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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Pflugers+Arch
2016 ; 468
(11-12
): 1957-1968
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Ciclopirox enhances pancreatic islet health by modulating the unfolded protein
response in diabetes
#MMPMID27757583
Mihailidou C
; Chatzistamou I
; Papavassiliou AG
; Kiaris H
Pflugers Arch
2016[Nov]; 468
(11-12
): 1957-1968
PMID27757583
show ga
Pancreatic dysfunction during diabetes is linked to the induction of endoplasmic
reticulum (ER) stress on pancreatic beta (?) cells. Our laboratory recently
discovered that p21 protects from diabetes by modifying the outcome of ER stress
response. In the present study, we explored the antidiabetic activity of
ciclopirox (CPX), an iron chelator and recently described activator of p21
expression. The effects of CPX in beta cell survival and function were assessed
in cultured islets in vitro as well as in diabetic mice in vivo. The consequences
of CPX in high glucose-induced insulin release and reactive oxygen species (ROS)
production were also evaluated. Islet survival assays confirmed the significance
of p21 in the regulation of glucotoxicity and suggested that CPX counteracts
glucotoxicity in a manner that depends on p21. In vivo, administration of CPX in
wild-type (WT) diabetic mice restored glucose homeostasis. In WT-cultured islets,
CPX suppressed the expression of ER stress markers BiP, GRP94, and CHOP and
reduced the levels of ROS during culture at high glucose. This reduction of ER
stress may be associated with the ability of CPX to inhibit insulin release. Iron
citrate stimulated insulin release, which was inhibited by CPX that functions as
an iron chelator. It is conceivable that inhibition of insulin production
constrains ER stress in islets promoting their survival and thus protecting from
diabetes in vivo. This unfolded protein response (UPR)-antagonizing activity of
CPX suggests application for the management not only of diabetes but also of
other conditions related to ER stress.
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