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Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-β generation and inflammatory reactions via inhibition of NF-κB and STAT3 activation in cultured astrocytes and microglial BV-2 cells.

Abstract

BACKGROUND

Amyloidogenesis is linked to neuroinflammation. The tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal, possesses anti-inflammatory properties in cultured macrophages, and in an arthritis animal model. Because astrocytes and microglia are responsible for amyloidogenesis and inflammatory reactions in the brain, we investigated the anti-inflammatory and anti-amyloidogenic effects of 2,4-bis(p-hydroxyphenyl)-2-butenal in lipopolysaccharide (LPS)-stimulated astrocytes and microglial BV-2 cells.

METHODS

Cultured astrocytes and microglial BV-2 cells were treated with LPS (1 μg/ml) for 24 h, in the presence (1, 2, 5 μM) or absence of 2,4-bis(p-hydroxyphenyl)-2-butenal, and harvested. We performed molecular biological analyses to determine the levels of inflammatory and amyloid-related proteins and molecules, cytokines, Aβ, and secretases activity. Nuclear factor-kappa B (NF-κB) DNA binding activity was determined using gel mobility shift assays.

RESULTS

We found that 2,4-bis(p-hydroxyphenyl)-2-butenal (1, 2, 5 μM) suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the production of nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in LPS (1 μg/ml)-stimulated astrocytes and microglial BV-2 cells. Further, 2,4-bis(p-hydroxyphenyl)-2-butenal inhibited the transcriptional and DNA binding activity of NF-κB--a transcription factor that regulates genes involved in neuroinflammation and amyloidogenesis via inhibition of IκB degradation as well as nuclear translocation of p50 and p65. Consistent with the inhibitory effect on inflammatory reactions, 2,4-bis(p-hydroxyphenyl)-2-butenal inhibited LPS-elevated Aβ42 levels through attenuation of β- and γ-secretase activities. Moreover, studies using signal transducer and activator of transcription 3 (STAT3) siRNA and a pharmacological inhibitor showed that 2,4-bis(p-hydroxyphenyl)-2-butenal inhibits LPS-induced activation of STAT3.

CONCLUSIONS

These results indicate that 2,4-bis(p-hydroxyphenyl)-2-butenal inhibits neuroinflammatory reactions and amyloidogenesis through inhibition of NF-κB and STAT3 activation, and suggest that 2,4-bis(p-hydroxyphenyl)-2-butenal may be useful for the treatment of neuroinflammatory diseases like Alzheimer's disease.

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  • Authors+Show Affiliations

    ,

    College of Pharmacy, Chungbuk National University, 12 Gaesin-dong, Heungduk-gu, Cheongju, Chungbuk 361-763, Korea.

    , , , , , ,

    Source

    Journal of neuroinflammation 8: 2011 Oct 07 pg 132

    MeSH

    Aldehydes
    Amyloid beta-Peptides
    Animals
    Astrocytes
    Cell Line
    Cyclooxygenase 2
    Fructose
    Humans
    Inflammation
    Interleukin-1beta
    Lipopolysaccharides
    Maillard Reaction
    Mice
    Microglia
    NF-kappa B
    Nitric Oxide
    Nitric Oxide Synthase Type II
    Reactive Oxygen Species
    STAT3 Transcription Factor
    Tumor Necrosis Factor-alpha
    Tyrosine

