Nrf2 protects against cerebral ischemia-reperfusion injury by suppressing programmed necrosis and inflammatory signaling pathways

Chen, Weiwei; Teng, Xue; Ding, Hongmei; Xie, Zhiyuan; Peng, Cheng; Liu, Zhihan; Tao, Feng; Zhang, Xia; Huang, Wenjuan; Geng, Deqin

doi:10.21037/atm-22-604

Cited by 12 publications

(4 citation statements)

References 41 publications

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“…Bai et al demonstrated that the EV71 virus led to apoptosis through excessive ROS via Nrf2 in Vero and RD cells . Chen et al also proved that Nrf2 regulated NQO1 to reduce ROS, which inhibited the NLRP3 inflammasome and necroptosis in cerebral ischemia–reperfusion injury . Our results proved that inhibition of Nrf2 increased 1,3-DCP-mediated ROS, which led to necroptosis in NRK-52E cells.…”

Section: Discussionsupporting

confidence: 70%

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

Fan

Lü

et al. 2022

J. Agric. Food Chem.

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1,3-Dichloro-2-propanol (1,3-DCP), as a food pollutant, exists in a variety of foods. Studies have shown that it has nephrotoxicity. In the study, we found that 1,3-DCP caused renal injury with necroptosis in C57BL/6J mice. The mechanism of 1,3-DCP-caused nephrotoxicity was further explored in NRK-52E cells in vitro. We found that 1,3-DCP caused cell necroptosis with the increase in lactate dehydrogenase (LDH) levels and the expressions of RIPK3 and MLKL. But pretreatment with a ROS inhibitor Nacetyl-L-cysteine (NAC), a RIPK3 inhibitor GSK'872, or RIPK3 gene silencing alleviated 1,3-DCP-induced cell necroptosis. The data indicated that 1,3-DCP induced necroptosis through the ROS/RIPK3/MLKL pathway in NRK-52E cells. In further mechanistic studies, we explored how 1,3-DCP induced ROS production. We found that 1,3-DCP inhibited the expressions of nuclear and cytoplasmic Nrf2. But pretreatment with an Nrf2 activator dimethyl fumarate (DMF) up-regulated the expressions of nuclear and cytoplasmic Nrf2 and down-regulated ROS levels and RIPK3 and MLKL expressions. We also examined the effects of mitophagy on 1,3-DCP-induced ROS. The data manifested that 1,3-DCP suppressed mitophagy in NRK-52E cells by decreasing LC3-II, Pink1, and Parkin levels, increasing p62 levels, and decreasing colocalization of LC3 and Mito-Tracker Red. Pretreatment with an autophagy activator rapamycin (Rapa) decreased 1,3-DCP-induced ROS. Taken together, our data identified that 1,3-DCP caused renal necroptosis through the ROS/RIPK3/MLKL pathway.

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Section: Discussionsupporting

confidence: 70%

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

Fan

Lü

et al. 2022

J. Agric. Food Chem.

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“…According to KEGG pathway enrichment, NRDEGs were primarily related to necroptosis ( Gong et al, 2019 ), NF−kappa B and NOD−like receptor pathways, which were all the immune inflammatory response pathways ( Arbibe et al, 2000 ; Caruso et al, 2014 ). Research has suggested that nuclear factor E2-related factor-2 (Nrf2) shows negative regulation on NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome during necroptosis ( Chen et al, 2022 ). Notably, the analysis results demonstrated the enrichment of necroptosis pathway in functional annotation, suggesting the role of necroptosis in AMI pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Novel diagnostic biomarkers related to necroptosis and immune infiltration landscape in acute myocardial infarction

