scholarly journals The Role of the Keap1/Nrf2 Pathway in the Cellular Response to Methylmercury

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yoshito Kumagai ◽  
Hironori Kanda ◽  
Yasuhiro Shinkai ◽  
Takashi Toyama
Keyword(s):  
Cellular Response ◽  
Cultured Cells ◽  
Protein Adducts ◽  
Negative Regulator ◽  
Cellular Damage ◽  
Cellular Proteins ◽  
Related Factor ◽  
Mehg Exposure ◽  
Nrf2 Pathway

Methylmercury (MeHg) is an environmental electrophile that covalently modifies cellular proteins with reactive thiols, resulting in the formation of protein adducts. While such protein modifications, referred to asS-mercuration, are thought to be associated with the enzyme dysfunction and cellular damage caused by MeHg exposure, the current consensus is that (1) there is a cellular response to MeHg through the activation of NF-E2-related factor 2 (Nrf2) coupled toS-mercuration of its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), and (2) the Keap1/Nrf2 pathway protects against MeHg toxicity. In this review, we introduce our findings and discuss the observations of other workers concerning theS-mercuration of cellular proteins by MeHg and the importance of the Keap1/Nrf2 pathway in protection against MeHg toxicity in cultured cells and mice.

Re-Examination of the Exacerbating Effect of Inflammasome Components during Radiation Injury

2021 ◽  
Author(s):  
W. June Brickey ◽  
Michael A. Thompson ◽  
Zhecheng Sheng ◽  
Zhiguo Li ◽  
Kouros Owzar ◽  
...  
Keyword(s):  
Cellular Response ◽  
Radiation Injury ◽  
Therapeutic Benefit ◽  
Acute Radiation ◽  
Cellular Damage ◽  
Inflammatory Factors ◽  
Experimental Conditions ◽  
Acute Radiation Injury ◽  
Radiation Induced

Radiation can be applied for therapeutic benefit against cancer or may result in devastating harm due to accidental or intentional release of nuclear energy. In all cases, radiation exposure causes molecular and cellular damage, resulting in the production of inflammatory factors and danger signals. Several classes of innate immune receptors sense the released damage associated molecules and activate cellular response pathways, including the induction of inflammasome signaling that impacts IL-1β/IL-18 maturation and cell death. A previous report indicated inflammasomes aggravate acute radiation syndrome. In contrast, here we find that inflammasome components do not exacerbate gamma-radiation-induced injury by examining heterozygous and gene-deletion littermate controls in addition to wild-type mice. Absence of some inflammasome genes, such as caspase-1/11 and Nlrp3, enhance susceptibility of treated mice to acute radiation injury, indicating importance of the inflammasome pathway in radioprotection. Surprisingly, we discover that the survival outcome may be sex-dependent as more inflammasome-deficient male mice are susceptible to radiation-induced injury. We discuss parameters that may influence the role of inflammasomes as radioprotective or radioexacerbating factors in recovery from radiation injury including the use of littermate controls, the sex of the animals, differences in microbiota within the colonies and other experimental conditions. Under the conditions tested, inflammasome components do not exacerbate radiation injury, but rather provide protective benefit.

scholarly journals Basic Concepts on the Role of Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) in Age-Related Diseases

2019 ◽  
Vol 20 (13) ◽  
pp. 3208 ◽  
Author(s):  
Fabiane Valentini Francisqueti-Ferron ◽  
Artur Junio Togneri Ferron ◽  
Jéssica Leite Garcia ◽  
Carol Cristina Vágula de Almeida Silva ◽  
Mariane Róvero Costa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Transcriptional Factor ◽  
Future Research ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Age Related ◽  
Basic Concepts

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is one of the most important oxidative stress regulator in the human body. Once Nrf2 regulates the expression of a large number of cytoprotective genes, it plays a crucial role in the prevention of several diseases, including age-related disorders. However, the involvement of Nrf2 on these conditions is complex and needs to be clarified. Here, a brief compilation of the Nrf2 enrollment in the pathophysiology of the most common age-related diseases and bring insights for future research on the Nrf2 pathway is described. This review shows a controversial response of this transcriptional factor on the presented diseases. This reinforces the necessity of more studies to investigate modulation strategies for Nrf2, making it a possible therapeutic target in the treatment of age-related disorders.

scholarly journals The spatiotemporal regulation of the Keap1–Nrf2 pathway and its importance in cellular bioenergetics

2015 ◽  
Vol 43 (4) ◽  
pp. 602-610 ◽  
Author(s):  
Albena T. Dinkova-Kostova ◽  
Liam Baird ◽  
Kira M. Holmström ◽  
Colin J. Meyer ◽  
Andrey Y. Abramov
Keyword(s):  
Protein Complex ◽  
Reciprocal Relationship ◽  
Acid Oxidation ◽  
Mitochondrial Activity ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Spatiotemporal Regulation ◽  
Cellular Bioenergetics ◽  
Cellular Defence

