Cyclophosphamide induces a significant increase in iron content in the liver and spleen of mice

2020 ◽  
Vol 39 (7) ◽  
pp. 973-983
Author(s):  
Y Sheng ◽  
Y-J Chen ◽  
Z-M Qian ◽  
J Zheng ◽  
Y Liu
Keyword(s):  
Oxidative Stress ◽  
Iron Content ◽  
Related Factor ◽  
Iron Regulatory Proteins ◽  
Iron Responsive Element ◽  
Ferroportin 1 ◽  
Tissue Iron ◽  
Transferrin Receptor 1 ◽  
Responsive Element ◽  
Available Information

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.

scholarly journals BRG1 Interacts with Nrf2 To Selectively Mediate HO-1 Induction in Response to Oxidative Stress

2006 ◽  
Vol 26 (21) ◽  
pp. 7942-7952 ◽  
Author(s):  
Jianyong Zhang ◽  
Tsutomu Ohta ◽  
Atsushi Maruyama ◽  
Tomonori Hosoya ◽  
Keizo Nishikawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Target Genes ◽  
Inducible Expression ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Gene Encoding ◽  
Z Dna ◽  
Responsive Element

ABSTRACT NF-E2-related factor 2 (Nrf2) regulates antioxidant-responsive element-mediated induction of cytoprotective genes in response to oxidative stress. The purpose of this study was to determine the role of BRG1, a catalytic subunit of SWI2/SNF2-like chromatin-remodeling complexes, in Nrf2-mediated gene expression. Small interfering RNA knockdown of BRG1 in SW480 cells selectively decreased inducible expression of the heme oxygenase 1 (HO-1) gene after diethylmaleate treatment but did not affect other Nrf2 target genes, such as the gene encoding NADPH:quinone oxidoreductase 1 (NQO1). Chromatin immunoprecipitation analysis revealed that Nrf2 recruits BRG1 to both HO-1 and NQO1 regulatory regions. However, BRG1 knockdown selectively decreased the recruitment of RNA polymerase II to the HO-1 promoter but not to the NQO1 promoter. HO-1, but not other Nrf2-regulated genes, harbors a sequence of TG repeats capable of forming Z-DNA with BRG1 assistance. Similarly, replacement of the TG repeats with an alternative Z-DNA-forming sequence led to BRG1-mediated activation of HO-1. These results thus demonstrate that BRG1, through the facilitation of Z-DNA formation and subsequent recruitment of RNA polymerase II, is critical in Nrf2-mediated inducible expression of HO-1.

scholarly journals Preventive and Therapeutic Effects of MG132 by Activating Nrf2-ARE Signaling Pathway on Oxidative Stress-Induced Cardiovascular and Renal Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Wenpeng Cui ◽  
Yang Bai ◽  
Ping Luo ◽  
Lining Miao ◽  
Lu Cai
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Signaling Pathway ◽  
Critical Role ◽  
Renal Diseases ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Responsive Element ◽  
And Function ◽  
Proteasomal Inhibitor

So far, cardiovascular and renal diseases have brought us not only huge economic burden but also serious society problems. Since effective therapeutic strategies are still limited, to find new methods for the prevention or therapy of these diseases is important. Oxidative stress has been found to play a critical role in the initiation and progression of cardiovascular and renal diseases. In addition, activation of nuclear-factor-E2-related-factor-2- (Nrf2-) antioxidant-responsive element (ARE) signaling pathway protects cells and tissues from oxidative damage. As a proteasomal inhibitor, MG132 was reported to activate Nrf2 expression and function, which was accompanied with significant preventive and/or therapeutic effect on cardiovascular and renal diseases under most conditions; therefore, MG132 seems to be a potentially effective drug to be used in the prevention of oxidative damage. In this paper, we will summarize the information available regarding the effect of MG132 on oxidative stress-induced cardiovascular and renal damage, especially through Nrf2-ARE signaling pathway.

scholarly journals Hereditary Hyperferritinemia-Cataract Syndrome Caused by a 29-Base Pair Deletion in the Iron Responsive Element of Ferritin L-Subunit Gene

Blood ◽  
1997 ◽  
Vol 90 (5) ◽  
pp. 2084-2088 ◽  
Author(s):  
Domenico Girelli ◽  
Roberto Corrocher ◽  
Luigi Bisceglia ◽  
Oliviero Olivieri ◽  
Leopoldo Zelante ◽  
...  
Keyword(s):  
Base Pair ◽  
Genetic Disorder ◽  
Dna Amplification ◽  
Negative Control ◽  
Stem Loop ◽  
Iron Regulatory Proteins ◽  
Iron Responsive Element ◽  
Ferritin Synthesis ◽  
Base Pair Deletion ◽  
Responsive Element

Abstract Iron availability regulates ferritin synthesis posttranscriptionally by the interaction between iron-regulatory proteins (IRPs) and an iron responsive element (IRE), a stem-loop sequence located on the 5′ untranslated region of ferritin mRNA. IRPs recognize IREs as a sequence/structure motif, blocking ferritin translation. Recently, we and others independently described families with a combination of hyperferritinemia (serum L-ferritin ≥ 1,000 μg/L, without iron overload) and congenital bilateral cataract, transmitted as an autosomal-dominant trait. The molecular basis were two distinct point mutations in the highly conserved CAGUG(X) hexaloop of L-ferritin IRE on chromosome 19. A new three-generation family with a similar phenotype and a unique genotype is here reported. DNA amplification by polymerase chain reaction and sequence analysis showed a 29-base pair deletion in the L-ferritin IRE, involving the whole 5′ sequence essential to the base pairing of the IRE stem. This deletion is predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Hereditary Hyperferritinemia-Cataract Syndrome (HHCS) appears as a new genetic disorder with a unique phenotype associated with at least four different mutations in the L-ferritin IRE. Hematologists should take into account HHCS in the differential diagnosis of unexplained hyperferritinemia.

scholarly journals Conservation in the Iron Responsive Element Family

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1365
Author(s):  
Karl Volz
Keyword(s):  
Translational Control ◽  
Tertiary Structure ◽  
Stem Loop ◽  
Iron Regulatory Proteins ◽  
Iron Responsive Element ◽  
Responsive Element ◽  
Iron Responsive Elements ◽  
Irp1 And Irp2 ◽  
Family Membership ◽  
Secondary And Tertiary Structure

Iron responsive elements (IREs) are mRNA stem-loop targets for translational control by the two iron regulatory proteins IRP1 and IRP2. They are found in the untranslated regions (UTRs) of genes that code for proteins involved in iron metabolism. There are ten “classic” IRE types that define the conserved secondary and tertiary structure elements necessary for proper IRP binding, and there are 83 published “IRE-like” sequences, most of which depart from the established IRE model. Here are structurally-guided discussions regarding the essential features of an IRE and what is important for IRE family membership.

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