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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 26, 2008
Contents
Drug Targets in Ageing and Age-Associated
Diseases
Executive Editors: C. Caruso and E. Jirillo
Editorial: Pp.
2635-2636
A Scientific Approach to Anti-Ageing Therapies: State of the
Art Pp. 2637-2642
E. Jirillo, G. Candore, T. Magrone and
C. Caruso
[Abstract] [Purchase
Article]
The Use of the Inhibitory Receptors for
Modulating the Immune Responses Pp. 2643-2650
S.M. Henson, R. Macaulay, S. Kiani-Alikhan
and A.N. Akbar
[Abstract] [Purchase
Article]
Post-Transcriptional Regulation of HSP70
Expression Following Oxidative Stress in SH-SY5Y Cells: The
Potential Involvement of the RNA-Binding Protein HuR Pp.
2651-2658
M. Amadio, G. Scapagnini, U. Laforenza,
M. Intrieri, L. Romeo, S. Govoni and A. Pascale
[Abstract] [Purchase
Article]
Elevated Plasma Levels of α-1-Anti-Chymotrypsin
in Age-Related Cognitive Decline and Alzheimer’s Disease:
A Potential Therapeutic Target Pp. 2659-2664
E. Porcellini, E.J. Davis, M. Chiappelli,
E. Ianni, G. Di Stefano, P. Forti, G. Ravaglia and
F. Licastro
[Abstract] [Purchase
Article]
Pharmacogenetics and Pharmagenomics,
Trends in Normal and Pathological Aging Studies: Focus on
p53 Pp. 2665-2671
C. Lanni, M. Racchi, D. Uberti, G. Mazzini,
S. Stanga, E. Sinforiani, M. Memo and S. Govoni
[Abstract] [Purchase
Article]
Association between the Polymorphisms
of TLR4 and CD14 Genes and Alzheimer’s Disease Pp.
2672-2677
C.R. Balistreri, M.P. Grimaldi, M. Chiappelli,
F. Licastro, L.Castiglia, F. Listì, S. Vasto, D. Lio,
C. Caruso and G. Candore
[Abstract] [Purchase
Article]
Pro-Inflammatory Gene Variants in Myocardial
Infarction and Longevity: Implications for Pharmacogenomics
Pp. 2678-2685
F. Listì, M. Caruso, E. Incalcaterra,
E. Hoffmann, G. Caimi, C.R. Balistreri, S. Vasto, V. Scafidi,
C. Caruso and G. Candore
[Abstract] [Purchase
Article]
Prognostic Role of Sub-Clinical Hypothyroidism
in Chronic Heart Failure Outpatients Pp.
2686-2692
M. Iacoviello, P. Guida, E. Guastamacchia,
V. Triggiani, C. Forleo, R. Catanzaro, M. Cicala, M. Basile,
S. Sorrentino and S. Favale
[Abstract] [Purchase
Article]
Relationship Among Fatty Liver, Adipose
Tissue Distribution and Metabolic Profile in Moderately Obese
Children: An Ultrasonographic Study Pp.
2693-2698
M. Chiloiro, G. Riezzo, S. Chiarappa, M.
Correale, V. Guerra, L. Amati, M.R. Noviello and
E. Jirillo
[Abstract] [Purchase
Article]
Body Composition and -174G/C Interleukin-6
Promoter Gene Polymorphism: Association with Progression of
Insulin Resistance in Normal Weight Obese Syndrome Pp.
2699-2706
L. Di Renzo, A. Bertoli, M. Bigioni, V.
Del Gobbo, M.G. Premrov, V. Calabrese, N. Di Daniele and
A. De Lorenzo
[Abstract] [Purchase
Article]
Role of Diet and Nutrition on the Alteration
of the Quality and Quantity of Stem Cells in Human Aging and
the Diseases of Aging Pp. 2707-2718
J.E. Trosko
[Abstract] [Purchase
Article]
Zinc, Metallothioneins and Longevity:
Interrelationships with Niacin and Selenium Pp.
2719-2732
E. Mocchegiani, M. Malavolta, E. Muti, L.
Costarelli, C. Cipriano, F. Piacenza, S. Tesei, R. Giacconi
and F. Lattanzio
[Abstract] [Purchase
Article]
Polyphenols from Red Wine Modulate Immune
Responsiveness: Biological and Clinical Significance Pp.