The Kelch-like ECH associated protein 1 (Keap1)–NF-E2 p45-related factor 2 (Nrf2) pathway regulates networks of proteins that protect against the cumulative damage of oxidants, electrophiles and misfolded proteins. The interaction between transcription factor Nrf2 and its main negative cytoplasmic regulator Keap1 follows a cycle whereby the protein complex sequentially adopts two conformations: ‘open’, in which Nrf2 binds to one monomer of Keap1, followed by ‘closed’, in which Nrf2 interacts with both members of the Keap1 dimer. Electrophiles and oxidants (inducers) are recognized by cysteine sensors within Keap1, disrupting its ability to target Nrf2 for ubiquitination and degradation. Consequently, the protein complex accumulates in the ‘closed’ conformation, free Keap1 is not regenerated and newly synthesized Nrf2 is stabilized to activate target-gene transcription. The prevailing view of the Keap1–Nrf2 pathway, for which there exists a wealth of experimental evidence, is that it lies at the heart of cellular defence, playing crucial roles in adaptation and survival under conditions of stress. More recently, the significance of Nrf2 in intermediary metabolism and mitochondrial physiology has also been recognized, adding another layer of cytoprotection to the repertoire of functions of Nrf2. One way by which Nrf2 influences mitochondrial activity is through increasing the availability of substrates (NADH and FADH2) for respiration. Another way is through accelerating fatty acid oxidation (FAO). These findings reinforce the reciprocal relationship between oxidative phosphorylation and the cellular redox state, and highlight the key role of Nrf2 in regulating this balance.

scholarly journals The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure

2019 ◽  
Vol 20 (16) ◽  
pp. 4009 ◽  
Author(s):  
Mirco Galiè ◽  
Viviana Covi ◽  
Gabriele Tabaracci ◽  
Manuela Malatesta
Keyword(s):  
Cellular Response ◽  
Tissue Injury ◽  
Scientific Evidence ◽  
Antioxidant Response ◽  
Ozone Exposure ◽  
Related Factor ◽  
Cellular Mechanisms ◽  
Medical Ozone ◽  
Living Organisms

Ozone (O3) is a natural, highly unstable atmospheric gas that rapidly decomposes to oxygen. Although not being a radical molecule, O3 is a very strong oxidant and therefore it is potentially toxic for living organisms. However, scientific evidence proved that the effects of O3 exposure are dose-dependent: high dosages stimulate severe oxidative stress resulting in inflammatory response and tissue injury, whereas low O3 concentrations induce a moderate oxidative eustress activating antioxidant pathways. These properties make O3 a powerful medical tool, which can be used as either a disinfectant or an adjuvant agent in the therapy of numerous diseases. In this paper, the cellular mechanisms involved in the antioxidant response to O3 exposure will be reviewed with special reference to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role in the efficacy of ozone therapy.

scholarly journals CD73 Is Critical for the Resolution of Murine Colonic Inflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Margaret S. Bynoe ◽  
Adam T. Waickman ◽  
Deeqa A. Mahamed ◽  
Cynthia Mueller ◽  
Jeffrey H. Mills ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dextran Sulfate ◽  
Adenosine Monophosphate ◽  
Negative Regulator ◽  
Cellular Damage ◽  
Wild Type ◽  
Extracellular Adenosine ◽  
Glycosyl Phosphatidylinositol ◽  
Cd73 Expression

CD73 is a glycosyl-phosphatidylinositol-(GPI-) linked membrane protein that catalyzes the extracellular dephosphorylation of adenosine monophosphate (AMP) to adenosine. Adenosine is a negative regulator of inflammation and prevents excessive cellular damage. We investigated the role of extracellular adenosine in the intestinal mucosa during the development of Dextran-Sulfate-Sodium-(DSS-)salt-induced colitis in mice that lack CD73 (CD73−/−) and are unable to synthesize extracellular adenosine. We have found that, compared to wild-type (WT) mice, CD73−/−mice are highly susceptible to DSS-induced colitis. CD73−/−mice exhibit pronounced weight loss, slower weight recovery, an increase in gut permeability, a decrease in expression of tight junctional adhesion molecules, as well as unresolved inflammation following the removal of DSS. Moreover, colonic epithelia in CD73−/−mice exhibited increased TLR9 expression, high levels of IL-1βand TNF-α, and constitutive activation of NF-κB. We conclude that CD73 expression in the colon is critical for regulating the magnitude and the resolution of colonic immune responses.

scholarly journals The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae

2009 ◽  
Vol 185 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Debrah M. Thompson ◽  
Roy Parker
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cell Survival ◽  
Cellular Response ◽  
Cellular Damage ◽  
Transfer Rnas ◽  
Endonucleolytic Cleavage ◽  
Response To Stress ◽  
Rnase T2

