HEME OXYGENASE-1: REDOXEGULATION AND ROLE IN THE HEPATIC OXIDATIVE STRESS RESPONSE

Shock ◽  
2004 ◽  
Vol 21 (Supplement) ◽  
pp. 125
Author(s):  
Michael Bauer
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Heme Oxygenase ◽  
Oxidative Stress Response ◽  
Heme Oxygenase 1 ◽  
Hepatic Oxidative Stress

scholarly journals Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kazushige Ota ◽  
Andrey Brydun ◽  
Ari Itoh-Nakadai ◽  
Jiying Sun ◽  
Kazuhiko Igarashi
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Heme Oxygenase ◽  
Transcriptional Activity ◽  
Oxidative Stress Response ◽  
Acute Injury ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Environmental Perturbations ◽  
Deficient Mice

Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects ofBach1deficiency on mice.Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells ofBach1-deficient animals, the levels of ROS inBach1-deficient HSCs were comparable to those in wild-type cells.Bach1−/−;p53−/−mice succumbed to spontaneous cancers as frequently asp53-deficient mice.Bach1deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation toBach1deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded thatBach1deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.

scholarly journals The Immunogenicity in Mice of HCV Core Delivered as DNA Is Modulated by Its Capacity to Induce Oxidative Stress and Oxidative Stress Response

Cells ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 208 ◽  
Author(s):  
Juris Jansons ◽  
Irina Sominskaya ◽  
Natalia Petrakova ◽  
Elizaveta S. Starodubova ◽  
Olga A. Smirnova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Oxidative Stress Response ◽  
Heme Oxygenase 1 ◽  
Quinone Oxidoreductase ◽  
Regulated Expression ◽  
Preclinical Trials ◽  
Cellular Immune ◽  
And Oxidative Stress ◽  
Modest Level

HCV core is an attractive HCV vaccine target, however, clinical or preclinical trials of core-based vaccines showed little success. We aimed to delineate what restricts its immunogenicity and improve immunogenic performance in mice. We designed plasmids encoding full-length HCV 1b core and its variants truncated after amino acids (aa) 60, 98, 152, 173, or up to aa 36 using virus-derived or synthetic polynucleotides (core191/60/98/152/173/36_191v or core152s DNA, respectively). We assessed their level of expression, route of degradation, ability to trigger the production of reactive oxygen species/ROS, and to activate the components of the Nrf2/ARE antioxidant defense pathway heme oxygenase 1/HO-1 and NAD(P)H: quinone oxidoreductase/Nqo-1. All core variants with the intact N-terminus induced production of ROS, and up-regulated expression of HO-1 and Nqo-1. The capacity of core variants to induce ROS and up-regulate HO-1 and Nqo-1 expression predetermined their immunogenicity in DNA-immunized BALB/c and C57BL/6 mice. The most immunogenic was core 152s, expressed at a modest level and inducing moderate oxidative stress and oxidative stress response. Thus, immunogenicity of HCV core is shaped by its ability to induce ROS and oxidative stress response. These considerations are important in understanding the mechanisms of viral suppression of cellular immune response and in HCV vaccine design.

scholarly journals Heme Oxygenase-1 at the Nexus of Endothelial Cell Fate Decision Under Oxidative Stress

2021 ◽  
Vol 9 ◽  
Author(s):  
Sindhushree Raghunandan ◽  
Srinivasan Ramachandran ◽  
Eugene Ke ◽  
Yifei Miao ◽  
Ratnesh Lal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Response ◽  
Cell Surface ◽  
Cell Survival ◽  
Cell Fate ◽  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Cell Fate Decisions

