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Toxicarioside H-mediated modulation of the immune microenvironment attenuates ovalbumin-induced allergic airway inflammation by inhibiting NETosis. In the presence of allergens like OVA, neutrophils and other inflammatory cells are recruited, triggering NETosis and the generation of reactive oxygen species (ROS). This process disrupts the balance of immune cells, affecting Th1 and Th2 cells, IL-17 and Treg cells, and memory T cells, thereby promoting allergic asthmatic inflammation. However, ToxH, similar to NEi or NAC, can inhibit NETosis and ROS production, thus modulating the immune environment in allergic asthma and reducing inflammation. [Display omitted] • The novel structural cardiac glycoside, Toxicarioside H (ToxH), effectively inhibits ovalbumin-induced allergic airway inflammation. • ToxH regulates the airway immune microenvironment by maintaining a balance between Th1 and Th2 cells, Th17 and Treg cells, as well as memory T cells. • ToxH mitigates airway inflammation and alters the airway immune microenvironment by suppressing NETosis and reducing ROS production. • Modulating the balance of immune cells in the lung microenvironment with ToxH may represent a promising strategy for treating allergic airway inflammation. Our team identified a new cardiac glycoside, Toxicarioside H (ToxH), in a tropical plant. Previous research has indicated the potential of cardenolides in mitigating inflammation, particularly in the context of NETosis. Therefore, this study sought to examine the potential of ToxH in attenuating allergic airway inflammation by influencing the immune microenvironment. An OVA-induced airway inflammation model was established in BALB/c mice. After the experiment was completed, serum, bronchoalveolar lavage fluid (BALF), and lung tissue samples were collected and further examined using H&E and PAS staining, flow cytometry, immunofluorescence observation, and Western blot analysis. Treatment with ToxH was found to be effective in reducing airway inflammation and mucus production. This was accompanied by an increase in Th1 cytokines (IFN-γ, IL-2, and TNF-β), and the Th17 cytokine IL-17, while levels of Th2 cytokines (IL-4, IL-5, and IL-13) and Treg cytokines (IL-10 and TGF-β1) were decreased in both the bronchoalveolar lavage fluid (BALF) and the CD45+ immune cells in the lungs. Additionally, ToxH inhibited the infiltration of inflammatory cells and decreased the number of pulmonary CD44+ memory T cells, while augmenting the numbers of Th17 and Treg cells. Furthermore, the neutrophil elastase inhibitor GW311616A was observed to suppress airway inflammation and mucus production, as well as alter the secretion of immune Th1, Th2, Th17, and Treg cytokines in the lung CD45+ immune cells. Moreover, our study also demonstrated that treatment with ToxH efficiently inhibited ROS generation, thereby rectifying the dysregulation of immune cells in the immune microenvironment in OVA-induced allergic asthma. Our findings indicate that ToxH could serve as a promising therapeutic intervention for allergic airway inflammation and various other inflammatory disorders. Modulating the balance of Th1/Th2 and Treg/Th17 cells within the pulmonary immune microenvironment may offer an effective strategy for controlling allergic airway inflammation. [ABSTRACT FROM AUTHOR]

• Pharmacological inhibition of EZH2 results in increasing MDSCs and attenuating CD8+ T cells in the tumor microenvironment of HCC. • Depletion of MDSCs by anti-Gr-1 antibody strengthens the antitumor effect of EZH2 inhibition. • EZH2 inhibition enhances the expressions of chemokines (C5a, CCL8, and CCL9) to promote MDSCs recruitment in the tumor microenvironment of HCC. Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive component 2 is overexpressed in a variety of cancers and recognized as a therapeutic target molecule. However, EZH2 possesses immunomodulatory functions in the tumor microenvironment (TME). The impact of EZH2 on TME of hepatocellular carcinoma (HCC) using immunocompetent mouse model was evaluated in the present study. UNC1999, an EZH2 inhibitor, impaired growth of the murine HCC cells (H22 cells) and induced apoptosis in a dose-dependent manner. Although UNC1999 significantly inhibited the growth of H22 cells-derived and Hepa1-6 cells-derived tumors in nonobese diabetic/severe combined immunodeficiency mice, its antitumor effect was diminished in allogenic BALB/c and C57BL/6 mice. Flow cytometric analyses of TME cells in BALB/c mice demonstrated a significant decrease in the number of interferon‑γ+ CD8+ T cells and regulatory T cells and a significant increase in the number of myeloid-derived suppressor cells (MDSCs). Administration of Gr-1 neutralizing antibody concomitant with UNC1999 restored antitumor effect accompanied by an increase in the number of CD8+ T cells followed by a decrease in the number of MDSCs. Chemokine antibody array demonstrated an enhanced expression of chemokines responsible for MDSCs recruitment such as C5a, CCL8, and CCL9. In conclusion, the study results demonstrated that EZH2 inhibitor contributed to attenuation of tumor immunity caused by TME arrangement. Combination therapy with EZH2 inhibitors and agents that reduce MDSCs might represent a novel therapeutic strategy for HCC. [ABSTRACT FROM AUTHOR]