The research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and... Show moreThe research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and glucocorticoids.Leptin plays an important role during TB infection and has a huge impact on insulin sensitivity in zebrafish larvae. Similarly to what has been observed in the murine model, leptin deficiency in zebrafish increased the bacterial burden and mortality during the infection, leading to hyperglycemia and the development of insulin resistance. In addition, a novel SHP-1/SHP-2 inhibitor, NSC-87877, was shown to represent a promising anti-diabetic drug that can be used for further DM2 research, as it is able to rescue the phenotype of the leptin-deficient zebrafish and to restore glucose transport to the tissues. In contrast to metformin, NSC-87877 can act at very early developmental stages and inhibits the function of SHP-1 and factors that underlay impaired glucose metabolism, whereas metformin is mostly known to improve insulin sensitivity. Additionally, treatment with the glucocorticoid beclomethasone attenuates the metabolic changes associated with the infection, and transcriptional alterations induced by beclomethasone treatment suggest that genes involved in glucose metabolism, insulin and leptin signaling all play an important role in the modulation of the metabolism.Our data show that zebrafish larvae represent an interesting model system to investigate the complex pathology of TB, and the studies described in this thesis in which this model has been used have provided novel insights into the molecular mechanisms underlying wasting syndrome and the possibilities for adjunctive glucocorticoid therapy to alleviate this metabolic state. Show less
This thesis focuses on two processes involved in fighting infections: metabolism and immune cell motility and navigation.Regarding metabolism, we present ZebraGEM 2.0, an improved whole-genome... Show moreThis thesis focuses on two processes involved in fighting infections: metabolism and immune cell motility and navigation.Regarding metabolism, we present ZebraGEM 2.0, an improved whole-genome scale metabolic reconstruction for zebrafish, that we used to study zebrafish metabolism upon infection with Mycobacterium marinum integrating gene expression data from control and infected zebrafish larvae. The chapters focusing on cell motility in response to the environment, revolve around the question of how the environmental inputs of cell-matrix interactions, cell-sized obstacles and cell-signalling upon wounding shape and guide cell motility. Show less
Kok, M.J.C. de; Schaapherder, A.F.; Wüst, R.C.I.; Zuiderwijk, M.; Bakker, J.A.; Lindeman, J.H.N.; Le Dévédec S.E. 2021
Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile... Show moreMetabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile technique for the elaboration of physiology and disease, studying metabolism using standard cell culture protocols is profoundly interfered by the Crabtree effect. This phenomenon refers to the adaptation of cultured cells to a glycolytic phenotype, away from aoxidative phosphorylation in glucose-containing medium, and questions the applicability of cell culture in certain fields of research. In this systematic review we aim to provide a comprehensive overview and critical appraisal of strategies reported to circumvent the Crabtree effect. Show less
Venetoclax is an oral BCL2 inhibitor undergoing investigation for use in relapsed or refractory multiple myeloma (RRMM), particularly in combination with proteasome inhibitors (VPI)[1,2]. An... Show moreVenetoclax is an oral BCL2 inhibitor undergoing investigation for use in relapsed or refractory multiple myeloma (RRMM), particularly in combination with proteasome inhibitors (VPI)[1,2]. An interim analysis of a current phase 2 trial of venetoclax with carfilzomib in RRMM demonstrated an overall response rate of 78% with a very good partial response rate of 56%[3,4]. However, a separate ongoing phase 3 trial of venetoclax with bortezomib found a decrease in overall survival due to increased fatal infections in the venetoclax arm compared to placebo. Better describing these infections may give insight into the pathophysiology and prove useful in mitigating strategies for use with VPI therapy in RRMM. Show less
Atherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the... Show moreAtherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the vessel wall. Over time, this accumulation of lipids and immune cells induce morphological abnormalities in the vessel wall which cause the vessel lumen to narrow. This narrowing of the lumen (stenosis) causes ischemia in the downstream tissue. Prolonged ischemia causes myocardial ischemia and/or stroke. The research described in my thesis examines a well-recognized risk factor of atherosclerosis, being dyslipidemia, from an entirely new perspective. More specifically, it describes how dyslipidemia affects intrinsic metabolic processes in T cells, the conductors of the immune response characterizing atherosclerosis, and how this affects their function. My research has contributed to knowledge on the pathophysiology of atherosclerosis and might one day pave the way for the development of novel therapeutic approaches to treat cardiovascular disease. Show less
