Статті в журналах: "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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

5

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

6

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

7

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

8

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

9

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

10

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 джерела

Анотація:

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.

Стилі APA, Harvard, Vancouver, ISO та ін.

11

Zhu, Xingguo, Caixia Xi, Alexander Ward, Mayuko Takezaki, Huidong Shi, Kenneth R. Peterson та Betty S. Pace. "NRF2 mediates γ-globin gene regulation through epigenetic modifications in a β-YAC transgenic mouse model". Experimental Biology and Medicine 245, № 15 (26 липня 2020): 1308–18. http://dx.doi.org/10.1177/1535370220945305.

Повний текст джерела

Анотація:

NRF2 is the master regulator for the cellular oxidative stress response and regulates γ-globin gene expression in human erythroid progenitors and sickle cell disease mice. To explore NRF2 function, we established a human β-globin locus yeast artificial chromosome transgenic/NRF2 knockout (β-YAC/NRF2−/−) mouse model. NRF2 loss reduced γ-globin gene expression during erythropoiesis and abolished the ability of dimethyl fumarate, an NRF2 activator, to enhance γ-globin transcription. We observed decreased H3K4Me1 and H3K4Me3 chromatin marks and association of TATA-binding protein and RNA polymerase II at the β-locus control region (LCR) and γ-globin gene promoters in β-YAC/NRF2−/− mice. As a result, long-range chromatin interaction between the LCR DNase I hypersensitive sites and γ-globin gene was decreased, while interaction with the β-globin was not affected. Further, NRF2 loss silenced the expression of DNA methylcytosine dioxygenases TET1, TET2, and TET3 and inhibited γ-globin gene DNA hydroxymethylation. Subsequently, protein-protein interaction between NRF2 and TET3 was demonstrated. These data support the ability of NRF2 to mediate γ-globin gene regulation through epigenetic DNA and histone modifications. Impact statement Sickle cell disease is an inherited hemoglobin disorder that affects over 100,000 people in the United States causing high morbidity and early mortality. Although new treatments were recently approved by the FDA, only one drug Hydroxyurea induces fetal hemoglobin expression to inhibit sickle hemoglobin polymerization in red blood cells. Our laboratory previously demonstrated the ability of the NRF2 activator, dimethyl fumarate to induce fetal hemoglobin in the sickle cell mouse model. In this study, we investigated molecular mechanisms of γ-globin gene activation by NRF2. We observed the ability of NRF2 to modulate chromatin structure in the human β-like globin gene locus of β-YAC transgenic mice during development. Furthermore, an NRF2/TET3 interaction regulates γ-globin gene DNA methylation. These findings provide potential new molecular targets for small molecule drug developed for treating sickle cell disease.

Стилі APA, Harvard, Vancouver, ISO та ін.

12

Li, Liang, Yin Wei Ho, Qin Huang, Min Li, Stephen J. Forman, Smita Bhatia, and Ravi Bhatia. "Nrf2 Deficiency Leads to Altered Hematopoietic Stem Cell Function and Increased Sensitivity to Alkylating Agent Induced Myeloid Dysplasia,." Blood 118, no. 21 (November 18, 2011): 3828. http://dx.doi.org/10.1182/blood.v118.21.3828.3828.

Повний текст джерела

Анотація:

Abstract Abstract 3828 Therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) is a lethal complication of cancer treatment. In a previous study we conducted gene expression analysis comparing peripheral blood stem cell (PBSC) CD34+ cells from patients who subsequently developed t-MDS/AML after autologous hematopoietic cell transplantation (aHCT) for Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) and matched controls that did not develop t-MDS/AML after aHCT. This study showed that the Nrf2-mediated oxidative stress response was one of the top ranked canonical pathways downregulated in t-MDS/AML cases compared to controls. Nrf2 is a basic region-leucine-zipper transcription factor that regulates expression of numerous detoxifying and antioxidant genes as well as ubiquitination and proteasomal degradation proteins. Since the Nrf2 pathway is a major cellular defense mechanism against oxidative and xenobiotic stresses, we hypothesized that downregulated Nrf2 response may cause increased toxicity after genotoxic therapeutic exposures and contribute to development of t-MDS/AML. To test this hypothesis, we studied Nrf2 knockout mice to determine the effects of Nrf2 deficiency on hematopoiesis under physiological conditions and after exposure to genotoxic stress. We did not observe significant differences in peripheral blood (PB) counts between Nrf2 knockout (KO) mice and wild-type (WT) mice. Analyses of hematopoietic cells from PB, bone marrow (BM) or spleen using multi-color flow cytometry demonstrated that the compositions of granulocyte, B cell and T cell lineages were similar between KO and WT mice. No differences in BM long-term hematopoietic stem cell (LT-HSC, Lin-c-Kit+Sca-1+ Flt3- CD48-CD150+), multi-potent progenitor (MPP, Lin-c-Kit+Sca-1+ Flt3- CD48+), common-myeloid progenitor (CMP, Lin-c-Kit+Sca-1-CD34+CD16/32-), granulocyte/monocyte progenitor (GMP, Lin-c-Kit+Sca-1-CD34+CD16/32+), or megakaryocyte/erythroid progenitor (MEP, Lin-c-Kit+Sca-1-CD34-CD16/32-) populations were seen between KO and WT mice. However, analysis of LT-HSC function using competitive repopulation assays demonstrated significantly reduced chimerism of donor derived cells in PB of recipient mice at 12 weeks and 16 weeks in KO group compared to WT control (42.49±3.09% vs. 54.75±2.13% at 12 weeks and 42.5±2.8% vs. 57.2±3.3% at 16 weeks for KO and WT respectively). Although we did not see significant differences in chimerism of donor-derived hematopoietic stem/progenitor cells in the BM of KO and WT groups at 16 weeks, we did observe significantly reduced contribution of donor-derived cells from the KO group compared to WT control in PB in secondary recipients as early as 8 weeks after secondary transplantation of BM cells (16.5±1.7% vs 61.9±1.5% for KO and WT respectively). These data indicate that Nrf2 deficiency causes cell-intrinsic functional defects in HSC self-renewal. In order to test if Nrf2 deficient hematopoietic cells are more sensitive to genotoxic stress compared to WT cells, we treated KO and WT mice with the alkylating agent ENU and monitored for hematological changes in PB. We did not observe significant differences in hematopoietic recovery after exposure to acute genotoxic stress between KO and WT mice. However, KO mice developed severe anemia at a significantly increased rate and with shorter latency compared to WT mice after ENU treatment (88% in KO vs. 28% in WT at 4 months, p=0.003). Anemic mice developed massive splenomegaly, and histological analysis showed loss of follicular structure and dramatic increase in erythropoiesis with areas of myeloid elements. Pathological examination of BM from anemic mice revealed normal cellularity but reduced erythropoiesis with expansion of myeloid cells. FACS analyses revealed expansion of myeloid (CD11b+, Gr-1+) and immature erythroid population (CD71+Ter119+/dim) in the spleen and BM, and increased CD11b+, Gr-1+ cells in PB. These findings are consistent with development of myeloid dysplasia in these mice. In conclusion, Nrf2 deficiency results in alterations in HSC self-renewal capacity under physiological condition, and leads to increased sensitivity to alkylator-induced myeloid dysplasia in mice. Disclosures: No relevant conflicts of interest to declare.

Стилі APA, Harvard, Vancouver, ISO та ін.

13

Li, Runqin, Dengfeng Ma, Zhihua Fu, Xiaoxuan Zheng, and Wenxiu Li. "Forsythiaside A inhibits hydrogen peroxide-induced inflammation, oxidative stress, and apoptosis of cardiomyocytes." Tropical Journal of Pharmaceutical Research 20, no. 10 (November 20, 2021): 2029–34. http://dx.doi.org/10.4314/tjpr.v20i10.3.

Повний текст джерела

Анотація:

Purpose: To investigate the effect of forsythiaside A on heart failure.Methods: An in vitro cell model of myocardial injury was established by incubating H9c2 primary cardiomyocytes with hydrogen peroxide (H2O2). Apoptosis was measured by flow cytometry. Expression of inflammatory factors, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and enzymelinkedimmunosorbent assay (ELISA). Oxidative stress was evaluated by measuring malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) levels by ELISA.Results: Incubation with H2O2 increased H9c2 cell apoptosis (p < 0.001). Treatment with forsythiaside A reduced Bax expression and enhanced Bcl-2 expression which suppressed apoptosis of H2O2- induced H9c2 cells. Forsythiaside A also attenuated the H2O2-induced increase in TNF-α and IL-6expressions in H9c2 cells (p < 0.001). The H2O2-induced increase in MDA and decrease in SOD and GSH-Px in H9c2 cells were reversed by treatment with forsythiaside A. IκBα protein expression was downregulated, whereas p65 phosphorylation (p-p65), p-IκBα, nuclear factor erythropoietin-2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) were upregulated in H2O2-induced H9c2 cells. Forsythiaside A increased IκBα, Nrf2, and HO-1 expression and decreased p-p65 and p-IκBα expression in H2O2-induced H9c2 cells.Conclusion: Forsythiaside A exerts anti-inflammatory, anti-oxidant, and anti-apoptotic effects against H2O2-induced H9c2 cells through inactivation of NF-κB pathway and activation of Nrf2/HO-1 pathway. These results support the potential clinical application of forsythiaside A for the treatment of heart failure.

Стилі APA, Harvard, Vancouver, ISO та ін.

14

Zolnourian, Ardalan, Ian Galea, and Diederik Bulters. "Neuroprotective Role of the Nrf2 Pathway in Subarachnoid Haemorrhage and Its Therapeutic Potential." Oxidative Medicine and Cellular Longevity 2019 (May 2, 2019): 1–21. http://dx.doi.org/10.1155/2019/6218239.

Повний текст джерела

Анотація:

The mechanisms underlying poor outcome following subarachnoid haemorrhage (SAH) are complex and multifactorial. They include early brain injury, spreading depolarisation, inflammation, oxidative stress, macroscopic cerebral vasospasm, and microcirculatory disturbances. Nrf2 is a global promoter of the antioxidant and anti-inflammatory response and has potential protective effects against all of these mechanisms. It has been shown to be upregulated after SAH, and Nrf2 knockout animals have poorer functional and behavioural outcomes after SAH. There are many agents known to activate the Nrf2 pathway. Of these, the actions of sulforaphane, curcumin, astaxanthin, lycopene,tert-butylhydroquinone, dimethyl fumarate, melatonin, and erythropoietin have been studied in SAH models. This review details the different mechanisms of injury after SAH including the contribution of haemoglobin (Hb) and its breakdown products. It then summarises the evidence that the Nrf2 pathway is active and protective after SAH and finally examines the evidence supporting Nrf2 upregulation as a therapy after SAH.

Стилі APA, Harvard, Vancouver, ISO та ін.

