Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-kappa B activation in cultured astrocytes and microglial BV-2 cells

Title
Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-kappa B activation in cultured astrocytes and microglial BV-2 cells
Author(s)
최동영송석영[송석영]정유연[정유연]황철주[황철주]이희범[이희범]석창현[석창현]김주환[김주환]이상민[이상민]서현옥[서현옥]현병국[현병국]한상배[한상배]함영완[함영완]황방연[황방연]홍진태[홍진태]
Keywords
NITRIC-OXIDE SYNTHASE; AMYLOID-BETA GENERATION; IN-VIVO MODELS; ALZHEIMERS-DISEASE; INFLAMMATORY RESPONSES; PRECURSOR PROTEIN; MEMORY IMPAIRMENT; OXIDATIVE DAMAGE; STAT3 ACTIVATION; LIPOPOLYSACCHARIDE
Issue Date
201407
Publisher
BIOMED CENTRAL LTD
Citation
JOURNAL OF NEUROINFLAMMATION, v.11
Abstract
Background: ent-Sauchinone is a polyphenolic compound found in plants belonging to the lignan family. ent-Sauchinone has been shown to modulate the expression of inflammatory factors through the nuclear factor-kappa B (NF-kappa B) signaling pathway. It is well known that neuroinflammation is associated with amyloidogenesis. Thus, in the present study, we investigated whether ent-Sauchinone could have anti-amyloidogenic effects through the inhibition of NF-kappa B pathways via its anti-inflammatory property. Methods: To investigate the potential effect of ent-Sauchinone on anti-neuroinflammation and anti-amyloidogenesis in in vitro studies, we used microglial BV-2 cells and cultured astrocytes treated with ent-Sauchinone (1, 5, and 10 mu M) for 24 hours. For the detection of anti-neuro-inflammatory responses, reative oxygen species (ROS) and Nitric oxide (NO) generation and inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression were measured with assay kits and western blotting. beta-secretase and beta-secretase activities and beta-amyloid levels were determined for measuring the anti-amyloidogenic effects of ent-Sauchinone by enzyme assay kits. NF-kappa B and STAT3 signals were detected with electromobility shift assay (EMSA) to study the related signaling pathways. The binding of ent-Sauchinone to STAT3 was evaluated by a pull-down assay and by a docking model using Autodock VINA software (Hoover's Inc., Texas, United states). Results: ent-Sauchinone (1, 5, and 10 mu M) effectively decreased lipopolysaccharide (LPS)-(1 mu g/ml) induced inflammatory responses through the reduction of ROS and NO generations and iNOS and COX-2 expressions in cultured astrocytes and microglial BV-2 cells. ent-Sauchinone also inhibited LPS-induced amyloidogenesis through the inhibition of beta-secretase and beta-secretase activity. NF-kappa B amyloid and STAT3, critical transcriptional factors regulating not only inflammation but also amyloidogenesis, were also inhibited in a concentration dependent manner by ent-Sauchinone by blocking the phosphorylation of I.B and STAT3 in cultured astrocytes and microglial BV-2 cells. The docking model approach showed that ent-Sauchinone binds to STAT3, and the employment of a STAT3 inhibitor and siRNA reversed ent-Sauchinone-induced inhibition NF-kappa B activation and A beta generation. Conclusions: These results indicated that ent-Sauchinone inhibited neuroinflammation and amyloidogenesis through the inhibition of STAT3-mediated NF-kappa B activity, and thus could be applied in the treatment of neuro-inflammatory diseases, including Alzheimer's disease.
URI
http://hdl.handle.net/YU.REPOSITORY/31592http://dx.doi.org/10.1186/1742-2094-11-118
ISSN
1742-2094
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약학대학 > 약학부 > Articles
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