scholarly journals ATM inhibition enhances Auranofin-induced oxidative stress and cell death in lung cell lines

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244060
Author(s):  
Vanessa Ehrenfeld ◽  
Jan R. Heusel ◽  
Simone Fulda ◽  
Sjoerd J. L. van Wijk
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Ataxia Telangiectasia ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Redox Balance ◽  
Lung Cells ◽  
Chromosomal Breakage ◽  
Atm Kinase ◽  
Cellular Reactive Oxygen Species

Ataxia-Telangiectasia (A-T), a pleiotropic chromosomal breakage syndrome, is caused by the loss of the kinase Ataxia-telangiectasia mutated (ATM). ATM is not only involved in the response to DNA damage, but also in sensing and counteracting oxidative stress. Since a disturbed redox balance has been implicated in the pathophysiology of A-T lung disease, we aimed to further explore the interplay between ATM and oxidative stress in lung cells. Using a kinetic trapping approach, we could demonstrate an interaction between the trapping mutant TRX1-CS and ATM upon oxidative stress. We could further show that combined inhibition of thioredoxin reductase (TrxR) and ATM kinase activity, using Auranofin and KU55933 respectively, induced an increase in cellular reactive oxygen species (ROS) levels and protein oxidation in lung cells. Furthermore, ATM inhibition sensitized lung cells to Auranofin-induced cell death that could be rescued by ROS scavengers. As a consequence, targeted reduction of ATM by TRX1 could serve as a regulator of oxidative ATM activation and contribute to the maintenance of the cellular redox homeostasis. These results highlight the importance of the redox-active function of ATM in preventing ROS accumulation and cell death in lung cells.

Effects of iron-related compounds and bilirubin on redox homeostasis in endometriosis and its malignant transformations

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hiroshi Shigetomi ◽  
Shogo Imanaka ◽  
Hiroshi Kobayashi
Keyword(s):  
Oxidative Stress ◽  
Redox Homeostasis ◽  
Redox Balance ◽  
Heme Iron ◽  
Total Iron ◽  
University Hospital ◽  
Free Iron ◽  
Significant Difference ◽  
Iron Heme ◽  
Related Compounds

Abstract Objectives The balance between oxidative stress and antioxidant defense has been reported to differ between women with endometriosis and patients with its malignant transformation. The aim of this study is to investigate changes in redox balance in endometriosis and endometriosis-related ovarian cancer (EAOC) by simultaneously measuring iron-related compounds and bilirubin. Methods This study included 235 patients with a histopathologically confirmed diagnosis of endometriosis (n=178) and EAOC (n=57). Cyst fluid samples were collected in Nara Medical University hospital from January 2013 to May 2019. The levels of iron-related compounds (total iron, heme iron, free iron, oxyhemoglobin [oxyHb], methemoglobin [metHb], and metHb/oxyHb ratio) and bilirubin were measured. Results Total iron, heme iron, free iron, metHb/oxyHb ratio, and bilirubin were significantly elevated in endometriosis compared to EAOC. In both endometriosis and EAOC, iron-related compounds in the cyst were correlated with each other. There was no statistically significant difference in oxyHb and metHb levels between the two groups, but the metHb/oxyHb ratio was significantly higher in endometriosis than in EAOC. Bilirubin was positively correlated with total iron and free iron in EAOC, but there was no correlation between bilirubin and iron-related compounds in endometriosis. Conclusions Iron-induced oxidative stress in endometriosis may exceed bilirubin-dependent antioxidant capability, while redox homeostasis in EAOC can be maintained by at least bilirubin.

scholarly journals The Protective Effect of Static Magnetic Fields with Different Magnetic Inductions against Fluoride Toxicity Is Related to the NRF2 Signaling Pathway

