Novel epoxy-tiglianes stimulate keratinocyte wound healing responses and re-epithelialization via protein kinase C activation

ABSTRACT: Impaired re-epithelialization is a hallmark of non-healing, chronic skin wounds. These represent major causes of patient morbidity, particularly amongst ever-increasing ageing and diabetic populations, posing significant challenges to healthcare providers worldwide. Despite many treatment options being available, these often offer limited benefits to healing outcomes. We address the need for more efficacious treatments through evaluation of novel epoxy-tigliane compounds as chronic wound pharmaceuticals, based on their effectiveness in promoting keratinocyte healing responses and re-epithelialization in vivo. Here, we identify that prototype epoxy-tigliane (EBC-46) and analogue (EBC-211), accelerate G1/S and S/G2 cell cycle transitions and proliferation in a normal human keratinocyte cell line of skin origin (HaCaTs). EBC-46 and EBC-211 further induce HaCaT migration/wound repopulation, even with mitomycin C treatment, suggesting epoxy-tiglianes can promote migration/repopulation independently of proliferation. Epoxy-tiglianes modulate keratin, DNA synthesis/replication, cell cycle/proliferation, motility/migration, differentiation, proteinase; and cytokine/chemokine gene expression, to facilitate enhanced responses. Although epoxy-tiglianes down-regulate cytokine/chemokine agonists of keratinocyte proliferation/migration, we demonstrate that enhanced HaCaT responses are mediated through protein kinase C (PKC) phosphorylation and abrogated by inhibition of PKC activation with bisindolylmaleimide-1 (BIM-1). By identifying how epoxy-tiglianes stimulate keratinocyte healing responses, we highlight their potential as novel therapeutics for impaired re-epithelialization associated with non-healing, chronic wounds.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122297 | GEO | 2019/08/01

REPOSITORIES: GEO