title: Ginsenoside Rh1 potentiates dexamethasone's anti-inflammatory effects for chronic inflammatory disease by reversing dexamethasone-induced resistance.
abstract: BACKGROUND
  Acquired 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.
  
  
  METHODS
  Ginsenoside 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.
  
  
  RESULTS
  Ginsenoside 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.
  
  
  CONCLUSIONS
  Rh1 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Binbin
authors.initials: B
authors.lastname: Cheng
authors.forename: Fanfu
authors.initials: F
authors.lastname: Fang
authors.forename: Li
authors.initials: L
authors.lastname: Weng
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Changquan
authors.initials: C
authors.lastname: Ling
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000517:prevention & control; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects*; D004357:Drug Synergism; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D036145:Ginsenosides / Q000494:pharmacology*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D036145:Ginsenosides; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; C425564:ginsenoside Rh1; D003907:Dexamethasone; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D005952:Glucose-6-Phosphatase