In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes. As described herein, we found that eIF5A regulates iNOS levels and that eIF5A depletion as well as the inhibition of hypusination protects against glucose intolerance in inflammatory mouse models of diabetes. We observed that following knockdown of eIF5A expression, mice were resistant to beta cell loss and the development of hyperglycemia in the low-dose streptozotocin model of diabetes. The depletion of eIF5A led to impaired translation of iNOS-encoding mRNA within the islet. A role for the hypusine residue of eIF5A in islet inflammatory responses was suggested by the observation that inhibition of hypusine synthesis reduced translation of iNOS-encoding mRNA in rodent beta cells and human islets and protected mice against the development of glucose intolerance the low-dose streptozotocin model of diabetes. Further analysis revealed that hypusine is required in part for nuclear export of iNOS-encoding mRNA, a process that involved the export protein exportin1. These observations identify the hypusine modification of eIF5A as a potential therapeutic target for preserving islet function under inflammatory conditions.
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http://dx.doi.org/10.1172/JCI38924 | DOI Listing |
Int J Biol Macromol
September 2022
Department of Pathophysiology, Faculty of Medicine, Jagiellonian University Medical College, Czysta street 18, 31-121 Cracow, Poland.
The aim of our studies was to determine the influence of a low-frequency electromagnetic field (EMF) on the phagocytosis of latex beads (LBs) and the expression level of proteins/genes in the human monocytic macrophage Mono Mac 6 (MM6) cell line in in vitro conditions. Before phagocytosis assay cells were pre-stimulated with infectious agents such as lipopolysaccharide (LPS), Staphylococcal enterotoxin B (SEB), or the proliferatory agent phytohaemagglutinin (PHA), and then exposed to EMF (30 mT, 7 Hz, 3 h). The expression of cytoplasmic proteins like iPLA, cPLA, iNOS, NLR3/4, and Hsp70 involved in the immune response pathways to phagocytosed particles were evaluated with the usage of the Western blot analysis.
View Article and Find Full Text PDFHua Xi Kou Qiang Yi Xue Za Zhi
June 2010
Dept. of Orthodontics, Stomatological School Affiliated Tongji University, Shanghai 200072, China.
Objective: This article tests a recombinant plasmid pEGFP-iNOS encoding human inducible nitric oxide synthase (iNOS) transient expression in rabbit periodontal ligament cells, and this may contribute to transfer iNOS gene to animal periodontal tissue in vivo.
Methods: Rabbit periodontal ligament cells were transfected with pEGFP-iNOS by means of lipofectamine media methods. Transient transfection were evaluated by fluorescent microscope.
J Clin Invest
June 2010
Department of Pediatrics and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
In both type 1 and type 2 diabetes, pancreatic islet dysfunction results in part from cytokine-mediated inflammation. The ubiquitous eukaryotic translation initiation factor 5A (eIF5A), which is the only protein to contain the amino acid hypusine, contributes to the production of proinflammatory cytokines. We therefore investigated whether eIF5A participates in the inflammatory cascade leading to islet dysfunction during the development of diabetes.
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