2733-2748
T. Magrone, G. Candore, C. Caruso, E. Jirillo
and V. Covelli
[Abstract] [Purchase
Article]
Elicitation of Immune Responsiveness
Against Antigenic Challenge in Age-Related Diseases: Effects
of Red Wine Polyphenols Pp. 2749-2757
T. Magrone, A. Tafaro, F. Jirillo, L. Amati,
E. Jirillo and V. Covelli
[Abstract] [Purchase
Article]
Molecular Effects Elicited In Vitro
by Red Wine on Human Healthy Peripheral Blood Mononuclear
Cells: Potential Therapeutical Application of Polyphenols
to Diet-Related Chronic Diseases Pp. 2758-2766
T. Magrone, M.A. Panaro, E. Jirillo and
V. Covelli
[Abstract] [Purchase
Article]
Abstracts
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Editorial: Drug Targets in Ageing and Age-Associated
Diseases
Ageing is a post-maturational process that, due to
a diminished homeostatic capacity and increased vulnerability,
reduces responsiveness to environmental stimuli.
Nowdays, individuals can live until 80-120 years but this
increase in lifespan is not free of disabilities and diseases.
Therefore, current attempts are aimed at finding out drug
targets by which one may correct functional deficits in ageing
and/or prevent age-associated diseases. Current knowledge
on ageing and age-associated diseases and anti-ageing therapies
will be reviewed in this issue of Current Pharmaceutical Design.
Jirillo and associates [1] will discuss the state of the art
of anti-ageing therapies with special reference to immunosenescence,
Alzheimer’s disease, cardiovascular diseases and diet
and age-related diseases.
Henson and associates [2] will examining the role of CTLA-4
and PD-1 in regulating immune response and their therapeutic
potential in the elderly.
Amadio and associates [3] will show that the RNA-binding protein
ELAV/HuR can affect, post-transcriptionally, the fate of HSP70
mRNA following H2O2-mediated
oxidative stress in SH-SY5Y human neuroblastoma cells. An
impairment of this regulatory mechanism may lead to the defective
cellular response to oxidative stress as evidenced in cerebral
senescence.
Porcellini and associates [4] will discuss on the role of
α-1-anti-chymotrypsin
(ACT) in Alzheimer’s disease and the development of
compounds able to interfere with ACT biological activity.
Lanni and associates [5] will focus on p53 which has been
involved in ageing and Alzheimer’s disease. With ageing
a conformational change of p53 occurs which impairs its ability
to activate an apoptotic program when cells are exposed to
noxious stimuli.
Balistreri and associates [6] will demonstrate a correlation
between the polymorphisms of TLR4 and CD14 genes and Alzheimer’s
disease with special reference to the +896A/G TLR4 single
nucleotide polymorphism.
Listì and associates [7] will report that -765G COX-2
and -1708A 5-LO single nucleotide polymorphisms are independent
positive risk factors for developing myocardial infarction,
thus allowing to determine which patients to treat with specific
inhibitors of the eicosanoids or their enzymes.
Iacoviello and associates [8] will show that high thyroid
stimulating hormone levels in chronic heart failure patients
are independently associated with a greater likelihood of
heart failure progression, thus supporting prospective studies
for establishing the most appropriate treatment of clinical
hypothyroidism in such patients.
Chiloiro and associates [9] will examine the relationship
between moderate obesity and glucose metabolism, insulin sensitivity
and suspected fatty liver in children. Results will clarify
that moderately obese children exhibit a clear increase of
insulin and insulin resistance which may lead to a future
metabolic syndrome.
Di Renzo and associates [10] will investigate the effect of
body fat mass on the relationships between -174G/C IL-6 promoter
gene polymorphism, IL-6 circulating level and insulin resistance.
Data will show that fat mass percentage is a major determinant
of increase in IL-6 production and insulin resistance.
Trosko [11] will emphasize the need to provide elderly subjects
with a correct dietary intake that might also affect stem
cells, whose alterations can compromise the ageing of that
organ.
Mocchegiani and associates [12] will demonstrate that the
association “zinc plus selenium” improves humoral
immunity in old subjects after influenza vaccination. Furthermore,
the association “zinc plus niacin (a precursor of NAD+)”
in elderly is in progress.
Magrone and associates [13-15] will investigate the ability
of red wine polyphenols to promote the in vitro release
from human healthy peripheral blood mononuclear cells of regulatory,
proinflammatory and antiinflammatory cytokines as well as
of immunoglobulins. The involvement of polyphenols in the
activation of p38 and ERK1/2 as well as nitric oxide production
will be discussed. Collectively, in vitro data will
show that a moderate use of red wine in humans is able to
elicit at cellular and molecular levels a protective response
for the host mostly in age-related disorders.
References
[1] Jirillo E, Candore G, Magrone T, Caruso C. A scientific
approach to anti-ageing therapies: state of the art. Curr
Pharm Des 2008; 14(26): 2637-2642.
