Desferrioxamine as a lipid chain‐breaking antioxidant in sickle erythrocyte membranes

Hartley, Andrew; Davies, Michael J.; Rice‐Evans, Catherine

doi:10.1016/0014-5793(90)80786-i

Cited by 56 publications

(27 citation statements)

References 23 publications

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“…Its possible antioxidative properties were also suggested in recent years. Soriani et al (1993) suggests the possible antioxidative role may be independent of its iron chelation; previous studies have shown the antioxidative chain-breaking ability of DFO (Hartley et al, 1990) and its possible ability to scavenge peroxyl radicals (Darley-Usmar et al, 1989) and superoxide radicals (Sinaceur et al, 1984). A recent study also suggested that DFO can inhibit the oxidative chemistry of peroxynitrite.…”

Section: Discussionmentioning

confidence: 92%

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Lan

Jiang

1997

J. Neural Transmission

151

112

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Summary.To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive ironinduced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical ('OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, "OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.

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Section: Discussionmentioning

confidence: 92%

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Lan

Jiang

1997

J. Neural Transmission

151

112

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“…A molecular option to therapeutically modulate HIF-1α activity is the iron chelator DFO (50)(51)(52). DFO has a crucial advantage over drugs, which purely upregulate HIF-1α levels, such as the PHD inhibitor dimethyloxalylglycine, in that it also has a direct antioxidant effect and is capable of reducing the oxidative stress associated with ischemia (53). In keeping with this mechanism, DFO has been found to play a protective role during hypoxic preconditioning in brain (51) and heart tissue (54) as well as in cutaneous ischemic preconditioning (23).…”

Section: Discussionmentioning

confidence: 99%

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

Duscher

Neofytou

Wong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

177

174

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There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.wound healing | diabetes | drug delivery | small molecule | angiogenesis D iabetes mellitus affects over 25 million people in the United States (1, 2) and costs nearly $250 billion per year (3). Chronic diabetic wounds and decubiti are important long-term sequalae of both diabetes mellitus types 1 and 2 (4). There is a high mortality in diabetic patients who develop decubiti (5-7), and owing to prolonged disability and the high rates of recurrence these wounds represent an especially severe complication of diabetes (8). This is further underscored by the fact that diabetic nonhealing wounds are the leading cause of nontraumatic amputations in the United States (3, 9-11). As such, there is a clear need for new approaches to effectively manage and treat diabetic ulcers.The propensity for wound development in diabetes is associated with a reduced capacity for ischemia-driven neovascularization (12, 13). Hypoxia inducible factor-1 (HIF-1), which consists of a highly regulated α-subunit and a constitutively expressed β-subunit, is a critical transcriptional regulator of the normal cellular response to hypoxia, promoting progenitor cell recruitment, proliferation, survival, and neovascularization (14, 15). In nondiabetics, hypoxia causes stabilization of HIF-1α protein by preventing the normal rapid proteasomal degradation of HIF-1α. It does this by inhibiting the prolyl hydroxylases (PHDs), which hydroxylate specific prolyl residues on HIF-1α. Without proline hydroxylation HIF-1α is not ...

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“…In addition to its ability to act as an iron chelator, DFX is also a peroxyl radical scavenger independent of its iron chelating ability, 27 and has been shown to act as a lipid chain-breaking antioxidant. 28 In this process, DFX is enzymatically oxidized to a nitroxide free radical, z9 These investigators have also noted that as long as the concentrations of DFX are kept below 10 -3 M, reactions of reactive oxygen species with DFX are minimal, and, as such, DFX can be used as the chelator of choice to inhibit the iron catalyzed Fenton reaction. 3°…”

Section: Fenton Reaction Fe(iii) + O2"---' Fe(ii) + 02mentioning

confidence: 99%

Oxidative mechanisms in the toxicity of metal ions

Stohs

Bagchi

1995

Free Radical Biology and Medicine

3,763

2,001

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The role of reactive oxygen species, with the subsequent oxidative deterioration of biological macromolecules in the toxicities associated with transition metal ions, is reviewed. Recent studies have shown that metals, including iron, copper, chromium, and vanadium undergo redox cycling, while cadmium, mercury, and nickel, as well as lead, deplete glutathione and protein-bound sulfhydryl groups, resulting in the production of reactive oxygen species as superoxide ion, hydrogen peroxide, and hydroxyl radical. As a consequence, enhanced lipid peroxidation, DNA damage, and altered calcium and sulfhydryl homeostasis occur. Fenton-like reactions may be commonly associated with most membranous fractions including mitochondria, microsomes, and peroxisomes. Phagocytic cells may be another important source of reactive oxygen species in response to metal ions. Furthermore, various studies have suggested that the ability to generate reactive oxygen species by redox cycling quinones and related compounds may require metal ions. Recent studies have suggested that metal ions may enhance the production of tumor necrosis factor alpha (TNFc0 and activate protein kinase C, as well as induce the production of stress proteins, Thus, some mechanisms associated with the toxicities of metal ions are very similar to the effects produced by many organic xenobiotics. Specific differences in the toxicities of metal ions may be related to differences in solubilities, absorbability, transport, chemical reactivity, and the complexes that are formed within the body. This review summarizes current studies that have been conducted with transition metal ions as well as lead, regarding the production of reactive oxygen species and oxidative tissue damage.

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Desferrioxamine as a lipid chain‐breaking antioxidant in sickle erythrocyte membranes

Cited by 56 publications

References 23 publications

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Transdermal deferoxamine prevents pressure-induced diabetic ulcers

Oxidative mechanisms in the toxicity of metal ions

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