Sim Kyeong Hwa, Lee Eunkyung, Shrestha Prafulla, Choi Bo-Hyun, Hong Jaewoo, Lee Youn Ju
Department of Pharmacology, School of Medicine, Daegu Catholic University, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Republic of Korea.
Department of Korean Medicine Development, National Institute for Korean Medicine Development, Gyeongsan 38540, Republic of Korea.
Biochem Pharmacol. 2025 Feb;232:116698. doi: 10.1016/j.bcp.2024.116698. Epub 2024 Dec 4.
Isobavachin, isolated from Psoralea corylifolia L. exhibits therapeutic potential for osteoporosis or skin disease. Here, we evaluated the pharmacological effects of isobavachin on IgE-dependent inflammatory allergic reactions, as well as the underlying mechanisms, in bone marrow-derived mast cells and a mouse model of passive cutaneous anaphylaxis (PCA). Isobavachin reduced IgE/Ag-stimulated degranulation, eicosanoid (leukotriene C and prostaglandin D) generation, and release of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α) and interleukin (IL)-6). Mechanistic studies revealed that isobavachin suppressed activation of Fyn, Lyn, spleen tyrosine kinase (Syk), and lymphocyte-specific-protein-kinase (Lck), receptor-proximal tyrosine kinases that initiate and play a central role in FcɛRI-mediated mast cell activation, as well as their common downstream signaling molecules including linker for activation of T cells, phospholipase Cγ1, AKT, mitogen-activated protein kinases (MAPKs), and intracellular Ca. Additionally, isobavachin increased phosphorylation of Src homology region 2 domain-containing phosphatase-1 (SHP-1), thereby strengthening its interaction with Syk and Lck as well as Fyn and Lyn, resulting in de-phosphorylation of these proximal tyrosine kinases. Genetic knockdown of SHP-1 reversed the inhibitory effects of isobavachin on mast cell activation, as well as the related signaling pathways, indicating that the inhibitory effects of isobavachin are mediated by negative regulation of SHP-1-dependent Fyn, Lyn, Syk and Lck. The anti-inflammatory properties of isobavachin were also examined in macrophages. Isobavachin suppressed production of lipopolysaccharide-stimulated production of pro-inflammatory cytokines and nitric oxide. Furthermore, oral administration of isobavachin attenuated mast cell-mediated PCA reactions in mice. These results suggest that isobavachin is a potential treatment for mast cell-mediated allergic inflammatory diseases.
从补骨脂中分离得到的异补骨脂素对骨质疏松症或皮肤病具有治疗潜力。在此，我们评估了异补骨脂素对骨髓来源的肥大细胞和被动皮肤过敏反应（PCA）小鼠模型中IgE依赖性炎症过敏反应的药理作用及其潜在机制。异补骨脂素可减少IgE/抗原刺激的脱颗粒、类花生酸（白三烯C和前列腺素D）生成以及促炎细胞因子（肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-6）的释放。机制研究表明，异补骨脂素可抑制Fyn、Lyn、脾酪氨酸激酶（Syk）和淋巴细胞特异性蛋白激酶（Lck）的激活，这些受体近端酪氨酸激酶在FcɛRI介导的肥大细胞激活中起启动和核心作用，以及它们的共同下游信号分子，包括T细胞激活连接蛋白、磷脂酶Cγ1、AKT、丝裂原活化蛋白激酶（MAPKs）和细胞内Ca。此外，异补骨脂素增加了含Src同源区2结构域的磷酸酶-1（SHP-1）的磷酸化，从而加强了其与Syk和Lck以及Fyn和Lyn的相互作用，导致这些近端酪氨酸激酶的去磷酸化。SHP-1的基因敲低逆转了异补骨脂素对肥大细胞激活以及相关信号通路的抑制作用，表明异补骨脂素的抑制作用是由SHP-1依赖性Fyn、Lyn、Syk和Lck的负调控介导的。还在巨噬细胞中检测了异补骨脂素的抗炎特性。异补骨脂素抑制脂多糖刺激的促炎细胞因子和一氧化氮的产生。此外，口服异补骨脂素可减轻小鼠肥大细胞介导的PCA反应。这些结果表明，异补骨脂素是治疗肥大细胞介导的过敏性炎症疾病的潜在药物。
