Rg x 3 6 5, a Rare Protopanaxatriol-Type Ginsenoside Fraction from Black Ginseng, Suppresses Inflammatory Gene iNOS via the Iinhibition of p-STAT-1 and NF-κ B

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of Rgx365 (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). Rgx365 was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1β and tumor necrosis factor [TNF]-α) in the lung tissue of LPS-treated mice. The results showed that Rgx365 induced the expression of HO-1, reduced LPS-activated NF-κB-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, Rgx365 induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1β production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to Rgx365 was reversed by siHO-1 RNA transfection. In LPS-treated mice, Rgx365 significantly reduced lung tissue iNOS protein levels and TNF-α levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that Rgx365 has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-κB, and thus it may be suitable for the treatment of inflammatory disease.