Abstract
IntroductionAcquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for compounds to improve the effect of classic steroids. We sought to unravel how a plant-original compound, ginsenoside Rh1, potentiates dexmethasone (DEX)’s potential anti-inflammation properties.MethodsGinsenoside Rh1 combined with DEX was applied in a short-term and long-term treatment protocol for inflammation. Its potential mechanism on anti-inflammation was explored. In addition, the effect of Rh1 on the side-effect induced by DEX was studied. Furthermore, the in vivo anti-inflammatory effects of Rh1 combined with DEX were evaluated in a collagen-induced arthritis (CIA) mice model.ResultsGinsenoside Rh1 potentiates DEX’s anti-inflammatory effects even after prolonged DEX treatment. Rh1 could improve the glucocorticoid receptor (GR)’s transrepression on nuclear factor kappa B (NF-κB) and transactivation on dual specificity protein phosphatase 1 (DUSP1), which is responsible for DEX’s anti-inflammatory effects. Parallel Western blot assay and radioligand binding analysis revealed that Rh1 could increase the expression and binding of GR. This is in sharp contrast to DEX alone, showing a direct link among prolonged treatment, decreasing GR and the abolishment of anti-inflammation. Interestingly, Rh1 does not enhance the transactivation of glucocorticoid-responsive elements (GRE) driven genes - gluconeogenic enzyme glucose-6-phosphatase (G6P) and phosphoenolpyruvate carboxykinasee phosphatase (PEPCK) in primary mouse hepatocytes, a mechanism partly held accountable for the metabolic side-effects. Similar results were found in CIA mice.ConclusionRh1 could potentiate DEX’s anti-inflammatory effects and does not cause a hyperglycemic side effect. Ginsenoside Rh1 combined with DEX may be a promising candidate treatment option for chronic inflammatory diseases in need of long-term immunosuppression therapies.
Highlights
Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for compounds to improve the effect of classic steroids
Ginsenoside Rh1 combined with DEX inhibited the expression of pro-inflammatory cytokines, even after long-time treatment Our recent research showed that ginsenoside Rh1 could reverse the reduction of glucocorticoid receptor (GR) expression and binding capacity induced by DEX (Additional file 1: Figure S1)
Ginsenoside Rh1 combined with DEX markedly attenuated inflammation in collagen-induced arthritis (CIA) model To evaluate the in vivo potency of Rh1 combined with DEX to suppress Ag-driven immune responses, we examined its effect in CIA
Summary
Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for compounds to improve the effect of classic steroids. Current research is focused on finding compounds with similar anti-inflammatory potency of the standard GCs but with reduced side effects [6,7,8,9]. It is currently unclear whether dissociating activation from repression of GR in a ligand will result in a beneficial therapeutic profile. Novel compounds that lack a capacity for steroid-inducible genes may show lessened anti-inflammatory effects [13,14,15]. The regulation of GR may be another efficient strategy for restoring glucocorticoid resistance
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