Qiao Xin, Cao Xiaojuan, Xu Shuang, Wang Cunlin, Guo Rui, Yao Xiaojuan, Zhang Qiong
School of Pharmacy, Shanxi Medical University, Taiyuan, China.
Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan, China.
Front Pharmacol. 2024 Dec 3;15:1505116. doi: 10.3389/fphar.2024.1505116. eCollection 2024.
Dysregulated and excessive inflammatory reactions can lead to tissue damage, which is the underlying cause of most human diseases. Menisoxoisoaporphine A (MA), a novel oxoisoaporphine alkaloid, was obtained from Menispermi Rhizoma, a traditional Chinese medicinal herb used in the treatment of inflammatory conditions in clinical practice. This suggests that MA has very promising potential for the development of anti-inflammatory therapeutics. Hence, this study aims to investigate the anti-inflammatory effects and underlying mechanisms of MA.
The anti-inflammatory effects of MA were evaluated in lipopolysaccharide (LPS)-induced mouse macrophage RAW264.7 cells. Its underlying mechanisms were explored through RNA sequencing and Western blotting. The binding modes and interactions sites between MA and phosphodiesterase 4B (PDE4B) were predicted using molecular docking and validated by molecular dynamics simulation.
MA treatment significantly reduced LPS-induced morphological changes, inflammatory cytokine relesae, and proinflammatory genes expression in RAW264.7 cells compared to the LPS-induced controls. Transcriptome sequencing analysis suggested that PDE4B might be a key target for MA to exert its therapeutic effect. Mechanismly, MA directly acted on Tyr405 site of PDE4B, thus leading to a sustained elevation of the cyclic adenosine monophosphate (cAMP) levels, which subsequently inactivated NF-κB signaling pathway by phosphorylating protein kinase A (PKA). MA inhibited the NF-κB-mediated inflammatory response depending on PDE4B.
MA, a natural and novel compound, exerted anti-inflammatory effects in LPS-induced RAW264.7 macrophage cells. It demonstrated a strong binding ability to the Tyr405 sites of PDE4B, thereby inhibiting NF-κB signaling pathway by regulating the cAMP-PKA axis. Elucidating the interaction between MA and PDE4B holds significant potential for the advancement of innovative therapeutic strategies aimed at inflammatory diseases. By strategically modulating this interaction, it may be feasible to achieve more precise regulation of inflammatory responses, thereby offering promising therapeutic benefits for conditions such as rheumatoid arthritis, asthma, and inflammatory bowel disease.
炎症反应失调和过度会导致组织损伤，这是大多数人类疾病的根本原因。甲氧基异阿朴啡碱A（MA）是一种新型的氧化异阿朴啡碱生物碱，从临床实践中用于治疗炎症的传统中草药北豆根中获得。这表明MA在开发抗炎治疗药物方面具有非常广阔的前景。因此，本研究旨在探讨MA的抗炎作用及其潜在机制。
在脂多糖（LPS）诱导的小鼠巨噬细胞RAW264.7细胞中评估MA的抗炎作用。通过RNA测序和蛋白质印迹法探索其潜在机制。使用分子对接预测MA与磷酸二酯酶4B（PDE4B）之间的结合模式和相互作用位点，并通过分子动力学模拟进行验证。
与LPS诱导的对照组相比，MA处理显著减少了LPS诱导的RAW264.7细胞的形态变化、炎性细胞因子释放和促炎基因表达。转录组测序分析表明，PDE4B可能是MA发挥其治疗作用的关键靶点。机制上，MA直接作用于PDE4B的Tyr405位点，从而导致环磷酸腺苷（cAMP）水平持续升高，随后通过磷酸化蛋白激酶A（PKA）使NF-κB信号通路失活。MA依赖于PDE4B抑制NF-κB介导的炎症反应。
MA是一种天然的新型化合物，在LPS诱导的RAW264.7巨噬细胞中发挥抗炎作用。它对PDE4B的Tyr405位点表现出很强的结合能力，从而通过调节cAMP-PKA轴抑制NF-κB信号通路。阐明MA与PDE4B之间的相互作用对于推进针对炎症性疾病的创新治疗策略具有重要潜力。通过策略性地调节这种相互作用，实现对炎症反应的更精确调节可能是可行的，从而为类风湿性关节炎、哮喘和炎症性肠病等疾病提供有前景的治疗益处。
