Naringenin Impairs Two-Pore Channel 2 Activity And Inhibits VEGF-Induced Angiogenesis.
Naringenin Impairs Two-Pore Channel 2 Activity And Inhibits VEGF-Induced Angiogenesis.
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DOI：
10.1038/s41598-017-04974-1
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发表时间：
2017-07-11
影响因子：
4.6
通讯作者：
Carpaneto A
中科院分区：
文献类型：
--
作者：
Pafumi I;Festa M;Papacci F;Lagostena L;Giunta C;Gutla V;Cornara L;Favia A;Palombi F;Gambale F;Filippini A;Carpaneto A
我们的研究引入了天然的类黄酮柚皮素作为一种新型的细胞内通道抑制剂，双孔通道2 (TPC2)，在异种系统中，即缺乏内源性TPC2的拟南芥液泡中，电生理证据表明。鉴于TPC2对细胞内钙信号传导的控制，我们证明了柚皮素可以抑制受VEGF、组胺或NAADP-AM刺激的人内皮细胞的细胞内钙反应，而不影响ATP或Angiopoietin-1（阴性对照）。在已建立的体内模型中，我们进一步探讨了柚皮素对tpc2依赖性生物活性的影响。在体内模型中，植入小鼠体内的含有vegf的基质塞在柚皮素存在下无法血管化。总的来说，目前的数据表明，柚皮素对TPC2活性的抑制和对VEGF血管生成反应的抑制与细胞内钙信号通路受损有关。TPC2抑制正在成为一系列重要病理条件的关键治疗步骤，包括黑色素瘤、帕金森病和埃博拉病毒感染的进展和转移潜力。柚皮素作为tpc2介导的信号传导抑制剂的鉴定为这一研究领域的发展提供了一种新的和潜在的相关工具。
Our research introduces the natural flavonoid naringenin as a novel inhibitor of an emerging class of intracellular channels, Two-Pore Channel 2 (TPC2), as shown by electrophysiological evidence in a heterologous system, i.e. Arabidopsis vacuoles lacking endogenous TPCs. In view of the control exerted by TPC2 on intracellular calcium signaling, we demonstrated that naringenin dampens intracellular calcium responses of human endothelial cells stimulated with VEGF, histamine or NAADP-AM, but not with ATP or Angiopoietin-1 (negative controls). The ability of naringenin to impair TPC2-dependent biological activities was further explored in an established in vivo model, in which VEGF-containing matrigel plugs implanted in mice failed to be vascularized in the presence of naringenin. Overall, the present data suggest that naringenin inhibition of TPC2 activity and the observed inhibition of angiogenic response to VEGF are linked by impaired intracellular calcium signaling. TPC2 inhibition is emerging as a key therapeutic step in a range of important pathological conditions including the progression and metastatic potential of melanoma, Parkinson’s disease, and Ebola virus infection. The identification of naringenin as an inhibitor of TPC2-mediated signaling provides a novel and potentially relevant tool for the advancement of this field of research.
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影响因子：
4
作者：
Hockey LN;Kilpatrick BS;Eden ER;Lin-Moshier Y;Brailoiu GC;Brailoiu E;Futter CE;Schapira AH;Marchant JS;Patel S
通讯作者：
Patel S
影响因子：
64.8
作者：
Kintzer AF;Stroud RM
通讯作者：
Stroud RM
DOI：
10.1073/pnas.1406029111
发表时间：
2014-11-04
影响因子：
11.1
作者：
Favia, Annarita;Desideri, Marianna;Filippini, Antonio
通讯作者：
Filippini, Antonio
影响因子：
20.3
作者：
Esposito, Bianca;Gambara, Guido;Filippini, Antonio
通讯作者：
Filippini, Antonio
影响因子：
8
作者：
Boccaccio, Anna;Scholz-Starke, Joachim;Carpaneto, Armando
通讯作者：
Carpaneto, Armando