Endothelial cells (ECs) form the inner lining of blood vessels and are central to sensing chemical perturbations that can lead to oxidative stress. The degree of stress is correlated with divergent phenotypes such as quiescence, cell death, or senescence. Each possible cell fate is relevant for a different aspect of endothelial function, and hence, the regulation of cell fate decisions is critically important in maintaining vascular health. This study examined the oxidative stress response (OSR) in human ECs at the boundary of cell survival and death through longitudinal measurements, including cellular, gene expression, and perturbation measurements. 0.5 mM hydrogen peroxide (HP) produced significant oxidative stress, placed the cell at this junction, and provided a model to study the effectors of cell fate. The use of systematic perturbations and high-throughput measurements provide insights into multiple regimes of the stress response. Using a systems approach, we decipher molecular mechanisms across these regimes. Significantly, our study shows that heme oxygenase-1 (HMOX1) acts as a gatekeeper of cell fate decisions. Specifically, HP treatment of HMOX1 knockdown cells reversed the gene expression of about 51% of 2,892 differentially expressed genes when treated with HP alone, affecting a variety of cellular processes, including anti-oxidant response, inflammation, DNA injury and repair, cell cycle and growth, mitochondrial stress, metabolic stress, and autophagy. Further analysis revealed that these switched genes were highly enriched in three spatial locations viz., cell surface, mitochondria, and nucleus. In particular, it revealed the novel roles of HMOX1 on cell surface receptors EGFR and IGFR, mitochondrial ETCs (MTND3, MTATP6), and epigenetic regulation through chromatin modifiers (KDM6A, RBBP5, and PPM1D) and long non-coding RNA (lncRNAs) in orchestrating the cell fate at the boundary of cell survival and death. These novel aspects suggest that HMOX1 can influence transcriptional and epigenetic modulations to orchestrate OSR affecting cell fate decisions.

scholarly journals Fluorescent tagging of endogenous Heme oxygenase-1 in human induced pluripotent stem cells for high content imaging of oxidative stress in various differentiated lineages

2021 ◽  
Author(s):  
Kirsten E. Snijders ◽  
Anita Fehér ◽  
Zsuzsanna Táncos ◽  
István Bock ◽  
Annamária Téglási ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Stress Response ◽  
Heme Oxygenase ◽  
Stress Responses ◽  
Heme Oxygenase 1 ◽  
Dependent Manner ◽  
Chemical Safety ◽  
Induced Pluripotent ◽  
Oxidative Stress Responses

AbstractTagging of endogenous stress response genes can provide valuable in vitro models for chemical safety assessment. Here, we present the generation and application of a fluorescent human induced pluripotent stem cell (hiPSC) reporter line for Heme oxygenase-1 (HMOX1), which is considered a sensitive and reliable biomarker for the oxidative stress response. CRISPR/Cas9 technology was used to insert an enhanced green fluorescent protein (eGFP) at the C-terminal end of the endogenous HMOX1 gene. Individual clones were selected and extensively characterized to confirm precise editing and retained stem cell properties. Bardoxolone-methyl (CDDO-Me) induced oxidative stress caused similarly increased expression of both the wild-type and eGFP-tagged HMOX1 at the mRNA and protein level. Fluorescently tagged hiPSC-derived proximal tubule-like, hepatocyte-like, cardiomyocyte-like and neuron-like progenies were treated with CDDO-Me (5.62–1000 nM) or diethyl maleate (5.62–1000 µM) for 24 h and 72 h. Multi-lineage oxidative stress responses were assessed through transcriptomics analysis, and HMOX1-eGFP reporter expression was carefully monitored using live-cell confocal imaging. We found that eGFP intensity increased in a dose-dependent manner with dynamics varying amongst lineages and stressors. Point of departure modelling further captured the specific lineage sensitivities towards oxidative stress. We anticipate that the newly developed HMOX1 hiPSC reporter will become a valuable tool in understanding and quantifying critical target organ cell-specific oxidative stress responses induced by (newly developed) chemical entities.

Oxidative Stress Response and Cytotoxicity of Electrophilic Compounds in Primary Human Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3444-3444
Author(s):  
Raymond P Wu ◽  
Tomoko Hayashi ◽  
Shiyin Yao ◽  
Christina C.N. Wu ◽  
Howard B Cottam ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Chronic Lymphocytic Leukemia ◽  
Oxidative Stress Response ◽  
Lymphocytic Leukemia ◽  
Heme Oxygenase 1 ◽  
Nrf2 Pathway ◽  
Nrf2 Activation ◽  
Unsaturated Carbonyls ◽  
Reactive Metals

