Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 4, No. 1, 2004
Contents
Melatonin Role in Experimental Arthritis Pp. 1-10
Daniel
P. Cardinali, Ana P. Garcia, Pilar Cano and Ana I. Esquifino
CD26/Dipeptidyl Peptidase IV: A Regulator of
Immune Function and a Potential Molecular Target for Therapy Pp. 11-18
Ugur
Aytac and
The HIV-1 Nef Protein: How An
AIDS Pathogenetic Factor Turns to a Tool for Combating AIDS Pp. 19-27
I.
Schiavoni, C. Muratori, V. Piacentini, A.M. Giammarioli and M. Federico
Immunological Modulation by
Lidocaine-Epinephrine and Prilocaine- Felypressin on the Functions Related to
Natural Immunity in Neutrophils and Macrophages Pp. 29-36
Yasutaka
Azuma and Kiyoshi Ohura
DI-2-Ethylhexyl Phthalate and Endocrine
Disruption: A Review Pp.
37-40
Giuseppe
Latini, Alberto Verrotti and Claudio De Felice
The Utility of Proteomic Patterns for the
Diagnosis of Cancer Pp.
41-50
Thomas
P. Conrads and Timothy D. Veenstra
HDL and Inflammation in Atherosclerosis Pp. 51-57
Lukas
E. Spieker, Frank Ruschitzka, Thomas F. Luscher and Georg Noll
Evidence for a Putative Relationship Between Type 2 Diabetes and Neoplasia with Particular
Reference to Breast Cancer: Role of Hormones,
E. Guastamacchia, F. Resta, V. Triggiani, A. Liso, B. Licchelli, S. Ghiyasaldin, C. Sabba and E. Tafaro
The Paracrine Role Played by Interleukin-1α
in the Testis Pp. 67-74
K. Svechnikov, C. Petersen, T. Sultana, A. Wahlgren, C. Zetterstrom, E. Colon, C. Bornestaf and O. Soder
Participation of Maternal and Fetal CRH in
Early Phases of Human Implantation: The Role of Antalarmin Pp. 75-78
A. Makrigiannakis, E. Zoumakis, S. Kalantaridou, G. Chrousos and A. Gravanis
Abstracts
[Back to top] Melatonin Role in Experimental Arthritis
Daniel
P. Cardinali, Ana P. Garcia, Pilar Cano and Ana I. Esquifino
Our perception of the
function of the pineal gland and its hormone melatonin has attained a new
dimension during the last decade. Through melatonin, the pineal becomes a
principal organ present in vertebrates involved in the control of rhythmic
adaptations to daily and seasonal cycles. Melatonin is synthesized and secreted
during the dark period of the light/dark cycle. The rhythmic nocturnal
melatonin secretion is directly generated by the circadian clock and is
entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be
used as a circadian mediator to any system than can "read" the
message. Melatonin acts as an arm of the circadian clock, giving a time-related
signal to a number of body functions; one of them is the circadian organization
of the immune response. This review discusses melatonin role in rheumatoid
arthritis. Animal studies employing Freund’s complete mycobacterial adjuvant
(FCA) as a model of rheumatoid arthritis are described. Immune and
neuroendocrine circadian rhythms were examined in FCA-injected rats, both in
the preclinical phase of arthritis (2-3 days after FCA injection) as well as in
the acute phase of the disease (18 days after FCA injection). In arthritic
rats, the 24-h organization of immune and neuroendocrine responses becomes
altered. Significant effects of immune response on diurnal rhythmicity of
adenohypophysial and hypophysiotropic hormones occurred in arthritic rats.
