Abstract
The present study aimed to identify a new selective glucocorticoid receptor (GR) ligand for the treatment of chronic inflammation in type 2 diabetes mellitus. The IN Cell Analyzer 1000 platform was employed to screen for compounds that may promote GR nuclear translocation. A mammalian two-hybrid system and transactivation assay-were used to analyze the selected GR ligands and evaluate their activities for GR transcription and the recruitment of co-activators. A novel selective GR ligand, compound Q40, was identified that was able to promote GR nuclear translocation in a short period of time. It increased the ability of GR to recruit co-activators in a concentration-dependent manner, but had no positive effect on GR transcriptional activity. In conclusion, an increase in the expression levels of gluconeogeneic genes, induced by the transcriptional activation of GR, is the predisposing factor most commonly associated with the side-effects of glucocorticoids. The results suggest that compound Q40 is a ligand of the GR and exerts an agonistic action on the recruitment of co-activators without sugar dysmetabolism-related side-effects. Thus, compound Q40 has the potential to be used as an anti-inflammatory adjuvant therapy with minimal side-effects in patients with type 2 diabetes mellitus.
Highlights
Type 2 diabetes mellitus is a glycolipid metabolic disorder that is characterized by high levels of blood glucose and lipids in the context of insulin resistance and relative insulin deficiency.Key words: glucocorticoid receptor, selective ligand, anti‐inflammatory therapyIt is a clinical syndrome caused by a combination of environmental and genetic factors
It has been demonstrated that the glucocorticoid receptor (GR) influences the key molecules of certain signaling pathways through rapid nongenomic effects, including the phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinase (JNK), 14‐3‐3 protein and T cell receptor (TCR) signaling pathways, which are able to regulate the expression of certain pro‐inflammatory factors [3]
Chronic inflammation plays a major role in the occurrence of insulin resistance
Summary
Type 2 diabetes mellitus is a glycolipid metabolic disorder that is characterized by high levels of blood glucose and lipids in the context of insulin resistance and relative insulin deficiency It is a clinical syndrome caused by a combination of environmental and genetic factors. One direct mechanism of action involves homodimerization of the GR, its translocation through active transport into the nucleus and binding to glucocorticoid response elements which are located in the promoter regions of certain genes. It subsequently recruits transcription factors or co‐activators, changes the structure of the chromosome and regulates the expression of genes associated with sugar dysmetabolism [5]. Activated GR complexes, with other transcription factors attached, prevent these transcription factors from binding to their target genes and repress the expression of inflammatory genes [6]
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