Wound Healing Effect of Gintonin Involves Lysophosphatidic Acid Receptor/Vascular Endothelial Growth Factor Signaling Pathway in Keratinocytes

Abstract

Gintonin, a novel compound of ginseng, is a ligand of the lysophosphatidic acid (LPA) receptor. The in vitro and in vivo skin wound healing effects of gintonin remain unknown. Therefore, the objective of this study was to investigate the effects of gintonin on wound healing-linked responses, especially migration and proliferation, in skin keratinocytes HaCaT. In this study, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay, Boyden chamber migration assay, scratch wound healing assay, and Western blot assay were performed. A tail wound mouse model was used for the in vivo test. Gintonin increased proliferation, migration, and scratch closure in HaCaT cells. It also increased the release of vascular endothelial growth factor (VEGF) in HaCaT cells. However, these increases, induced by gintonin, were markedly blocked by treatment with Ki16425, an LPA inhibitor, PD98059, an ERK inhibitor, 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester), a calcium chelator, and U73122, a PLC inhibitor. The VEGF receptor inhibitor axitinib also attenuated gintonin-enhanced HaCaT cell proliferation. Gintonin increased the phosphorylation of AKT and ERK1/2 in HaCaT cells. In addition, gintonin improved tail wound healing in mice. These results indicate that gintonin may promote wound healing through LPA receptor activation and/or VEGF release-mediated downstream signaling pathways. Thus, gintonin could be a beneficial substance to facilitate skin wound healing.

Gintonin Isolated from Ginseng Inhibits the Epithelial—Mesenchymal Transition Induced by TGF-β in A549 Lung Cancer Cells

“…The expression of Vim is induced by TGF-β1 activation, Snail expression, and ERK phosphorylation [ 26 ]. The suppression of Vim and N-cad not only reduces motility during cancer metastasis, but also partially restores the epithelial cell phenotype in numerous cancer cell lines [ 23 , 26 ]. Therefore, GT can successfully suppress EM transition, preventing cancer cell migration and invasion.…”

“…The GT-enriched fraction of P. ginseng was prepared following our previous protocols [ 14 , 23 ]. Four-year-old ginseng was extracted using ethanol (yield: 35%).…”

“…Ethanol extraction and centrifugation were performed, followed by lyophilization of the precipitate to produce the GT-enriched fraction. Our previous study identified the GT-enriched fraction as containing fatty acids (7.53% linoleic acid, 2.82% palmitic acid, and 1.46% oleic acid), 0.6% lysophospholipids and phospholipids, and 1.75% phosphatidic acids, as determined using liquid chromatography–mass spectrometry/mass spectrometry [ 14 , 23 , 31 ]. The GT-enriched fraction was dissolved in dimethyl sulfoxide (DMSO) for further analysis and diluted with media before treatment in A549 cells.…”

“…GT exhibits various health benefits, such as anti-Alzheimer’s disease effects, through the LPA receptor-mediated non-amyloidogenic pathway [ 17 ]. GT also improves cognitive function in older patients with Alzheimer’s disease [ 18 , 19 ], increases hippocampal neurogenesis [ 20 ], possesses anti-depressant activity [ 21 ], exerts in vivo anti-metastatic effects [ 22 ], and protects against cardiovascular diseases [ 23 ]. However, to the best of our knowledge, detailed studies on the inhibition of the intracellular signaling pathway of cancer metastasis by GT have yet to be performed.…”

Extraction Optimization, Characterization and Biological Activities of Polysaccharide Extracts from Nymphaea hybrid

“…The rate of cell migration is a crucial determinant in skin wound healing. Hen investigating factors that influence epidermal keratinocyte and dermal fibrob migration may help develop targeted therapies to improve cutaneous wound healing [ Figure 11 presents the percentage of cell viability and migration rate for NHE as a ratio the untreated control [72]. The microscopic images depicting the wound gap closure a 0, 24 and 48 h treatment with NHE are shown in Figure 12A-C, respectively.…”