Silencing astrocyte elevated gene‐1 attenuates lipopolysaccharide‐induced inflammation and mucosal barrier injury in NCM460 cells by suppressing the activation of NLRP3 inflammasome

Yang, Peng; Li, Hongyan; Chen, Dandan

doi:10.1002/cbin.11078

Cited by 8 publications

(3 citation statements)

References 41 publications

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“…Endothelial cells are connected to each other by connexins, such as zonula occludens 1 (ZO-1) and vascular endothelial cadherin (VE-Cad), to maintain endothelial permeability. It has been shown that activation of the NLRP3 inflammasome degrades endothelial connexin (18). At the same time, IL-1β released by NLRP3 inflammasome activation can also reduce the adhesion strength of vascular endothelial cells, lead to increased vascular permeability, and induce retinal microvascular leakage (19), thereby increasing the risk of blindness.…”

Section: Discussionmentioning

confidence: 99%

Gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway

Ye¹,

Feng²,

Hu³

2023

Ann Transl Med

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Background: This study aimed to investigate the effect and mechanism of gambogic acid (GA) on the apoptosis and inflammation of human retinal endothelial cells (HRECs) under high glucose conditions. Methods: HRECs were cultured in a high glucose medium to simulate retinal endothelial cell injury induced by diabetic retinopathy. Flow cytometry was used to analyze the apoptosis level of HRECs. Cell viability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Western blotting was applied to detect the intracellular apoptosis-related proteins and expression levels of NADPH oxidase 4 (NOX4), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), and interleukin (IL)-1β. Enzyme linked immunosorbent assay (ELISA) was utilized to detect the expression of IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) in the cell supernatants. The messenger RNA (mRNA) levels of IL-6, IL-8, IL-10, and TNF-α were detected by reverse transcription-polymerase chain reaction (RT-qPCR). Results:We observed that high glucose induced the apoptosis and inflammation of HRECs. In addition, the high glucose environment promoted NOX/NLRP3 pathway activation. The activity of HRECs was not significantly affected by the presence of 20 μM or less of GA, and 15 μM of GA could restore the diminished activity of HRECs induced by high glucose. The apoptosis of HRECs cultured under high glucose conditions was significantly inhibited (P<0.05), the levels of IL-6, IL-8, and TNF-α in the cell supernatant were significantly decreased (P<0.05), and the levels of IL-10 were significantly increased (P<0.05). Meanwhile, the relative mRNA expression levels of IL-6, IL-8, and TNF-α in HRECs were significantly decreased (P<0.05), while those of IL-10 were significantly increased (P<0.05). The activity of the high glucose-induced NOX4/NLRP3 pathway in HRECs was significantly inhibited after treatment with 15 μM of GA (P<0.05). Following activation of the NOX4/NLRP3 pathway in HRECs, the apoptosis level was significantly increased (P<0.05), and the inflammatory response was aggravated (P<0.05). Inhibiting the activity of the intracellular NOX4/NLRP3 pathway markedly inhibited cell apoptosis and the inflammatory response (P<0.05).Conclusions: GA can inhibit the apoptosis and inflammation of HRECs under high glucose conditions by inhibiting the activity of the NOX4/NLRP3 pathway. This has a significant inhibitory effect on diabetic retinopathy, which is worthy of further study.

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Section: Discussionmentioning

confidence: 99%

Gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway

Ye¹,

Feng²,

Hu³

2023

Ann Transl Med

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“…Another study revealed that inhibiting AEG-1 and its downstream pro-inflammatory cytokines mitigated blood–spinal cord barrier leakage and improved hind limb motor function during spinal cord ischemia–reperfusion [27]. Moreover, silencing the AEG-1 gene in NCM460 cells treated with LPS led to upregulation of ZO-1 and Occludin, thereby conferring protection against LPS-induced mucosal barrier damage [28]. These findings corroborate our results, demonstrating a complex interplay between AEG-1 and cellular barrier dysfunction.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