Abstract Abstract 3444 Poster Board III-332 Introduction The transcription factor Nrf2 [NFE2L2] is the master regulator of the oxidative stress response pathway. At low oxidative states, Nrf2 is degraded by an E3 ubiquitin ligase complex containing KEAP1. Reactive oxygen species or certain electrophiles cause Nrf2 accumulation and nuclear translocation by inactivating Keap1 through oxidation or adduction of its free thiols. Recent work has found that various electrophilic natural products (parthenolide, isothiocyanates) and synthetic molecules (ethacrynic acid, EA and 2-methoxyestradiol, 2-ME) are selectively cytotoxic to PBMCs from Chronic Lymphocytic Leukemia (CLL) patients. The high oxidative stress state of CLL cells was hypothesized to be the mechanism of specificity. However, the effect, if any, of electrophilic compounds on Nrf2 signaling in CLL is unknown, because Nrf2 activation has never been assessed in this leukemia. The purpose of the present studies is to determine if the Nrf2 pathway is active in primary CLL, and if it can be modified by electrophilic agents that are cytotoxic to CLL cells. Materials and Methods Peripheral blood mononuclear cells (PBMCs) from normal donors and CLL patients were isolated by Ficoll density-gradient centrifugation. B cells were purified with the negative selection method using RosetteSep human B cell isolation kit (Stemcell Technologies). Steady-state levels of Nrf2 and its target gene heme oxygenase 1 (HO-1) were compared between PBMCs from normal donors and CLL patients by immunoblotting and quantitative PCR. Five structural classes of small molecules with known electrophilic or potential oxidant activity were tested, including β,β-unsaturated carbonyls, isothiocyanates, thiol reactive metals, flavones and polyphenols. An initial screen for Nrf2 induction by the compounds was performed using a HepG2 cell line expressing β-lactamase under the control of the Antioxidant Response Element, an element essential for Nrf-2 mediated transcription. Cytotoxicity to normal donor and primary human CLL PBMCs was tested by tetrazolium reduction assay. To identify the active chemical moiety we catalytically reduced the unsaturated group on two of these compounds and tested them for Nrf2 activation and CLL selective cytotoxicity. To confirm Keap1 adduction as the mechanism of Nrf2 activation, we synthesized EA conjugated to biotin. Biotin-EA treated CLL cells were lysed and the lysate was passed through streptavidin agarose resin to collect EA modified proteins. Western blot analysis was performed with antibodies specific to Keap1 protein to determine if Keap1 is one of the targets. Results Comparison between normal and CLL PBMCs shows that the Nrf2 pathway is both more highly expressed and more active in the CLL cells. Thus, electrophilic molecules induced HO-1 synthesis in primary leukemia cells. Purified normal B lymphocytes and CLL cells had similar Nrf2 expression that was significantly higher than PBMCs from normal donors. Compounds containing α,β-unsaturated carbonyls and thiol reactive metals were strong activators of Nrf2, and were also found to be selectively cytotoxic to CLL PBMCs compared to normal PBMCs. Reduction of the α,β-unsaturation abrogated Nrf2 activation and CLL toxicity, suggesting that this functional group is critical for both functions. Furthermore, binding studies with biotin-EA demonstrated that Keap1 was the target of electrophilic modification in CLL PBMCs. To our knowledge this is the first study of Nrf2 signaling in primary human CLL. This work is supported by the Leukemia and Lymphoma Society and by the NIH. Disclosures No relevant conflicts of interest to declare.

The Oxidative Stress Response In Erythroid Precursors Is Mediated By tp53

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 7-7
Author(s):  
Troy C. Lund ◽  
Michelle L. Carter ◽  
Ashley C. Kramer ◽  
Nardina Nash ◽  
Bruce R. Blazar
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Conflicts Of Interest ◽  
Oxidative Stress Response ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Qrt Pcr ◽  
Erythroid Precursors ◽  
Cardiac Edema ◽  
Anti Oxidant

