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Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization.

ABSTRACT: BACKGROUND AND PURPOSE:Isoacteoside (is a phenylethanoid isolated from Monochasma savatieri Franch. ex Maxim., which is an anti-inflammatory herb widely used in traditional Chinese medicine. However, the exact mechanism of the anti-inflammatory activity of isoacteoside is not completely understood. In this study, its anti-inflammatory mechanism was elucidated in mouse macrophages. EXPERIMENTAL APPROACH:The expression of the NF-?B pathway, MAPK pathway, iNOS, TNF-?, IL-6 and IL-1? was evaluated using Western blotting, quantitative real-time PCR or ELISA. TLR4 dimerization was determined by transfecting HEK293T cells with TLR4 plasmids. The in vivo anti-inflammatory effect of isoacteoside was determined using mouse models of xylene-induced ear oedema, LPS-induced endotoxic shock and LPS-induced endotoxaemia-associated acute kidney injury (AKI). KEY RESULTS:Isoacteoside suppressed COX-2, iNOS, TNF-?, IL-6 and IL-1? expression. Furthermore, isoacteoside attenuated the LPS-induced transcriptional activity of NF-?B by decreasing the levels of phosphorylated I?B-? and IKK and NF-?B/p65 nuclear translocation. In addition, isoacteoside inhibited LPS-induced transcriptional activity of AP-1 by reducing the levels of phosphorylated JNK1/2 and p38MAPK. Isoacteoside blocked LPS-induced TLR4 dimerization, resulting in a reduction in the recruitment of MyD88 and TIR-domain-containing adapter-inducing interferon-? (TRIF) and the phosphorylation of TGF-?-activated kinase-1 (TAK1). Pretreatment of mice with isoacteoside effectively inhibited xylene-induced ear oedema and LPS-induced endotoxic death and protected against LPS-induced AKI. CONCLUSIONS AND IMPLICATIONS:Isoacteoside blocked TLR4 dimerization, which activates the MyD88-TAK1-NF-?B/MAPK signalling cascades and TRIF pathway. Our data indicate that isoacteoside is a potential lead compound for the treatment of inflammatory diseases.

SUBMITTER: Gao H

PROVIDER: S-EPMC5554315 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization.

Gao Hongwei H Cui Yankun Y Kang Naixin N Liu Xin X Liu Yanli Y Zou Yue Y Zhang Ziyu Z Li Xiaoran X Yang Shilin S Li Ji J Wang Chunming C Xu Qiong-Ming QM Chen Xiuping X

British journal of pharmacology 20170714 17

<h4>Background and purpose</h4>Isoacteoside (is a phenylethanoid isolated from Monochasma savatieri Franch. ex Maxim., which is an anti-inflammatory herb widely used in traditional Chinese medicine. However, the exact mechanism of the anti-inflammatory activity of isoacteoside is not completely understood. In this study, its anti-inflammatory mechanism was elucidated in mouse macrophages.<h4>Experimental approach</h4>The expression of the NF-κB pathway, MAPK pathway, iNOS, TNF-α, IL-6 and IL-1β ...[more]

PMID: 28616865

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Project description:Objectives: Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct anti-inflammatory effect and anti-atherogenic effects of PNLA on activated purified CD14 monocytes from peripheral blood of patients with rheumatoid arthritis (RA) in vitro. Methods: Flow cytometry was used to assess the proportions of CD14 monocytes expressing TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptome (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing. Results: PNLA reduced percentage of monocytes expressing cytokines: TNF-a by 23% (p=0.048), IL-6 by 25% (p=0.011), IL-1B by 23% (p=0.050), IL-8 by 20% (p=0.066). Pathway analysis identified upstream activation of peroxisomes proliferator-activated receptors (PPARs), sirtuin3, and let7miRNA, KLF15 which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-a, and IL-6 signal transduction, were inhibited. Canonical Pathway analysis showed that PNLA inhibited oxidative phosphorylation (p=9.14E-09) and mitochondrial dysfunction (p=4.18E-08), while the sirtuin (SIRTs) signalling pathway was activated (p=8.89E-06) which interfere with the pathophysiologic process of atherosclerosis. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and Acetyl-CoA Acyltranferase2 (ACAA2); genes implicated in regulation of lipid and cell metabolism, inflammation, and mitochondrial dysfunction. Conclusion: PNLA has potential anti-atherogenic and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation regulates key miRNAs that are involved in metabolic, mitochondrial, and inflammatory pathways.

Dataset Information

Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization.

Publications

Isoacteoside, a dihydroxyphenylethyl glycoside, exhibits anti-inflammatory effects through blocking toll-like receptor 4 dimerization.

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