15

Nettleton, Margaret, Luis E. Almeida, Sayuri Kamimura, Richard G. Lee, Gene Hung, and Zena Quezado. "Antisense Oligonucleotide Against Kelch-like Ech-Associated protein1 Ameliorates Liver Injury in Sickle Cell Mice." Blood 128, no. 22 (December 2, 2016): 1294. http://dx.doi.org/10.1182/blood.v128.22.1294.1294.

Повний текст джерела

Анотація:

Abstract A great deal of evidence links the manifestations and associated morbidities of sickle cell disease (SCD) to ischemia/reperfusion injury and increased oxidative stress. Recent studies using humanized SCD mice show that thermal and mechanical hyperalgesia is associated with microglia activation and increased oxidative stress in the spinal cord, which are all ameliorated by treatment with antioxidants. In kidneys of SCD mice, at baseline, there is elevated heme content and increased oxidative stress (increased lipid peroxidation and severe medullary congestion). Synthesis inhibition of the antioxidant glutathione, precipitates increased sickling in kidney cortex and medulla. In SCD patients presenting with acute chest syndrome, researchers have shown that F(2)-isoprostanes, markers of oxidative injury, are significantly elevated and decline to baseline levels after exchange blood transfusions. In sickle cell patients, plasma levels of pentosidine and CML, established biomarkers of oxidative stress, correlate with the hemolytic rate, endothelial activation (adhesion molecules levels), and with the presence of hemolysis-related complications. Taken together these studies indicate that oxidative stress plays a significant role in SCD-related pain and organ injury. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the expression of genes involved in cellular defense against oxidative stress and is constitutively inhibited by Kelch-like ECH-associated protein1 (Keap1). With increased oxidative stress, Keap1 is inactivated and Nrf2 stabilizes, translocates to the nucleus, and binds to antioxidant response elements (ARE) within promoters of genes that increase antioxidant capacity. In two recent studies, researchers have shown that genetic and pharmacologic inhibition of Keap1 ameliorates inflammation and liver and lung damage in SCD mice. Therefore, this pathway holds great promise as a possible therapeutic target in SCD. Here, we investigated the feasibility of using an antisense oligonucleotide (ASO) against Keap1 (Keap1ASO) to knockdown expression of Keap1 in SCD mice. Keap1ASO and controlASO were obtained from IONIS Pharmaceuticals (ionispharma.com).We then treated homozygous Townes (sickling) SCD mice (8-12 weeks old) with 40mg/kg Keap1ASO (n=4) or controlASO (n=4). Both controlASO and Keap1ASO were administered subcutaneously, once a week for four weeks. We showed that a 4-week treatment with Keap1ASO yielded significant Keap1 mRNA expression knockdown (Figure 1). Further, the knockdown of Keap1ASO was associated with remarkable improvement in liver injury shown by significant reduction in areas of liver necrosis in Keap1ASO-treated compared to controlASO-treated sickling mice (Figure 2). Further, these effects of Keap1ASO were not associated with significant changes in white or red blood cell counts, liver glutathione levels, transaminases or total bilirrubin. These findings are in keeping with those of others showing that genetic inhibition of Keap1 ameliorates organ injury in SCD mice without affecting erythropoiesis. Taken together, these preliminary data support the hypothesis that oxidative stress has an important role in the pathobiology of organ injury in SCD mice and that knockdown of Keap1 mRNA with Keap1ASO treatment ameliorates organ damage in SCD mice. Disclosures Lee: Ionis Pharmaceuticals: Employment, Equity Ownership. Hung:IONIS Pharmaceuticals: Employment, Equity Ownership. Quezado:IONIS Pharmaceuticals: Research Funding.

Стилі APA, Harvard, Vancouver, ISO та ін.

16

Li, Liang, Yin Wei Ho, Ling Li, Qin Huang, Min Li, Stephen J. Forman, Smita Bhatia, and Ravi Bhatia. "Nrf2 Deficiency Leads to Reduced Hematopoietic Stem Cell Self-Renewal and Increased Sensitivity to Genotoxic Stressors Through Impaired P53 Function." Blood 120, no. 21 (November 16, 2012): 397. http://dx.doi.org/10.1182/blood.v120.21.397.397.

Повний текст джерела

Анотація:

Abstract Abstract 397 Nrf2 is a basic region-leucine-zipper transcription factor that regulates expression of numerous genes required for oxidative stress response, drug and toxin detoxification, protein ubiquitination, and proteasomal degradation of damaged proteins. Therefore Nrf2 represents a major cellular defense mechanism against oxidative and toxic stresses. We have shown that CD34+ hematopoietic stem/progenitor cells (HSPC) drawn from peripheral blood stem cell (PBSC) autografts of lymphoma patients who develop therapy-related myelodysplasia or acute myeloid leukemia (t-MDS/AML) after autologous hematopoietic cell transplantation (aHCT) demonstrate significantly reduced expression of Nrf2-mediated stress response pathway genes compared to cells from patients who do not develop t-MDS/AML (Cancer Cell 20, 591–605). We have extended these findings to study the role of Nrf2 in HSPC regulation and the response to genotoxic chemotherapeutic agents by using an Nrf2 knockout (KO) mouse model. Nrf2 KO mice demonstrated impaired bone marrow (BM) long-term hematopoietic stem cell (LT-HSC) function, manifested by significantly reduced competitive engraftment of BM cells in recipient mice at 16 weeks compared to wild-type (WT) controls (42.5±2.8% vs. 57.2±3.3% peripheral blood engraftment for KO and WT donors respectively, p<0.01). An even more significant defect in engraftment of KO cells was seen after transplantation to secondary recipients (16.4±1.7% vs. 61.9±1.5% peripheral blood engraftment at 8 weeks for KO and WT donors respectively, p<0.01). Nrf2 KO mice also demonstrated increased sensitivity to ENU treatment compared to WT mice. ENU (100mg/kg) treatment resulted in severe anemia at 7 months in 100% of KO mice compared with 36% of WT mice (p<0.001). Furthermore, anemia developed at a median of 5 months in Nrf2 KO mice compared to 10 months in WT controls. Pathological examination of BM from anemic mice revealed reduced erythropoiesis with impaired erythroid maturation and expansion of myeloid cells, consistent with myeloid dysplasia. Q-RT-PCR analysis demonstrated significantly reduced expression of Nrf2 target genes, including Hmo-1, Nqo-1, Gclc and Gpx1, in BM c-kit+ HSPC from KO mice compared to WT mice (p<0.05). Interestingly, expression of several P53 target genes including Bax, Puma, Cdkn1a and Necdin were also significantly reduced in BM c-kit+ cells from Nrf2 KO compared to WT mice. We also observed reduced P53 target gene expression in Nrf2 KO c-Kit cells compared with WT cells 4 hours after treatment with ENU (p<0.05), indicating impaired P53 response in Nrf2 deficient HSPC. To examine the P53 response to DNA damaging agents in LT-HSC, we exposed Nrf2 KO and WT mice to 2Gy irradiation and selected BM LT-HSC (Lin-Sca-1+c-kit+Flt-3-CD150+CD48-) using flow cytometry 12 hours after irradiation. Q-RT-PCR analysis showed significantly reduced expression of P53 target genes Bax, Puma and Necdin (p<0.05), and a trend towards reduced expression of Cdkn1a (p=0.08), in Nrf2 KO compared to WT LT-HSC. Immunofluorescence microscopy showed significantly reduced nuclear and increased cytoplasmic localization of P53 in Nrf2 KO compared to WT LT-HSC. Western blotting analysis showed increased levels of ubquitinated proteins in BM c-kit+ HSPC from Nrf2 KO compared to WT mice, and immunoprecipitation followed by Western blotting for P53 revealed increased high molecular weight bands indicative of ubiquitinated P53 in Nrf2 KO HSPC. Nrf2 is a key regulator of protein ubiquitination and proteasomal degradation, and these results suggest that abnormal cytoplasmic accumulation of ubiquitinated P53 may contribute to altered P53 function in Nrf2 deficient HSPC. In conclusion, our results show that Nrf2 deficiency results in impaired HSC self-renewal capacity under physiological conditions, and significantly increased sensitivity to genotoxic stress, potentially explained by altered P53 protein modulation in Nrf2 deficient HSPC. These observations suggest that Nrf2 deficiency could contribute to development of t-MDS/AML following exposure to genotoxic agents, and support further evaluation of Nrf2 as a potential target of chemopreventive efforts. Disclosures: No relevant conflicts of interest to declare.

Стилі APA, Harvard, Vancouver, ISO та ін.

17

Zhang, Xueyan, Yihan Yu, Hanyu Lei, Yufeng Cai, Jie Shen, Ping Zhu, Qingnan He, and Mingyi Zhao. "The Nrf-2/HO-1 Signaling Axis: A Ray of Hope in Cardiovascular Diseases." Cardiology Research and Practice 2020 (January 30, 2020): 1–9. http://dx.doi.org/10.1155/2020/5695723.

Повний текст джерела

Анотація:

Cardiovascular disease, which can lead to angina and shortness of breath, remains one of the most serious threats to human health. Owing to its imperceptible symptoms, it is difficult to determine the pathogenesis and treatment methods for cardiovascular disease. Nuclear factor erythropoietin-2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) is a protein found in all cells of the human body. It is activated, transferred to the nucleus, and bound to DNA by antioxidant response elements (AREs). As a regulator of the antioxidant system, it upregulates the expression of HO-1 to reduce oxidative stress. Nrf2/HO-1 also has the ability to modulate calcium levels to prevent ferroptosis, pyroptosis, autophagy, programmed cell necrosis, alkaliptosis, and clockophagy. In view of the importance of Nrf2/HO-1 in the regulation of homeostasis, this review summarizes current research on the relationship between cardiovascular disease and Nrf2/HO-1. Normal cardiovascular diseases, such as viral myocarditis and myocardial ischemia-reperfusion injury, have been treated with Nrf2/HO-1. Rheumatic heart disease, cardiac tumors, arteriosclerosis, arrhythmia, hypertensive heart disease, and myocardial infarction have also been treated during experiments. Research has demonstrated the clinical application of Nrf2/HO-1 in pediatric cardiovascular disease; further clinical trials will help elucidate the potential of the Nrf2/HO-1 signaling axis.

Стилі APA, Harvard, Vancouver, ISO та ін.

18

Yu, Yean, Baohong Feng, Li Yan, Zhimin Bi, Geli Zhu, and Fen Jiang. "Ruscogenin protects against cisplatin-induced apoptosis, inflammation, and oxidative stress of renal tubular epithelial cells." Tropical Journal of Pharmaceutical Research 20, no. 6 (February 7, 2022): 1159–64. http://dx.doi.org/10.4314/tjpr.v20i6.9.

