Wound Healing Effect of HDACi Repositioned Molecules in the Therapy for Chronic Wounds Models

Abstract

Globally, chronic wounds impact the health of millions of people, negatively affecting quality of life and healthcare budgets. Some of the crucial steps and pathways in healing mechanisms are the hypoxic response and the expression of host defence peptides, which are decreased in diseases related to chronic wounds such as diabetes mellitus and cardiovascular diseases. It has been shown that histone deacetylase inhibitors can induce the expression of Host Defence Peptides (HDP) by inducing the stabilisation and activation of hypoxia-inducible factor 1-α (HIF-1α), promoting wound healing pathways, although their high cost and side effects limit clinical research. With the help of bioinformatics tools, we found potential histone deacetylase inhibitor candidates in an FDA-approved drugs database. The candidates, 1,3-Diphenylurea (DiPU), 2'-Aminoacetanilide (Ace), and Tert-butyl (2-aminophenyl) carbamate (N-boc), show wound healing effects in HaCaT cells, increasing cell migration possibly via HIF-1α, inducing the expression of LL-37 and vascular endothelial growth factor (VEGF), while in a mouse ring angiogenesis model, Ace and N-boc have angiogenic effects. In a model of basal primary keratinocytes from donors with diabetes mellitus (DM), without DM, and from Diabetic Foot Ulcers (DFU), it was observed that only DiPU is capable of inducing LL-37 in all scenarios. There is limited information about histone deacetylase inhibitors and wound healing but in this paper, we observe promising results and a proposed mechanism that involved specifically Histone Deacetylase 1 inhibition (HDAC1).