A5085858115- Protein Tyrosine Phosphatases
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- Bioactive Compounds and Antitumor Agents
- Trace Elements in Health
- Microtubule and mitosis dynamics
- Protein Kinase Regulation and GTPase Signaling
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- 14-3-3 protein interactions
- Biochemical and Molecular Research
- RNA modifications and cancer
- DNA Repair Mechanisms
- Galectins and Cancer Biology
- Enzyme function and inhibition
- ATP Synthase and ATPases Research
- Synthesis and biological activity
- Cancer Treatment and Pharmacology
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Microbial Natural Products and Biosynthesis
- Click Chemistry and Applications
- MicroRNA in disease regulation
- Cancer Mechanisms and Therapy
- Marine Sponges and Natural Products
University of Virginia
2016-2025
University of Pittsburgh
2008-2023
Discovery Institute
2005-2023
UPMC Hillman Cancer Center
1998-2023
Charlottesville Medical Research
2016-2019
Weatherford College
1994-2014
University of South Carolina
2012
Wayne State University
2012
Carnegie Mellon University
2012
University at Albany, State University of New York
2012
Resistance to antineoplastic agents is the major obstacle curative therapy of cancer. Tumor cell lines with acquired resistance agent cis -diamminedichloroplatinum(II) overexpressed metallothionein and demonstrated cross-resistance alkylating such as chlorambucil melphalan. Human carcinoma cells that maintained high levels because chronic exposure heavy metals were resistant -diamminedichloroplatinum(II), melphalan, chlorambucil. Furthermore, transfected bovine papilloma virus expression...
Abstract microRNAs (miRNA) are small noncoding RNAs that participate in diverse biological processes by suppressing target gene expression. Altered expression of miR-21 has been reported cancer. To gain insights into its potential role tumorigenesis, we generated knockout colon cancer cells through targeting. Unbiased microarray analysis combined with bioinformatics identified cell cycle regulator Cdc25A as a target. suppressed defined sequence 3′-untranslated region. We found is induced...
Acute lung injury (ALI) leading to acute respiratory distress syndrome is the major cause of COVID-19 lethality. Cell entry SARS-CoV-2 occurs via interaction between its surface spike protein (SP) and angiotensin-converting enzyme-2 (ACE2). It unknown if viral alone capable altering vascular permeability in lungs or producing vivo. To that end, we intratracheally instilled S1 subunit (S1SP) K18-hACE2 transgenic mice overexpress human ACE2 examined signs COVID-19-associated 72 h later....
Embryonic cells from transgenic mice with targeted disruption of metallothionein I and II genes expressed no detectable either constitutively or after treatment cadmium, in contrast to cultured that were wild type heterozygous for the loss genes. Metallothionein null most sensitive cytotoxic effects membrane permeant oxidant tert-butylhydroperoxide, redox cycling toxin paraquat. No marked differences seen among type, heterozygous, glutathione levels activity CuZn-superoxide dismutase,...
Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined of synthetic LXR ligand T0901317, can be used vivo, on Abeta production vitro and APP23 transgenic mice. T0901317 applied a variety models, including immortalized fibroblasts from...
The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of peripheral cholesterol efflux and plasma high density lipoprotein metabolism. In adult rat brain we found expression ABCA1 in neurons the hypothalamus, thalamus, amygdala, cholinergic basal forebrain, hippocampus. Large nucleus basalis together with CA1 CA3 pyramidal were among most abundantly immunolabeled neurons. Glia cells largely negative. Because homeostasis may have an essential role central nervous system...
Female C57Bl/6 mice treated by constant s.c. infusion for 1 week with 100 mg of bleomycin per kg body weight develop a more pronounced pulmonary fibrosis than BALB/c mice. Within 4 weeks after treatment, the content mRNAs encoding fibronectin, alpha 2I procollagen and 1III was increased. The increases were greater occurred earlier in compared to Fibronectin mRNA increased 12-fold only 3-fold mice, whereas 4-fold 2-fold (2-fold). sequential mice: fibronectin elevated first, followed...
Abstract Compounds that selectively prevent or disrupt the association between c-Myc oncoprotein and its obligate heterodimeric partner Max (Myc-Max compounds) have been identified previously by high-throughput screening of chemical libraries. Although these agents specifically inhibit growth c-Myc–expressing cells, their clinical applicability is limited low potency. We describe here several modifications one original compounds, 10058-F4, which result in significant improvements efficacy....
The development of preclinical models amenable to live animal bioactive compound screening is an attractive approach discovering effective pharmacological therapies for disorders caused by misfolded and aggregation-prone proteins. In general, however, drug labor resource intensive, has been hampered the lack robust assay designs high throughput work-flows. Based on their small size, tissue transparency ease cultivation, use C. elegans should obviate many technical impediments associated with...
Abstract Presently, the zebrafish is only vertebrate model compatible with contemporary paradigms of drug discovery. Zebrafish embryos are amenable to automation necessary for high‐throughput chemical screens, and optical transparency makes them potentially suited image‐based screening. However, lack tools automated analysis complex images presents an obstacle using as a screening model. We have developed system imaging analyzing in multi‐well plates regardless embryo orientation without...
The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set then computationally selected from their 140 000 repository 30 quinolinediones of which 8 had vitro mean inhibitory concentrations <1 μM. most was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), 20- 450-fold more...
Metallothioneins (MTs) are major intracellular, zinc-binding proteins with antioxidant properties. Mouse embryonic cells null for MT due to loss of functional I and II genes (MT−/−) were more susceptible apoptotic death after exposure <i>tert</i>-butyl hydroperoxide or the anti-cancer agents cytosine arabinoside, bleomycin, melphalan, and<i>cis</i>-dichlorodiammineplatinum(II) compared wild-type mouse (MT+/+). We measured basal levels tumor suppressor protein p53 effector Bax found both...
Small molecules provide powerful tools to interrogate biological pathways but many important pathway participants remain refractory inhibitors. For example, Cdc25 dual-specificity phosphatases regulate mammalian cell cycle progression and are implicated in oncogenesis, potent selective inhibitors lacking for this enzyme class. Thus, we evaluated 10,070 compounds a publicly available chemical repository of the National Cancer Institute vitro inhibitory activity against oncogenic, full-length,...
Metallothioneins (MT) are ubiquitous low molecular weight metal-binding proteins that may act as antioxidants.We examined the sensitivity of NIH 3T3 cells transfected with a plasmid containing mouse metallothionein-I gene (NIH3T3/MT) to membrane permeant oxidant, tert-butyl hydroperoxide (tBH).NIH3T3/MT had 4-fold increase in intracellular metallothionein compared an inverted (NIH3T3/TM).Newly expressed appeared be localized cytoplasm determined by immunofluorescence and confocal...
Bleomycin (BLM) produces pulmonary fibrosis in mice when given as a single intratracheal injection, i.v. injection or multiple s.c. injections. All of these models are associated with significant disadvantages including variable distribution lesions, high mortality requirement for procedures. We have developed convenient method BLM treatment that avoids difficulties and yields extensive, reproducible mice. Osmotic minipumps containing (100 mg/kg) were implanted C57Bl/6 the drug was delivered...