Повний текст джерела

Анотація:

Purpose: To determine the potential effect of ruscogenin in cisplatin-induced nephrotoxicity. Methods: Rat renal tubular epithelial cells (NRK-52E) were treated with 50 μM cisplatin to establish an in vitro cell model of nephrotoxicity. Cytotoxicity was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, flow cytometry, and western blot. Different concentrations of ruscogenin (2.5, 5, and 10 μM) were incubated with cisplatin-treated NRK-52E cells. Alterations in the nod-like receptor family, the pyrin domain-containing protein (NLRP3) inflammasome, toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB), and nuclear factor erythropoietin-2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) components were determined using western blot. Flow cytometry was also used to investigate the levels of reactive oxygen species (ROS). Results: Ruscogenin significantly increased cell viability (p < 0.01) and suppressed apoptosis of NRK- 52E cells (p < 0.01), attenuating cisplatin-induced cytotoxicity. The NLRP3 inflammasome was activated in cisplatin-treated NRK-52E cells with enhanced NLRP3, interleukin 1 beta, and cleaved caspase-1; however, ruscogenin significantly decreased the expression of NLRP3 inflammasome components (p < 0.01). Ruscogenin attenuated cisplatin-induced expression of TLR4, myeloid differentiation primary response 88, and NF-κB. Further, cisplatin induction enhanced ROS formation, with increased malondialdehyde and decreased glutathione reductase and catalase levels. Ruscogenin attenuated cisplatin-induced ROS accumulation in NRK-52E cells through up-regulation of Nrf2 and HO-1. Conclusion: Ruscogenin protects against cisplatin-induced apoptosis, inflammation, and oxidative stress in renal tubular epithelial cells via suppression of TLR4/NF-κB activation and promotion of Nrf2/HO-1 activation. Therefore, ruscogenin provides a potential therapeutic strategy for mitigating cisplatin-induced nephrotoxicity.

Стилі APA, Harvard, Vancouver, ISO та ін.

19

Keleku-Lukwete, Nadine, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, et al. "Keap1-Nrf2 System: Potential Role in Prevention of Sickle Cell Disease Organs Damages and Inflammation." Blood 126, no. 23 (December 3, 2015): 411. http://dx.doi.org/10.1182/blood.v126.23.411.411.

Повний текст джерела

Анотація:

Abstract Chronic hemolysis in sickle cell disease (SCD) gives rise to intermittent vessel occlusion. Recurrent ischemia-reperfusion generates high levels of reactive oxygen species (ROS) that leads to cell damage. On the other hand, lysed red blood cells (RBC) released free heme into blood stream, which contributes to generation of oxidant microenvironment. ROS burden generated by heme and ischemia-reperfusion injury contributes to endothelial cell activation that promotes inflammatory response with activation of inflammatory mediators. Sickle cell patients bearing high white blood cell (WBC) count develop severe complications of the disease. Nrf2 is a transcription factor that mediates adaptation to oxidative stress and cell defense. Under homeostatic conditions, Nrf2 is trapped by Keap1 and degraded by proteasome pathway. Upon exposure to stress stimuli, such as ROS and electrophiles, Nrf2 is stabilized and activates transcription of cytoprotective and antioxidants genes. Therefore, we hypothesized that Nrf2 activation might be important for tissue protection in SCD. To evaluate the therapeutic effect of Nrf2 activation on SCD, we used a SCD knock-in mouse model bearing human mutated globin loci. Since Keap1 negatively regulated Nrf2 in normal conditions, we crossed the SCD model mice with Keap1 hypomorphic knockdown (Keap1F/-) mice to generate compound mutant (SCD::Keap1F/-) mice, in which Nrf2 was constitutively activated. Histological analysis of the liver and lung revealed that congestive reaction and necrotic area observed in the SCD mice were significantly reduced in the SCD::Keap1F/- mice. Moreover, liver damage marker alanine transferase (ALT) were also decreased in SCD::Keap1F/- mice compared with SCD mice. We further examined inflammation status using human IL6 reporter mouse system and found that inflammation, which was mainly observed in lung of SCD mice, was markedly improved in the SCD::Keap1F/- mice. Expression levels of inflammatory cytokines IL6 and IL1β in the lung as well as adhesion molecules VCAM and P-selectin in the aorta of SCD::Keap1F/- mice were lower than those of the SCD mice. These results indicate that Nrf2 activation improves organ damage and inflammation in the SCD mice. On the other hand, hemolysis of sickle cells and compensatory stress erythropoiesis did not change substantially between the SCD and the SCD::Keap1F/- mice. These results indicate that Nrf2 activation improves organ damage and inflammation independently from improvement of hemolysis. Previous reports show that free heme released from sickle cells gives rise to ROS-mediate pathological process as inflammation and organ damage in SCD. We therefore measured plasma free heme and downstream product indirect bilirubin in the SCD::Keap1F/- mice, and found that both heme and indirect bilirubin was decreased in the SCD::Keap1F/- mice. These results demonstrate that Nrf2 activation improves SCD symptoms at least in part by elimination of free heme. To determine whether chemical compounds that serve as Nrf2 inducers have a protective potential of SCD mice organs, we treated 6-weeks aged mice with an Nrf2 inducer CDDO-Im (20 μmol/kg) 3 times per week for 3 weeks. CDDO-Im administration progressively reduced WBC numbers in the SCD::Keap1F/- mice. Also we observed decrease in the expression level of IL6 and IL1β in the lung and necrotic area in the liver in CDDO-Im-treated SCD::Keap1F/- mice. These results indicate that administration of a chemical Nrf2 inducer relieves inflammation and organ damage in the SCD mice. Collectively, these data provide the evidence that Nrf2 activation improves ROS-mediated organ damages and inflammation. Associated in the therapy of SCD, Nrf2 inducers could be of benefit to SCD patients. Disclosures No relevant conflicts of interest to declare.

Стилі APA, Harvard, Vancouver, ISO та ін.

20

Zhu, Xingguo, Alexander H. Ward, Caixia Xi та Betty S. Pace. "NRF2 Mediates Epigenetic Changes in DNA and Chromatin Structure to Regulate γ-Globin Gene Expression in a Human βYAC Transgenic Mouse Model". Blood 132, Supplement 1 (29 листопада 2018): 1053. http://dx.doi.org/10.1182/blood-2018-99-116438.

Повний текст джерела

Анотація:

Abstract NRF2 is the master regulator for the cellular anti-oxidative stress response and previously shown to activate γ-globin gene expression in human erythroid progenitor cells. The goal of this study was to expand on these findings by exploring the in vivo function of NRF2 using the human β-globin locus YAC transgenic (βYAC) mouse carrying the entire 248kb human β-globin locus (HBB). We observed that NRF2 activation by chronic dimethyl fumarate treatment of βYAC mice, induced human γ-globin gene expression, but had no effect on the adult β-globin gene. Subsequently in a novel βYAC/NRF2 knockout mouse model established in our laboratory, we demonstrated that NRF2 loss increased mouse erythroid CD71 levels while reducing human γ-globin gene expression during erythropoiesis in mouse embryonic E13.5 and E18.5 day fetal livers and peripheral blood. Furthermore, the ability of dimethyl fumarate to induce γ-globin gene expression was abolished after NRF2 loss. By western blot analysis of nuclear protein, we confirmed that part of the mechanism of globin gene regulation by NRF2 loss involves a decline of global histone H3 lysine 4 trimethylation levels, without changing histone acetylation. Interestingly, NRF2 loss decreased the protein levels of the DNA methylcytosine dioxygenases including TET1, TET2 and TET3. Analysis of DNA methylation/hydroxymethylation levels by DNA dot-blot assay of mouse E13.5 fetal livers isolated from βYAC/NRF2 knockout mice, showed inhibition of genome wide DNA hydroxymethylation, while DNA methylation was not affected. In addition, DNA immunoprecipitation confirmed decreased hydroxymethylation in the HBB locus control region (LCR) enhancer and γ-globin gene region. These data suggest an essential role of NRF2 in modifying chromatin structure and assembling transcription complexes to regulate γ-globin gene expression. ChIP assay to assess in vivo DNA-protein interactions showed decreased associations of histone H3 lysine 4 monomethylation and trimethylation, TATA-binding protein and RNA polymerase II to the LCR and γ-globin promoter after NRF2 loss. Final studies were conducted to evaluate long-range chromatin interactions between the LCR and individual globin genes by chromosome conformation capture assay. We observed decreased interactions between the LCR and γ-globin gene promoter region after NRF2 loss while interactions in the adult β-globin was not affected suggesting NRF2 preferentially mediates γ-globin gene regulation. In conclusion, our data suggest that NRF2 alters γ-globin expression through epigenetic DNA/histone modifications in addition to direct DNA binding. Therefore, activation of NRF2 expression using small chemical compounds is an innovative strategy to induce γ-globin gene transcription for the treatment of β-hemoglobinopathies. This work was supported by funding from the National Heart, Lung, and Blood Institute to XZ through the Hemoglobinopathy Translational Research Skills Core component of U01 grant HL117684 and R01 grant HL069234 to BSP. Disclosures No relevant conflicts of interest to declare.

Стилі APA, Harvard, Vancouver, ISO та ін.

21

Singh, Mrinalini, Rajkumar Tulsawani, Praveen Koganti, Amitabh Chauhan, Manimaran Manickam, and Kshipra Misra. "Cordyceps sinensisIncreases Hypoxia Tolerance by Inducing Heme Oxygenase-1 and Metallothionein via Nrf2 Activation in Human Lung Epithelial Cells." BioMed Research International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/569206.

Повний текст джерела

Анотація:

Cordyceps sinensis, an edible mushroom growing in Himalayan regions, is widely recognized in traditional system of medicine. In the present study, we report the efficacy ofCordyceps sinensisin facilitating tolerance to hypoxia using A549 cell line as a model system. Treatment with aqueous extract ofCordyceps sinensisappreciably attenuated hypoxia induced ROS generation, oxidation of lipids and proteins and maintained antioxidant status similar to that of controls via induction of antioxidant gene HO1 (heme oxygenase-1), MT (metallothionein) and Nrf2 (nuclear factor erythroid-derived 2-like 2). In contrast, lower level of NFκB (nuclear factor kappaB) and tumor necrosis factor-αobserved which might be due to higher levels of HO1, MT and transforming growth factor-β. Further, increase in HIF1 (hypoxia inducible factor-1) and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Interestingly,Cordyceps sinensistreatment under normoxia did not regulate the expression HIF1, NFκB and their regulated genes evidencing thatCordyceps sinensisper se did not have an effect on these transcription factors. Overall,Cordyceps sinensistreatment inhibited hypoxia induced oxidative stress by maintaining higher cellular Nrf2, HIF1 and lowering NFκB levels. These findings provide a basis for possible use of Cordyceps sinensis in tolerating hypoxia.

Стилі APA, Harvard, Vancouver, ISO та ін.

22

Atta, Mustafa S., Ali H. El-Far, Foad A. Farrag, Mohamed M. Abdel-Daim, Soad K. Al Jaouni, and Shaker A. Mousa. "Thymoquinone Attenuates Cardiomyopathy in Streptozotocin-Treated Diabetic Rats." Oxidative Medicine and Cellular Longevity 2018 (October 30, 2018): 1–10. http://dx.doi.org/10.1155/2018/7845681.

