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A random-pattern skin flap plays an important role in the field of wound repair; the mechanisms that influence the survival of random-pattern skin flaps have been extensively studied but little attention has been paid to endogenous counterinjury substances and mechanism. Previous reports reveal that the apelin-APJ axis is an endogenous counterinjury mechanism that has considerable function in protecting against infection, inflammation, oxidative stress, necrosis, and apoptosis in various organs. As an in vivo study, our study proved that the apelin/APJ axis protected the skin flap by alleviating vascular oxidative stress and the apelin/APJ axis works as an antioxidant stress factor dependent on CaMKK/AMPK/GSK3 β signaling. In addition, the apelin/APJ-manipulated CaMKK/AMPK/GSK3 β -dependent mechanism improves HUVECs' resistance to oxygen and glucose deprivation/reperfusion (OGD/R), reduces ROS production and accumulation, maintained the normal mitochondrial membrane potential, and suppresses oxidative stress in vitro. Besides, activation of the apelin/APJ axis promotes vascular migration and angiogenesis under relative hypoxia condition through CaMKK/AMPK/GSK3 β signaling. In a word, we provide new evidence that the apelin/APJ axis is an effective antioxidant and can significantly improve the vitality of random flaps, so it has potential be a promising clinical treatment., Competing Interests: The authors have no conflicts of interest., (Copyright © 2021 Zhi-Ling Lou et al.)

Hypertrophic scars are fibroproliferative disorders of excessive wound healing due to an imbalance between synthesis and degradation and the mechanism leading to hypertrophic scars formation is poorly understood and currently no successful treatment modality exists. We hypothesize epidermal stem cells (ESCs), which could inhibit epidermal fibrosis, plays a substantial contributory role in the pathogenesis of hypertrophic scars. Accepting the hypothesis to be correct, a therapy that inhibits cell and extracellular matrix proliferation can be used to prevent the hypertrophic scars formation. Current therapies are only partially effective and safe because they couldn't inhibit the cell and extracellular matrix proliferation and eliminate other relative factors of hypertrophic scars formation at all, such as: absence of epidermal-mesenchymal interaction, and at the same time inducing death (apoptosis and necrosis) of other normal cells. A more efficient prevention of hypertrophic scars could be achieved using tissue engineering skin enriched with ESCs and introduced recombinant genes into ESCs which could inhibit hypertrophic scars formation.

The proliferation of human skin dermal fibroblasts (HDFs) is a critical step in skin fibrosis, and transforming growth factor-beta1 (TGF-β1) exerts pro-oxidant and fibrogenic effects on HDFs. In addition, the oxidative stress system has been implicated in the pathogenesis of skin disease. However, the role of NADPH oxidase as a mediator of TGF-β1-induced effects in HDFs remains unknown. Thus, our aim was to investigate the role of NADPH in human skin dermal fibroblasts. Primary fibroblasts were cultured and pretreated with various stimulants. Real-time Q-PCR and Western blotting analyses were used for mRNA and protein detection. In addition, siRNA technology was applied for gene knock-down analysis. Hydrogen peroxide production and 20,70- dichlorofluorescein diacetate (DCFDA) measurement assay were performed. Here, our findings demonstrated that HDFs express key components of non-phagocytic NADPH oxidase mRNA. TGFβ1 induced NOX2 and reactive oxygen species formation via NADPH oxidase activity. In contrast, NOX3 was barely detectable, and other NOXs did not display significant changes. In addition, TGF-β1 phosphorylated MAPKs and increased activator protein-1 (AP-1) in a redox-sensitive manner, and NOX2 suppression inhibited baseline and TGF-β1-mediated stimulation of Smad2 phosphorylation. Moreover, TGF-β1 stimulated cell proliferation, migration, collagen I and fibronectin expression, and bFGF and PAI-1 secretion: these effects were attenuated by diphenylene iodonium (DPI), an NADPH oxidase inhibitor, and NOX2 siRNA. Importantly, NOX2 siRNA suppresses collagen production in primary keloid dermal fibroblasts. These findings provide the proof of concept for NADPH oxidase as a potential target for the treatment of skin fibrosis. [ABSTRACT FROM AUTHOR]