An adenosine A3 receptor agonist inhibits DSS-induced colitis in mice through modulation of the NF-κB signaling pathway

Ren, Tianhua; Tian, Ting; Xiao, Feng; Ye, Shicai; Wang, Hao; Wu, Wanlong; Qiu, Yumei; Yu, Caiyuan; Yang, He; Zeng, Juncheng; Cen, Junwei; Zhou, Yu

doi:10.1038/srep09047

Cited by 48 publications

(49 citation statements)

References 37 publications

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“…23 Out of many proinflammatory cytokines, TNF-α is known to have a crucial role in the pathogenesis of colitis and the clinical inhibition of TNF-α (infliximab and adalimumab) has been shown to reduce disease pathology and morbidity in IBD patients. 21,25 Moreover, it has also been reported that the increase in the production of proinflammatory cytokines and the expression of NF-κB signaling in the mucus of IBD patients and in the mouse DSS-induced acute colitis model. 21,25 Moreover, it has also been reported that the increase in the production of proinflammatory cytokines and the expression of NF-κB signaling in the mucus of IBD patients and in the mouse DSS-induced acute colitis model.…”

Section: Discussionmentioning

confidence: 99%

“…23,25 Myeloperoxidase is an enzyme most abundantly found in azurophilic granules of neutrophils and monocytes. 23,25 Myeloperoxidase is an enzyme most abundantly found in azurophilic granules of neutrophils and monocytes.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, the freed NF-κB translocates into the nucleus where it binds to the specific site of the target genes to regulate their transcription 16,25. The activation of NF-κB due to the presence of external stimuli, the IκB kinase (IKK)phosphorylates IκB protein, leading to their subsequent ubiquitination and degradation and the dissociation of NF-κB.…”

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confidence: 99%

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Rosmarinus officinalis L. extract ameliorates intestinal inflammation through MAPKs/NF-κB signaling in a murine model of acute experimental colitis

et al. 2016

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We investigated the anti-inflammatory and anti-colitis effects of Rosmarinus officinalis L. extract (RE) by using both in vitro LPS-activated mouse RAW 264.7 macrophages and in vivo dextran sulfate sodium (DSS)-induced experimental murine colitis and suggested the underlying possible mechanisms. Liquid Chromatography-Mass Spectrometry (LC-MS) analysis was performed to identify the major components present in the RE. The clinical signs, biochemistry, immunoblot, ELISA and histology in colon tissues were assessed in order to elucidate the beneficial effect of RE. RE suppressed the LPS-induced pro-inflammatory cytokine production and the expressions of inflammatory proteins in macrophages. Administration of RE (50 and 100 mg kg(-1)) also significantly reduced the severity of DSS-induced murine colitis, as assessed by the clinical symptoms, colon length and histology. RE administration prevented the DSS-induced activation of p38, ERK and JNK MAPKs, attenuated IκBα phosphorylation and subsequent nuclear translocation and DNA binding of NF-κB (p65). RE also suppressed the COX-2 and iNOS expressions, decreased the levels of TNF-α and IL-6 cytokines and the myeloperoxidase activity in the colon tissue. Histological observation revealed that RE administration alleviated mucosal damage and inflammatory cell infiltration induced by DSS in the colon tissue. Hence, RE could be used as a new preventive and therapeutic food ingredient or as a dietary supplement for inflammatory bowel disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Rosmarinus officinalis L. extract ameliorates intestinal inflammation through MAPKs/NF-κB signaling in a murine model of acute experimental colitis

et al. 2016

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“…A2aAR regulates several biological processes including inflammation. Upregulation of A2aAR reportedly suppressed inflammation in rats with colitis [28]. Therefore, we evaluated the role of A2aAR in UC.…”

Section: Discussionmentioning

confidence: 99%

microRNA-15 Activates NF-κB Pathway via Down Regulating Expression of Adenosine A2 Receptor in Ulcerative Colitis

