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Discovery of a New Pterocarpan-Type Antineuroinflammatory Compound from Sophora tonkinensis through Suppression of the TLR4/NFκB/MAPK Signaling Pathway with PU.1 as a Potential Target.
- Source :
-
ACS chemical neuroscience [ACS Chem Neurosci] 2019 Jan 16; Vol. 10 (1), pp. 295-303. Date of Electronic Publication: 2018 Sep 28. - Publication Year :
- 2019
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Abstract
- Neuroinflammation underlies many neuro-degenerative diseases. In this paper, we report the identification of a new pterocarpan-type anti-inflammatory compound named sophotokin isolated from Sophora tonkinensis. S. tonkinensis has been used traditionally for treatment of conditions related to inflammation. Our initial screening showed that sophotokin dose-dependently inhibits lipopolysaccharide (LPS)-stimulated production of NO, TNF-α, PGE2, and IL-1β in microglial cells. This antineuroinflammatory effect was associated with sophotokin's blockade of LPS-induced production of the inflammatory mediators iNOS and COX-2. Western blot and qPCR analysis demonstrated that sophotokin inhibits both the p38-MAPK and NF-κB signal pathways. Further studies revealed that sophotokin also suppresses the expression of cluster differentiation 14 (CD14) in the toll-like receptor 4 (TLR4) signaling pathway. Following down-regulation of MyD88 and TRAF6, sophotokin inhibits the activation of the NF-κB and MAPK signal pathways in LPS-induced BV-2 cells. In silico studies suggested that sophotokin could interact with PU.1-DNA complex through hydrogen binding at sites 1 and 2 of the complex, blocking the DNA binding. This suggests that PU.1 may be a potential target of sophotokin. Taken together, these results suggest that sophotokin may have therapeutic potential for diseases related to neuroinflammation. The mechanism of antineuroinflammatory effects involves inhibition of the TLR4 signal pathway at the sites of NF-κB and MAPK with PU.1 as a likely upstream target.
- Subjects :
- Animals
Anti-Inflammatory Agents chemistry
Anti-Inflammatory Agents isolation & purification
Cell Line
Cell Survival drug effects
Cell Survival physiology
Drug Discovery methods
Inflammation Mediators antagonists & inhibitors
Inflammation Mediators metabolism
Mice
Mitogen-Activated Protein Kinases metabolism
Molecular Docking Simulation methods
NF-kappa B metabolism
Neuroprotective Agents chemistry
Neuroprotective Agents isolation & purification
Neuroprotective Agents pharmacology
Plant Extracts chemistry
Plant Extracts isolation & purification
Plant Extracts pharmacology
Proto-Oncogene Proteins metabolism
Pterocarpans chemistry
Pterocarpans isolation & purification
Signal Transduction drug effects
Signal Transduction physiology
Toll-Like Receptor 4 metabolism
Trans-Activators metabolism
Anti-Inflammatory Agents pharmacology
Mitogen-Activated Protein Kinases antagonists & inhibitors
NF-kappa B antagonists & inhibitors
Proto-Oncogene Proteins antagonists & inhibitors
Pterocarpans pharmacology
Sophora
Toll-Like Receptor 4 antagonists & inhibitors
Trans-Activators antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1948-7193
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- ACS chemical neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 30223643
- Full Text :
- https://doi.org/10.1021/acschemneuro.8b00243