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Статті в журналах з теми "Erythropoiesis, Nrf2, Oxidative stress"
1
Mbiandjeu, Serge Cedrick Toya, Alessandro Mattè, Enrica Federti, Massimiliano Perduca, Immacolata Andolfo, Achille Iolascon, Maria Teresa Valenti, et al. "The Novel Role That Nrf2 Plays in Erythropoiesis during Aging." Blood 134, Supplement_1 (November 13, 2019): 3502. http://dx.doi.org/10.1182/blood-2019-125920.
Повний текст джерелаАнотація:
Erythropoiesis is a dynamic and multistep process, resulting in generation of red cells from hematopoietic stem cells. Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nrf2 is a key transcription factor that participates in acute response to oxidative stress and controls the expression of anti-oxidant and cytoprotective systems. We previously documented activation of Nrf2 during β-thalassemic erythropoiesis. In addition, a previous study reported a mild chronic hemolytic anemia as a result of increased erythrophagocytosis in mice genetically lacking Nrf2 (PNAS, 2004). Here, we show an age-dependent worsening of anemia in Nrf2-/- mice characterized by accelerated senescence of circulating erythrocytes in association with reticulocytopenia, suggesting a perturbation of erythroblast maturation. Indeed, we found ineffective erythropoiesis in 12 months-old Nrf2-/- mice with extramedullary erythropoiesis, increased ROS levels, reduction in the expression of Nrf2 related anti-oxidant proteins and apoptosis of erythroid precursor cells. In agreement, we observed an age dependent sensitivity of Nrf2-/- mice to stress erythropoiesis induced by either phenyhydrazine (PHZ) or doxorubicine. In 12-month-old mice we observed (i) activation of the unfoldeld protein response system (UPR) due to endosomal reticulum stress and (ii) impaired autophagy. The cytoprotective processes were unable to fully counteract oxidation re-directing cells towards apoptosis as supported by the increased activity of caspase-3. To understand the impact of oxidation in this model of accelerated senescence, we treated Nrf2-/- mice with astaxanthin, a powerful anti-oxidant but with low oral bioavailability, by administrating it in the form of PLGA loaded nanoparticles (ATS-NP). Treatment of Nrf2-/- mice with ATS-NP ameliorated the age-dependent anemia and decreased ineffective erythropoiesis through (i) inactivation of UPR system; (ii) improvement of autophagy and (iii) reduction in caspase-3 activity. In future studies, we plan to evaluate the impact of ATS-NP administration in other models of pathologic erythropoiesis. In summary, we propose that Nrf2, a key transcriptional factor plays a key protective role in regulating aged related oxidation and ensures normal erythroid maturation and growth. Disclosures No relevant conflicts of interest to declare.
2
Zhu, Xingguo, Caixia Xi, Bobby Thomas, and Betty S. Pace. "Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model." Blood 131, no. 5 (February 1, 2018): 558–62. http://dx.doi.org/10.1182/blood-2017-10-810531.
Повний текст джерелаАнотація:
Key Points NRF2 knockout inhibits fetal hemoglobin expression during gestational erythropoiesis in SCD mice. Loss of the cellular antioxidant response mediated by NRF2 exacerbates spleen damage, inflammation, and oxidative stress in SCD mice.
3
Campbell, Michelle R., Mehmet Karaca, Kelly N. Adamski, Brian N. Chorley, Xuting Wang, and Douglas A. Bell. "Novel Hematopoietic Target Genes in the NRF2-Mediated Transcriptional Pathway." Oxidative Medicine and Cellular Longevity 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/120305.
Повний текст джерелаАнотація:
Nuclear factor- (erythroid-derived 2) like 2 (NFE2L2, NRF2) is a key transcriptional activator of the antioxidant response pathway and is closely related to erythroid transcription factorNFE2. Under oxidative stress, NRF2 heterodimerizes with small Maf proteins and binds cis-acting enhancer sequences found near oxidative stress response genes. Using the dietary isothiocyanate sulforaphane (SFN) to activate NRF2, chromatin immunoprecipitation sequencing (ChIP-seq) identified several hundred novel NRF2-mediated targets beyond its role in oxidative stress. Activated NRF2 bound the antioxidant response element (ARE) in promoters of several known and novel target genes involved in iron homeostasis and heme metabolism, including known targetsFTLandFTH1, as well as novel binding in the globin locus control region. Five novel NRF2 target genes were chosen for followup:AMBP, ABCB6, FECH, HRG-1 (SLC48A1), andTBXAS1. SFN-induced gene expression in erythroid K562 and lymphoid cells were compared for each target gene. NRF2 silencing showed reduced expression in lymphoid, lung, and hepatic cells. Furthermore, stable knockdown of NRF2 negative regulator KEAP1 in K562 cells resulted in increasedNQO1, AMBP, andTBXAS1expression. NFE2 binding sites in K562 cells revealed similar binding profiles as lymphoid NRF2 sites in all potential NRF2 candidates supporting a role forNRF2in heme metabolism and erythropoiesis.
4
Beneduce, Elisabetta, Alessandro Mattè, Luigia De Falco, Serge Cedrick, Emanuela Tolosano, Deborah Chiabrando, Angela Siciliano, Achille Iolascon, Mohandas Narla, and Lucia De Franceschi. "Fyn Kinase Is Involved in EPO Receptor Signaling and Is Required to Harmonize the Response to Oxidation." Blood 130, Suppl_1 (December 7, 2017): 9. http://dx.doi.org/10.1182/blood.v130.suppl_1.9.9.
