scholarly journals Cellular models of altered base excision repair reveal a differential contribution of reactive oxygen species‐induced 7,8‐dihydro‐8‐oxo‐2′‐deoxyguanosine to the cytotoxic mechanisms of platinum anticancer drugs cisplatin and oxaliplatin

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Thomas J Preston ◽  
Jeffrey T Henderson ◽  
Gordon P McCallum ◽  
Peter G Wells
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Drugs ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cellular Models ◽  
Platinum Anticancer Drugs ◽  
Base Excision ◽  
Differential Contribution

scholarly journals Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO3-Induced DNA Damage

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Maria A. Spassova ◽  
David J. Miller ◽  
Alexander S. Nikolov
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Dose Response ◽  
Excision Repair ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Repair Processes ◽  
Base Excision

We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemicalKBrO3which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibitsKBrO3-caused oxidative damage. Our modeling revealed that sustained exposure toKBrO3can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical’s toxicity dose dependence based on the dose-response of early genotoxic events.

scholarly journals Link between Base Excision Repair (BER), Reactive Oxygen Species (ROS), and Cancer

2021 ◽  
Author(s):  
Nour Fayyad ◽  
Farah Kobaisi ◽  
Mohammad Fayyad-Kazan ◽  
Ali Nasrallah ◽  
Hussein Fayyad-Kazan ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Base Excision

scholarly journals Assessment of Physico-Chemical and Toxicological Properties of Commercial 2D Boron Nitride Nanopowder and Nanoplatelets

2021 ◽  
Vol 22 (2) ◽  
pp. 567
Author(s):  
Brixhilda Domi ◽  
Kapil Bhorkar ◽  
Carlos Rumbo ◽  
Labrini Sygellou ◽  
Spyros N. Yannopoulos ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Boron Nitride ◽  
A549 Cells ◽  
Reactive Oxygen ◽  
Slight Reduction ◽  
Oxygen Species ◽  
Potential Toxicity ◽  
Cellular Models ◽  
Physico Chemical ◽  
The Impact

Boron nitride (BN) nanomaterials have been increasingly explored for potential applications in chemistry and biology fields (e.g., biomedical, pharmaceutical, and energy industries) due to their unique physico-chemical properties. However, their safe utilization requires a profound knowledge on their potential toxicological and environmental impact. To date, BN nanoparticles have been considered to have a high biocompatibility degree, but in some cases, contradictory results on their potential toxicity have been reported. Therefore, in the present study, we assessed two commercial 2D BN samples, namely BN-nanopowder (BN-PW) and BN-nanoplatelet (BN-PL), with the objective to identify whether distinct physico-chemical features may have an influence on the biological responses of exposed cellular models. Morphological, structural, and composition analyses showed that the most remarkable difference between both commercial samples was the diameter of their disk-like shape, which was of 200–300 nm for BN-PL and 100–150 nm for BN-PW. Their potential toxicity was investigated using adenocarcinomic human alveolar basal epithelial cells (A549 cells) and the unicellular fungus Saccharomycescerevisiae, as human and environmental eukaryotic models respectively, employing in vitro assays. In both cases, cellular viability assays and reactive oxygen species (ROS) determinations where performed. The impact of the selected nanomaterials in the viability of both unicellular models was very low, with only a slight reduction of S. cerevisiae colony forming units being observed after a long exposure period (24 h) to high concentrations (800 mg/L) of both nanomaterials. Similarly, BN-PW and BN-PL showed a low capacity to induce the formation of reactive oxygen species in the studied conditions. Even at the highest concentration and exposure times, no major cytotoxicity indicators were observed in human cells and yeast. The results obtained in the present study provide novel insights into the safety of 2D BN nanomaterials, indicating no significant differences in the toxicological potential of similar commercial products with a distinct lateral size, which showed to be safe products in the concentrations and exposure conditions tested.

scholarly journals Overproduction of reactive oxygen species – obligatory or not for induction of apoptosis by anticancer drugs

2016 ◽  
Vol 28 (4) ◽  
pp. 383-396 ◽  
Author(s):  
Donika Ivanova ◽  
◽  
Zhivko Zhelev ◽  
Ichio Aoki ◽  
Rumiana Bakalova ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Drugs ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Induction Of Apoptosis

AML1/ETO Confers a Mutator Phenotype In Acute Myeloid Leukemia Associated with Downregulation of the Base-Excision-Repair Gene OGG1,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3441-3441
Author(s):  
Victoria J Forster ◽  
Andrea Beyerle ◽  
Olaf Heidenreich ◽  
James M Allan
Keyword(s):  
Base Excision Repair ◽  
Myeloid Leukemia ◽  
Excision Repair ◽  
Oxygen Species ◽  
Leukemic Transformation ◽  
Repair Gene ◽  
Mutator Phenotype ◽  
Hematopoietic Precursor ◽  
Base Excision ◽  
Tk6 Cells

