Drug induced organ toxicity is the main problem of the drug development and drug usage in the clinic. The liver and kidneys are the most sensitive organs towards drug induced toxicity. The liver... Show moreDrug induced organ toxicity is the main problem of the drug development and drug usage in the clinic. The liver and kidneys are the most sensitive organs towards drug induced toxicity. The liver neutralizes xenobiotic to which human are exposed to while the kidneys remove waste products from the blood. Due to their detoxification function, these organs are continuously exposed to high amount of toxicants leading to potential injury. Investigating the molecular and cellular mechanisms contributing to drug-induced liver injury (DILI) and drug-induced kidney injury (DIKI) will open new avenues that can help in the prediction of induced organ injury caused by drugs as well as other xenobiotics.In this thesis, we mapped the dynamics of cellular stress responses in the liver and kidneys upon the exposure of a set of model compounds in order to gain a more holistic insight in DILI and DIKI. We conducted multiple extensive in vitro and in vivo studies to understand the dynamics of these cellular responses and determined the translation of our findings from in vitro to in vivo. Transcriptomics analysis was central in the research which was complemented with other methodologies, such as reporter cell assay, immunohistochemistry, to unravel the mechanisms of drug-induced organ toxicity in both liver and kidney. Show less
Drug-induced organ toxicity is a major concern for pharmaceutical industry, due to removal of a high number of drugs from the market, as well as for public health, due to numerous hospitalizations... Show moreDrug-induced organ toxicity is a major concern for pharmaceutical industry, due to removal of a high number of drugs from the market, as well as for public health, due to numerous hospitalizations and patient death. The organs that are the primary target for such toxicities are the liver and the kidneys since both organs are continuously exposed to high concentrations of drugs and have high metabolic capacities. The immune system has been shown to be involved in the toxicity of several drugs- inducing liver and kidney injury. In particular, the cytokine tumor necrosis factor _ (TNF-_) has been shown to be the main constituent of the inflammatory processes responsible for the aggravation of drug-induced liver and kidney injuries. In this thesis, the role of TNF-_ in drug-induced organ injury was investigated. The main question was to assess the possible synergy between TNF-_ and druginduced cytotoxicities, and to unravel the underlying molecular mechanisms of such a synergy. Show less
Atherosclerosis is the underlying cause of most cardiovascular diseases. The evidence to support a cholesterol-atherosclerosis link has been revealed in the past three decades. There is a growing... Show moreAtherosclerosis is the underlying cause of most cardiovascular diseases. The evidence to support a cholesterol-atherosclerosis link has been revealed in the past three decades. There is a growing consensus that therapeutic lowering of plasma VLDL- and LDL-cholesterol levels and raising of HDL-cholesterol level will reduce the risk of cardiovascular incidence. This dissertation is dedicated to the regulation of lipid metabolism pathways, both in plasma and liver, and its subsequent effects on atherosclerotic lesion progression and regression. The first part of the thesis focuses on the hepatic lipid metabolism and the pharmaceutical interventions in the liver. The second part of the thesis focuses on the concept of atherosclerotic lesion regression, shedding insights in the role of LXR activation and application of mouse models in regression studies. In Chapter 8, the results obtained from all the experiments mentioned above are summarized and discussed with respect to the implications of these studies for future investigations. Show less
