scholarly journals Effects of multi-component mixtures of polyaromatic hydrocarbons and heavy metal/loid(s) on Nrf2-antioxidant response element (ARE) pathway in ARE reporter-HepG2 cells

2016 ◽  
Vol 5 (4) ◽  
pp. 1160-1171 ◽  
Author(s):  
Sasikumar Muthusamy ◽  
Cheng Peng ◽  
Jack C. Ng
Keyword(s):  
Oxidative Stress ◽  
Heavy Metal ◽  
Stress Response ◽  
Hepg2 Cells ◽  
Polyaromatic Hydrocarbons ◽  
Antioxidant Response ◽  
Oxidative Stress Response ◽  
Antioxidant Response Element ◽  
Response Element

The effect of mixtures of PAHs and heavy metal/loid(s) on the Nrf2 antioxidant pathway in HepG2-ARE cells was determined as an indicator of the oxidative stress response.

scholarly journals PICH, an ATP-dependent chromatin remodeling protein, transcriptionally co-regulates oxidative stress response.

2021 ◽  
Author(s):  
Anindita Dutta ◽  
Apurba Das ◽  
Deep Bisht ◽  
Vijendra Arya ◽  
Rohini Muthuswami
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Stress Response ◽  
Chromatin Remodeling ◽  
Dna Sequences ◽  
Target Genes ◽  
Antioxidant Response ◽  
Oxidative Stress Response ◽  
Antioxidant Genes

Cells respond to oxidative stress by elevating the levels of antioxidants, signaling, and transcriptional regulation often implemented by chromatin remodeling proteins.  The study presented in this paper shows that the expression of PICH, an ATP-dependent chromatin remodeler, is upregulated during oxidative stress in HeLa cells. We also show that PICH regulates the expression of Nrf2, a transcription factor regulating antioxidant response, both in the absence and presence of oxidative stress. In turn, Nrf2 regulates the expression of PICH in the presence of oxidative stress. Both PICH and Nrf2 together regulate the expression of antioxidant genes and this transcriptional regulation is dependent on the ATPase activity of PICH. In addition, H3K27ac modification also plays a role in activating transcription in the presence of oxidative stress. Co-immunoprecipitation experiments show that PICH and Nrf2 interact with H3K27ac in the presence of oxidative stress. Mechanistically, PICH recognizes ARE sequences present on its target genes and introduces a conformational change to the DNA sequences leading us to hypothesize that PICH regulates transcription by remodeling DNA. PICH ablation leads to reduced expression of Nrf2 and impaired antioxidant response leading to increased ROS content, thus, showing PICH is essential for the cell to respond to oxidative stress.

scholarly journals The Human Cytomegalovirus US27 Gene Product Constitutively Activates Antioxidant Response Element-Mediated Transcription through Gβγ, Phosphoinositide 3-Kinase, and Nuclear Respiratory Factor 1

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Jordan M. Boeck ◽  
Gregory A. Stowell ◽  
Christine M. O'Connor ◽  
Juliet V. Spencer
Keyword(s):  
Stress Response ◽  
Human Cytomegalovirus ◽  
Antioxidant Response ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Nuclear Respiratory Factor ◽  
Cxcr4 Signaling ◽  
Stress Response Genes ◽  
Nuclear Respiratory Factor 1 ◽  
Phosphoinositide 3 Kinase

