Naturwissenschaften
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Auflistung Naturwissenschaften nach Instituten/Kliniken "Institut für Experimentelle und Klinische Pharmakologie und Toxikologie"
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Item A metabolomics and lipidomics profile of ischemic stroke(2022) Folberth, JuliaItem Etablierung und Charakterisierung von Langzeitkulturen humaner Herzschnitte(2011) Brandenburger, MatthiasItem Item Interaction of adipokines with orexin signalling(2018) Frevel, EvaItem Investigation of the role of Gαq/11 signaling in brain endothelial cells(2025) Spyropoulos, DimitriosThe aging population is projected to increase in the next decades posing new challenges for societies. Normal aging can severely affect the cognitive function of individuals even in the absence of overt pathologies but currently, the therapeutic options are limited. Therefore, based on scientific evidence that aging vasculature is linked to the development of age-dependent cognitive decline, deepening our knowledge of the cerebrovascular system could unravel new potential pharmacological targets. The current study, aimed to understand the role of Gαq/11 proteins in the brain endothelium. Based on previous work, it was hypothesized that brain endothelial Gαq/11 proteins affect the cognitive function of aging mice. The hypothesis was tested with behavioral tests during the lifespan of aging mice with specific brain endothelial deletion of the genes that express the Gαq/11 proteins (Gαq/11beKO mice). The results provided evidence that the Gαq/11 proteins do not affect the memory function of young mice but have a significant effect on the cognitive function of aged mice. Immunohistological stainings on aged mice revealed increased formation of string vessels in the brains of Gαq/11beKO mice compared to control mice. String vessels are structures positive for basement membrane markers and negative for endothelial cell markers presumably resulting from collapsed vessels. Interestingly, no significant differences were found in the other parameters investigated such as neuroinflammation, neuronal and synaptic density, myelination, or blood-brain barrier (BBB) leakage. Based on literature research and previous findings of our group, shear stress was identified as a possible factor to be involved in the formation of string vessels. Mechanical stimulation of primary mouse brain endothelial cells (MPBECs) was found to induce intracellular calcium ([Ca2+]i) increase and activation of the NF-κB pathway independent from the Gαq/11 pathway. Furthermore, long-term cultivation of MPBECs under flow was identified to lead to significant morphological and proteomic changes compared to static conditions. Finally, based on the proteomic analysis, which revealed that shear stress induces angiogenic pathways in MPBECs, it was found that thrombomodulin (THBD) as well as Gαq/11 proteins are involved in in vitro migration and proliferation respectively. All in all, the current study provides evidence that the brain endothelial Gαq/11 signaling is important for cognitive function in aged mice . Future work could shed light on the exact underlying mechanisms of the observed phenotype, which could probably involve string vessel-induced hypoxia. Finally, we provide a comprehensive proteomic database that could be further exploited to unravel novel mechanosensory targets.Item Metabolic and cellular factors determining the therapeutic effects of dimethyl fumarate(2025-06-12) Kosińska, JoannaItem Item The reactive pyruvate metabolite dimethylglyoxal in experimental disease models and the role of Ilvbl in its generation in the brain(2025) Costalunga, RiccardoReactive glucose metabolites are involved in neurological complications of diabetes by the generation of advanced glycated end products (AGEs), which are formed by the interaction between α-dicarbonyls and proteins. AGEs induce oxidative stress, inflammation and tissue damage and have been associated with neuropathy, nephropathy and retinopathy. So far, only the α-dicarbonyls 3-deoxyglucosone, glyoxal and methylglyoxal have been recognized as reactive glucose metabolites and associated with complications in diabetes. Only recently, the α-dicarbonyl dimethylglyoxal (DMG) has been categorized as mammal cellular pyruvate metabolite, and its levels were higher in the plasma of type-1 diabetic mice and in the serum of patients with diabetes. In this thesis, I investigated the α-dicarbonyl DMG in mouse models under pathological conditions and its metabolic pathway in mammals using liquid chromatography coupled to tandem mass spectrometry (LC-MS2). Here, plasma DMG concentrations were upregulated in mouse experimental models of type-1 and type-2 diabetes. In contrast, high-fat diet did not influence the serum levels of DMG, suggesting that diabetic conditions – but not obesity itself – are associated with plasma DMG upregulation and accumulation. Moreover, DMG levels were enormously augmented in the ipsilateral side of a mouse model of hyperglycemic stroke compared to sham control. Interestingly, DMG levels were also higher in the contralateral hemisphere of the brain of mice with stroke compared to sham controls, showing that the contralateral hemisphere is also affected by ischemic stroke. Furthermore, the current study confirmed that DMG is a post-glycolytic product in mammals and its levels are increased under hypoxic conditions in vitro. Then, I investigated the role of the gene ilvB acetolactate synthase-like (Ilvbl), the mammal orthologue gene of acetolactate synthase that generates DMG from pyruvate in bacteria, yeast and plants. Importantly, Ilvbl knockout reduced DMG levels in the brain of mice with type-1 diabetes or hyperglycemic stroke, showing that Ilvbl has conserved its role in DMG generation in mammals. Moreover, DMG interacted with lysine, generating the glycated amino acid Nε-3-hydroxy-2-butanonelysine (HBL), confirming that DMG is a reactive compound and can glycate proteins generating AGEs. Thus, DMG induced oxidative stress and neuroinflammation in mouse hippocampal neuronal (HT-22) cells, probably based on protein glycation. In conclusion, this study characterizes the α-dicarbonyl DMG in experimental models under pathological conditions, showing that DMG could play a significant role in diabetic complications and ischemic stroke complications. DMG is the only α-dicarbonyl generated after glycolysis, and the current discovery could explain why cells consuming lactate – such as neurons – are not protected by dicarbonyl stress. Importantly, this study shows that ILVBL plays a significant role in the DMG generation from pyruvate in the brain of acute or chronic hyperglycemic mice. Further investigation on DMG and the attenuation of its concentrations may lead to improvement in diabetic and ischemic stroke complications.Item Use of non-invasive brain stimulation to modulate endogenous cortical activity across brain states(2024) Koo-Poeggel, Ping Chai