Disease states atherosclerosis

PTKs have been implicated in the regulation of a variety of biological responses such as cell proliferation, migration, differentiation, and survival. They have been demonstrated to play significant roles in the development of many disease states, including immunodeficiency, atherosclerosis, psoriasis, osteoporosis, diabetes, and cancer. In recent clinical trials impressive antitumor effects of PTK inhibitors have been observed. In future, PTK inhibitors may therefore become important drugs for the treatment of specific cancers. 

Although atherosclerosis and rheumatoid arthritis (RA) are distinct disease states, both disorders are chronic inflammatory conditions and may have common mechanisms of disease perpetuation. At sites of inflammation, such as the arterial intima undergoing atherogen-esis or the rheumatoid joint, oxygen radicals, in the presence of transition-metal ions, may initiate the peroxidation of low-density lipoprotein (LDL) to produce oxidatively modified LDL (ox-LDL). Ox-LDL has several pro-inflammatory properties and may contribute to the formation of arterial lesions (Steinberg et /., 1989). Increased levels of lipid peroxidation products have been detected in inflammatory synovial fluid (Rowley et /., 1984 Winyard et al., 1987a Merry et al., 1991 Selley et al., 1992 detailed below), but the potential pro-inflammatory role of ox-LDL in the rheumatoid joint has not been considered. We hypothesize that the oxidation of LDL within the inflamed rheumatoid joint plays a pro-inflammatory role just as ox-LDL has the identical capacity within the arterial intima in atherosclerosis. 

The disturbance of balance between superoxide and nitric oxide occurs in a variety of common disease states. For example, altered endothelium-dependent vascular relaxation due to a decrease in NO formation has been shown in animal models of hypertension, diabetes, cigarette smoking, and heart failure [21]. Miller et al. [22] suggested that a chronic animal model atherosclerosis closely resembles the severity of atherosclerosis in patients. On the whole, the results obtained in humans, for example, in hypertensive patients [23] correspond well to animal experiments. It is important that endothelium-dependent vascular relaxation in patients may be improved by ascorbic acid probably through the reaction with superoxide. 

Our most common lethal disease is atherosclerosis, which causes constriction and blockage of arteries of the heart, brain, and other organs. In the United States, Europe, and Japan half of all deaths can be attributed to this ailment.a,b There seems to be a variety of causes. However, there is agreement that the disease begins with injury to the endothelial cells that form the inner lining of the arteries.3/C/d This is followed by the aggregation of blood platelets at the sites of injury and infiltration of smooth muscle cells, which may be attracted by 12-hydrox-yeicosotetraenoic acid and other chemoattractants formed by activated platelets.c "Foam cells" laden with cholesterol and other lipids appear, and the lesions enlarge to become the characteristic plaques (atheromas). 

Disorders in lipoprotein metabolism are critical in the etiology of several disease states, such as coronary heart disease and atherosclerosis. Thus, there is considerable interest in the development of novel methods for the analysis of lipoprotein complexes. A simple chromatographic method for the separation of high-density lipoprotein (HDL), low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) from intact serum or plasma has been reported recently [65]. The separation was achieved by using an hydroxyapatite column and elution with pH 7.4 phosphate buffer with lOOpl injections of whole... 

However, apart from disease states, there is a natural evolution of cytokine production with aging, including decreased T cell proinflammatory IL-2 and interferon-7 (type II pro-inflammatory IFN-7), decreased non-T cell antiinflammatory type I IFN (IFN-a and IFN-/3), and increased non-T cell proinflammatory IL-1, IL-6, and tumor necrosis factor a (TNF-o) [90], The IL-6 is one of the pathogenic elements of inflammatory and age-related diseases (AD and atherosclerosis) and has been defined as the cytokine for gerontologists [91]. 

Angiotensin II is an octapeptide, which was initially described as a potent vasoconstrictor agent. However, its functions have since been expanded to include regulation of cell growth, inflammation, electrolyte and water balance, hormone secretion, sympathetic nervous system activity, differentiation, and apoptosis. The discovery that it is produced both systemically and locally was instrumental in establishing a pivotal role for the peptide in several disease states, including hypertension, coronary heart disease, myocarditis, congestive heart failure, atherosclerosis, and nephrosclerosis. 

Increased levels of ROS due to oxidative stress have been consistently found in cardiovascular diseases as atherosclerosis or hypertension [18]. There is certain evidence that the free radicals involved in Parkinson s disease are mainly due to the production of increased levels of free radicals during oxidative metabolism of dopamine [19]. Oxidative stress, manifested by protein oxidation and lipid peroxidation (LP), among other alterations, is a characteristic of Alzheimer s disease [20] and in the pathogenesis of diabetes related complications. Treatment with antioxidants seemed to be a promising therapeutic option for these diseases [21], The inflammatory nature of rheumatoid arthritis implies that a state of oxidative stress may also exist in this disease [22,23]. Also, free radicals have a certain role in Huntington s disease [24,25], age related degeneration [26], and some autoimmune disorders [27],... 

