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

Abstract

Background

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 NR4A1in mast cells, yet its role in allergic responses remains largely unknown.

Objectives

The aim of this study was to clarify the role of NR4A1in mast cell activation and anaphylaxis.

Methods

To evaluate the function of NR4A1in mast cells, the impacts of siRNA knockdown, gene knockout, adenoviral overexpression, and pharmacological inhibition of NR4A1on FcεRI signaling and effector functions in mouse bone marrow‐derived 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)/AMP‐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 Syk activation independently of LKB1/AMPK.

Conclusions

NR4A1 positively regulates mast cell activation by antagonizing the LKB1‐AMPK‐dependent negative regulatory axis. This finding may provide a novel therapeutic strategy for the development of anti‐allergic compounds.

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Exogenous estrogen therapy, testicular cancer, and the male to female transgender population: a case report

Over the last 40 years, there has been a significant increase in the incidence of testicular cancer. The epidemiologic evidence to understand this phenomenon is unclear, however exogenous estrogen exposure is ...

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Female urethral dilatation (bougierung): a case report

Primary bladder neck obstruction is a rare clinical entity, reported to be responsible for 2.7–8% of lower urinary tract symptoms. It can lead to various urinary storage and voiding symptoms. The mainstay of t...

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Strategic differences in phosphorus stabilization by alum and dolomite amendments in calcareous and red soils

Abstract

Surplus phosphorus (P) above agronomic requirements can negatively affect the water status of connected surface and subsurface water bodies. The in situ stabilization of soil P through soil amendment has been recognized as an efficient way to reduce this environmental pressure. However, the mechanism of how P is stabilized during this process and how plant available P is affected are unknown. This can be achieved by sequential chemical extraction and synchrotron-based X-ray absorption near-edge structure (XANES) spectroscopy investigations. Therefore, in the present study, P-enriched calcareous and red soils were amended with alum, dolomite, and a 1:1 mixture of alum and dolomite (MAD) at a 20 g/kg soil rate, and soil properties and P fractions were measured after a 45-day period. Results showed that alum amendment significantly decreased CaCl₂-P and Olsen-P contents in calcareous and red soils when compared with dolomite. However, dolomite incorporation maintained relatively high P availability and even increased CaCl₂-P and Olsen-P contents by 1.32% and 40.5% in red soil, respectively, compared to control. Amendment with MAD was not as effectively as the alum in P stabilization. Sequential inorganic P extraction indicated that alum dominantly contributed labile P transformed to Al-P in both soils. P K-edge XANES spectroscopy measurements further explained that alum adsorbed phosphate in calcareous soil and precipitated phosphate as AlPO₄ in red soil. Results of P fractionation and Mehlich-3-extracted Ca showed that dolomite mainly adsorbed loosely bound P in calcareous soil and red soil. However, dolomite incorporation in red soil led to Al-P and Fe-P release. The P sorption isotherms showed that dolomite and alum increased soil P sorption maxima and decreased the degree of P saturation (DPS) in both soils, while dolomite declined the Langmuir bonding energy in red soil. Differences in P stabilization by alum and dolomite addition across soil types were closely related to their characteristics, and soil properties changed, especially soil pH.

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Association of somatosensory dysfunction with symptom duration in burning mouth syndrome

Abstract

Objectives

A standardized battery of quantitative sensory tests developed by the German Research Network on Neuropathic Pain (DFNS) was used to assess the association between somatosensory dysfunction and disease duration in patients with burning mouth syndrome (BMS).

Materials and methods

The 28 female participants with BMS were classified according to disease duration: ≤ 6 months (subchronic BMS, n = 15) and > 6 months (chronic BMS, n = 13); 29 age- and sex-matched healthy volunteers (control group) were recruited from staff of a dental hospital. The DFNS quantitative sensory testing protocol was applied at the ulnar surface of the right forearm and the tip of the tongue. Values for BMS patients and controls were compared and analyzed.

Results

The mechanical detection threshold (MDT) was significantly higher (i.e., loss of sensation) at the tongue tip in the chronic BMS group than in the control group (p = 0.011), whereas mechanical pain sensitivity (MPS) at the forearm was significantly higher (i.e., gain of sensation) in the chronic BMS group than in the control group (Z score = − 2.13 and 1.99, respectively). Multivariate analyses revealed that BMS patients could be discriminated from controls by using pressure pain threshold at the tongue (79.3%) (in the subchronic BMS group) and by MDT and MPS at the tongue tip and MPS at the forearm (96.6 and 89.7%, respectively) (in the chronic BMS group).

Conclusions

In BMS patients with long disease duration, MDT showed loss of sensation.

Clinical relevance

Increased MPS suggests that a neuropathic mechanism in the peripheral and central nervous systems is involved in BMS development.

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Reduced ecotoxicity and improved biodegradability of cationic biocides based on ester-functionalized pyridinium ionic liquids

Abstract

Ester-functionalized pyridinium ionic liquids (ILs), 1-decyloxycarbonylmethylpyridinium chloride (PyrСOOC₁₀-Cl), and 1-dodecyloxycarbonylmethylpyridinium chloride (PyrСOOC₁₂-Cl) have been synthesized and studied for their environmental toxicity. Simple long-chain pyridinium ILs, 1-dodecylpyridinium chloride (PyrC₁₂-Cl), and commercial disinfectant cetylpyridinium chloride (CPC) were used as reference compounds. Both ester-functionalized ILs and CPC showed significantly reduced antibacterial activity compared to PyrC₁₂-Cl. However, ester-functionalized ILs were found to have excellent antifungal activity towards Candida albicans fungus strains, similar to PyrC₁₂-Cl and much higher than for CPC. The molecular docking of ILs in the active site of the known antifungal target N-myristoyltransferase (Nmt) C. albicans has been conducted. The obtained results indicate the possibility of ILs binding into the Nmt pocket. The high stability of the complexes, especially for PyrCOOC₁₀-Cl, is ensured by hydrogen bonding, electrostatic anion-pi interactions, as well as hydrophobic pi-alkyl and alkyl interactions that was confirmed by calculated binding energy values. The acute toxicity studies of ester-functionalized ILs on D. rerio (zebrafish) hydrobiont have shown their dramatically reduced ecotoxicity compared to PyrC₁₂-Cl and CPC. Thus, LD₅₀ values of 15.2 mg/L and 16.8 mg/L were obtained for PyrCOOC₁₀-Cl and PyrCOOC₁₂-Cl, respectively, whereas CPC had LD₅₀ value of 0.018 mg/L. The primary biodegradation test CEC L-33-A93 of ILs indicated an improved biodegradability of ester-functionalized compounds compared to simple long-chain ILs. Based on the obtained results, PyrCOOC₁₀-Cl may be considered as very promising cationic biocide due to the combination of soft antimicrobial activity and reduced ecotoxicity, as well as improved biodegradability.

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Recycling Discarded Drugs: Improving Access to Oral Antineoplastic Drugs

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