Inhibitory effect of a 2,4-bis(4-hydroxyphenyl)-2-butenal diacetate on neuro-inflammatory reactions via inhibition of STAT1 and STAT3 activation in cultured astrocytes and microglial BV-2 cells

Kim, Jin A.; Yun, Hyung-Mun; Jin, Peng; Lee, Hee Pom; Han, Jin; Udumula, Venkatareddy; Moon, Dong Cheul; Han, Sang Bae; Oh, Ki Wan; Ham, Young Wan; Jung, Heon-Sang; Song, Ho Sueb; Hong, Jin Tae

doi:10.1016/j.neuropharm.2013.06.032

Cited by 16 publications

(19 citation statements)

References 56 publications

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“…Fujishita et.al showed that IL-6 by itself had a neuroprotective effect on neurons [29]. Research has indicated that GFAP-expressing astrocytes are activated and provide neuronal protection via ERK [30] and/or STAT3 [31] signaling during inflammation. Other studies have suggested that an intricate regulatory system controls inflammation between neurons and glial cells via cell-to-cell contact rather than with diffusible factors from neurocytes [32].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection by IFN-γviaastrocyte-secreted IL-6 in acute neuroinflammation

Sun

Jia

et al. 2017

Oncotarget

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Inflammation eliminates pathogenic infections while also threatening the integrity of the central nervous system. In this study, using in vivo and in vitro models of acute neuroinflammation, we investigated the mechanisms by which inflammation and astrocytes affect neuronal apoptosis. The in vitro model mimicked acute neuroinflammation by incubation in IFN-γ-containing media with primary cultured cerebellar granule neurons, with or without cultured astrocytes. This quickly induced neuronal apoptosis characterized by cleaved caspase-3 expression, Hoechst 33342 staining, and intercellular Ca2+ influx, whereas the presence of astrocytes significantly protected neurons from these effects. IFN-γ in the inflammation media also promoted astrocyte secretion of IL-6, essential for protection. The supernatants of rat peripheral blood mononuclear cells stimulated by lymphocyte mitogen lipopolysaccharide or concanavalin A were used as inflammation media to verify the results. The in vivo model involved a peripheral challenge with lipopolysaccharide, with or without recombinant IFN-γ, in C57BL/6 mice. This confirmed the in vitro results: anti-IFN-γ antibodies exacerbated the acute course of neuroinflammation and led to neurocyte apoptosis in vivo. The pro-inflammatory cytokine IFN-γ provided neuroprotection during acute neuroinflammation via induction of astrocyte-secreted IL-6. The findings provide novel insights into the mechanisms of neuroprotection by IFN-γ during acute neuroinflammation, and may impact therapies for inflammation-related central nervous system injury and disease.

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Section: Discussionmentioning

confidence: 99%

Neuroprotection by IFN-γviaastrocyte-secreted IL-6 in acute neuroinflammation

Sun

Jia

et al. 2017

Oncotarget

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“…EMSA was performed as described previously (Kim et al ., ). The relative density of the protein bands was scanned for densitometry using MyImage and quantified by Labworks 4.0 software (UVP, Inc., Upland, CA, USA).…”

Section: Emsamentioning

confidence: 97%

“…The Maillard reaction may produce, non‐enzymically, coloured or colourless products, such as glucose‐tyrosine, glucose‐lysine, fructose‐lysine, ribose‐lysine, xylose‐arginine, xylose‐glycine and xylose‐tryptophan (Aeschbacher, ; Valls‐Bellés et al ., ). Recently, we synthesized (E)‐2,4‐bis( p ‐hydroxyphenyl)‐2‐butenal using tyrosine and fructose under typical Maillard reaction conditions, including high temperature and pressure (Hwang et al ., ), and described its antioxidant and anti‐inflammatory properties in brain macrophages (Nah et al ., ; Kim et al ., ), as well as anti‐cancer and anti‐amyloidogenic effects through inhibition of the NF‐κB and STAT pathways via antioxidant mechanisms (Ban et al ., ; Jin et al ., ; Kim et al ., ). In the present study, we have investigated whether (E)‐2,4‐bis( p ‐hydroxyphenyl)‐2‐butenal can provide antioxidant and anti‐inflammatory activities, and thus anti‐arthritic activities through the inhibition of NF‐κB/IKK and STAT3 pathways in a macrophage cell line and in human synoviocytes in vitro and in a model of collagen‐induced arthritis (CIA) in mice.…”