Повний текст джерела

Анотація:

Diabetic cardiomyopathy is a diabetic complication due to oxidative stress injuries. This study examined the protecting influence of thymoquinone (TQ) on diabetes-caused cardiac complications. The intracellular means by which TQ works against diabetes-caused cardiac myopathy in rats is not completely understood. In this study, Wistar male rats (n=60) were assigned into four groups: control, diabetic (diabetes induced by IP infusion of streptozotocin, 65 mg/kg), diabetic + TQ (diabetic rats given TQ (50 mg/kg) administered once per day by stomach gavage), and TQ (50 mg/kg) for 12 weeks. TQ supplementation appreciably recovered the cardiac parameters alongside significant declines in plasma nitric oxide concentrations and total superoxide dismutase (T.SOD) activities. Importantly, TQ downgraded expression of cardiac-inducible nitric oxide synthase in addition to significantly upregulating vascular endothelial growth factor and erythropoietin genes and nuclear factor-erythroid-2-related factor 2 (Nrf2) protein. TQ normalized plasma triacylglycerol and low-density lipoprotein-cholesterol and significantly improved the high-density lipoprotein-cholesterol levels. Additionally, TQ administration improved the antioxidant ability of cardiac tissue via significantly increased cardiac T.SOD and decreased cardiac malondialdehyde levels. Oral supplementation with TQ prevented diabetic-induced cardiomyopathy via its inhibitory effect on the E-selectin level, C-reactive protein, and interleukin-6. The TQ protecting effect on the heart tissue was shown by normalization of the plasma cardiac markers troponin I and creatine kinase. This experiment shows the aptitude of TQ to protect cardiac muscles against diabetic oxidative stress, mainly through upregulation of Nrf2, which defeated oxidative damage by improvement of the antioxidant power of cardiac muscle that consequently protected the cardiac muscles and alleviated the inflammatory process.

Стилі APA, Harvard, Vancouver, ISO та ін.

23

Singla, Amika, David S. Moons, Natasha T. Snider, Elizabeth R. Wagenmaker, V. Bernadene Jayasundera, and M. Bishr Omary. "Oxidative stress, Nrf2 and keratin up-regulation associate with Mallory-Denk body formation in mouse erythropoietic protoporphyria." Hepatology 56, no. 1 (April 25, 2012): 322–31. http://dx.doi.org/10.1002/hep.25664.

Повний текст джерела

Стилі APA, Harvard, Vancouver, ISO та ін.

24

Song, Zhichun, Wei Wang, Xiaoren Zhang, Hongsheng Yu, Chunsheng Qu, Shu Dai, and Xiaodong Wang. "Evodiamine attenuates cadmium-induced nephrotoxicity through activation of Nrf2/HO-1 pathway." Tropical Journal of Pharmaceutical Research 20, no. 8 (February 16, 2022): 1579–84. http://dx.doi.org/10.4314/tjpr.v20i8.5.

Повний текст джерела

Анотація:

Purpose: To investigate the protective role of evodiamine, a naturally occurring anti-inflammatory, antioxidant, and anti-apoptotic compound, against cadmium-induced cytotoxicity in proximal tubular cells (human kidney 2; HK-2). Methods: HK-2 cells were treated with different concentrations of evodiamine (5, 20, 50 μM) for 2 h and then incubated with 40 μM cadmium chloride for another 24 h. Cell viability and apoptosis were evaluated using thiazolyl blue tetrazolium bromide (MTT) and flow cytometry, respectively. Oxidative stress was assayed by measuring the levels of malonaldehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) and glutathione peroxidase (GSH-PX). Results: Cadmium chloride treatment in HK-2 cells significantly reduced cell viability (p < 0.01) and increased apoptosis compared to the control. Evodiamine pretreatment attenuated the cadmium chloride-provoked decrease in cell viability and increase in apoptosis. Evodiamine also decreased expression of cleaved caspase-3 and cleaved caspase-9 in HK-2 cells. Cadmium chloride exposure provoked kidney injury, as evidenced by increased MDA levels and decreased SOD, GSH, and GSH-PX levels. Pretreatment with evodiamine ameliorated kidney injury, as shown by decreased MDA expression and increased SOD, GSH, and GSH-PX expression. Evodiamine exposure significantly enhanced protein expression of nuclear factor erythropoietin-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1). Conclusion: Evodiamine exerts an anti-apoptotic and anti-oxidative effect against cadmium chloride-induced nephrotoxicity via Nrf2/HO-1 pathway activation. These findings represent a potential therapeutic strategy for cadmium-provoked nephrotoxicity.

Стилі APA, Harvard, Vancouver, ISO та ін.

25

Ji, Lei, Xue Zhong, Xingxing Xia, Wei Yu та Yuping Qin. "Protective effect of syringaresinol on rats with diabetic nephropathy via regulation of Nrf2/HO-1 and TGF- β1/Smads pathways". Tropical Journal of Pharmaceutical Research 20, № 2 (12 січня 2022): 275–80. http://dx.doi.org/10.4314/tjpr.v20i2.8.

Повний текст джерела

Анотація:

Purpose: To investigate the protective role of syringaresinol in a rat model of diabetic nephropathy (DN). Methods: Streptozotocin was injected intraperitoneally into rats to establish the diabetic model. Streptozotocin-induced rats were orally administered syringaresinol, and pathological changes in kidneys were assessed using hematoxylin and eosin staining. Enzyme-linked immunosorbent assay (ELISA) was used to determine kidney injury indicators, 24-h urine proteins, blood urea nitrogen (BUN), and serum creatinine (SCR). Blood glucose was measured using a blood glucose meter, while levels of malonaldehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in kidney were also measured using ELISA. Results: Pathological changes in the kidneys were observed in rats post-streptozotocin treatment. Administration of syringaresinol reduced the lesion degree, with improved pathological morphology in kidney. Syringaresinol administration significantly attenuated streptozotocin-increased levels of BUN, SCR, 24-h urine protein, and blood glucose (p < 0.01). Streptozotocin-induced oxidative stress, shown by enhanced MDA level and reduced levels of SOD, CAT, and GSH-PX, was reversed in rat kidneys following syringaresinol administration. However, the expression levels of nuclear factor erythropoietin- 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) proteins decreased, while transforming growth factor-beta 1 (TGF-β1) and signal transducer and transcriptional modulator (Smad) 2/3/7 proteins increased in rats post-streptozotocin treatment. Syringaresinol administration reversed the effects of streptozotocin on protein expression of Nrf2, HO-1, TGF-β1, and Smad 2/3/7. Conclusion: Syringaresinol exerted a protective effect against DN through activation of Nrf2 and inactivation of TGF-β1/Smad pathways. Thus, the compound can potentially be developed for management of diabetic nephropathy.

Стилі APA, Harvard, Vancouver, ISO та ін.

26

Bokorová, Radka, Jaroslav Polak, Anna Jonasova, Radana Neuwirtova, Marie Lauermannova, Jaroslav Cermak, Marketa Stastna, et al. "Importance of Transcription Factor Nrf2 for Cereblon Expression and Clinical Response to Combination of Lenalidomide and Erythropoietin in Lower-Risk Myelodysplastic Syndromes." Blood 132, Supplement 1 (November 29, 2018): 5507. http://dx.doi.org/10.1182/blood-2018-99-115803.

Повний текст джерела

Анотація:

Abstract INTRODUCTION Nrf2 (nuclear factor, erythroid-derived 2-like 2 or NF-E2-related factor 2) is a transcription factor involved in antioxidant response by reducing oxidative stress. Erythropoietin (EPO) was described as an inducer of Nrf2 in the brain. Nrf2 binds to the promoter of gene coding for cereblon (CRBN) and stimulates CRBN expression (Lee et al. Biochem.Biphys Res Commun 2010; 399: 711-715). We showed that the high level of full length CRBN mRNA and CRBN protein is important for the efficacy of lenalidomide (LEN) in lower-risk MDS patients (Jonasova et al. Eur J Haematol 2015; 95: 27-34; Fuchs et al. Leuk Res 2017; 55 S1: S132, abstr. 227). Addition of EPO to LEN restored transfusion independence of MDS patients when their anemia relapsed during the course of LEN treatment (Jonasova et al. Leuk Res 2018; 69: 12-17). LEN inhibits E3 ubiquitin ligase RNF41 (ring finger protein 41), which polyubiquitinates EPO receptor (EPOR) and marks it for degradation in proteasomes. (Basiorka et al. Cancer Res 2016; 76: 3531-3540). AIMS The aim of our study was to evaluate the levels of Nrf2 mRNA and CRBN mRNA in mononuclear cells obtained from peripheral blood of lower-risk MDS patients after addition of EPO to lenalidomide in MDS patients who relapsed during LEN monotherapy. The further goal was to study the effect of LEN, EPO and combination of LEN plus EPO in cell lines (SKM-1 leukemic cell line established from a patient with progression of MDS to myelomonocytic leukemia and in MDS-L cells a human myeloblastic cell line, established as a MDS92 subline from the bone marrow of an MDS patient with del(5q) (Matsuoka et al. Leukemia 2010; 24: 748-755). METHODS Nrf2 mRNA and full-length CRBN mRNA levels were quantified in 9 lower-risk MDS patients with del(5q) and in 2 MDS patients with normal chromosome 5 [nondel(5q)] who were previously resistant to EPO treatment. All patients with median hemoglobin level 80 g/l were transfusion dependent before starting the therapy with LEN (5 or 10 mg/day). Recombinant human EPO (rHuEPO) in dose of 40,000 IU s.c. per week was combined with LEN in these MDS patients who relapsed during LEN monotherapy or were resistant to LEN [one non(del5q) patient]. Four lower-risk MDS patients responsive to EPO after diagnosis were also used for comparison of Nrf2 mRNA and full-length CRBN mRNA levels. Mononuclear cells were isolated by Ficoll-Paque PLUS gradient separation, then washed by phosphate buffered saline and remaining red cells were lysed. Both SKM-1 and MDS-L cells were incubated without or with LEN, EPO and combination of LEN plus EPO for 19, 24 and 43 hours. The end concentration of added Epo was 2U/ml and LEN 10 µM. The levels of Nrf2 mRNA and full length CRBN mRNA were measured using the reverse transcription-quantitative TaqMan PCR assay. RESULTS The levels of Nrf2 mRNA and full-length CRBN mRNA in peripheral blood mononuclear cells correspond during rHuEPO monotherapy of four responsive lower-risk MDS patients. In these cases no increase of Nrf2 mRNA and CRBN mRNA levels was found. Increased Nrf2 mRNA and CRBN mRNA levels in peripheral blood mononuclear cells were found after addition of rHuEPO to lenalidomide in six MDS patients with del(5q) and one non(del5q) MDS patient who relapsed during LEN monotherapy. All these patients responded to combination of rHuEPO and lenalidomide by increased hemoglobin levels. Addition of or rHuEPO to lenalidomide was without effect on Nrf2 mRNA and CRBN mRNA levels in one non(del5q) patient who was resistant to LEN. Experiments with SKM-1 and MDS-L cells showed that rHuEPO alone did not increased Nrf2 mRNA and CRBN mRNA levels. However LEN and in a greater extent the combination of rHuEPO and LEN increased Nrf2 mRNA and CRBN mRNA levels. CONCLUSIONS Our findings indicate that transcription factor Nrf2 is involved in CRBN expression in mononuclear cells obtained from peripheral blood of lower-risk MDS patients and in SKM-1 and MDS-L cells in culture. Expression of both Nrf2 and CRBN is stimulated by lenalidomide and in a greater extent by combination of lenalidomide and rHuEPO. Measurement of CRBN mRNA level as an important factor for prediction of the efficacy of not only lenalidomide monotherapy but also of combination of LEN and rHuEPO. This work was supported by the research project for conceptual development of research organization (00023736; Institute of Hematology and Blood Transfusion, Prague) and Grant Agency of Charles University, project number 924616. Disclosures No relevant conflicts of interest to declare.

