Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system, and its dysfunction has been implicated in numerous pathologies. Here we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor Keap1 and the subsequent changes in Nrf2 signaling. We also developed a topical small interfering RNA (siRNA)–based therapy to restore redox homeostasis within diabetic wounds. Western blotting demonstrated that chronic hyperglycemia–associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response, and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.
Ionizing radiation is a common therapeutic modality and following irradiation dermal changes, including fibrosis and atrophy, may lead to permanent changes. We have previously demonstrated that occupancy of A2A receptor (A 2A R) stimulates collagen production, so we determined whether blockade or deletion of A 2A R could prevent radiation-induced fibrosis. After targeted irradiation (40 Gy) of the skin of wild-type (WT) or A 2A R knockout (A2ARKO) mice, the A 2A R antagonist ZM241385 was applied daily for 28 d. In irradiated WT mice treated with the A 2A R antagonist, there was a marked reduction in collagen content and skin thickness, and ZM241385 treatment reduced the number of myofibroblasts and angiogenesis. After irradiation, there is an increase in loosely packed collagen fibrils, which is significantly diminished by ZM241385. Irradiation also induced an increase in epidermal thickness, prevented by ZM241385, by increasing the number of proliferating keratinocytes. Similarly, in A2ARKO mice, the changes in collagen alignment, skin thickness, myofibroblast content, angiogenesis, and epidermal hyperplasia were markedly reduced following irradiation. Radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2ARKO mice. Radiation therapy is administered to a significant number of patients with cancer, and radiation reactions may limit this therapeutic modality. Our findings suggest that topical application of an A 2A R antagonist prevents radiation dermatitis and may be useful in the prevention or amelioration of radiation changes in the skin.-Perez-Aso, M., Mediero, A., Low, Y. C., Levine, J., Cronstein, B. N. Adenosine A2A receptor plays an important role in radiation-induced dermal injury. FASEB J. 30, 457-465 (2016). www.fasebj.org
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Background: Both bone marrow (BMSCs) and adiposederived (ASCs) mesenchymal stem cells have recently been described as a promising strategy to promote transplant tolerance. However, the unique immunoregulatory properties of BMSCs and ASCs and their individual ability to suppress an alloimmune response have not been directly compared.Methods: BMSCs and ASCs were isolated from Lewis, Brown Norway (BN), and ACI rats. In a mixed lymphocyte reaction (MLR), CFSE-labeled Lewis rat splenocytes were cultured either 1) alone, 2) with irradiated Lewis splenocytes, 3) with irradiated BN rat splenocytes, or 4) with phytohaemagglutinin (PHA). Group 3 and 4 were further cocultured with either varying doses of sorted BMSCs or ASCs from different passages, or media harvested from stem cell cultures to assess for immunomodulatory effects. Additionally, in Group 3, MSCs were added on day 3 to the MLR (delayed regulation), or were removed after 3-day of co-culture from the MLR (interrupted regulation).
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