Natural feed contaminant zearalenone decreases the expressions of important pro- and anti-inflammatory mediators and mitogen-activated protein kinase/NF-κB signalling molecules in pigs

Zearalenone (ZEA) is an oestrogenic mycotoxin produced byFusariumspecies, considered to be a risk factor from both public health and agricultural perspectives. In the presentin vivostudy, a feeding trial was conducted to evaluate thein vivoeffect of a ZEA-contaminated diet on immune response in young pigs. The effect of ZEA on pro-inflammatory (TNF-α, IL-8, IL-6, IL-1β and interferon-γ) and anti-inflammatory (IL-10 and IL-4) cytokines and other molecules involved in inflammatory processes (matrix metalloproteinases (MMP)/tissue inhibitors of matrix metalloproteinases (TIMP), nuclear receptors: PPARγ and NF-κB1, mitogen-activated protein kinases (MAPK): mitogen-activated protein kinase kinase kinase 7 (TAK1)/mitogen-activated protein kinase 14 (p38α)/mitogen-activated protein kinase 8 (JNK1)/ mitogen-activated protein kinase 9 (JNK2)) in the liver of piglets was investigated. The present results showed that a concentration of 316 parts per billion ZEA leads to a significant decrease in the levels of pro- and anti-inflammatory cytokines at both gene expression and protein levels, correlated with a decrease in the levels of other inflammatory mediators, MMP and TIMP. The results also showed that dietary ZEA induces a dramatic reduction in the expressions ofNF-κB1andTAK1/p38αMAPK genes in the liver of the experimentally intoxicated piglets, and has no effect on the expression ofPPARγmRNA. The present results suggest that the toxic action of ZEA begins in the upstream of the MAPK signalling pathway by the inhibition of TAK1, a MAPK/NF-κB activator. In conclusion, the present study shows that ZEA alters several important parameters of the hepatic cellular immune response. From an economic point of view, these data suggest that, in pigs, ZEA is not only a powerful oestrogenic mycotoxin but also a potential hepatotoxin when administered through the oral route. Therefore, the present results represent additional data from cellular and molecular levels that could be taken into account in the determination of the regulation limit of the tolerance to ZEA.

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In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma

The Journal of Immunology ◽

10.4049/jimmunol.169.10.5955 ◽

2002 ◽

Vol 169 (10) ◽

pp. 5955-5961 ◽

Cited By ~ 30

Author(s):

Barun K. Choudhury ◽

James S. Wild ◽

Rafeul Alam ◽

Dennis M. Klinman ◽

Istvan Boldogh ◽

...

Keyword(s):

Protein Kinase ◽

Mitogen Activated Protein Kinase ◽

Cpg Oligodeoxynucleotide ◽

Mitogen Activated Protein ◽

Anti Inflammatory

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CGH2466, a combined adenosine receptor antagonist, p38 mitogen-activated protein kinase and phosphodiesterase type 4 inhibitor with potent in vitro and in vivo anti-inflammatory activities

British Journal of Pharmacology ◽

10.1038/sj.bjp.0706132 ◽

2005 ◽

Vol 144 (7) ◽

pp. 1002-1010 ◽

Cited By ~ 13

Author(s):

Alexandre Trifilieff ◽

Thomas H Keller ◽

Neil J Press ◽

Trevor Howe ◽

Peter Gedeck ◽

...

Keyword(s):

Protein Kinase ◽

Receptor Antagonist ◽

Adenosine Receptor ◽

Mitogen Activated Protein Kinase ◽

Adenosine Receptor Antagonist ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Phosphodiesterase Type

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Compound K Inhibits Interleukin-1β-induced Expression of Inflammatory Mediators and Matrix Metalloproteinases by Inhibiting Mitogen-activated Protein Kinase Activation in Chondrocytes

Journal of Rheumatic Diseases ◽

10.4078/jrd.2018.25.3.188 ◽

2018 ◽

Vol 25 (3) ◽

pp. 188 ◽

Cited By ~ 1

Author(s):

Eun Hye Park ◽

Ji Soo Kim ◽

Jeong Seok Lee ◽

Yun Jong Lee ◽

Yeong Wook Song ◽

...