Повний текст джерелаАнотація:
Abstract Erythropoiesis is a complex multistep process during which committed erythroid progenitors undergo terminal differentiation to produce circulating mature red cells. Erythroid differentiation is characterized by the production of reactive oxygen species (ROS) both in response to erythropoietin (EPO) and to the large amount of iron imported into the cells for heme biosynthesis. During erythropoiesis, ROS might function as second messenger by modulating intracellular signaling pathways. Fyn, an Src kinase, has been previously reported to participate in signaling pathways in response to ROS in various cell types. Here, we explore the potential contribution of Fyn to normal and stress erythropoiesis by studying 2-4 months-old Fyn knockout mouse strain (Fyn-/-) and C57B6/2J as wild-type controls. Fyn-/- mice showed a mild compensated microcytic anemia associated with signs of dyserythropoiesis. Increased ROS levels and Annexin-V+ cells were presented in all Fyn-/- erythroblast subpopulations compared to wild-type, suggesting a possible reduction in the efficiency of erythropoietin (EPO) signaling pathway in the absence of Fyn. Indeed, in Fyn-/- erythroblasts we observed a reduction in Tyr-phosphorylation state of EPO-R associated with a compensatory activation of Jak2 without major change in Lyn activity. A reduction in STAT5 activation resulting in down-regulation of Cish, a known direct STAT5 target gene, was noted in Fyn-/- erythroblasts. This was paralleled by a reduction in GATA1 and increased HSP70 nuclear translocation compared to wild type, supporting a higher cellular pro-oxidant environment in the absence of Fyn. Using the vitro cell forming colony unit assay, we found a lower in CFU-E and BFU-E cells production, which once again was associated with decreased activation of EPO mediated cascade in the absence of Fyn. To explore the possible role of Fyn in stress erythropoiesis, mice were treated with either phenylhydrazine (PHZ) or doxorubicin (Doxo). Fyn-/- mice showed prolonged anemia after either PHZ or Doxo treatment with a delayed hematologic recovery compared to wild-type animals. When we analyzed the expression of a battery of ARE-genes related to oxidative response such as catalase, Gpx, heme-oxygenase 1 and peroxiredoxin-2, we noted up-regulated expression of these genes in sorted Fyn-/- erythroblasts compared to wild-type cells. In agreement, we observed increased activation of the redox-sensitive transcriptional factor Nrf2 targeting ARE-genes, whose regulation has been previously linked to Fyn. In fact, Nrf2 is switched-off by Fyn, ubiquitylated and delivered to the autophagosome by the p62 cargo protein. In Fyn-/- sorted erythroblasts, we observed (i) accumulation of p62 in large clusters; and (ii) reduction of Nrf2-p62 complex compared to wild-type cells. To address the question whether the perturbation of Nrf2-p62 system results in impairment of autophagy in the absence of Fyn, we used Lysotrack to explore late phases of autophagy. Lysosomal progression was defective in Fyn-/- reticulocytes and it was associated with accumulation of p62 during in vitro reticulocyte maturation. These data indicate that the absence of Fyn blocks the Nrf2 post-induction response to oxidation, resulting in impaired autophagy. To validate our working hypothesis, we treated Fyn-/- mice with Rapamycin, an inducer of autophagy. In Fyn-/- mice, Rapamycin treatment resulted in decrease dyserythropoiesis, ROS levels and Annexin V+ cells, associated with reduction in accumulation of p62 in Fyn-/- erythroblasts. As a proof of concept, we treated both mouse strains with PHZ with or without Rapamycin. This latter worsened PHZ induced acute anemia in wild-type mice but not in Fyn-/- animals. Collectively, our data enabled us to document a novel role for Fyn in erythropoiesis, contributing to EPO-R activation and harmonizing the Nrf2-p62 adaptive cellular response against oxidation during normal and more importantly in stress erythropoiesis. Disclosures No relevant conflicts of interest to declare.
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Keleku-Lukwete, Nadine, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, et al. "Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation." Proceedings of the National Academy of Sciences 112, no. 39 (September 14, 2015): 12169–74. http://dx.doi.org/10.1073/pnas.1509158112.
Повний текст джерелаАнотація:
Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells’ hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.
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Gbotosho, Oluwabukola, Maria G. Kapetanaki, Mark A. Ross, Samit Ghosh, Frances Weidert, Grant C. Bullock, Solomon Fiifi Ofori-Acquah, Gregory J. Kato, and Simon Watkins. "Nrf2 Null Mice Are Deficient in CD169+ Macrophages, Associated with Impaired Erythroid Response and Delayed Recovery from Acute Blood Loss." Blood 134, Supplement_1 (November 13, 2019): 1038. http://dx.doi.org/10.1182/blood-2019-127295.
Повний текст джерелаАнотація:
Erythropoiesis occurs in specialized niches in the bone marrow consisting of a central macrophage, surrounded by differentiating erythroblasts. This central macrophage has been identified by several markers including, CD169 (Sialoadhesin or Siglec-1), F4/80, CD11b, VCAM-1, ER-HR3 and Ly-6G. These CD169+ macrophages support erythropoiesis both at steady state and during stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular oxidative defense system. It modulates hematopoietic stem cells but its loss produces no visible phenotype in steady state hematological parameters. However, the importance of Nrf2 and macrophage subsets has not been fully characterized during recovery from stress erythropoiesis. We examined specific subsets of CD169+ macrophage populations in Nrf2 knockout (Nrf2−/−) mice as well as the role of Nrf2 in recovery from stress erythropoiesis in vivo. We quantified the expression of CD169, F4/80 and CD11b, markers of central macrophages, in the BM and spleen of Nrf2+/+ and Nrf2-/- mice at steady state. Surprisingly, Nrf2-/- mice showed a phenotype characterized by lower percentages of cells expressing known macrophage markers. We observed a significant decrease of 47% (p≤0.01), 24% (p≤0.01) and 50% (p≤0.01) in BM macrophage subpopulations expressing F4/80hiCD169hi, F4/80hiCD11bhi and CD169hiCD11bhi respectively, in age-matched Nrf2-/- mice compared to Nrf2+/+ control mice (Fig. 1a). In the spleen, we also observed a similar significant deficiency in BM macrophages (p≤0.01). Further validating this phenotype, immunofluorescence staining of isolated spleen tissue showed that expression of CD169+ macrophages was dramatically lower in spleen sections of Nrf2-/- mice than in Nrf2+/+ control mice. We hypothesized that our macrophage-deficient mice would display a defect in recovery from blood loss. Five to seven days after acute blood loss, immature erythroid progenitors (CD71hiTer119hi) increased in marrow by about 5-fold in Nrf2+/+ mice (p≤0.001, Fig. 1b), and mature erythroid progenitors (CD71loTer119hi) increased in marrow by 12-fold (p≤0.05) but the erythroid marrow response was impaired significantly in the macrophage deficient Nrf2-/- mice. To extend our observations regarding macrophage deficiency and impaired erythroid response, we chose a more functional outcome of recovery from anemia after high-grade blood loss produced by daily phlebotomies over 3 consecutive days to induce stress erythropoiesis in Nrf2+/+ and Nrf2-/- mice. We found significantly lower packed cell volume values specifically on Days 2, 4 and 10, implying delayed erythroid recovery (p≤0.05, two-way ANOVA). The Nrf2-/- mice also showed a significant decline in total hemoglobin than the Nrf2+/+ mice (p≤0.05). Additionally, peripheral blood reticulocyte response to blood loss is delayed in Nrf2 deficient mice compared to age-matched controls (11.0 ± 0.6% vs. 14.8 ± 0.6%, p≤0.001). We analyzed expression of heme-oxygenase 1 (HO-1), a well-known Nrf2-regulated gene. HO-1 mRNA expression increased 3-fold and 23-fold in Nrf2+/+ mice animals subjected to phlebotomy and hemin treatment compared to 2-fold and 12-fold expression in Nrf2-deficient mice (p≤0.05). We demonstrate for the first time that Nrf2-deficient mice have a deficiency of macrophages that includes subsets considered erythroblastic island (EI) macrophages, and that this deficiency is associated with impaired erythroid response to induced stress. Secondly, our multiple phlebotomies data in aggregate demonstrate that Nrf2-/- mice deficient in BM macrophages have significant delay in functional erythroid response and recovery from experimentally-induced anemia. Thirdly, impaired inducibility of HO-1 is a known feature of Nrf2-/- mice, which we confirmed in our results, could be contributing to the impairment in erythroid response. However, it is not likely that restricted iron trafficking to erythroid progenitors occurs in Nrf2-/- mice, since there is no characteristic alteration of mean corpuscular volume and mean corpuscular hemoglobin in peripheral blood. This is an area worthy of additional investigation. We conclude that the Nrf2 gene plays a previously unappreciated role in erythroid biology that appears to be mediated through macrophage function. Disclosures Ofori-Acquah: Shire Human Genetic Therapies Inc: Other: Financial Relationship. Kato:Bayer: Research Funding; Novartis, Global Blood Therapeutics: Consultancy, Research Funding.
