BACKGROUND: The frequency of allergic diseases is constantly rising. Dysregulated production of isotype E immunoglobulins is one of the key factors behind allergic reactions and its modulation is therefore an important target for pharmacological intervention. Natural products of the pseurotin family were reported to be inhibitors of IgE production in B-cells. Mechanistic details underlying these effects are however not well understood. PURPOSE: In the present study, we synthesized new analogs of natural pseurotins and extensively investigated their inhibitory effects on activation, proliferation and differentiation of B-cells, as well as on the production of IgE. STUDY DESIGN: Effects of two natural pseurotins (pseurotins A and D) and a collection of fully synthetic pseurotin analogs were studied on mouse B-cells stimulated by the combination of IL-4 and E. coli lipopolysaccharide. The IgE production was determined along with cell viability and cell proliferation. The phosphorylation of selected members of the STAT transcription factor family was subsequently investigated. Finally, the in vivo effect of pseurotin D on the ovalbumin-induced delayed type hypersensitivity response was tested in mice. RESULTS: We discovered that several fully synthetic pseurotin analogs were able to decrease the production of IgE in stimulated B-cells with potency comparable to that of pseurotins A and D. We found that the two natural pseurotins and the active synthetic analogs inhibited the phosphorylation of STAT3, STAT5 and STAT6 proteins in stimulated B-cells, resulting in the inhibition of B-cell proliferation and differentiation into the plasma cells. In vivo, pseurotin D decreased ovalbumin-induced foot pad edema. CONCLUSION: Our results advance the current mechanistic understanding of the pseurotin-induced inhibition of IgE production in B-cells by linking the effect to STAT signaling, and associated modulation of B-cell proliferation and differentiation. Together with our finding that structurally simpler pseurotin analogs were able to reproduce the effects of natural pseurotins, the presented work has implications for the future research on these secondary metabolites in the context of allergic diseases.
- MeSH
- aktivace lymfocytů účinky léků MeSH
- B-lymfocyty cytologie účinky léků fyziologie MeSH
- buněčná diferenciace účinky léků MeSH
- edém chemicky indukované farmakoterapie MeSH
- Escherichia coli chemie MeSH
- fosforylace účinky léků MeSH
- imunoglobulin E krev metabolismus MeSH
- imunoglobulin M krev metabolismus MeSH
- lipopolysacharidy farmakologie MeSH
- myši inbrední C57BL MeSH
- ovalbumin toxicita MeSH
- plazmatické buňky cytologie fyziologie MeSH
- pyrrolidinony chemie farmakologie MeSH
- transkripční faktory STAT metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
There is an arising and concerning issue in the field of bacterial resistance, which is confirmed by the number of deaths associated with drug-resistant bacterial infections. The aim of this study was to compare the effects of antibiotics on Staphylococcus aureus non-resistant strain and strains resistant to cadmium or lead ions. Metal resistant strains were created by the gradual addition of 2 mM solution of metal ions (cadmium or lead) to the S. aureus culture. An increasing antimicrobial effect of ampicillin, streptomycin, penicillin and tetracycline (0, 10, 25, 50, 75, 150, 225 and 300 µM) on the resistant strains was observed using a method of growth curves. A significant growth inhibition (compared to control) of cadmium resistant cells was observed in the presence of all the four different antibiotics. On the other hand, the addition of streptomycin and ampicillin did not inhibit the growth of lead resistant strain. Other antibiotics were still toxic to the bacterial cells. Significant differences in the morphology of cell walls were indicated by changes in the cell shape. Our data show that the presence of metal ions in the urban environment may contribute to the development of bacterial strain resistance to other substances including antibiotics, which would have an impact on public health.
In this review is presented general mechanism of bacterial resistence against metals. Bacteria was adapting to outer conditions during the evolotion. Ability of resistence is carried by genetic informations in DNA which may be located in different parts of cell. According to character of resistence there are different localization of genetic information where metal resistance is coded. It dependes on the fact if the metal is essential or non-essential (plasmid, chromosome, transposome). There are six postulated mechanisms of metal resistence in microorganisms, metal exclusion by permeability barrier, active transport of metal away from the cell, intracellular sequeatration of the metal by protein biding, extracellular sequestration, enzymatic detoxification to less toxic form, reduction in metal sensitivity of cellular targets.
- Klíčová slova
- toxicita kovů, kovová rezistence,
- MeSH
- bakteriální léková rezistence * fyziologie genetika MeSH
- biochemické jevy účinky léků MeSH
- buňky účinky léků MeSH
- těžké kovy * farmakokinetika toxicita MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
