Comprehensive Assessment of Oxidatively Induced Modifications of DNA in a Rat Model of Human Wilson's Disease.

Mol Cell Proteomics

From the ‡Environmental Toxicology Graduate Program and §Department of Chemistry, University of California, Riverside, California 92521;

Published: March 2016

Defective copper excretion from hepatocytes in Wilson's disease causes accumulation of copper ions with increased generation of reactive oxygen species via the Fenton-type reaction. Here we developed a nanoflow liquid chromatography-nanoelectrospray ionization-tandem mass spectrometry coupled with the isotope-dilution method for the simultaneous quantification of oxidatively induced DNA modifications. This method enabled measurement, in microgram quantities of DNA, of four oxidative stress-induced lesions, including direct ROS-induced purine cyclonucleosides (cPus) and two exocyclic adducts induced by byproducts of lipid peroxidation, i.e. 1,N(6)-etheno-2'-deoxyadenosine (εdA) and 1,N(2)-etheno-2'-deoxyguanosine (εdG). Analysis of liver tissues of Long-Evans Cinnamon rats, which constitute an animal model of human Wilson's disease, and their healthy counterparts [i.e. Long-Evans Agouti rats] showed significantly higher levels of all four DNA lesions in Long-Evans Cinnamon than Long-Evans Agouti rats. Moreover, cPus were present at much higher levels than εdA and εdG lesions. In contrast, the level of 5-hydroxymethyl-2'-deoxycytidine (5-HmdC), an oxidation product of 5-methyl-2'-deoxycytidine (5-mdC), was markedly lower in the liver tissues of Long-Evans Cinnamon than Long-Evans Agouti rats, though no differences were observed for the levels of 5-mdC. In vitro biochemical assay showed that Cu(2+) ions could directly inhibit the activity of Tet enzymes. Together, these results suggest that aberrant copper accumulation may perturb genomic stability by elevating oxidatively induced DNA lesions, and by altering epigenetic pathways of gene regulation.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813702PMC
http://dx.doi.org/10.1074/mcp.M115.052696DOI Listing

Publication Analysis

Top Keywords

oxidatively induced
12
wilson's disease
12
long-evans cinnamon
12
long-evans agouti
12
model human
8
human wilson's
8
induced dna
8
liver tissues
8
tissues long-evans
8
higher levels
8

Similar Publications

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by the pro-gressive loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms. Current treatments primarily offer symptomatic relief without halt-ing disease progression. This has driven the exploration of natural compounds with neuropro-tective properties.

View Article and Find Full Text PDF

Background: Postmenopausal women (PMW) who complete menopause at a late age (55+ years) have lower cardiovascular disease risk than PMW who complete menopause at a normal age (45-54 years). However, the influence of late-onset menopause on vascular endothelial dysfunction is unknown. Moreover, the mechanisms by which a later age at menopause may modulate endothelial function remain to be determined.

View Article and Find Full Text PDF

The synthesis of high-performance catalysts for volatile organic compounds (VOCs) degradation under humid conditions is essential for their practical industrial application. Herein, a codoping strategy was adopted to synthesize the N-CoO-C catalyst with N, C codoping for low-temperature ethyl acetate (EA) degradation under humid conditions. Results showed that N-CoO-C exhibited great catalytic activity ( = 177 °C) and water resistance (5.

View Article and Find Full Text PDF

L. fruits and leaf extracts have a broad range of immunomodulatory, anti-inflammatory, and antioxidant effects; however, their effects on cardiac protection have not been investigated. The study aims to test the biological activity of L.

View Article and Find Full Text PDF

The self-assembled ferritin protein nanocage plays a pivotal role during oxidative stress, iron metabolism, and host-pathogen interaction by executing rapid iron uptake, oxidation and its safe-storage. Self-assembly creates a nanocompartment and various pores/channels for the uptake of charged substrates (Fe) and develops a concentration gradient across the protein shell. This phenomenon fuels rapid ferroxidase activity by an upsurge in the substrate concentration at the catalytic sites.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!