State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
Chem Biol Interact. 2022 Aug 1;362:109998. doi: 10.1016/j.cbi.2022.109998. Epub 2022 May 29.
The emerging cholinergic anti-inflammatory pathway plays a key role in regulating inflammation. Steroids are known to possess remarkable anti-inflammatory activity. However, the links between steroids and the cholinergic anti-inflammatory pathway remain unidentified. In this study, eight steroids (1-8) featuring five different structural types were characterized from an endophytic fungus Aspergillus tennesseensis 1022LEF, and were subsequently evaluated for their potential role in regulating the cholinergic anti-inflammatory pathway. As a result, compound 8, with the best potency, showed remarkable anti-inflammatory activity at the nanomolar to low micromolar level. Further pharmacological study indicated that 8 notably increased α7nAchR expression and inhibited the activation of its down-stream signaling pathways. Collectively, the present study not only highlighted the potential correlation between steroids and the cholinergic anti-inflammatory pathway, but also identified 8 as a dual-functional modulator via directly inhibition to acetylcholinesterase as well as up-regulation of α7nAchR expression.
新兴的胆碱能抗炎途径在调节炎症中起着关键作用。众所周知，类固醇具有显著的抗炎活性。然而，类固醇与胆碱能抗炎途径之间的联系仍不清楚。在这项研究中，从内生真菌曲霉 1022LEF 中分离出了 8 种具有五种不同结构类型的类固醇（1-8），并对它们在调节胆碱能抗炎途径中的潜在作用进行了评估。结果表明，化合物 8 具有最佳的活性，在纳摩尔至低微摩尔水平表现出显著的抗炎活性。进一步的药理学研究表明，8 显著增加了α7nAchR 的表达，并抑制了其下游信号通路的激活。综上所述，本研究不仅强调了类固醇与胆碱能抗炎途径之间的潜在相关性，还发现 8 是一种双重功能调节剂，可通过直接抑制乙酰胆碱酯酶和上调α7nAchR 的表达。
