scholarly journals Nrf2 is a central regulator of the metabolic landscape in macrophages and finetunes their inflammatory response

2021 ◽  
Author(s):  
Dylan Gerard Ryan ◽  
Elena V Knatko ◽  
Alva Casey ◽  
Jens L Hukelmann ◽  
Alejandro J Brenes ◽  
...  
Keyword(s):  
High Resolution Mass Spectrometry ◽  
Redox Homeostasis ◽  
Metabolic Stress ◽  
Metabolic Reprogramming ◽  
Negative Regulator ◽  
Related Factor ◽  
Dependent Manner ◽  
Nrf2 Activation ◽  
Inflammatory Macrophages ◽  
Mitochondrial Adaptation

To overcome oxidative, inflammatory, and metabolic stress, cells have evolved networks of cytoprotective proteins controlled by nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator the Kelch-like ECH associated protein 1 (Keap1). Here, we used high-resolution mass-spectrometry to characterize the proteomes of macrophages with genetically altered Nrf2 status. Our analysis revealed significant differences among the genotypes in cellular metabolism and redox homeostasis, which we validated with respirometry and metabolomics, as well as in anti-viral immune pathways and the cell cycle. Nrf2 status significantly affected the proteome following lipopolysaccharide (LPS) stimulation, with alterations in redox, carbohydrate and lipid metabolism, and innate immunity observed. Of note, Nrf2 activation was found to promote mitochondrial fusion in inflammatory macrophages. The Keap1 inhibitor, 4-octyl itaconate (4-OI), a derivative of the mitochondrial immunometabolite itaconate, remodeled the inflammatory macrophage proteome, increasing redox and suppressing anti-viral immune effectors in a Nrf2-dependent manner. These data suggest that Nrf2 activation facilitates metabolic reprogramming and mitochondrial adaptation, and finetunes the innate immune response in macrophages.

scholarly journals NRF2 as a regulator of cell metabolism and inflammation in cancer

2020 ◽  
Vol 41 (4) ◽  
pp. 405-416 ◽  
Author(s):  
Feng He ◽  
Laura Antonucci ◽  
Michael Karin
Keyword(s):  
Oxidative Stress ◽  
Cancer Risk ◽  
Poor Prognosis ◽  
Cell Metabolism ◽  
Transcriptional Regulator ◽  
Negative Control ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Activation

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.

scholarly journals Allyl Isothiocyanate Protects Acetaminophen-Induced Liver Injury via NRF2 Activation by Decreasing Spontaneous Degradation in Hepatocyte

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3585
Author(s):  
Min Woo Kim ◽  
Ju-Hee Kang ◽  
Hyun Jin Jung ◽  
Se Yong Park ◽  
Thu Han Le Phan ◽  
...  
Keyword(s):  
Target Genes ◽  
Nuclear Translocation ◽  
Biological Effects ◽  
Allyl Isothiocyanate ◽  
Heme Oxygenase 1 ◽  
Toxic Metabolite ◽  
Related Factor ◽  
Dependent Manner ◽  
Nrf2 Activation ◽  
Nrf2 Target Gene

Acetaminophen (APAP) is one of the most frequently prescribed analgesic and anti-pyretic drugs. However, APAP-induced hepatotoxicity is a major cause of acute liver failure globally. While the therapeutic dose is safe, an overdose of APAP produces an excess of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), subsequently resulting in hepatotoxicity. Allyl isothiocyanate (AITC), a bioactive molecule in cruciferous plants, is reported to exert various biological effects, including anti-inflammatory, anti-cancer, and anti-microbial effects. Notably, AITC is known for activating nuclear factor erythroid 2-related factor 2 (NRF2), but there is limited evidence supporting the beneficial effects on hepatocytes and liver, where AITC is mainly metabolized. We applied a mouse model in the current study to investigate whether AITC protects the liver against APAP-induced injury, wherein we observed the protective effects of AITC. Furthermore, NRF2 nuclear translocation and the increase of target genes by AITC treatment were confirmed by in vitro experiments. APAP-induced cell damage was attenuated by AITC via an NRF2-dependent manner, and rapid NRF2 activation by AITC was attributed to the elevation of NRF2 stability by decreasing its spontaneous degradation. Moreover, liver tissues from our mouse experiment revealed that AITC increases the expression of heme oxygenase-1 (HO-1), an NRF2 target gene, confirming the potential of AITC as a hepatoprotective agent that induces NRF2 activation. Taken together, our results indicate the potential of AITC as a natural-product-derived NRF2 activator targeting the liver.