2020 ◽  
Vol 10 (18) ◽  
pp. 6509
Author(s):  
Magdalena Kimsa-Dudek ◽  
Agata Krawczyk ◽  
Agnieszka Synowiec-Wojtarowicz
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Magnetic Induction ◽  
Redox Homeostasis ◽  
Fluoride Toxicity ◽  
Static Magnetic Fields ◽  
Nrf2 Signaling Pathway

A redox imbalance disrupts the cellcycle and the proliferation process, and contributes to the initiation of programmed cell death. One of the pathways that are important for redox homeostasis is the Nrf2-ARE signaling pathway. Fluoride as well as static magnetic fields (SMF) are associated with the concepts of oxidative stress, and thus programmed cell death. Therefore, this study aimed to assess the connection between oxidative stress and apoptosis in human cells co-exposed to fluoride and a SMF with a different magnetic induction and to determine whether the Nrf2-signaling pathway is involved in these effects. The research was realized using normal human dermal fibroblasts that had been co-exposed to fluoride (0.3 mmol/L) and a SMF with a different magnetic induction (0.45 T, 0.55 T, 0.65 T) for 12 h. The mRNA levels of the cellular antioxidant system-related genes and apoptosis-related genes were assessed using the quantitative reverse transcription polymerase chain reaction (RT-qPCR) method. Our results indicated that the increased activity of antioxidant enzymes (SOD1 (superoxide dismutase 1), SOD2 and GSR (glutathione reductase)) suggests the restoration of the cell redox homeostasis that had been disturbed by fluoride, and also that the genes whose expression is associated with the induction of apoptosis are down regulated as a result of exposure to a SMF. The SMF with a 0.65 T flux density had the strongest effect on the fibroblasts. Moreover, our findings demonstrated that the Nrf2 transcription factor plays a crucial role in the protective effect of a SMF against fluoride toxicity in human cells. The results of these studies can form the basis for developing therapeutic strategies for apoptosis and oxidative stress-related diseases.

Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses

2020 ◽  
Vol 29 (6) ◽  
pp. 990-1001 ◽  
Author(s):  
Dmitry A Ovchinnikov ◽  
Sarah L Withey ◽  
Hannah C Leeson ◽  
U Wang Lei ◽  
Ashmitha Sundarrajan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Stress Responses ◽  
Ataxia Telangiectasia ◽  
Compound Heterozygous ◽  
Gene Correction ◽  
Atm Kinase ◽  
Atm Protein ◽  
Induced Apoptosis ◽  
And Oxidative Stress

Abstract Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double-stranded breaks and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac (PB) transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets, KAP-1 and H2AX. Restoration of ATM function also normalizes radiosensitivity, mitochondrial ROS production and oxidative-stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis.

scholarly journals Expression of Thioredoxin/Thioredoxin Reductase System Genes in Aphid-Challenged Maize Seedlings

2020 ◽  
Vol 21 (17) ◽  
pp. 6296
Author(s):  
Hubert Sytykiewicz ◽  
Iwona Łukasik ◽  
Sylwia Goławska ◽  
Iwona Sprawka ◽  
Artur Goławski ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Rhopalosiphum Padi ◽  
Thioredoxin Reductase ◽  
Redox Balance ◽  
Electrical Penetration Graph ◽  
Metopolophium Dirhodum ◽  
Transcriptional Reprogramming ◽  
Maize Varieties ◽  
Maize Plants ◽  
Thioredoxin Reductases

