Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers.

Diabetic foot ulceration (DFU) is a chronic complication of diabetes that is characterized by impaired wound healing in the lower extremities. DFU remains a major clinical challenge because of poor understanding of its pathogenic mechanisms. Impaired wound healing in diabetes is characterized by decreased angiogenesis, reduced bone marrow-derived endothelial progenitor cell (EPC) recruitment, and decreased fibroblast and keratinocyte proliferation and migration. Recently, increasing evidence has suggested that increased hypoxic conditions and impaired cellular responses to hypoxia are essential pathogenic factors of delayed wound healing in DFU. Hypoxia-inducible factor-1 (HIF-1, a heterodimer of HIF-1α and HIF-1ß) is a master regulator of oxygen homeostasis that mediates the adaptive cellular responses to hypoxia by regulating the expression of genes involved in angiogenesis, metabolic changes, proliferation, migration, and cell survival. However, HIF-1 signalling is inhibited in diabetes as a result of hyperglycaemia-induced HIF-1α destabilization and functional repression. Increasing HIF-1α expression and activity using various approaches promotes angiogenesis, EPC recruitment, and granulation, thereby improving wound healing in experimental diabetes. The mechanisms underlying HIF-1α regulation in diabetes and the therapeutic strategies targeting HIF-1 signalling for the treatment of diabetic wounds are discussed in this review. Further investigations of the pathways involved in HIF-1α regulation in diabetes are required to advance our understanding of the mechanisms underlying impaired wound healing in diabetes and to provide a foundation for developing novel therapeutic approaches to treat DFU.

Low nuclear expression of HIF-hydroxylases PHD2/EGLN1 and PHD3/EGLN3 are associated with poor recurrence-free survival in clear cell renal cell carcinoma.

BACKGROUND: Hypoxia inducible factors, HIF-1α and HIF-2α, and their main regulators, the prolyl hydroxylase domain proteins (PHDs), mediate cellular response to hypoxia and contribute to tumor progression in clear cell renal cell carcinoma (ccRCC). These biomarkers may improve the value of traditional histopathological features in predicting disease progression after nephrectomy for localized ccRCC and guide patient selection for adjuvant treatments. PATIENTS AND METHODS: In this study, we analyzed the associations of PHD2 and PHD3 with histopathological tumor features and recurrence-free survival (RFS) in a retrospective cohort of 173 patients who had undergone surgery for localized ccRCC at Helsinki University Hospital (HUH), Finland. An external validation cohort of 191 patients was obtained from Turku University Hospital (TUH), Finland. Tissue-microarrays (TMA) were constructed using the primary tumor samples. Clinical parameters and follow-up information from 2006 to 2019 were obtained from electronic medical records. The cytoplasmic and nuclear expression of PHD2, and PHD3 were scored based on immunohistochemical staining and their associations with histopathological features and RFS were evaluated. RESULTS: Nuclear PHD2 and PHD3 expression in cancer cells were associated with lower pT-stage and Fuhrman grade compared with negative nuclei. Patients with positive nuclear expression of PHD2 and PHD3 in cancer cells had favorable RFS compared with patients having negative tumors. The nuclear expression of PHD2 was independently associated with a decreased risk of disease recurrence or death from RCC in multivariable analysis. These results were observed in both cohorts. CONCLUSIONS: The absence of nuclear PHD2 and PHD3 expression in ccRCC was associated with poor RFS and the nuclear expression of PHD2 predicted RFS regardless of other known histopathological prognostic factors. Nuclear PHD2 and PHD3 are potential prognostic biomarkers in patients with localized ccRCC and should be further investigated and validated in prospective studies.