Annals of medicine
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The pathophysiology of tobacco-related diseases is complex and multifactorial. Among the approximately 4,000 compounds in tobacco smoke are carcinogens such as nitrosamines, irritants such as a variety of phenolic compounds, volatiles such as carbon monoxide, and of course nicotine. ⋯ This review discusses the mechanisms by which nicotine contributes to tobacco-related disease, with a focus on the surprising new finding that nicotine is a potent angiogenic agent. Nicotine hijacks an endogenous nicotinic cholinergic pathway present in endothelial cells that is involved in physiological, as well as pathological angiogenesis.
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For many years the functional sequelae of chronic coronary artery disease (CAD) were considered irreversible. Evidence accrued over the past three decades proves that this concept is not necessarily true. Non-randomised studies demonstrated that coronary revascularisation (CR) confers symptomatic and prognostic benefits to patients with CAD and heart failure. ⋯ PET studies have shown that resting myocardial blood flow is preserved in most cases of HM while its main feature is a severe impairment of coronary flow reserve. Thus, the pathophysiology of HM is more complex than initially postulated. Recent evidence that repetitive ischaemia in patients can be cumulative and lead to more severe and prolonged stunning, lends further support to the hypothesis that, at least initially, stunning and HM are two facets of the same coin.
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Caveolae are vesicular organelles (50-100-nm in diameter) that are particularly abundant in cells of the cardiovascular system, including endothelial cells, smooth muscle cells, macrophages, cardiac myocytes and fibroblasts. In these cell types, caveolae function both in protein trafficking and signal transduction, as well as in cholesterol homeostasis. Caveolins are the structural proteins that are both necessary and sufficient for the formation of caveolae membrane domains. ⋯ These disease phenotypes include: atherosclerosis, cardiac hypertrophy, cardiomyopathy, pulmonary hypertension, and neointimal hyperplasia (smooth muscle cell proliferation). In addition, caveolins play a significant role in other disease phenotypes, such as cancer, diabetes, bladder dysfunction, and muscular dystrophy, as we discuss in this review. Thus, caveolin-deficient mice will serve as important new animal models to dissect the intricate role of caveolae and caveolins in the pathogenesis of human diseases.
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Oxidized derivatives of cholesterol have been investigated actively for decades in the context of the oxidative hypothesis of atherosclerosis. Oxysterols arise in our tissues as a result of enzymatic or non-enzymatic oxidation reactions and are also obtained from dietary sources. ⋯ Work during the past few years has revealed that oxysterols have a potential as signaling molecules that may play important roles in lipid metabolism, especially the reverse cholesterol transport process. This finding has recently moved oxysterols and the protein mediators of their biological effects, liver X receptors and cytosolic oxysterol binding proteins, into the center stage of atherosclerosis research.
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The metabolism and elimination of drugs is mainly mediated by cytochrome P450 (CYP) enzymes, aided by conjugative enzymes and transport proteins. An integral aspect of this elimination process is the induction of drug metabolism through activation of gene expression of metabolic and transport proteins. ⋯ This review outlines the basic properties of CAR and PXR, their ligands and target genes, and the mechanisms of the induction process. The implications of nuclear receptor-mediated induction for drug research are also discussed.