Acute lung injury (ALI) is a severe lung disease with limited therapeutic strategies. Munronoid I, a limonoid, which is extracted and purified from Munronia sinica, exhibits effective anti-neoplastic activities. In this study, we attempted to determine the anti-inflammatory effects of Munronoid I using both the lipopolysaccharide (LPS)-induced in vivo murine ALI models and in vitro assays. Our results demonstrated that Munronoid I treatment ameliorated LPS-induced ALI and inflammation in mice. Moreover, it also significantly inhibited LPS-induced pathological injuries, infiltration of inflammatory cells, and production of IL-1β and IL-6. Furthermore, the in vitro assay showed that Munronoid I could inhibit the LPS-induced expression of inflammatory mediators such as iNOS, COX2, and production of pro-inflammatory cytokines by suppressing the activation of NF-κB signaling pathway in mouse peritoneal macrophages. Munronoid I reduced the LPS-, tumor necrosis factor alpha (TNF-α)- or interleukin 1 beta (IL-1β)-induced transforming growth factor beta-activated kinase 1 (TAK1) phosphorylation and protein expression. Furthermore, the Munronoid I also promoted K48-linked ubiquitination and proteasomal degradation of TAK1. Taken together, these results demonstrated that Munronoid I exhibited anti-inflammatory activities both in vitro and in vivo, which might be a potential therapeutic candidate for the treatment of ALI and pulmonary inflammation.

中文翻译：

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天然分子 Munronoid I 通过促进 K48 连接的泛素化和 TAK1 降解来减轻 LPS 诱导的急性肺损伤。


急性肺损伤（ALI）是一种严重的肺部疾病，治疗策略有限。 Munronoid I 是一种从 Munronia sinica 中提取纯化的柠檬苦素类化合物，具有有效的抗肿瘤活性。在本研究中，我们尝试使用脂多糖 (LPS) 诱导的体内小鼠 ALI 模型和体外测定来确定 Munronoid I 的抗炎作用。我们的结果表明，Munronoid I 治疗可改善 LPS 诱导的小鼠 ALI 和炎症。此外，它还显着抑制LPS引起的病理损伤、炎症细胞的浸润以及IL-1β和IL-6的产生。此外，体外实验表明，Munronoid I 可以通过抑制小鼠腹腔巨噬细胞中 NF-κB 信号通路的激活，抑制 LPS 诱导的 iNOS、COX2 等炎症介质的表达以及促炎细胞因子的产生。 Munronoid I 降低 LPS、肿瘤坏死因子 α (TNF-α) 或白细胞介素 1 β (IL-1β) 诱导的转化生长因子 β 激活激酶 1 (TAK1) 磷酸化和蛋白质表达。此外，Munronoid I 还促进 K48 连接的 TAK1 泛素化和蛋白酶体降解。总而言之，这些结果表明 Munronoid I 在体外和体内均表现出抗炎活性，这可能是治疗 ALI 和肺部炎症的潜在候选药物。