In this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin... Show moreIn this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin gene on cachexia and diabetes in rodent and zebrafish animal models. 3) how tuberculosis infection and resulting metabolic reprogramming are dependent on leptin signaling in mice and zebrafish larvae. Show less
The research described in this thesis shows that hypercholesterolemia, a well-established risk factor for atherosclerosis, can impact skin lipid pool and barrier function already at young age. In... Show moreThe research described in this thesis shows that hypercholesterolemia, a well-established risk factor for atherosclerosis, can impact skin lipid pool and barrier function already at young age. In the field of atherosclerosis, we showed that the small peptide Lyp-1 can be used as a targeting molecule in liposomal formulations to deliver liver X receptor agonist to plaque resident foam cells/lipid-rich macrophages. Elucidation of the mechanisms underlying the intercommunication between plasma lipids and skin lipids may also bring valuable opportunities to prevent and treat dermatological pathologies in dyslipidemic patients; perhaps in combination with anti-atherogenic therapies. Thus, by deepening our knowledge we may improve our advice to the patients and ultimately improve their quality of life. Show less
In the last few decades, childhood allergy has alarmingly increased to epidemic levels in industrialized countries. Conversely, chronic helminth infections, which are highly prevalent in developing... Show moreIn the last few decades, childhood allergy has alarmingly increased to epidemic levels in industrialized countries. Conversely, chronic helminth infections, which are highly prevalent in developing countries, are negatively associated with allergic disorders. The work in this thesis revealed that, using B-cell IL-10-deficient mice, Schistosoma mansoni-mediated protection against experimental ovalbumin-induced allergic airway inflammation (AAI) was specifically dependent on splenic IL-10-producing CD1dhi regulatory B (Breg) cells. Furthermore, we demonstrated that another B cell subset, located in the lungs, provided protection against AAI, by showing a reduced capacity to initiate Th2 cytokine responses. Markedly, we found a similarly elevated population of IL-10-producing CD1dhi B cells in peripheral blood of Schistosoma haematobium-infected Gabonese children compared to uninfected children. We observed that schistosome-induced Breg cells reduced effector T-cell cytokines and induced more Treg cells. What is interesting in this aspect, is that we found that the Breg cell compartment of patients with allergic asthma is impairment in number and activity. Therefore, the identification of the mechanisms that underlying Breg cell induction by helminths, and the identification the helminth-derived molecules involved, may open novel avenues for the treatment of allergic disease disorders by driving potent Breg cells Show less
The main underlying mechanism resulting in cardiovascular complications is the formation of atherosclerotic lesions in arteries. The progression of the lesion is hallmarked by a chronic... Show moreThe main underlying mechanism resulting in cardiovascular complications is the formation of atherosclerotic lesions in arteries. The progression of the lesion is hallmarked by a chronic inflammatory immune response in the arterial wall. Activated T helper cells differentiate into subsets, each producing a specific set of cytokines. T helper cell subsets contribute to the formation of the lesions, with a pro-atherogenic role for T helper 1 and a protective role for regulatory T cells. Cytokines of the IL-12 family play a crucial role in de differentiation of T helper cells. In this thesis I studied the role of IL-12 family members IL-27, IL-30 and IL-35 in atherosclerotic lesion formation. Furthermore the contribution of IL-37, part of the IL-1 family, was studied. In addition to modifications in lesion size and composition, I focus on the effects of the cytokines on T cell activation and differentiation. Show less
The studies in this thesis are performed to provide additional and improved insight into the effects and interplay of dietary lipids and metabolic inflammation on cardiac performance in the... Show moreThe studies in this thesis are performed to provide additional and improved insight into the effects and interplay of dietary lipids and metabolic inflammation on cardiac performance in the presence or absence of atherosclerosis and myocardial infarctions (MI). We show that high-fat diet feeding has mild but significant detrimental effects on cardiac function. In contrast to our expectations, this effect is not likely to be mediated by Toll-like receptor 2 or Toll-like receptor 4. Also, we demonstrated in mice that high-fat diet feeding does not significantly aggravate cardiac dysfunction post-MI. Deficiency of RP105, a modulator of inflammation, improved cardiac function after induction of MI. In addition, ABCA1 had adverse effects on cardiac function post-MI, possibly via a reduced activation of immune cells. This confirms the important role of inflammation in recovery after MI. Furthermore, we elucidated a possible reason for the failure of niacin in recent clinical trials and found that niacin__s anti-atherogenic properties are most potent by lowering LDL-cholesterol on top of statin treatment. Altogether, these results provide novel insights and targets for the prevention or treatment of cardiovascular diseases. Show less
Chronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new... Show moreChronic stress is considered a vulnerability factor for depression. A key symptom is anhedonia; a reduced response to positive stimuli. Drugs are effective for only 20-40% of the patients and new drugs are urgently needed. The objective of the research was to develop a mouse model of depression that would express anhedonia, induced by chronic stress. Mice were repeatedly exposed to the non-physical presence of a rat. Alterations in stress system activity were measured. Anhedonia was assessed by studying the behavioral response to positive stimuli. As a potential therapeutical approach we assessed reward expectation, and studied the effect of repeated administration of mifepristone (glucocorticoid receptor antagonist), directly targeting stress system regulation. Our model induced changes in the sensitivity of the reward system that contributed to cognitive impairments underlying anhedonia. The effects could partially be restored by additional reward. Mifepristone in na_ve mice suppressed stress system activity, which could indicate a similar direction of effects in stressed mice if provided. Concluding, our chronic stress mouse model induces anhedonia. The new methodology to reduce stress by either providing additional positive stimuli or mifepristone, increases the well being of the mice and may prove a new drug target to treat depression in humans. Show less
The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN... Show moreThe studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM. Show less
Stress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid... Show moreStress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid receptors as nuclear transcription factors. The lack of the p66Shc gene reduces OS and increases lifespan in mice. Main aim of the study was to elucidate whether the interactions linking OS and the neuroendocrine system represent a crucial determinant of aging in p66Shc-/- mice. Thus, the contribution of p66Shc to behaviour and neuroendocrine regulations was assessed from early post-natal life to senescence. Mutant old mice were characterized by a slow-down in physical and emotional aging; adult subjects showed increased behavioural plasticity and lower emotionality associated to increased central levels of Brain-derived neurotrophic factor, reduced oxidative stress markers and greater resilience to stress-induced changes in the internal milieu. A role has been recently described for p66Shc in regulating energetic metabolism. Intriguingly, we found metabolic and emotional aspects to be strictly related and possibly mediated by maternal behaviour in these mutants. Our results shed light on the role played by OS and metabolism in longevity and emotionality/mood disorders and point to p66Shc as a candidate gene in the trade-off between fertility and lifespan. Show less
Atherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i... Show moreAtherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i.e. elevated plasma levels apo-B-containing lipoproteins) is a major causative factor in atherogenesis. It is equally clear that atherogenesis has an inflammatory component which is thought to drive the progression of the disease. However, while the lipid component in atherosclerosis development is relatively well-understood, the origin and exact contribution of the inflammatory component remains largely unknown. The aim of this thesis is to further define and delineate the contribution of the inflammatory component to the atherosclerotic process and to elucidate the link between cholesterol and inflammation in atherosclerotic lesion formation and progression. The studies of this thesis show that, besides plasma cholesterol, inflammation contributes to a substantial extent to atherogenesis. Intervention strategies directed at lowering apoB-containing lipoproteins and reducing inflammation may therefore be more effective than current lipid-lowering strategies. Direct experimental evidence for this assumption mainly comes from animal experiments as described in this thesis. Human intervention studies are necessary to evaluate whether these findings can also be translated to the human situation. Show less
Synthetic peptide vaccines aiming at the induction of a protective CD8+ T-cell response against infectious or malignant diseases are widely used in the clinic but, despite their success in animal... Show moreSynthetic peptide vaccines aiming at the induction of a protective CD8+ T-cell response against infectious or malignant diseases are widely used in the clinic but, despite their success in animal models, they do not yet live up to their promise in humans. This thesis assesses the development of synthetic peptide vaccines, weighs it against the immunological concepts that have emerged, and identifies the key issues that play a role in the failure or success of a synthetic peptide vaccine. The current state-of-the-art peptide vaccine is a complete synthetic inflammatory product that is ingested by professional antigen-presenting cells and stimulates both CD4+ and CD8+ T cells. Show less
An adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to... Show moreAn adverse early life event is considered a risk factor for stress-related psychiatric disorders in genetically predisposed individuals, probably because of its lasting effect on susceptibility to stress. The objective of this thesis research was to examine in the mouse CD1 strain the immediate and permanent effects of an adverse early experience on the neuroendocrine stress system. For this purpose the hypothalamic-pituitary-adrenal (HPA) axis was examined of mouse pups that were refrained from maternal care, a laboratory model for neglect mimicking aspects of abuse. The data show that the infants__ stress response system readily adapts to daily repeated 8 hours of maternal separation, but that it continues to respond to a novelty stressor. The rapid adaptation to repeated maternal absence seems rather due to the ability to predict return of the mother than to adjust metabolism to episodic food deprivation. If maternal separation was extended to a single episode of 24 hours the immediate outcome was more profound but transient, although subtle effects on stress reactions and cognitive performance did persist. The findings demonstrate the amazing plasticity of the newborn brain and provide a basis to study the mechanistic underpinning of vulnerability or resilience to psychopathology. Show less
Hyperlipidemie is een belangrijk gezondheidsrisico in de westerse samenleving en direct gerelateerd aan diabetes en overgewicht. Zowel eetgewoontes als genetische afwijkingen kunnen zorgen voor een... Show moreHyperlipidemie is een belangrijk gezondheidsrisico in de westerse samenleving en direct gerelateerd aan diabetes en overgewicht. Zowel eetgewoontes als genetische afwijkingen kunnen zorgen voor een verstoord vetmetabolisme en ophoping van cholesterol en triglyceriden in het bloed. Pati_nten die lijden aan Familiaire Dysbetalipoproteinemie hebben een genetisch defect in apolipoproteine E (apoE). ApoE is een eiwit dat een centrale rol speelt in het vetmetabolisme. ApoE bevindt zich op lipoproteine deeltjes die cholesterol en triglyceriden door het bloed vervoeren en zorgt voor interactie met enzymen en receptoren. Een genetisch defect in apoE zal resulteren in verhoogde niveaus van "very-low density lipoprotein" (VLDL) deeltjes in de bloedbaan. In dit proefschrift zijn de positieve en negatieve effecten van apoE in VLDL metabolisme besproken. Negatieve effecten zijn een klaringsdefect dat is geassocieerd met APOE2, maar ook een toename van productie snelheid en verminderde lipolyse van VLDL door overexpressie van APOE4. We vonden dat wanneer het C-terminale domein van APOE4 wordt verwijderd, dit eiwit de APOE2-geassocieerde hyperlipidemie verlaagt. Deze getrunceerde variant van APOE4 heeft niet het lipiden verhogende effect van apoE. Verder hebben we nieuwe inzichten verkregen in de rol van LPL-gemedieerde VLDL-TG hydrolyse in APOE-geassocieerde hyperlipidemie en de interactie tussen LPL, apoE en de back-up lever receptor LRP Show less
All organisms are composed of cells and the cell's nucleus contains DNA. The induction of DNA damage is a threat to organisms. Signalling of DNA damage and subsequent repair is of substantial... Show moreAll organisms are composed of cells and the cell's nucleus contains DNA. The induction of DNA damage is a threat to organisms. Signalling of DNA damage and subsequent repair is of substantial importance. Double-strand breaks (DSBs) in DNA can be induced by ionising radiation and DNA damaging agents but also arise as intermediates in several cellular processes (e.g. meiosis). DSBs are among the most genotoxic DNA lesions and their accurate repair is crucial. Genetic instability resulting from unrepaired DSBs can lead to cell death and, in a multicellular organism, to cancer. There are two major DSB repair pathways: homologous recombination (HR) and non-homologous endjoining (NHEJ). By NHEJ, broken DNA is sealed together, irrespective of sequence homology, in a not necessarily error-free way. HR, in which a homologous DNA molecule is needed as a template, accurately repairs DSBs. In this thesis we mainly focus on recombinational repair proteins of the RAD52 epistasis group and involved in HR. We analyse the biochemical properties of two Rad52 homologs in S. pombe, Rad22A and Rad22B. We examine combined mutations in RAD52 and RAD54 homologs in S. pombe and mice. We investigate the importance of sumolyation of recombinational repair proteins. We also introduce mice deficient in Sycp1, important for coordination during meiosis and the formation of crossovers Show less
In this thesis we focus on atherosclerosis as the main cause of cardiovascular disease. Since inflammation and cell death are important processes in the onset and progression of atherosclerosis, we... Show moreIn this thesis we focus on atherosclerosis as the main cause of cardiovascular disease. Since inflammation and cell death are important processes in the onset and progression of atherosclerosis, we investigate the role of several genes involved in inflammation and cell death in the vessel wall and their effect on atherosclerosis. We use several ways to modulate gene expression. Examples from different chapters are whole body deletion of TNF (2), local gene targeting of Fas Ligand to the cap of the plaque (3), conditional gene targeting of mdm2, thereby upregulating p53 (4), and beta-galactosidase (5), and pharmacological targeting of PPARs (6). In this thesis we use various mouse models of atherosclerosis, such as the apoE deficient mouse, the "humanized" apoE3*Leiden mouse and accelerated atherosclerosis induced by collar placement. Show less
