AIMS/HYPOTHESIS: Chronic foot ulceration is a severe complication of diabetes, driving morbidity and mortality. The mechanisms underlying delaying wound healing in diabetes are incompletely understood and tools to identify such pathways are eagerly awaited. METHODS: Wound biopsies were obtained from 75 patients with diabetic foot ulcers. Matched subgroups of rapidly healing (RH, n = 17) and non-healing (NH, n = 11) patients were selected. Proteomic analysis was performed by labelling with isobaric tag for relative and absolute quantification and mass spectrometry. Differentially expressed proteins were analysed in NH vs RH for identification of pathogenic pathways. Individual sample gene/protein validation and in vivo validation of candidate pathways in mouse models were carried out. RESULTS: Pathway analyses were conducted on 92/286 proteins that were differentially expressed in NH vs RH. The following pathways were enriched in NH vs RH patients: apoptosis, protease inhibitors, epithelial differentiation, serine endopeptidase activity, coagulation and regulation of defence response. SerpinB3 was strongly upregulated in RH vs NH wounds, validated as protein and mRNA in individual samples. To test the relevance of serpinB3 in vivo, we used a transgenic mouse model with α1-antitrypsin promoter-driven overexpression of human SERPINB3. In this model, wound healing was unaffected by SERPINB3 overexpression in non-diabetic or diabetic mice with or without hindlimb ischaemia. In an independent validation cohort of 47 patients, high serpinB3 protein content was confirmed as a biomarker of healing improvement. CONCLUSIONS/ INTERPRETATION: We provide a benchmark for the unbiased discovery of novel molecular targets and biomarkers of impaired diabetic wound healing. High serpinB3 protein content was found to be a biomarker of successful healing in diabetic patients.
AIMS/HYPOTHESIS: Chronic foot ulceration is a severe complication of diabetes, driving morbidity and mortality. The mechanisms underlying delaying wound healing in diabetes are incompletely understood and tools to identify such pathways are eagerly awaited. METHODS: Wound biopsies were obtained from 75 patients with diabetic foot ulcers. Matched subgroups of rapidly healing (RH, n = 17) and non-healing (NH, n = 11) patients were selected. Proteomic analysis was performed by labelling with isobaric tag for relative and absolute quantification and mass spectrometry. Differentially expressed proteins were analysed in NH vs RH for identification of pathogenic pathways. Individual sample gene/protein validation and in vivo validation of candidate pathways in mouse models were carried out. RESULTS: Pathway analyses were conducted on 92/286 proteins that were differentially expressed in NH vs RH. The following pathways were enriched in NH vs RH patients: apoptosis, protease inhibitors, epithelial differentiation, serine endopeptidase activity, coagulation and regulation of defence response. SerpinB3 was strongly upregulated in RH vs NH wounds, validated as protein and mRNA in individual samples. To test the relevance of serpinB3 in vivo, we used a transgenic mouse model with α1-antitrypsin promoter-driven overexpression of humanSERPINB3. In this model, wound healing was unaffected by SERPINB3 overexpression in non-diabetic or diabeticmice with or without hindlimb ischaemia. In an independent validation cohort of 47 patients, high serpinB3 protein content was confirmed as a biomarker of healing improvement. CONCLUSIONS/ INTERPRETATION: We provide a benchmark for the unbiased discovery of novel molecular targets and biomarkers of impaired diabetic wound healing. High serpinB3 protein content was found to be a biomarker of successful healing in diabeticpatients.
Authors: Sabine A Eming; Manuel Koch; Andreas Krieger; Bent Brachvogel; Sandra Kreft; Leena Bruckner-Tuderman; Thomas Krieg; John D Shannon; Jay W Fox Journal: J Proteome Res Date: 2010-09-03 Impact factor: 4.466
Authors: Björn Schwanhäusser; Dorothea Busse; Na Li; Gunnar Dittmar; Johannes Schuchhardt; Jana Wolf; Wei Chen; Matthias Selbach Journal: Nature Date: 2011-05-19 Impact factor: 49.962
Authors: Christoph Krisp; Frank Jacobsen; Matthew J McKay; Mark P Molloy; Lars Steinstraesser; Dirk A Wolters Journal: Proteomics Date: 2013-07-30 Impact factor: 3.984
Authors: Paul Kirk; Aviva Witkover; Charles R M Bangham; Sylvia Richardson; Alexandra M Lewin; Michael P H Stumpf Journal: J Comput Biol Date: 2013-08-02 Impact factor: 1.479
Authors: Stephan Morbach; Heike Furchert; Ute Gröblinghoff; Heribert Hoffmeier; Kerstin Kersten; Gerd-Thomas Klauke; Ulrike Klemp; Thomas Roden; Andrea Icks; Burkhard Haastert; Gerhard Rümenapf; Zulfiqarali G Abbas; Manish Bharara; David G Armstrong Journal: Diabetes Care Date: 2012-07-18 Impact factor: 19.112
Authors: Thanh Dinh; Francesco Tecilazich; Antonios Kafanas; John Doupis; Charalambos Gnardellis; Ermelindo Leal; Ana Tellechea; Leena Pradhan; Thomas E Lyons; John M Giurini; Aristidis Veves Journal: Diabetes Date: 2012-06-11 Impact factor: 9.461
Authors: Kenzie Birse; Kelly B Arnold; Richard M Novak; Stuart McCorrister; Souradet Shaw; Garrett R Westmacott; Terry B Ball; Douglas A Lauffenburger; Adam Burgener Journal: J Virol Date: 2015-06-17 Impact factor: 5.103
Authors: Yang Zhao; Man Wang; Bo Meng; Ying Gao; Zhichao Xue; Minjun He; You Jiang; Xinhua Dai; Dan Yan; Xiang Fang Journal: Front Chem Date: 2021-06-11 Impact factor: 5.221