18β-Glycyrrhetinic acid, the major bioactive component of Glycyrrhizae Radix, attenuates airway inflammation by modulating Th2 cytokines, GATA-3, STAT6, and Foxp3 transcription factors in an asthmatic mouse model.

18β-Glycyrrhetinic acid (18Gly), the major bioactive component of Glycyrrhizae Radix, possesses anti-ulcerative, anti-inflammatory, and other pharmacological properties. Although 18Gly is associated with immunoregulatory functions of allergic diseases, the pathophysiological mechanisms of 18Gly action in allergic inflammatory lung disease have not been examined. Moreover, there are no in vivo studies on the anti-asthmatic effects of 18Gly in allergic asthma. We investigated its effect and mechanism of action in airway inflammation in a BALB/c mouse model of allergic asthma. Interestingly, 18Gly strongly suppressed airway hyperresponsiveness, accumulation of inflammatory cells, and levels of T helper type 2 (Th2) cytokines (interleukin (IL)-5 and IL-13) in bronchoalveolar lavage fluid (BALF). It also attenuated lung IL-5, IL-13, and IL-4 expression, but it upregulated peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression in lungs. Moreover, it exerted immunomodulatory effects by suppressing Th2 cytokines (IL-5, IL-13) production through upregulation of forkhead box p3 (Foxp3), and downregulation of signal transducer and activator of transcription (STAT6), GATA-binding protein 3 (GATA-3), and retinoic acid-related orphan receptor γ t (RORγt) expression. These results suggest that the anti-asthmatic activity of 18Gly may occur by the suppression of IL-5, IL-13, and OVA-specific Immunoglobulin E (IgE) production through inhibition of the RORγt, STAT6, GATA-3 pathways and upregulation of the Foxp3 transcription pathway. Also, 18Gly treatment was protective against the oxidative stress by inducing significant decrease of reactive oxygen species (ROS) generation in MH-S alveolar macrophage cells. Our results suggest that 18Gly can improve allergic asthma and can be a novel therapeutic component for the treatment of allergic asthma.

Kim SH ，Hong JH ，Lee JE ，Lee YC ... -  《-》

Oleanolic acid suppresses ovalbumin-induced airway inflammation and Th2-mediated allergic asthma by modulating the transcription factors T-bet, GATA-3, RORγt and Foxp3 in asthmatic mice.

The natural product oleanolic acid is commonly found in a variety of medicinal plants. It is a triterpenoid compound known for its anti-inflammatory effects as well as various other pharmacological properties. The aim of the current study was to use a mouse model of allergic asthma to investigate whether oleanolic acid has anti-asthmatic effects, and if so, to determine the mechanism of these effects. Oleanolic acid suppressed eosinophil infiltration, allergic airway inflammation, and Penh, which occurred by suppressing the production of IL-5, IL-13, IL-17, and ovalbumin-specific IgE through the upregulation of T-bet and Foxp3, and the downregulation of GATA-3 and RORγt. The therapeutic effect of oleanolic acid was due to suppression of Th2 cytokines (IL-5 and IL-13), B cell-dependent production of OVA-specific IgE, and Gr-1 expression through the T-bet, GATA-3, retinoic acid-related orphan receptor γ t (RORγ t) and forkhead box p3 (Foxp3) transcription pathways. It is therefore reasonable to suggest that the anti-inflammatory and anti-asthmatic effects of oleanolic acid may be exerted through inhibition of the GATA-3 and RORγt pathways.

Kim SH ，Hong JH ，Lee YC 《-》

Ursolic acid, a potential PPARγ agonist, suppresses ovalbumin-induced airway inflammation and Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthma.

Allergic asthma is a chronic airway disorder characterized by airway hyperresponsiveness to allergens, chronic airway inflammation, airway edema, increased mucus secretion, excess production of Th2 cytokines, and eosinophil accumulation in the lungs. Ursolic acid is known for its pharmacological effects, such as its anti-tumor, anti-inflammatory and antimicrobial activities. To investigate the anti-asthmatic effects and mechanism of ursolic acid, we studied the development of pulmonary eosinophilic inflammation and enhanced pause (Penh) in a mouse model of allergic asthma. In this study, BALB/c mice were systemically sensitized to ovalbumin followed by intratracheal, intraperitoneal, and aerosol allergen challenges. We investigated the effect of ursolic acid and Cyclosporin A (CsA) on Penh, pulmonary eosinophilic infiltration, various immune cell phenotypes, Th2 cytokines, IL-17 production, and ovalbumin specific IgE production in a mouse model of asthma. In BALB/c mice, ursolic acid had suppressed eosinophil infiltration, allergic airway inflammation, and Penh, which occurred by suppressing the production of IL-5, IL-13, IL-17, and ovalbumin-specific IgE by blocking the GATA-3 and STAT6 pathways. Our data suggest the therapeutic mechanism of ursolic acid in asthma is based on reductions of Th2 cytokines (IL-5 and IL-13), ovalbumin-specific IgE production, and eosinophil infiltration via the Th2-GATA-3, STAT6, and IL-17-NF-κB pathways.

Kim SH ，Hong JH ，Lee YC 《-》

The Ethanol Extract of Holotrichia diomphalia Larvae, Containing Fatty acids and Amino acids, Exerts Anti-Asthmatic Effects through Inhibition of the GATA-3/Th2 Signaling Pathway in Asthmatic Mice.

Hong JH ，Kim SH ，Lee YC 《MOLECULES》

Peucedanum japonicum extract attenuates allergic airway inflammation by inhibiting Th2 cell activation and production of pro-inflammatory mediators.

The root of Peucedanum japonicum Thunberg is traditionally used to treat coughs, colds, headache and inflammatory diseases in Korea and Japan. Its effects on allergic lung inflammation have not been investigated. To investigate the anti-asthmatic effects of Peucedanum japonicum extract (PJE) using a murine model of asthma and a lipopolysaccharide (LPS)-stimulated macrophage cell line. Mice underwent two rounds of sensitization with ovalbumin 1 week apart followed by four intranasal ovalbumin challenges on days 13-16. The control group received saline only. Two ovalbumin-sensitized groups were orally administered vehicle or PJE (200mg/kg) 5 days a week starting 1 week before the first ovalbumin sensitization. The third group was orally administered the asthma medication Montelukast (10mg/kg) on days 12-16. All animals were sacrificed on day 17. The lungs were assessed for histological features, inflammatory cell infiltration, Th2 cell activation and GATA-binding protein-3 (GATA-3) expression. The bronchoalveolar lavage fluid (BALF) was assessed for type 2 cytokine levels. The effect of PJE on the in vitro Th2 polarization of naïve CD4+ splenocytes and the production of pro-inflammatory mediators and cytokines by LPS-stimulated RAW 264.7 cells was evaluated. PJE treatment inhibited OVA-induced inflammatory cell infiltration, eosinophilia, Th2 activation, and GATA-3 expression in the lung, reduced the interleukin (IL)-5 and IL-13 levels in BALF, down-regulated Th2 activation in vitro, and inhibited the macrophage production of inducible nitric oxide, cyclooxygenase-2, tumor necrosis factor-α, and IL-6. PJE attenuated allergic airway inflammation by inhibiting Th2 cell activation and macrophage production of inflammatory mediators. Peucedanum japonicum may be candidate therapy for allergic lung inflammation.

Chun JM ，Lee AR ，Kim HS ，Lee AY ，Gu GJ ，Moon BC ，Kwon BI ... -  《-》