2. Academic Validation
  3. 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: [email protected].
  • 11 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. Electronic address: [email protected].
  • 12 Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. Electronic address: [email protected].
PMID: 35576655 DOI: 10.1016/j.bmc.2022.116811
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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