@article{WorkuStichDaugschiesetal.2015,
  author    = {Worku, Netsanet and Stich, August and Daugschies, Arwid and Wenzel, Iris and Kurz, Randy and Thieme, Rene and Kurz, Susanne and Birkenmeier, Gerd},
  title     = {Ethyl Pyruvate Emerges as a Safe and Fast Acting Agent against Trypanosoma brucei by Targeting Pyruvate Kinase Activity},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {9},
  doi       = {10.1371/journal.pone.0137353},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150002},
  pages     = {e0137353},
  year      = {2015},
  abstract  = {Background Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100\% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties. Results The current study covers the efficacy and corresponding target evaluation of ethyl pyruvate on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, phasecontrast microscopic video imaging and ex vivo toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki = 3.0\(\pm\)0.29 mM). The potential of ethyl pyruvate as a trypanocidal compound is also strengthened by its fast acting property, killing cells within three hours post exposure. This has been demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, ethyl pyruvate produces minimal side effects in human red cells and is known to easily cross the blood-brain-barrier. This makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug-resistance tests indicate irreversible cell death and a low incidence of resistance development under experimental conditions. Conclusion Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross the blood-brain-barrier, ethyl pyruvate could be considered as new candidate agent to treat the hemo-lymphatic as well as neurological stages of sleeping sickness.},
  language  = {en}
}
@article{WeilandBeezWestermaieretal.2021,
  author    = {Weiland, Judith and Beez, Alexandra and Westermaier, Thomas and Kunze, Ekkehard and Sir{\´e}n, Anna-Leena and Lilla, Nadine},
  title     = {Neuroprotective strategies in aneurysmal subarachnoid hemorrhage (aSAH)},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {11},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22115442},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260755},
  year      = {2021},
  abstract  = {Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.},
  language  = {en}
}
@article{TrivanovicVolkmannStoeckletal.2023,
  author    = {Trivanovic, Drenka and Volkmann, Noah and Stoeckl, Magdalena and Tertel, Tobias and Rudert, Maximilian and Giebel, Bernd and Herrmann, Marietta},
  title     = {Enhancement of immunosuppressive activity of mesenchymal stromal cells by platelet-derived factors is accompanied by apoptotic priming},
  series = {Stem Cell Reviews and Reports},
  volume    = {19},
  journal   = {Stem Cell Reviews and Reports},
  number    = {3},
  doi       = {10.1007/s12015-022-10471-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324669},
  pages     = {713-733},
  year      = {2023},
  abstract  = {The pro-inflammatory phase of bone healing, initiated by platelet activation and eventually hematoma formation, impacts bone marrow mesenchymal stromal cells (MSCs) in unknown ways. Here, we created platelet-rich plasma (PRP) hydrogels to study how platelet-derived factors modulate functional properties of encapsulated MSCs in comparison to a non-inflammatory fibrin (FBR) hydrogel environment. MSCs were isolated from human bone marrow, while PRP was collected from pooled apheresis thrombocyte concentrates and used for hydrogel preparation. After their encapsulation in hydrogels for 72 h, retrieved MSCs were analyzed for immunomodulatory activities, apoptosis, stem cell properties, senescence, CD9\(^+\), CD63\(^+\) and CD81\(^+\) extracellular vesicle (EV) release, and metabolism-related changes. PRP-hydrogels stimulated immunosuppressive functions of MSCs, along with their upregulated susceptibility to cell death in communication with PBMCs and augmented caspase 3/7 activity. We found impaired clonal growth and cell cycle progression, and more pronounced β-galactosidase activity as well as accumulation of LC3-II-positive vacuoles in PRP-MSCs. Stimuli derived from PRP-hydrogels upregulated AKT and reduced mTOR phosphorylation in MSCs, which suggests an initiation of survival-related processes. Our results showed that PRP-hydrogels might represent a metabolically stressful environment, inducing acidification of MSCs, reducing polarization of the mitochondrial membrane and increasing lipid accumulation. These features were not detected in FBR-MSCs, which showed reduced CD63\(^+\) and CD81\(^+\) EV production and maintained clonogenicity. Our data revealed that PRP-derived hematoma components cause metabolic adaptation of MSCs followed by increased immune regulatory functions. For the first time, we showed that PRP stimuli represent a survival challenge and "apoptotic priming" that are detrimental for stem cell-like growth of MSCs and important for their therapeutic consideration.},
  language  = {en}
}
@article{TomeNaegeleAdamoetal.2014,
