High-throughput screening and bioinformatic analysis to ascertain compounds that prevent saturated fatty acid-induced β-cell apoptosis.
High-throughput screening and bioinformatic analysis to ascertain compounds that prevent saturated fatty acid-induced β-cell apoptosis.
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DOI：
10.1016/j.bcp.2017.05.007
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发表时间：
2017-08-15
影响因子：
5.8
通讯作者：
Levine, Fred
中科院分区：
文献类型：
--
作者：
Lee, Seung-Hee;Cunha, Daniel;Piermarocchi, Carlo;Paternostro, Giovanni;Pinkerton, Anthony;Ladriere, Laurence;Marchetti, Piero;Eizirik, Decio L.;Cnop, Miriam;Levine, Fred
胰腺β细胞脂毒性是2型糖尿病发病机制的一个重要特征。为了研究脂肪酸导致β细胞死亡的机制并开发新的预防方法，在β细胞系INS1上进行了高通量筛选。这些细胞暴露在棕榈酸酯中以诱导细胞死亡，并确定了逆转棕榈酸酯诱导的细胞毒性的化合物。屏幕上的点击率通过越来越严格的测试漏斗进行分析，最终以棕榈酸酯处理的原始人类胰岛的研究结束。不在筛选文库中但通过生物信息学分析确定的MAP4K4抑制剂和内源性大麻素ANANDAME在抑制棕榈酸酯诱导的INS1细胞以及原代大鼠和人胰岛的凋亡方面是有效的。这些目标可以作为开发2型糖尿病治疗方法的起点。
Pancreatic β-cell lipotoxicity is a central feature of the pathogenesis of type 2 diabetes. To study the mechanism by which fatty acids cause β-cell death and develop novel approaches to prevent it, a high-throughput screen on the β-cell line INS1 was carried out. The cells were exposed to palmitate to induce cell death and compounds that reversed palmitate-induced cytotoxicity were ascertained. Hits from the screen were analyzed by an increasingly more stringent testing funnel, ending with studies on primary human islets treated with palmitate. MAP4K4 inhibitors, which were not part of the screening libraries but were ascertained by a bioinformatics analysis, and the endocannabinoid anandamide were effective at inhibiting palmitate-induced apoptosis in INS1 cells as well as primary rat and human islets. These targets could serve as the starting point for the development of therapeutics for type 2 diabetes.
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影响因子：
46.9
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通讯作者：
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影响因子：
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Eizirik, Decio L.
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Eizirik, Decio L.
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