Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5
Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5
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DOI：
10.4093/dmj.2018.0052
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发表时间：
2019-04-01
影响因子：
5.9
通讯作者：
Lee, In-Kyu
中科院分区：
文献类型：
--
作者：
Karunakaran, Udayakumar;Elumalai, Suma;Lee, In-Kyu
背景：慢性高血糖对胰腺β细胞功能和更新具有有害影响。最近的研究支持这样的观点，即细胞周期蛋白依赖性激酶5（CDK 5）在高血糖条件下的β细胞衰竭中起作用。然而，关于CDK 5如何损害β细胞功能知之甚少。杨梅素是一种天然黄酮类化合物，具有治疗2型糖尿病的潜力。本研究旨在探讨杨梅素对高糖诱导的胰岛β细胞凋亡的影响，并探讨杨梅素与CDK 5之间的关系。方法：将INS-1细胞和离体大鼠胰岛置于高糖（30 mM）条件下，观察杨梅素对高糖诱导的胰岛β细胞凋亡的影响。进行对接研究以验证杨梅苷和CDK 5之间的相互作用。通过实时逆转录聚合酶链反应和Western印迹分析测定内质网（ER）应激标志物的基因表达和蛋白水平。高糖诱导CDK 5活化，同时通过下调肌内质网钙ATP酶2b（SERCA 2b）基因表达诱导内质网应激，减少胰腺十二指肠同源盒1（PDX 1）的核积聚。导致β细胞凋亡。对接研究预测，杨梅素通过直接结合在ATP结合口袋中来抑制CDK 5活化。杨梅素可抵消HG引起的PDX 1和SERCA 2b水平的降低。结论：杨梅素通过抑制内质网应激，可能通过抑制CDK 5的失活，上调PDX 1和SERCA 2b的表达，从而保护胰岛β细胞免受HG诱导的凋亡。
Background: Chronic hyperglycemia has deleterious effects on pancreatic beta-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in beta-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair beta-cell function. Myricetin, a natural flavonoid, has therapeutic potential for the treatment of type 2 diabetes mellitus. In this study, we examined the effect of myricetin on high glucose (HG)-induced beta-cell apoptosis and explored the relationship between myricetin and CDK5.Methods: To address this question, we subjected INS-1 cells and isolated rat islets to HG conditions (30 mM) in the presence or absence of myricetin. Docking studies were conducted to validate the interaction between myricetin and CDK5. Gene expression and protein levels of endoplasmic reticulum (ER) stress markers were measured by real-time reverse transcription polymerase chain reaction and Western blot analysis.Results: Activation of CDK5 in response to HG coupled with the induction of ER stress via the down regulation of sarcoendoplasmic reticulum calcium ATPase 2b (SERCA2b) gene expression and reduced the nuclear accumulation of pancreatic duodenal homeobox 1 (PDX1) leads to beta-cell apoptosis. Docking study predicts that myricetin inhibit CDK5 activation by direct binding in the ATP-binding pocket. Myricetin counteracted the decrease in the levels of PDX1 and SERCA2b by HG. Moreover, myricetin attenuated HG-induced apoptosis in INS-1 cells and rat islets and reduce the mitochondrial dysfunction by decreasing reactive oxygen species production and mitochondrial membrane potential (Delta psi m) loss.Conclusion: Myricetin protects the beta-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.