scholarly journals Molecular Mechanisms Underlying Hepatocellular Carcinoma Induction by Aberrant NRF2 Activation-Mediated Transcription Networks: Interaction of NRF2-KEAP1 Controls the Fate of Hepatocarcinogenesis

2020 ◽  
Vol 21 (15) ◽  
pp. 5378 ◽  
Author(s):  
Effi Haque ◽  
M. Rezaul Karim ◽  
Aamir Salam Teeli ◽  
Magdalena Śmiech ◽  
Paweł Leszczynski ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Precancerous Lesions ◽  
Redox Homeostasis ◽  
Detoxification Enzymes ◽  
Related Factor ◽  
Basic Leucine Zipper ◽  
Nrf2 Activation

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

scholarly journals Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Jiangang Zhao ◽  
Xu Lin ◽  
Di Meng ◽  
Liping Zeng ◽  
Runzhou Zhuang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Small Cell Lung ◽  
Antioxidant Genes ◽  
Nrf2 Activation ◽  
Underlying Mechanisms

Nuclear factor erythroid-2–related factor-2 (NFE2L2/Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Both Kelch-like ECH-associated protein 1 (Keap1) mutations and Nrf2 mutations contribute to the activation of Nrf2 in non-small cell lung cancer (NSCLC). Nrf2 activity is associated with poor prognosis in NSCLC. Metabolic reprogramming represents a cancer hallmark. Increasing studies reveal that Nrf2 activation promotes metabolic reprogramming in cancer. In this review, we discuss the underlying mechanisms of Nrf2-mediated metabolic reprogramming and elucidate its role in NSCLC. Inhibition of Nrf2 can alter metabolic processes, thus suppress tumor growth, prevent metastasis, and increase sensitivity to chemotherapy in NSCLC. In conclusion, Nrf2 may serve as a therapeutic target for the treatment of NSCLC.

scholarly journals Metabolic Dynamics of In Vitro CD8+ T Cell Activation

Metabolites ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 12
Author(s):  
Joy Edwards-Hicks ◽  
Michael Mitterer ◽  
Erika L. Pearce ◽  
Joerg M. Buescher
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Membrane Lipids ◽  
High Resolution Mass Spectrometry ◽  
Acyl Chain ◽  
Metabolic Reprogramming ◽  
Dependent Manner ◽  
Polyamine Biosynthesis ◽  
Data Set

CD8+ T cells detect and kill infected or cancerous cells. When activated from their naïve state, T cells undergo a complex transition, including major metabolic reprogramming. Detailed resolution of metabolic dynamics is needed to advance the field of immunometabolism. Here, we outline methodologies that when utilized in parallel achieve broad coverage of the metabolome. Specifically, we used a combination of 2 flow injection analysis (FIA) and 3 liquid chromatography (LC) methods in combination with positive and negative mode high-resolution mass spectrometry (MS) to study the transition from naïve to effector T cells with fine-grained time resolution. Depending on the method, between 54% and 98% of measured metabolic features change in a time-dependent manner, with the major changes in both polar metabolites and lipids occurring in the first 48 h. The statistical analysis highlighted the remodeling of the polyamine biosynthesis pathway, with marked differences in the dynamics of precursors, intermediates, and cofactors. Moreover, phosphatidylcholines, the major class of membrane lipids, underwent a drastic shift in acyl chain composition with polyunsaturated species decreasing from 60% to 25% of the total pool and specifically depleting species containing a 20:4 fatty acid. We hope that this data set with a total of over 11,000 features recorded with multiple MS methodologies for 9 time points will be a useful resource for future work.

scholarly journals The Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism

2021 ◽  
Vol 22 (9) ◽  
pp. 4376
Author(s):  
Moon-Young Song ◽  
Da-Young Lee ◽  
Kyung-Soo Chun ◽  
Eun-Hee Kim
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Strategy ◽  
Cancer Metabolism ◽  
Redox Homeostasis ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Anticancer Effects ◽  
Cytoprotective Enzymes ◽  
Metabolic Oxidative Stress

The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers.

scholarly journals Quercetin Alleviates Oxidative Damage by Activating Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Porcine Enterocytes

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 375
Author(s):  
Hai Jia ◽  
Yunchang Zhang ◽  
Xuemeng Si ◽  
Yuhang Jin ◽  
Da Jiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Cell Injury ◽  
Redox Homeostasis ◽  
Specific Inhibitor ◽  
Epithelial Cell Line ◽  
Related Factor ◽  
Protein Abundance ◽  
Dependent Manner ◽  
Nuclear Factor

