Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 5, Issue 1, 2005

Active prevention of coronary heart disease (CHD) is usually started immediately after the first clinical manifestation of CHD. Secondary prevention focuses on risk reduction in patients with established CHD who are at high risk of recurrent cardiac events and death from cardiac causes. It is important to remember that the two main causes of death in these patients are sudden cardiac death (SCD) and heart failure (HF), often resulting from myocardial ischemia and subsequent necrosis. The main mechanism underlying recurrent cardiac events is myocardial ischemia resulting from atherosclerotic plaque rupture or ulceration. Plaque rupture is usually the consequence of intraplaque inflammation in relation with a high lipid content of the lesion, high concentration of leukocytes and lipid peroxidation products. Thus, in patients with established CHD, the three main aims of the preventive strategy are to prevent malignant ventricular arrhythmia and the development of severe ventricular dysfunction (and heart failure) and to minimize the risk of plaque inflammation and ulceration.

Cardiovascular diseases are the leading cause of morbidity, disability and death worldwide. The importance of the burden of cardiovascular diseases varies geographically and evolves simultaneously to the change in societies. The changes in patterns of diseases and their interaction with socio-economic transformation have been termed “epidemiological transition”. The present paper presents public health perspective of the evolution of cardiovascular risk profile associated to high dietary salt consumption in both developed and developing countries. The model of primary prevention of hypertension through non-pharmacological methods is presented as an effective population approach to reduce the risk of cardiovascular morbidity and mortality. In particular, the results of randomized controlled trials unequivocally show the efficacy of moderate sodium restriction in lowering blood pressure in both normotensive and hypertensive individuals. The effect of this measure is larger in hypertensives, elderly and “low-renin” black populations. Finally, the appropriateness and efficacy of a population approach to reduce salt consumption in developed as well in developing countries are discussed.

A dietary pattern characterized by high sodium and low potassium intake contributes unequivocally to a rise in blood pressure and eventually to hypertension. The purpose of this review is to discuss here the complex relationship among dietary potassium, potassium homeostasis and blood pressure regulation. Potassium is the major intracellular cation in the body. The fine regulation of its balance rely on a close interplay between extrarenal and renal mechanisms aimed to maintain the large concentration gradient between intracellular and extracellular potassium. Apparently, the homeostatic control of potassium balance is less effective in preventing subtle or major potassium deficiencies induced by chronic subnormal potassium intake. The hypothesis that low potassium intake may cause a rise in blood pressure derives from epidemiological surveys showing an inverse relationship between individual blood pressure levels and 24-hour urinary potassium excretion. The results of the clinical trials confirmed that an increase of potassium intake lowers blood pressure in patients with hypertension and, to a lesser extent, in normotensive subjects. Furthermore, there is promising evidence that an increase in potassium intake (namely from fruit and vegetables) is associated with a reduction in stroke mortality. We conclude that increasing dietary potassium through an increase in the consumption of fruit and vegetables is an important public health target.

The Mediterranean diet is currently attracting interest because of its health benefits that may be due, in part, to the high content of this diet in antioxidant phytochemicals. The variety and amount of phytochemicals taken with the consumption of primary and composite foods of the Mediterranean diet may provide better antiatherogenic properties than single phytochemicals. Flavonoids are the most important group of plant antioxidants. The Mediterranean diet is characterized by high intake of olive oil, fruit, vegetables, cereals, and legumes, some of which are good sources of flavonoids. Flavonoids consist of six principal classes: flavones, flavonols, flavan-3-ols, flavanones, anthocyanidins and isoflavones. The flavonoid intake from a traditional Greek plant-based weekly menu was calculated and the daily average flavonoid intake was found 118.6 mg / d, of which flavanones contribute 32% (38.5 mg / d), catechins (the most important group of flavan-3-ols) contribute 28% (32.7 mg / d), flavonols 22% (26.4 mg / d), anthocyanidins 9% (11 mg / d), flavones 8% (8.7 mg / d) and isoflavones contribute 1% (1.3 mg / d). Herbs and spices, which are commonly used in the traditional Greek cuisine, although added in small quantities, significantly contribute to the flavonol and flavone intake due to frequent consumption. The Greek version of the Mediterranean diet with its high consumption of fruit and vegetables is characterized by high intake of flavonoids in comparison to diets in northern European countries.

Atherosclerosis remains a major cause of morbidity and mortality worldwide. Conventional risk factors do not completely account for the development of atherosclerosis and its complications. Accumulating data suggest that endothelial dysfunction has independent prognostic implications. It has been implicated in the initiation of atherosclerosis, the precipitation of acute ischaemia, and the determination of the extent of injury following such complications. Atherosclerosis develops as a consequence of lipid accumulation in the vessel wall, a co-existent inflammatory response and proliferation of smooth muscle cells; endothelial dysfunction can be added to this pathogenic triad. The endothelium regulates numerous blood vessel functions, including vascular tone, cell adhesiveness, and coagulation through the production of mediators. The best characterized of these are the vasodilators, nitric oxide (NO), prostacyclin, and endothelium derived hyperpolarising factor (EDHF), and the vasoconstrictors thromboxane and endothelin. Endothelial dysfunction may encourage the adhesion and transmigration of monocytes and platelets to initiate and promote atherosclerosis. In addition, endothelial dysfunction may precipitate the acute complications of atherosclerosis through vasospasm and thrombosis, and may be a determinant of the transition from stable chronic atherosclerosis, to the development of acute coronary syndromes. Understanding of the biology of the endothelium in atherosclerosis may lead to novel therapies that will retard its progression, and reduce the incidence or consequences of acute complications.

