TY  - JOUR
A1  - Liang, Chunguang
A1  - Rios-Miguel, Ana B.
A1  - Jarick, Marcel
A1  - Neurgaonkar, Priya
A1  - Girard, Myriam
A1  - François, Patrice
A1  - Schrenzel, Jacques
A1  - Ibrahim, Eslam S.
A1  - Ohlsen, Knut
A1  - Dandekar, Thomas
T1  - Staphylococcus aureus transcriptome data and metabolic modelling investigate the interplay of Ser/Thr kinase PknB, its phosphatase Stp, the glmR/yvcK regulon and the cdaA operon for metabolic adaptation
JF  - Microorganisms
N2  - Serine/threonine kinase PknB and its corresponding phosphatase Stp are important regulators of many cell functions in the pathogen S. aureus. Genome-scale gene expression data of S. aureus strain NewHG (sigB\(^+\)) elucidated their effect on physiological functions. Moreover, metabolic modelling from these data inferred metabolic adaptations. We compared wild-type to deletion strains lacking pknB, stp or both. Ser/Thr phosphorylation of target proteins by PknB switched amino acid catabolism off and gluconeogenesis on to provide the cell with sufficient components. We revealed a significant impact of PknB and Stp on peptidoglycan, nucleotide and aromatic amino acid synthesis, as well as catabolism involving aspartate transaminase. Moreover, pyrimidine synthesis was dramatically impaired by stp deletion but only slightly by functional loss of PknB. In double knockouts, higher activity concerned genes involved in peptidoglycan, purine and aromatic amino acid synthesis from glucose but lower activity of pyrimidine synthesis from glucose compared to the wild type. A second transcriptome dataset from S. aureus NCTC 8325 (sigB\(^−\)) validated the predictions. For this metabolic adaptation, PknB was found to interact with CdaA and the yvcK/glmR regulon. The involved GlmR structure and the GlmS riboswitch were modelled. Furthermore, PknB phosphorylation lowered the expression of many virulence factors, and the study shed light on S. aureus infection processes.
KW  - metabolism
KW  - flux balance analysis
KW  - phosphorylation
KW  - regulation
KW  - riboswitch
KW  - PknB
KW  - Stp
KW  - yvcK/glmR operon
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248459
SN  - 2076-2607
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Grebinyk, Anna
A1  - Prylutska, Svitlana
A1  - Grebinyk, Sergii
A1  - Prylutskyy, Yuriy
A1  - Ritter, Uwe
A1  - Matyshevska, Olga
A1  - Dandekar, Thomas
A1  - Frohme, Marcus
T1  - Complexation with C\(_{60}\) fullerene increases doxorubicin efficiency against leukemic cells in vitro
JF  - Nanoscale Research Letters
N2  - Conventional anticancer chemotherapy is limited because of severe side effects as well as a quickly evolving multidrug resistance of the tumor cells. To address this problem, we have explored a C\(_{60}\) fullerene-based nanosized system as a carrier for anticancer drugs for an optimized drug delivery to leukemic cells.Here, we studied the physicochemical properties and anticancer activity of C\(_{60}\) fullerene noncovalent complexes with the commonly used anticancer drug doxorubicin. C\(_{60}\)-Doxorubicin complexes in a ratio 1:1 and 2:1 were characterized with UV/Vis spectrometry, dynamic light scattering, and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The obtained analytical data indicated that the 140-nm complexes were stable and could be used for biological applications. In leukemic cell lines (CCRF-CEM, Jurkat, THP1 and Molt-16), the nanocomplexes revealed 3.5 higher cytotoxic potential in comparison with the free drug in a range of nanomolar concentrations. Also, the intracellular drug's level evidenced C\(_{60}\) fullerene considerable nanocarrier function.The results of this study indicated that C\(_{60}\) fullerene-based delivery nanocomplexes had a potential value for optimization of doxorubicin efficiency against leukemic cells.
KW  - C-60 fullerene
KW  - doxorubicin
KW  - noncovalent complex
KW  - leukemic cells
KW  - cytotoxicity
KW  - accumulation
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228257
VL  - 14
IS  - 61
ER  - 
TY  - JOUR
A1  - Gupta, Shishir K.