The cellular response to stress conditions involves a decision between survival or cell death when damage is severe. A conserved stress response in eukaryotes involves endonucleolytic cleavage of transfer RNAs (tRNAs). The mechanism and significance of such tRNA cleavage is unknown. We show that in yeast, tRNAs are cleaved by the RNase T2 family member Rny1p, which is released from the vacuole into the cytosol during oxidative stress. Rny1p modulates yeast cell survival during oxidative stress independently of its catalytic ability. This suggests that upon release to the cytosol, Rny1p promotes cell death by direct interactions with downstream components. Thus, detection of Rny1p, and possibly its orthologues, in the cytosol may be a conserved mechanism for assessing cellular damage and determining cell survival, analogous to the role of cytochrome c as a marker for mitochondrial damage.

scholarly journals Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3β in MPP+-Induced Cell Damage

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1377 ◽  
Author(s):  
Güliz Armagan ◽  
Elvin Sevgili ◽  
Fulya Tuzcu Gürkan ◽  
Fadime Aydın Köse ◽  
Tuğçe Bilgiç ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Cellular Damage ◽  
Glycogen Synthase Kinase 3Β ◽  
Nrf2 Pathway ◽  
Gsk 3Β

Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3β (GSK-3β) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP+-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3β enzyme inhibition against MPP+. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3β enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3β along with PPARγ activation may be responsible for neuroprotection.

scholarly journals KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1885
Author(s):  
Kristen S. Hill ◽  
Anthony McDowell ◽  
J. Robert McCorkle ◽  
Erin Schuler ◽  
Sally R. Ellingson ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cellular Response ◽  
A549 Cells ◽  
Small Cell ◽  
Related Factor ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Nrf2 Pathway ◽  
Inactivating Mutation ◽  
Further Development

Artesunate is the most common treatment for malaria throughout the world. Artesunate has anticancer activity likely through the induction of reactive oxygen species, the same mechanism of action utilized in Plasmodium falciparum infections. Components of the kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which regulates cellular response to oxidative stress, are mutated in approximately 30% of non-small-cell lung cancers (NSCLC); therefore, we tested the hypothesis that KEAP1 is required for artesunate sensitivity in NSCLC. Dose response assays identified A549 cells, which have a G333C-inactivating mutation in KEAP1, as resistant to artesunate, with an IC50 of 23.6 µM, while H1299 and H1563 cells were sensitive to artesunate, with a 10-fold lower IC50. Knockdown of KEAP1 through siRNA caused increased resistance to artesunate in H1299 cells. Alternatively, the pharmacological inhibition of NRF2, which is activated downstream of KEAP1 loss, by ML385 partially restored sensitivity of A549 cells to artesunate, and the combination of artesunate and ML385 was synergistic in both A549 and H1299 cells. These findings demonstrate that KEAP1 is required for the anticancer activity of artesunate and support the further development of NRF2 inhibitors to target patients with mutations in the KEAP1/NRF2 pathway.

scholarly journals Role of Oxidative Stress and Nrf2/KEAP1 Signaling in Colorectal Cancer: Mechanisms and Therapeutic Perspectives with Phytochemicals

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 743
Author(s):  
Da-Young Lee ◽  
Moon-Young Song ◽  
Eun-Hee Kim
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Inflammatory Diseases ◽  
Negative Regulator ◽  
Related Factor ◽  
Cancer Society ◽  
Incidence And Mortality

Colorectal cancer still has a high incidence and mortality rate, according to a report from the American Cancer Society. Colorectal cancer has a high prevalence in patients with inflammatory bowel disease. Oxidative stress, including reactive oxygen species (ROS) and lipid peroxidation, has been known to cause inflammatory diseases and malignant disorders. In particular, the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-related protein 1 (KEAP1) pathway is well known to protect cells from oxidative stress and inflammation. Nrf2 was first found in the homolog of the hematopoietic transcription factor p45 NF-E2, and the transcription factor Nrf2 is a member of the Cap ‘N’ Collar family. KEAP1 is well known as a negative regulator that rapidly degrades Nrf2 through the proteasome system. A range of evidence has shown that consumption of phytochemicals has a preventive or inhibitory effect on cancer progression or proliferation, depending on the stage of colorectal cancer. Therefore, the discovery of phytochemicals regulating the Nrf2/KEAP1 axis and verification of their efficacy have attracted scientific attention. In this review, we summarize the role of oxidative stress and the Nrf2/KEAP1 signaling pathway in colorectal cancer, and the possible utility of phytochemicals with respect to the regulation of the Nrf2/KEAP1 axis in colorectal cancer.

Sign in / Sign up

Export Citation Format

Share Document