induced attenuation of ferroptotic events in the liver of diabetic mice, such as accumulation of pro-oxidative parameters (iron, lipofuscin, 4-HNE), decrease in expression level/activity of antioxidative defense-related molecules (GPX4, Nrf2, xCT, GSH, GCL, HO-1, SOD), and HMGB1 translocation from nucleus into cytosol. We concluded that ferroptosis contributes to diabetes-related pathological changes in the liver and that the targeting of ferroptosis represents a promising approach in the management of diabetes-induced liver injury.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Involvement of Ferroptosis in Diabetes-Induced Liver Pathology

Stančić

Veličković

Markelić

et al. 2022

IJMS

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“…So, we also detected the lipid ROS level of INS-1 cell to investigate the ferroptosis. Previous studies showed that HG stimulation led to the impaired cell viability and the accumulation of ROS, lipid peroxides and iron in β cells [ 29 , 39 ]. Our study observed the similar result, and found that silencing miR-144-3p could rescue the impaired cell viability of INS-1 cells owing to HG.…”

Section: Discussionmentioning

confidence: 99%

Targeting ferroptosis with miR-144-3p to attenuate pancreatic β cells dysfunction via regulating USP22/SIRT1 in type 2 diabetes

Zhang

Liu

Wang

et al. 2022

Diabetol Metab Syndr

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Background Recently, ferroptosis has been implicated in the pathologic process of several diseases including type 2 diabetes mellitus (T2DM). However, molecular mechanisms underlying ferroptosis in T2DM remain obscure. Methods Twenty four mice were included in this study. T2DM model mice were established by a high-fat diet combined with streptozotocin injection. INS-1 cells were stimulated with high glucose (HG). Cell viability was detected by CCK-8 kit. The levels of GSH, MDA, iron, and lipid ROS, and SOD activity, were detected by the corresponding kits. The interaction between miR-144-3p and USP22 was validated by dual-luciferase reporter assay. The relationship between USP22 and its substrate was verified using Co-IP and ubiquitination assays. The mRNA and protein expressions were examined by RT-qPCR and western blot, respectively. The functions of β cells in vitro and in vivo were evaluated glucose-stimulated insulin secretion test and HOMA-β, respectively. Results Ferroptosis occurred in the pancreas of T2DM mice and HG-induced INS-1 cells. Silencing miR-144-3p blocked the effect of HG on the cell viability and accumulation of lipid peroxides, thereby improving the insulin secretion in INS-1 cells. Mechanistically, USP22 is a direct target of miR-144-3p, which could stabilize SIRT1 expression, thereby suppressing ferroptosis. Overexpressing USP22 attenuated deleterious roles of HG in INS-1 cells; but its roles were reversed by up-regulating miR-144-3p. In vivo study demonstrated that miR-144-3p antagomir exerted an anti-hyperglycemic effect and regulated the ferroptosis-related proteins in the pancreas. Conclusion The up-regulation of miR-144-3p suppressed USP22/SIRT1 to induce ferroptosis, which causes pancreatic β cells dysfunction, thereby promoting T2DM development.

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“…With the in-depth study of the pathological mechanism of ferroptosis, many ferroptosis inhibitors have been discovered and identified, such as ferrostatin-1, liproxstatin-1, vitamin E, and Zileuton. In a model of diabetes, ferrostatin-1 reduces accumulation of lipid peroxides and infiltration of macrophage, and increases the number of insulin-associated cells, protecting islets from streptozotocin (STZ)-induced damage (Stancic et al, 2022). Vitamin E is an antioxidant that can reduce plasma glucose concentrations, insulin levels, etc.…”

Section: Ferroptosis Inhibitorsmentioning

confidence: 99%

Oxidative Stress and Lipid Peroxidation: Prospective Associations Between Ferroptosis and Delayed Wound Healing in Diabetic Ulcers

Feng

Wang

et al. 2022

Front. Cell Dev. Biol.

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Diabetic ulcers are one of the major complications of diabetes, and patients usually suffer from amputation and death due to delayed ulcer wound healing. Persistent inflammation and oxidative stress at the wound site are the main manifestations of delayed wound healing in diabetic ulcers. In addition, chronic hyperglycemia in patients can lead to circulatory accumulation of lipid peroxidation products and impaired iron metabolism pathways leading to the presence of multiple free irons in plasma. Ferroptosis, a newly discovered form of cell death, is characterized by intracellular iron overload and accumulation of iron-dependent lipid peroxides. These indicate that ferroptosis is one of the potential mechanisms of delayed wound healing in diabetic ulcers and will hopefully be a novel therapeutic target for delayed wound healing in diabetic patients. This review explored the pathogenesis of diabetic ulcer wound healing, reveals that oxidative stress and lipid peroxidation are common pathological mechanisms of ferroptosis and delayed wound healing in diabetic ulcers. Based on strong evidence, it is speculated that ferroptosis and diabetic ulcers are closely related, and have value of in-depth research. We attempted to clarify prospective associations between ferroptosis and diabetic ulcers in terms of GPX4, iron overload, ferroptosis inhibitors, AGEs, and HO-1, to provide new ideas for exploring the clinical treatment of diabetic ulcers.

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Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions

Cited by 29 publications

References 96 publications

Involvement of Ferroptosis in Diabetes-Induced Liver Pathology

Involvement of Ferroptosis in Diabetes-Induced Liver Pathology

Targeting ferroptosis with miR-144-3p to attenuate pancreatic β cells dysfunction via regulating USP22/SIRT1 in type 2 diabetes

Oxidative Stress and Lipid Peroxidation: Prospective Associations Between Ferroptosis and Delayed Wound Healing in Diabetic Ulcers

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