A1  - Srivastava, Mugdha
A1  - Osmanoglu, Özge
A1  - Xu, Zhuofei
A1  - Brakhage, Axel A.
A1  - Dandekar, Thomas
T1  - Aspergillus fumigatus versus genus Aspergillus: conservation, adaptive evolution and specific virulence genes
JF  - Microorganisms
N2  - Aspergillus is an important fungal genus containing economically important species, as well as pathogenic species of animals and plants. Using eighteen fungal species of the genus Aspergillus, we conducted a comprehensive investigation of conserved genes and their evolution. This also allows us to investigate the selection pressure driving the adaptive evolution in the pathogenic species A. fumigatus. Among single-copy orthologs (SCOs) for A. fumigatus and the closely related species A. fischeri, we identified 122 versus 50 positively selected genes (PSGs), respectively. Moreover, twenty conserved genes of unknown function were established to be positively selected and thus important for adaption. A. fumigatus PSGs interacting with human host proteins show over-representation of adaptive, symbiosis-related, immunomodulatory and virulence-related pathways, such as the TGF-β pathway, insulin receptor signaling, IL1 pathway and interfering with phagosomal GTPase signaling. Additionally, among the virulence factor coding genes, secretory and membrane protein-coding genes in multi-copy gene families, 212 genes underwent positive selection and also suggest increased adaptation, such as fungal immune evasion mechanisms (aspf2), siderophore biosynthesis (sidD), fumarylalanine production (sidE), stress tolerance (atfA) and thermotolerance (sodA). These genes presumably contribute to host adaptation strategies. Genes for the biosynthesis of gliotoxin are shared among all the close relatives of A. fumigatus as an ancient defense mechanism. Positive selection plays a crucial role in the adaptive evolution of A. fumigatus. The genome-wide profile of PSGs provides valuable targets for further research on the mechanisms of immune evasion, antimycotic targeting and understanding fundamental virulence processes.
KW  - molecular evolution
KW  - phylogenetic analysis
KW  - adaptation
KW  - recombination
KW  - positive selection
KW  - human pathogenic fungi
KW  - genus Aspergillus
KW  - Aspergillus fumigatus
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246318
SN  - 2076-2607
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Bencurova, Elena
A1  - Gupta, Shishir K.
A1  - Sarukhanyan, Edita
A1  - Dandekar, Thomas
T1  - Identification of antifungal targets based on computer modeling
JF  - Journal of Fungi
N2  - Aspergillus fumigatus is a saprophytic, cosmopolitan fungus that attacks patients with a weak immune system. A rational solution against fungal infection aims to manipulate fungal metabolism or to block enzymes essential for Aspergillus survival. Here we discuss and compare different bioinformatics approaches to analyze possible targeting strategies on fungal-unique pathways. For instance, phylogenetic analysis reveals fungal targets, while domain analysis allows us to spot minor differences in protein composition between the host and fungi. Moreover, protein networks between host and fungi can be systematically compared by looking at orthologs and exploiting information from host–pathogen interaction databases. Further data—such as knowledge of a three-dimensional structure, gene expression data, or information from calculated metabolic fluxes—refine the search and rapidly put a focus on the best targets for antimycotics. We analyzed several of the best targets for application to structure-based drug design. Finally, we discuss general advantages and limitations in identification of unique fungal pathways and protein targets when applying bioinformatics tools.
KW  - Aspergillus
KW  - metabolic pathways
KW  - computational modelling
KW  - drug design
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197670
SN  - 2309-608X
VL  - 4
IS  - 3
ER  - 
TY  - JOUR
A1  - Grebinyk, Anna
A1  - Prylutska, Svitlana
A1  - Chepurna, Oksana
A1  - Grebinyk, Sergii
A1  - Prylutskyy, Yuriy
A1  - Ritter, Uwe
A1  - Ohulchanskyy, Tymish Y.
