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

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

  • Bioorg Med Chem. 2022 Jul 15;66:116811. doi: 10.1016/j.bmc.2022.116811.
Yuan Lin 1 Kanjana Wongkrajang 2 Xiaofei Shen 3 Ping Wang 4 Zongyuan Zhou 5 Thipphawan Chuprajob 6 Nilubon Sornkaew 7 Na Yang 8 Lijuan Yang 5 Xiaoxia Lu 5 Ratchanaporn Chokchaisiri 9 Apichart Suksamrarn 10 Guolin Zhang 11 Fei Wang 12
Affiliations

Affiliations

  • 1 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Sichuan Xincheng Biological Co., LTD, Chengdu, China.
  • 2 Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand; Department of Chemistry, Faculty of Science and Technology, Pibulsongkram Rajabhat University, Phitsanulok, Thailand.
  • 3 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China; Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 4 Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 5 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
  • 6 Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand; Department of Chemistry, Faculty of Science, Siam University, Bangkok, Thailand.
  • 7 Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand.
  • 8 West China-Frontier PharmaTech Co., Ltd, Chengdu, China.
  • 9 Department of Chemistry, School of Science, University of Phayao, Phayao, Thailand.
  • 10 Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, Thailand. Electronic address: asuksamrarn@yahoo.com.
  • 11 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. Electronic address: zhanggl@cib.ac.cn.
  • 12 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. Electronic address: wangfei@cib.ac.cn.
Abstract

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.

Keywords

Diarylheptanoid; JAK2-STAT3; NF-κB; Sepsis; α7 nAchR.

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