  author    = {Tome, Filipa and N{\"a}gele, Thomas and Adamo, Mattia and Garg, Abhroop and Marco-Ilorca, Carles and Nukarinen, Ella and Pedrotti, Lorenzo and Peviani, Alessia and Simeunovic, Andrea and Tatkiewicz, Anna and Tomar, Monika and Gamm, Magdalena},
  title     = {The low energy signaling network},
  series = {Frontiers in Plant Science},
  volume    = {5},
  journal   = {Frontiers in Plant Science},
  number    = {353},
  issn      = {1664-462X},
  doi       = {10.3389/fpls.2014.00353},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115813},
  year      = {2014},
  abstract  = {Stress impacts negatively on plant growth and crop productivity, causing extensive losses to agricultural production worldwide. Throughout their life, plants are often confronted with multiple types of stress that affect overall cellular energy status and activate energy-saving responses. The resulting low energy syndrome (LES) includes transcriptional, translational, and metabolic reprogramming and is essential for stress adaptation. The conserved kinases sucrose-non-fermenting-1-related protein kinase-1 (SnRK1) and target of rapamycin (TOR) play central roles in the regulation of LES in response to stress conditions, affecting cellular processes and leading to growth arrest and metabolic reprogramming. We review the current understanding of how TOR and SnRK1 are involved in regulating the response of plants to low energy conditions. The central role in the regulation of cellular processes, the reprogramming of metabolism, and the phenotypic consequences of these two kinases will be discussed in light of current knowledge and potential future developments.},
  language  = {en}
}
@phdthesis{Siegl2014,
  author    = {Siegl, Christine},
  title     = {Degradation of Tumour Suppressor p53 during Chlamydia trachomatis Infections},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108679},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The intracellular pathogen Chlamydia is the causative agent of millions of new infections per year transmitting diseases like trachoma, pelvic inflammatory disease or lymphogranuloma venereum. Undetected or recurrent infections caused by chlamydial persistence are especially likely to provoke severe pathologies. To ensure host cell survival and to facilitate long term infections Chlamydia induces anti-apoptotic pathways, mainly at the level of mitochondria, and restrains activity of pro-apoptotic proteins. Additionally, the pathogen seizes host energy, carbohydrates, amino acids, lipids and nucleotides to facilitate propagation of bacterial progeny and growth of the chlamydial inclusion. At the beginning of this study, Chlamydia-mediated apoptosis resistance to DNA damage induced by the topoisomerase inhibitor etoposide was investigated. In the course of this, a central cellular protein crucial for etoposide-mediated apoptosis, the tumour suppressor p53, was found to be downregulated during Chlamydia infections. Subsequently, different chlamydial strains and serovars were examined and p53 downregulation was ascertained to be a general feature during Chlamydia infections of human cells. Reduction of p53 protein level was established to be mediated by the PI3K-Akt signalling pathway, activation of the E3-ubiquitin ligase HDM2 and final degradation by the proteasome. Additionally, an intriguing discrepancy between infections of human and mouse cells was detected. Both activation of the PI3K-Akt pathway as well as degradation of p53 could not be observed in Chlamydia-infected mouse cells. Recently, production of reactive oxygen species (ROS) and damage to host cell DNA was reported to occur during Chlamydia infection. Thus, degradation of p53 strongly contributes to the anti-apoptotic environment crucial for chlamydial infection. To verify the importance of p53 degradation for chlamydial growth and development, p53 was stabilised and activated by the HDM2-inhibiting drug nutlin-3 and the DNA damage-inducing compound etoposide. Unexpectedly, chlamydial development was severely impaired and inclusion formation was defective. Completion of the chlamydial developmental cycle was prevented resulting in loss of infectivity. Intriguingly, removal of the p53 activating stimulus allowed formation of the bacterial inclusion and recovery of infectivity. A similar observation of growth recovery was made in infected cell lines deficient for p53. As bacterial growth and inclusion formation was strongly delayed in the presence of activated p53, p53-mediated inhibitory regulation of cellular metabolism was suspected to contribute to chlamydial growth defects. To verify this, glycolytic and pentose phosphate pathways were analysed revealing the importance of a functioning PPP for chlamydial growth. In addition, increased expression of glucose-6-phosphate dehydrogenase rescued chlamydial growth inhibition induced by activated p53. The rescuing effect was even more pronounced in p53-deficient cells treated with etoposide or nutlin-3 revealing additional p53-independent aspects of Chlamydia inhibition. Removal of ROS by anti-oxidant compounds was not sufficient to rescue chlamydial infectivity. Apparently, not only the anti-oxidant capacities of the PPP but also provision of precursors for nucleotide synthesis as well as contribution to DNA repair are important for successful chlamydial growth. Modulation of host cell signalling was previously reported for a number of pathogens. As formation of ROS and DNA damage are likely to occur during infections of intracellular bacteria, several strategies to manipulate the host and to inhibit induction of apoptosis were invented. Downregulation of the tumour suppressor p53 is a crucial point during development of Chlamydia, ensuring both host cell survival and metabolic support conducive to chlamydial growth.},
