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Evaluation of novel epoxy-tigliane compounds as modulators of dermal fibroblast-myofibroblast differentiation, scar tissue resolution and fibrosis; and elucidation of their underlying mechanisms of action

Dally, Jordanna 2018. Evaluation of novel epoxy-tigliane compounds as modulators of dermal fibroblast-myofibroblast differentiation, scar tissue resolution and fibrosis; and elucidation of their underlying mechanisms of action. PhD Thesis, Cardiff University.
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Abstract

EBC-46 and EBC-211 are novel epoxy-tiglianes found to occur naturally within seeds of the Fontain’s Blushwood Tree, indigenous to the Queensland tropical rainforest in Australia. The Australian biotechnology company, QBiotics Group, has demonstrated that EBC-46 stimulates enhanced dermal wound healing responses in vivo, following cancer treatment and tumour destruction in domesticated animals. Consequently, QBiotics is developing EBC-46 as both a human and veterinary anti-cancer therapy. However, little is known on how the epoxy-tiglianes induce their exceptional healing effects; manifested as rapid wound re-epithelialisation, wound contraction/closure and minimal scarring. This study aimed to determine how EBC-46 and EBC-211 mediate these exceptional wound healing effects in vitro, via analysis of dermal fibroblast (DF)/myofibroblast genotypic and phenotypic responses; following epoxy-tigliane treatment (0.001 - 10 μg/mL). A number of wound healing responses were assessed, such as transforming growth factor-β1 (TGF-β1)-driven DF-myofibroblast differentiation, extracellular matrix (ECM) synthesis/turnover, global gene expression and underlying signalling pathways. Studies exhibited that EBC-46 and EBC-211 significantly inhibited α-smooth muscle actin (αSMA) expression, stress fibre formation and myofibroblast formation at 0.1 μg/mL and 10 μg/mL, respectively. Such concentrations were also shown to reduce type I/III collagen; and up-regulate matrix metalloproteinase-1 (MMP-1) gene and protein levels. The epoxy-tiglianes also increased elastin, hyaluronan and pericellular coat synthesis, via up-regulated hyaluronan synthase (HAS) expression. Microarray analysis and protein level validation identified numerous differentially expressed genes in epoxy-tigliane-treated DFs. Up-regulated genes included proteinases and other ‘anti-fibrotic’ genes; while down-regulated genes included protease inhibitors, myofibroblast- and cytoskeletal-related genes; as well as other ‘pro-fibrotic’ genes. Inhibitory effects upon TGF-β1-driven, DF-myofibroblast differentiation were shown to be protein kinase C (PKC)-dependent. This study has provided evidence to explain the reduced scarring responses observed in epoxy-tigliane-treated skin; highlighting the potential of epoxy-tiglianes as novel therapeutics for excessive scarring situations.

Item Type: Thesis (PhD)
Date Type: Submission
Status: Unpublished
Schools: Dentistry
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: skin; fibrosis; QBiotics; fibroblasts; differentiation; myofibroblasts; wound healing; epoxy-tiglianes
Date of First Compliant Deposit: 6 March 2019
Last Modified: 06 Mar 2019 15:49
URI: http://orca.cf.ac.uk/id/eprint/120278

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