Leiden University Scholary Publications
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Towards near-infrared light-activated combination chemotherapy
Get PDFThe goal of the research presented in this thesis was to explore the chemical space of ruthenium(II) photocages, investigate their ability to host potent chemotherapy drugs, and to red shift the activation wavelength of the most promising PACT candidates to conduct biological studies. At first, we developed a method for the ortho-amination of pyridine N-oxides, providing an easy access to valuable building blocks based on quinoline, bipyridine, naphthyridine, phenanthroline, biisoquinoline and terpyridine. We then used this tool to construct a family of the new pentadentate ligands and respective ruthenium complexes capable of caging different approved and experimental anticancer medications. The resulting prodrugs showed good response to longwave visible light, efficiently releasing drug moieties based on primary amines, thioethers, nitriles, pyridines, imidazo[1.2-b]pyridazines, β-carbolines, and imidazoles. The follow up in vitro studies confirmed the potential of this construct to be used against cancer. Additionally, we performed the modification of previously developed ruthenium based agent to be tested with red light in vivo, which demonstrated the convincing applicability of PACT in actual tumor treatment and set the ground for further preclinical development.Metals in Catalysis, Biomimetics & Inorganic Material
In-situ and ex-situ EPS-corona formation on ZnO QDs mitigates their environmental toxicity in the freshwater microalgae Chlorella sp.
Get PDFThe current work seeks to understand how the interactions between ZnO QDs and extracellular polymeric substances (EPS) may vary based on the types of EPS (loosely and tightly bound) and modes of eco-corona formation (In-situ or ex-situ). In-situ eco-corona refers to formation of an EPS layer on the QDs during the interactions with the algae whereas the ex-situ condition refers to forming the layer before the interactions. ZnO QDs were added at 0.25, 0.5, and 1.0 mg/L concentrations for pristine, in-situ, and ex-situ corona treatments with the cells. Pristine ZnO QDs induced significant oxidative stress in algal cells, as evident from increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase activity. This decreased the photosynthetic efficiency and caused significant growth inhibition in algae. In contrast, both the in-situ and ex-situ corona treatments with loosely bound and tightly bound EPS reduced the oxidative stress, improved the photosynthetic efficiency, and diminished growth inhibition effects. This study asserts the importance of EPS in reducing the toxicity of ZnO QDs, while maintaining the fluorescence activity. This ensures the sustainable usage of the ZnO QDs without any harm to aquatic ecosystems.Environmental Biolog
Electron-withdrawing effects in cobalt porphyrin catalysts boost homogeneous photocatalytic hydrogen evolution in neutral aqueous solutions
Get PDFNWOMetals in Catalysis, Biomimetics & Inorganic Material
Establishing control: the Krio elite and the transformation of labour relations in colonial Sierra Leone, 1868-1919
Get PDFThis thesis examines the efforts by the Krio elite in Sierra Leone to control the colony’s economic and political system by establishing control over the nascent wage labour force in the period between 1868 and 1919. The main argument is that control over labour Krio elite was indispensable to the ambition of the Krio elite to turn Sierra Leone into a self-governing or even a politically independent entity. As the Krio elite itself lacked the capital to independently hire and control large numbers of wage workers, it depended on the colonial government. After consolidating a measure of influence within the colonial system by the 1860s, the Krio elite was increasingly excluded from positions of power within the colonial hierarchy. The cultural nationalism that emerged in response to the exclusion of the Krio was accompanied by attempts to create an economic base for an independent Sierra Leone. The colonial government proved unable to enact largescale reforms of labour relations. The demand for wage workers grew, both in Freetown and abroad, creating a demand for migrant labour from Sierra Leone. This provided workers with the means to evade government control over their labour. Cities, Migration and Global Interdependence 1350-200
The endocannabinoid 2-arachidonoylglycerol is released and transported on demand via extracellular microvesicles
Get PDFWhile it is known that endocannabinoids (eCB) modulate multiple neuronal functions, the molecular mechanism governing their release and transport remains elusive. Here, we propose an "on-demand release" model, wherein the formation of microvesicles, a specific group of extracellular vesicles (EVs) containing the eCB, 2-arachidonoylglycerol (2-AG), is an important step. A coculture model system that combines a reporter cell line expressing the fluorescent eCB sensor, G protein-coupled receptor-based (GRAB)eCB2.0, and neuronal cells revealed that neurons release EVs containing 2-AG, but not anandamide, in a stimulus-dependent process regulated by protein kinase C, Diacylglycerol lipase, Adenosinediphosphate (ADP) ribosylation factor 6 (Arf6), and which was sensitive to inhibitors of eCB facilitated diffusion. A vesicle contained approximately 2,000 2-AG molecules. Accordingly, hippocampal eCB-mediated synaptic plasticity was modulated by Arf6 and transport inhibitors. The "on-demand release" model, supported by mathematical analysis, offers a cohesive framework for understanding eCB trafficking at the molecular level and suggests that microvesicles carrying signaling lipids in their membrane regulate neuronal functions in parallel to canonical synaptic vesicles.Molecular Physiolog
Review of Azzouz, A. (2023) Domicide: architecture, war and the destruction of home in Syria
Get PDFMiddle Eastern Studie
Deciphering the Ubiquitin CODE by chemical tools
Get PDFThe scope of this PhD dissertation encompasses the study of Ub CODE signaling and druggability of E3 ligases by in-house developed chemical tools, aiming at its deciphering and modulation. The research presented in this thesis was performed at the Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. The research was supported by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 765445.LUMC / Geneeskund
Unraveling the drivers of antimicrobial pharmacokinetic variability in individuals with obesity and hospitalized patients with multimorbidity
Get PDFObesity may alter how a person absorbs, distributes, metabolizes or excretes medication. This thesis describes how obesity affects drug levels in the blood for antimicrobial agents, such as ciprofloxacin and fluconazole. For ciprofloxacin the influence of multimorbidity, e.g. ICU-patients with obesity or gastrointestinal mucositis in hematology patients, on drug levels is also explored. The studies show that men with severe obesity excrete fluconazole more quickly, increasing the risk of treatment failure which requires a higher loading dose. For ciprofloxacin, higher doses are advised for obese patients when impaired tissue treating is anticipated. The influence of obesity on drug metabolism is unpredictable, making it difficult to determine if standard dosing regimens are appropriate for severely obese patients. This lack of information can lead to underdosing, reducing effectiveness, or overdosing, increasing side effects. The findings highlight the need to study obese individuals during drug development, as is already done for people with liver/kidney issues, children, and the elderly. Research in a small group of severely obese individuals can provide valuable insights to determine whether weight-based or fixed dosing regimens are more appropriate for new drugs.St. Antonius Onderzoeksfonds;
Tergooi MC wetenschapsfondsPharmacolog
