A5035230812- Redox biology and oxidative stress
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Epigenetics and DNA Methylation
- Pulmonary Hypertension Research and Treatments
- Insect and Pesticide Research
- Fungal and yeast genetics research
- Free Radicals and Antioxidants
- Bioinformatics and Genomic Networks
- Antioxidant Activity and Oxidative Stress
- Gene Regulatory Network Analysis
- Computational Drug Discovery Methods
- Genomics, phytochemicals, and oxidative stress
- Inflammatory mediators and NSAID effects
- Cancer-related gene regulation
- Cancer-related molecular mechanisms research
- Click Chemistry and Applications
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Synthesis and Biological Evaluation
- Genetic Syndromes and Imprinting
- Chemical Synthesis and Analysis
- Sulfur Compounds in Biology
- Glutathione Transferases and Polymorphisms
- Peptidase Inhibition and Analysis
- RNA modifications and cancer
Vanderbilt University Medical Center
2018-2025
College of Wooster
2012-2024
Vanderbilt University
2004-2022
University Medical Center
2018
University Hospital and Clinics
2018
University College London
2012-2013
Genomics (United Kingdom)
2012-2013
Cancer Institute (WIA)
2013
London Cancer
2013
Northwestern University
2008
A constellation of reactive intermediates -electrophiles and free radicals -capable damaging cellular constituents is generated during normal physiological or pathophysiological processes.The consequences this damage include enhanced mutation rates, altered cell signaling, events summarized in other articles Perspective series.In many cases, the initially convert into second-generation capable inducing further damage.Cells have adapted to existence by evolution defense mechanisms that either...
Stress response pathways allow cells to sense and respond environmental changes adverse pathophysiological states. Pharmacological modulation of cellular stress has implications in the treatment human diseases, including neurodegenerative disorders, cardiovascular disease, cancer. The quinone methide triterpene celastrol, derived from a traditional Chinese medicinal herb, numerous pharmacological properties, it is potent activator mammalian heat shock transcription factor HSF1. However, its...
The cellular phenotype is described by a complex network of molecular interactions. Elucidating properties that distinguish disease from the healthy state therefore critical importance for gaining systems-level insights into mechanisms and ultimately developing improved therapies. By integrating gene expression data with protein interaction we here demonstrate cancer cells are characterised an increase in entropy. In addition, formally differences between normal tissue anticorrelated local...
Background Endometrial cancer incidence is continuing to rise in the wake of current ageing and obesity epidemics. Much risk for endometrial development influenced by environment lifestyle. Accumulating evidence suggests that epigenome serves as interface between genome hypermethylation stem cell polycomb group target genes an epigenetic hallmark cancer. The objective this study was determine functional role factors development. Methods Findings Epigenome-wide methylation analysis >27,000...
Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) represents a distinct clinical epidemiological condition compared with HPV-negative (HPV-) HNSCC. To test the possible involvement of epigenetic modulation by HPV in HNSCC, we conducted genome-wide DNA-methylation analysis.Using laser-capture microdissection 42 formalin-fixed paraffin wax-embedded (FFPE) HNSCCs, generated profiles 18 HPV+ 14 HPV- samples, using Infinium 450 k BeadArray technology. Methylation...
Reactive intermediates produced during oxidative stress are believed to contribute the development and progression of a variety age-related diseases. 4-hydroxy-2-nonenal (HNE), an abundant product polyunsaturated fatty acid oxidation decomposition, reacts extensively with DNA proteins, depletes intracellular glutathione, alters many cell signaling cascades, including those regulating apoptosis. Using microarray technology, global changes in gene expression were monitored temporally at...
Epigenetic changes have been associated with ageing and cancer. Identifying interpreting epigenetic such phenotypes may benefit from integration protein interactome models. We here develop validate a novel integrative epigenome-interactome approach to identify differential methylation hotspots phenotype of interest. apply the algorithm cancer ageing, demonstrating existence these phenotypes. Importantly, we discover tissue independent age-associated targeting stem-cell differentiation...