Стилі APA, Harvard, Vancouver, ISO та ін.

27

Arellano-Buendía, Abraham Said, Luis Gerardo Castañeda-Lara, María L. Loredo-Mendoza, Fernando E. García-Arroyo, Pedro Rojas-Morales, Raúl Argüello-García, Juan G. Juárez-Rojas, et al. "Effects of Allicin on Pathophysiological Mechanisms during the Progression of Nephropathy Associated to Diabetes." Antioxidants 9, no. 11 (November 15, 2020): 1134. http://dx.doi.org/10.3390/antiox9111134.

Повний текст джерела

Анотація:

This study aimed to assess the impact of allicin on the course of diabetic nephropathy. Study groups included control, diabetes, and diabetes-treated rats. Allicin treatment (16 mg/kg day/p.o.) started after 1 month of diabetes onset and was administered for 30 days. In the diabetes group, the systolic blood pressure (SBP) increased, also, the oxidative stress and hypoxia in the kidney cortex were evidenced by alterations in the total antioxidant capacity as well as the expression of nuclear factor (erythroid-derived 2)-like 2/Kelch ECH associating protein 1 (Nrf2/Keap1), hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor (VEGF), erythropoietin (Epo) and its receptor (Epo-R). Moreover, diabetes increased nephrin, and kidney injury molecule-1 (KIM-1) expression that correlated with mesangial matrix, the fibrosis index and with the expression of connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), and α-smooth muscle actin (α-SMA). The insulin levels and glucose transporter protein type-4 (GLUT4) expression were decreased; otherwise, insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) expression was increased. Allicin increased Nrf2 expression and decreased SBP, Keap1, HIF-1α, and VEGF expression. Concurrently, nephrin, KIM-1, the mesangial matrix, fibrosis index, and the fibrotic proteins were decreased. Additionally, allicin decreased hyperglycemia, improved insulin levels, and prevented changes in (GLUT4) and IRSs expression induced by diabetes. In conclusion, our results demonstrate that allicin has the potential to help in the treatment of diabetic nephropathy. The cellular mechanisms underlying its effects mainly rely on the regulation of antioxidant, antifibrotic, and antidiabetic mechanisms, which can contribute towards delay in the progression of renal disease.

Стилі APA, Harvard, Vancouver, ISO та ін.

28

Bokorová, Radka, Ota Fuchs, Denisa Myslivcova, and Jaroslav Cermak. "Arsenic Trioxide Upregulates Cereblon mRNA Expression and Potentiates Sensitivity of SKM-1 and MDS-L Cells to Lenalidomide." Blood 134, Supplement_1 (November 13, 2019): 5397. http://dx.doi.org/10.1182/blood-2019-126443.

Повний текст джерела

Анотація:

INTRODUCTION Arsenic trioxide (ATO) was approved in the United States and Europe for the treatment of acute promyelocytic leukemia (APL). ATO was also studied in multiple myeloma (MM) and myelodysplastic syndrome (MDS), where it induced growth inhibition and apoptosis. ATO produced trilineage responses in MDS by several mechanisms of action. These mechanisms included induction of cell cycle arrest, apoptosis and autophagy, generation of reactive oxygen species (ROS), release of cytochrome c and activation of caspases, induction of differentiation and anti-angiogenesis. We showed that the high level of full-length cereblon (CRBN) mRNA and CRBN protein is important for the efficacy of lenalidomide (LEN) in lower-risk MDS patients (Jonasova et al. Eur J Haematol 2015; 95: 27-34; Fuchs et al. Leuk Res 2017; 55 (S1): S132, abstr. 227). ATO potentiated CRBN expression levels in MM cell lines (Jian et al. Oncol Lett 2017; 14:3243-3248). AIMS The aim of our study was to evaluate the levels of CRBN mRNA and Nrf2 (nuclear factor, erythroid-derived 2-like 2 or NF-E2-related factor 2) mRNA in SKM-1 (leukemic cell line established from a patient with progression of MDS to myelomonocytic leukemia) and MDS-L (a human myeloblastic cell line established from the bone marrow of an MDS patient with del(5q); Matsuoka et al. Leukemia 2010; 24: 748-755) cells treated with various concentrations of ATO as a single agent or with combinations of ATO with LEN, erythropoietin (EPO) and prednisone for 24 hours. We tested our hypothesis that ATO induced the transcription factor Nrf2 mRNA levels and increased CRBN mRNA expression as a single agent and also in combinations with LEN, EPO and prednisone. METHODS Full-length CRBN mRNA and Nrf2 mRNA levels were quantified in SKM-1 and MDS-L cells incubated without (controls) or with 0.05; 0.1; 0,5 and 1.0 microM ATO as a single agent for 24 hours using the reverse transcription-quantitative TaqMan PCR assay. Total RNA was extracted from cells, reverse transcribed and TaqMan PCR assay was provided for CRBN mRNA, Nrf2 mRNA and glyceraldehyde-3- phosphate dehydrogenase (GAPDH), a housekeeping gene. The effect of ATO (0.1 microM) in combinations with LEN (10 microM), EPO (2U/ml) and prednisone (100 microM) on full-length CRBN mRNA and Nrf2 mRNA levels was also studied in SKM-1 and MDS-L cells. RESULTS The levels of full-length CRBN mRNA and Nrf2 mRNA corresponded in both cell lines, SKM-1 and MDS-L, treated with ATO as a single agent or in combinations with LEN, EPO and prednisone. The most prominent effect of ATO as a single agent on the levels of both mRNAs was gained in 0.1 microM concentration in SKM-1 cells and 0.5 microM in MDS-L cells. Positive effects of combinations of ATO and prednisone; ATO, prednisone and LEN; or ATO, prednisone, LEN and EPO in both cell lines on the levels of full-length CRBN mRNA and Nrf2 mRNA were also detected. CONCLUSIONS Our findings showed that ATO induced CRBN mRNA and Nrf2 mRNA levels in SKM-1 and MDS-L cell lines and potentiated sensitivity of these cells to LEN and to combinations of LEN with EPO and prednisone. We speculate that one of the mechanism of ATO action is a generation of reactive oxygen species (ROS) and oxidative stress responses which induce expression of transcription factor Nrf2. This transcription factor stimulates CRBN mRNA expression. LEN is an immunomodulatory drug and therefore in vitro studies are not sufficient. Further in vivo studies are required to study the effect of ATO and its combinations with LEN, EPO and prednisone. This work was supported by the research project for conceptual development of research organization (00023736; IHBT, Prague, Czech Republic) and Grant Agency of Charles University, project number 924616. Disclosures No relevant conflicts of interest to declare.

Стилі APA, Harvard, Vancouver, ISO та ін.

29

Maciel, Thiago Trovati, Caroline Carvalho, Rachel Rignault, Biree Andemariam, Betty S. Pace, Jennifer Isler OCain, and Rahul Ballal. "IMR-261, a Novel Oral Nrf2 Activator, Induces Fetal Hemoglobin in Human Erythroblasts, Reduces VOCs, and Ameliorates Ineffective Erythropoiesis in Experimental Mouse Models of Sickle Cell Disease and Beta-Thalassemia." Blood 138, Supplement 1 (November 5, 2021): 853. http://dx.doi.org/10.1182/blood-2021-149528.

Повний текст джерела

Анотація:

Abstract Background Sickle cell disease (SCD) is an autosomal recessive disorder where mutated hemoglobin (HbS) polymerizes and can lead to irreversible red blood cell (RBC) sickling and painful vaso-occlusive crisis (VOC). The RBC sickling is amplified by inflammation, resulting in tissue and organ damage. The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates the expression of antioxidant genes in response to oxidative stress, regulates inflammation, inhibits the NFkB pathway, and induces fetal hemoglobin (HbF), making it an attractive target in SCD and beta-thalassemia. IMR-261 is a novel oral activator of Nrf2 and has been tested in Phase 2 clinical trials (previously as CXA-10). Methods & Results CD14+ human monocytes were exposed to IMR-261 at 3µM and 10µM for 3 hours, to determine via quantitative PCR (qPCR) its ability to induce expression of antioxidant genes. IMR-261 at 10 µM significantly increased (p<0.05) the expression of Nrf2-dependent genes (p<0.05), including HMOX1, HSPA1A, HSP90, GCLM, SOD1 and TXNRD1. Human monocytes were treated with lipopolysaccharide (LPS) to test the ability of IMR-261 to block inflammatory genes with a NFkB target dataset. IMR-261 significantly inhibited (p<0.05) LPS-induced expression of IL-1-beta, TNF-alpha and IL-6 in human monocytes. To test the effects of IMR-261 on HbF induction, human erythroblasts were derived from CD34+ blood marrow progenitor cells sourced from healthy or SCD subjects. IMR-261 induced expression of the gamma-globin gene (4.0-fold change at 3µM and 7.18-fold change at 6 µM). This was accompanied by increased %F-cells (2.8-fold change at 3µM and 3.0-fold change at 6 µM). IMR-261 was also tested in the Townes HbSS mouse model of SCD to assess the potential for HbF induction. Mice were dosed with IMR-261 at 12.5 mg/kg or 37.5 mg/kg BID for 4 weeks (N=4-8/group). After 4 weeks of treatment, IMR-261 at 12.5 mg/kg and 37.5 mg/kg resulted in a significant increase in HbF relative to control, and 37.5 mg/kg resulted in a significant increase in %F-cells relative to control (Table 1, p<0.05). In addition, both doses of IMR-261 led to significant increases in RBC counts and total hemoglobin (Hb) (Table 1, p<0.05). IMR-261 at 37.5 mg/kg also significantly decreased (p<0.05) both reticulocyte counts and spleen cellularity. The ability of IMR-261 to reduce VOCs was assessed in separate Townes HbSS mice after the administration of TNF-alpha (0.5 µg/mice i.p.). IMR-261 was dosed at 37.5 mg/kg BID for 5 days before triggering VOCs. RBCs were stained with Ter-119 antibodies on spleen and liver of mice. Compared to controls, IMR-261 significantly reduced the presence of RBC on occluded vessels. This was coupled with a reduction of P-selectin (3109±97 Mean Fluorescence Units [MFI] in vehicle-treated vs. 1974±379 MFI in IMR-261 group, p<0.05) and L-selectin (375±20 MFI in vehicle-treated vs. 242±60 MFI in IMR-261 group, p<0.05). IMR-261 also reduced select hemolysis biomarkers: bilirubin (11.2±0.3 mg/dL in vehicle-treated vs. 8.4±0.7 mg/dL in IMR-261 group, (p<0.05) and free-heme (325±52 µM in vehicle-treated vs. 203±51 µM in IMR-261 group, p<0.05). A beta-thalassemia experimental model Hbb th1/th1 was tested to evaluate whether IMR-261 could improve ineffective erythropoiesis seen in beta-thalassemia. IMR-261 treatment at 37.5 mg/kg BID significantly increased hemoglobin levels, RBC counts and hematocrit (p<0.05), with significant reductions observed in reticulocytes (p<0.05). flow cytometry analysis (CD71/Ter119) showed that IMR-261 significantly decreased late basophilic and polychromatic erythroblasts (Ery.B) and increased orthochromatic erythroblasts and reticulocytes (Ery.C) cell numbers in the spleen (p<0.05). Conclusions IMR-261 activates Nrf2-dependent antioxidant genes and inhibits NFkB-induced pro-inflammatory genes in human monocytes. In human erythroblasts, IMR-261 significantly increased HbF and %F-cells. In vivo SCD models show that IMR-261 significantly induced HbF and %F-cells, improved hemolytic markers, and decreased VOCs. IMR-261 also increased Hb and improved ineffective erythropoiesis in a beta-thalassemia in-vivo model. Together these data suggest that IMR-261 is a promising, novel, oral therapy that warrants clinical testing in SCD and beta-thalassemia. Figure 1 Figure 1. Disclosures Maciel: Imara Inc.: Research Funding. Carvalho: Imara Inc.: Research Funding. Rignault: Imara Inc.: Research Funding. Pace: Imara Inc.: Consultancy. OCain: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Ballal: Imara Inc.: Current Employment, Current equity holder in publicly-traded company.