Zhang

2018

Cell Physiol Biochem

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Background/Aims: The role of miR-15 in ulcerative colitis (UC) is unclear. In this study, we found that miR-15 downregulated the expression of adenosine A2a receptor (A2aAR) in the colonic tissues of patients with UC and in HT-29 human colonic epithelial cells. Methods: The study population comprised patients with UC (n=23), irritable bowel syndrome (IBS, n=22), and healthy subjects (n = 20). The levels of miR-15, A2aAR, and protein in colon tissue biopsies were determined by real-time quantitative reverse transcription polymerase chain reaction, immunofluorescence staining, and Western blotting. The TargetScan prediction algorithm was used to identify the miR-15 binding site in the 3′-UTR of A2aAR. To assess the effects of miR-15 on A2aAR levels, HT-29 cells were transfected with miR-15 mimics. Results: Relative to expression in healthy subjects, A2aAR expression was decreased in UC patients and was similar in IBS patients. MiR-15 levels were higher in UC patients than in IBS patients or healthy subjects. A2aAR was the target of miR-15 in HT-29 cells, which downregulated A2aAR mRNA levels. MiR-15 mimics induced nuclear translocation of NF-κB p65 and upregulated the expression of IL-8 and IFN-γ in colonic epithelial cells; these effects were reversed by an miR-15 inhibitor. A2aAR knockdown confirmed that miR-15 activated the NF-κB cascade. Conclusion: Our data suggest that miR-15 modulates inflammatory and immune responses by suppressing the expression of A2aAR and regulating the NF-κB cascade.

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“…They modulate NF‐κB, phosphoinositide‐3‐kinase–protein kinase B‐Akt (PI3K‐PKB/Akt), Wnt and mitogen‐activated protein kinase pathways. Expression of A 3 AdR is upregulated in patients with arthritis, Crohn's disease and colon cancer . It was demonstrated that sustained activation of A 3 AdRs with 2‐CI‐IB‐MECA impaired oligodendrocyte viability through generation of ROS and mitochondrial membrane depolarization …”

Section: Adverse Effects and Toxicity Of Adenosine Receptor Ligandsmentioning

confidence: 99%

Safety issues of compounds acting on adenosinergic signalling

Schmidt

Ferk

2017

Journal of Pharmacy and Pharmacology

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Objectives Much research has been performed on the field of identifying the roles of adenosine and adenosinergic signalling, but a relatively low number of marketing authorizations have been granted for adenosine receptor (AdR) ligands. In part, this could be related to their safety issues; therefore, our aim was to examine the toxicological and adverse effects data of different compounds acting on adenosinergic signalling, including different AdR ligands and compounds resembling the structure of adenosine. We also wanted to present recent pharmaceutical developments of experimental compounds that showed promising results in clinical trial setting. Key findings Safety issues of compounds modulating adenosinergic signalling were investigated, and different mechanisms were presented. Structurally different classes of compounds act on AdRs, the most important being adenosine, adenosine derivatives and other non-nucleoside compounds. Many of them are either not selective enough or are targeting other targets of adenosinergic signalling such as metabolizing enzymes that regulate adenosine levels. Many other targets are also involved that are not part of adenosinergic signalling system such as GABA receptors, different channels, enzymes and others. Some synthetic AdR ligands even showed to be genotoxic. Summary Current review presents safety data of adenosine, adenosine derivatives and other non-nucleoside compounds that modulate adenosinergic signalling. We have presented different mechanisms that participate to an adverse effect or toxic outcome. A separate section also deals with possible organ-specific toxic effects on different in-vitro and in-vivo models.

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An adenosine A3 receptor agonist inhibits DSS-induced colitis in mice through modulation of the NF-κB signaling pathway

Cited by 48 publications

References 37 publications

Rosmarinus officinalis L. extract ameliorates intestinal inflammation through MAPKs/NF-κB signaling in a murine model of acute experimental colitis

Rosmarinus officinalis L. extract ameliorates intestinal inflammation through MAPKs/NF-κB signaling in a murine model of acute experimental colitis

microRNA-15 Activates NF-κB Pathway via Down Regulating Expression of Adenosine A2 Receptor in Ulcerative Colitis

Safety issues of compounds acting on adenosinergic signalling

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