Abstract
Natural products are a rich resource for the discovery of therapeutic substances. By directly using 504 fine fractions from isolated traditional Chinese medicine plants, we performed a transgenic zebrafish based screen for anti-angiogenesis substances. One fraction, DYVE-D3, was found to inhibit the growth of intersegmental vessels in the zebrafish vasculature. Bioassay-guided isolation of DYVE-D3 indicates that the flavonoid kaempferol was the active substance. Kaempferol also inhibited the proliferation and migration of HUVECs in vitro. Furthermore, we found that kaempferol suppressed angiogenesis through inhibiting VEGFR2 expression, which can be enhanced by FGF inhibition. In summary, this study shows that the construction of fine fraction libraries allows efficient identification of active substances from natural products.
Highlights
To overcome the above disadvantages, we developed an alternative strategy beginning with the fine fractionation of the natural products
We performed a pilot screen of 504 fractions on a transgenic zebrafish model to test the utility of the traditional Chinese medicine (TCM) library
Modern phytochemical studies on D. versipellis show that a series of lignans, especially aryl-tetralin lignan podophyllotoxin, are the representative substances[28]
Summary
To overcome the above disadvantages, we developed an alternative strategy beginning with the fine fractionation of the natural products. The vascular intersegmental vessels (ISVs) have a stereotyped pattern and are well suited for angiogenic assays This pattern can be directly visualized using the endothelial cell specific transgenic zebrafish line Tg(kdrl:GRCFP)zn[1] in which GFP is under the control of vascular endothelial growth factor receptor 2 (VEGFR2, known as kdrl or flk, Entrez Gene ID: 796537) promoter[10]. Utilizing this line allows for a quick, easy, and continuous observation of the vasculature in live embryos under a fluorescence microscope. We show that kaempferol inhibits the proliferation and migration of vascular endothelial cells through the suppression of VEGF and FGF signalling pathways
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