Стилі APA, Harvard, Vancouver, ISO та ін.

30

Ruan, Baiye, Yuanting Chen, Imhoi Koo, Jingwei Cai, John Mcguigan, Molly Hall, Andrew Patterson, and Robert Paulson. "Nitric Oxide Dependent Metabolism Regulates the Proliferation and Differentiation of Stress Erythroid Progenitors." Blood 138, Supplement 1 (November 5, 2021): 921. http://dx.doi.org/10.1182/blood-2021-146531.

Повний текст джерела

Анотація:

Abstract Infection and tissue damage induce inflammation, which increases myelopoiesis at the expense of steady state erythropoiesis. Stress erythropoiesis is induced to compensate for the loss of erythroid output until the inflammation is resolved and bone marrow erythropoiesis can resume. Steady state erythropoiesis constantly produces erythrocytes, while stress erythropoiesis generates a bolus of new erythrocytes through the rapid expansion of immature progenitor cells which is followed by the synchronous differentiation of progenitors. We hypothesized that the proliferation of early progenitor cells and their transition to differentiation is regulated by changes in metabolism. Metabolomics and isotope tracing analysis was performed to assess the intracellular metabolic profiles in proliferating progenitors isolated from in vitro stress erythropoiesis cultures. We observed an active engagement of glucose metabolism in glycolysis and anabolic biosynthesis, while the levels of TCA intermediates suggested that TCA cycle and mitochondrial respiration were blocked. Concomitantly, inducible nitric oxide synthase (iNOS) was induced in progenitor cells to increase the production of nitric oxide (NO), which was demonstrated to be crucial for proliferating progenitor metabolism. Inhibition or genetic mutation of iNOS decreased NO levels resulting in the suppression of progenitor proliferation in vitro and in vivo. As evaluated by RNA-seq, inhibition of iNOS suppressed cell proliferation-related pathways including cell cycle and nucleotide metabolism, while upregulating erythroid differentiation genes. These data suggest that iNOS-derived NO production establishes a metabolism that promotes the proliferation of progenitor cells while inhibiting their differentiation. Notably, proliferating progenitor cells displayed low levels of the metabolite itaconate and decreased expression of Immunoresponsive gene 1 (Irg1), the enzyme that catalyzes itaconate synthesis from cis-aconitate. Further analysis showed that the addition of 4-Octyl itaconate (OI), a cell-permeable itaconate derivative, inhibited iNOS-derived NO production by activating nuclear factor erythroid 2-related factor 2 (Nrf2), which in turn impaired progenitor expansion. These results indicate that itaconate production is inhibited to enable the accumulation of NO and the NO dependent metabolism required for progenitor cell proliferation during the initial expansion stage of stress erythropoiesis. In contrast, the transition to differentiation is marked by elevated itaconate synthesis, Nrf2 activation, and attenuated iNOS expression. We hypothesized that the inhibition of NO production alters metabolism and in concert with new cell signaling removes the NO-dependent inhibition of erythroid program, which allows the differentiation of progenitor cells. We tested this mechanism by examining the effects of iNOS inhibitors and mutants in iNOS, Irg1 and Nrf2 on progenitor cells isolated from differentiation cultures. iNOS deficiency led to the activation of erythroid transcriptional program, and increased numbers of mature progenitors as well as stress BFU-Es. In contrast, Irg1 and Nrf2 mutants showed impaired transition to erythroid differentiation, while they had elevated iNOS expression and NO production. Further analysis showed that treatment with either OI or iNOS inhibitor inhibited NO production in Irg1 and Nrf2 deficient progenitors, and consequently rescued the defects in erythroid differentiation. These data support a model in which inflammation inhibits steady state erythropoiesis, while at the same time promoting stress erythropoiesis to maintain homeostasis. Our work reveals a dynamic and tight coordination between pro-inflammatory signals and progenitor cell metabolism in regulating the proliferation and differentiation of stress erythroid progenitors, and highlights the therapeutic potential of targeting metabolic and inflammatory signaling pathways in inflammatory anemia. Disclosures Paulson: Forma Therapeutics: Consultancy.

Стилі APA, Harvard, Vancouver, ISO та ін.

31

Sajadimajd, Soraya, and Mozafar Khazaei. "Oxidative Stress and Cancer: The Role of Nrf2." Current Cancer Drug Targets 18, no. 6 (June 11, 2018): 538–57. http://dx.doi.org/10.2174/1568009617666171002144228.

Повний текст джерела

Анотація:

Oxidative stress due to imbalance between ROS production and detoxification plays a pivotal role in determining cell fate. In response to the excessive ROS, apoptotic signaling pathway is activated to promote normal cell death. However, through deregulation of biomolecules, high amount of ROS promotes carcinogenesis in cells with defective signaling factors. In this line, NRF2 appears to be as a master regulator, which protects cells from oxidative and electrophilic stress. Nrf2 is an intracellular transcription factor that regulates the expression of a number of genes to encode anti-oxidative enzymes, detoxifying factors, anti-apoptotic proteins and drug transporters. Under normal condition, Nrf2 is commonly degraded in cytoplasm by interaction with Keap1 inhibitor as an adaptor for ubiquitination factors. However, high amount of ROS activates tyrosine kinases to dissociate Nrf2: Keap1 complex, nuclear import of Nrf2 and coordinated activation of cytoprotective gene expression. Nevertheless, deregulation of Nrf2 and/or Keap1 due to mutation and activated upstream oncogenes is associated with nuclear accumulation and constitutive activation of Nrf2 to protect cells from apoptosis and induce proliferation, metastasis and chemoresistance. Owning to the interplay of ROS and Nrf2 signaling pathways with carcinogenesis, Nrf2 modulation seems to be important in the personalization of cancer therapy.

Стилі APA, Harvard, Vancouver, ISO та ін.

32

Chen, Qin M., and Anthony J. Maltagliati. "Nrf2 at the heart of oxidative stress and cardiac protection." Physiological Genomics 50, no. 2 (February 1, 2018): 77–97. http://dx.doi.org/10.1152/physiolgenomics.00041.2017.

Повний текст джерела

Анотація:

The NFE2L2 gene encodes the transcription factor Nrf2 best known for regulating the expression of antioxidant and detoxification genes. Gene knockout approaches have demonstrated its universal cytoprotective features. While Nrf2 has been the topic of intensive research in cancer biology since its discovery in 1994, understanding the role of Nrf2 in cardiovascular disease has just begun. The literature concerning Nrf2 in experimental models of atherosclerosis, ischemia, reperfusion, cardiac hypertrophy, heart failure, and diabetes supports its cardiac protective character. In addition to antioxidant and detoxification genes, Nrf2 has been found to regulate genes participating in cell signaling, transcription, anabolic metabolism, autophagy, cell proliferation, extracellular matrix remodeling, and organ development, suggesting that Nrf2 governs damage resistance as well as wound repair and tissue remodeling. A long list of small molecules, most derived from natural products, have been characterized as Nrf2 inducers. These compounds disrupt Keap1-mediated Nrf2 ubquitination, thereby prohibiting proteasomal degradation and allowing Nrf2 protein to accumulate and translocate to the nucleus, where Nrf2 interacts with sMaf to bind to ARE in the promoter of genes. Recently alternative mechanisms driving Nrf2 protein increase have been revealed, including removal of Keap1 by autophagy due to p62/SQSTM1 binding, inhibition of βTrCP or Synoviolin/Hrd1-mediated ubiquitination of Nrf2, and de novo Nrf2 protein translation. We review here a large volume of literature reporting historical and recent discoveries about the function and regulation of Nrf2 gene. Multiple lines of evidence presented here support the potential of dialing up the Nrf2 pathway for cardiac protection in the clinic.

Стилі APA, Harvard, Vancouver, ISO та ін.

33

Miller, William P., Siddharth Sunilkumar, Joseph F. Giordano, Allyson L. Toro, Alistair J. Barber, and Michael D. Dennis. "The stress response protein REDD1 promotes diabetes-induced oxidative stress in the retina by Keap1-independent Nrf2 degradation." Journal of Biological Chemistry 295, no. 21 (April 15, 2020): 7350–61. http://dx.doi.org/10.1074/jbc.ra120.013093.

Повний текст джерела

Анотація:

The transcription factor nuclear factor erythroid-2–related factor 2 (Nrf2) plays a critical role in reducing oxidative stress by promoting the expression of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. We recently demonstrated that increased expression of the stress response protein regulated in development and DNA damage 1 (REDD1) is necessary for the development of oxidative stress in the retina of streptozotocin-induced diabetic mice. In the present study, we tested the hypothesis that REDD1 suppresses the retinal antioxidant response to diabetes by repressing Nrf2 function. We found that REDD1 ablation enhances Nrf2 DNA-binding activity in the retina and that the suppressive effect of diabetes on Nrf2 activity is absent in the retina of REDD1-deficient mice compared with WT. In human MIO-M1 Müller cell cultures, REDD1 deletion prevented oxidative stress in response to hyperglycemic conditions, and this protective effect required Nrf2. REDD1 suppressed Nrf2 stability by promoting its proteasomal degradation independently of Nrf2's interaction with Kelch-like ECH-associated protein 1 (Keap1), but REDD1-mediated Nrf2 degradation required glycogen synthase kinase 3 (GSK3) activity and Ser-351/Ser-356 of Nrf2. Diabetes diminished inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser-9 in the retina of WT mice but not in REDD1-deficient mice. Pharmacological inhibition of GSK3 enhanced Nrf2 activity and prevented oxidative stress in the retina of diabetic mice. The findings support a model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which, in turn, phosphorylates Nrf2 to promote its degradation.

