The cystine-knot miniproteins (TCMPs) present in tomato fruit and tomato-based products have been shown to exert anti-angiogenic effects by inhibiting in vitro endothelial cell migration. The bioavailability and the potential anti-angiogenic effects of TCMPs were investigated in vivo using the zebrafish as animal model. TCMP purified from tomato fruit was administered to zebrafish embryos assaying changes in vessel development. TCMP at 500 nM inhibited the formation of subintestinal vessels in zebrafish, a process susceptible to the activity of antiangiogenic compounds. To explore the potential of TCMPs for oral administration, we investigated the effects of in vitro gastrointestinal digestion of TCMPs extracted from tomato fruit and tomato paste demonstrating that are resistant to proteolysis. To quantify the intestinal transport of TCMPs we used the differentiated Caco-2 cells model. After 24h incubation, 37.73 ± 9.34% of TCMPs crossed the epithelium, without altering the integrity of the cell layer. In conclusion, we show that the gastrointestinal process does not alter the in vivo biological activities of TCMPs, making them a good candidates for further drug development.
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