[2] Henson SM, Macaulay R, Kiani-Alikhan S, Akbar AM. The
use of the inhibitory receptors for modulating the immune
responses. Curr Pharm Des 2008; 14(26): 2643-2650.
[3] Amadio M, Scapagnini G, Laforenza U, Intrieri M, Romeo
L, Govoni S, Pascale A. Post-transcriptional regulation of
HSP70 expression following oxidative stress in SH-SY5Y cells:
the potential involvement of the RNA-binding protein HuR.
Curr Pharm Des 2008; 14(26): 2651-2658.
[4] Porcellini E, Davis EJ, Chiappelli M, Ianni E, Di Stefano
G, Forti P, Ravaglia G, Licastro F. Elevated plasma levels
of α-1-anti-chymotrypsin
in age-related cognitive decline and Alzheimer’s disease:
a potential therapeutic target. Curr Pharm Des 2008; 14(26):
2659-2664.
[5] Lanni C, Racchi M, Uberti D, Mazzini G, Stanga S, Sinforiani
E, Memo M, Govoni S. Pharmacogentics and pharmacogenomics,
trends in normal and pathological ageing studies: focus on
p53. Curr Pharm Des 2008; 14(26): 2665-2671.
[6] Balistreri CR, Grimaldi MP, Chiappelli M, Licastro F,
Castiglia L, Listì F, Vasto S, Lio D, Caruso C, Candore
G. Association between the polymorphisms of TLR4 and CD14
genes and Alzheimer’s disease. Curr Pharm Des 2008;
14(26): 2672-2677.
[7] Listì F, Caruso M, Incalcaterra E, Hoffmann E,
Caimi G, Balistreri CR, Vasto S, Scafidi V, Caruso C, Candore
G. Pro-inflammatory gene variants in myocardial infarction
and longevity: implications for pharmacogenomics. Curr Pharm
Des 2008; 14(26): 2678-2685.
[8] Iacoviello M, Guida P, Guastamacchia E, Triggiani V, Forleo
C, Catanzaro R, Cicala M, Basile M, Sorrentino S, Favale S.
Prognostic role of sub-clinical hypothyroidism in chronic
heart failure outpatients. Curr Pharm Des 2008; 14(26): 2686-2692.
[9] Chiloiro M, Riezzo G, Chiarappa S, Correale M, Guerra
V, Amati L, Noviello MR, Jirillo E. relationship among fatty
liver, adipose tissue distribution and metabolic profile in
moderately obese children: an ultrasonographic study. Curr
Pharm Des 2008; 14(26): 2693-2698.
[10] Di Renzo L, Bertoli A, Bigioni M, Del Gobbo V, Premrov
MG, Calabrese V, Di Daniele N, De Lorenzo A. Body composition
and -174G/C interleukin-6 promoter gene polymorphism: association
with progression of insulin resistance in normal weight obese
syndrome. Curr Pharm Des 2008; 14(26): 2699-2706.
[11] Trosko JE. Role of diet and nutrition on the alteration
of the quality and quantity of stem cells in human aging and
the disease of aging. Curr Pharm Des 2008; 14(26): 2707-2718.
[12] Mocchegiani E, Malavolta M, Muti E, Costarelli L, Cipriano
C, Piacenza F, Tesei S, Giacconi R, Lattanzio F. Zinc, metallothioneins
and longevity: interrelationships with niacin and selenium.
Curr Pharm Des 2008; 14(26): 2719-2732.
[13] Magrone T, Candore G, Caruso C, Jirillo E, Covelli V.
Polyphenols from red wine modulate immune responsiveness:
biological and clinical significance. Curr Pharm Des 2008;
14(26): 2733-2748.
[14] Magrone T, Tafaro A, Jirillo F, Amati L, Jirillo E, Covelli
V. Elicitation of immune responsiveness against antigenic
challenge in age-related diseases. Effects of red wine polyphenols.
Curr Pharm Des 2008; 14(26): 2749-2757.
[15] Magrone T, Panaro MA, Jirillo E, Covelli V. Molecular
effects elicited in vitro by red wine on human healthy
peripheral blood mononuclear cells: potential therapetical
application of polyphenols to diet-related chronic diseases.
Curr Pharm Des 2008; 14(26): 2758-2766.