Abstract Abstract 3441 The translocation t(8;21)(q22;q22) is the most common cytogenetic abnormality in acute myeloid leukemia (AML), detected in around 15% of all cases. The translocation fuses the DNA binding domain of AML1 (RUNX1) to the almost full-length ETO (RUNX1T1, MTG8) protein converting a transcriptional modulator essential for hematopoiesis into a constitutive repressor. Expression of AML1/ETO in animal models is not sufficient for leukemogenesis, and further mutations are required. AML1/ETO has been detected in the Guthrie cards of pediatric patients who subsequently developed t(8;21) AML, suggesting that AML1/ETO+ hematopoietic precursor cells remain latent for many years before leukemic transformation. The mechanisms by which additional mutations are acquired are not well characterised. AML1/ETO affects DNA repair gene expression and is associated with lower levels of 8-oxoguanine DNA glycosylase (OGG1) in patient samples and transduced primary CD34+ cells. OGG1 removes oxidatively damaged guanine bases from the DNA strand as an initial step of the base-excision repair pathway. Taken together, these observations suggest the existence of a pre-leukemic, AML1/ETO-expressing hematopoietic precursor which is susceptible to the acquisition of further DNA mutations by virtue of compromised DNA repair function. In order to test this hypothesis we investigated the effect of AML1/ETO expression on susceptibility to spontaneous and exposure driven mutation in TK6 cells. TK6 lymphoblastoid cells have one functional copy of the thymidine kinase (TK) gene, allowing for quantification of mutant cells by functionally screening for the TK−/− phenotype. TK6 cells were lentivirally transduced with the pHR-SINcPPT-SIEW vector containing AML1/ETO; and EGFP as an expression marker. Expression was confirmed by flow cytometry, western blotting and qRT-PCR. Serial dilution assays were performed to generate AML1/ETO+ TK6 clonal populations with AML1/ETO expression varying from 10–150% of that found in Kasumi-1; a t(8;21)+ patient-derived cell line. We also used the PIGA gene as a second mutational target. Loss of this glycosyl-phosphatidylinositol (GPI) anchor results in an absence of GPI-linked proteins from the cell membrane, including CD55 and CD59. Cells that are simultaneously negative for two or more GPI-linked proteins are considered to be PIGA mutants and are detected using fluorochrome-conjugated antibodies. Preliminary mutation results on AML1/ETO+ TK6 clones revealed that the fusion gene conferred an approximate 2 fold higher background TK−/− mutation frequency (MF) (2.1 × 10−6−2.6 × 10−6) compared to controls (0.9 × 10−61.1 × 10−6), and a 2–4 fold higher PIGA MF (Controls: 0.32 × 10−4−1.4 × 10−4 and AML1/ETO+ Clones: 2.7 × 10−4– 5.7 × 10−4), suggesting that AML1/ETO confers a moderate mutator phenotype even without exposure to genotoxic agents. Furthermore, spontaneous MF was proportional to AML1/ETO expression, with higher-expressing clones displaying a higher MF than lower expressers and control cells. When treated with low-dose doxorubicin (a chemotherapeutic anthracyline that induces strand breaks in DNA but can also generate reactive oxygen species (ROS)), AML1/ETO+ TK6 clones had a substantially higher TK−/− MF (0.5 × 10−5– 1.2 × 10−5) in comparison to controls; wild-type TK6 and backbone vector-alone transduced TK6 (1.8x 10−6−3.2 × 10−6) (p<0.001). Quantitative PCR revealed a significant 2-fold reduction in OGG1 levels in TK6 lentivirally transduced with AML1/ETO (p<0.05). Furthermore, siRNA mediated knockdown of AML1/ETO in the t(8;21)+ cell lines Kasumi-1 and SKNO-1 resulted in a substantial increase of OGG1, providing strong evidence that AML1/ETO directly regulates OGG1 expression. Consistent with downregulation of OGG1 and susceptibility to ROS-induced mutation, AML1/ETO+ clones had a 2–4 fold higher PIGA MF (0.6 × 10−3−1.3 × 10−3) compared to controls (1.6 × 10−4−3.3 × 10−4) when treated with hydrogen peroxide. We have shown that AML1/ETO confers a mutator phenotype on cells that is associated with downregulation of OGG1, providing a plausible explanation for the particular susceptibility of AML1/ETO+ cells to mutation induction by agents that generate reactive oxygen species. This work suggests a mechanism by which AML1/ETO translocated pre-leukemic hematopoetic cells acquire additional mutations, ultimately leading to leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mutation at position 5628 in the mitochondrial tRNAAla gene in a Chinese pedigree with maternally diabetes mellitus

2019 ◽  
Author(s):  
Ke Li ◽  
Lijun Wu ◽  
Wei Lin ◽  
Tianlan Zhao ◽  
Qiang Qi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Reactive Oxygen Species ◽  
Protein Synthesis ◽  
Cell Lines ◽  
Reactive Oxygen ◽  
Molecular Characteristics ◽  
Ros Generation ◽  
Oxygen Species ◽  
Cellular Models ◽  
Mitochondrial Diabetes

Abstract Background: To investigate the clinical, genetic and molecular characteristics of mitochondrial diabetes mellitus (MDM). Methods: Resultant variants were evaluated for evolutionary conservation, allelic frequencies, and structural and functional consequences. The mitochondrial function including mitochondrial tRNAAla levels, protein synthesis, membrane potential, adenosine triphosphate (ATP) production, and reactive oxygen species (ROS) generation were measured using lymphoblastoid cell lines carrying the m.5628T>C mutation and 2 controls .Results: We observed differences in the severity and age of onset in diabetes in affected maternally-related individuals, and through amolecular of the complete mitochondrial genome in this family, we identified a homoplasmic m.5628T>C mutation, located at conventional position 31 of tRNAAla, and we further detected distinct sets of mtDNA polymorphisms belonging to haplogroup L1. The identified mutation was further found be important for tRNA identity and stability. Using cellular models, we were able to determine that the respiratory deficiency caused arising as a consequence of the m.5628T>C mutation led to decreased efficiency of mitochondrial tRNAAla levels, protein synthesis, mitochondrial ATP synthesis and a reduced mitochondrial membrane potential.These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cell lines. Conclusions: These data provide a direct evidence that novel m.5628T>C mutation may be associated with MDM, thus, offering novel insights into the understanding of pathophysiology of MDM.

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