Role of the nuclear receptor subfamily 4a in mast cells in the development of irritable bowel syndrome

Li, Ruidi; Chen, Shuhui; Gu, Xinpei; An, Shuhong; Wang, Zhaojin

doi:10.1016/j.csbj.2022.02.017

Cited by 4 publications

(5 citation statements)

References 98 publications

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“…Psychological stress activates MC through regulation of CRHR1 and CRHR2, and leads to degranulation and release of cytokines or chemokines [ 7 , 17 ]; we then investigated whether these effects are administrated by JM25-1. With psychologically stressed rat models, JM25-1 has been shown to substantially inhibit CRHR1 ( Figure 5 B), TNFα ( Figure 5 D), IL-18 ( Figure 5 E), IL-1β ( Figure 5 F) and IL-6 ( Figure 5 G), but promoted CRHR2 ( Figure 5 C) production.…”

Section: Resultsmentioning

confidence: 99%

“…), which impair the intracellular tight junction (TJ) between the intestinal epithelial cells [ 7 , 10 , 11 ]. CRH receptor subtype 1 (CRHR1) and subtype 2 (CRHR2) on MC are positive and negative modulators, respectively, tuning the degranulation of stress-induced MC [ 12 , 13 ].Psychological stress is a common cause and induces a long-term depressive symptom for IBS, a disorder with an increase of MC and accompanied by intestinal dysbiosis in the gastrointestinal tract [ 14 , 15 , 16 , 17 ]. Certainly, targeting MC is one of the main approaches for dysregulated mucosal permeability [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

Sun

Liu

et al. 2022

Pharmaceuticals

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Mast cell (MC) plays a central role in intestinal permeability; however, few MC-targeting drugs are currently available for protection of the intestinal barrier in clinical practice. A nonfluorinated Lidocaine analog 2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1) displays anti-allergic effect, but its impact on MC remains elusive. In this study, we explored whether JM25-1 has therapeutic potential on intestinal barrier defect through stabilizing MC. JM25-1 alleviated release of β-hexosaminidase and cytokine production of MC. The paracellular permeability was redressed by JM25-1 in intestinal epithelial cell monolayers co-cultured with activated MC. In vivo, JM25-1 diminished intestinal mucosal MC amount and cytokine production, especially downregulating the expression of CRHR1, accompanied by an increase of CRHR2. Protective effects appeared in JM25-1-treated stress rats with a recovery of weight and intestinal barrier integrity. Through network pharmacology analysis, JM25-1 showed a therapeutic possibility for irritable bowel syndrome (IBS) with predictive targeting on PI3K/AKT/mTOR signaling. As expected, JM25-1 reinforced p-PI3K, p-AKT, p-mTOR signaling in MC, while the mTOR inhibitor Rapamycin reversed the action of JM25-1 on the expression of CRHR1 and CRHR2. Moreover, JM25-1 successfully remedied intestinal defect and declined MC and CRHR1 expression in rat colon caused by colonic mucus of IBS patients. Our data implied that JM25-1 possessed therapeutic capacity against intestinal barrier defects by targeting the CRH receptors of MC through PI3K/AKT/mTOR signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

Sun

Liu

et al. 2022

Pharmaceuticals

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“…The NR4A family, also known as the orphan nuclear receptors, consists of NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor-1), which are thought to be involved in diverse functions in various tissues, including cell proliferation, apoptosis, and fatty acid metabolism [47,48]. All three genes belonging to the NR4A family are known to be rapidly and transiently induced following corticotropin-releasing hormone treatment [49] and activate the hypothalamic-pituitary-adrenal (HPA) axis, suggesting that NR4A members may be involved in CRH-mediated stress responses via the HPA axis [50]. The results of the enrichment analysis using the list of upregulated genes in red junglefowl may reflect an active stress response, which could be attributed to the high level of vigilance exhibited by this species.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Signatures of Domestication Revealed by Meta-Analysis of Pig, Chicken, Wild Boar, and Red Junglefowl Gene Expression Data