Calogero Caruso
Immunosenescence group study,
Department of Pathobiology and Biomedical Methodologies,
University of Palermo, Palermo,
Italy
Emilio Jirillo
Immunology
University of Bari and IRCCS “De Bellis”
Castellana Grotte, Bari
Italy
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A Scientific Approach to Anti-Ageing Therapies: State of the
Art
E. Jirillo, G. Candore, T. Magrone and
C. Caruso
A lasting dream of human beings is to reverse or at least
postpone ageing. During the last years, an increasing number
of scientific meetings, articles, and books have been devoted
to anti-ageing therapies. This subject, full of misleading,
simplistic, or wrong ideas, is very popular among the general
public, whose imagery has been fascinated by all possible
tools to delay ageing, getting immortality. Here, we discuss
anti-ageing strategies aimed not to rejuvenate but to slow
ageing and delay the onset of age-related diseases. These
approaches should be able to substantially slow down the ageing
process, extending our productive, youthful lives.
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The Use of the Inhibitory Receptors for Modulating the Immune
Responses
S.M. Henson, R. Macaulay, S. Kiani-Alikhan
and A.N. Akbar
Inhibitory receptors of the CD28 family, CTLA-4 and PD-1
deliver negative signals that regulate the balance between
T cell activation, tolerance, and immunopathology. Manipulation
of these pathways has been utilized by pathogens and tumors
to establish chronic infections or to promote tumor survival.
In this review, we examine the role of CTLA-4 and PD-1 in
regulating immune response and discuss their therapeutic potential
during aging.
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Post-Transcriptional Regulation of HSP70 Expression Following
Oxidative Stress in SH-SY5Y Cells: The Potential Involvement
of the RNA-Binding Protein HuR
M. Amadio, G. Scapagnini, U. Laforenza,
M. Intrieri, L. Romeo, S. Govoni and A. Pascale
Brain aging is associated with a progressive imbalance
between intracellular concentration of Reactive Oxygen Species
(ROS) and cells ability to activate defensive genes. Heat
Shock Protein 70 (HSP70) has been shown to act as a fundamental
defensive mechanism for neurons exposed to an oxidant challenge,
and its expression decreases during senescence. In the present
report we show that the RNA-binding protein ELAV/HuR can affect,
post-transcriptionally, the fate of HSP70 mRNA following H2O2-mediated
oxidative stress in SH-SY5Y human neuroblastoma cells. As
a consequence of H2O2
treatment (1mM for 30 minutes), HSP70 mRNA accumulates in
the ribosomes associated to the cytoskeleton, where parallel
Western blotting experiments reveal statistically significant
increase for both HuR and HSP70 protein levels. We also confirm
the capability of HuR to bind to HSP70 mRNA, and describe
how the biological effect of this ELAV protein on the HSP70
mRNA could be due to a direct phosphorylation in serine/threonine
residues of HuR itself by the early (10 minutes) H2O2-mediated
activation of PKCα.
Our findings shed light on the post-transcriptional regulation
of HSP70 expression, suggesting the existence of a new molecular
cascade –involving PKC/HuR/HSP70- that possibly represents
an early event in the cellular response to H2O2-mediated
oxidative stress in SH-SY5Y human neuroblastoma cells. The
present results lead us to speculate that an impairment in
this regulatory mechanism might directly contribute to the
defective cellular response to oxidative stress, thus helping
to dissect a potential tool useful to counteract some aspects
associated to cerebral senescence.
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Elevated Plasma Levels of α-1-Anti-Chymotrypsin
in Age-Related Cognitive Decline and Alzheimer’s Disease:
A Potential Therapeutic Target
E. Porcellini, E.J. Davis, M. Chiappelli,
E. Ianni, G. Di Stefano, P. Forti, G. Ravaglia and
F. Licastro
α-1-antichymotrypsin
(ACT), is an acute phase protein and a protease inhibitor
produced by the liver and brain. ACT is involved in the pathogenesis
of Alzheimer’s disease (AD), since elevated ACT concentration
was found in cerebrospinal fluid (CSF) and brain from AD.
ACT has also been shown to influence amyloid deposition in
vitro and in animal models of AD.
In this investigation 830 healthy controls, 69 subjects with
cognitive impairment and not dementia (CIND), 53 patients
with severe clinical AD and 142 patients with mild AD were
investigated. Plasma levels of ACT were measured with a new
competitive immune enzyme linked immune-assay (ELISA). ACT
levels were higher in AD patients than in CIND or controls.
An age dependent increase of plasma ACT was present in both
healthy elderly and CIND. Patients with mild clinical AD were
followed up for two years and stratified according to the
rate of clinical deterioration.
CT plasma levels were elevated in AD patients that showed
an accelerated rate of cognitive deterioration during the
follow up; this increment being prominent in AD with the Apolipoprotein
E (APOE) ε
4 allele. Therefore, increased peripheral ACT levels
in APOE 4 positive patients appear to predict an accelerated
clinical progression. Plasma ACT might be used as a surrogate
marker to monitor the conversion of pre-dementia stages to
AD and the progression of the disease. The development of
compounds able to interfere with the ACT biological activity
(protease inhibition and/or promotion of amyloid deposition)
might have therapeutic relevance for the disease.