ABSTRACTHuman cytomegalovirus (HCMV) is a widespread pathogen that modulates host chemokine signaling during persistent infection in the host. HCMV encodes four proteins with homology to the chemokine receptor family of G protein-coupled receptors (GPCRs): US27, US28, UL33, and UL78. Each of the four receptors modulates host CXCR4 signaling. US28, UL33, and UL78 impair CXCR4 signaling outcomes, while US27 enhances signaling, as evidenced by increased calcium mobilization and cell migration to CXCL12. To investigate the effects of US27 on CXCR4 during virus infection, fibroblasts were infected with bacterial artificial chromosome-derived clinical strain HCMV TB40/E-mCherry(wild type [WT]), mutants lacking US27 (TB40/E-mCherry-US27Δ [US27Δ]) or all four GPCRs (TB40 E-mCherry-allΔ), or mutants expressing only US27 but not US28, UL33, or UL78 (TB40/E-mCherry-US27wt[US27wt]). CXCR4 gene expression was significantly higher in WT- and US27wt-infected fibroblasts. This effect was evident at 3 h postinfection, suggesting that US27 derived from the parental virion enhanced CXCR4 expression. Reporter gene assays demonstrated that US27 increased transcriptional activity regulated by the antioxidant response element (ARE), and small interfering RNA treatment indicated that this effect was mediated by NRF-1, the primary transcription factor for CXCR4. Increased translocation of NRF-1 into the nucleus of WT-infected cells compared to mock- or US27Δ-infected cells was confirmed by immunofluorescence microscopy. Chemical inhibitors targeting Gβγ and phosphoinositide 3-kinase (PI3K) ablated the increase in ARE-driven transcription, implicating these proteins as mediators of US27-stimulated gene transcription. This work identifies the first signaling pathway activated by HCMV US27 and may reveal a novel regulatory function for this orphan viral receptor in stimulating stress response genes during infection.IMPORTANCEHuman cytomegalovirus (HCMV) is the most common congenital infection worldwide, causing deafness, blindness, and other serious birth defects. CXCR4 is a human chemokine receptor that is crucial for both fetal development and immune responses. We found that the HCMV protein US27 stimulates increased expression of CXCR4 through activation of the transcription factor nuclear respiratory factor 1 (NRF-1). NRF-1 regulates stress response genes that contain the antioxidant response element (ARE), and HCMV infection is associated with increased expression of many stress response genes when US27 is present. Our results show that the US27 protein activates the NRF-1/ARE pathway, stimulating higher expression of CXCR4 and other stress response genes, which is likely to be beneficial for virus replication and/or immune evasion.

scholarly journals Immunohistochemical Study of Nrf2-Antioxidant Response Element as Indicator of Oxidative Stress Induced by Cadmium in Developing Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Sergio Montes ◽  
Daniel Juárez-Rebollar ◽  
Concepción Nava-Ruíz ◽  
Aurora Sánchez-García ◽  
Yesica Heras-Romero ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Morphological Changes ◽  
Antioxidant Response ◽  
Protective Mechanism ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Expression Of Genes ◽  
Old Rats ◽  
Kidney Liver

In developing animals, Cadmium (Cd) induces toxicity to many organs including brain. Reactive oxygen species (ROS) are often implicated in Cd-inducedtoxicity and it has been clearly demonstrated that oxidative stress interferes with the expression of genes as well as transcriptional factors such as Nrf2-dependent Antioxidant Response Element (Nrf2-ARE). Cd-generated oxidative stress and elevated Nrf2 activity have been reportedin vitroandin situcells. In this study we evaluated the morphological changes and the expression pattern of Nrf2 and correlated them with the Cd concentrations in different ages of developing rats in heart, lung, kidney, liver, and brain. The Cd content in different organs of rats treated with the metal was increased in all ages assayed. Comparatively, lower Cd brain levels were found in rats intoxicated at the age of 12 days, then pups treated at 5, 10, or 15 days old, at the same metal dose. No evident changes, as a consequence of cadmium exposure, were evident in the morphological analysis in any of the ages assayed. However, Nrf2-ARE immunoreactivity was observed in 15-day-old rats exposed to Cd. Our results support that fully developed blood-brain barrier is an important protector against Cd entrance to brain and that Nrf2 increased expression is a part of protective mechanism against cadmium-induced toxicity.

scholarly journals Astragaloside IV Protects Against Oxidative Stress in Calf Small Intestine Epithelial Cells via NFE2L2-Antioxidant Response Element Signaling

2019 ◽  
Vol 20 (24) ◽  
pp. 6131 ◽  
Author(s):  
Yafang Wang ◽  
Fugui Jiang ◽  
Haijian Cheng ◽  
Xiuwen Tan ◽  
Yifan Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Small Intestine ◽  
Epithelial Cells ◽  
Reactive Oxygen Species Generation ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Astragaloside Iv ◽  
Response Element

Oxidative stress can damage intestinal epithelial cell integrity and function, causing gastrointestinal disorders. Astragaloside IV (ASIV) exhibits a variety of biological and pharmacological properties, including anti-inflammatory and antioxidant effects. The purpose of this research was to investigate the cytoprotective action of ASIV and its mechanisms in calf small intestine epithelial cells with hydrogen peroxide (H2O2)-induced oxidative stress. ASIV pretreatment not only increased cell survival, but it also decreased reactive oxygen species generation and apoptosis, enhanced superoxide dismutase, catalase, and glutathione peroxidase levels, and it reduced malondialdehyde formation. Furthermore, pretreatment with ASIV elevated the mRNA and protein levels of nuclear factor erythroid 2-related factor 2 (NFE2L2), heme oxygenase-1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1). The NFE2L2 inhibitor ML385 inhibited NFE2L2 expression and then blocked HMOX1 and NQO1 expression. These results demonstrate that ASIV treatment effectively protects against H2O2-induced oxidative damage in calf small intestine epithelial cells through the activation of the NFE2L2-antioxidant response element signaling pathway.

