Plant exudates appeared long time ago in the history line of life in the early Devonian. They are typical saps produced by specialized cells. They can be naturally excreted outside or right after... Show morePlant exudates appeared long time ago in the history line of life in the early Devonian. They are typical saps produced by specialized cells. They can be naturally excreted outside or right after plants are damaged or infected. Through time, diverse cultures recognized them as valuable sources of natural medicines. Of various types of plant exudates, the most outstanding are gums, mucilage, essential oils, oleoresins, resins, phloem like saps, and latexes. Regardless of their commercial importance, in the aspect of biology, plant exudates are believed to be involved in plant defense mechanisms, but their roles still remain unclear. In this thesis, based on diverse experiments, many features of plant exudates were unveiled. Interestingly, even if plant exudates possess a broad chemical diversity, their specialized biological functions resulted in less variation of their metabolomes as compared with their bearing tissues. This lower variation indicates that plant exudates might partake of a general-broad defense against herbivores and pathogens in their bearing tissues. This defense involves both mechanical and chemical traits which might complement and modulate each other, eventually resulting in a chemo-mechanical defense layer. Of the diverse chemicals in plant exudates, terpenes are one of the most common metabolites in these saps. Show less
The focus of this thesis is uveal melanoma (UM) which, once metastasized, is lethal due to lack of effective treatment options. To repress p53 activity approximately 65% of UM tumors express high... Show moreThe focus of this thesis is uveal melanoma (UM) which, once metastasized, is lethal due to lack of effective treatment options. To repress p53 activity approximately 65% of UM tumors express high levels of the p53 inhibitory proteins MDMX or MDM2. The aim of this thesis is to unravel the oncogenic function of MDMX and provide new treatment options for patients with metastasized UM. Chapter 2 describes the regulation of the transcriptome by MDMX in UM and proposes novel p53-independent effects of MDMX, i.e. FOXO inhibition. In chapter 3 the opportunities of a combined targeting of two common signaling pathways as therapeutic intervention for metastasized UM patients is investigated. Genetic interference with either MDMX or PKC δ expression or activity showed that beneficial effects can already be achieved by a more specific targeting, which is presumable less toxic to the patient. In chapter 4 it is described, opposed to what has been reported before, that enhancer of zeste homolog 2 (EZH2) inhibition poses a valuable novel therapeutic invention for UM. In chapter 5 it is shown that combining two clinically approved drugs, Quisinostat and Flavopiridol, could serve as an effective therapeutic intervention for UM patients. Show less
Haaften, C. van; Eendenburg, J. van; Boot, A.; Corver, W.E.; Haans, L.; Wezel, T. van; Trimbos, J.B. 2017
The plant kingdom has evolved an enormous number of chemically diverse metabolites that protect plants from biotic and abiotic stresses. The large number of metabolites in a given plant indicates... Show moreThe plant kingdom has evolved an enormous number of chemically diverse metabolites that protect plants from biotic and abiotic stresses. The large number of metabolites in a given plant indicates interactions between metabolites are very likely. The co-occurrence of plant metabolites comprise a natural background where these metabolites have to function and this is often overlooked or ignored in ecological studies. The main goal of this thesis is to understand the importance of metabolite interactions I used assays with a generalist herbivore to study the interactions between chlorogenic acid (CGA), pyrrolizidine alkaloids (PAs) and fractions from Jacobaea plants. I found that PA free bases, PA N-oxides (the oxidized form of free base) and CGA decreased thrips survival. Although PA free bases and CGA decreased thrips survival, the combination of the two toxins was less toxic than the single toxins. In contrast, the combination of PA N-oxides with CGA enhanced the toxicity against thrips in a synergistic way. Adding PAs to different plant fractions showed that metabolite interactions on thrips survival are common as in all tested combinations we found antagonistic and synergistic effects. Clearly, bioactivity of a metabolite is strongly dependent upon the co-occurrence of metabolites in the plant cell. Show less
Haaften, C. van; Boot, A.; Corver, W.E.; Eendenburg, J.D.H. van; Trimbos, B.J.M.Z.; Wezel, T. van 2015
Embryonic EPDCs are crucial for proper myocardial architecture and coronary vessel formation, both through their physical contribution and their regulatory role in these developmental processes.... Show moreEmbryonic EPDCs are crucial for proper myocardial architecture and coronary vessel formation, both through their physical contribution and their regulatory role in these developmental processes. This thesis reports for the first time on the role of Epicardium-Derived Cells (EPDCs) in the adult ischemic heart. It is demonstrated that transplanted adult EPDCs, isolated from human adult epicardial tissue, improve left ventricular function of the ischemic mouse heart. This is probably instigated by an early paracrine-mediated stimulation of the injected EPDCs on the surrounding host tissue, as indicated by increased wall thickness, augmented vascular density (mouse origin), and enhanced DNA-damage repair activity of the endogenous tissue. Cardiac healing in the EPDC-recipients is further characterized by advanced WT-1 expression, a marker for undifferentiated EPDCs, indicating induction of endogenous epicardial activity. Strikingly, the benefit of EPDC injection can be further enhanced by adding complementary cardiomyocyte progenitor cells to the EPDC transplant, explained by synergistic paracrine actions of the two different cell types. Two different techniques for assessment of left ventricular function in the post-infarct failing mouse heart are evaluated. It is shown that both conductance catheter and magnetic resonance imaging are reliable methods, each having specific unique features which need to be considered during experimental set-up. Show less
