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Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway.

ABSTRACT: The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-?B. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases that are underlined by both oxidative stress and inflammation. Coumarins are natural products with promising pharmacological activities, including antioxidant, anticancer, antimicrobial, and anti-inflammatory efficacies. Coumarins are found in many plants, fungi, and bacteria and have been widely used as complementary and alternative medicines. Some coumarins have shown an ability to activate Nrf2 signaling in different cells and animal models. The present review compiles the research findings of seventeen coumarin derivatives of plant origin (imperatorin, visnagin, urolithin B, urolithin A, scopoletin, esculin, esculetin, umbelliferone, fraxetin, fraxin, daphnetin, anomalin, wedelolactone, glycycoumarin, osthole, hydrangenol, and isoimperatorin) as antioxidant and anti-inflammatory agents, emphasizing the role of Nrf2 activation in their pharmacological activities. Additionally, molecular docking simulations were utilized to investigate the potential binding mode of these coumarins with Keap1 as a strategy to disrupt Keap1/Nrf2 protein-protein interaction and activate Nrf2 signaling.

SUBMITTER: Hassanein EHM

PROVIDER: S-EPMC7196981 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway.

Hassanein Emad H M EHM Sayed Ahmed M AM Hussein Omnia E OE Mahmoud Ayman M AM

Oxidative medicine and cellular longevity 20200422

The Keap1/Nrf2/ARE system is a central defensive mechanism against oxidative stress which plays a key role in the pathogenesis and progression of many diseases. Nrf2 is a redox-sensitive transcription factor controlling a variety of downstream antioxidant and cytodefensive genes. Nrf2 has a powerful anti-inflammatory activity mediated via modulating NF-<i>κ</i>B. Therefore, pharmacological activation of Nrf2 is a promising therapeutic strategy for the treatment/prevention of several diseases tha ...[more]

PMID: 32377290

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Project description:BackgroundNucleolar protein 16 (NOP16) is present in the protein complex of the nucleolus. The NOP16 promoter contains a c-Myc binding site, and the transcriptional regulation by c-Myc directly regulates NOP16 expression levels.ObjectiveDysregulation of NOP 16 is currently reported in only a small number of cancers. In this study, the expression profile of NOP 16 in hepatocellular carcinoma (LIHC) and its clinical significance were analyzed.MethodsNOP16 expression in hepatocellular carcinoma (LIHC) and its relationship with the clinical characters of LIHC were examined using the Cancer Genome Atlas (TCGA), the Gene Expression comprehensive database (GEO), Kaplan-Meier survival analysis, univariate Cox analysis, multivariate Cox analysis, ROC curve analysis of KEGG enrichment, GSEA enrichment, in vitro experiments (e.g., siRNA interference of NOP16 expression in hepatoma cells, Keap1-Nrf2 pathway, cell cycle, cell apoptosis and Transwell assays), and LIHC single-cell sequencing (scRNA).ResultsPan-cancer analysis revealed that NOP16 was highly expressed in 20 cancer types, including LIHC, and high NOP16 expression was an independent adverse prognostic factor in LIHC patients. The expression levels of NOP16 mRNA and protein were significantly increased in tumour tissues of LIHC patients compared to normal tissues. The functions of co-expressed genes were primarily enriched in the cell cycle and reactive oxygen species metabolism. The experimental results showed that knockdown of NOP16 activated the Keap/Nrf2 signalling pathway and inhibited the invasion, migration, and EMT progression of LIHC cells. LIHC scRNA-seq data showed that NOP16 was primarily expressed in T lymphocytes.ConclusionsNOP16 promoted cancer development in LIHC and caused an imbalance in Keap/Nrf2 signalling, which subsequently caused the aberrant expression of genes typical for EMT, cell cycle progression and apoptosis. NOP16 is a potential prognostic marker and therapeutic target for hepatocellular carcinoma progression.

Project description:Introduction: This study aimed to assess the alleviative effect of quercetagetin (QG) on zearalenone (ZEN)-induced liver injury in rabbits. Methods: Ninety 41-day-old healthy Hyla rabbits were randomly assigned into three groups, including a control (fed with basic diet), ZEN addition group (fed with basic diet + 600 μg/kg ZEN), and ZEN + QG addition group (fed with basic diet + 600 μg/kg ZEN + 100 mg/kg QG), with 30 rabbits per group. The duration of the experiment was 28 days. Results: The results revealed no significant differences in the average daily gain, average daily feed intake, the gain to feed ratio and the liver, kidney and spleen organ indexes (p > 0.05) between the rabbits across the three groups. However, the sacculus rotundus index of the rabbits in the control group was significantly higher than that in the ZEN + QG group (p < 0.05). The intake of ZEN-contaminated diet also significantly increased the activities or levels of alanine transaminase, alkaline phosphatase, total bile acid (TBA), total bilirubin, malondialdehyde, and interleukin-4 (IL-4) and enhanced the abundance of kelch-like ECH-associated protein 1 (Keap1), heat shock protein 70 (HSP70) and cysteine-aspartic acid protease-3 (Caspase-3) mRNA in the blood or liver tissue in ZEN group, compared to the control group (p < 0.05). On the contrary, the activities or levels of immunoglobulin A, complement 3, total antioxidant capacity, glutathione peroxidase (GSH-Px), superoxide dismutase, interleukin-10, and the abundance of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) mRNA were significantly decreased (p < 0.05). Supplementing the diet with QG still maintained significantly higher levels of TBA and IL-4, and the abundance of GSH-Px, HSP70, IL-4, and Caspase-3 mRNA in the blood and liver of rabbits in the ZEN + QG group than in the control group (p < 0.05). At the same time, the other indicators were restored to levels in the control group (p > 0.05). Discussion: In conclusion, QG alleviated the ZEN-induced oxidative damage and liver injury caused by inflammatory reaction through the Keap1-Nrf2-antioxidant response element (ARE) signal pathway, which protected the liver. This study revealed the alleviative effect of QG on the hepatotoxicity of ZEN in rabbits for the first time, providing a new perspective for applying QG and developing a ZEN antidote.

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Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway.

Publications

Coumarins as Modulators of the Keap1/Nrf2/ARE Signaling Pathway.

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