Myricetin Protects Against High Glucose-Induced β-Cell Apoptosis by Attenuating Endoplasmic Reticulum Stress via Inactivation of Cyclin-Dependent Kinase 5

Abstract

Background Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and turnover. Recent studies support the view that cyclin-dependent kinase 5 (CDK5) plays a role in β-cell failure under hyperglycemic conditions. However, little is known about how CDK5 impair β-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 β-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 β-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 (Δψm) loss. Conclusion Myricetin protects the β-cells against HG-induced apoptosis by inhibiting ER stress, possibly through inactivation of CDK5 and consequent upregulation of PDX1 and SERCA2b.

CDK5: Key Regulator of Apoptosis and Cell Survival

“…CDK5 has also been demonstrated to play a role in the activity of dopamine-and cAMP-regulated neuronal phosphoprotein 32, which controls dopamine signaling in specific neurons in adult mice [68,86]. Lastly, in addition to the roles for CDK5 previously discussed, CDK5 function has also been implicated in many other cellular processes such as cell cycle control and gene regulation, cell survival and apoptosis, membrane dynamics, focal adhesion formation, intracellular trafficking, and glucose metabolism, overall demonstrating the varied and essential roles of CDK5 in proper cell function [1,33,36,68,69,87,88].…”

“…CDK5 has also been identified to play important roles in processes such as cell death and proliferation, angiogenesis, migration of epithelial and cancer cells, inflammation, myogenesis, glucose metabolism, and insulin secretion in non-neuronal cells [53,87,[89][90][91][92]. These studies have investigated CDK5 function in cells such as cells of hematopoietic lineage, HEK293, COS7, MEF, HCT116, HeLa, adipoctyes, pancreatic β cells, and many other non-neuronal cell types [53,91].…”

Myricetin bioactive effects: moving from preclinical evidence to potential clinical applications

“…Myricetin antidiabetic activity has been reported by several authors in the last few years and limited reports are also available on its anti-obesity activity but in this review, we focused on only its antidiabetic potential. Karunakaran et al [101] reported the in vitro effect of myricetin on high glucose-induced β-cell apoptosis, possibly via cyclin-dependent kinase 5 (CDK5) inhibition. Data revealed that myricetin (20 μM) significantly protect β-cells reducing apoptosis in INS-1 cells and rat islets that were incubated with glucose at the concentration of 30 mM for 24 and 48 h, respectively.…”

Oral DhHP-6 for the Treatment of Type 2 Diabetes Mellitus

“…The oxidative damage model of INS-1 cells was mainly induced by several inducers, such as high glucose [48,49], palmitic acid [50], and hydrogen peroxide [51,52]. In this study, we used H 2 O 2 as an oxidizing agent, which is commonly used to cause irreversible oxidative damage in various cell models [53].…”