Jiang,

Wang,

et al. 2024

Aids

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Objective: This study aims to investigate the functions and mechanistic pathways of Astrocyte Elevated Gene-1 (AEG-1) in the disruption of the blood–retinal barrier (BRB) caused by the HIV-1 envelope glycoprotein gp120. Design: We utilized ARPE-19 cells challenged with gp120 as our model system. Methods: Several analytical techniques were employed to decipher the intricate interactions at play. These included PCR, Western blot, and immunofluorescence assays for the molecular characterization, and transendothelial electrical resistance (TEER) measurements to evaluate barrier integrity. Results: We observed that AEG-1 expression was elevated, whereas the expression levels of tight junction proteins Zo-1, Occludin, and Claudin5 were downregulated in gp120-challenged cells. TEER measurements corroborated these findings, indicating barrier dysfunction. Additional mechanistic studies revealed that the activation of NFκB and MMP2/9 pathways mediated the AEG-1-induced barrier destabilization. Through the use of lentiviral vectors, we engineered cell lines with modulated AEG-1 expression levels. Silencing AEG-1 alleviated gp120-induced downregulation of tight junction proteins and barrier impairment while concurrently inhibiting the NFκB and MMP2/9 pathways. Conversely, overexpression of AEG-1 exacerbated these pathological changes, further compromising the integrity of the BRB. Conclusion: Gp120 upregulates the expression of AEG-1 and activates the NFκB and MMP2/9 pathways. This in turn leads to the downregulation of tight junction proteins, resulting in the disruption of barrier function.

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“…Zhao et al found that the of AEG-1 expression was up-regulated in streptozocin-induced diabetic cardiomyopathy mice (Zhao et al 2018) Furthermore, Peng et al reported that AEG-1 low-expression could suppresses NLRP3 expression and promote caspase-1 activation, which further reduced the levels of IL-1β and IL-18. while AEG-1 overexpression deteriorated LPS-induced mucosal barrier injury and activation of NLRP3 inflammasome (Peng et al 2019). At present, the roles and potential molecular mechanism of AGE-1 in EMs have not been reported.…”

Section: Introductionmentioning

confidence: 99%

AEG-1 aggravates inflammation via promoting NALP3 inflammasome formation in murine endometriosis lesions

Zhao

Chen

et al. 2019

Animal Cells and Systems

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Endometriosis (EMs) is one of the most common gynaecological diseases in women of childbearing age. Astrocyte elevated gene-1 (AEG-1) is associated with the invasion, migration, apoptosis and prognosis of various cancers. However, the roles of AEG-1 in EMs and its corresponding molecular mechanism are still unknown. In this study, animal models of EMs were established and mice were divided into two groups (n = 10): Sham group and EMs group. The EMs cells were isolated from EMs model. The AEG-1 gene was knocked down by shRNA, while the SOCS1 gene was knocked down by siRNA. Histological changes, AEG-1 expression in tissues and inflammatory factors level were detected by H&E staining, immunohistochemistry and ELISA, respectively. RT-qPCR and western blotting were used to determine the expression level of related proteins. The present study found AEG-1 was up-regulated in the EMs model. Enhanced AEG-1 promoted inflammatory cell infiltration, and elevated the levels of IL-1β, IL-6, and TNF-α in EM group (p < 0.05). Besides, AEG-1 overexpression promoted the expression of NALP3, ASC and Cleavedcaspase-1, while decreased SOCS1 level (p < 0.05). Decrease of SOCS1 further promoted the formation of NALP3 inflammasome. The inhibitory effect of AEG-1 on SOCS1 was weakened after the addition of MG-132 (p < 0.01). Furthermore, silencing AEG-1 alone increased SOCS1 level, decreased the levels of inflammatory cytokines, thereby inhibited the formation of NALP3 inflammasome. All these results demonstrated that AEG-1 aggravated inflammation via promoting NALP3 inflammasome formation in murine endometriosis lesions.

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Silencing astrocyte elevated gene‐1 attenuates lipopolysaccharide‐induced inflammation and mucosal barrier injury in NCM460 cells by suppressing the activation of NLRP3 inflammasome

Cited by 8 publications

References 41 publications

Gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway

Gambogic acid affects high glucose-induced apoptosis and inflammation of retinal endothelial cells through the NOX4/NLRP3 pathway

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood–retinal barrier

AEG-1 aggravates inflammation via promoting NALP3 inflammasome formation in murine endometriosis lesions

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