The work in this thesis describes the fundamental role of Lkb1 as a conductor of metabolism-related processes in zebrafish larvae. We show that Lkb1 is essential for the regulation of glucose... Show moreThe work in this thesis describes the fundamental role of Lkb1 as a conductor of metabolism-related processes in zebrafish larvae. We show that Lkb1 is essential for the regulation of glucose metabolism, the activation of autophagy, and hematopoiesis under conditions of metabolic stress. Furthermore, we also uncovered gene transcription profiles and hematological characteristics that are specific to lkb1 larvae, and independent of metabolic stress. Finally, we illustrate and highlight the potential of lkb1 larvae as screening platform in research related to metabolism, hematopoiesis, and tumors bearing LKB1 mutations. Overall, we have strengthened the value of lkb1 zebrafish larvae as a model to study the effects of Lkb1-inactivation on various metabolism-related processes Show less
Bacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments. Actinobacteria, with their... Show moreBacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments. Actinobacteria, with their beautiful morphologies and complex multicellular life cycle, are a striking example. These filamentous bacteria produce many enzymes and natural products, including two-thirds of all known antibiotics, which makes them highly relevant for medical, biotechnological and industrial applications. In Streptomyces, complex and intertwining regulatory networks, consisting of pathway-specific and global regulators, control development and antibiotic production in response to environmental stimuli and stresses. This thesis explores how the model organism Streptomyces coelicolor senses environmental signals, related to oxygen stress and the availability of aminosugars, and how the bacterium translates these into appropriate responses. Show less
Toledo, J.B.; Arnold, M.; Kastenmüller, G.; Chang, R.; Baillie, R.A.; Han, X.; ... ; Kaddurah-Daouk, R. 2017
IntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our... Show moreIntroductionThe Alzheimer's Disease Research Summits of 2012 and 2015 incorporated experts from academia, industry, and nonprofit organizations to develop new research directions to transform our understanding of Alzheimer's disease (AD) and propel the development of critically needed therapies. In response to their recommendations, big data at multiple levels are being generated and integrated to study network failures in disease. We used metabolomics as a global biochemical approach to identify peripheral metabolic changes in AD patients and correlate them to cerebrospinal fluid pathology markers, imaging features, and cognitive performance.MethodsFasting serum samples from the Alzheimer's Disease Neuroimaging Initiative (199 control, 356 mild cognitive impairment, and 175 AD participants) were analyzed using the AbsoluteIDQ-p180 kit. Performance was validated in blinded replicates, and values were medication adjusted.Results Multivariable-adjusted analyses showed that sphingomyelins and ether-containing phosphatidylcholines were altered in preclinical biomarker-defined AD stages, whereas acylcarnitines and several amines, including the branched-chain amino acid valine and α-aminoadipic acid, changed in symptomatic stages. Several of the analytes showed consistent associations in the Rotterdam, Erasmus Rucphen Family, and Indiana Memory and Aging Studies. Partial correlation networks constructed for Aβ1–42, tau, imaging, and cognitive changes provided initial biochemical insights for disease-related processes. Coexpression networks interconnected key metabolic effectors of disease.DiscussionMetabolomics identified key disease-related metabolic changes and disease-progression-related changes. Defining metabolic changes during AD disease trajectory and its relationship to clinical phenotypes provides a powerful roadmap for drug and biomarker discovery. Show less
In this thesis, metabolomics is used to study the role of the host-virus interaction on a metabolic level. A special emphasis is directed on the role of inflammation and oxidative stress on... Show more In this thesis, metabolomics is used to study the role of the host-virus interaction on a metabolic level. A special emphasis is directed on the role of inflammation and oxidative stress on the metabolic level, as part of the innate immune response against viral infection. We chose respiratory syncytial virus (RSV) and hepatitis B virus (HBV) as candidate viruses to metabolically study their role in acute respiratory infection and chronic hepatitis B infection. Secondly we also investigated infant metabolic and immunological consequences of in utero exposure to antiretroviral intervention and human immunodeficiency virus (HIV). Collectively, established targeted metabolomics approaches in conjunction with newly developed metabolomics methodologies and complemented with other “omics” techniques, were used to address pertinent questions related to host metabolic functioning and alterations during viral infection. In vitro RSV studies together with in vivo patient based studies relating to chronic HBV infection and in utero exposure too antiretroviral and HIV were used to address these questions. The work is divided into three research parts containing: i. the analytical methodology development work, ii. in vitro based metabolomics and iii. patient based metabolomics. Show less
Ommen, B. van; Greef, J. van der; Ordovas, J.M.; Daniel, H. 2014
