TY  - JOUR
A1  - Blättner, Sebastian
A1  - Das, Sudip
A1  - Paprotka, Kerstin
A1  - Eilers, Ursula
A1  - Krischke, Markus
A1  - Kretschmer, Dorothee
A1  - Remmele, Christian W.
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Schuelein-Voelk, Christina
A1  - Hertlein, Tobias
A1  - Mueller, Martin J.
A1  - Huettel, Bruno
A1  - Reinhardt, Richard
A1  - Ohlsen, Knut
A1  - Rudel, Thomas
A1  - Fraunholz, Martin J.
T1  - Staphylococcus aureus Exploits a Non-ribosomal Cyclic Dipeptide to Modulate Survival within Epithelial Cells and Phagocytes
JF  - PLoS Pathogens
N2  - Community-acquired (CA) Staphylococcus aureus cause various diseases even in healthy individuals. Enhanced virulence of CA-strains is partly attributed to increased production of toxins such as phenol-soluble modulins (PSM). The pathogen is internalized efficiently by mammalian host cells and intracellular S. aureus has recently been shown to contribute to disease. Upon internalization, cytotoxic S. aureus strains can disrupt phagosomal membranes and kill host cells in a PSM-dependent manner. However, PSM are not sufficient for these processes. Here we screened for factors required for intracellular S. aureus virulence. We infected escape reporter host cells with strains from an established transposon mutant library and detected phagosomal escape rates using automated microscopy. We thereby, among other factors, identified a non-ribosomal peptide synthetase (NRPS) to be required for efficient phagosomal escape and intracellular survival of S. aureus as well as induction of host cell death. By genetic complementation as well as supplementation with the synthetic NRPS product, the cyclic dipeptide phevalin, wild-type phenotypes were restored. We further demonstrate that the NRPS is contributing to virulence in a mouse pneumonia model. Together, our data illustrate a hitherto unrecognized function of the S. aureus NRPS and its dipeptide product during S. aureus infection.
KW  - cell death
KW  - cytotoxicity
KW  - Staphylococcus aureus
KW  - host cells
KW  - neutrophils
KW  - macrophages
KW  - transposable elements
KW  - epithelial cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180380
VL  - 12
IS  - 9
ER  - 
TY  - JOUR
A1  - Otto, Christoph
A1  - Hahlbrock, Theresa
A1  - Eich, Kilian
A1  - Karaaslan, Ferdi
A1  - Jürgens, Constantin
A1  - Germer, Christoph-Thomas
A1  - Wiegering, Armin
A1  - Kämmerer, Ulrike
T1  - Antiproliferative and antimetabolic effects behind the anticancer property of fermented wheat germ extract
JF  - BMC Complementary and Alternative Medicine
N2  - Background
Fermented wheat germ extract (FWGE) sold under the trade name Avemar exhibits anticancer activity in vitro and in vivo. Its mechanisms of action are divided into antiproliferative and antimetabolic effects. Its influcence on cancer cell metabolism needs further investigation. One objective of this study, therefore, was to further elucidate the antimetabolic action of FWGE. The anticancer compound 2,6-dimethoxy-1,4-benzoquinone (DMBQ) is the major bioactive compound in FWGE and is probably responsible for its anticancer activity. The second objective of this study was to compare the antiproliferative properties in vitro of FWGE and the DMBQ compound.

Methods
The IC\(_{50}\) values of FWGE were determined for nine human cancer cell lines after 24 h of culture. The DMBQ compound was used at a concentration of 24 μmol/l, which is equal to the molar concentration of DMBQ in FWGE. Cell viability, cell cycle, cellular redox state, glucose consumption, lactic acid production, cellular ATP levels, and the NADH/NAD\(^+\) ratio were measured.

Results
The mean IC\(_{50}\) value of FWGE for the nine human cancer cell lines tested was 10 mg/ml. Both FWGE (10 mg/ml) and the DMBQ compound (24 μmol/l) induced massive cell damage within 24 h after starting treatment, with changes in the cellular redox state secondary to formation of intracellular reactive oxygen species. Unlike the DMBQ compound, which was only cytotoxic, FWGE exhibited cytostatic and growth delay effects in addition to cytotoxicity. Both cytostatic and growth delay effects were linked to impaired glucose utilization which influenced the cell cycle, cellular ATP levels, and the NADH/NAD\(^+\) ratio. The growth delay effect in response to FWGE treatment led to induction of autophagy.

Conclusions
FWGE and the DMBQ compound both induced oxidative stress-promoted cytotoxicity. In addition, FWGE exhibited cytostatic and growth delay effects associated with impaired glucose utilization which led to autophagy, a possible previously unknown mechanism behind the influence of FWGE on cancer cell metabolism.
KW  - cytostatic
KW  - FWGE
KW  - benzoquinone
KW  - cancer cells
KW  - reactive oxygen species
KW  - autophagy
KW  - cytotoxicity
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146013
VL  - 16
IS  - 160
ER  -