Oxidative stress has been implicated in the etiology of multiple gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease. This study was conducted to evaluate effects of natural product quercetin on diquat-induced oxidative stress in porcine enterocytes and underlying mechanisms. Intestinal porcine epithelial cell line 1 (IPEC-1) cells pretreated with or without quercetin (5 μM, 24 h) were incubated with vehicle or diquat (100 μM) for 6 h. The results showed that diquat treatment induced apoptosis in a caspase-3-dependent manner, as accompanied by elevated reactive oxygen species (ROS) production, increased mitochondrial depolarization, and reduced the abundance of tight junction proteins. These adverse effects of diquat were remarkably abrogated by quercetin administration. Further study indicated that the protective effect of quercetin was associated with elevated protein abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased intracellular glutathione (GSH) content. Interestingly, the beneficial effects of quercetin on diquat-induced oxidative damage were abolished by all-trans-retinoic acid (Atra), a specific inhibitor of Nrf2, indicating a Nrf2-dependent regulation manner. The results show that quercetin attenuates diquat-induced cell injury by promoting protein abundance of Nrf2 and regulating GSH-related redox homeostasis in enterocytes. These findings provide new insights into a function role of quercetin in maintaining intestinal homeostasis.

scholarly journals Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1α-Mediated Mitochondrial Biogenesis in the Spinal Cord

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Jia Sun ◽  
Jia-Yan Li ◽  
Long-Qing Zhang ◽  
Dan-Yang Li ◽  
Jia-Yi Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Related Factor ◽  
Dependent Manner ◽  
Nrf2 Activation

Background. Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. Methods. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB. Results. RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor. Conclusions. Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

scholarly journals Deletion of CISH in Human Pluripotent Stem Cell-Derived Natural Killer Cells Enhances Anti-Tumor Activity Via Metabolic Reprogramming

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 619-619 ◽  
Author(s):  
Huang Zhu ◽  
Robert Blum ◽  
Zhengming Wu ◽  
Zhipeng Meng ◽  
Kun-Liang Guan ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Nk Cells ◽  
Immune Cells ◽  
Mitochondrial Respiration ◽  
Nk Cell ◽  
Metabolic Reprogramming ◽  
Negative Regulator ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Anti Tumor Activity

Cellular metabolism is now recognized to play a key role in regulating function and differentiation of immune cells. Immune cells undergo dynamic metabolic shifts to support their activity. Recent studies have shown the importance of metabolism to regulate NK cell function under different conditions. IL-15 can regulate NK cell metabolism in a dose- and time- dependent manner. However, whether improving metabolic fitness of NK cells can lead to improved anti-tumor activity is largely unknown. Here, we deleted CIS (encoded by the CISH gene in human induced pluripotent stem cells (iPSC)-derived NK cells (CISH-/- iPSC-NK) using CRISPR/Cas9 technology. CIS is known to function as a critical negative regulator of IL-15 signaling and a potent inhibitory checkpoint in NK cell-mediated anti-tumor activity. Surprisingly, more than 3000 differentially expressed genes were identified in CISH-/- iPSC-NK cells through RNA sequencing analysis. Gene ontology (GO) enrichment analysis showed that the top 2 up-regulated signaling pathways were associated with leukocyte differentiation and activation. Notably, more than 50 genes that involved in positive regulation of lymphocyte activation including genes associated with NK cell effector functions were significantly up-regulated in CISH-/- iPSC-NK cells compared with unmodified iPSC-NK cells. As expected, CISH-/- iPSC-NK cells exhibited increased sensitivity to IL-15 stimulation. Specifically, IL-15 stimulated JAK1 tyrosine phosphorylation, STAT3 and STAT5 phosphorylation were all dramatically increased in CISH-/- iPSC-NK cells, compared with unmodified iPSC-NK cells. In addition, when incubated with low concentrations of IL-15 (5 ng/ml), a concentration that does not support the growth and functions of unmodified iPSC-NK cells, CISH-/- iPSC-NK cells maintained significantly better expansion with >10 fold expansion for CISH-/- iPSC-NK cells in 3 weeks, whereas most of WT iPSC-NK cells died under these conditions (p<0.001). These CISH-/- iPSC-NK cells exhibited improved cytotoxic against acute myeloid leukemia (AML) cell lines K562 and Molm-13. More importantly, in an AML (MOLM-13) xenograft model, CISH-/- iPSC-NK cells displayed significantly increased in vivo persistence thus lead to significantly better control of tumor progression. To further understand the underling mechanisms contributing to the increased functionality in CISH-/- iPSC-NK cells, we then analyzed the metabolic profiles of these cells using Agilent Seahorse assays. After treatment with low concentration IL-15 for 7 days, CISH-/- iPSC-NK cells displayed both increased glucose metabolism and increased mitochondrial respiration profiles when compared with unmodified iPSC-NK cells. Increased glucose metabolism include a significant increase in basal glycolysis (p=0.0003, 84.5 ± 1.0 vs 61.1 ± 1.8 mpH/min, n=6), and glycolytic capacity (p=0.0049, 15.2±0.4 vs 11.7±0.5 mpH/min, n=6). And increased mitochondrial respiration profile is characterized by an increase in the spare respiratory capacity (p=0.0009, 16.3±1.9 vs 6.9±0.5 pmol/min, n=6), maximal respiration (p<0.0001, 31.6±1.9 vs 15.7±0.8 pmol/min, n=6) and ATP-linked respiration (p<0.0001, 11.5 ± 0.4 vs 7.0±0.3 pmol/min, n=6). Interestingly, limiting the increase of glucose metabolism and mitochondrial respiration via utilization of an mTOR inhibitor (rapamycin) attenuated the increased functionality in CISH-/- iPSC-NK cells. The findings presented here show that deletion of CISH in iPSC-NK cells enhance anti-tumor activity, at least in part via metabolic reprogramming. These findings suggest that improving NK cell functions for cancer immunotherapy through metabolic reprogramming provides a promising therapeutic strategy. Disclosures Guan: OncoImmune: Equity Ownership. Kaufman:FATE Therapeutics: Consultancy, Research Funding.