Abstract Oxidative stress plays a key role in acute and especially chronic anemia as well red blood cell storage. Recent findings suggest that both erythroid precursors as well as mature red cells have increased sensitively to oxidative stress. Modeling oxidative stress in animals has been a challenge as many of the central genes in the oxidative stress response pathway are necessary for life and knockout animals die of overwhelming oxidative stress early in life. The zebrafish model allows pro-oxidant exposure early in hematopoietic development, and gata1DsRed1 transgenic animals allow clear identification of erythroid precursors. We capitalized on these advantages of the zebrafish to interrogate the effects of oxidative stress on erythroid precursors. After 72 hours of exposure to the strong pro-oxidant naphthol at 10 – 30 µg, embryonic zebrafish up-regulated several anti-oxidant genes including: hypoxia-inducible factor (hif1a), nuclear factor (erythroid derived)-like 2 (nrf2), ferritin heavy chain (fth1a), thioredoxin (txn), and heme oxygenase 1 (hmox1); 1.5, 2.3, 2.5, and 3.0-fold respectively (p < 0.05) as shown by qRT-PCR. To understand if a common pathway was driving anti-oxidant gene expression, we performed an in silico promoter analysis of these genes and discovered several tp53 binding sites within 4 kb upstream of the first exon in each gene. We showed naphthol was able to induce tp53 expression 3-fold over baseline by qRT-PCR. We next took advantage of the tp53 mutant line tp53M214K which has a mutation in the DNA binding region of tp53 rendering it non-functional similar to a complete knockout. We found that tp53M214K fish were highly sensitive to pro-oxidant exposure with 80% of embryos showing severe to moderate anemia and cardiac edema after 72 hours of exposure to naphthol (versus 25% in wild-type control animals, n = 100/group; p < 0.001). There was also a 3-fold decrease in the number of hemoglobin staining cells in naphthol treated tp53M214K animals as shown by o-dianisidine staining (versus control animals, n = 10/group; p < 0.01). A dose-response between the amount of pro-oxidant exposure and severity of anemia/edema also existed as determined by correlation of pro-oxidant concentration to an edema severity scale. We next measured the amount of reactive oxygen species (ROS) generated after naphthol exposure using CellROX detection assays and found that tp53M214K animals showed a doubling in ROS generated compared to wild-type (n = 30/group, p < 0.01) in whole animals. To disable tp53 by an alternative manner, we employed a known tp53 inhibitor, pifithrin, to inactivate tp53. Exposure of animals to pifithrin simultaneous with naphthol recapitulated the finding that inhibition of tp53 increased sensitivity to ROS as 90% of exposed embryos displayed moderate to severe anemia induced cardiac edema (versus 30% in controls, n = 100/group; p < 0.01). Although pifithrin combined with naphthol exposure caused no increase in ROS above that seen with naphthol alone. Our hypothesis is that the anemic phenotype is largely caused by hemolysis in erythroid precursors. The gata1DsRed1 zebrafish has labeled erythroid precursors, and using our experimental system we were able to specifically measure a dose responsive induction of ROS in erythroid precursors after naphthol exposure. Furthermore, gata1DsRed1 animals harboring tp53M214K showed a 20-fold increase in ROS after naphthol exposure (versus tp53+/+ animals, n = 10/group; p < 0.01). Accompanying the increase ROS is apoptosis of erythroid precursors as shown by flow cytometry for gata1DsRed1 cells. In conclusion, we show that amongst the many functions of tp53, providing an anti-oxidant response is also a mechanism though which erythroid precursors metabolize ROS after exposure to pro-oxidants. Understanding the mechanisms by which the anti-oxidant response is regulated will allow us to potentially find more effective drug-able targets to treat the oxidative stress that accompanies acute and chronic anemia’s. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Diannexin Can Ameliorate Acute Respiratory Distress Syndrome in Rats by Promoting Heme Oxygenase-1 Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Ying-nan Ju ◽  
Qi-hang Tai ◽  
Guang-xiao Xu ◽  
Xiao-qing Zhao ◽  
Hai-bin Sun ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Lung Tissue ◽  
Distress Syndrome ◽  
Weight Ratio ◽  
Dry Weight ◽  
Oxidative Stress Response ◽  
Heme Oxygenase 1 ◽  
Protein Levels ◽  
Alveolar Capillary

Background. The recombinant protein diannexin can inhibit platelet-mediated events, which contribute to acute respiratory distress syndrome (ARDS). Here, we investigated the effect of diannexin and its effect on heme oxygenase-1 (HO-1) in ARDS. Methods. A total of 32 rats were randomized into sham, ARDS, diannexin (D), and diannexin+HO-1 inhibitor (DH) groups. Alveolar-capillary permeability was evaluated by testing the partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio, lung wet/dry weight ratio, and protein levels in the lung. Inflammation was assessed by measuring cytokine levels in the bronchial alveolar lavage fluid (BALF) and serum and nuclear factor-κB (NF-κB) in the lung tissue. Inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and myeloperoxidase (MPO) were measured to evaluate the oxidative stress response. Lung tissue pathology and apoptosis were also evaluated. We measured HO-1 expression in the lung tissue to investigate the effect of diannexin on HO-1 in ARDS. Results. Compared with the ARDS group, diannexin improved PaO2/FiO2, lung wet/dry weight ratio, and protein levels in the BALF and decreased levels of cytokines and NF-κB in the lung and serum. Diannexin inhibited the oxidative stress response and significantly ameliorated pathological lung injury and apoptosis. The partial reversal of diannexin effects by a HO-1 inhibitor suggests that diannexin may promote HO-1 expression to ameliorate ARDS. Conclusions. We showed that diannexin can improve alveolar-capillary permeability, inhibit the oxidative stress response and inflammation, and protect against ARDS-induced lung injury and apoptosis.

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