The Effect Of Cordycepin On Pancreatic β Cells And Its Molecular Mechanism

Type 1 diabetes(type 1 diabetes mellitus,T1DM)is caused by the destruction of pancreatic β-cells,which is mianly mediated by the pancreatic infiltrating immune cells to trigger a progressive decrease of pancreatic β-cells and eventually the elevated blood glucose in the body.Epidemiological data in recent decades show that the incidence and lethality of T1 DM are increasing year by year,which has posed a major threat to public health.Cordycepin is the main active ingredient extracted from the traditional Chinese medicine Cordyceps sinensis,which shows various pharmacological effects such as anti-inflammation and antioxidation.There are few reports on the role of cordycepin in regulating blood glucose,and the mechanism of action is still unclear.In this study,the effects of cordycepin on pancreatic β-cells were investigated by CCK8,Celltox,flow cytometry and western immunoblotting.The main findings are as follows:1.In normal culture environment,cordycepin was able to concentration-dependently and time-dependently decrease the viability of pancreatic β-cell line MIN6 and increase apoptosis,but had no significant effect on the viability of primary islets.Inflammatory environment,endoplasmic reticulum stress,lipotoxicity and DNA damage are important factors in islet β-cell failure in T1 DM.In MIN6 cell line,cordycepin treatment exacerbated pro-inflammatory cytokine-induced apoptosis,and decreased palmitic acid,tunicamycin,and streptozotocin-induced apoptosis.In mouse primary islets,cordycepin had no significant effect on the viability of cells exposed to pro-inflammatory cytokines,tunicamycin,and palmitic acid,but was able to significantly reduce streptozotocin-induced cell apoptosis.2.The mechanism of cordycepin in reducing STZ-induced apoptosis of β cells.RNA-seq revealed that cordycepin mainly regulated the DNA repair signaling pathway.Western blotting results showed that cordycepin significantly reduced the expression ofγ-H2 AX,a marker of DNA damage.Cordycepin also upregulated the phosphorylation of ATM protein and AMPK protein,and the level of intracellular ROS levels.3.In the animal model of streptozotocin induced T1 DM,cordycepin intervention did not prevent the onset of T1 DM.Cordycepin intervention had no therapeutic effect in diabetic mice.Taken together,this study suggests that at the cellular level,cordycepin may inhibit the pro-apoptotic effect of STZ-induced DNA damage on islet β by suppressing γ-H2 AX protein expression and promoting ATM protein and AMPK phosphorylation.At the mice level,the role of cordycepin on in the pathogenesis of T1 DM still needs to be further explored.