A1  - Matyshevska, Olga
A1  - Dandekar, Thomas
A1  - Frohme, Marcus
T1  - Synergy of chemo- and photodynamic therapies with C\(_{60}\) Fullerene-Doxorubicin nanocomplex
JF  - Nanomaterials
N2  - A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C\(_{60}\) fullerene (C\(_{60}\)) were applied in 1:1 and 2:1 molar ratio, exploiting C\(_{60}\) both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox’s nuclear and C\(_{60}\)'s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox's antiproliferative activity and C\(_{60}\)'s photoinduced pro-oxidant activity. When cells were treated with 2:1 C\(_{60}\)-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C\(_{60}\)-Dox enabled a nanomolar concentration of Dox and C\(_{60}\) to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC\(_{50}\) 16, 9 and 7 × 10\(^3\)-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C\(_{60}\)'s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C\(_{60}\)-mediated Dox delivery and C\(_{60}\) photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C\(_{60}\)-Dox nanoformulation provides a promising synergetic approach for cancer treatment.
KW  - photodynamic chemotherapy
KW  - synergistic effect
KW  - C\(_{60}\) fullerene
KW  - Doxorubicin
KW  - nanocomplex
KW  - leukemic cells
KW  - apoptosis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193140
SN  - 2079-4991
VL  - 9
IS  - 11
ER  - 
TY  - JOUR
A1  - Dandekar, Thomas
A1  - Eisenreich, Wolfgang
T1  - Host-adapted metabolism and its regulation in bacterial pathogens
JF  - Frontiers in Cellular and Infection Microbiology
N2  - No abstract available.
KW  - bacterial pathogens
KW  - enteric pathogens
KW  - metabolism
KW  - host-pathogen adaption
KW  - isotopolog profiling
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196876
SN  - 2235-2988
VL  - 5
IS  - 28
ER  - 
TY  - JOUR
A1  - Dandekar, Thomas
A1  - Fieselmann, Astrid
A1  - Fischer, Eva
A1  - Popp, Jasmin
A1  - Hensel, Michael
A1  - Noster, Janina
T1  - Salmonella - how a metabolic generalist adopts an intracellular lifestyle during infection
JF  - Frontiers in Cellular and Infection Microbiology
N2  - The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, "-omics" data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology.
KW  - enterica serovar Typhimurium
KW  - bacterial invasion
KW  - mouse model
KW  - defenses
KW  - regulation
KW  - "-omics"
KW  - virulence
KW  - Salmonella-containing vacuole (SCV)
KW  - metabolism
KW  - nitric oxide
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149029
VL  - 4
IS  - 191
ER  - 
TY  - INPR
A1  - Dandekar, Thomas
T1  - Qubit transition into defined Bits: A fresh perspective for cosmology  and unifying theories
N2  - In this view point we do not change cosmology after the hot fireball starts (hence agrees well with observation), but the changed start suggested and resulting later implications lead to an even better fit with current observations (voids, supercluster and galaxy formation; matter and no antimatter) than the standard model with big bang and inflation: In an eternal ocean of qubits, a cluster of qubits crystallizes to defined bits. The universe does not jump into existence (“big bang”) but rather you have an eternal ocean of qubits in free super-position of all their quantum states (of any dimension, force field and particle type) as permanent basis. The undefined, boiling vacuum is the real “outside”, once you leave our everyday universe. A set of n Qubits in the ocean are “liquid”, in very undefined state, they have all their m possibilities for quantum states in free superposition. However, under certain conditions the qubits interact, become defined, and freeze out, crystals form and give rise to a defined, real world with all possible time series and world lines. GR holds only within the crystal.  In our universe all n**m quantum possibilities are nicely separated and crystallized out to defined bit states: A toy example with 6 qubits each having 2 states illustrates, this is completely sufficient to encode space using 3 bits for x,y and z, 1 bit for particle type and 2 bits for its state. Just by crystallization, space, particles and their properties emerge from the ocean of qubits, and following the arrow of entropy, time emerges, following an arrow of time and expansion from one corner of the toy universe to everywhere else. This perspective provides time as emergent feature considering entropy: crystallization of each world line leads to defined world lines over their whole existence, while entropy ensures direction of time and higher representation of high entropy states considering the whole crystal and all slices of world lines. The crystal perspective is also economic compared to the Everett-type multiverse, each qubit has its m quantum states and n qubits interacting forming a crystal and hence turning into defined bit states has only n**m states and not more states. There is no Everett-type world splitting with every decision but rather individual world trajectories reside in individual world layers of the crystal. Finally, bit-separated crystals come and go in the qubit ocean, selecting for the ability to lay seeds for new crystals. This self-organizing reproduction selects over generations also for life-friendliness. Mathematical treatment introduces quantum action theory as a framework for a general lattice field theory extending quantum chromo dynamics where scalar fields for color interaction and gravity have to be derived from the permeating qubit-interaction field. Vacuum energy should get appropriately low by the binding properties of the qubit crystal. Connections to loop quantum gravity, string theory and emergent gravity are discussed. Standard physics (quantum computing; crystallization, solid state physics) allow validation tests of this perspective and will extend current results.
