Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic ß cells.

BACKGROUND: Pancreatic ß cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying ß cell failure is important to develop ß cell protective approaches. SCOPE OF REVIEW: Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in ß cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in ß cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human ß cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into ß cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in ß cells. MAJOR CONCLUSIONS: Pancreatic ß cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.

Comparative study of cholic acid compounds of bezoar on anti-cerebral infarction and regulating endoplasmic reticulum stress / 药物评价研究

Objective Using middle cerebral artery occlusion (MCAO) model to observe protective effect of effective components of bezoar on brain damage.To discuss the anti-cerebral ischemia mechanism and compare the efficacy of effective components of bezoar from the endoplasmic reticulum stress intervention angle.Methods Rats were stratified randomly divided into sham group,model group,Qingkailing group (positive drug,3 mL/kg),taurine group,ursodeoxycholic acid (UDCA,78 mg/kg) group,taurine-conjugated ursodeoxycholic acid (TUDCA,100 mg/kg) group.Through establish MCAO model in rats,observed the scores of the neurologic impairment,measured infarct volume by TTC.Immunohistochemistry and Western blotting were Used to detect the content of P-PERK,P-EIF2α,and ATF4.Results Compared with sham group,neurologic impairment scores of model group significantly reduced (P ＜ 0.01).Compared with model group,Qingkailing group,UDCA group,and TUDCA group significantly improved neurological function in rats (P ＜ 0.05,0.01).Compared model group,all the treatment groups could significantly reduce the volume of cerebral infarction (P ＜ 0.01).Compared with sham group,expression of P-PERK,P-EIF2α,and ATF4 was significantly increased (P ＜ 0.01).Compared with model group,all the treatment groups reduced the expression of P-PERK,P-EIF2α,and ATF4 in varying degrees,effect of Qingkailing and TUDCA were more obvious.Conclusion The effective components ofbezoar alleviate cerebral ischemia reperfusion injury in rats by inhibiting endoplasmic reticulum stress,the effect of TUDCA is better than that of taurine and UDCA.