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Review
. 2021 Jun 24:9:707479.
doi: 10.3389/fbioe.2021.707479. eCollection 2021.

Antioxidant Therapy and Antioxidant-Related Bionanomaterials in Diabetic Wound Healing

Wenqian Zhang  1   2 , Lang Chen  1   2 , Yuan Xiong  1   2 , Adriana C Panayi  3 , Abudula Abududilibaier  1   2 , Yiqiang Hu  1   2 , Chenyan Yu  1   2 , Wu Zhou  1   2 , Yun Sun  2   4 , Mengfei Liu  1   2 , Hang Xue  1   2 , Liangcong Hu  1   2 , Chenchen Yan  1   2 , Xuedong Xie  1   2 , Ze Lin  1   2 , Faqi Cao  1   2 , Bobin Mi  1   2 , Guohui Liu  1   2
Affiliations
Review

Antioxidant Therapy and Antioxidant-Related Bionanomaterials in Diabetic Wound Healing

Wenqian Zhang et al. Front Bioeng Biotechnol. .

Abstract

Ulcers are a lower-extremity complication of diabetes with high recurrence rates. Oxidative stress has been identified as a key factor in impaired diabetic wound healing. Hyperglycemia induces an accumulation of intracellular reactive oxygen species (ROS) and advanced glycation end products, activation of intracellular metabolic pathways, such as the polyol pathway, and PKC signaling leading to suppression of antioxidant enzymes and compounds. Excessive and uncontrolled oxidative stress impairs the function of cells involved in the wound healing process, resulting in chronic non-healing wounds. Given the central role of oxidative stress in the pathology of diabetic ulcers, we performed a comprehensive review on the mechanism of oxidative stress in diabetic wound healing, focusing on the progress of antioxidant therapeutics. We summarize the antioxidant therapies proposed in the past 5 years for use in diabetic wound healing, including Nrf2- and NFκB-pathway-related antioxidant therapy, vitamins, enzymes, hormones, medicinal plants, and biological materials.

Keywords: antioxidative therapy; bionanomaterials; diabetes mellitus; oxidative stress; wound healing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Nrf2 pathway and related antioxidant therapy. Nrf2 pathway and related antioxidant therapy. This figure shows the activation of the Nrf2 pathway and effects of antioxidant therapy targeting this pathway. Under unstressed conditions, Keap1 interacts with Nrf2 and the cell’s actin cytoskeleton to keep Nrf2 inactive in the cytoplasm and promote ubiquitination and degradation of Nrf2. Oxidative stress causes Nrf2 to detach from Keap1 and translocate to the nucleus where it heterodimerizes with Maf. The Nrf2-Maf heterodimer binds to ARE to induce the expression of antioxidant and metabolic genes including NQO1, MnSOD, HO-1, GCL, and GSTs. Oxidative stress can be regulated by activating the Nrf2 pathway. siKeap1 downregulates the levels of Keap1 by incorporating into an RNA-induced silencing complex (RISC) and inducing degradation of the complementary mRNA of Keap1. Nrf2 activators, such as SF, CA, DMF, RTA408 and genistein, stimulate the Nrf2 pathway and ameliorate oxidative stress.
FIGURE 2
FIGURE 2
NFκB pathway and related antioxidant therapy. NFκB pathway and related antioxidant therapy. This figure shows the activation of the NFκB pathway and the effects of antioxidant therapy targeting this pathway. In resting state, NFκB dimers form a complex with the inhibitory protein IκB, which is located in the cytoplasm. Inflammatory signals (such as TNF-α) induce phosphorylation of IκB through upstream kinases (IKK), resulting in the ubiquitination and degradation of IκB. Active NFκB translocates to the nucleus and activates target genes including TNF-α, IL-1β, IL-6, COX-2, iNOS, and NOX-2, resulting in oxidative stress and inflammation. Oxidative stress can be regulated by inhibiting the NFκB pathway. MiR-146a can target and repress tumor necrosis factor receptor-associated factor 6 (TRAF6), inhibiting the activation of IKK and the NFκB pathway. SIRT1 activators, such as resveratrol, berberine and SRT1720, suppress binding of NFκB to inflammation-related gene promoters and their transcriptional activities by activating SIRT1, a NAD-dependent class III histone deacetylase that leads to deacetylation of the p65 subunit.
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