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Selenadiazole derivatives reverse islet amyloid polypeptide-induced beta cell apoptosis through inhibition of fibril formation
Yi Wang 1,XiaoLing Li 2,LiJuan Ma 2,Yi Luo 2,WenJie Zheng* 2,Wong Yum-Shing 3,Tianfeng Chen* 2 * #
1.Department of Chemistry, Jinan University, GuangZhou 510632
2.Department of Chemistry, Jinan University, Guangzhou 510632, China
3.School of Life Sciences and State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong S.A.R., China
*Correspondence author
#Submitted by
Subject:
Funding: none
Opened online:22 April 2013
Accepted by: none
Citation: Yi Wang,XiaoLing Li,LiJuan Ma.Selenadiazole derivatives reverse islet amyloid polypeptide-induced beta cell apoptosis through inhibition of fibril formation[OL]. [22 April 2013] http://en.paper.edu.cn/en_releasepaper/content/4537976
 
 
Islet amyloid deposition misfolded by human islet amyloid polypeptide (hIAPP) could induce pancreatic β cell dysfunction, and finally resulting in cell apoptosis. Many studies have showed that inhibition of hIAPP aggregation could effectively reverse the β cell apoptosis. Therefore, hIAPP could be a good target for the therapeutics of type 2 diabetics. In the present study, we found that selenadiazole derivatives 1,2,5]selenadiazolo[3,4-d]pyrimidine-5,7- diamine (SePD) acted as an effective inhibitor of hIAPP fibril formation. ThT flourescent assay showed that SePD inhibited the formation of hIAPP fibrils dose-dependently. Kinetic and dose effects of hIAPP oligomer growth by TEM images indicated the inhibition of hIAPP fibrillation and generation of oligomer induced by SePD. The fibril-like structure stringed by oligomers could be distinguished from the virgin fibril. AFM images revealed that the difference in dose was directly linked to the changes of the conformational behavior of the peptide. Biological studies were conducted to investigate the in vitro protective effects of SePD on INS-1E rat insulinoma beta cells against hIAPP-induced cell death, as well as the underlying mechanisms. The results showed that, SePD blocked the hIAPP-induced apoptosis by suppression of caspase activation, mitochondrial dysfunction and ROS overproduction. These results support the potential therapeutic role of SePD in type II diabetes by preventing hIAPP-induced loss of pancreatic beta cells.
Keywords:Selenadiazole derivatives; Iislet amyloid polypeptide; Beta cells; Apoptosis; Fibril formation
 
 
 

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