Drynaria fortunei (kunze) J. Sm is a species of perennial overgrowth fern plants, and the dried root tuber, named Gusuibu in Chinese, has been widely used as a traditional Chinese material medica for thousand years. It has been reported to possess various biological activities in multiple experimental models. Naringin, a flavanone glycoside, and naringenin, the aglycone of naringin, have been considered as potential active ingredients in Drynaria fortunei (kunze) J. Sm. In the present study, our results showed that in a zebrafish model, treatment with Drynaria fortunei–derived extract (DE) or naringin did not affect the normal formation of the subintestinal veins (SIVs) compared to the control group. Interestingly, treatment with naringenin showed an inhibitory effect on SIVs formation in zebrafish embryos, which demonstrates its potential antiangiogenic activity. In a chemically-induced blood vessel loss model in zebrafish, we found that both DE and naringin exhibited remarkably pro-angiogenesis activity on the restoration of blood vessel loss. Real-time qPCR analysis was used to investigate the gene expression of angiogenic markers in the zebrafish experiments. The results showed that naringin significantly reversed VRI-induced down-regulation of flt1 mRNA expression, which encodes VEGFR-1, suggesting that naringin may promote angiogenesis via up-regulating the expression of flt1. In an in vitro study of cultured human umbilical vein endothelial cells (HUVECs), our results showed that naringin did not promote endothelial cell proliferation, but it obviously promoted HUVEC migration. Taken together, these results suggest that naringin and naringenin have differential angiogenesis activities where naringin, as a novel angiogenic agent, has the potential to be developed as a therapeutic agent for diseases associated with insufficient angiogenesis, such as ischemia heart disease

槲蕨是水龍骨科多年蔓生蕨類植物，它的乾燥根莖被作為中藥骨碎補已有悠久 的歷史，並且很多研究表明骨碎補具有多種生物活性。其中黃酮類化合物柚皮 苷和其苷元柚皮素都被認為是具有生物活性的黃酮類化合物。本研究結果表明， 在正常的斑馬魚模型中，骨碎補提取物和柚皮苷都不會影響斑馬魚胚胎的腸下 靜脈（SIVs）的發育，但柚皮素可以抑制腸下靜脈的形成，從而表明其可能具 有抑制血管新生的作用。而在內皮細胞生長因子受體酪氨酸激酶抑制劑（VRI） 誘導的血管損傷模型中，骨碎補提取物和柚皮苷都可以修復血管損傷，表現出 明顯的促血管新生的作用；通過實時定量螢光 PCR 檢測血管新生特徵基因的表 達，發現柚皮苷可以明顯的逆轉 VRI 引起的 flt1 的下調，表明柚皮苷可能是通 過上調血管內皮細胞生長因子受體 1（VEGFR-1）的表達，從而發揮促進血管新 生的作用。在人臍靜脈內皮細胞模型上，柚皮苷雖然不能促進細胞的增殖，但 可以促進細胞遷移，明顯的增加細胞遷移的距離。綜上所述，柚皮苷和柚皮素 對血管有不同的作用，其中柚皮苷作為一個新穎的活性成分，具有被開發的潛 力，用以治療血管新生不足的疾病，如缺血性心臟病。