scholarly journals Nrf2 Activates Augmenter of Liver Regeneration (ALR) via Antioxidant Response Element and Links Oxidative Stress to Liver Regeneration

2013 ◽  
Vol 19 (1) ◽  
pp. 237-244 ◽  
Author(s):  
Rania Dayoub ◽  
Arndt Vogel ◽  
Jutta Schuett ◽  
Madeleine Lupke ◽  
Susannah M. Spieker ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Regeneration ◽  
Antioxidant Response ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Augmenter Of Liver Regeneration

scholarly journals Overlapping antioxidant response element and PMA responseelement sequences mediate basal and β-naphthoflavone-induced expression of the human γ-glutamylcysteine synthetase catalytic subunit gene

1998 ◽  
Vol 332 (2) ◽  
pp. 373-381 ◽  
Author(s):  
Angela C. WILD ◽  
Jerry J. GIPP ◽  
R. Timothy MULCAHY
Keyword(s):  
Hepg2 Cells ◽  
Constitutive Expression ◽  
Antioxidant Response ◽  
Regulatory Subunit ◽  
Antioxidant Response Element ◽  
Induced Expression ◽  
Response Element ◽  
Relative Significance ◽  
Glutamylcysteine Synthetase ◽  
Gc Box

γ-Glutamylcysteine synthetase (GCS), the rate-limiting enzyme in the de novo synthesis of GSH, is a heterodimer, consisting of a catalytic (GCSh) and a regulatory subunit (GCSl). We previously demonstrated that the constitutive and β-naphthoflavone (β-NF)-induced expression of the GCSh gene is mediated by a distal antioxidant response element (ARE), ARE4, located 3.1 kb upstream of the transcriptional start site [Mulcahy, Wartman, Bailey and Gipp (1997) J. Biol. Chem. 272, 7445–7454]. ARE4 consists of a consensus ARE sequence (5´-GTGACTCAGCG-3´) containing an embedded PMA-responsive element (TRE, underlined). The relative significance of the two overlapping response elements to constitutive and β-NF-induced expression of the GCSh gene was determined by mutational analyses. The internal activator protein-1 (AP-1)-binding sequence mediated constitutive expression of promoter/reporter transgenes, but was not required for β-NF responsiveness. In gel-shift experiments, the TRE was necessary for binding of proteins from nuclear extracts prepared from untreated HepG2 cells. In contrast, induction by β-NF was dependent on an intact ARE sequence, particularly the terminal GC box of ARE4. The GC box of ARE4 was shown to be essential for both basal and β-NF-induced expression of reporter constructs. This element also influenced binding of nuclear proteins to ARE4, specifically in extracts isolated from β-NF-treated HepG2 cells. Because previous studies indicated that ARE4 may co-operate with a separate putative ARE, the role of the neighbouring sequence (ARE3), located 34 bases downstream of ARE4, was also evaluated. Mutation of this element within a GCSh promoter/reporter did not modify the basal or β-NF-induced expression of the transgene, demonstrating that ARE3 does not influence the constitutive or β-NF-induced expression of the GCSh gene.

scholarly journals Macrophage Migration Inhibitory Factor as an Emerging Drug Target to Regulate Antioxidant Response Element System

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Hiroshi Yukitake ◽  
Masayuki Takizawa ◽  
Haruhide Kimura
Keyword(s):  
Oxidative Stress ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Response ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Antioxidant Response Element ◽  
Response Element

Oxidative stress is involved in pathophysiology and pathological conditions of numerous human diseases. Thus, understanding the mechanisms underlying the redox homeostasis in cells and organs is valuable for discovery of therapeutic drugs for oxidative stress-related diseases. Recently, by applying chemical biology approach with an ARE activator, BTZO-1, we found macrophage migration inhibitory factor (MIF) as a new regulator of antioxidant response element- (ARE-) mediated gene transcription. BTZO-1 and its active derivatives bound to MIF and protected cells and organs from oxidative insults via ARE activation in animal models with oxidative stress such as ischemia/reperfusion injury, inflammatory bowel diseases, and septic shock. In this review, we briefly highlight key findings in understanding the MIF-ARE system.

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