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Restoration of Nrf2 Signaling Normalizes the Regenerative Niche

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...

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Autores principales: Soares, Marc A., Cohen, Oriana D., Low, Yee Cheng, Sartor, Rita A., Ellison, Trevor, Anil, Utkarsh, Anzai, Lavinia, Chang, Jessica B., Saadeh, Pierre B., Rabbani, Piul S., Ceradini, Daniel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314719/
https://www.ncbi.nlm.nih.gov/pubmed/26647385
http://dx.doi.org/10.2337/db15-0453
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author Soares, Marc A.
Cohen, Oriana D.
Low, Yee Cheng
Sartor, Rita A.
Ellison, Trevor
Anil, Utkarsh
Anzai, Lavinia
Chang, Jessica B.
Saadeh, Pierre B.
Rabbani, Piul S.
Ceradini, Daniel J.
author_facet Soares, Marc A.
Cohen, Oriana D.
Low, Yee Cheng
Sartor, Rita A.
Ellison, Trevor
Anil, Utkarsh
Anzai, Lavinia
Chang, Jessica B.
Saadeh, Pierre B.
Rabbani, Piul S.
Ceradini, Daniel J.
author_sort Soares, Marc A.
collection PubMed
description 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.
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spelling pubmed-53147192017-03-01 Restoration of Nrf2 Signaling Normalizes the Regenerative Niche Soares, Marc A. Cohen, Oriana D. Low, Yee Cheng Sartor, Rita A. Ellison, Trevor Anil, Utkarsh Anzai, Lavinia Chang, Jessica B. Saadeh, Pierre B. Rabbani, Piul S. Ceradini, Daniel J. Diabetes Signal Transduction 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. American Diabetes Association 2016-03 2015-12-08 /pmc/articles/PMC5314719/ /pubmed/26647385 http://dx.doi.org/10.2337/db15-0453 Text en © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Signal Transduction
Soares, Marc A.
Cohen, Oriana D.
Low, Yee Cheng
Sartor, Rita A.
Ellison, Trevor
Anil, Utkarsh
Anzai, Lavinia
Chang, Jessica B.
Saadeh, Pierre B.
Rabbani, Piul S.
Ceradini, Daniel J.
Restoration of Nrf2 Signaling Normalizes the Regenerative Niche
title Restoration of Nrf2 Signaling Normalizes the Regenerative Niche
title_full Restoration of Nrf2 Signaling Normalizes the Regenerative Niche
title_fullStr Restoration of Nrf2 Signaling Normalizes the Regenerative Niche
title_full_unstemmed Restoration of Nrf2 Signaling Normalizes the Regenerative Niche
title_short Restoration of Nrf2 Signaling Normalizes the Regenerative Niche
title_sort restoration of nrf2 signaling normalizes the regenerative niche
topic Signal Transduction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314719/
https://www.ncbi.nlm.nih.gov/pubmed/26647385
http://dx.doi.org/10.2337/db15-0453
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