  subject      = {Chlamydia-trachomatis-Infektion},
  language  = {en}
}
@article{SchmitzKodererElMeseryetal.2021,
  author    = {Schmitz, Werner and Koderer, Corinna and El-Mesery, Mohamed and Gobik, Sebastian and Sampers, Rene and Straub, Anton and K{\"u}bler, Alexander Christian and Seher, Axel},
  title     = {Metabolic fingerprinting of murine L929 fibroblasts as a cell-based tumour suppressor model system for methionine restriction},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {6},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22063039},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259198},
  year      = {2021},
  abstract  = {Since Otto Warburg reported in 1924 that cancer cells address their increased energy requirement through a massive intake of glucose, the cellular energy level has offered a therapeutic anticancer strategy. Methionine restriction (MetR) is one of the most effective approaches for inducing low-energy metabolism (LEM) due to the central position in metabolism of this amino acid. However, no simple in vitro system for the rapid analysis of MetR is currently available, and this study establishes the murine cell line L929 as such a model system. L929 cells react rapidly and efficiently to MetR, and the analysis of more than 150 different metabolites belonging to different classes (amino acids, urea and tricarboxylic acid cycle (TCA) cycles, carbohydrates, etc.) by liquid chromatography/mass spectrometry (LC/MS) defines a metabolic fingerprint and enables the identification of specific metabolites representing normal or MetR conditions. The system facilitates the rapid and efficient testing of potential cancer therapeutic metabolic targets. To date, MS studies of MetR have been performed using organisms and yeast, and the current LC/MS analysis of the intra- and extracellular metabolites in the murine cell line L929 over a period of 5 days thus provides new insights into the effects of MetR at the cellular metabolic level.},
  language  = {en}
}
@phdthesis{Schmalbach2014,
  author    = {Schmalbach, Katja},
  title     = {Identification of factors influencing 17beta-estradiol metabolism in female mammary gland},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-109300},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The female sex hormone 17beta-estradiol, produced naturally in the body, seems to play an important role in the development of breast cancer, since (i) it can be activated to reactive metabolites, which are known to damage DNA and (ii) the stimulation of the estrogen receptor alpha by 17beta-estradiol enhances cell proliferation. Both processes together increase mutation frequency and subsequently lead to transformation of epithelial cells. Therefore, the aim of this work was to characterize the influence of polymorphisms and lifestyle factors on 17beta-estradiol metabolism in normal mammary gland tissue. [...] In sum, the tissue specific 17beta-estradiol metabolism was described in mammary gland tissue homogenate, whereas differences in proliferation of epithelial cells were only reflected in isolated epithelial cells. Factors associated with breast cancer risk (age, BMI and age-related changes in mammary gland morphology) were shown to affect 17beta-estradiol tissue levels. The 17beta-estradiol mediated genotoxicity was evaluated using bioinformatically calculated DNA adduct fluxes, which were predominately influenced by individual mRNA patterns rather than individual genotypes and (DNA adduct fluxes) were correlated with known breast cancer risk factors (age, parity, BMI and polymorphism of glutathione-S-transferase theta 1).},
  subject      = {Milchdr{\"u}se},
  language  = {en}
}
@article{SchererFleishmanJonesetal.2021,
  author    = {Scherer, Marc and Fleishman, Sarel J. and Jones, Patrik R. and Dandekar, Thomas and Bencurova, Elena},
  title     = {Computational Enzyme Engineering Pipelines for Optimized Production of Renewable Chemicals},
  series = {Frontiers in Bioengineering and Biotechnology},
  volume    = {9},
  journal   = {Frontiers in Bioengineering and Biotechnology},
  issn      = {2296-4185},
  doi       = {10.3389/fbioe.2021.673005},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240598},
  year      = {2021},
