Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways

Zhong, Jia; Yu, Ruyang; Zhou, Qilyu; Liu, Ping; Liu, Zhongjie; Bian, Yifei

doi:10.1039/d1fo00155h

Cited by 32 publications

(22 citation statements)

References 55 publications

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“…The NF-κB and MAPK signaling pathways are well known to be involved in inflammation and immune regulation [40]. NF-κB is a nuclear transcription factor in cells and regulates the inflammatory response by modulating the transcription of inflammatory genes [18]. In an inflammatory environment, NF-κB p65 is phosphorylated and translocated into the nucleus, thereby promoting the transcription of inflammatory markers and inducing irreversible inflammatory injury, which is the important mechanism for regulating inflammatory diseases [31,32,41].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, intestinal epithelial barrier dysfunction is related to the progression of intestinal inflammation. Increasing evidence has indicated that the activation of NLRP3 inflammasome was essential for the pathogenesis of intestinal inflammation and intestinal epithelial barrier dysfunction [18,19]. The NLRP3 inflammasome is a vital part of the innate immune system and is composed of NLRP3, caspase-1 and apoptosis-associated speck-like protein containing CARD (ASC).…”

Section: Introductionmentioning

confidence: 99%

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Staphylococcal Enterotoxin A Induces Intestinal Barrier Dysfunction and Activates NLRP3 Inflammasome via NF-κB/MAPK Signaling Pathways in Mice

Liu

Chi

Yang

et al. 2022

Toxins

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Staphylococcal enterotoxin A (SEA), the toxin protein secreted by Staphylococcus aureus, can cause staphylococcal food poisoning outbreaks and seriously threaten global public health. However, little is known about the pathogenesis of SEA in staphylococcal foodborne diseases. In this study, the effect of SEA on intestinal barrier injury and NLRP3 inflammasome activation was investigated by exposing BALB/c mice to SEA with increasing doses and a potential toxic mechanism was elucidated. Our findings suggested that SEA exposure provoked villi injury and suppressed the expression of ZO-1 and occludin proteins, thereby inducing intestinal barrier dysfunction and small intestinal injury in mice. Concurrently, SEA significantly up-regulated the expression of NLRP3 inflammasome-associated proteins and triggered the mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling pathways in jejunum tissues. Notably, selective inhibitors of MAPKs and NF-κB p65 ameliorated the activation of NLRP3 inflammasome stimulated by SEA, which further indicated that SEA could activate NLRP3 inflammasome through NF-κB/MAPK pathways. In summary, SEA was first confirmed to induce intestinal barrier dysfunction and activate NLRP3 inflammasome via NF-κB/MAPK signaling pathways. These findings will contribute to a more comprehensive understanding of the pathogenesis of SEA and related drug-screening for the treatment and prevention of bacteriotoxin-caused foodborne diseases via targeting specific pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Staphylococcal Enterotoxin A Induces Intestinal Barrier Dysfunction and Activates NLRP3 Inflammasome via NF-κB/MAPK Signaling Pathways in Mice

Liu

Chi

Yang

et al. 2022

Toxins

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“…TNF-α is an additional pro-inflammatory cytokine that has been implicated in IBD and causes increased intestinal epithelial TJ permeability ( 40 , 95 , 96 ). The TNF-α-induced increase in intestinal TJ permeability was also dependent on NF-κB p50/p65 activation ( 40 , 97 – 103 ). However, important differences are noted concerning how the enterocyte NF-κB p50/p65 was activated and how the TJ barrier was regulated.…”

Section: Mechanisms Of the Il-1β-induced Modulation Of The Intestinal Tj Barriermentioning

confidence: 99%

IL-1β and the Intestinal Epithelial Tight Junction Barrier

2021

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The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn’s disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1β (IL-1β), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1β-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1β-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1β on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1β modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.

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“…Recently, a growing body of evidence has demonstrated that the pharmacological agents, e.g., Ezetimibe ketone, Desfluoro-ezetimibe, NK-252, Bardoxolone, and TBHQ could induce activation of NRF2 ( 58 – 61 ). Here we proposed naringenin, a citrus flavonoid shown to have cytotoxic and antiproliferative effects on various cancer cell types ( 62 ) and regulates immunological pathways ( 63 ), to be another kind of potential NRF2 conditioning agent. With the development of immunotherapies such as cancer vaccine, immune checkpoint inhibitors, oncolytic virus, and chimeric antigen receptor T cell (CAR-T) therapy ( 64 ), a combination of NRF2-targeting agonists and immunotherapies may provide multiple feasible approaches to new BC treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Naringenin Regulates FKBP4/NR3C1/NRF2 Axis in Autophagy and Proliferation of Breast Cancer and Differentiation and Maturation of Dendritic Cell

et al. 2022

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NRF2 is an important regulatory transcription factor involved in tumor immunity and tumorigenesis. In this study, we firstly identified that FKBP4/NR3C1 axis was a novel negative regulator of NRF2 in human breast cancer (BC) cells. The effect of FKBP4 appeared to be at protein level of NRF2 since it could not suppress the expression of NRF2 at mRNA level. Bioinformatics analysis and in vitro experiments further demonstrated that FKBP4 regulated NRF2 via regulating nuclear translocation of NR3C1. We then reported that naringenin, a flavonoid, widely distributed in citrus and tomato, could suppress autophagy and proliferation of BC cells through FKBP4/NR3C1/NRF2 signaling pathway in vitro and in vivo. Naringenin was also found to promote dendritic cell (DC) differentiation and maturation through FKBP4/NR3C1/NRF2 axis. Therefore, our study found that naringenin could induce inhibition of autophagy and cell proliferation in BC cells and enhance DC differentiation and maturation, at least in part, though regulation of FKBP4/NR3C1/NRF2 signaling pathway. Identification of FKBP4/NR3C1/NRF2 axis would provide insights for novel anti-tumor strategy against BC among tumor microenvironment.

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Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways

Abstract: The microvasculature endothelium accurately regulates the passage of molecules across the gut-vascular barrier (GVB), which plays an essential role in the intestinal immunity. Naringenin is with reported therapeutic potential against...

Cited by 32 publications

References 55 publications

Staphylococcal Enterotoxin A Induces Intestinal Barrier Dysfunction and Activates NLRP3 Inflammasome via NF-κB/MAPK Signaling Pathways in Mice

Staphylococcal Enterotoxin A Induces Intestinal Barrier Dysfunction and Activates NLRP3 Inflammasome via NF-κB/MAPK Signaling Pathways in Mice

IL-1β and the Intestinal Epithelial Tight Junction Barrier

Naringenin Regulates FKBP4/NR3C1/NRF2 Axis in Autophagy and Proliferation of Breast Cancer and Differentiation and Maturation of Dendritic Cell

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