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Pharmacogenetics and Pharmagenomics, Trends in Normal and
Pathological Aging Studies: Focus on p53
C. Lanni, M. Racchi, D. Uberti, G. Mazzini,
S. Stanga, E. Sinforiani, M. Memo and S. Govoni
In spite of the fact that the aging organism is the result
of complex life-long gene/environment interactions, making
peculiar the susceptibility to diseases and the response to
drugs, pharmacogenetics studies are largely neglected in the
aged. Altered response to drugs, cardiovascular and metabolic
alterations, cancer and dementia are among the age associated
ailments. The latter two are the major contributors to illness
burden for the aged. Aging, dementia and cancer share a critical
set of altered cellular functions in the response to DNA damage,
genotoxic stress, and other insults. Aging in higher animals
may be influenced by the balance of cell survival versus death,
a decision often governed by checkpoint proteins in dividing
cells. The paper is mainly focused on one of such proteins,
p53 which has been recently shown to be involved in aging
and Alzheimer’s Disease (AD). Within this reference
frame we studied p53 in aged controls and demented patients
finding that with aging there is an increase of mutant like
conformation state of p53 in peripheral blood cells, which
is more pronounced in AD patients. As a result of such conformational
change, p53 partially loses its activity and may become unable
to properly activate an apoptotic program when cells are exposed
to a noxious stimulus. Moreover we found that the tertiary
structure of p53 and the sensitivity to p53-dependent apoptosis
are affected by low concentrations of soluble beta amyloid,
the peptide that accumulates in AD brain but also present
in peripheral tissues. It is possible that p53 conformers
may occur in the presence of misfolded molecules such as,
but not limited to, beta amyloid. In particular at neuronal
level the altered function of cell cycle proteins may affect
synaptic plasticity rather than cell duplication.
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Association between the Polymorphisms
of TLR4 and CD14 Genes and Alzheimer’s Disease
C.R. Balistreri, M.P. Grimaldi, M. Chiappelli,
F. Licastro, L.Castiglia, F. Listì, S. Vasto, D. Lio,
C. Caruso and G. Candore
Alzheimer's disease (AD) is a heterogeneous and progressive
neurodegenerative disease which in Western society mainly
accounts for clinical dementia. Inflammation plays a key role
in AD and dissecting the genetics of inflammation may provide
an answer to the possible treatment. Hence, the better understanding
of different molecular and cellular inflammatory mechanisms
is crucial for complete knowledge of AD pathophysiology, and
for its prevention and drug therapy. Accordingly, in the present
study we evaluated whether the pro-inflammatory polymorphisms
of lipopolysac-caride-receptors, +896A/G Toll-Like Receptor
(TLR4) and -260C/T CD14, are risk factors for AD. The study
included both 626 AD patients (427 women and 199 men; age
range: 53-98 years; mean age: 74.88 ± 8.44) from Northern
Italy and age and gender matched controls. Our results demonstrate
that the +896A/G TLR4 single nucleotide polymorphism (SNP)
is associated with AD, whereas no association has been observed
with -260C/T CD14 SNP. Furthermore, no differences have been
observed evaluating the combined presence of +896A+TLR4/-260T+CD14
“high responder”(pro-inflammatory-profile). However,
our results showing the involvement of TLR4 in AD pathophysiology,
strengthen the suggestion that systemic inflammation plays
a key role in AD. Carriers of high responder SNP, affected
by mild cognitive impairment might, be the ideal target for
a preventive treatment with biologics as monoclonal antibodies
directed against the pro-inflammatory cytokines to decrease
the level of systemic inflammation involved in AD pathophysiology.
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Pro-Inflammatory Gene Variants in Myocardial Infarction and
Longevity: Implications for Pharmacogenomics
F. Listì, M. Caruso, E. Incalcaterra,
E. Hoffmann, G. Caimi, C.R. Balistreri, S. Vasto, V. Scafidi,
C. Caruso and G. Candore
Inflammation and genetics play an important role in the
pathogenesis of coronary heart disease (CHD). However, despite
the increasing appreciation of the role of genetics in CHD
and myocardial infarction (MI) pathogenesis, pharmacogenomic
approaches to uncover drug target have not been extensively
explored. Cyclo-oxygenases (COXs) and 5-lipoxygenase (5-LO)
are the key enzymes in the conversion of arachidonic acid
to prostaglandins (PG) and leukotrienes (LT) and are implicated
in a wide variety of inflammatory disorders, including atherosclerosis.
