Abstract
BackgroundCutaneous wound healing is a complex process involving several signaling pathways such as the Wnt and extracellular signal-regulated kinase (ERK) signaling pathways. Valproic acid (VPA) is a commonly used antiepileptic drug that acts on these signaling pathways; however, the effect of VPA on cutaneous wound healing is unknown.Methods and FindingsWe created full-thickness wounds on the backs of C3H mice and then applied VPA. After 7 d, we observed marked healing and reduced wound size in VPA-treated mice. In the neo-epidermis of the wounds, β-catenin and markers for keratinocyte terminal differentiation were increased after VPA treatment. In addition, α-smooth muscle actin (α-SMA), collagen I and collagen III in the wounds were significantly increased. VPA induced proliferation and suppressed apoptosis of cells in the wounds, as determined by Ki67 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining analyses, respectively. In vitro, VPA enhanced the motility of HaCaT keratinocytes by activating Wnt/β-catenin, ERK and phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathways.ConclusionsVPA enhances cutaneous wound healing in a murine model and induces migration of HaCaT keratinocytes.
Highlights
Cutaneous wound healing is a complex and dynamic process involving soluble mediators, blood cells, extracellular matrix, and parenchymal cells [1]
We investigated the activation status of the Wnt/b-catenin signaling pathway during the wound healing process in a murine model to characterize the role of this pathway in cutaneous wound healing
We created full-thickness wounds on the backs of mice and monitored levels of b-catenin and wound healing markers. b-Catenin was highly expressed in epidermal keratinocytes and dermal fibroblasts at 7 and 10 d after wounding (Figure 1A)
Summary
Cutaneous wound healing is a complex and dynamic process involving soluble mediators, blood cells, extracellular matrix, and parenchymal cells [1]. Wnt signaling pathway plays important roles in development, organogenesis and normal homeostasis [8,9,10]. This pathway is divided into canonical b-catenin-dependent signaling and noncanonical b-catenin-independent signaling pathways [11], both of which are involved in wound healing [5]. In the canonical Wnt signaling pathway, which is often called Wnt/b-catenin pathway, b-catenin is elevated during the proliferative phase of wound healing [12,13] and regulates mesenchymal cell proliferation, motility, and invasiveness in normal and hyperplastic cutaneous wounds [14]. Cutaneous wound healing is a complex process involving several signaling pathways such as the Wnt and extracellular signal-regulated kinase (ERK) signaling pathways. Valproic acid (VPA) is a commonly used antiepileptic drug that acts on these signaling pathways; the effect of VPA on cutaneous wound healing is unknown
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