title: Comparison of the Hydroxylase Inhibitor Dimethyloxalylglycine and the Iron Chelator Deferoxamine in Diabetic and Aged Wound Healing.
abstract: BACKGROUND
  A hallmark of diabetes mellitus is the breakdown of almost every reparative process in the human body, leading to critical impairments of wound healing. Stabilization and activity of the transcription factor hypoxia-inducible factor (HIF)-1α is impaired in diabetes, leading to deficits in new blood vessel formation in response to injury. In this article, the authors compare the effectiveness of two promising small-molecule therapeutics, the hydroxylase inhibitor dimethyloxalylglycine and the iron chelator deferoxamine, for attenuating diabetes-associated deficits in cutaneous wound healing by enhancing HIF-1α activation.
  
  
  METHODS
  HIF-1α stabilization, phosphorylation, and transactivation were measured in murine fibroblasts cultured under normoxic or hypoxic and low-glucose or high-glucose conditions following treatment with deferoxamine or dimethyloxalylglycine. In addition, diabetic wound healing and neovascularization were evaluated in db/db mice treated with topical solutions of either deferoxamine or dimethyloxalylglycine, and the efficacy of these molecules was also compared in aged mice.
  
  
  RESULTS
  The authors show that deferoxamine stabilizes HIF-1α expression and improves HIF-1α transactivity in hypoxic and hyperglycemic states in vitro, whereas the effects of dimethyloxalylglycine are significantly blunted under hyperglycemic hypoxic conditions. In vivo, both dimethyloxalylglycine and deferoxamine enhance wound healing and vascularity in aged mice, but only deferoxamine universally augmented wound healing and neovascularization in the setting of both advanced age and diabetes.
  
  
  CONCLUSIONS
  This first direct comparison of deferoxamine and dimethyloxalylglycine in the treatment of impaired wound healing suggests significant therapeutic potential for topical deferoxamine treatment in ischemic and diabetic disease.
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Dominik
authors.initials: D
authors.lastname: Duscher
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Michael
authors.initials: M
authors.lastname: Januszyk
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Zeshaan N
authors.initials: ZN
authors.lastname: Maan
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whittam
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hu
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Walmsley
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Yixiao
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Sacha M
authors.initials: SM
authors.lastname: Khong
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.affiliation: Stanford, Calif.; Linz, Austria; and Munich, Germany.|From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000367:Age Factors; D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D003676:Deferoxamine / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000503:physiopathology; D006943:Hyperglycemia / Q000503:physiopathology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000600:Amino Acids, Dicarboxylic; D007502:Iron Chelating Agents; D006899:Mixed Function Oxygenases; D003676:Deferoxamine; C040947:oxalylglycine