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Sheng, Y., Y.-J. Chen, Z.-M. Qian, J. Zheng, and Y. Liu. "Cyclophosphamide induces a significant increase in iron content in the liver and spleen of mice." Human & Experimental Toxicology 39, no. 7 (March 4, 2020): 973–83. http://dx.doi.org/10.1177/0960327120909880.
Повний текст джерелаАнотація:
Objective: Oxidative stress is one of the major mechanisms of cyclophosphamide (CPX)-induced toxicities. However, it is unknown how CPX induces oxidative stress. Based on the available information, we speculated that CPX could increase iron content in the tissues and then induce oxidative stress. Method: We tested this hypothesis by investigating the effects of CPX on iron and ferritin contents, expression of transferrin receptor 1 (TfR1), ferroportin 1 (Fpn1), iron regulatory proteins (IRPs), hepcidin, and nuclear factor erythroid 2-related factor-2 (Nrf2) in the liver and spleen, and also on reticulocyte count, immature reticulocyte fraction, and hemoglobin (Hb) in the blood in c57/B6 mouse. Results: We demonstrated that CPX could induce a significant increase in iron contents and ferritin expression in the liver and spleen, notably inhibit erythropoiesis and Hb synthesis and lead to a reduction in iron usage. The reduced expression in TfR1 and Fpn1 is a secondary effect of CPX-induced iron accumulation in the liver and spleen and also partly associated with the suppressed IRP/iron-responsive element system, upregulation of hepcidin, and downregulation of Nrf2. Conclusions: The reduced iron usage is one of the causes for iron overload in the liver and spleen and the increased tissue iron might be one of the mechanisms for CPX to induce oxidative stress and toxicities.
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Kang, Gyeoung Jin, Eun Ji Kim, and Chang Hoon Lee. "Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation." Antioxidants 9, no. 12 (December 10, 2020): 1259. http://dx.doi.org/10.3390/antiox9121259.
Повний текст джерелаАнотація:
Heart disease is the number one mortality disease in the world. In particular, cardiac fibrosis is considered as a major factor causing myocardial infarction and heart failure. In particular, oxidative stress is a major cause of heart fibrosis. In order to control such oxidative stress, the importance of nuclear factor erythropoietin 2 related factor 2 (NRF2) has recently been highlighted. In this review, we will discuss the activation of NRF2 by docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and the specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated lipids, including DHA and EPA. Additionally, we will discuss their effects on cardiac fibrosis via NRF2 activation.
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Nezu, Masahiro, and Norio Suzuki. "Roles of Nrf2 in Protecting the Kidney from Oxidative Damage." International Journal of Molecular Sciences 21, no. 8 (April 22, 2020): 2951. http://dx.doi.org/10.3390/ijms21082951.
Повний текст джерелаАнотація:
Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.
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Federti, Enrica, Francesca Vinchi, Iana Iatcenko, Alessandra Ghigo, Alessandro Mattè, Serge Cedrick, Angela Siciliano, et al. "Nrf2 Plays a Key Role in Iron-Overload Cardiomyopathy." Blood 138, Supplement 1 (November 5, 2021): 3068. http://dx.doi.org/10.1182/blood-2021-146157.
Повний текст джерелаАнотація:
Abstract Cardiomyopathy due to iron-overload is a severe complication of patients undergoing chronic transfusion regimen such as β-thalassemia and myelodysplastic syndromes. Previous studies have shown the key role of Nrf2, a redox-related transcriptional factor, in both β-thalassemia erythropoiesis and iron homeostasis (Matte A et al. ARS 2018, 2019; Lim PJ et al Nat Metab, 2019). Here, we compared Nrf2 knockout male mice (Nrf2 -/-) and C57BL-6J as wild-type (WT) controls, with a focus on cardiac function. Nrf2 -/- mice were characterized by a mild chronic hemolytic anemia associated with ineffective erythropoiesis, similar to what observed in murineβ-thalassemia (Toya SCM et al., Blood, 2019). Aging Nrf2 -/- mice developed systolic and diastolic dysfunction, associated with increased cardiac oxidative stress, degradation of the calcium-dependent SERCA2A transporter and activation of metalloproteinase MMP9, involved in both SERCA2A degradation and heart remodeling. In Nrf2 -/- mice, we observed increased plasma NTBI, heart iron deposition and elevated expression of cardiac ferroportin when compared to WT animals. Moreover, cardiac Hamp mRNA levels were down-regulated in aging Nrf2 -/- mice when compared to WT mice. This pattern was consistent with progressive cardiac iron overload in absence of Nrf2. Interestingly, activation of TGF-b receptor and PDGF-B-related pathway as well as increased collagen deposition were observed in hearts from 12 months old Nrf2 -/- mice. Taken together our data suggest an aging-associated development of iron-overload cardiomyopathy in mice genetically lacking Nrf2. To evaluate the role of Nrf2 in iron overload cardiomyopathy, Nrf2 -/- and WT mice were exposed to dietary iron supplementation (2.5% w/w carbonyl iron for 28 days). Nrf2 -/- mice developed cardiac hypertrophy which was accompanied by a worsening in collagen deposition and persistent activation of PDGF-B pathway. This was associated with inflammatory vasculopathy. The biologic importance of Nrf2 is supported by the cardiac activation of Nrf2, degradation of SERC2A and activation of TGF-b receptor and PDGF-B pathway in a mouse model of beta thalassemia intermedia, the Hbb3th/+ mice. Collectively our data support the crucial role of Nrf2 in the protection of cardiomyocytes against iron cytotoxicity which significantly develops in aging as well as in β-thalassemia. Disclosures Vinchi: Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vifor Pharma: Research Funding; PharmaNutra: Research Funding; Novartis: Research Funding. Ghigo: Kither Biotech: Other: Board member and Co-Founder. Iolascon: Bluebird Bio: Other: Advisory Board; Celgene: Other: Advisory Board.
Дисертації з теми "Erythropoiesis, Nrf2, Oxidative stress"
1
Qaisiya, Mohammed Ali Hassan. "UNCONJUGATED BILIRUBIN MEDIATED OXIDATIVE STRESS, ER STRESS, AND ACTIVATION OF NRF2 PATHWAY." Doctoral thesis, Università degli studi di Trieste, 2014. http://hdl.handle.net/10077/10137.