Section: Introductionmentioning

confidence: 99%

Anti‐arthritis effects of (E)‐2,4‐bis(p‐hydroxyphenyl)‐2‐butenal are mediated by inhibition of the STAT3 pathway

Ban

Kim

Lee

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSEProducts of Maillard reactions between aminoacids and reducing sugars are known to have anti-inflammatory properties. Here we have assessed the anti-arthritis effects of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal and its possible mechanisms of action. EXPERIMENTAL APPROACHWe used cultures of LPS-activated macrophages (RAW264.7 cells) and human synoviocytes from patients with rheumatoid arthritis for in vitro assays and the collagen-induced arthritis model in mice. NO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities were measured in vitro and in joint tissues of arthritic mice, along with clinical scores and histopathological assessments. Binding of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal to STAT3 was evaluated by a pull-down assay and its binding site was predicted using molecular docking studies with Autodock VINA. KEY RESULTS(E)-2,4-bis(p-hydroxyphenyl)-2-butenal (2.5-10 μg·mL −1 ) inhibited LPS-inducedNO generation, iNOS and COX2 expression, and NF-κB/IKK and STAT3 activities in macrophage and human synoviocytes. This compound also suppressedcollagen-induced arthritic responses in mice by inhibiting expression of iNOS and COX2, and NF-κB/IKK and STAT3 activities; it also reduced bone destruction and fibrosis in joint tissues. A pull-down assay showed that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal interfered with binding of ATP to STAT3. Docking studies suggested that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal bound to the DNA-binding interface of STAT3 possibly inhibiting ATP binding to STAT3 in an allosteric manner. CONCLUSIONS AND IMPLICATIONS(E)-2,4-bis(p-hydroxyphenyl)-2-butenal exerted anti-inflammatory and anti-arthritic effects through inhibition of the NF-κB/STAT3 pathway by direct binding to STAT3. This compound could be a useful agent for the treatment of arthritic disease. AbbreviationsCIA, collagen-induced arthritis; CFA, complete Freund's adjuvant; FLS, fibroblast-like synoviocytes; IKKβ, IκB kinase β BJP British Journal of Pharmacology

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“…We previously identified BHPB, a tyrosine-fructose MR product as a STAT3 inhibitor, which has potential therapeutic properties against multiple diseases including RA15161718192021222333. Despite its multiple pharmacological properties, the major drawback of BHPB in drug development is its lack of drug-likeness properties and limited chemical stability.…”

Section: Discussionmentioning

confidence: 99%

“…This action mediates the potent therapeutic effects of BHPB against RA14 as well as Alzheimer’s disease151617, and tumour growth181920212223. However, its drug-likeness is not relevant for drug development because it has a low chemical stability, low solubility, and high toxicity.…”

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confidence: 99%

Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3

Son

Kim

Nah

et al. 2016

Sci Rep

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Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA.

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Inhibitory effect of a 2,4-bis(4-hydroxyphenyl)-2-butenal diacetate on neuro-inflammatory reactions via inhibition of STAT1 and STAT3 activation in cultured astrocytes and microglial BV-2 cells

Cited by 16 publications

References 56 publications

Neuroprotection by IFN-γviaastrocyte-secreted IL-6 in acute neuroinflammation

Neuroprotection by IFN-γviaastrocyte-secreted IL-6 in acute neuroinflammation

Anti‐arthritis effects of (E)‐2,4‐bis(p‐hydroxyphenyl)‐2‐butenal are mediated by inhibition of the STAT3 pathway

Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3

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