A novel small molecule 1,2,3,4,6-penta-O-galloyl-α-D-glucopyranose mimics the antiplatelet actions of insulin.
A novel small molecule 1,2,3,4,6-penta-O-galloyl-α-D-glucopyranose mimics the antiplatelet actions of insulin.
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DOI：
10.1371/journal.pone.0026238
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Akbar H
中科院分区：
文献类型：
--
作者：
Perveen R;Funk K;Thuma J;Wulf Ridge S;Cao Y;Akkerman JW;Chen X;Akbar H
1，2，3，4，6-五-O-没食子酰基-α-D-吡喃葡萄糖（α-PGG）是一种口服降糖有效的小分子，它能与胰岛素受体结合并激活胰岛素介导的葡萄糖转运。胰岛素已被证明与血小板上的受体结合并抑制血小板活化。在这项研究中，我们测试了我们的假设，如果胰岛素具有抗血小板特性，那么胰岛素模拟小分子应该模仿胰岛素的抗血小板作用。人血小板与胰岛素或α-PGG孵育可诱导胰岛素受体和IRS-1的磷酸化，并阻断ADP或胶原诱导的聚集。用α-PGG预处理血小板可抑制凝血酶诱导的P-选择素释放、ATP分泌和聚集。加入ADP或凝血酶的血小板显着降低基础环AMP水平。用α-PGG预孵育血小板可阻断ADP或凝血酶诱导的血小板cAMP水平的降低，但不能改变基础或PGE 1诱导的cAMP水平的升高。在血小板阻断剂中加入α-PGG可诱导血小板胞浆钙升高和Akt磷酸化。给予野生型小鼠α-PGG（20 mg kg−1）可阻断ADP或胶原诱导的离体血小板聚集。这些数据表明，α-PGG至少部分通过诱导胰岛素受体磷酸化抑制血小板活化，从而抑制激动剂诱导的：（a）环AMP降低;（B）胞浆钙升高;和（c）Akt磷酸化。这些发现与我们早期关于α-PGG模拟胰岛素信号传导的报告一起表明，α-PGG抑制血小板活化模拟胰岛素的抗血小板作用。
We have shown that 1,2,3,4,6-penta-O-galloyl-α-D-glucopyranose (α-PGG), an orally effective hypoglycemic small molecule, binds to insulin receptors and activates insulin-mediated glucose transport. Insulin has been shown to bind to its receptors on platelets and inhibit platelet activation. In this study we tested our hypothesis that if insulin possesses anti-platelet properties then insulin mimetic small molecules should mimic antiplatelet actions of insulin. Incubation of human platelets with insulin or α-PGG induced phosphorylation of insulin receptors and IRS-1 and blocked ADP or collagen induced aggregation. Pre-treatment of platelets with α-PGG inhibited thrombin-induced release of P-selectin, secretion of ATP and aggregation. Addition of ADP or thrombin to platelets significantly decreased the basal cyclic AMP levels. Pre-incubation of platelets with α-PGG blocked ADP or thrombin induced decrease in platelet cyclic AMP levels but did not alter the basal or PGE1 induced increase in cAMP levels. Addition of α-PGG to platelets blocked agonist induced rise in platelet cytosolic calcium and phosphorylation of Akt. Administration of α-PGG (20 mg kg−1) to wild type mice blocked ex vivo platelet aggregation induced by ADP or collagen. These data suggest that α-PGG inhibits platelet activation, at least in part, by inducing phosphorylation of insulin receptors leading to inhibition of agonist induced: (a) decrease in cyclic AMP; (b) rise in cytosolic calcium; and (c) phosphorylation of Akt. These findings taken together with our earlier reports that α-PGG mimics insulin signaling suggest that inhibition of platelet activation by α-PGG mimics antiplatelet actions of insulin.
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影响因子：
4.8
作者：
Li, ZY;Zhang, GY;Du, XP
通讯作者：
Du, XP
影响因子：
4.8
作者：
Ferreira, IA;Eybrechts, KL;Akkerman, JWN
通讯作者：
Akkerman, JWN
DOI：
10.1016/s0006-291x(88)81000-3
发表时间：
1988-12-30
影响因子：
3.1
作者：
FALCON, C;PFLIEGLER, G;VERMYLEN, J
通讯作者：
VERMYLEN, J
影响因子：
20.3
作者：
Hers, Ingeborg
通讯作者：
Hers, Ingeborg
DOI：
10.1152/ajpheart.2001.280.4.h1480
发表时间：
2001-04-01
影响因子：
4.8
作者：
Li, Y;Woo, V;Bose, R
通讯作者：
Bose, R