Wu,

Fan,

Cen

et al. 2024

PeerJ

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Background Acute myocardial infarction (AMI) can occur suddenly, which may induce deadly outcomes, and the population suffering from AMI presents a younger trend. Necroptosis, the new cell necrosis type, is associated with the pathogenic mechanisms of diverse cardiovascular diseases (CVDs). Its diagnostic value and molecular mechanisms in AMI are still unclear. Objective: This study focused on determining key necroptosis-related genes as well as immune infiltration in AMI. Methods We first examined the GSE66360 dataset for identifying necroptosis-related differentially expressed genes (NRDEGs). Thereafter, GO and functional annotation were performed, then a PPI network was built. In addition, “CIBERSORT” in R was applied in comparing different immune infiltration degrees in AMI compared with control groups. The receiver operating characteristic (ROC) curve was plotted to evaluate whether hub NRDEGs could be used in AMI diagnosis. Associations of immune cells with candidate NRDEGs biomarkers were examined by Spearman analysis. Finally, hub NRDEGs were validated by cell qPCR assays and another two datasets. Results A total of 15 NRDEGs were identified and multiple enrichment terms associated with necroptosis were discovered through GO and KEGG analysis. Upon module analysis, 10 hub NRDEGs were filtered out, and the top six hub NRDEGs were identified after ROC analysis. These top six NRDEGs might have a certain effect on modulating immune infiltrating cells, especially for mast cells activated, NK cells activated and neutrophils. Finally, two AMI datasets and qPCR assay came to identical findings. Conclusion Our results offer the reliable molecular biomarkers and new perspectives for necroptosis in AMI, which lay a certain foundation for developing novel anti-AMI therapeutic targets.

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“…The KEGG analyses indicated that NRGs are mainly enriched in the shigellosis and NOD-like receptor signaling pathways in addition to necroptosis. Interestingly, the NOD-like receptor was found to be linked to neuronal necroptosis in cerebral ischemia-reperfusion injury [ 31 ]. Blériot, C. et al .…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of a prognostic signature based on necroptosis-related genes in hepatocellular carcinoma

Peng

Wang

et al. 2023

PLoS ONE

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Background Necroptosis is a necrotic programmed cell death with potent immunogenicity. Due to the dual effects of necroptosis on tumor growth, metastasis and immunosuppression, we evaluated the prognostic value of necroptosis-related genes (NRGs) in hepatocellular carcinoma (HCC). Methods We first analyzed RNA sequencing and clinical HCC patient data obtained to develop an NRG prognostic signature based on the TCGA dataset. Differentially expressed NRGs were further evaluated by GO and KEGG pathway analyses. Next, we conducted univariate and multivariate Cox regression analyses to build a prognostic model. We also used the dataset obtained from the International Cancer Genome Consortium (ICGC) database to verify the signature. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to investigate the immunotherapy response. Furthermore, we investigated the relationship between the prediction signature and chemotherapy treatment response in HCC. Results We first identified 36 differentially expressed genes out of 159 NRGs in hepatocellular carcinoma. Enrichment analysis showed that they were mainly enriched in the necroptosis pathway. Four NRGs were screened by Cox regression analysis to establish a prognostic model. The survival analysis revealed that the overall survival of patients with high-risk scores was significantly shorter than that of patients with low-risk scores. The nomogram demonstrated satisfactory discrimination and calibration. The calibration curves validated a fine concordance between the nomogram prediction and actual observation. The efficacy of the necroptosis-related signature was also validated by an independent dataset and immunohistochemistry experiments. TIDE analysis revealed that patients in the high-risk group were possibly more susceptible to immunotherapy. Furthermore, high-risk patients were found to be more sensitive to conventional chemotherapeutic medicines such as bleomycin, bortezomib, and imatinib. Conclusion We identified 4 necroptosis-related genes and established a prognostic risk model that could potentially predict prognosis and response to chemotherapy and immunotherapy in HCC patients in the future.

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Nrf2 protects against cerebral ischemia-reperfusion injury by suppressing programmed necrosis and inflammatory signaling pathways

Cited by 12 publications

References 41 publications

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

1,3-Dichloro-2-propanol-Induced Renal Tubular Cell Necroptosis through the ROS/RIPK3/MLKL Pathway

Novel diagnostic biomarkers related to necroptosis and immune infiltration landscape in acute myocardial infarction

Construction and validation of a prognostic signature based on necroptosis-related genes in hepatocellular carcinoma

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