Squamosamide Derivative FLZ Protects Pancreatic β-Cells from Glucotoxicity by Stimulating Akt-FOXO1 Pathway.
Squamosamide Derivative FLZ Protects Pancreatic β-Cells from Glucotoxicity by Stimulating Akt-FOXO1 Pathway.
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Squamosamide 衍生物 FLZ 通过刺激 Akt-FOXO1 途径保护胰腺 β 细胞免受糖毒性
DOI：
10.1155/2015/803986
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发表时间：
2015
影响因子：
4.3
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Kong X;Zhang L;Hua X;Ma X
慢性高血糖增加细胞凋亡，减少葡萄糖刺激的胰岛素分泌。虽然保护剂已被广泛搜索，但迄今尚未发现。在这里，我们测试了FLZ，一种从中草药中合成的squamosamide衍生物，作为INS-1 E细胞和小鼠胰岛中抗葡萄糖毒性的潜在候选物。β细胞在30 mM葡萄糖中的慢性培养导致细胞活力进行性降低，伴有细胞凋亡增加和胰岛素分泌减少。FLZ以剂量依赖性方式逆转这些对细胞凋亡和胰岛素的影响。FLZ治疗也增加了叉头盒O 1蛋白磷酸化，减少其核定位。相反，FLZ增加胰腺和十二指肠同源框-1的表达及其核定位，增加p-Akt介导的效果。Akt选择性抑制剂MK-2206可完全阻断FLZ的抗糖毒性作用。此外，FLZ治疗增加胞浆ATP/ADP比值。综上所述，我们的结果表明FLZ可能是一种潜在的治疗药物，以治疗高血糖诱导的β细胞衰竭。
Chronic hyperglycemia increases apoptosis and reduces glucose-stimulated insulin secretion. Although protective agents have been searched extensively, none has been found so far. Here we tested FLZ, a synthetic derivative of squamosamide from a Chinese herb, as a potential candidate for antiglucotoxicity in INS-1E cells and mouse islets. Chronic culture of β-cells in 30 mM glucose caused progressive reduction of cell viability, accompanied with increased apoptosis and reduced insulin secretion. These effects on apoptosis and insulin were reversed by FLZ in a dose-dependent manner. FLZ treatment also increased forkhead box O1 protein phosphorylation and reduced its nuclear location. On the contrary, FLZ increased pancreatic and duodenal homeobox-1 expression and its nuclear localization, an effect mediated by increased p-Akt. Consistently, Akt selective inhibitor MK-2206 completely abolished antiglucotoxicity effect of FLZ. Furthermore, FLZ treatment increased cytosolic ATP/ADP ratio. Taken together, our results suggest that FLZ could be a potential therapeutic agent to treat the hyperglycemia-induced β-cell failure.
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影响因子：
8.2
作者：
Kluth, O.;Mirhashemi, F.;Scherneck, S.;Kaiser, D.;Kluge, R.;Neschen, S.;Joost, H. -G.;Schuermann, A.
通讯作者：
Schuermann, A.
影响因子：
--
作者：
Lim, Sangbin;Rashid, Md Abdur;Kim, Sung Soo
通讯作者：
Kim, Sung Soo
影响因子：
2.9
作者：
Bao, Xiu-Qi;Kong, Xiang-Chen;Zhang, Dan
通讯作者：
Zhang, Dan
影响因子：
4.1
作者：
Hou, Zhi-Qiang;Li, Hong-Liang;Li, Guang-Wei
通讯作者：
Li, Guang-Wei
影响因子：
7.7
作者：
Park, Keun-Gyu;Lee, Kyeong-Min;Lee, In-Kyu
通讯作者：
Lee, In-Kyu