Uno,

Bono

2024

Preprint

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Domesticated animals have undergone significant changes in their behavior, morphology, and physiological functions during domestication. To identify the changes in gene expression associated with domestication, we collected RNA-seq data of pigs, chickens, wild boars, and red junglefowl from public databases and performed a meta-analysis. Gene expression was quantified and the expression ratio between domesticated animals and their wild ancestors (DW-ratio) was calculated. Genes were classified as "upregulated," "downregulated," or "unchanged" based on their DW-ratio, and DW-score was calculated for each gene. Gene set enrichment analysis revealed that genes upregulated in pigs were related to defense from viral infection, whereas those upregulated in chickens were associated with aminoglycan and carbohydrate derivative catabolic processes. Genes commonly upregulated in pigs and chickens are involved in the immune response, olfactory learning, epigenetic regulation, cell division, and extracellular matrix. In contrast, genes upregulated in wild boar and red junglefowl are related to stress response, cell proliferation, cardiovascular function, neural regulation, and energy metabolism. These findings provide valuable insights into the genetic basis of the domestication process and highlight potential candidate genes for breeding applications.

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“…Epigenetic and transcriptional alterations were reported that activator of nuclear receptor family 4a (NR4a) receptor, belongs to larger nuclear receptors superfamily of eukaryotic transcription factors, is participated in a variety of biological process including anti‐inflammatory capacity, memory formation, and neuroprotection as mediators of CREB experiencing pathological activators [ 57 ]. An animal study has demonstrated that a dramatic increase of NR4a, which may result in inflammatory activations, which contribute to the hypersensitivity in mice that are suffering chronic water‐avoidance stress [ 58 ]. Therefore, its unique sensitivity and epigenetic resilence in mediating anti‐inflammatory response is crucial for promoting TNF‐a‐induced pain states.…”

Section: Discussionmentioning

confidence: 99%

Store‐operated calcium entry mediates hyperalgesic responses during neuropathy

Wang,

Huang

et al. 2023

FEBS Open Bio

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Neuropathic pain (NP), resulting from nerve injury, alters neural plasticity in spinal cord and brain via the release of inflammatory mediators. The remodeling of store‐operated calcium entry (SOCE) involves the refilling of calcium in the endoplasmic reticulum via STIM1 and Orai1 proteins, and is crucial for maintaining neural plasticity and neurotransmitter release. The mechanism underlying SOCE‐mediated NP remains largely unknown. In this study, we found SOCE‐mediated calcium refilling was significantly higher during neuropathic pain, and the major component Orai1 was specifically co‐localized with neuronal markers. Intrathecal injection of SOCE antagonist SKF96365 remarkably alleviated nerve injury‐ and formalin‐induced pain, and suppressed c‐Fos expression in response to innocuous mechanical stimulation. RNA sequencing revealed that SKF96365 altered the expression of spinal transcription factors, including Fos, Junb, and Socs3, during neuropathic pain. In order to identify the genes critical for SKF96365‐induced effects, we performed weighted gene co‐expression network analysis (WGCNA) to identify the genes most correlated with paw withdrawal latency phenotypes. Of the 16 modules, MEsalmon module was the most highly correlated with SKF9636‐induced effects. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the enriched genes of MEsalmon module were significantly related to Toll‐like receptor signaling, steroid biosynthesis, and chemokine signaling, which may mediate the analgesic effect caused by SKF9636 treatment. Additionally, the SOCE antagonist YM‐58483 produced similar analgesic effects in nerve injury‐ and formalin‐induced pain. Our results suggest that manipulation of spinal SOCE signaling might be an promising target for pain relief by regulating neurotransmitter production and spinal transcription factor expression.

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Role of the nuclear receptor subfamily 4a in mast cells in the development of irritable bowel syndrome

Cited by 4 publications

References 98 publications

A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

A Novel Mast Cell Stabilizer JM25-1 Rehabilitates Impaired Gut Barrier by Targeting the Corticotropin-Releasing Hormone Receptors

Transcriptional Signatures of Domestication Revealed by Meta-Analysis of Pig, Chicken, Wild Boar, and Red Junglefowl Gene Expression Data

Store‐operated calcium entry mediates hyperalgesic responses during neuropathy

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