Повний текст джерелаАнотація:
2012/2013Elevati livelli plasmatici di bilirubina non coniugata (UCB) sono responsabili dell’ittero neontale che è fisiologico nella maggior parte dei casi. L’iperbilirubinemia severa e prolungata nel tempo può causare encefalopatia da bilirubina e Kernicterus che, se non trattati, possono lasciare pesanti sequele neurologiche e nei casi più gravi condurre a morte. La neurotossicità da bilirubina è ancora una delle principali cause di malattie neurologiche nei paesi via di sviluppo ed è un problema riemergente nei paesi sviluppati a causa delle anticipate dimissioni dall’ospedale dei neonati. I meccanismi molecolari responsabili della neurotossicità da bilirubina non sono ancora completamente chiariti. Questo lavoro riporta i risultati ottenuti durante il mio progetto di dottorato volto a studiare il “molecular signalling” coinvolto nella neurotossicità da bilirubina. L’obiettivo principale è stato valutare gli effetti di concentrazioni pro-ossidanti di bilirubina sullo stato redox cellulare e sullo stress del reticolo endoplasmico (ER stress). Ci siamo focalizzati sulla pathway che coinvolge Nrf2, analizzando i geni indotti dalla bilirubina per effetto di Nrf2 e studiando il signalling a monte coinvolto nella sua attivazione. Parallelamente abbiamo anche studiato la cascata di segnali coinvolti nell’ER stress. Tutti gli esperimenti sono stati condotti nella linea cellulare di neuroblastoma umano SH-SY5Y, alcuni ripetuti anche nella linea di epatocarcinoma HepG2 e in colture primarie di astrociti dalla corteccia cerebrale di ratto. I nostri risultati mostrano che concentrazioni tossiche di bilirubina inducono un 40% di mortalità cellulare tra 1 e 4 ore di trattamento che si mantiene stabile fino alle 24 ore di trattamento. Le cellule trattate con UCB mostrano un incremento del livello dei ROS intracellulare dopo 1 ora seguito dall’accumulo nucleare dell’Nrf2 endogeno dopo 3 ore. La bilirubina aumenta l’induzione della trascrizione dell’ARE-GFP reporter gene associata ad una up-regolazione di diversi geni target di Nrf2. L’induzione dell’espressione genica può essere suddivisa in due categorie principali:la risposta precoce (4h-8h) e la risposta tardiva (16h-24h).La risposta precoce inizia con l’induzione dell’espressione di ATF3 dopo 4 ore di trattamento ed è seguita da i trasportatori di amminoacidi (xCT and Gly1) dopo 8h. Per la risposta tardiva abbiamo visto l’induzione dell’espressione genica degli enzimi coinvolti nella sintesi del glutatione. (γGCL and TNX1),nella risposta antiossidante e di detossificazione (HO-1, NQO1, FTH)e nell’omeostasi del NADPH (ME1, and G6PD). In seguito al silenziamento specifico di Nrf2, il trattamento con bilirubina diminuisce l’induzione dell’mRNA solo dell’HO-1 (75%), del NQO1 (56%) e della FTH (40%) Inoltre l’induzione dell’HO-1 è ridotta se le cellule vengono pretrattate con l’antiossidante NAC (65%) e con specifici inibitori per PKC (80%), P38α (40%) and MEK1/2 (25%). Risulta evidente che l’induzione di ATF3 è la prima risposta generata dal trattamento con UCB. Di seguito abbiamo osservato un’induzione sequenziale dei marker dell’ER stress: da quelli coinvolti nel signaling di PERK a 4h (PERK, ATF3, ATF4, CHOP), dalla diminuzione della proteina della ciclina D1 dopo 1 h e dall’induzione di IRE1 (XBP1), ATF6, e BiP dopo 8h di trattamento. Da notare però che il silenzia mento di PERK non riduce l’induzione dell’espressione dell’mRNA di ATFs/CHOP, ma induce l’espressione dell’mRNA di GCN2. Riassumendo noi abbiamo dimostrato che la bilirubina causa mortalità cellulare, produce la formazione di ROS, provoca l’accumulo di Nrf2 nel nucleo e induce la risposta antiossidante mediata dalle sequenze ARE. La bilirubina induce l’espressione di diversi geni coinvolti nella risposta antiossidante, tra tutti l’HO-1 e il NQO1 sono indotti dalla bilirubina in maniera dipendente da Nrf2. Abbiamo anche dimostrato che lo stress ossidativo (OS) e la PKC sono i principali fattori coinvolti nell’attivazione di Nrf2/HO-1. I risultati ottenuti dimostrano che l’induzione di ATFs/CHOP e di PERK sono uno dei primi eventi associati alla tossicità da bilirubina. Allo stesso tempo il silenziamento di PERK non influisce sull’induzione di ATFs/CHOP mentre induce GCN2, suggerendo un meccanismo di compensazione tra il signalling di PERK e GCN2. Concludendo i nostri dati dimostrano che lo stress ossidativo e lo stress del reticolo endoplasmico sono coinvolti nella neurotossicità indotta da UCB nella linea di neuroblastoma umano SH-SY5Y. Le cellule sviluppano una risposta adattativa alla bilirubina inducendo OS and ER stress e aumentando l’espressione dei geni coinvolti nella risposta antiossidante (in parte via Nrf2 pathway) e nello stress del reticolo endoplasmico (UPR).
Elevated levels of unconjugated bilirubin (UCB) are responsible for neonatal jaundice, and in some case, severe hyperbilirubinemia exposes babies to bilirubin encephalopathy and kernicterus with the risk of neurological sequela and death. Bilirubin neurotoxicity is still a major cause of neurological injury in the developing countries and is a re-emerged problem in the developed countries, due to the early hospital discharge of newborns after birth. The molecular mechanisms of UCB induced neurotoxicty are incompletely elucidated. Present thesis are reported the results obtained during my PhD course aimed to investigate the molecular signaling involved in UCB induced neurotoxicity .The main goal of this work was to evaluate the effects of the pro-oxidant concentration of UCB on cellular redox state and ER stress. We focused on Nrf2 pathway, analyzing the genes induced by UCB at Nrf2-dependent manner and the up-stream signaling involved in Nrf2 pathway activation. In parallel, we also studied the ER stress cascade signaling. All experiments were conducted in SH-SY5Y neuroblastoma cell line, with some performed in HepG2 cells and primary culture of cortical astrocytes. Our results showed that SH-SY5Y neuroblastoma cells incubated with toxic concentration of UCB suffer a 40% loss of cell viability between 1h to 4h, reaching a plateau until 24h after UCB treatment. Treated cells showed an increased level of intracellular ROS after 1h followed by the nuclear accumulation of endogenous Nrf2 after 3h. UCB enhanced the transcriptional activation of ARE-GFP reporter gene associated with an up-regulation of several Nrf2 target genes. Expression response could be divided into two main categories: early (4h-8h) and late response (16h-24h). As far as early genes, UCB mediates a sequential transcription starting with the ATF3 up-regulation at 4h and followed by the induction of amino acid transporters at 8h (xCT and Gly1). On the contrary, for late genes, we observed an up-regulation of the enzymes involved in GSH synthesis (γGCL and TNX1), antioxidant/detoxification (HO-1, NQO1, FTH), and NADPH homeostasis (ME1, and G6PD). Specific Nrf2 siRNA against Nrf2 decreased the induction only of HO-1 (75%), NQO1 (56%), and FTH (40%) upon UCB exposure. HO-1 induction was reduced in cells pre-treated with antioxidant NAC (65%) and with specific signaling inhibitors for PKC (80%), P38α (40%) and MEK1/2 (25%). It was evident that ATF3 up-regulation at 4h represents the earliest response to UCB exposure. We observed a sequential activation of UPR sensors starting with PERK signaling at 4h (up-regulation of PERK, ATF3, ATF4, CHOP at 4h, and loss of cyclin D1 protein at 1h), followed by IRE1 (XBP1), ATF6, and BiP at 8h after UCB treatment. Interestingly, PERK siRNA does not changed the induction of ATFs/CHOP while induced GCN2 mRNA upon UCB exposure. In summary, we demonstrated that UCB mediates loss of cell viability, ROS generation, Nrf2 nuclear accumulation and induction of ARE. Nrf2 pathway activation was associated with the induction of multiple antioxidant genes, among all, HO-1 and NQO1 are induced by UCB at Nrf2-dependent manner. We observed that OS and PKC are the major up-stream signaling involved in Nrf2/HO-1 activation. Results demonstrated ATFs/CHOP induction and ER stress (initiated by PERK signaling) as one of the earliest event associated with UCB toxicity. However, PERK siRNA does not affected ATFs/CHOP induction by UCB while induced GCN2, suggesting a compensatory mechanism between PERK and GCN2 signaling. In conclusion, our data demonstrate that OS and ER stress are involved in UCB induced neurotoxicity in SH-SY5Y cells. The cells undergo an adaptive response against UCB induced OS and ER stress, through activation of multiple antioxidant genes (in part via Nrf2 pathway), and activation of sequential UPR sensors
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Lee, Sang C., Jack Zhang, Josh Strom, Danzhou Yang, Thai Nho Dinh, Kyle Kappeler, and Qin M. Chen. "G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress." AMER SOC MICROBIOLOGY, 2017. http://hdl.handle.net/10150/622753.