Pulmonary vascular remodeling and oxidative stress are common to many adult lung diseases. However, little is known about the relevance of mesenchymal stem cells (MSCs) in these processes. We tested hypothesis that dysfunctional MSCs directly participate microcirculation. employed a genetic model deplete extracellular superoxide dismutase (EC‐SOD) coupled with lineage tracing analysis. crossed floxp sod3 mT/mG reporter mice strain expressing Cre recombinase under control ABCG2 promoter....
The heat shock transcription factor HSF1 governs the response to shock, oxidative stresses, and xenobiotics through unknown mechanisms. We demonstrate that diverse thiol-reactive molecules potently activate budding yeast Hsf1. Hsf1 activation by compounds is not consistent with stresses of misfolding cytoplasmic proteins or cytotoxicity. Instead, we Hsp70 chaperone Ssa1, which represses in absence stress, hypersensitive modification a probe. Strikingly, mutation two conserved cysteine...
Recently, it has been demonstrated that DNA methylation, a covalent modification of can regulate gene expression, is modified as function age. However, the biological and clinical significance this age-associated epigenetic drift unclear. To shed light on potential significance, we here adopt systems approach study genes undergoing changes in methylation context protein interaction network, focusing their topological properties. In contrast to what observed for other age-related classes,...
The oxidation of polyunsaturated fatty acids during oxidative stress gives rise to a series toxic α,β-unsaturated aldehydes, including the electrophile 4-hydroxy-2-nonenal (4-HNE) and related 4-hydroperoxy-2-nonenal (4-HPNE) 4-oxo-2-nonenal (4-ONE). We synthesized these compounds, as well resolved enantiomers 4-HNE, compared their toxicities apoptotic responses in human colorectal cancer cell line RKO. All molecules execute similar death at comparable doses over almost identical time frames...
Caveolin-1 (CAV1) is an essential component of caveolae and implicated in numerous physiological processes. Recent studies have identified heterozygous mutations the CAV1 gene patients with pulmonary arterial hypertension (PAH), but mechanisms by which these impact assembly contribute to disease remain unclear. To address this question, we examined consequences a familial PAH-associated frameshift mutation CAV1, P158PfsX22, on function. We show that C-terminus P158 protein contains...
Previously, we determined that diethyl acetylenedicarboxylate (DAD), a protein cross-linker, was significantly more toxic than analogous monofunctional electrophiles. We hypothesized other cross-linkers enhance toxicity similarly. In agreement with this hypothesis, the bifunctional electrophile divinyl sulfone (DVSF) 6-fold ethyl vinyl (EVSF) in colorectal carcinoma cells and greater 10-fold Saccharomyces cerevisiae. DVSF DAD caused oligomerization of yeast thioredoxin 2 (Trx2p) vitro...
Epigenetic processes - including DNA methylation are increasingly seen as having a fundamental role in chronic diseases like cancer. It is well known that levels at particular genes or loci differ between normal and diseased tissue. Here we investigate whether the intra-gene architecture corrupted cancer variability of individual CpGs within defined gene able to discriminate cancerous from tissue, associated with heterogeneous tumour phenotype, by expression. We analysed 270985 annotated...
The yeast peroxiredoxin Ahp1, like related anti-oxidant enzymes in other species, undergoes urmylation, a lysine-directed conjugation to ubiquitin-like modifier Urm1. Ahp1 assembles into homodimer that detoxifies peroxides via forming intersubunit disulfides between peroxidatic and resolving cysteines are subsequently reduced by the thioredoxin system. Although urmylation coincides with oxidative stress, it is unclear how this modification happens on molecular level whether affects activity....
Poly(ADP-ribose) polymerase-1 (PARP-1) influences numerous cellular processes, including DNA repair, transcriptional regulation, and caspase-independent cell death, by utilizing NAD+ to synthesize long chains of poly(ADP-ribose) (PAR) on target proteins, itself. During the apoptotic response, caspases-3 -7 cleave PARP-1, thereby inhibiting its activity. Here, we have examined role PARP-1 activation cleavage in latter stages apoptosis response fragmentation. poly(ADP-ribosyl)ation correlated...