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Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

ABSTRACT: 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-1?). In diabetes, HIF-1? function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1? transactivation. We examined whether local enhancement of HIF-1? activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1? activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1? 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.

SUBMITTER: Duscher D

PROVIDER: S-EPMC4291638 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

Duscher Dominik D Neofytou Evgenios E Wong Victor W VW Maan Zeshaan N ZN Rennert Robert C RC Inayathullah Mohammed M Januszyk Michael M Rodrigues Melanie M Malkovskiy Andrey V AV Whitmore Arnetha J AJ Walmsley Graham G GG Galvez Michael G MG Whittam Alexander J AJ Brownlee Michael M Rajadas Jayakumar J Gurtner Geoffrey C GC

Proceedings of the National Academy of Sciences of the United States of America 20141222 1

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 ...[more]

PMID: 25535360

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Project description:Label‑free quantitative mass spectrometry was used to analyze the differences in the granulation tissue protein expression profiles of patients with diabetic foot ulcers (DFUs) before and after negative‑pressure wound therapy (NPWT) to understand how NPWT promotes the healing of diabetic foot wounds. A total of three patients with DFUs hospitalized for Wagner grade 3 were enrolled. The patients received NPWT for one week. The granulation tissue samples of the patients prior to and following NPWT for one week were collected. The protein expression profiles were analyzed with label‑free quantitative mass spectrometry and the differentially expressed proteins (DEPs) in the DFU patients prior to and following NPWT for one week were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were conducted to annotate the DEPs and DEP‑associated signaling pathways. Western blotting and ELISA were performed to validate the results. By comparing the differences in the protein profiles of granulation tissue samples prior to and following NPWT for one week, 36 proteins with significant differences were identified (P<0.05); 33 of these proteins were upregulated and three proteins were downregulated. NPWT altered proteins mainly associated with antioxidation and detoxification, the cytoskeleton, regulation of the inflammatory response, complement and coagulation cascades and lipid metabolism. The functional validation of the DEPs demonstrated that the levels of cathepsin S in peripheral blood and granulation tissue were significantly lower than those prior to NPWT (P<0.05), while the levels of protein S isoform 1, inter α‑trypsin inhibitor heavy chain H4 and peroxiredoxin‑2 in peripheral blood and granulation tissue were significantly higher than those prior to NPWT (P<0.05). The present study identified multiple novel proteins altered by NPWT and laid a foundation for further studies investigating the mechanism of action of NPWT.

Dataset Information

Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

Publications

Transdermal deferoxamine prevents pressure-induced diabetic ulcers.

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