Potent, selective and cell penetrant inhibitors of SF-1 by functional ultra-high-throughput screening.

The steroidogenic factor 1 (SF-1, also known as NR5A1) is a transcription factor belonging to the nuclear receptor superfamily. Whereas most of the members of this family have been extensively characterized, the therapeutic potential and pharmacology of SF-1 still remains elusive. Described here is the identification and characterization of selective inhibitory chemical probes of SF-1 by a rational ultra-high-throughput screening (uHTS) strategy.

EDGE: a centralized resource for the comparison, analysis, and distribution of toxicogenomic information.

Transcriptional profiling via microarrays holds great promise for toxicant classification and hazard prediction. Unfortunately, the use of different microarray platforms, protocols, and informatics often hinders the meaningful comparison of transcriptional profiling data across laboratories. One solution to this problem is to provide a low-cost and centralized resource that enables researchers to share toxicogenomic data that has been generated on a common platform.

Application of genomics to toxicology research.

Traditional models of toxicity have relied on dissecting chemical action into pharmacokinetic and pharmacodynamic processes. However, the integration of genomic information with toxicology will enhance our basic understanding of these processes and significantly change the way we apply toxicological information to risk assessment and regulatory problems. In this article, we summarize the application of gene expression information and polymorphism discovery to four areas in toxicology: toxicity testing, cross-species extrapolation, understanding mechanism of action, and susceptibility.

Identification of toxicologically predictive gene sets using cDNA microarrays.

We have developed an approach to classify toxicants based upon their influence on profiles of mRNA transcripts. Changes in liver gene expression were examined after exposure of mice to 24 model treatments that fall into five well-studied toxicological categories: peroxisome proliferators, aryl hydrocarbon receptor agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxia-inducing agents. Analysis of 1200 transcripts using both a correlation-based approach and a probabilistic approach resulted in a classification accuracy of between 50 and 70%.

Serum proteins of rats exposed to organic solvents examined by horizontal two-dimensional electrophoresis with an immobilized pH gradient in the first dimension.

Serum proteins of rats, exposed to methoxyethylacetate and a combination of methoxyethylacetate and isobutylacetate, were analyzed by horizontal high resolution two-dimensional gel electrophoresis with immobilized pH gradients in the first dimension. A total of 410 polypeptides were detected with either increasing or decreasing spot intensities after rat exposure to the organic solvents.

Cis-acting sequences from mouse rDNA promote plasmid DNA amplification and persistence in mouse cells: implication of HMG-I in their function.

Searching for amplification promoting sequences within the murine rDNA cistrons, we isolated two elements from the nontranscribed spacer region. These 370 bp and 423 bp long cis-acting elements, referred to as muNTS1 and muNTS2, are localized 4.1 kb and 4.

Distinct mouse DNA sequences enable establishment and persistence of plasmid DNA polymers in mouse cells.

Distinct elements isolated from mouse genomic DNA confer on plasmid DNA the ability to persist at high copy numbers in mouse L fibroblasts (1). Field inversion gel electrophoresis demonstrated that - in contrast to our previous assumption - the persisting plasmid DNA does not exist extrachromosomally but as clusters of tandem repeats integrated into genomic DNA. Digestion with restriction endonucleases that do not cut within the plasmid DNA results in fragments of 50-300 kb in length indicating reiteration of 10-50 plasmid DNA molecules.

Murine genomic DNA sequences replicating autonomously in mouse L cells.

Plasmids that replicate autonomously in mouse L cells were constructed by inserting random genomic DNA fragments from Ltk- cells into a plasmid containing the HSV-1 thymidine kinase gene with a truncated low-efficiency promoter. HAT resistance was used as a selective marker. The presence of free plasmids in the DNA of transformants was demonstrated by hybridization with a specific plasmid probe, by electron microscopic visualization of circular DNA, and by recovering these plasmids by E.

[Clinical aspects and therapy of sudden deafness. Data of a patient sample of the ear, nose, throat clinic of the Wiesbaden City Clinic 1974-1982].

1974 to 1982 202 hospitalized patients, aged 17 to 87 years, suffering from a sudden hearing loss at first were treated between 3 and 26 days (average period 13 days) with 400 mg naftidrofuryl in low molecular weight dextrans, physiologic saline solution, glucose or leavulose solutions daily. After leaving hospital the patients received 2 dragees at 100 mg naftidrofuryl thrice a day. Provided that treatment starts within four days after the occurrence the average hearing loss measured by pure-tone audiometry was 49.