scholarly journals Compound NSC84167 selectively targets NRF2-activated pancreatic cancer by inhibiting asparagine synthesis pathway

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Bingbing Dai ◽  
Jithesh J. Augustine ◽  
Ya’an Kang ◽  
David Roife ◽  
Xinqun Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Synthetic Lethality ◽  
Ex Vivo ◽  
Protein Translation ◽  
Metabolic Reprogramming ◽  
Related Factor ◽  
Pancreatic Cancers ◽  
Nrf2 Activation

AbstractNuclear factor erythroid 2-related factor 2 (NRF2) is aberrantly activated in about 93% of pancreatic cancers. Activated NRF2 regulates multiple downstream molecules involved in cancer cell metabolic reprogramming, translational control, and treatment resistance; however, targeting NRF2 for pancreatic cancer therapy remains largely unexplored. In this study, we used the online computational tool CellMinerTM to explore the NCI-60 drug databases for compounds with anticancer activities correlating most closely with the mRNA expression of NQO1, a marker for NRF2 pathway activity. Among the >100,000 compounds analyzed, NSC84167, termed herein as NRF2 synthetic lethality compound-01 (NSLC01), was one of the top hits (r = 0.71, P < 0.001) and selected for functional characterization. NSLC01 selectively inhibited the viabilities of four out of seven conventional pancreatic cancer cell lines and induced dramatic apoptosis in the cells with high NRF2 activation. The selective anticancer activity of NSLC01 was further validated with a panel of nine low-passage pancreatic patient-derived cell lines, and a significant reverse correlation between log(IC50) of NSLC01 and NQO1 expression was confirmed (r = −0.5563, P = 0.024). Notably, screening of a panel of nine patient-derived xenografts (PDXs) revealed six PDXs with high NQO1/NRF2 activation, and NSLC01 dramatically inhibited the viabilities and induced apoptosis in ex vivo cultures of PDX tumors. Consistent with the ex vivo results, NSLC01 inhibited the tumor growth of two NRF2-activated PDX models in vivo (P < 0.01, n = 7–8) but had no effects on the NRF2-low counterpart. To characterize the mechanism of action, we employed a metabolomic isotope tracer assay that demonstrated that NSLC01-mediated inhibition of de novo synthesis of multiple amino acids, including asparagine and methionine. Importantly, we further found that NSLC01 suppresses the eEF2K/eEF2 translation elongation cascade and protein translation of asparagine synthetase. In summary, this study identified a novel compound that selectively targets protein translation and induces synthetic lethal effects in NRF2-activated pancreatic cancers.

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