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21982455

    Citation

    Lee, Young-Jung, et al. "Inhibitory Effect of a Tyrosine-fructose Maillard Reaction Product, 2,4-bis(p-hydroxyphenyl)-2-butenal On Amyloid-β Generation and Inflammatory Reactions Via Inhibition of NF-κB and STAT3 Activation in Cultured Astrocytes and Microglial BV-2 Cells." Journal of Neuroinflammation, vol. 8, 2011, p. 132.
    Lee YJ, Choi DY, Choi IS, et al. Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-β generation and inflammatory reactions via inhibition of NF-κB and STAT3 activation in cultured astrocytes and microglial BV-2 cells. J Neuroinflammation. 2011;8:132.
    Lee, Y. J., Choi, D. Y., Choi, I. S., Han, J. Y., Jeong, H. S., Han, S. B., ... Hong, J. T. (2011). Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-β generation and inflammatory reactions via inhibition of NF-κB and STAT3 activation in cultured astrocytes and microglial BV-2 cells. Journal of Neuroinflammation, 8, p. 132. doi:10.1186/1742-2094-8-132.
    Lee YJ, et al. Inhibitory Effect of a Tyrosine-fructose Maillard Reaction Product, 2,4-bis(p-hydroxyphenyl)-2-butenal On Amyloid-β Generation and Inflammatory Reactions Via Inhibition of NF-κB and STAT3 Activation in Cultured Astrocytes and Microglial BV-2 Cells. J Neuroinflammation. 2011 Oct 7;8:132. PubMed PMID: 21982455.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Inhibitory effect of a tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal on amyloid-β generation and inflammatory reactions via inhibition of NF-κB and STAT3 activation in cultured astrocytes and microglial BV-2 cells. AU - Lee,Young-Jung, AU - Choi,Dong-Young, AU - Choi,Im Seup, AU - Han,Jin-Yi, AU - Jeong,Heon-Sang, AU - Han,Sang Bae, AU - Oh,Ki-Wan, AU - Hong,Jin Tae, Y1 - 2011/10/07/ PY - 2011/03/13/received PY - 2011/10/07/accepted PY - 2011/10/11/entrez PY - 2011/10/11/pubmed PY - 2012/3/31/medline SP - 132 EP - 132 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 8 N2 - BACKGROUND: Amyloidogenesis is linked to neuroinflammation. The tyrosine-fructose Maillard reaction product, 2,4-bis(p-hydroxyphenyl)-2-butenal, possesses anti-inflammatory properties in cultured macrophages, and in an arthritis animal model. Because astrocytes and microglia are responsible for amyloidogenesis and inflammatory reactions in the brain, we investigated the anti-inflammatory and anti-amyloidogenic effects of 2,4-bis(p-hydroxyphenyl)-2-butenal in lipopolysaccharide (LPS)-stimulated astrocytes and microglial BV-2 cells. METHODS: Cultured astrocytes and microglial BV-2 cells were treated with LPS (1 μg/ml) for 24 h, in the presence (1, 2, 5 μM) or absence of 2,4-bis(p-hydroxyphenyl)-2-butenal, and harvested. We performed molecular biological analyses to determine the levels of inflammatory and amyloid-related proteins and molecules, cytokines, Aβ, and secretases activity. Nuclear factor-kappa B (NF-κB) DNA binding activity was determined using gel mobility shift assays. RESULTS: We found that 2,4-bis(p-hydroxyphenyl)-2-butenal (1, 2, 5 μM) suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the production of nitric oxide (NO), reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) in LPS (1 μg/ml)-stimulated astrocytes and microglial BV-2 cells. Further, 2,4-bis(p-hydroxyphenyl)-2-butenal inhibited the transcriptional and DNA binding activity of NF-κB--a transcription factor that regulates genes involved in neuroinflammation and amyloidogenesis via inhibition of IκB degradation as well as nuclear translocation of p50 and p65. Consistent with the inhibitory effect on inflammatory reactions, 2,4-bis(p-hydroxyphenyl)-2-butenal inhibited LPS-elevated Aβ42 levels through attenuation of β- and γ-secretase activities. Moreover, studies using signal transducer and activator of transcription 3 (STAT3) siRNA and a pharmacological inhibitor showed that 2,4-bis(p-hydroxyphenyl)-2-butenal inhibits LPS-induced activation of STAT3. CONCLUSIONS: These results indicate that 2,4-bis(p-hydroxyphenyl)-2-butenal inhibits neuroinflammatory reactions and amyloidogenesis through inhibition of NF-κB and STAT3 activation, and suggest that 2,4-bis(p-hydroxyphenyl)-2-butenal may be useful for the treatment of neuroinflammatory diseases like Alzheimer's disease. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/21982455/Inhibitory_effect_of_a_tyrosine_fructose_Maillard_reaction_product_24_bis_p_hydroxyphenyl__2_butenal_on_amyloid_β_generation_and_inflammatory_reactions_via_inhibition_of_NF_κB_and_STAT3_activation_in_cultured_astrocytes_and_microglial_BV_2_cells_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-8-132 DB - PRIME DP - Unbound Medicine ER -