Hee-Yun Kim1, Sun-Young Nam1, Jae-Bum Jang2, Youngjin Choi3, In-Cheol Kang4, Hyung-Min Kim5, Hyun-Ja Jeong6. 1. Department of Pharmacology, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea. 2. Department of Pharmaceutical Engineering and Inflammatory Disease Research Center, Hoseo University, Asan, Chungnam, 31499, Republic of Korea. 3. Department of Food Technology and Inflammatory Disease Research Center, Hoseo University, 20 Hoseo-ro, 79 Beon-gil, Baebang-eup, Asan, Chungnam, 31499, Republic of Korea. 4. Biochip Research Center and Inflammatory Disease Research Center, Hoseo University, Asan, Chungnam, 31499, Republic of Korea. 5. Department of Pharmacology, Graduate School, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea. hmkim@khu.ac.kr. 6. Department of Food Technology and Inflammatory Disease Research Center, Hoseo University, 20 Hoseo-ro, 79 Beon-gil, Baebang-eup, Asan, Chungnam, 31499, Republic of Korea. hjjeong@hoseo.edu.
Abstract
OBJECTIVE: We selected a hit compound, 2-(4-{2-[(phenylthio)acetyl]-carbonohydrazonoyl}-phenoxy)acetamide (PA), by a molecular docking simulation between 636,565 compounds and caspase-1 protein. We examined the effect of PA on allergic rhinitis (AR) animal model. METHODS: We assessed the therapeutic effects and the regulatory mechanisms of ovalbumin (OVA)-sensitized mouse model of AR. RESULTS: A molecular docking simulation and a kinetic assay indicated that PA regulates the caspase-1 activation through the interaction with the caspase-1 active site. In the AR animal model, PA significantly reduced the rub scoring increased by OVA. The up-regulated IgE, histamine, interleukin (IL)-1β, and thymic stromal lymphopoietin (TSLP) levels in the serum of OVA-sensitized mice were significantly decreased by the treatment with PA. Protein levels of IL-1β, IL-5, IL-6, IL-13, tumor necrosis factor-α, TSLP, cyclooxygenase-2, macrophage inflammatory protein-2, and intercellular adhesion molecule-1 were also significantly inhibited by the treatment with PA in the nasal mucosa tissues of the OVA-sensitized mice. In the PA-treated mice, the number of eosinophils and mast cells infiltrated by OVA-sensitization were also reduced. In addition, PA reduced the mast cell-derived caspase-1 activity and expression in the nasal mucosa tissues of the OVA-sensitized mice. CONCLUSIONS: PA showed the possibility to regulate AR in OVA-induced AR models, suggesting that it has therapeutic potential for the management of AR as a lead compound.
OBJECTIVE: We selected a hit compound, 2-(4-{2-[(phenylthio)acetyl]-carbonohydrazonoyl}-phenoxy)acetamide (PA), by a molecular docking simulation between 636,565 compounds and caspase-1 protein. We examined the effect of PA on allergic rhinitis (AR) animal model. METHODS: We assessed the therapeutic effects and the regulatory mechanisms of ovalbumin (OVA)-sensitized mouse model of AR. RESULTS: A molecular docking simulation and a kinetic assay indicated that PA regulates the caspase-1 activation through the interaction with the caspase-1 active site. In the AR animal model, PA significantly reduced the rub scoring increased by OVA. The up-regulated IgE, histamine, interleukin (IL)-1β, and thymic stromal lymphopoietin (TSLP) levels in the serum of OVA-sensitized mice were significantly decreased by the treatment with PA. Protein levels of IL-1β, IL-5, IL-6, IL-13, tumor necrosis factor-α, TSLP, cyclooxygenase-2, macrophage inflammatory protein-2, and intercellular adhesion molecule-1 were also significantly inhibited by the treatment with PA in the nasal mucosa tissues of the OVA-sensitized mice. In the PA-treated mice, the number of eosinophils and mast cells infiltrated by OVA-sensitization were also reduced. In addition, PA reduced the mast cell-derived caspase-1 activity and expression in the nasal mucosa tissues of the OVA-sensitized mice. CONCLUSIONS: PA showed the possibility to regulate AR in OVA-induced AR models, suggesting that it has therapeutic potential for the management of AR as a lead compound.
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