Стилі APA, Harvard, Vancouver, ISO та ін.

34

Abdul-Aziz, Amina, David J. MacEwan, Kristian M. Bowles, and Stuart A. Rushworth. "Oxidative Stress Responses and NRF2 in Human Leukaemia." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/454659.

Повний текст джерела

Анотація:

Oxidative stress as a result of elevated levels of reactive oxygen species (ROS) has been observed in almost all cancers, including leukaemia, where they contribute to disease development and progression. However, cancer cells also express increased levels of antioxidant proteins which detoxify ROS. This includes glutathione, the major antioxidant in human cells, which has recently been identified to have dysregulated metabolism in human leukaemia. This suggests that critical balance of intracellular ROS levels is required for cancer cell function, growth, and survival. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcription factor plays a dual role in cancer. Primarily, NRF2 is a transcription factor functioning to protect nonmalignant cells from malignant transformation and oxidative stress through transcriptional activation of detoxifying and antioxidant enzymes. However, once malignant transformation has occurred within a cell, NRF2 functions to protect the tumour from oxidative stress and chemotherapy-induced cytotoxicity. Moreover, inhibition of the NRF2 oxidative stress pathway in leukaemia cells renders them more sensitive to cytotoxic chemotherapy. Our improved understanding of NRF2 biology in human leukaemia may permit mechanisms by which we could potentially improve future cancer therapies. This review highlights the mechanisms by which leukaemic cells exploit the NRF2/ROS response to promote their growth and survival.

Стилі APA, Harvard, Vancouver, ISO та ін.

35

Mundal, Siv Boon, Johanne Johnsen Rakner, Gabriela Brettas Silva, Lobke Marijn Gierman, Marie Austdal, Purusotam Basnet, Mattijs Elschot, et al. "Divergent Regulation of Decidual Oxidative-Stress Response by NRF2 and KEAP1 in Preeclampsia with and without Fetal Growth Restriction." International Journal of Molecular Sciences 23, no. 4 (February 10, 2022): 1966. http://dx.doi.org/10.3390/ijms23041966.

Повний текст джерела

Анотація:

Utero-placental development in pregnancy depends on direct maternal–fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal–fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR.

Стилі APA, Harvard, Vancouver, ISO та ін.

36

Inam Sameh Arif, Yassir Mustafa Kamal, and Israa Burhan Raoof. "Nrf2 as a modulator of oxidative stress." Al Mustansiriyah Journal of Pharmaceutical Sciences 21, no. 4 (April 19, 2022): 17–23. http://dx.doi.org/10.32947/ajps.v21i4.798.

Повний текст джерела

Анотація:

Nrf2 is active protein presents in the cytoplasm in the cells of the body. In the presence of an activators, Nrf2 can enter the nucleus which bind to Antioxidant Responses Elements (ARE) or otherwise named human ARE (hARE) which control the whole antioxidants activity in human cell. Many factors may contribute to defective or overwhelmed cellular antioxidants activities for instances aging and cellular damages. These cellular damages can be produced by free radicals or oxidative stress. In the mechanism, if Nrf2 activated in the nucleus, can caused the production of collaborative antioxidants enzymes especially: catalase, glutathione (GLT) and superoxide dismutase (SOD) as a responsible for detoxification of free radical inside the cells.

Стилі APA, Harvard, Vancouver, ISO та ін.

37

Cho, Hye-Youn, Sekhar P. Reddy, and Steven R. Kleeberger. "Nrf2 Defends the Lung from Oxidative Stress." Antioxidants & Redox Signaling 8, no. 1-2 (January 2006): 76–87. http://dx.doi.org/10.1089/ars.2006.8.76.

Повний текст джерела

Стилі APA, Harvard, Vancouver, ISO та ін.

38

Strom, Joshua, Beibei Xu, Xiuqing Tian, and Qin M. Chen. "Nrf2 protects mitochondrial decay by oxidative stress." FASEB Journal 30, no. 1 (September 4, 2015): 66–80. http://dx.doi.org/10.1096/fj.14-268904.

Повний текст джерела

Стилі APA, Harvard, Vancouver, ISO та ін.

39

Kaspar, James W., Suryakant K. Niture, and Anil K. Jaiswal. "Nrf2:INrf2 (Keap1) signaling in oxidative stress." Free Radical Biology and Medicine 47, no. 9 (November 2009): 1304–9. http://dx.doi.org/10.1016/j.freeradbiomed.2009.07.035.

Повний текст джерела

Стилі APA, Harvard, Vancouver, ISO та ін.

40

Chen, Bo, Yanrong Lu, Younan Chen, and Jingqiu Cheng. "The role of Nrf2 in oxidative stress-induced endothelial injuries." Journal of Endocrinology 225, no. 3 (April 27, 2015): R83—R99. http://dx.doi.org/10.1530/joe-14-0662.

Повний текст джерела

Анотація:

Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)–antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1–ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

Стилі APA, Harvard, Vancouver, ISO та ін.

41

Murphy, Kelsey, Killian Llewellyn, Samuel Wakser, Josef Pontasch, Natasha Samanich, Matthew Flemer, Kenneth Hensley, Dong-Shik Kim, and Joshua Park. "Mini-GAGR, an intranasally applied polysaccharide, activates the neuronal Nrf2-mediated antioxidant defense system." Journal of Biological Chemistry 293, no. 47 (October 3, 2018): 18242–69. http://dx.doi.org/10.1074/jbc.ra117.001245.

Повний текст джерела

Анотація:

Oxidative stress triggers and exacerbates neurodegeneration in Alzheimer's disease (AD). Various antioxidants reduce oxidative stress, but these agents have little efficacy due to poor blood–brain barrier (BBB) permeability. Additionally, single-modal antioxidants are easily overwhelmed by global oxidative stress. Activating nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream antioxidant system are considered very effective for reducing global oxidative stress. Thus far, only a few BBB-permeable agents activate the Nrf2-dependent antioxidant system. Here, we discovered a BBB-bypassing Nrf2-activating polysaccharide that may attenuate AD pathogenesis. Mini-GAGR, a 0.7-kDa cleavage product of low-acyl gellan gum, increased the levels and activities of Nrf2-dependent antioxidant enzymes, decreased reactive oxygen species (ROS) under oxidative stress in mouse cortical neurons, and robustly protected mitochondria from oxidative insults. Moreover, mini-GAGR increased the nuclear localization and transcriptional activity of Nrf2 similarly to known Nrf2 activators. Mechanistically, mini-GAGR increased the dissociation of Nrf2 from its inhibitor, Kelch-like ECH-associated protein 1 (Keap1), and induced phosphorylation and nuclear translocation of Nrf2 in a protein kinase C (PKC)- and fibroblast growth factor receptor (FGFR1)-dependent manner. Finally, 20-day intranasal treatment of 3xTg-AD mice with 100 nmol of mini-GAGR increased nuclear p-Nrf2 and growth-associated protein 43 (GAP43) levels in hippocampal neurons, reduced p-tau and β-amyloid (Aβ) peptide–stained neurons, and improved memory. The BBB-bypassing Nrf2-activating polysaccharide reported here may be effective in reducing oxidative stress and neurodegeneration in AD.

Стилі APA, Harvard, Vancouver, ISO та ін.

42

Zhao, Feijie, Xinxin Ci, Xiaxia Man, Jiajia Li, Zhentong Wei, and Songling Zhang. "Food-Derived Pharmacological Modulators of the Nrf2/ARE Pathway: Their Role in the Treatment of Diseases." Molecules 26, no. 4 (February 15, 2021): 1016. http://dx.doi.org/10.3390/molecules26041016.

Повний текст джерела

Анотація:

Oxidative stress, which refers to unbalanced accumulation of reactive oxygen species (ROS) levels in cells, has been linked to acute and chronic diseases. Nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays a vital role in regulating cytoprotective genes and enzymes in response to oxidative stress. Therefore, pharmacological regulation of Nrf2/ARE pathway is an effective method to treat several diseases that are mainly characterized by oxidative stress and inflammation. Natural products that counteract oxidative stress by modulating Nrf2 have contributed significantly to disease treatment. In this review, we focus on bioactive compounds derived from food that are Nrf2/ARE pathway regulators and describe the molecular mechanisms for regulating Nrf2 to exert favorable effects in experimental models of diseases.

Стилі APA, Harvard, Vancouver, ISO та ін.

43

Wang, Yun, Yu-Han Gu, Ming Liu, Yang Bai, Li-Ye Liang, and Huai-Liang Wang. "TBHQ Alleviated Endoplasmic Reticulum Stress-Apoptosis and Oxidative Stress by PERK-Nrf2 Crosstalk in Methamphetamine-Induced Chronic Pulmonary Toxicity." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/4310475.

Повний текст джерела

Анотація:

Methamphetamine (MA) leads to cardiac and pulmonary toxicity expressed as increases in inflammatory responses and oxidative stress. However, some interactions may exist between oxidative stress and endoplasmic reticulum stress (ERS). The current study is designed to investigate if both oxidative stress and ERS are involved in MA-induced chronic pulmonary toxicity and if antioxidant tertiary butylhydroquinone (TBHQ) alleviated ERS-apoptosis and oxidative stress by PERK-Nrf2 crosstalk. In this study, the rats were randomly divided into control group, MA-treated group (MA), and MA plus TBHQ-treated group (MA + TBHQ). Chronic exposure to MA resulted in slower growth of weight and pulmonary toxicity of the rats by increasing the pulmonary arterial pressure, promoting the hypertrophy of right ventricle and the remodeling of pulmonary arteries. MA inhibited the Nrf2-mediated antioxidative stress by downregulation of Nrf2, GCS, and HO-1 and upregulation of SOD2. MA increased GRP78 to induce ERS. Overexpression and phosphorylation of PERK rapidly phosphorylated eIF2α, increased ATF4, CHOP, bax, caspase 3, and caspase 12, and decreased bcl-2. These changes can be reversed by antioxidant TBHQ through upregulating expression of Nrf2. The above results indicated that TBHQ can alleviate MA-induced oxidative stress which can accelerate ERS to initiate PERK-dependent apoptosis and that PERK/Nrf2 is likely to be the key crosstalk between oxidative stress and ERS in MA-induced chronic pulmonary toxicity.

Стилі APA, Harvard, Vancouver, ISO та ін.

44

Ngo, Vy, Nadun C. Karunatilleke, Anne Brickenden, Wing-Yiu Choy, and Martin L. Duennwald. "Oxidative Stress-Induced Misfolding and Inclusion Formation of Nrf2 and Keap1." Antioxidants 11, no. 2 (January 27, 2022): 243. http://dx.doi.org/10.3390/antiox11020243.