Keyword(s):

Protein Kinase ◽

Matrix Metalloproteinases ◽

Inflammatory Mediators ◽

Mitogen Activated Protein Kinase ◽

Interleukin 1Β ◽

Compound K ◽

Induced Expression ◽

Kinase Activation ◽

Protein Kinase Activation ◽

Mitogen Activated Protein

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Differential effect of p38 and MK2 kinase inhibitors on the inflammatory and toxicity biomarkers in vitro

Human & Experimental Toxicology ◽

10.1177/0960327117715901 ◽

2017 ◽

Vol 37 (5) ◽

pp. 521-531 ◽

Cited By ~ 2

Author(s):

RK Singh ◽

M Diwan ◽

SG Dastidar ◽

AK Najmi

Keyword(s):

Protein Kinase ◽

Caspase 3 ◽

Kinase Inhibitors ◽

Inflammatory Responses ◽

Interferon Γ ◽

Mitogen Activated Protein Kinase ◽

Toxicity Biomarkers ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Background: Many inflammatory responses including chemotaxis, production of nitric oxide, and modulation of pro-inflammatory cytokines in immunological cells are mediated by p38MAPK. Due to its pivotal role, p38MAPK has been extensively explored as a molecular target for inhibition of chronic inflammation; however, it has not been successful so far due to serious toxicity issues. Among several downstream substrates of p38, mitogen-activated protein kinase-activated protein kinase 2 (MK2) has been reported to be a direct and essential downstream component in regulation of innate immune and inflammatory responses. Thus, in this study, we aimed to understand relative molecular differences between p38 and MK2 kinase inhibition in terms of a comparative anti-inflammatory potential along with molecular regulation of toxicity biomarkers such as Phospho c-Jun N-Terminal Kinase (pJNK), caspase-3, and hepatic enzyme levels in relevant human cells in vitro. Results: Both p38 and MK2 inhibitors attenuated lipopolysaccharide-induced pro-inflammatory biomarkers expression. In addition, both these kinase inhibitors inhibited release of Th1 and Th17 cytokines in phytohemagglutinin-induced cells with MK2 inhibitor showing a better potency for inhibition of Th1 cytokine release, interferon-γ. In the mechanistic differentiation studies, p38 inhibitors displayed an increase in pJNK and caspase-3 activity in U937 cells and elevation in aspartate transaminase enzyme in HepG2 cells, whereas MK2 inhibitor did not show such adverse toxic effects. Conclusion: Taken together, inhibition of MK2 kinase can be a relatively preferred strategy as an anti-inflammatory therapy over direct inhibition of p38 kinase in p38MAPK pathway.

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Anti-inflammatory Mechanism of Rhein in Treating Asthma Based on Network Pharmacology

10.21203/rs.3.rs-16994/v3 ◽

2020 ◽

Author(s):

Junfang Feng ◽

Ou Chen ◽

Yibiao Wang

Keyword(s):

Protein Kinase ◽

Signalling Pathway ◽

Mitogen Activated Protein Kinase ◽

Signalling Pathways ◽

Network Pharmacology ◽

Active Growth ◽

Inflammatory Mechanism ◽

Mitogen Activated Protein ◽

Anti Inflammatory

Abstract Background: Network pharmacological methods were used to predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma, and to elucidate its mechanism of action. In addition, we validated the anti-inflammatory effects of rhein in human bronchial epithelial (HBE) cells.Methods: The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform 2.3 (TCMSP), and molecular docking was also performed. A network of predicted rhein targets was established and analysed with Cytoscape 3.7.1. The anti-inflammatory targets in the Therapeutic Target Database 2020 (TTD) were searched to build a protein-protein interaction network (PPI), which was merged with the ingredient-target network to screen anti-inflammatory targets associated with rhein. A network of anti-inflammatory rhein targets during the in vivo treatment of asthma was constructed to screen the anti-inflammatory targets related to asthma. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed with the Enrichr database and Cytoscape 3.7.1. The expression levels of proteins in the mitogen-activated protein kinase / nuclear factor kappa-B (MAPK/NF-κB) signalling pathway were assessed by western blot analysis.Results: Altogether, Eighty-three targets were obtained. Epidermal active growth factor receptor (EGFR), E-selecting (E-SELE), macrophage migration inhibitory factor (MIF), and mitogen-activated protein kinase 14 (MAPK14) might be important anti-inflammatory targets of rhein during asthma treatment. We selected the MAPK signalling pathway to determine the anti-inflammatory effects of rhein.Conclusion: The anti-inflammatory mechanism of the treatment of asthma with rhein may be related to MAPK14, EGFR, E-SELE and MIF as well as their signalling pathways. To prevent the exacerbation of asthma, instead of targeting a single pathway or a single target, all these targets and their signalling pathways should be controlled holistically. Rhein may reduce inflammation by inhibiting the MAPK/NF-κB pathway.

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