Several disease states can result from abnormal blood clots. For example, strokes were mentioned previously. However, the most common and deadliest thrombotic disease is myocardial infarction (MI). Atherosclerosis has long been associated with reduced cardiac function and elevated mortality due to rupture of atherosclerotic plaques. The rupture of an atherosclerotic plaque usually results not only in blockage due to the plaque itself but also in the immediate formation of an occlusive blood clot, which results in an MI. Immediately after the initiation of an MI, a zone of necrosis begins to develop around the area as ischemia proceeds. It is during this early phase of ischemia (several hours) that therapeutic intervention not only can be life-saving but also can minimize the amount of necrotic heart tissue formed. 

Aberrant thrombus formation and deposition on blood vessel walls imderlies the pathogenesis of acute cardiovascular disease states which remain the principal cause of morbidity and mortality in the industrialized world [1,2,3]. Plasma proteins, proteases and specific cellular receptors that participate in hemostasis have emerged as important risk considerations in thrombosis and thromboembolic disorders. The clinical manifestations of the above disease states include acute coronary artery and cerebrovascular syndromes, peripheral arterial occlusion, deep vein thrombosis and pulmonary/renal embolism [3]. The most dilabilitating acute events precipitated by these disorders are myocardial infarction and stroke. In addition, the interplay between hemostatic factors and hypertension (4) or atherosclerosis (5) dramatically enhances the manifestation of these pathologic states. 

In evaluating drugs in man, there also have been improvements in methodology, particularly in the design of better controlled experiments and the use of statistical techniques to interpret the data. This has been more significant in disease conditions in which subjective factors may obscure the interpretation of results. However, in some major diseases, as for example atherosclerosis, osteoporosis, and connective tissue degenerations, the absence of reliable qualitative measures for early identification of the disease state and quantitative measures for comparing improvements or deteriorations have become a much more serious limitation than they were 10 years ago. The requirement for proof of efficacy of a... 

Coronary heart disease and atherosclerosis are major contributors to morbidity and mortality in the United States and other developed countries. Epidemiological studies suggest that decreased mortality from coronary heart disease is associated with moderate consumption of alcohol, and especially of red wine [7], Numerous studies indicate that resveratrol inhibits platelet aggregation [8-10, 12, 16, 54, 55], alters eicosanoid synthesis [15, 55], modulates lipoprotein mechanisms [14, 56-58], inhibits vascular smooth muscle cell proliferation [59], and acts as an estrogen receptor agonist [60]. On the other hand, at least one earlier study indicated that it promoted atherosclerotic development, rather than protected against it, by a mechanism that appeared to be independent of observed... 

Miscellaneous - One of the major problems facing researchers in the atherosclerosis field is the lack of a good laboratory model that resembles the human disease state. Several leads in this area were described during the year. Kramsch and coworkers reported that they Induced severe coronaiy atherosclerosis with 60 6 narrowing of the arterial lumen in all of 40 Macaca Irus monkeys fed a lipid diet for 18 months. The lesions resembled human disease in distribution and microscopic appearance. Similar deposits were also induced in rabbits by homocysteine administration and by allergic injury. ... 

The study commission s basic approach to primary prevention of atherosclerosis in this country is threefold. They suggest a reduction of hypolipidemia and associated disease states by dietary restrictions, pharmacologic control of elevated blood pressure and elimination of cigarette smoking. 

Blood and lymphatic vessels are soft tissues with densities which exhibit nonlinear stress-strain relationships [1]. The walls of blood and lymphatic vessels show not only elastic [2, 3] or pseudoelastic [4] behavior, but also possess distinctive inelastic character [5, 6] as well, including viscosity, creep, stress relaxation and pressure-diameter hysteresis. The mechanical properties of these vessels depend largely on the constituents of their walls, especially the collagen, elastin, and vascular smooth muscle content. In general, the walls of blood and lymphatic vessels are anisotropic. Moreover, their properties are affected by age and disease state. This section presents the data concerning the characteristic dimensions of arterial tree and venous system the constituents and mechanical properties of the vessel walls. Water permeability or hydraulic conductivity of blood vessel walls have been also included, because this transport property of blood vessel wall is believed to be important both in nourishing the vessel walls and in affecting development of atherosclerosis [7-9]. 

Niacin is a water-soluble vitamin that has been available as a lipid-lowering medication and in prevention of atherosclerosis for half a century (Ganji et al. 2003 Olsson 2010). Numerous studies have documented its beneficial effects on reducing cardiovascular disease (CVD) (Olsson 2010). Clinically, the most well-known effect of niacin deficiency is pellagra which, as noted above, is manifested by dermatitis, diarrhoea and dementia (Bodor and Offermanns 2008 Ganji, et al. 2003). In this chapter we look at the effects of niacin on human physiology and its consequent effects on disease states. 

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