In fact, PGE2 activates Matrix Metallo-proteinases whereas
LTB4 is a chemoactractant for monocytes and activates gene
expression in inflammatory cells. We have tested the hypothesis
that anti-inflammatory variants of these genes confer genetic
resistance to MI and conversely favour longevity. So, we analyzed
MI patients, age-related controls and centenarians. The pro-inflammatory
alleles of COX-2 and 5-LO were overrepresented in MI and under-represented
in centenarians whereas age-related controls displayed intermediate
values. MI is a multifactorial disease, hence MI might be
the result of a cumulative effect which contributes with different
timing to achieve a threshold where the chance to develop
the diseases is very high. In particular, differences in inflammatory
status can contribute to the chance of developing a risk phenotype.
However, these studies might contribute to the determination
of a risk profile which may allow both the early identification
of individuals susceptible to disease and the possible discovery
of potential targets for drug.
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Prognostic Role of Sub-Clinical Hypothyroidism in Chronic
Heart Failure Outpatients
M. Iacoviello, P. Guida, E. Guastamacchia,
V. Triggiani, C. Forleo, R. Catanzaro, M. Cicala, M. Basile,
S. Sorrentino and S. Favale
Background. It has been suggested that low thyroid hormones
levels may be associated with increased mortality in patients
with cardiovascular disease.
Aim. To evaluate the prognostic role of thyroid function
deficiency in patients with chronic heart failure (CHF).
Methods. We evaluated 338 consecutive outpatients
with stable CHF receiving conventional therapy, all of whom
underwent a physical examination, electrocardiography and
echocardiography. Blood samples were drawn to assess renal
function, and Na+, hemoglobin, NT-proBNPs, fT3, fT4 and TSH
levels. Patients with hyperthyroidism were excluded.
Results. During the follow-up (15±8
months), heart failure progression was observed in 79 patients
(including 18 who died of heart failure after hospitalisation
and six who underwent transplantation). Univariate regression
analysis showed that TSH (p<0.0001),
fT3 (p<0.0001),
fT4 (p=0.016) and fT3/fT4 (p<0.0001)
were associated with heart failure progression but multivariate
analysis showed that only TSH considered as a continuous variable
(p = 0.001) as well as sub-clinical hypothyroidism (TSH >5.5
mUI/l; p=0.014) remained significantly associated with the
events.
Conclusions. In CHF patients TSH levels even slightly
above normal range are independently associated with a greater
likelihood of heart failure progression. This supports the
need for prospective studies aimed at clarifying the most
appropriate therapeutic approach to sub-clinical hypothyroidism
in such patients.
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Relationship Among Fatty Liver, Adipose Tissue Distribution
and Metabolic Profile in Moderately Obese Children: An Ultrasonographic
Study
M. Chiloiro, G. Riezzo, S. Chiarappa, M.
Correale, V. Guerra, L. Amati, M.R. Noviello and
E. Jirillo
We examined the relationship between moderate obesity
and glucose metabolism, insulin sensitivity and suspected
fatty liver in children. We measured body mass index (BMI),
z-score BMI, caliper skinfold thickness, waist and hip circumference
in 94 participants (mean age 9.7 ±2.2
years). Fasting blood glucose, insulin, HOMA score, lipid
profile and transaminases (ALT, AST) were measured. Fatty
liver and skinfold thickness were evaluated by means of ultrasound.
The z-score BMI was 2.01 ±0.39
(mean ±
SD), and the duration of obesity was 4.3±3.03
years. A positive correlation was found between caliper and
US skinfold thickness for tricipital (r= 0.33; p= 0.003) and
sovrailiac skinfold (r= 0.34; p=0.003). Fatty liver was diagnosed
in 64% of children and it was positively related to anthropometric
measurements. The three sub-groups–group 0 (normal US
liver and normal transaminases); group 1 (US fatty liver and
normal transaminases); group 2 (US fatty liver and elevated
transaminases)–showed a difference concerning z-score
BMI, insulin and HOMA parameters (Tukey test: z score BMI
group 1 vs group 0 and 2 vs group 0; serum insulin: group
2 vs group 1 and group 2 vs group 0; HOMA IR: group 2 vs group
1 and group 2 vs group 0). Moderately obese children with
steatosis exhibited a clear increase of insulin and insulin
resistance which represents indices of a future metabolic
syndrome. In addition, it is important to perform a liver
ultrasound since transaminases seems to be not adequate for
the diagnosis of fatty liver.
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Body Composition and -174G/C Interleukin-6 Promoter Gene Polymorphism:
Association with Progression of Insulin Resistance in Normal
Weight Obese Syndrome
L. Di Renzo, A. Bertoli, M. Bigioni, V.
Del Gobbo, M.G. Premrov, V. Calabrese, N. Di Daniele and
A. De Lorenzo
Insulin resistance and obesity are intimately related
to a chronic low grade systemic inflammation. Interleukin-6
(IL-6) may influence the pathogenesis of obesity-related diseases.
