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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.
Highlights
Inflammation is a first defense initiated by the immune system to noxious stimuli, infections and tissue injury [1]
Appropriate inflammatory responses are protective for the body, but excessive responses lead to inflammation related diseases such as cancer, cardiovascular diseases and rheumatoid arthritis [2,3]
Acute inflammation is a reaction during infectious challenge and tissue injury, whereas chronic inflammation is a persistent reaction caused by tissue damage [18]
Summary
Inflammation is a first defense initiated by the immune system to noxious stimuli, infections and tissue injury [1]. Appropriate inflammatory responses are protective for the body, but excessive responses lead to inflammation related diseases such as cancer, cardiovascular diseases and rheumatoid arthritis [2,3]. Inflammation has been investigated intensively in recent years, owing to its biological complexity and its close relationship with diverse pathological conditions, it is still a therapeutic challenge to develop novel anti-inflammatory drugs with high efficacy and low side effects [4,5]. TLRs are key transmembrane receptors that play a significant role in recognizing microbial infections in mammals [6]. TLR4, a key member of the TLR family, participates in the intrinsic immune response by recognizing pathogen-associated molecular patterns (PAMPs) [7]. After recognizing lipopolysaccharide (LPS), and recruiting its adaptor protein MyD88, TLR4 triggers the activation of the Molecules 2019, 24, 3731; doi:10.3390/molecules24203731 www.mdpi.com/journal/molecules
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