Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Int J Med Microbiol ; 305(1): 96-109, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25500547

ABSTRACT

Isoquinolines (IQs) are natural substances with an antibiotic potential we aim to optimize. Specifically, IQ-238 is a synthetic analog of the novel-type N,C-coupled naphthylisoquinoline (NIQ) alkaloid ancisheynine. Recently, we developed and tested other IQs such as IQ-143. By utilizing genome-wide gene expression data, metabolic network modelling and Voronoi tessalation based data analysis - as well as cytotoxicity measurements, chemical properties calculations and principal component analysis of the NIQs - we show that IQ-238 has strong antibiotic potential for staphylococci and low cytotoxicity against murine or human cells. Compared to IQ-143, systemic effects are less pronounced. Most enzyme activity changes due to IQ-238 are located in the carbohydrate metabolism. Validation includes metabolite measurements on biological replicates. IQ-238 delineates key properties and a chemical space for a good therapeutic window. The combination of analysis methods allows suggestions for further lead development and yields an in-depth look at staphylococcal adaptation and network changes after antibiosis. Results are compared to eukaryotic host cells.


Subject(s)
Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Isoquinolines/pharmacology , Isoquinolines/toxicity , Staphylococcus aureus/drug effects , Staphylococcus epidermidis/drug effects , Animals , Cell Line , Computational Biology , Gene Expression Profiling , Humans , Metabolic Networks and Pathways , Mice
2.
Eur J Immunol ; 44(5): 1285-98, 2014 May.
Article in English | MEDLINE | ID: mdl-24470136

ABSTRACT

Suppressory B-cell function controls immune responses and is mainly dependent on IL-10 secretion. Pharmacological manipulation of B-cell-specific IL-10 synthesis could, thus, be therapeutically useful in B-cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL-10-secreting B cells. The aim of the study was to identify the molecular events selectively driving IL-10 production in TLR9-stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9-induced B-cell-derived IL-10 transcription and secretion, while IL-6 transcription and release, B-cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9-induced IL-10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9-induced IL-6, IL-10 secretion was highly sensitive to targeting of spleen tyrosine kinase (syk) and Bruton's tyrosine kinase. Further analyses demonstrated increased phosphorylation of Ca(2+) /calmodulin kinase II (CaMKII) in TLR9-stimulated B cells and selective reduction of TLR9-induced secretion of IL-10 upon treatment with CaMKII inhibitors, with negligible impact on IL-6 levels. Altogether, our results identify calcineurin antagonists as selective inhibitors of IL-10 transcription and syk/Bruton´s tyrosine kinase-induced Ca(2+) /calmodulin- and CaMKII-dependent signaling as a pathway regulating the release of TLR9-induced B-cell-derived IL-10.


Subject(s)
B-Lymphocyte Subsets/immunology , Calcium Signaling/physiology , Interleukin-10/immunology , Toll-Like Receptor 9/immunology , Transcription, Genetic/physiology , Agammaglobulinaemia Tyrosine Kinase , B-Lymphocyte Subsets/cytology , Calcineurin/immunology , Calcineurin/metabolism , Calcineurin Inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Calcium-Calmodulin-Dependent Protein Kinase Type 2/immunology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Cell Proliferation , Enzyme Inhibitors/pharmacology , Female , Gene Expression Regulation/physiology , Humans , Interleukin-10/metabolism , Interleukin-6/biosynthesis , Interleukin-6/immunology , Intracellular Signaling Peptides and Proteins/immunology , Intracellular Signaling Peptides and Proteins/metabolism , Male , NFATC Transcription Factors/immunology , NFATC Transcription Factors/metabolism , Protein-Tyrosine Kinases/immunology , Protein-Tyrosine Kinases/metabolism , Syk Kinase
SELECTION OF CITATIONS
SEARCH DETAIL
...