KW  - qubit
KW  - cosmology
KW  - phase transition
KW  - unified theories
KW  - crystallization
KW  - emergent gravity
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266418
ER  - 
TY  - JOUR
A1  - Temme, Sebastian
A1  - Friebe, Daniela
A1  - Schmidt, Timo
A1  - Poschmann, Gereon
A1  - Hesse, Julia
A1  - Steckel, Bodo
A1  - Stühler, Kai
A1  - Kunz, Meik
A1  - Dandekar, Thomas
A1  - Ding, Zhaoping
A1  - Akhyari, Payam
A1  - Lichtenberg, Artur
A1  - Schrader, Jürgen
T1  - Genetic profiling and surface proteome analysis of human atrial stromal cells and rat ventricular epicardium-derived cells reveals novel insights into their cardiogenic potential
JF  - Stem Cell Research
N2  - Epicardium-derived cells (EPDC) and atrial stromal cells (ASC) display cardio-regenerative potential, but the molecular details are still unexplored. Signals which induce activation, migration and differentiation of these cells are largely unknown. Here we have isolated rat ventricular EPDC and rat/human ASC and performed genetic and proteomic profiling. EPDC and ASC expressed epicardial/mesenchymal markers (WT-1, Tbx18, CD73,CD90, CD44, CD105), cardiac markers (Gata4, Tbx5, troponin T) and also contained phosphocreatine. We used cell surface biotinylation to isolate plasma membrane proteins of rEPDC and hASC, Nano-liquid chromatography with subsequent mass spectrometry and bioinformatics analysis identified 396 rat and 239 human plasma membrane proteins with 149 overlapping proteins. Functional GO-term analysis revealed several significantly enriched categories related to extracellular matrix (ECM), cell migration/differentiation, immunology or angiogenesis. We identified receptors for ephrin and growth factors (IGF, PDGF, EGF, anthrax toxin) known to be involved in cardiac repair and regeneration. Functional category enrichment identified clusters around integrins, PI3K/Akt-signaling and various cardiomyopathies. Our study indicates that EPDC and ASC have a similar molecular phenotype related to cardiac healing/regeneration. The cell surface proteome repository will help to further unravel the molecular details of their cardio-regenerative potential and their role in cardiac diseases.
KW  - Biology
KW  - Epicardium-derived cells
KW  - Human atrial stromal cells
KW  - Cell surface proteomics
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172716
VL  - 25
ER  - 
TY  - JOUR
A1  - Alnusaire, Taghreed S.
A1  - Sayed, Ahmed M.
A1  - Elmaidomy, Abeer H.
A1  - Al-Sanea, Mohammad M.
A1  - Albogami, Sarah
A1  - Albqmi, Mha
A1  - Alowaiesh, Bassam F.
A1  - Mostafa, Ehab M.
A1  - Musa, Arafa
A1  - Youssif, Khayrya A.
A1  - Refaat, Hesham
A1  - Othman, Eman M.
A1  - Dandekar, Thomas
A1  - Alaaeldin, Eman
A1  - Ghoneim, Mohammed M.
A1  - Abdelmohsen, Usama Ramadan
T1  - An in vitro and in silico study of the enhanced antiproliferative and pro-oxidant potential of Olea europaea L. cv. Arbosana leaf extract via elastic nanovesicles (spanlastics)
JF  - Antioxidants
N2  - The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC\(_{50}\) values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC\(_{50}\) 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC\(_{50}\) 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential.
KW  - olive
KW  - metabolomic profiling
KW  - antiproliferative
KW  - pro-oxidant
KW  - encapsulation
KW  - spanlastic
KW  - nanocarrier
KW  - docking
KW  - molecular dynamics simulation
KW  - Olea
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250064
SN  - 2076-3921
VL  - 10
IS  - 12
ER  -