Iron toxicity mediated by oxidative stress enhances tissue damage in an animal model of diabetes

Abstract

Although iron is a first-line pro-oxidant that modulates clinical manifestations of various systemic diseases, including diabetes, the individual tissue damage generated by active oxidant insults has not been demonstrated in current animal models of diabetes. We tested the hypothesis that oxidative stress is involved in the severity of the tissues injury when iron supplementation is administered in a model of type 1 diabetes. Streptozotocin (Stz)-induced diabetic and non-diabetic Fischer rats were maintained with or without a treatment consisting of iron dextran ip at 0.1 mL day(-1) doses administered for 4 days at intervals of 5 days. After 3 weeks, an extensive increase (p < 0.001) in the production of reactive oxygen species (ROS) in neutrophils of the diabetic animals on iron overload was observed. Histological analysis revealed that this treatment also resulted in higher (p < 0.05) tissue iron deposits, a higher (p < 0.001) number of inflammatory cells in the pancreas, and apparent cardiac fibrosis, as shown by an increase (p < 0.05) in type III collagen levels, which result in dysfunctional myocardial. Carbonyl protein modification, a marker of oxidative stress, was consistently higher (p < 0.01) in the tissues of the iron-treated rats with diabetes. Moreover, a significant positive correlation was found between ROS production and iron pancreas stores (r = 0.42, p < 0.04), iron heart stores (r = 0.54, p < 0.04), and change of the carbonyl protein content in pancreas (r = 0.49, p < 0.009), and heart (r = 0.48, p < 0.02). A negative correlation was still found between ROS production and total glutathione content in pancreas (r = -0.50, p < 0.03) and heart (r = -0.45, p < 0.04). In conclusion, our results suggest that amplified toxicity in pancreatic and cardiac tissues in rats with diabetes on iron overload might be attributed to increased oxidative stress.

Protective effects of tumor necrosis factor alpha inhibitors on methotrexate-induced pancreatic toxicity

“…According to the literature, increased oxidative stress leads to the release of proinflammatory cytokines, leading to further tissue damage. [22][23][24] Methotrexate is used for the treatment of pancreatic cancer, but has been shown to destroy the beta cells of the pancreas, primarily through oxidative stress. 1,2,5,24 In support of the data in the literature, we determined that in our study the number of insulin and somatostatin-positive cells significantly decreased in Group 2, when compared to that in Group 1 (Fig.…”

“…5,24 It has also been reported that ROS play a key role in decreasing immune system defense. 5,24,25 In addition, intense proinflammatory cytokine release, due to excessive ROS formation, has been reported during MTX treatment for cancer and autoimmune diseases.…”

“…5,24 It has also been reported that ROS play a key role in decreasing immune system defense. 5,24,25 In addition, intense proinflammatory cytokine release, due to excessive ROS formation, has been reported during MTX treatment for cancer and autoimmune diseases. 5,6,24,25 Accumulation of ROS leads to neutrophil infiltration and proinflammatory cytokine release, which triggers apoptosis.…”

“…5,24,25 In addition, intense proinflammatory cytokine release, due to excessive ROS formation, has been reported during MTX treatment for cancer and autoimmune diseases. 5,6,24,25 Accumulation of ROS leads to neutrophil infiltration and proinflammatory cytokine release, which triggers apoptosis. 5,6,24,25 Methotrexate is used for the treatment of pancreatic cancer, but has been shown to destroy the beta cells of the pancreas, primarily through oxidative stress.…”

Biotechnology of siderophores in high-impact scientific fields

“…This importance is observed at all levels of the tree of life. However, in humans, iron concentration higher than normal levels could become toxic by increasing oxidative stress, eventually translating to myocardial malfunction and inflammation responses to the pancreas (1). Other studies have suggested damages to adipose tissue and liver in obese persons (2).…”