| Summary: | Iron (Fe) is an essential metal for facilitating several cellular functions, e.g. DNA synthesis, enzyme activities, and erythropoiesis, in our bodies. However, when the iron homeostasis is not tightly regulated, our body functions could not be carried out properly and would even cause diseases. Excessive iron deposition due to genetic disorders (primary iron overload) or chronic hemolytic anemia (secondary iron overload) could be harmful by inducing oxidative stress and
further causing organ injuries and dysfunctions, e.g. hepatic cirrhosis and cardiac hypertrophy. Patients with sickle cell disease (SCD) may have secondary iron overload via hemolysis and ineffective erythropoiesis. Iron absorption is upregulated to complement ineffective erythropoiesis. In addition, chronic blood transfusions are necessary for those who have severe symptoms of SCD or anemia and will further intensify the iron burden and oxidative stress. Thus, iron chelators usually
accompany blood transfusion in order to decrease excess iron disposition. However, currently FDA-approved iron chelators show significant side effects, which results in low patients' compliance. N,N' bis-(2-mercaptoethyl)isophthalamide) (NBMI; emeramide), a novel metal chelator, has shown efficacy in decreasing iron burden in a mouse model of primary iron overload. Previous in vivo test on rats also indicated its low toxicity. Therefore, NBMI was proposed to test its efficacy on iron
chelation along with safety on a secondary iron overload mouse model of SCD by comparing to the most widely used iron chelator, deferasirox (DFX). I found that NBMI had limited effect on decreasing iron level in sickling mice (HbSS). Drug toxicity was not observed. Interestingly, NBMI treatment resulted in decreased oxidative stress in the liver and kidneys of HbSS mice. Although the iron level was not considerably decreased by NBMI compared to DFX, it is possible that NBMI becomes
hydrophilic after binding to iron and stays in the tissues. Since non-heme iron levels were measured, the assay does not differentiate NBMI-bound iron and free iron (unbound form). Since free, labile iron causes oxidative stress, NBMI-bound iron could be no longer harmful and may not induce oxidative damage. These results indicate that NBMI could potentially be used as an antioxidant supplement to protect the body from oxidative stress in SCD patients.
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