| Immunology,
Endocrine & Metabolic Agents in Medicinal Chemistry
ISSN: 1871-5222
Current Medicinal Chemistry
- Immunology, Endocrine and Metabolic Agents
Volume 5, Number 1, February 2005
Contents
Advances in Nutrition Research and Strategies
for Disease Prevention
Guest Editor: Alfonso Siani
Editorial
Alfonso Siani
[Editorial
In PDF]
Dietary Prevention of Coronary Heart Disease
Pp. 3-12
M. de Lorgeril and P. Salen
[Abstract] [Full
text article]
Dietary Salt and Disease Prevention: A Global
Perspective Pp. 13-20
G. B. Gomez and F. P. Cappuccio
[Abstract] [Full
text article]
Dietary Potassium in Cardiovascular Prevention:
Nutritional and Clinical Implications Pp. 21-31
P. Russo, G. Barba, A. Venezia and A. Siani
[Abstract] [Full
text article]
The Antioxidant Properties of Greek Foods and
the Flavonoid Content of the Mediterranean Menu Pp.
33-45
E. Vasilopoulou, K. Georga, M. Bjoerkov Joergensen, A.
Naska and A. Trichopoulou
[Abstract] [Full
text article]
The Atherosclerosis Time-Line and the Role of
the Endothelium Pp. 47-52
R. Kharbanda and R.J. MacAllister
[Abstract] [Full
text article]
The Role of Insulin Resistance and Hyperinsulinemia
in Cancer Causation Pp. 53-60
E. Giovannucci
[Abstract] [Full
text article]
Dietary Phytochemicals in Chemoprevention of Cancer
Pp. 61-72
M. Russo, I. Tedesco, G. Iacomino, R. Palumbo, G. Galano
and G. L. Russo
[Abstract] [Full
text article]
Combating Obesity by Targeting Nuclear Receptors
Pp. 73-84
J.R. Szewczyk and D.D. Sternbach
[Abstract] [Full
text article]
Estrogen, Immunity & Autoimmune Disease Pp.
85-91
Greg Nalbandian and Susan Kovats
[Abstract] [Full
text article]
Abstracts
[Back to top]
Editorial
Alfonso Siani
[Editorial
In PDF]
At the start of the millennium, nutritional sciences stand
at the threshold of a new frontier. In fact, an increasing
body of scientific evidence put the emphasis on the promising
use of foods to promote better health, thus suggesting a role
for nutrition in the prevention of chronic diseases such as
cardiovascular disease, obesity, some cancers and so forth.
Under this perspective, nutrition means more than just the
adequate provision of essential major and minor nutrients.
These new concepts are of particular importance in view of
the increasing demand of general population, particularly
the elderly, for an improved quality of life faced to the
continuously increasing cost of health care. Paradoxically,
despite overwhelming evidence that nutrition has a great potential
to prevent and cure epidemically diffused chronic diseases,
the field still fails to receive adequate resources. With
the understanding of the complex biological processes at the
basis for the association between nutrition and disease, we
have become increasingly focused in the topics we study. However,
since Confucius said, “The essence of knowledge is that,
having acquired it, one must apply it”, the endeavor
of scientist involved in the field of nutrition was the transfer
of rigorous information to the people that most need to apply
it.
This “Hot-topic” issue of Current Medicinal Chemistry
– Immunology, Endocrine & Metabolic Agents represents
a timely effort to establish the current state of knowledge
in the exciting field of preventive nutrition. The issue consists
of seven original reviews written by internationally recognized
authorities, covering important aspects of the complex role
of nutrition in the etiology of chronic disease. The authors
comprehensively reviewed not only prevention and public health
themes but also physiological mechanisms and potential modes
of therapy.
The issue begins with an overview by de Lorgeril and Salen
at the University of Grenoble on the nutritional resources
for the primary and secondary prevention of ischaemic heart
disease. The “diet-heart connection” is discussed
focusing on the specific role of different dietary fats, of
alcohol and antioxidants in the preventive strategies of recurrent
cardiac events and death from cardiac causes.
Gabriela B Gomez and Francesco P Cappuccio at the St George's
Hospital Medical School of London describe, in a global perspective,
the complex relationship between dietary salt and the development
of disease and raise the question of implementing sodium restriction
as public health strategy both in industrialized and in developing
countries.
Another dietary cation playing a major role in the prevention
of high blood pressure and cardiovascular disease is potassium.
Alfonso Siani and his colleagues at the Institute of Food
Sciences of Avellino review the extensive research evidence
that supports the health benefits of an adequate dietary potassium
intake.
Antonia Trichopulou and her colleagues at the University
of Athens lead the reader to the discovery of the health properties
of antioxidant phytochemicals contained in herbs and spices
of the traditional Greek cuisine. The molecular basis of the
physiological effects of these compounds is discussed as a
putative explanation of the health benefits of the so-called
Mediterranean diet.
Rajesh Kharbanda, of the University of Cambridge, and Raymond
MacAllister of the University College in London provide a
clear description of the role of endothelial dysfunction in
the pathogenesis of atherosclerosis. The review discusses
the multiple pathways of endothelial regulation and the therapeutic
options targeted to the arterial wall.
Edward Giovannucci at the Harvard School of Public Health
describes the fascinating hypothesis that insulin resistance
may represent the crossroad between the cluster of abnormalities
grouped under the definition of “metabolic syndrome”
and colon cancer and other malignancies. Dietary and metabolic
factors at the basis of this association are discussed.
Finally, Gianluigi Russo and his colleagues at the Institute
of Food Sciences of Avellino discuss the chemopreventive role
of phytochemicals of vegetable origin in the carcinogenic
process.
In summary, this issue provides an overview of various lines
of research linking dietary and metabolic factors to the development
of disease. The Editor’s hope is that these papers will
help to establish the present state of knowledge and thereby
will stimulate further discussion and research on the effects
of diet and nutrients on health status.
[Back to top]
Dietary Prevention of Coronary Heart Disease
M. de Lorgeril and P. Salen
[Full
text article]
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.
[Back to top]
Dietary Salt and Disease Prevention: A Global Perspective
G. B. Gomez and F. P. Cappuccio
[Full
text article]
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.
[Back to top]
Dietary Potassium in Cardiovascular Prevention: Nutritional
and Clinical Implications
P. Russo, G. Barba, A. Venezia and A. Siani
[Full
text article]
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.
[Back to top]
The Antioxidant Properties of Greek Foods and the Flavonoid
Content of the Mediterranean Menu
E. Vasilopoulou, K. Georga, M. Bjoerkov Joergensen,
A. Naska and A. Trichopoulou
[Full
text article]
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.
[Back to top]
The Atherosclerosis Time-Line and the Role of the Endothelium
R. Kharbanda and R.J. MacAllister,
[Full
text article]
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.
[Back to top]
The Role of Insulin Resistance and Hyperinsulinemia in Cancer
Causation
E. Giovannucci
[Full
text article]
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.
[Back to top]
Dietary Phytochemicals in Chemoprevention of Cancer
M. Russo, I. Tedesco, G. Iacomino, R. Palumbo,
G. Galano and G. L. Russo
[Full
text article]
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.
[Back to top]
Combating Obesity by Targeting Nuclear Receptors
J.R. Szewczyk and D.D. Sternbach
[Full
text article]
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 Trans-membrane
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.
[Back to top]
Estrogen, Immunity & Autoimmune Disease
Greg Nalbandian and Susan Kovats
[Full
text article]
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.
|