Повний текст джерелаАнотація:
Inhibition of protein synthesis serves as a general measure of cellular consequences of chemical stress. A few proteins are translated selectively and influence cell fate. How these proteins can bypass the general control of translation remains unknown. We found that low to mild doses of oxidants induce de novo translation of the NRF2 protein. Here we demonstrate the presence of a G-quadruplex structure in the 5' untranslated region (UTR) of NRF2 mRNA, as measured by circular dichroism, nuclear magnetic resonance, and dimethylsulfate footprinting analyses. Such a structure is important for 5'-UTR activity, since its removal by sequence mutation eliminated H2O2-induced activation of the NRF2 5' UTR. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics revealed elongation factor 1 alpha (EF1a) as a protein binding to the G-quadruplex sequence. Cells responded to H2O2 treatment by increasing the EF1a protein association with NRF2 mRNA, as measured by RNA-protein interaction assays. The EF1a interaction with small and large subunits of ribosomes did not appear to change due to H2O2 treatment, nor did post translational modifications, as measured by two-dimensional (2-D) Western blot analysis. Since NRF2 encodes a transcription factor essential for protection against tissue injury, our data have revealed a novel mechanism of cellular defense involving de novo NRF2 protein translation governed by the EF1a interaction with the G-quadruplex in the NRF2 5' UTR during oxidative stress.
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Tao, Shasha, Pengfei Liu, Gang Luo, de la Vega Montserrat Rojo, Heping Chen, Tongde Wu, Joseph Tillotson, Eli Chapman, and Donna D. Zhang. "p97 Negatively Regulates NRF2 by Extracting Ubiquitylated NRF2 from the KEAP1-CUL3 E3 Complex." AMER SOC MICROBIOLOGY, 2017. http://hdl.handle.net/10150/623934.
Повний текст джерелаАнотація:
Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation ( the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system ( UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBX containing protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.
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Maltagliati, Anthony, and Anthony Maltagliati. "Nrf2: A Candidate Therapeutic Target to Dampen Oxidative Stress in Acute Myocardial Infarction." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/623086.
Повний текст джерелаАнотація:
This literature review posits that the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an attractive candidate therapeutic target in the setting of acute myocardial infarction (AMI). This transcription factor binds to antioxidant response elements (ARE) in the promoter region of a battery of genes that collectively encode an array of antioxidant, phase II drug metabolism, metabolically stabilizing, and overall cytoprotective enzymes, facilitating their transcription at basal levels and increasing transcription in response to various cellular stressors. Following a brief background tutorial on normal cardiac myocyte cellular physiology, key events that occur early in ischemia and reperfusion are outlined and integrated. These include ionic and metabolic dysregulation, electron transport chain uncoupling, mitochondrial depolarization, and the generation of reactive oxygen species (ROS). Abrupt changes in response to ischemia prime opening of the mitochondrial permeability transition pore (MPTP) and cardiac myocytes to generate a burst of ROS upon reperfusion–two key events that contribute to the umbrella term ischemia-reperfusion injury (IRI). How ROS damage cells is then outlined, and through a ROS-centric viewpoint, a case will be made as to how exogenous upregulation of Nrf2 could protect and/or salvage at-risk tissue immediately subjected to infarction and neighboring tissue in the peri-infarct zone (PIZ). The history of how Nrf2 came to be known as the "master regulator of oxidative stress" is reviewed, as well as the discovery of the canonical mechanism of Nrf2 regulation via Kelch-like ECH-associated protein 1 (Keap1) and other alternative mechanisms of endogenous Nrf2 regulation. Finally, compiling interdisciplinary evidence from research publications around the world, the benefits of therapeutically targeting Nrf2 are considered given the timescale and context of acute MI. Drug delivery methods, potential challenges, and limitations are then considered. Cardiac tissue is a dynamic substrate that exhibits changes for up to 90 days after AMI and patient outcomes are directly related to the extent of tissue lost following infarction/reperfusion. Targeting Nrf2 addresses an unmet need, as current clinical therapies focus on precluding occlusions and prompt reperfusion of infarcted tissue, but do not explicitly target at-risk tissue following infarcts and/or present-day reperfusion methodologies.
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Todorovic, Michael. "Assessing the Role of the Oxidative Stress Response ‘Master Regulator’ Nrf2 in Parkinson’s Disease." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367349.
Повний текст джерелаАнотація:
Parkinson’s disease (PD) is a complex neurodegenerative disorder influenced by a combination of genetic and environmental factors. The molecular mechanisms that underlie PD are unknown. However, oxidative stress and impairment of antioxidant defence mechanisms have been implicated as major contributors to disease pathogenesis. Previously, we have reported a PD patient-derived cellular model, generated from biopsies of the olfactory mucosa, termed hONS cells. These cells have demonstrated disease-specific differences in gene expression and metabolic activity associated with the Nrf2-mediated antioxidant defence pathway.
To date, few studies have examined the role of the Nrf2 encoding gene, NFE2L2, in PD. This thesis comprehensibly assessed whether rare and common NFE2L2 genetic variations modify susceptibility to PD using a large Australian case-control sample (PD=1,338; controls=1,379). We employed a haplotype-tagging approach that identified an association with the tagging SNP rs2364725 and PD (OR = 0.849 (0.760-0.948), P = 0.004). Further genetic screening for rare variants in patient-derived cell lines produced no obvious pathogenic variants in the coding regions of NFE2L2. In addition, we were able to identify some age-at-onset modifying SNPs and replicate an ‘early-onset’ haplotype that contains a previously identified ‘functional promoter’ SNP (rs6721961).Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Natural Sciences
Science, Environment, Engineering and Technology
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Strom, Joshua. "A Critical Role of Nrf2 In Protecting Cardiomyocytes Against Oxidative Stress and Ischemic Injury." Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/333336.
