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ER? Accelerates Diabetic Wound Healing by Ameliorating Hyperglycemia-Induced Persistent Oxidative Stress.

ABSTRACT: Delayed wound healing in diabetic patients is a serious diabetic complication, resulting in major health problems as well as high mortality and disability. The detailed mechanism still needs to be fully understood. In this study, we aim to investigate potential mechanisms and explore an efficient strategy for clinical treatment of diabetic wound healing. Human umbilical endothelial cells were exposed to hyperglycemia for 4 days, then switched to normoglycemia for an additional 4 days. The cells were harvested for the analysis of reactive oxygen species (ROS) generation, gene expression and VEGF signaling pathway. Furthermore, the diabetic wound model was established in rats for the evaluation of wound healing rates under the treatment of either ER? agonist/antagonist or SOD mimetic MnTBAP. Our results show that transient hyperglycemia exposure results in persistent ROS overgeneration after the switch to normoglycemia, along with suppressed expression of ER?, SOD2, and the VEGF signaling pathway. Either ER? expression or activation diminishes ROS generation. In vivo experiments with diabetic rats show that ER? activation or SOD mimetic MnTBAP diminishes ROS generation in tissues and accelerates diabetic wound healing. Transient hyperglycemia exposure induces ROS generation and suppresses ER? expression, subsequently resulting in SOD2 suppression with additional elevated ROS generation. This forms a positive-feed forward loop for ROS generation with persistent oxidative stress. ER? expression or activation breaks this loop and ameliorates this effect, thereby accelerating diabetic wound healing. We conclude that ER? accelerates diabetic wound healing by ameliorating hyperglycemia-induced persistent oxidative stress. This provides a new strategy for clinical treatment of diabetic wound healing based on ER? activation.

SUBMITTER: Zhou X

PROVIDER: S-EPMC6667639 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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ERβ Accelerates Diabetic Wound Healing by Ameliorating Hyperglycemia-Induced Persistent Oxidative Stress.

Zhou Xueqing X Li Min M Xiao Meifang M Ruan Qiongfang Q Chu Zhigang Z Ye Ziqing Z Zhong Liyan L Zhang Haimou H Huang Xiaodong X Xie Weiguo W Li Ling L Yao Paul P

Frontiers in endocrinology 20190724

Delayed wound healing in diabetic patients is a serious diabetic complication, resulting in major health problems as well as high mortality and disability. The detailed mechanism still needs to be fully understood. In this study, we aim to investigate potential mechanisms and explore an efficient strategy for clinical treatment of diabetic wound healing. Human umbilical endothelial cells were exposed to hyperglycemia for 4 days, then switched to normoglycemia for an additional 4 days. The cells ...[more]

PMID: 31396159

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Project description:BackgroundDiabetes significantly delays wound healing through oxidative stress, inflammation and impaired re-epithelialization that lead to defective regulation of the healing process, although the related mechanism remains unclear. Here, we aim to investigate the potential role and mechanism for the beneficial effect of betulinic acid (BA) on diabetic wound healing.MethodsThe molecular effect of BA on hyperglycemia-mediated gene expression, oxidative stress, inflammation and glucose uptake was evaluated in endothelial, fibroblast and muscle cells. Burn injury was introduced to streptozotocin-induced diabetic rats and BA administration through either an intraperitoneal (IP) or topical (TOP) technique was used for wound treatment. Glucose tolerance was evaluated in both muscle tissue and fibroblasts, while oxidative stress and inflammation were determined in both the circulatory system and in wound tissues. The effect of BA on the wound healing process was also evaluated.ResultsBA treatment reversed hyperglycemia-induced glucose transporter type 4 (GLUT4) suppression in both muscle and fibroblast cells. This treatment also partly reversed hyperglycemia-mediated suppression of endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and nuclear factor NFκB p65 subunit (NFκB p65) activation in endothelial cells. An in vivo rat study showed that BA administration ameliorated diabetes-mediated glucose intolerance and partly attenuated diabetes-mediated oxidative stress and inflammation in both the circulatory system and wound tissues. BA administration by both IP and TOP techniques significantly accelerated diabetic wound healing, while BA administration by either IP or TOP methods alone had a significantly lower effect.ConclusionsBA treatment ameliorates hyperglycemia-mediated glucose intolerance, endothelial dysfunction, oxidative stress and inflammation. Administration of BA by both IP and TOP techniques was found to significantly accelerate diabetic wound healing, indicating that BA could be a potential therapeutic candidate for diabetic wound healing.

Dataset Information

ER? Accelerates Diabetic Wound Healing by Ameliorating Hyperglycemia-Induced Persistent Oxidative Stress.

Publications

ERβ Accelerates Diabetic Wound Healing by Ameliorating Hyperglycemia-Induced Persistent Oxidative Stress.

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