國家衛生研究院 NHRI:Item 3990099045/7666
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    题名: Aryl hydrocarbon receptor (AhR) controls cellular redox and metabolic homeostasis in mast cells
    作者: Tseng, HC;Hsu, SC;Chang, HW;Yang, SJ;Kawasaki, H;Kuo, CC;Huang, SK
    贡献者: Division of Environmental Health and Occupational Medicine
    摘要: Background: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is essential in the detoxification process and in maintaining cellular homeostasis through, in part, its activation by endogenous ligands. But, the nature of the ‘endogenous’ ligands and the mechanisms by which the AhR-ligand axis regulates the homeostasis remain to be defined. We hypothesized that the AhR-ligand axis is linked to the metabolic balance as well as control of the redox balance. Methods: To test this hypothesis, we first developed a virtual screening tool, modeled through the receptor-fitting structural features including the planarity and the molecular size of a prototypic ligand, dioxin. A cell-based bioassay was utilized for discovery of candidate ligands. Also, a combined genomics and lipidomics approach was used to characterize the ‘metabolic shift’ as the result of the AhR-ligand interaction or the absence thereof in mast cells, an important cell type in allergic diseases. Results: Our current efforts have verified a number of novel AhR ligands from the screening of a library of 196 bioactive lipids, suggesting the presence of endogenous lipid metabolites acting as candidate ligands. Further, our dataset from analysis of the LC-MS profiles in AhR-null mast cells demonstrated a significant change in arachidonic acid (AA) metabolism, with two eicosanoid metabolic pathways involving thromboxane B2 (TXB2) and leukotriene B4 (LTB4) being the most prominent. Also, significantly altered gene expression patterns were noted in AhR-null mast cells, including those known to be involved in AA and lipid metabolism. Interestingly, AhR ligand-induced ROS in mast cells could be inhibited, in part, by inhibitors for Ptgs1 and Alox5, suggesting the likely importance of eicosanoid metabolites in mediating the AhR’s functional impact. Conclusion(s): Taken together, these results provide the evidence linking the AhR-ligand axis, metabolic and redox balance, and suggest its importance in controlling mast cell and allergic response.
    日期: 2013-11
    關聯: Allergy. 2013 Nov;68(Suppl. S98):54.
    Link to: http://dx.doi.org/10.1111/all.12291
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0105-4538&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000325897100159
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