Повний текст джерелаАнотація:
Coronary heart disease (CHD) remains the single leading cause of natural death worldwide. Despite significant advances in the diagnosis and treatment, CHD accounts for 1 out of every 6 deaths in the United States. Myocardial infarct (MI) as a result of CHD causes irreversible damage to the heart through the loss of viable myocardial tissue. Patients surviving the initial MI are at risk of developing heart failure due to lost contractile function and adverse cardiac remodeling. Improvement in the survival rates for MI have led to an increase in the incidence of heart failure, affecting approximately 5 million people in the United States. Although treatment of heart failure has improved, the mortality rates of heart failure remain high with 1 in 5 dying within the first year of diagnosis and 50% dying within 5 years. The cost of caring for heart failure patients ranks number one in Medicare. Oxidative stress plays an important role in the etiology and pathophysiology of CHD and heart failure. The transcription factor Nrf2 is a master regulator of cellular antioxidant defense mechanisms, controlling the expression of numerous antioxidant and detoxification genes through the Antioxidant Response Element (ARE) in the promoter regions. The cytoprotective effects of Nrf2 have been demonstrated in a variety of organs and disease states; however, the role of Nrf2 in the heart and heart disease has not been defined. The work presented here defines roles of Nrf2 in limiting cardiac injury and the progression to heart failure (Chapter II), protecting cardiac myocytes from oxidative stress through the preservation of mitochondria (Chapter III), and mediating the infarct reducing effects of statins, one of the most prescribed pharmacological agent (Chapter IV). In order to investigate a role of Nrf2 in the pathology of ischemic injury in the heart, a mouse model of ischemia and myocardial infarct by occlusion of the left anterior descending coronary artery was used. Nrf2 knockout mice subjected to ischemia/reperfusion injury experienced a larger infarct size than wild-type mice. Furthermore, mice lacking Nrf2 experienced a higher mortality rate and an accelerated progression to heart failure, indicated by severely compromised contractile function and reduced cardiac output, within 10 days following an MI. Morphological examination revealed maladaptive remodeling, including myocyte hypertrophy, heart enlargement, and dilated left ventricle, in Nrf2 KO mice that was absent in WT mice. Analysis of cardiac function by echocardiogram revealed increased left ventricular mass, increased systolic volume, decreased fraction shortening, reduced ejection fraction, and decreased cardiac output in Nrf2 KO mice. Nrf2 KO mice also demonstrated expression of biomarkers of heart failure, such as expression of fetal gene program, with elevated levels of β-MHC, ANF, and BNP mRNA in the myocardium. Interestingly, a lack of immune cell infiltrate and myofibroblasts as well as a deficiency in collagen deposition were observed in the infarcted region of hearts from Nrf2 KO mice. These data indicate that Nrf2 plays an important role in protecting the myocardium from ischemic injury and the progression to heart failure. Lack of Nrf2 response results in deficiency of wound healing and instead initiation of maladaptive remodeling, leading to heart failure. Mitochondria are key sources of reactive oxygen species (ROS) generation, as well as important targets for ROS-induced cell injury. Cardiac myocytes have the highest content of mitochondria among all cell types and can be particularly susceptible to mitochondrial dysfunction due to the high metabolic demand associated with the contractile function of the heart. With cardiomyocytes (CMCs) isolated from neonatal rats and kept under tissue culture conditions, mitochondria exist in elaborated networks. Such networks were replaced by predominately individual punctate mitochondria 24 hours after exposure to a sublethal dose of H₂O₂. Mitochondrial morphology was altered with membrane swelling and disorganization of inner cristae with areas of condensation. Disrupted mitochondrial morphology was associated with a loss of membrane potential and decreased expression of mitochondrial proteins involved in the electron transport chain, such as cytochrome b and cytochrome c. Nrf2 overexpression prevented H₂O₂ from inducing morphological changes in mitochondria and the reduction of cytochrome b and cytochrome c expresssion. Although Nrf2 is known as a transcription factor regulating antioxidant and detoxification genes, Nrf2 overexpression did not significantly reduce the level of protein oxidation as measured by carbonyl formation. Instead, we found that Nrf2 localizes to the outer mitochondrial membrane, suggesting a direct role of Nrf2 in mitochondrial protection. As further evidence of a direct role in mitochondrial protection, a cell-free system of mitochondria isolated from the myocardium of Nrf2 knockout mice were more sensitive to permeability transition, an indicator of mitochondrial dysfunction. Combined, these data suggest that Nrf2 protects mitochondria from oxidant injury likely through direct interaction with mitochondria. In the clinic, statins are now commonly administered for patients experiencing MI or CHD. Statins have become mainstays in the treatment of hypercholesterolemia and atherosclerosis as inhibitors of the rate limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase. In addition, statins have been shown to elicit pleiotropic effects, including plaque stabilization, maintenance of endothelial function, anti-inflammatory actions, and antioxidant capabilities, independent of effects on cholesterol synthesis. Recently, these pleiotropic effects have been implicated in providing acute protection against ischemia and reperfusion injury, which has led to the use of high dose statins clinically before revascularization of an ischemic event. I have found that administration of atorvastatin in mice induced Nrf2 protein levels in the heart, brain, lung, and liver. While atorvastatin reduced infarct size following an MI in wild-type mice, this protective effect was lost in mice lacking Nrf2. Failure of atorvastatin to protect against MI in Nrf2 knockout mice indicates that Nrf2 plays a critical role in mediating the protective effects of acute statin treatment. Nrf2 induction by statins is a novel discovery. In order to understand the mechanism of such statin effect, I used an in vitro cell system, in which a variety of statins, atorvastatin, simvastatin, lovastatin, and pravastatin, were found to elevate Nrf2 protein levels. Elevation of Nrf2 by statins was independent of increased protein stability or transcriptional regulation. Instead, statins increased Nrf2 mRNA association with ribosomal complexes and induced Nrf2 protein through a translational mechanism. Recruitment of Nrf2 mRNA to ribosomes and induction of Nrf2 protein was dependent on activation of PI3 kinase. These studies provide evidence that Nrf2 plays a critical role in protecting cardiac myocytes and the heart from oxidative stress and MI. In the absence of Nrf2, mice experienced worse cardiac injury following MI and quickly advanced to heart failure. Mechanistically, this work has identified a novel role of Nrf2 in preserving mitochondrial morphology and integrity during oxidative stress through a direct interaction with the outer mitochondrial membrane. Finally, a newly defined role of Nrf2 induction by statins in mediating protection against MI by acute statin therapy indicates that modulation of Nrf2 may represent a viable pharmacological target for cardiac protection in humans.
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Hintsala, H. R. (Hanna-Riikka). "Oxidative stress and cell adhesion in skin cancer." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526212692.
