Abstract
BackgroundGlucocorticoids (GCs) are anti-inflammatory drugs widely used to treat acute and chronic inflammatory diseases. However, despite their excellent efficacy, the long-term use of GCs is relatively limited owing to their adverse effects. Recent studies have sought to reduce these adverse effects by developing dissociated GCs that bind to GC receptors (GRs) to induce potent anti-inflammatory effects without the transcription of GC response element (GRE)-promoted genes. Some species of the genus Salsola are used in traditional Chinese medicine to treat cancer, hypertension, and inflammation. In this study, we investigated the potential dissociated GC activities and underlying mechanisms of Salsola komarovii (SK), which is native to Korea.MethodsTo determine whether SK ethanol extract (SEE) directly interacts with the GR, an in vitro fluorescence polarization based-GR competitor assay was performed. The effect of SEE on the transcriptional activity of nuclear factor (NF)-κB and GRE was confirmed in HepG2 cells using the Cignal reporter assay. The anti-inflammatory effect of SK was determined by assessing lipopolysaccharide (LPS)-induced interleukin (IL)-6 production. To confirm whether SEE induces GRE-driven gene expression, preadipocyte differentiation followed by lipid deposition was performed in the presence of SEE.ResultsSEE exhibited GR binding activity in the fluorescence polarization competitive binding assay and induced GR nuclear translocation. It also interfered with the nuclear translocation of NF-κB and the NF-κB-dependent transcriptional activity based on the immunofluorescence analysis and reporter assay, respectively. SEE exerted anti-inflammatory effects by reducing LPS-induced IL-6 production as effectively as hydrocortisone (positive control). SK did not induce GRE-driven gene expression and preadipocyte differentiation, which is one of the major adverse effects of GCs.ConclusionsCollectively, these results suggest that SK could be a novel and safe anti-inflammatory agent with dissociated GC properties and, therefore, it has great potential for use in treating inflammatory disorders.
Highlights
Glucocorticoids (GCs) are anti-inflammatory drugs widely used to treat acute and chronic inflammatory diseases
SK ethanol extract (SEE) activates the GC receptor (GR) as a ligand To investigate whether SEE directly interacts with the GR, an in vitro fluorescence polarization based-GR competitor assay was performed (Fig. 1a and b)
SEE competed with the fluormone GS for binding to the fulllength GR (IC50 = 0.01839%, Fig. 1a)
Summary
Glucocorticoids (GCs) are anti-inflammatory drugs widely used to treat acute and chronic inflammatory diseases. Recent studies have sought to reduce these adverse effects by developing dissociated GCs that bind to GC receptors (GRs) to induce potent anti-inflammatory effects without the transcription of GC response element (GRE)promoted genes. GCs, as immune suppressive drugs that do not regulate NF-κB, have been used to treat inflammatory disorders [10] because GC-bound GR suppresses inflammatory responses by preventing NF-κB from transcribing pro-inflammatory genes, the process is called tethering. The compound 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride is a stable analog of the hydroxy phenyl aziridine precursor found in Salsola tuberculatiformis and ginsenoside Rg1 is the most abundant and well-known triterpene saponin in Panax ginseng These compounds were found to exhibit dissociated GC activity with reduced adverse effects [13, 14]. There are only a few studies on plant-derived anti-inflammatory agents with dissociated GC activity
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