Apratyramide, a Marine-Derived Peptidic Stimulator of VEGF-A and Other Growth Factors with Potential Application in Wound Healing

Abstract

A novel linear depsipeptide enriched with tyrosine-derived moieties, termed apratyramide, was isolated from an apratoxin-producing cyanobacterium. The structure was determined using a combination of NMR spectroscopy, mass spectrometry, and chiral analysis of the acid hydrolyzate and confirmed by total synthesis. Apratyramide up-regulated multiple growth factors at the transcript level in human keratinocyte (HaCaT) cells and induced the secretion of vascular endothelial growth factor A (VEGF-A) from HaCaT cells, suggesting the compound's potential wound-healing properties through growth factor induction. Transcriptome analysis and sequential validation supported the hypothesis and indicated its mode of action (MOA) through the unfolded protein response (UPR) pathway, which is functionally related to wound healing and angiogenesis. The conditioned medium of HaCaT cells treated with apratyramide induced angiogenesis in vitro. An ex vivo rabbit corneal epithelial model was applied to confirm the VEGF-A induction in this wound-healing model.

Applying a Chemogeographic Strategy for Natural Product Discovery from the Marine Cyanobacterium Moorena bouillonii

“…genomes, on average [ 8 , 9 , 10 ]. Consistent with this finding, some 70 different isolated and structurally defined compounds have been reported from M. bouillonii ( Table S1 ) [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. These display a broad structural diversity, and include peptides [ 41 ], cyclodepsipeptides [ 16 ], macrolides [ 12 ] and glycosidic macrolides [ 35 ], and lipids [ 43 ].…”

“…M. bouillonii has a wide distribution across the tropical Western Pacific and Indian Oceans. However, M. bouillonii metabolites have only been described from collections made from a limited number of discrete locations, including Papua New Guinea [ 14 , 19 , 23 , 25 , 28 , 33 , 34 , 35 , 39 , 41 , 43 ], Guam [ 11 , 12 , 15 , 16 , 18 , 20 , 22 , 24 , 29 , 36 , 37 , 42 ], Palau [ 11 , 18 , 38 , 40 , 44 ], Malaysia [ 26 , 27 ], Palmyra Atoll [ 13 , 21 ], Fiji [ 31 ] (The organism in this manuscript is reported as M. producens , however the manuscript includes a photo of the organism, which displays a morphology characteristic of shrimp-woven M. bouillonii . The 16S rRNA gene-based classification was inconclusive and known compounds previously isolated from M. bouillonii were reported.…”

“…Orthogonally, it has become a common strategy to look in underexplored geographical locations in order to find new and unique natural products. This has led natural products discovery efforts to interesting and exotic habitats, including tropical coral reefs [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], hypersaline lakes [ 54 ], the Arctic [ 55 ] and Antarctic [ 56 ], hydrothermal vents [ 57 ], and the deep sea [ 58 ]. In spite of the acknowledgement that sampling in new geographical locations can allow access to new natural products, there are few examples of systematically applying geographical knowledge in order to inform natural product discovery.…”

VEGF-A Inhibition as a Potential Therapeutic Approach in Merkel Cell Carcinoma

“…In accordance with our previous results, VEGF-A expression was detected at the RNA and protein levels in all investigated MCC cell lines and in supernatants ( Figure 1def), thereby confirming VEGF-A production by MCC tumor cells. Notably, VEGF-A expression was generally higher than in HaCaT cells (see Supplementary Figure S1 online), an established VEGF-Aeexpressing cell culture system (Cai et al, 2018).…”

Figure 2: The HE staining images of burned rat tissue.

“…Chemokines interact with inflammatory factors such as TNF-α and IL-1 to induce VEGF and PDGF in wound keratinocytes and macrophages (Larouche et al, 2018;Ridiandries, Tan & Bursill, 2018;Thomas & Apovian, 2017). VEGF can specifically act on vascular endothelial cells, and has the function of maintaining vascular integrity, improving vascular permeability, and promoting angiogenesis (Cai et al, 2017;Komi, Khomtchouk & Santa Maria, 2020).…”