Повний текст джерелаАнотація:
Abstract Skin is the largest organ in our body protecting us from ultraviolet radiation and xenobiotics. UV-radiation is a common cause of squamocellular carcinoma and melanoma of the skin that cause morbidity and mortality world wide. Reactive oxygen species are constantly formed by, for example, cellular respiration and UV-radiation, and they can readily react with virtually any macromolecule within cell structures causing damage to DNA, proteins and lipids. Oxidative stress (OS) is a homeostatic process that is dysregulated in cancer cells to their benefit. Nuclear factor erythroid-2-related factor 2 (Nrf2) is the main regulator of antioxidant response and it has been shown to be upregulated in various cancers enabling their survival and growth. By using immunohistochemistry we studied the change and prognostic significance of OS markers in melanoma from paraffin embedded patient samples. Nrf2 expression is increased in melanoma, associating with deeper invasion and a worse melanoma-specific outcome. In addition, epithelial-to-mesenchymal transition markers Slug, Twist and Zeb1 showed altered expression levels in relation to invasion and metastasis associating also with Nrf2. With the help of target inhibition molecules Vemurafenib and MEK-inhibitor CI-1040, In vitro study showed that BRAF- and NRAS-mutations might activate Nrf2. Furthermore, Nrf2-regulated antioxidant enzyme peroxiredoxin I showed decreased expression in malignant melanomas and metastases compared to benign naevi. Intriguing findings were made from the surrounding structures of melanomas e.g. loss of expression of an oxidative lesion marker 8-hydroxy-2’-deoxyguanosine in adjacent endothelial cells associated with worse melanoma-specific survival. Changes in the expression of adhesion molecules claudins 1-5 and 7 were studied in the progression of cutaneous squamous cell carcinomas and preneoplastic lesions. Change in claudin composition can alter epidermal permeability and cell polarity. Efficiency of oncological treatment modalities is frequently based on oxidative stress damage. Nrf2-inhibition could offer the means to increase the sensitivity of cancerous tissue to oxidative insults and hinder proliferative and survival signalling. Later research should focus on the relation of Nrf2 with other signalling and observations made from the tumour microenvironmentTiivistelmä Iho on elimistön suurin elin, ja se suojaa meitä auringon ultravioletti (UV)-säteilyltä ja muilta ulkoisilta tekijöiltä. UV-säteily on yhteinen etiologinen tekijä ihon levyepiteelikarsinoomalle ja melanoomalle, jotka aiheuttavat maailmanlaatuisesti paljon sairastavuutta ja kuolleisuutta. Reaktiivisia happiradikaaleja muodostuu esimerkiksi soluhengityksestä ja UV-säteilystä, ja ne voivat reagoida minkä tahansa makromolekyylin kanssa aiheuttaen vaurioita solun perimäainekseen, proteiineihin ja lipidirakenteisiin. Oksidatiivisen stressin (OS) säätely on tärkeä homeostaattinen prosessi, joka vinoutuu syöpäsolujen hyödyksi. Nuclear factor erythroid-2-related factor 2 (Nrf2) on antioksidanttivasteen pääsäätelytekijä, ja sen ilmentyminen on lisääntynyt useissa syövissä lisäten syöpäsolun selviytymistä ja kasvua. Tutkimme potilasaineiston ja immunohistokemian avulla OS:n merkkiaineiden muutoksia melanoomassa ja niiden merkitsevyyttä taudin ennusteelle. Nrf2:n ilmentyminen on lisääntynyt melanoomassa liittyen syvempään invaasioon ja huonompaan tautispesifiseen ennusteeseen. Lisäksi epiteliaali-mesenkymaalitransition merkkiaineiden, Slug, Twist ja Zeb1 ekspression muutoksia havaittiin syvyyskasvun ja metastasoinnin yhteydessä assosioituen myös Nrf2 ilmentymiseen. In vitro- tutkimus osoitti spesifisten inhibiittoreiden avulla, että BRAF- ja NRAS-mutaatiot saattavat aktivoida Nrf2 melanoomassa. Myös Nrf2:n säätelemän entsyymin peroksiredoksiini I:n ilmentyminen on vähentynyt melanoomassa ja metastaaseissa verrattuna hyvänlaatuisiin pigmenttiluomiin. Merkittäviä muutoksia havaittiin myös melanoomaa ympäröivistä rakenteista, esimerkiksi OS:n vauriomarkkerin 8-hydroksi-2’-deoksiguanosiinin vähentynyt ilmentyminen endoteelisoluissa liittyi huonompaan tautispesifiseen ennusteeseen. Lisäksi tutkimme soluväliliitosproteiinien klaudiinien 1–5 sekä 7 ilmentymistä levyepiteelikarsinoomissa ja niiden esiasteissa. Klaudiinien muutokset voivat vaikuttaa ihon permeabiliteettiin ja solujen polarisaatioon. Onkologisten hoitomuotojen teho perustuu usein happiradikaalien aiheuttamiin vaurioihin. Nrf2-inhibitio voisi tarjota keinon lisätä syöpäkudoksen herkkyyttä näille vaurioille sekä estää syöpäsolun selviytymissignalointia. Tulevat tutkimukset tulisivat keskittyä Nrf2 signaloinnin ja muun solusignaloinnin välisiin suhteisiin sekä havaintoihin kasvaimen mikroympäristön muutoksista
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Woolridge, Cooper JàNay K. B. S. "Galactomyces Ferment Filtrate Suppresses Melanization and Oxidative Stress in Epidermal Melanocytes." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1511799237125245.
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Amin, Ahmed [Verfasser]. "NRF2 mediated oxidative stress response activity during early in vitro bovine embryo development / Ahmed Amin." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/107726920X/34.
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Edwards, Heather Gray. "Protection from oxidative stress in the cardiac H9C2-cell line by the transcription factor NRF2." Auburn, Ala., 2007. http://repo.lib.auburn.edu/07M%20Dissertations/GRAY-EDWARDS_HEATHER_53.pdf.
Повний текст джерелаКниги з теми "Erythropoiesis, Nrf2, Oxidative stress"
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Morales-Gonzalez, Jose Antonio, Angel Morales-Gonzalez, and Eduardo Osiris Madrigal-Santillan, eds. A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2. InTech, 2016. http://dx.doi.org/10.5772/62743.
Повний текст джерелаЧастини книг з теми "Erythropoiesis, Nrf2, Oxidative stress"
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Bhattacharjee, Shamee. "Epigenetic Regulators of NRF2." In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, 1437–55. Singapore: Springer Nature Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-5422-0_73.
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Bhattacharjee, Shamee. "Epigenetic Regulators of NRF2." In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, 1–19. Singapore: Springer Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-1247-3_73-1.
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Chen, Chang-Hwei. "Nrf2-ARE Pathway: Defense Against Oxidative Stress." In Xenobiotic Metabolic Enzymes: Bioactivation and Antioxidant Defense, 145–54. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-41679-9_13.
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Chatterjee, Nirmalya, and Debamita Chatterjee. "Regulation of Antioxidant Nrf2 Signaling: An Important Pathway in COPD." In Oxidative Stress in Lung Diseases, 161–75. Singapore: Springer Singapore, 2019. http://dx.doi.org/10.1007/978-981-32-9366-3_7.
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Agrawal, Madhunika, and Satyam Kumar Agrawal. "Implications of NRF2 in Cancer Progression and Therapeutics." In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, 1577–93. Singapore: Springer Nature Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-5422-0_79.
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Agrawal, Madhunika, and Satyam Kumar Agrawal. "Implications of NRF2 in Cancer Progression and Therapeutics." In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, 1–17. Singapore: Springer Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-1247-3_79-1.
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Morita, Masanobu, and Hozumi Motohashi. "Survival Strategy and Disease Pathogenesis According to the Nrf2-Small Maf Heterodimer." In Oxidative Stress in Vertebrates and Invertebrates, 63–82. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9781118148143.ch5.