The aim of this study is to investigate the effect of body’s
fat mass on the relationships between -174G/C IL-6 promoter
gene polymorphism, IL-6 circulating level and insulin resistance.
A population of 150 Caucasian women was studied, subdivided
according to their body composition in non-obese (NW), Normal
Weight Obese (NWO) and preobese-obese (OB).
The NWO subjects were found in an intermediate position between
the NW and OB subjects in terms of body weight, fat mass percentage
(FM%), abdominal FAT%, hs-CRP and plasma triglyceride level.
Fasting plasma IL-6 concentration was positively correlated
with the homeostasis model assessment for insulin resistance
(HOMA-IR) in all subjects analyzed (P=0.0014). In NWO and
OB women a significantly increased IL-6 mean value was observed
compared with NW subjects. In G/G population, the IL-6 plasma
level of NWO and OB was significantly higher with respect
to NW. No significant differences of IL-6 concentrations were
observed in the three groups carrying G/C genotype. NWO and
OB women homozygous for the allele C have significantly lower
value of IL-6 with respect to NW subjects. IL-6 concentration
was positively correlated with FM% in G/G (R2=0.397,
P<0.001)
and was negatively correlated in C/C (R2=0.459,
P=0.002). No significant correlation was observed in G/C genotype
(R2=0.041, P=0.173).
In conclusion our study confirms that, at least in Italian
Caucasian females, the FM% is a major determinant of an increase
in IL-6 production and insulin resistance. -174 G/C IL-6 promoter
polymorphism represents a marker which could help to identify,
time in advance, “vulnerable” individuals at risk
of age and obesity related diseases.
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Role of Diet and Nutrition on the Alteration of the Quality
and Quantity of Stem Cells in Human Aging and the Diseases
of Aging
J.E. Trosko
An integrative synthesis of concepts and an explosion
of experimental and epidemiological findings allow new insights
as to how the interactions of genetic, environmental, dietary,
cultural (social, psychological, economic) factors can influence
the aging and diseases of aging processes. Although the net
effect of the best dietary maintenance of homeostatic control
of cell proliferation, cell differentiation and apoptosis,
systems breakdown of the human being and death will inevitably
be the ultimate end result. Reduction of the quantity of the
stem cell pool in any tissue will affect the “aging”
of that organ. This, in turn, will affect the homeostatic
maintenance of the organ systems of the human. Clearly, not
all organs of the body age uniformly. The quality of the stem
cells in any organ, depending on circumstances, can contribute
to various disease pathogeneses. In the case where the quality
of the stem cells is altered in utero or early postnatal development
by some mutagenic mechanism that could lead to the initiation
step of carcinogenesis, then the individual can, to some degree,
control the fate of those prenatally and early postnatally-derived
initiated stem cells by choosing those environmentally and
dietary factors that either enhance or prevent the clonal
expansion of these initiated stem cells during the promotion
phase of carcinogenesis. This might explain the Barker hypothesis
which suggests that prenatal and early postnatal exposures
to toxic agents can lead to diseases later in life.
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Zinc, Metallothioneins and Longevity:
Interrelationships with Niacin and Selenium
E. Mocchegiani, M. Malavolta, E. Muti, L.
Costarelli, C. Cipriano, F. Piacenza, S. Tesei, R. Giacconi
and F. Lattanzio
Ageing is an inevitable biological process with gradual
and spontaneous biochemical and physiological changes and
increased susceptibility to diseases. Some nutritional factors
(zinc, niacin, selenium) may remodel these changes leading
to a possible escaping of diseases, with the consequence of
healthy ageing, because they are involved in improving immune
functions, metabolic homeostasis and antioxidant defence.
Experiments performed “in vitro” (human
lymphocytes exposed to endotoxins) and “in vivo”
(old mice or young mice with low zinc dietary intake) show
that zinc is important for immune efficiency (both innate
and adaptive), metabolic homeostasis (energy utilization and
hormone turnover) and antioxidant activity (SOD enzyme). Niacin
is a precursor of NAD+, the substrate for the activity of
DNA repair enzyme PARP-1 and, consequently, may contribute
to maintaining genomic stability. Selenium provokes zinc release
by Metallothioneins (MT), via reduction of glutathione
peroxidase. This fact is crucial in ageing because high MT
may be unable to release zinc with subsequent low intracellular
free zinc ion availability for immune efficiency, metabolic
harmony and antioxidant activity. Taking into account the
existence of zinc transporters (ZnT and ZIP family) for cellular
zinc efflux and influx, respectively, the association between
zinc transporters and MT is crucial in maintaining satisfactory
intracellular zinc homeostasis in ageing. Improved immune
performance, metabolic homeostasis, antioxidant defence occur
in elderly after physiological zinc supplementation, which
also induces prolonged survival in old, nude and neonatal
thymectomized mice. The association “zinc plus selenium”
improves humoral immunity in old subjects after influenza
vaccination. The association “zinc plus niacin”
in elderly is actually in progress.