  abstract  = {To enable a sustainable supply of chemicals, novel biotechnological solutions are required that replace the reliance on fossil resources. One potential solution is to utilize tailored biosynthetic modules for the metabolic conversion of CO2 or organic waste to chemicals and fuel by microorganisms. Currently, it is challenging to commercialize biotechnological processes for renewable chemical biomanufacturing because of a lack of highly active and specific biocatalysts. As experimental methods to engineer biocatalysts are time- and cost-intensive, it is important to establish efficient and reliable computational tools that can speed up the identification or optimization of selective, highly active, and stable enzyme variants for utilization in the biotechnological industry. Here, we review and suggest combinations of effective state-of-the-art software and online tools available for computational enzyme engineering pipelines to optimize metabolic pathways for the biosynthesis of renewable chemicals. Using examples relevant for biotechnology, we explain the underlying principles of enzyme engineering and design and illuminate future directions for automated optimization of biocatalysts for the assembly of synthetic metabolic pathways.},
  language  = {en}
}
@article{SchanbacherHermannsLorenzetal.2023,
  author    = {Schanbacher, Constanze and Hermanns, Heike M. and Lorenz, Kristina and Wajant, Harald and Lang, Isabell},
  title     = {Complement 1q/tumor necrosis factor-related proteins (CTRPs): structure, receptors and signaling},
  series = {Biomedicines},
  volume    = {11},
  journal   = {Biomedicines},
  number    = {2},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines11020559},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304136},
  year      = {2023},
  abstract  = {Adiponectin and the other 15 members of the complement 1q (C1q)/tumor necrosis factor (TNF)-related protein (CTRP) family are secreted proteins composed of an N-terminal variable domain followed by a stalk region and a characteristic C-terminal trimerizing globular C1q (gC1q) domain originally identified in the subunits of the complement protein C1q. We performed a basic PubMed literature search for articles mentioning the various CTRPs or their receptors in the abstract or title. In this narrative review, we briefly summarize the biology of CTRPs and focus then on the structure, receptors and major signaling pathways of CTRPs. Analyses of CTRP knockout mice and CTRP transgenic mice gave overwhelming evidence for the relevance of the anti-inflammatory and insulin-sensitizing effects of CTRPs in autoimmune diseases, obesity, atherosclerosis and cardiac dysfunction. CTRPs form homo- and heterotypic trimers and oligomers which can have different activities. The receptors of some CTRPs are unknown and some receptors are redundantly targeted by several CTRPs. The way in which CTRPs activate their receptors to trigger downstream signaling pathways is largely unknown. CTRPs and their receptors are considered as promising therapeutic targets but their translational usage is still hampered by the limited knowledge of CTRP redundancy and CTRP signal transduction.},
  language  = {en}
}
@article{SchadtIsraelBeezetal.2023,
  author    = {Schadt, Fabian and Israel, Ina and Beez, Alexandra and Alushi, Kastriot and Weiland, Judith and Ernestus, Ralf-Ingo and Westermaier, Thomas and Samnick, Samuel and Lilla, Nadine},
  title     = {Analysis of cerebral glucose metabolism following experimental subarachnoid hemorrhage over 7 days},
  series = {Scientific Reports},
  volume    = {13},
  journal   = {Scientific Reports},
  number    = {1},
  doi       = {10.1038/s41598-022-26183-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300725},
  year      = {2023},
  abstract  = {Little is known about changes in brain metabolism following SAH, possibly leading towards secondary brain damage. Despite sustained progress in the last decade, analysis of in vivo acquired data still remains challenging. The present interdisciplinary study uses a semi-automated data analysis tool analyzing imaging data independently from the administrated radiotracer. The uptake of 2-[18F]Fluoro-2-deoxy-glucose ([\(^{18}\)F]FDG) was evaluated in different brain regions in 14 male Sprague-Dawley rats, randomized into two groups: (1) SAH induced by the endovascular filament model and (2) sham operated controls. Serial [\(^{18}\)F]FDG-PET measurements were carried out. Quantitative image analysis was performed by uptake ratio using a self-developed MRI-template based data analysis tool. SAH animals showed significantly higher [\(^{18}\)F]FDG accumulation in gray matter, neocortex and olfactory system as compared to animals of the sham group, while white matter and basal forebrain region showed significant reduced tracer accumulation in SAH animals. All significant metabolic changes were visualized from 3 h, over 24 h (day 1), day 4 and day 7 following SAH/sham operation. This [\(^{18}\)F]FDG-PET study provides important insights into glucose metabolism alterations following SAH—for the first time in different brain regions and up to day 7 during course of disease.},
  language  = {en}
}