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Sykiotis, Gerasimos P., Mahidur Rahman, and Dirk Bohmann. "Modulation of Oxidative Stress by Keap1/Nrf2 Signaling inDrosophila: Implications for Human Diseases." In Oxidative Stress in Vertebrates and Invertebrates, 309–26. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2011. http://dx.doi.org/10.1002/9781118148143.ch22.
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Sagar, Satish, Christabelle Rajesh, and Prakash Radhakrishnan. "Targeting Oxidative Stress Specific NRF2 in Pancreatic Cancer Stem Cells." In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, 2021–41. Singapore: Springer Nature Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-5422-0_95.
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Sagar, Satish, Christabelle Rajesh, and Prakash Radhakrishnan. "Targeting Oxidative Stress Specific NRF2 In Pancreatic Cancer Stem Cells." In Handbook of Oxidative Stress in Cancer: Therapeutic Aspects, 1–21. Singapore: Springer Singapore, 2022. http://dx.doi.org/10.1007/978-981-16-1247-3_95-1.
Повний текст джерелаТези доповідей конференцій з теми "Erythropoiesis, Nrf2, Oxidative stress"
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Li, Jian, James Baker, Clare Murray, Nicky Cooper, Cathy Lucas, Craig Fox, Dave Singh, and Simon Lea. "The effects of Nrf2 activators and oxidative stress on COPD alveolar macrophages." In ERS International Congress 2020 abstracts. European Respiratory Society, 2020. http://dx.doi.org/10.1183/13993003.congress-2020.3307.
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Ahmed, Amira, Huda Farah, Omnia Ahmed, Dina Elsayegh, Abdelrahman Elgamal, and Nasser Moustafa Rizk. "Profile Of Oxidative Stress Genes In Response To Obesity Treatment." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0150.
Повний текст джерелаАнотація:
Background: Oxidative stress (OS) is an imbalance between free radical production and the antioxidants defense in the body. Previous studies demonstrated the correlation of OS to the increased risk of developing metabolic disorders such as obesity. Sulforaphane (SFN), a bioactive compound, can protect against inflammation and OS, thus an effective anti-obesity supplement. Aim: This study explores the impact of SNF on OS in diet induced obese (DIO) mice via profiling of OS genes and pathways in skeletal muscles related to the anti-obesity effect. Methods: Wild-type CD1 male mice and the knockout of nuclear factor (erythroid-derived 2) like 2 (NrF2) mice were fed a high-fat diet (HFD) for 16 weeks; to induce obesity. Subsequently, each group was subdivided into two subgroups and received either Vehicle (25μl) or SFN (5 mg/kg BW) for four weeks. Body weight was measured daily, and a glucose tolerance test (GTT) was performed after 21 days of treatment. Afterward, mice were decapitated, blood and tissue samples were collected and snap-frozen immediately. Total RNA was extracted from Skeletal muscle and epididymal white adipose tissue (eWAT), leptin expression was measured in (eWAT), and 84 OS genes in skeletal muscle were examined using RT-PCR. Results: Significant reduction in body weight in SFN treated WT mice, while no change in KO mice. Plasma glucose, leptin, and leptin gene expression (eWAT) were significantly reduced in the WT-DIO SFN treated group, while no changes were detected in KO mice. SFN decreases OS damage in skeletal muscles, such as lipid peroxidation and production of reactive oxygen species (ROS). Conclusion: This study demonstrated that SFN had lowered body weight in WT-DIO mice by decreasing OS damage in skeletal muscles through the NrF2 pathway and can be a potential anti-obesity drug.
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Abalenikhina, Y. V., A. A. Seidkuliyeva, E. D. Rokunov, D. S. Nemtinov, A. V. Shchulkin, and E. N. Yakusheva. "PARTICIPATION OF NUCLEAR FACTOR OF ERYTHROID ORIGIN-2 IN REGU-LATION P-GLYCOPROTEIN IN MODELING ENDOGENOUS OXIDATIVE STRESS." In NOVEL TECHNOLOGIES IN MEDICINE, BIOLOGY, PHARMACOLOGY AND ECOLOGY. Institute of information technology, 2022. http://dx.doi.org/10.47501/978-5-6044060-2-1.251-257.
Повний текст джерелаАнотація:
The article discusses the mechanisms of regulation of the P-glycoprotein transporter protein (Pgp) in cells of the Caco2 line under conditions of modeling endogenous oxidative stress caused by exposure to DL-butyonine sulfoximine (BSO, a glutathione synthesis inhibitor). Ex-periments have shown that exposure to BSO at concentrations of 10-100 μM leads to a de-crease in the concentration of glutathione, an increase in the amount of Pgp and nuclear factor of erythroid origin 2 (Nrf2). Inhibition of Nrf2 contributed to the normalization of Pgp levels, which proves the participation of the transcription factor in the regulation of the transporter protein under the conditions of modeling endogenous oxidative stress.
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Pokrzywinski, Kaytee L., and V. Ashutosh Rao. "Abstract LB-291: microRNA regulation of Nrf2: A link between autophagy and oxidative stress." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-lb-291.
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Wächter, K., A. Navarrete Santos, G. Szabó, and A. Simm. "AGE-Rich Bread Crust Extract Boosts Oxidative Stress Interception via Stimulation of the NRF2 Pathway." In 51st Annual Meeting of the German Society for Thoracic and Cardiovascular Surgery (DGTHG). Georg Thieme Verlag KG, 2022. http://dx.doi.org/10.1055/s-0042-1742787.
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Lan, Aixian, Wenjun Li, Yao Liu, Xinyan Zhang, Shanshan Zhou, Olesya Palko, Hao Chen, et al. "Abstract 829: Chemoprevention of oxidative stress-associated oral carcinogenesis by sulforaphane depends on NRF2 and the isothiocyanate moiety." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-829.
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Kubo, Y., H. Dick, M. Tohidnezhad, A. Fragoulis, H. Jahr, CJ Wruck, and T. Pufe. "Effect of Methysticin on osteoblast function under oxidative stress through Nrf2/HO-1 signaling pathway: in vitro study." In Jahreskongress DVO OSTEOLOGIE 2021. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0040-1722129.
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Ning, Shoucheng, Thillai Veerapazham Sekar, Ramasamy Paulmurugan, Jan Scicinski, Bryan Oronsky, Donna Peehl, and Susan J. Knox. "Abstract 906: Molecular imaging of RRx-001-induced oxidative stress in Nrf2-luciferase expressing SCC VII tumors in mice." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-906.
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Singh, Bhupendra, Amruta Ronghe, Anwesha Chatterjee, and Hari K. Bhat. "Abstract 3696: Resveratrol inhibits oxidative stress and prevents estrogen-induced breast carcinogenesis via activation of NRF2-mediated protective pathways." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3696.
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Gaikwad, Snehal M., Adriana Zingone, Aleksandra Michalowski, Susana Najera, Anaisa Quintanilla-Artega, Sayeh Gorjifard, John Simmons, et al. "Abstract 5850: Nrf2-mediated oxidative stress response is altered during acquired resistance to the proteasome inhibitor, oprozomib, in multiple myeloma." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5850.
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