Discovery of diarylheptanoids that activate α7 nAchR-JAK2-STAT3 signaling in macrophages with anti-inflammatory activity in vitro and in vivo

• Published in: Bioorganic & medicinal chemistry 2022-07, Vol.66, p.116811-116811, Article 116811
• Main Authors: Lin, Yuan, Wongkrajang, Kanjana, Shen, Xiaofei, Wang, Ping, Zhou, Zongyuan, Chuprajob, Thipphawan, Sornkaew, Nilubon, Yang, Na, Yang, Lijuan, Lu, Xiaoxia, Chokchaisiri, Ratchanaporn, Suksamrarn, Apichart, Zhang, Guolin, Wang, Fei
• Format: Article
• Language: English
• Subjects: Diarylheptanoid; JAK2-STAT3; NF-κB; Sepsis; α7 nAchR
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2022.116811

[Display omitted] Acute inflammatory diseases, such as sepsis, are life-threatening illnesses. Regulating the α7 nicotinic acetylcholine receptor (α7 nAchR)-mediated signaling may be a promising strategy to treat sepsis. Diarylheptanoids have long been found to exhibit anti-inflammatory properties. However, the possible mechanism of diarylheptanoids has rarely been investigated. In this study, we isolated and synthesized 49 diarylheptanoids and analogues and evaluated their anti-inflammatory activities. Among them, compounds 28 and 40 markedly blocked lipopolysaccharide (LPS)-induced production of nitric oxide (NO), interleukin-1β (IL-1β) and interleukin-6 in murine RAW264.7 cells. Furthermore, compounds 28 and 40 also effectively attenuated LPS-induced sepsis, acute lung injury, and cytokines release in vivo. Mechanistically, compounds 28 and 40 significantly induced phosphorylation of janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling and suppression of nuclear factor-κB (NF-κB) pathway. Furthermore, blocking α7 nAchR could effectively abolish compounds 28 and 40-mediated activation of JAK2-STAT3 signaling as well as inhibition of NF-κB activation and NO production in LPS-exposed RAW264.7 cells. Collectively, our findings have identified a new diarylheptanoid, compound 28, as an agonist of α7 nAchR-JAK2-STAT3 signaling, which can be potentially developed as a valuable candidate for the treatment of sepsis, and provide a new lead structure for the development of anti-inflammatory agents targeting α7 nAchR-JAK2-STAT3 signaling.