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

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-?B 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-?B, thus reducing the expression of the pro-inflammatory cytokines iNOS, NO, COX-2, IL-6 and TNF-?; 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.

SUBMITTER: Ye S

PROVIDER: S-EPMC6832138 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Ye Shaoxia S Zheng Qiyao Q Zhou Yang Y Bai Bai B Yang Depo D Zhao Zhimin Z

Molecules (Basel, Switzerland) 20191016 20

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 w ...[more]

PMID: 31623197

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Project description:Subacute rumen acidosis (SARA) will cause an increase in endotoxin, which will have a negative effect on the bovine rumen epithelial cells (BREC). Flavonoids are effective in treating inflammation caused by endotoxin. Quercetin is a vital flavonoid widely occurring in fruits and vegetables and has received significant interest as a prospective anti-inflammatory antioxidant. Nonetheless, quercetin's protective machinery against such damage to BREC induced by lipopolysaccharide (LPS) remains unclear. A combined quercetin and LPS-induced BREC inflammation model was utilized to elucidate the effect of quercetin protecting BREC from LPS-induced injury. After treating BREC with different doses of LPS (1, 5, and 10 μg/mL) for 6 h or 24 h, the mRNA expression of inflammatory factors was detected. Our experimental results show the establishment of the BREC inflammation model via mRNA high expression of pro-inflammatory cytokines in BREC following 6 h treatment with 1 µg/mL LPS. The promotive effect of 80 μg/mL quercetin on BREC growth via the cell counting kit-8 (CCK8) assay was observed. The expression of pro-inflammatory cytokines and chemokines, notably tumor necrosis factor α (TNF-α), Interleukin 1β (IL-1β), IL-6, CC-motif chemokine ligand 2 (CCL2), CCL20, CCL28, and CXC motif chemokine 9 (CXCL9), etc., was significantly reduced by quercetin supplementation. We also analyzed the mRNA detection of related pathways by qRT-PCR. Our validation studies demonstrated that quercetin markedly curbed the mRNA expression of the toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein (MyD88) and the nuclear factor-κB (NF-κB) in LPS-treated BREC. In addition, western blot result outcomes confirmed, as expected, that LPS significantly activated phosphorylation of p44/42 extracellular regulated protein kinases (ERK1/2) and NF-κB. Unexpectedly, this effect was reversed by adding quercetin. To complement western blot results, we assessed p-ERK1/2 and p-p65 protein expression using immunofluorescence, which gave consistent results. Therefore, quercetin's capacity to bar the TLR4-mediated NF-κB and MAPK signaling pathways may be the cause of its anti-inflammatory effects on LPS-induced inflammatory reactions in BREC. According to these results, quercetin may be utilized as an anti-inflammatory medication to alleviate inflammation brought on by high-grain feed, and it also lays out a conceptual foundation regarding the development and utilization of quercetin in the later stage.

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Dataset Information

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

Publications

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

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