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  2. Chlojaponilactone B Attenuates Lipopolysaccharide-Induced Inflammatory Responses by Suppressing TLR4-Mediated ROS Generation and NF-κB Signaling Pathway

Chlojaponilactone B Attenuates Lipopolysaccharide-Induced Inflammatory Responses by Suppressing TLR4-Mediated ROS Generation and NF-κB Signaling Pathway

  • Molecules. 2019 Oct 16;24(20):3731. doi: 10.3390/molecules24203731.
Shaoxia Ye 1 Qiyao Zheng 2 Yang Zhou 3 Bai Bai 4 Depo Yang 5 6 Zhimin Zhao 7 8
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. yeshx9@mail2.sysu.edu.cn.
  • 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. zhengqy5@mail2.sysu.edu.cn.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. zhouy596@mail2.sysu.edu.cn.
  • 4 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. baib6@mail2.sysu.edu.cn.
  • 5 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. lssydp@mail.sysu.edu.cn.
  • 6 Guangdong Technology Research Center for Advanced Chinese Medicine, Guangzhou 510006, Guangdong, China. lssydp@mail.sysu.edu.cn.
  • 7 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China. zhaozhm2@mail.sysu.edu.cn.
  • 8 Guangdong Technology Research Center for Advanced Chinese Medicine, Guangzhou 510006, Guangdong, China. zhaozhm2@mail.sysu.edu.cn.
Abstract

The lindenane-type sesquiterpenoid chlojaponilactone B (1), isolated from Chloranthus japonicus, has been reported to possess anti-inflammatory properties. The present study aimed to further explore the molecular mechanisms underlying the anti-inflammatory activity of 1. RNA-seq analyses revealed the significant changes in the expression levels of genes related to multiple inflammatory pathways upon treatment of lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophages with 1. Real time PCR (RT-PCR) and Western blotting were used to confirm the modulations in the expression of essential molecules related to inflammatory responses. Compound 1 inhibited toll like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) activation upon LPS stimulation, influencing the expression of NF-κB and pro-inflammatory mediators. Molecular docking studies showed that 1 bound to TLR4 in a manner similar to that of TAK-242, a TLR4 Inhibitor. Moreover, our results showed that 1 suppressed inflammatory responses by inhibiting TLR4 and subsequently decreasing Reactive Oxygen Species (ROS) generation, downregulating the NF-κB, thus reducing the expression of the pro-inflammatory cytokines iNOS, NO, COX-2, IL-6 and TNF-α; these effects were similar to those of TAK-242. We proposed that 1 should be considered as a potential anti-inflammatory compound in future research.

Keywords

Chloranthus japonicus; NF-κB; RNA-seq; ROS; TLR4; chlojaponilactone B; inflammation.

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