Abstract
Chloranthalactone B (CTB), a lindenane-type sesquiterpenoid, was obtained from the Chinese medicinal herb Sarcandra glabra, which is frequently used as a remedy for inflammatory diseases. However, the anti-inflammatory mechanisms of CTB have not been fully elucidated. In this study, we investigated the molecular mechanisms underlying these effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CTB strongly inhibited the production of nitric oxide and pro-inflammatory mediators such as prostaglandin E₂, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 in RAW264.7 cells stimulated with LPS. A reverse-transcription polymerase chain reaction assay and Western blot further confirmed that CTB inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β at the transcriptional level, and decreased the luciferase activities of activator protein (AP)-1 reporter promoters. These data suggest that inhibition occurred at the transcriptional level. In addition, CTB blocked the activation of p38 mitogen-activated protein kinase (MAPK) but not c-Jun N-terminal kinase or extracellular signal-regulated kinase 1/2. Furthermore, CTB suppressed the phosphorylation of MKK3/6 by targeting the binding sites via formation of hydrogen bonds. Our findings clearly show that CTB inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways. Therefore, CTB could potentially be used as an anti-inflammatory agent.
Keywords:
Sarcandra glabra; chloranthalactone B; inflammation; sesquiterpene.
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Cell Line
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / antagonists & inhibitors
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Dinoprostone / biosynthesis
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Gene Expression Regulation
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Inflammation / prevention & control
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lactones / pharmacology*
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Lipopolysaccharides / antagonists & inhibitors*
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase 3 / antagonists & inhibitors
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MAP Kinase Kinase 3 / chemistry
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MAP Kinase Kinase 3 / genetics
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MAP Kinase Kinase 3 / metabolism
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MAP Kinase Kinase 6 / antagonists & inhibitors
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MAP Kinase Kinase 6 / chemistry
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MAP Kinase Kinase 6 / genetics
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MAP Kinase Kinase 6 / metabolism
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Macrophages / drug effects*
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Macrophages / metabolism
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Macrophages / pathology
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Mice
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Molecular
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Nitric Oxide / antagonists & inhibitors
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Sesquiterpenes / pharmacology*
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Signal Transduction
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Transcription Factor AP-1 / antagonists & inhibitors*
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transcription, Genetic
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anti-Inflammatory Agents
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IL1B protein, mouse
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Interleukin-1beta
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Interleukin-6
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Lactones
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Lipopolysaccharides
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Sesquiterpenes
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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chloranthalactone B
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interleukin-6, mouse
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Nitric Oxide
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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JNK Mitogen-Activated Protein Kinases
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 3
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MAP Kinase Kinase 6
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Map2k3 protein, mouse
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Map2k6 protein, mouse
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Dinoprostone