In the past several decades, research has defined a cluster of metabolic abnormalities with insulin resistance as a major component. Key metabolic disturbances for this syndrome include dyslipidemia (low concentrations of HDL cholesterol, and elevated concentrations of triglycerides, VLDL, and small dense LDL), hypertension, chronic inflammation, procoagulation and impaired fibrinolysis. More recently, an impressive body of epidemiologic data indicates that colon cancer, and possibly some other malignancies, are associated with the insulin resistance syndrome. This evidence includes studies of determinants of the insulin resistance syndrome (obesity, abdominal distribution of adiposity, physical inactivity), metabolic consequences (type 2 diabetes, hypertriglyceridemia, hyperglycemia), and plasma or serum markers (insulin, C-peptide) in relation to colon cancer risk. The mechanism underlying these associations is unknown, but may involve the influence of hyperinsulinemia in enhancing free or bioavailable IGF-1 levels. For other cancers related to obesity, the evidence is suggestive but less firm as that for colon cancer. The role of diet on insulin resistance and hyperinsulinemia is multifactorial; future studies should focus on the comprehensive dietary pattern on insulin resistance and hyperinsulinemia as well as on cancer risk, instead of individual factors. Future studies should also be based on better measurements of insulin resistance, β-cell depletion, and insulin response to assess better which aspects of the insulin resistance are most closely related to cancer risk.

Regular consumption of fruit and vegetables is associated with reduced risks of cancer, cardiovascular disease and other aging-related diseases. Convincing evidence exists suggesting that an increased fruit, vegetables, and grains consumption is a relatively easy and practical strategy to significantly reduce the incidence of chronic diseases. Cancer chemoprevention intends to interrupt the carcinogenesis process, which includes initiation, promotion and progression of otherwise normal cells to reduce cancer. Despite the failure of β-carotene clinical trial to prevent lung cancer, the development of diet-derived constituents represents one of the major goal in cancer chemoprevention. A key question is whether a purified phytochemical has the same protective effects as does the whole food or mixture of foods in which the phytochemical is present. Putative chemopreventive agents are identified on the basis of epidemiological and in vitro and in vivo studies. All these compounds present tumor-suppressing properties in animal models of carcinogenesis, and they interfere with cellular processes involved in tumor formation, such as suppression of NF-kB and AP1 activation, induction of apoptosis, downregulation of β-catenin expression and activation of ARE / EpRE-dependent gene expression. Phase I clinical trials have been completed only for few of these phytochemicals, and pilot phase II-III trials are planned. In this review, we will begin by describing the different methodological approaches in studying chemopreventive agents, followed by the description of the mechanisms by which these compounds act. Finally, we will review more in details data concerning well-known and promising chemopreventive phytochemicals.

Obesity is emerging as the main health threat of the 21st century. According to the CDC 65% of all individuals in the U. S. are overweight or obese. Mortality increases exponentially with increasing BMI; the grossly obese (BMI>40) have three times the death rate of “ideal” weight individuals. Obese individuals are also twice as likely to have diabetes and three times as likely to be hypertensive. A 16-year study has shown that obesity accounted for 14-20 % of all cancer deaths. It has been demonstrated that even modest (10%) reduction in body weight, can ameliorate or prevent the onset of these pathologies. It is estimated that obesity associated annual health cost exceeds $70 billion. Currently available therapies include a centrally acting appetite suppressant (Meridia®) and an inhibitor of fat absorption (Xenical®). There are a number of clinical and pre-clinical activities ongoing with anti-obesity drugs. Most of those drugs target 7 Transmembrane G-Protein Coupled Receptors (7TM GPCR's) such as Melanocortin-4 Receptor (MC4R), Melanin Concentrating Hormone (MCH), Cholecystokinine-1 Receptor (CCK-1R), Cannabinoid-1 Receptor (CB-1), 5HydroxyTryptamine 2c Receptor (5HT2c), Histamine-3 Receptor (H-3R). With the exponential increase of newly discovered nuclear receptors, this class is quickly becoming one of the most important targets for drug discovery. Emerging knowledge about the genetics of nuclear receptors is pointing strongly toward the important role that they play in metabolic control. In addition recent experimental data in animals models demonstrate that modulation of various nuclear receptors can result in reduction in weight gain and / or weight loss.

Sex biases in autoimmunity and infection, together with immune cell expression of estrogen and androgen receptors, suggest that sex steroid hormones directly modulate immune cells, although the mechanism(s) by which this might occur is not completely understood. The female predisposition to autoimmunity, and alteration of disease symptoms during pregnancy, has led to the idea that lower physiological amounts of estrogen are stimulatory to the immune system, while pharmacological doses or pregnancy levels of estrogen modulate cell mediated immunity. These differences in immune function during naturally occurring variation in estrogen levels have been corroborated through studies of exogenous estrogen treatment in vivo or in vitro. The resolution of immune responses is dependent upon the nature of soluble mediators produced by the innate and adaptive immune system, and estrogen modulation of cytokine and chemokine profiles often correlates with amelioration or exacerbation of autoimmunity. In this review, we will summarize recently published studies that demonstrate effects of estrogen on autoimmune responses in humans and in murine model systems, with a focus on CD4+ T helper cell differentiation and cytokine production, B cell function and autoantibody production, hematopoietic cell differentiation and proinflammatory estrogen metabolites. It is of interest to understand the effects of estrogens on both normal immunity and autoimmune disease models because both estrogens and selective estrogen receptor modulators currently are being assessed for clinical efficacy in the treatment of autoimmunity and cancer.