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  2. Iso-seco-tanapartholide activates Nrf2 signaling pathway through Keap1 modification and oligomerization to exert anti-inflammatory effects

Iso-seco-tanapartholide activates Nrf2 signaling pathway through Keap1 modification and oligomerization to exert anti-inflammatory effects

  • Free Radic Biol Med. 2022 Jan;178:398-412. doi: 10.1016/j.freeradbiomed.2021.12.259.
Dongrong Zhu 1 Yuanzheng Xia 1 Shang Li 1 Min Kong 1 Chen Chen 1 Guimin Xue 1 Lingyi Kong 2 Jianguang Luo 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: [email protected].
Abstract

Covalent modification of Keap1 results in reducing ubiquitination and the accumulation of Nrf2, which subsequently initiates the transcription of cellular anti-oxidant and anti-inflammatory genes. Iso-seco-tanapartholide (IST), a sesquiterpene isolated from the traditional Chinese medicine Artemisia argyi, had been reported to possess NF-κB inhibitory activity. However, its deep anti-inflammatory effects and direct target have never been reported. Here we show that IST activated Nrf2 and increased its target gene expression. In particular, LPS-caused inflammation in vitro and in vivo was mitigated by IST-induced Nrf2 activation but aggravated by Nrf2 inhibition. Mechanically, IST targeted Keap1 proteins via alkylating its cysteine residues 151, 273, 288, and so on. Subsequently, the modifying agent IST was displaced by intermolecular sulfhydryl disulfide interchange to lead to a disulfide dimer of Keap1. The resulting conformational change of Keap1 liberated Nrf2 from sequestration and allowed it translocation to the nucleus to activate the transcriptional program. Further studies demonstrated that Keap1 dimer formation contributed to the anti-inflammatory effects of IST. Taken together, our findings reveal a new mechanism for Nrf2 activation and provide a potential lead compound to treat inflammatory diseases through targeting Keap1.

Keywords

Anti-inflammatory; Iso-seco-tanapartholide; Keap1 dimer; Nrf2; Oligomerization.

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