Novel inhibitors of macrophage migration inhibitory factor prevent cytokine-induced beta cell death
2014
Аутори:
Vujičić, MilicaNikolić, Ivana
Krajnović, Tamara
Cheng, Kai-Fan
VanPatten, Sonya
He, Mingzhu
Stošić-Grujičić, Stanislava
Stojanović, Ivana D.
Al-Abed, Yousef
Saksida, Tamara
Тип документа:
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт:
Macrophage migration inhibitory factor is a multifunctional cytokine
involved in the regulation of immune processes and also in apoptosis
induction. Elevated MIF expression is detrimental for insulin-producing
beta cells and MIF inhibition protected beta cells from several
cytotoxic insults such as inflammatory cytokines, high fatty acids or
high glucose concentrations. Therefore, the aim of this study was to
investigate two newly synthesized small molecule MIF inhibitors (K664-1
and K647-1) and to compare them with previously established effects of
the prototypical MIF inhibitor, ISO-1. Our results indicate that K664-1
and K647-1 are 160- and 40-fold more effective in inhibition of MIF's
tautomerase activity than ISO-1. Also, new inhibitors confer beta cell
protection from cytokine-triggered apoptosis at significantly lower
concentrations than LSO-1. Although all three MIF inhibitors inhibit
caspase 3 activity, K664-1 and K647-1 suppress pro-apoptotic BAX protein
expression and up-regulate anti-apoptotic Bcl-2 mRNA. Finally, all three
MIF inhibitors operate through blockade of nitric oxide production
stimulated by cytokines. In conclusion, two novel MIF inhibitors are
more potent than ISO-1 and operate through inhibition of the
mitochondria-related apoptotic pathway. We propose that these compounds
represent a unique class of anti-MIF antagonists that should be further
tested for therapeutic use. (C) 2014 Elsevier B.V. All rights reserved.
Кључне речи:
Macrophage migiration inhibitory factor; Diabetes; Cytokines; ApoptosisИзвор:
European Journal of Pharmacology, 2014, 740, 683-689
DOI: 10.1016/j.ejphar.2014.06.009
ISSN: 1879-0712