Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province, China.
Int Immunopharmacol. 2024 Apr 20;131:111789. doi: 10.1016/j.intimp.2024.111789. Epub 2024 Mar 13.
Physalin H (PH), a withanolide isolated from Physalisangulata L. has been reported to have anti-inflammatory effect. However, its impact on acute lung injury (ALI) remains unexplored. In this study, we observed that PH significantly alleviated inflammation in LPS-stimulated macrophages by suppressing the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and down-regulating the expression of the inflammation-related genes. RNA sequencing analysis revealed a significant up-regulation of the NRF2 pathway by PH. Further investigation elucidated that PH attenuated the ubiquitination of NRF2 by impeding the interaction between NRF2 and KEAP1, thereby facilitating NRF2 nuclear translocation and up-regulating the expression of target genes. Consequently, it regulated redox system and exerted anti-inflammatory effect. Consistently, PH also significantly alleviated pathological damage and inflammation in LPS-induced ALI mice model, which could be reversed by administration of an NRF2 inhibitor. Collectively, these results suggest that PH ameliorates ALI by activating the KEAP1/NRF2 pathway. These findings provide a foundation for further development of pH as a new anti-inflammatory agent for ALI therapy.
石竹烯 H（PH）是从石竹科植物中分离得到的一种孕烷型三萜类化合物，具有抗炎作用。然而，其对急性肺损伤（ALI）的影响尚未被探索。在本研究中，我们观察到 PH 通过抑制促炎细胞因子（TNF-α、IL-1β 和 IL-6）的释放和下调炎症相关基因的表达，显著减轻 LPS 刺激的巨噬细胞中的炎症。RNA 测序分析显示 PH 显著上调了 NRF2 通路。进一步研究表明，PH 通过阻碍 NRF2 与 KEAP1 的相互作用来抑制 NRF2 的泛素化，从而促进 NRF2 核转位并上调靶基因的表达。因此，它调节了氧化还原系统并发挥了抗炎作用。同样，PH 还显著减轻了 LPS 诱导的 ALI 小鼠模型中的病理损伤和炎症，而 NRF2 抑制剂的给药可逆转这种作用。综上所述，这些结果表明 PH 通过激活 KEAP1/NRF2 通路改善 ALI。这些发现为进一步将 PH 开发为治疗 ALI 的新型抗炎药物提供了依据。
