Shikonin, a constituent of Lithospermum erythrorhizon exhibits anti-allergic effects by suppressing orphan nuclear receptor Nr4a family gene expression as a new prototype of calcineurin inhibitors in mast cells

Wang, Xiaoyu; Hayashi, Satoru; Umezaki, Masahito; Yamamoto, Takeshi; Kageyama-Yahara, Natsuko; Kondo, Takashi; Kadowaki, Makoto

doi:10.1016/j.cbi.2014.10.021

Cited by 35 publications

(23 citation statements)

References 30 publications

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“…In contrast to our present findings, overexpression of NR4A1 in endothelial cells, macrophages, and gut epithelial cells inhibited inflammation through repression of NF‐κB . NR4A1 has also been observed to act as a negative regulator of NF‐κB signaling in peritoneal macrophages isolated from NR4A1 −/− mice . This discrepancy may be attributed to cell type‐ and stimulus‐specific contexts or to certain extrinsic effects arising from global deletion of NR4A1 in all tissues that secondarily affect specific cell functions.…”

Section: Discussioncontrasting

confidence: 99%

“…This may account for the additional, AMPK‐independent effect of NR4A1 on mast cell activation. The pro‐inflammatory function of NR4A1 in mast cells observed here is consistent with the result of a recent report showing that NR4A1 knockdown decreased IgE/Ag‐induced TNF‐α expression …”

Section: Discussionsupporting

confidence: 92%

“…Recently, it was reported that FcεRI crosslinking increased NR4A1 expression, and its knockdown decreases tumor necrosis factor (TNF)‐α expression in mouse and human mast cells, suggesting a pro‐allergic role for NR4A1. However, the precise role of NR4A1 in mast cells and the mechanisms through which it regulates FcεRI signaling are largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

Jin

Deng

et al. 2019

Allergy

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Background: Nuclear receptor subfamily 4 group A member 1 (NR4A1), an orphan nuclear receptor, has been implicated in several biological events such as metabolism, apoptosis, and inflammation. Recent studies indicate a potential role for NR4A1 in mast cells, yet its role in allergic responses remains largely unknown.Objectives: The aim of this study was to clarify the role of NR4A1 in mast cell activation and anaphylaxis. Methods: To evaluate the function of NR4A1 in mast cells, the impacts of siRNA knockdown, gene knockout, adenoviral overexpression, and pharmacological inhibition of NR4A1 on FcεRI signaling and effector functions in mouse bone marrowderived mast cells (BMMCs) in vitro and on anaphylactic responses in vivo were evaluated. Results: Knockdown or knockout of NR4A1 markedly suppressed degranulation and lipid mediator production by FcεRI-crosslinked BMMCs, while its overexpression augmented these responses. Treatment with a NR4A1 antagonist also blocked mast cell activation to a similar extent as NR4A1 knockdown or knockout. Moreover, mast cell-specific NR4A1-deficient mice displayed dampened anaphylactic responses in vivo. Mechanistically, NR4A1 promoted FcεRI signaling by counteracting the liver kinase B1 (LKB1)/adenosine monophosphate-activated protein kinase (AMPK) axis. Following FcεRI crosslinking, NR4A1 bound to the LKB1/AMPK complex and sequestered it in the nucleus, thereby promoting FcεRI downstream signaling pathways. Silencing or knockout of LKB1/AMPK largely abrogated the effect of NR4A1 on mast cell activation. Additionally, NR4A1 facilitated spleen tyrosine kinase activation independently of LKB1/AMPK.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

Jin

Deng

et al. 2019

Allergy

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“…Therefore, we also tested whether CAC-0982 suppressed the expression and secretion of TNF-α and IL-4 in antigenstimulated mast cells. Consistently with the previous reports (Park et al, 2011;Wang et al, 2014), the increase of expression of IL-4 and TNF-α was evident by antigen stimulation for 15 min in mast cells (Fig. 3A).…”

Section: Effect Of Cac-0982 On the Expression And Secretion Of Tnf-α supporting

confidence: 93%

An indoxyl compound 5-bromo-4-chloro-3-indolyl 1,3-diacetate, CAC-0982, suppresses activation of Fyn kinase in mast cells and IgE-mediated allergic responses in mice

Lee

Kim

et al. 2015

Toxicology and Applied Pharmacology

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“…This study aims to optimize the LE extraction process, since the pharmacological activity of the extract depends on the concentration of SK. SK and its derivatives are helpful in tissue regeneration and wound healing [5], as well as antitumor [6], anti-inflammatory [7], anti-allergic [8], and antibacterial activities [9]. Due to these good intrinsic properties, SK has been commonly used in treatments for internal and external wounds [2,5].…”

Section: Introductionmentioning

confidence: 99%

Polyvinyl Alcohol/Lithospermum Erythrorhizon Nanofibrous Membrane: Characterizations, In Vitro Drug Release, and Cell Viability

Lou

Lee

et al. 2017

Applied Sciences

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Abstract:This study proposes an optimization process of the Lithospermum erythrorhizon (LE) extraction with a higher purity of shikonin (SK). The influence of extraction temperature on the concentration of SK is examined, and an in vitro cell viability assay is used to examine the optimal concentration of SK. Afterwards, polyvinyl alcohol (PVA)/LE solutions at ratios of 90/10, 80/20, and 70/30 w/w are electrospun into LE electrospun nanofibrous membranes (LENMs). The optimal manufacture parameters of LENMs are evaluated based on the test results of in vitro drug release test and cell viability assay. The optimal concentration occurs when the extraction temperature is −10 • C. The purity of the LE extract reaches 53.8% and the concentration of SK is 1.07 mg/mL. Moreover, the cell viability of nanofibrous membranes significantly increases to 136.8% when 0.7 µM SK is used. The diameter of nanofibers of LENM is decreased by 43.9% when the ratio of PVA solution to LE extract is 70/30 (w/w). 80/20 (w/w) LENM has the maximum amount of drug release of 79% for a continuous period of 48 h. In particular, 90/10 (w/w) LENM can create the maximum cell proliferation of 157.5% in a 24-h in vitro cell viability assay. This suggests that LENM has great potential to be used in facilitating tissue regeneration and wound healing.

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Shikonin, a constituent of Lithospermum erythrorhizon exhibits anti-allergic effects by suppressing orphan nuclear receptor Nr4a family gene expression as a new prototype of calcineurin inhibitors in mast cells

Cited by 35 publications

References 30 publications

The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis

An indoxyl compound 5-bromo-4-chloro-3-indolyl 1,3-diacetate, CAC-0982, suppresses activation of Fyn kinase in mast cells and IgE-mediated allergic responses in mice

Polyvinyl Alcohol/Lithospermum Erythrorhizon Nanofibrous Membrane: Characterizations, In Vitro Drug Release, and Cell Viability

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