Thioredoxins (Trxs) and thioredoxin reductases (TrxRs) encompass a highly complex network involved in sustaining thiol-based redox homeostasis in plant tissues. The purpose of the study was to gain a new insight into transcriptional reprogramming of the several genes involved in functioning of Trx/TrxR system in maize (Zea mays L.) seedlings, exposed to the bird cherry-oat aphid (Rhopalosiphum padi L.) or the rose-grass aphid (Metopolophium dirhodum Walk.) infestation. The biotests were performed on two maize genotypes (susceptible Złota Karłowa and relatively resistant Waza). The application of real-time qRT-PCR technique allowed to identify a molecular mechanism triggered in more resistant maize plants, linked to upregulation of thioredoxins-encoding genes (Trx-f, Trx-h, Trx-m, Trx-x) and thioredoxin reductase genes (Ftr1, Trxr2). Significant enhancement of TrxR activity in aphid-infested Waza seedlings was also demonstrated. Furthermore, we used an electrical penetration graph (EPG) recordings of M. dirhodum stylet activities in seedlings of the two studied maize varieties. Duration of phloem phase (E1 and E2 models) of rose-grass aphids was about three times longer while feeding in Waza plants, compared to Złota Karłowa cv. The role of activation of Trx/TrxR system in maintaining redox balance and counteracting oxidative-induced damages of macromolecules in aphid-stressed maize plants is discussed.

scholarly journals Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis

2015 ◽  
Vol 112 (14) ◽  
pp. 4453-4458 ◽  
Author(s):  
Michael B. Harbut ◽  
Catherine Vilchèze ◽  
Xiaozhou Luo ◽  
Mary E. Hensler ◽  
Hui Guo ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Redox Balance ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Gram Positive Bacteria ◽  
Bactericidal Activities ◽  
Orally Bioavailable ◽  
Thiol Redox

Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds againstMycobacterium tuberculosisunder nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicatingM. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, includingBacillus subtilisandEnterococcus faecalis, and drug-sensitive and drug-resistant strains ofEnterococcus faeciumandStaphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistantS. aureusinfection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.

Daucosterol disturbs redox homeostasis and elicits oxidative-stress mediated apoptosis in A549 cells via targeting thioredoxin reductase by a p53 dependent mechanism

2019 ◽  
Vol 855 ◽  
pp. 112-123 ◽  
Author(s):  
Tamilselvam Rajavel ◽  
Gunasekeran Banu Priya ◽  
Venkatesan Suryanarayanan ◽  
Sanjeev Kumar Singh ◽  
Kasi Pandima Devi
Keyword(s):  
Oxidative Stress ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Dependent Mechanism

scholarly journals Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurodegenerative disease trajectory

2017 ◽  
Vol 45 (6) ◽  
pp. 1295-1303 ◽  
Author(s):  
Scott W. Burnside ◽  
Giles E. Hardingham
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disease ◽  
Glutamate Uptake ◽  
Redox Homeostasis ◽  
Neuronal Loss ◽  
Redox Balance ◽  
Antioxidant Defences ◽  
Disease Trajectory ◽  
Inflammatory Status ◽  
The Brain

Diverse neurodegenerative diseases share some common aspects to their pathology, with many showing evidence of disruption to the brain's numerous homeostatic processes. As such, imbalanced inflammatory status, glutamate dyshomeostasis, hypometabolism and oxidative stress are implicated in many disorders. That these pathological processes can influence each other both up- and downstream makes for a complicated picture, but means that successfully targeting one area may have an effect on others. This targeting requires an understanding of the mechanisms by which homeostasis is maintained during health, in order to uncover strategies to boost homeostasis in disease. A case in point is redox homeostasis, maintained by antioxidant defences co-ordinately regulated by the transcription factor Nrf2, and capable of preventing not only oxidative stress but also inflammation and neuronal loss in neurodegenerative disease models. The emergence of other master regulators of homeostatic processes in the brain controlling inflammation, mitochondrial biogenesis, glutamate uptake and energy metabolism raises the question as to whether they too can be targeted to alter disease trajectory.

scholarly journals Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1101
Author(s):  
Mei-Chun Chen ◽  
Li-Lin Hsu ◽  
Sheng-Fan Wang ◽  
Yi-Ling Pan ◽  
Jeng-Fan Lo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Redox Homeostasis ◽  
Glucose Deprivation ◽  
Metabolic Flexibility ◽  
Mitochondrial Oxidative Stress ◽  
Cancer Cell Death ◽  
Adaptation Response

Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.

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