## 4 Discussion  
Patients with AD generally suffer from chronic pruritus, and scratching worsens skin inflammation by damaging the skin barrier and inducing the production of inflammatory mediators [28,29]. In this context, the inhibition of clinical symptoms is one of the most important therapeutic strategies for AD. The current AD-like model exhibited AD-like skin lesions and severe scratching; however, fRGM inhibited the clinical symptoms, along with reducing IgE levels. Elevated IgE and IgE-mediated immune responses involve the characteristic symptoms of AD through allergic inflammation, which is the main hallmark of AD pathogenesis [29]. In particular, mast cells are major effector cells related to IgE-mediated hypersensitivity reactions, and their activation promotes the production of pro-inflammatory cytokines, together with Th1-derived mediators (i.e., TNF-\(\alpha\), IFN-\(\gamma\), IL-\(\beta\), IL-\(6\), and IL-\(10\)) [2,30]. Here, histopathological analyses revealed that fRGM improved AD-like skin lesions by reducing epidermal thickening, collagen deposition, and dermal infiltration of inflammatory cells and mast cells. The immunohistochemical analyses suggested the  
Figure 7: Histopathological changes in the lymph nodes of the AD-like model. (**a**) Representative images in H&E stain and immunostains for IFN-\(\gamma\), iNOS-\(2\), TNF-\(\alpha\), IL-\(1\beta\), and IL-\(2\) in the lymph node. In H&E stains, the parenchyma in the upper is highly magnified in the lower. (**b**) Total and cortical thicknesses in the central region (mm). (**c**) Number of cortical follicles (follices/mm\({}^{2}\)). (**d**) Immunoreactive cells in the parenchyma (\(\times 10\) cells/mm\({}^{2}\)). Values are represented as means \(\pm\) SDs. \(\ddagger\): \(p\) < 0.01 and \(\ddagger\): \(p\) < 0.05 vs. the Intact group; ***:**\(p\) < 0.01 and ***:**\(p\) < 0.05 vs. AD Con. antioxidant, anti-inflammatory, and anti-apoptotic effects of the fRGM. Similarly, topical treatment of red ginseng has shown anti-AD effects by alleviating skin lesions and inhibiting production of IgE, mast cell infiltration, and inflammatory progression [10, 11, 12, 13, 14]. These findings suggest that fRGM still contains the bioactive compounds involved in anti-AD effects by inhibiting the production of IgE and the subsequent inflammatory progression, even though most fRGM is discarded as a byproduct of red ginseng extraction. Atopic immune activation is characterized by a Th2-dominated reaction; Th2 cells are responsible for IgE synthesis, and predominantly release IL-4, IL-5, IL-10, and IL-13 [3, 31]. Among these cytokines, IL-4 and IL-13 activate mast cells and basophils by promoting IgE isotype switching in B cells and Th2 dominance, and IL-5 and IL-10 involve eosinophil activation and infiltration into the skin lesions, which in turn elicit an allergic immune response [3, 32]. Subsequently, chronic AD demonstrates Th1-derived mediators and tissue remodeling with collagen deposition and dermal thickening, leading to the further production of IgE and inflammatory mediators by recruiting activated immune cells [30, 33]. Here, the AD-like skin lesions upregulated the mRNA expressions of TNF-\(\alpha\) and Th2 cytokines, including IL-4, IL-5, and IL-13, with increased immunostains for TNF-\(\alpha\), IFN-\(\gamma\), IL-19, IL-2 and iNOS. However, fRGM inhibited the expression of inflammatory mediators, and resulted in mild fibrosis by reducing collagen deposition and expression of MMP-9 as a remodeling marker in patients with AD [34]. The allergic inflammatory response is associated mainly with the activation of intracellular signaling pathways, such as mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-\(\kappa\)B) [35]. Red ginseng has been reported to exert anti-inflammatory effects via the inhibition of the MAPK and NF-\(\kappa\)B pathways in AD-like models [11, 36]. RGM, particularly triterpene glycoside compounds, has also shown anti-inflammatory effects by targeting the NF-\(\kappa\)B pathway [21, 37].