Повний текст джерела

Анотація:

Cells that experience high levels of oxidative stress respond by inducing antioxidant proteins through activation of the protein transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is negatively regulated by the E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1), which binds to Nrf2 to facilitate its ubiquitination and ensuing proteasomal degradation under basal conditions. Here, we studied protein folding and misfolding in Nrf2 and Keap1 in yeast, mammalian cells, and purified proteins under oxidative stress conditions. Both Nrf2 and Keap1 are susceptible to protein misfolding and inclusion formation upon oxidative stress. We propose that the intrinsically disordered regions within Nrf2 and the high cysteine content of Keap1 contribute to their oxidation and the ensuing misfolding. Our work reveals previously unexplored aspects of Nrf2 and Keap1 regulation and/or dysregulation by oxidation-induced protein misfolding.

Стилі APA, Harvard, Vancouver, ISO та ін.

45

Dutta, Anindita, Apurba Das, Deepa Bisht, Vijendra Arya, and Rohini Muthuswami. "PLK-1 Interacting Checkpoint Helicase, PICH, Mediates Cellular Oxidative Stress Response." Epigenomes 6, no. 4 (October 18, 2022): 36. http://dx.doi.org/10.3390/epigenomes6040036.

Повний текст джерела

Анотація:

Cells respond to oxidative stress by elevating the levels of antioxidants, signaling, and transcriptional regulation, often implemented by chromatin remodeling proteins. The study presented here shows that the expression of PICH, a Rad54-like helicase belonging to the ATP-dependent chromatin remodeling protein family, is upregulated during oxidative stress in HeLa cells. We also show that PICH regulates the expression of Nrf2, a transcription factor regulating antioxidant response in both the absence and presence of oxidative stress. The overexpression of PICH in PICH-depleted cells restored Nrf2 as well as antioxidant gene expression. In turn, Nrf2 regulated the expression of PICH in the presence of oxidative stress. ChIP experiments showed that PICH is present on the Nrf2 as well as antioxidant gene promoters, suggesting that the protein might be regulating the expression of these genes directly by binding to the DNA sequences. In addition, Nrf2 and histone acetylation (H3K27ac) also played a role in activating transcription in the presence of oxidative stress. Both Nrf2 and H3K27ac were found to be present on PICH and antioxidant promoters. Their occupancy was dependent on the PICH expression as fold enrichment was found to be decreased in PICH-depleted cells. PICH ablation led to the reduced expression of Nrf2 and impaired antioxidant response, leading to increased ROS content and thus showing PICH is essential for the cell to respond to oxidative stress.

Стилі APA, Harvard, Vancouver, ISO та ін.

46

Zhou, X., Z. Chen, W. Zhong, R. Yu, and L. He. "Effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts." Human & Experimental Toxicology 38, no. 7 (April 12, 2019): 833–45. http://dx.doi.org/10.1177/0960327119842273.

Повний текст джерела

Анотація:

In the development of dental fluorosis, oxidative stress is considered as the key mechanism. Endoplasmic reticulum (ER) stress can induce oxidative stress and activate the important antioxidative factor nuclear factor erythroid 2-related factor 2 (Nrf2) in a PKR-like ER kinase (PERK)-dependent manner, but combining ER stress and oxidative stress, the role of PERK-Nrf2 signaling pathway involved in fluoride-regulated ameloblasts is not fully defined. Here, we studied the effect of fluoride on PERK-Nrf2 signaling pathway in mouse ameloblasts. We found that low-dose and continuous fluoride exposure increased binding immunoglobulin protein expression and activated PERK–activating transcription factor 4 signaling pathway. Meanwhile, the expression of Nrf2 and its target genes (glutamylcysteine synthetase and glutathione S-transferase-P1) enhanced following ER stress. Tunicamycin increased the expression of PERK, leading to Nrf2 nuclear import, and tauroursodeoxycholate suppressed Nrf2 activation through PERK during ER stress, indicating that PERK activation is required for Nrf2 nuclear entry. Furthermore, tert-butylhydroquinone triggered the overexpression of Nrf2 to reduce ER stress, but luteolin inhibited Nrf2 nuclear localization to elevate ER stress. In summary, this study proved that fluoride under certain dose can induce ER stress and promote Nrf2 nuclear import via PERK activation and suggested that antioxidation mechanism mediated by PERK-Nrf2 can alleviate fluoride-induced ER stress effectively.

Стилі APA, Harvard, Vancouver, ISO та ін.

47

Minton, Thomas, Kelly Hares, Kevin Kemp, Neil Scolding, and Claire Rice. "123 Oxidative stress responses – potential biomarkers in multiple sclerosis." Journal of Neurology, Neurosurgery & Psychiatry 93, no. 9 (August 12, 2022): e2.76. http://dx.doi.org/10.1136/jnnp-2022-abn2.167.

Повний текст джерела

Анотація:

IntroductionOxidative stress is implicated in the pathophysiology of multiple sclerosis (MS). To investigate their potential as MS biomarkers, we compared plasma levels of two master regulators of antioxidant processes nuclear factor erythroid 2 related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), as well as downstream antioxidant enzymes superoxide dismutase 1 (SOD1) and catalase.MethodsPlasma levels of Nrf2, PGC1α and SOD1 were measured using enzyme-linked immunosorbent assay (ELISA). Plasma catalase levels were measured using a catalase activity assay. The results were analysed using a multiple regression model.ResultsPlasma PGC1α concentrations were higher in people with MS compared to controls and lower in patients with primary progressive MS than those with relapsing remitting MS. Plasma Nrf2 levels were increased in those on disease modifying therapy with Dimethyl fumarate, which was most pronounced 6 weeks post-initiation. Plasma Nrf2 levels fell in patients commencing Ocrelizumab. Plasma catalase activity was higher in patients with MS when compared to control, and higher in patients with progressive MS phenotypes. No statistically significant changes in plasma SOD1 levels were observed.ConclusionsOur findings support further investigation of the potential for plasma PGC1α, Nrf2 and catalase as disease biomarkers in MS.

Стилі APA, Harvard, Vancouver, ISO та ін.

48

Yu, Chao, and Jian-Hui Xiao. "The Keap1-Nrf2 System: A Mediator between Oxidative Stress and Aging." Oxidative Medicine and Cellular Longevity 2021 (April 19, 2021): 1–16. http://dx.doi.org/10.1155/2021/6635460.

Повний текст джерела

Анотація:

Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to the disruption of redox signals and causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence-related diseases and in aging itself. The Kelch-like ECH-associated protein 1- (Keap1-) nuclear factor-erythroid 2-related factor 2 (Nrf2) system can be used to monitor oxidative stress; Keap1-Nrf2 is closely associated with aging and controls the transcription of multiple antioxidant enzymes. Simultaneously, Keap1-Nrf2 signaling is also modulated by a more complex regulatory network, including phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), protein kinase C, and mitogen-activated protein kinase. This review presents more information on aging-related molecular mechanisms involving Keap1-Nrf2. Furthermore, we highlight several major signals involved in Nrf2 unbinding from Keap1, including cysteine modification of Keap1 and phosphorylation of Nrf2, PI3K/Akt/glycogen synthase kinase 3β, sequestosome 1, Bach1, and c-Myc. Additionally, we discuss the direct interaction between Keap1-Nrf2 and the mammalian target of rapamycin pathway. In summary, we focus on recent progress in research on the Keap1-Nrf2 system involving oxidative stress and aging, providing an empirical basis for the development of antiaging drugs.

Стилі APA, Harvard, Vancouver, ISO та ін.

49

Guo, Jinzhou, Jingxin Ma, Kun Cai, Haining Chen, Ke Xie, Binren Xu, Desen Quan, and Jingyan Du. "Isoflavones from Semen Sojae Preparatum Improve Atherosclerosis and Oxidative Stress by Modulating Nrf2 Signaling Pathway through Estrogen-Like Effects." Evidence-Based Complementary and Alternative Medicine 2022 (April 7, 2022): 1–13. http://dx.doi.org/10.1155/2022/4242099.

Повний текст джерела

Анотація:

Atherosclerosis (AS) often occurs in cardiovascular disease, which is a chronic vascular disease and is harmful to human health. Oxidative stress is involved in its etiology. This study aimed to determine the effectiveness of Isoflavones from semen sojae preparatum (ISSP) in inhibiting oxidative stress and its important molecular mechanisms through in vivo and in vitro experiments. ApoE−/− mice were used to establish atherosclerosis models through a high-fat diet, and endothelial cells were used to establish oxidative stress injury models through ox-LDL induction. The degree of oxidative stress damage was assessed by detecting changes in ET-1, LDH, SOD, and MDA indicators. It was observed that after ISSP treatment, the oxidative stress damage of mice and endothelial cells was improved. The Nrf2/AER signaling pathway is an important antioxidant pathway that has attracted our attention. Western blotting and qRT-PCR were used to detect the expression of Nrf2, HO-1, and NQO1 in mice aortae and endothelial cells. The results showed that the Nrf2 signaling pathway was activated after ISSP intervention. In addition, in this study, after preantagonizing the estrogen receptors GPR30 and ERβ, it was observed that the effects of ISSP in treating endothelial cell oxidative damage and activating the Nrf2 signaling pathway were weakened. After silencing Nrf2 by Nrf2-siRNA transfection, the effect of ISSP in treating endothelial cell oxidative damage was inhibited. This study shows that ISSP may reduce oxidative stress damage and atherosclerosis through the Nrf2 signaling pathway, and this effect may involve the GPR30 and ERβ estrogen receptors.

Стилі APA, Harvard, Vancouver, ISO та ін.

50

Kozieł, Marta Justyna, Karolina Kowalska, and Agnieszka Wanda Piastowska-Ciesielska. "Nrf2: a main responsive element in cells to mycotoxin-induced toxicity." Archives of Toxicology 95, no. 5 (February 8, 2021): 1521–33. http://dx.doi.org/10.1007/s00204-021-02995-4.

Повний текст джерела

Анотація:

AbstractNuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor participating in response to cellular oxidative stress to maintain the redox balance. Generation of reactive oxygen species (ROS) and, in consequence, oxidative stress, are physiological as well as pathological processes which take place in almost all types of cells. Nrf2, in response to oxidative stress, activates expression and production of antioxidant enzymes to remove free radicals. However, the role of Nrf2 seems to be more sophisticated and its increased expression observed in cancer cells allows to draw a conclusion that its role is tissue—and condition—dependent. Interestingly, Nrf2 might also play a crucial role in response to environmental factors like mycotoxins. Thus, the aim of the study is to review the role of Nrf2 in cells exposed to most common mycotoxins to check if the Nrf2 signaling pathway serves as the main response element to mycotoxin-induced oxidative stress in human and animal cells and if it can be a target of detoxifying agents.

Стилі APA, Harvard, Vancouver, ISO та ін.

Статті в журналах з теми "Erythropoiesis, Nrf2, Oxidative stress"

Оформте джерело за APA, MLA, Chicago, Harvard та іншими стилями