Ginsenoside compound K plays an anti-inflammatory effect without inducing glucose metabolism disorder in adjuvant-induced arthritis rats.

Ginsenoside compound K (GCK) possesses a glucocorticoid (GC)-like structure and functions as an agonist of the glucocorticoid receptor (GR), thereby exerting anti-inflammatory effects through GR activation. However, it remains unclear whether GCK leads to hyperglycemia, which is a known adverse reaction associated with classical GCs. In this study, we have successfully demonstrated that GCK exerts its anti-inflammatory effects in a rat model of adjuvant arthritis without impacting gluconeogenesis and pentose phosphate pathways, thus avoiding any glucose metabolism disorders. By employing the GR mutant plasmid, we have identified the binding site between GCK and GR as GRM560T, which differs from the binding site shared by dexamethasone (DEX) and GR. Notably, compared to DEX, GCK induces distinct levels of phosphorylation at S211 on GR upon binding to activate steroid receptor coactivator 1 (SRC1)-a co-factor responsible for mediating anti-inflammatory effects-while not engaging peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-an associated coactivator involved in gluconeogenesis.

Ginsenoside Compound K Reduces Psoriasis-related Inflammation by Activation of the Glucocorticoid Receptor in Keratinocytes.

AIM: To investigate the effects and mechanism of Ginsenoside Compound K (GCK) on psoriasis, focusing on the glucocorticoid receptor (GR) in keratinocytes. METHODS: An imiquimod (IMQ)-induced psoriasis-like dermatitis mouse model was generated to evaluate the anti-inflammatory effect of GCK. Hematoxylin and eosin (H&E) staining was used to assess skin pathological changes. Protein expression of K17 and p-p65 in mice skin was assayed by immunohistochemical. Protein expression and phosphorylation of p65 IκB were assayed by Western blot. Protein expression of K1, K6, K10, K16, K17, and GR were assayed by Western blot and immunofluorescence. Enzyme-linked immunosorbent assay (ELISA) was used to determine cytokine levels of TNF-α, IL-6, CXCL-8, and ICAM-1. Real-time polymerase chain reaction (RT-PCR) was used to quantify TNF-α, IL-6, IL-8, and ICAM-1 mRNA expression. Cell viability was determined by Cell Counting Kit-8(CCK-8) assay. A high-content cell-imaging system was used to assay cell proliferation. Nuclear translocation of p65 and GR was assayed by imaging flow cytometry and immunofluorescence microscopy. Small interfering RNA was used to confirm the role of GR in the anti-inflammatory and immunoregulatory effect of GCK in normal human epidermal keratinecytes (NHEKs). RESULTS: GCK reduced the psoriasis area, severity index, and epidermal thickening in IMQ-induced mice. GCK significantly attenuated the mRNA levels of IL-6, IL-8, TNF-α, and ICAM-1 and reduced epidermal hyperproliferation in the skin of IMQ-induced mice. GCK inhibited in vitro activation of NF-κB, leading to attenuated release of inflammatory mediators (IL-6, IL-8, TNF-α, and ICAM-1) and suppression of NHEK hyperproliferation and abnormal differentiation. These inhibitory effects of GCK were diminished by GR silencing in NHEKs. CONCLUSION: GCK suppressed psoriasis-related inflammation by suppressing keratinocyte activation, which may be related to promoting GR nuclear translocation and inhibiting NF-κB activation. In summary, GCK appears to be a GR activator and a promising therapeutic candidate for antipsoriatic agents.

Ginsenoside compound K exerts anti-inflammatory effects through transcriptional activation and transcriptional inhibition of glucocorticoid receptor in rheumatoid arthritis fibroblast-like synoviocytes.

Ginsenoside compound K (GCK) has anti-inflammatory and immunoregulatory effects, and glucocorticoid receptor (GR) has been considered as its potential target. But the mechanism by which GCK exerts its anti-inflammatory effects after GR activation remains unclear. In this study, molecular docking, isothermal titration calorimetry, siRNA of GR and GRA458T mutation were used to confirm the anti-inflammatory mechanism of GCK targeting GR in fibroblast-like synoviocytes (FLS). The results showed that the key binding sites of GR and GCK were identified as ASN564, MET560 and ASN638, with binding levels at the µm level. In addition, the inhibitory effect of GCK on the proliferation of FLS and the secretion of inflammatory cytokines (IL-6, IL-8, and IL-1ß) were mediated by transcriptional activation of GR, but on the migration, invasion, and TNF-α secretion of FLS were mediated by transcriptional inhibition of GR. These actions exert anti-inflammatory effects through indirect and direct inhibition of NF-κB transcriptional activity, respectively. In conclusion, this study elucidates that GCK can directly bind to and activate GR. Furthermore, after activation, GR mediates the anti-inflammatory effects of GCK through two mechanisms: transcriptional activation and transcriptional inhibition.