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Polyphenols from Red Wine Modulate Immune Responsiveness:
Biological and Clinical Significance
T. Magrone, G. Candore, C. Caruso, E. Jirillo
and V. Covelli
Many studies have been conducted on the effects of red
wine polyphenols on certain diseases, primarily, coronary
heart disease (CHD) and, in this respect, evidence has been
demonstrated that intake of red wine is associated with a
reduction of CHD symptomatology. In this framework, the purpose
of this review is to illustrate the effects of polyphenols
on immune cells from human healthy peripheral blood. Data
will show that polyphenols are able to stimulate both innate
and adaptive immune responses. In particular, the release
of cytokines such as interleukin (IL)-12, interferon (IFN)-γ,
and IL-10 as well as immunoglobulins may be important for
host protection in different immune related disorders.
Another important aspect pointed out in this review is the
release of nitric oxide (NO) from peripheral blood mononuclear
cells (PBMC), stimulated by red wine polyphenols despite the
fact that the majority of studies have reported NO production
only by endothelial cells. Release of NO from PBMC may play
an important role in cardiovascular disease, because it is
known that this molecule acts as an inhibitor of platelet
aggregation. On the other hand, NO exerts a protective role
against infectious organisms.
Finally, some molecular cytoplasmatic pathways elicited by
polyphenols able to regulate certain immune responses will
also be discussed. In particular, it seems that p38, a molecule
belonging to the MAPK family, is involved in the release of
IFN-γ
and, therefore, in NO production.
All these data confirm the beneficial effects of polyphenols
in some chronic diseases.
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Elicitation of Immune Responsiveness Against Antigenic Challenge
in Age-Related Diseases: Effects of Red Wine Polyphenols
T. Magrone, A. Tafaro, F. Jirillo, L. Amati,
E. Jirillo and V. Covelli
Polyphenols contained in red wine possess a broad array
of properties which seem to be beneficial to human and animal
health. We have investigated the ability of red wine polyphenols
to promote the in vitro release of both proinflammatory
and antiinflammatory cytokines from human healthy mononuclear
cells, as well as of immunoglobulins from B cells.
Following red wine (Negroamaro) pretreatment of lymphomonocytes,
results will show a production of regulatory [Interleukin(IL)-12],
proinflammatory (IL-1β
and IL-6), and anti-inflammatory (IL-10) cytokines, as well
as of IgA and IgG. The fine balance between inflammation and
antiinflammation, as well as the role of humoral immune response
either systemic or mucosal will be discussed as a consequence
of red wine intake.
Finally, since ageing is characterized by a decline of many
immune functions, our results suggest that moderate use of
red wine may be beneficial in age-related disorders where
the host immune response is very often not effective against
a variety of antigens.
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Molecular Effects Elicited In Vitro by Red Wine on
Human Healthy Peripheral Blood Mononuclear Cells: Potential
Therapeutical Application of Polyphenols to Diet-Related Chronic
Diseases
T. Magrone, M.A. Panaro, E. Jirillo and
V. Covelli
Red wine represents a source of polyphenols which exhibit
a number of biological effects on various systems. In this
respect, there is evidence that red wine polyphenols constitute
one of the ingredients of the Mediterranean diet which is
associated to a reduced risk of coronary heart disease according
to current literature. Here, we have evaluated in vitro
the molecular mechanisms elicited by polyphenols from red
wine (Negroamaro) on human healthy mononuclear cells. In particular,
we have investigated the involvement of polyphenols in the
activation of p38 and ERK1/2 molecules belonging to the MAPK
kinase family and on the expression of IκBα
and p65/NFκB.
Results will demonstrate that in cells both the expression
of p38 and ERK1/2 augments in the presence of red wine polyphenols,
but their expression drops in the presence of polyphenols
plus lipopolysaccharides (LPS). This indicates that in Gram-negative
infections polyphenols may attenuate triggering of inflammatory
mediators as a response to LPS stimulation. Finally, the regulatory
role of polyphenols on IκBα
and p65/NFκB
expression is discussed, pointing out that red wine might
favor anti-atherogenic mechanisms in the course of cardiovascular
disease.
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