Melatonin treatment prevented alteration of 24-h rhythms of serum ACTH,
prolactin and luteinizing hormone in rats injected with FCA. In addition,
melatonin treatment prevented alteration of the 24-h variation in hypothalamic
monoamine transmitter turnover during the preclinical phase of Freund’s
adjuvant arthritis in rats. A comparison between the inflammatory and immune
responses elicited by physiological and pharmacological doses of melatonin in
FCA arthritis is reported. Pinealectomized rats exhibited a significantly less
pronounced inflammatory response, which was restored to normal by a low
melatonin dose (0.3 mg/ml of drinking water), whereas a high melatonin
dose (30 mg/ml) that resulted in a 50-60-fold increase in plasma
melatonin, augmented the inflammatory and immune response. These results should
be considered in the light of recent reports that rheumatoid arthritis patients
have increased nocturnal plasma levels of melatonin and that their synovial
macrophages respond to melatonin with an increased cytokine production.
[Back to top] CD26/Dipeptidyl Peptidase IV: A Regulator of
Immune Function and a Potential Molecular Target for Therapy
Ugur
Aytac and
CD26 is a 110 kDa
surface-bound ectopeptidase with intrinsic dipeptidyl peptidase IV (DPP IV)
activity, which has multiple biological functions. In this review, we will
focus specifically on work demonstrating that CD26 has a key role in immune
function as a T cell activation molecule and a regulator of the functional
effect of selected biological factors through its DPP IV enzyme activity. As
further evidence of the important role played by this multifaceted molecule in
immune regulation, we will also discuss experimental attempts from our
laboratory and others to influence immune-mediated conditions
through CD26 monoclonal
antibodies and DPP
IV activity with various agents,
including anti-CD26 monoclonal antibodies and DPP IV chemical inhibitors. Of
special significance from a clinical perspective is also CD26 effect on glucose
metabolism through its DPP IV activity and its potential role as a therapeutic
target in diabetes. In addition, we will review recent studies that describe
the physical and functional interaction of CD26 with other essential cellular
structures and the biological consequences of their association. In particular,
we will present recent data from our laboratory that demonstrates the
correlation between CD26, especially its DPP IV activity, and the key nuclear
protein topoisomerase II alpha, an interaction that has important clinical
implications. In summary, we will examine the biology of the multifaceted
CD26/DPP IV molecule, focusing particularly on its function in immune
regulation and its potential role as a molecular target for novel treatment
modalities for a number of disease states, ranging from autoimmune diseases, diabetes to malignancies.
[Back to top] The HIV-1 Nef Protein: How An
AIDS Pathogenetic Factor Turns to a Tool for Combating AIDS
I.
Schiavoni, C. Muratori, V. Piacentini, A.M. Giammarioli and M. Federico
Nef is one of the six
regulatory proteins coded by the Human Immunodeficiency Virus (HIV)-1 and –2,
and by the Simian Immunodeficiency Virus (SIV). Accumulating experimental
evidences indicate that Nef is required for the optimal infectivity of HIV
viral particles, and that it plays a critical role in the AIDS pathogenesis
progressing. We previously cloned and sequenced a functionally defective HIV-1
genome (F12HIV-1) whose nef gene showed a rather
unusual feature, i.e. its expression blocks the HIV-1 release by interfering
with the viral assembling/release. Such a striking phenotype appeared to be the result of
three amino acid substitutions, and
coupled with the loss of the most part of the Nef
functions described for the wild type counterpart. The F12Nef properties
encouraged the designing of new strategies of anti HIV-1 gene therapy we
afforded by recovering an inducible lentivirus vector expressing F12Nef as the
cytoplasmic domain of a transmembrane fusion protein including a selectable
marker (i.e. the Nerve Growth Factor receptor) as the ecto- and transmembrane
domains. As expected, the expression of such a chimeric protein resulted in a
potent protection of transduced cells from the HIV-1 spread.
In sum, and
surprisingly enough, we generated a reagent effectively counteracting the HIV-1
replication through the combination of a slightly mutated AIDS pathogenetic
factor together with a lentivirus vector, i.e. the result of artifactual
modifications of the HIV-1 genome.
[Back to top] Immunological Modulation by
Lidocaine-Epinephrine and Prilocaine- Felypressin on the Functions Related to
Natural Immunity in Neutrophils and Macrophages
Yasutaka
Azuma and Kiyoshi Ohura
There is accumulating
evidence that local anesthetics have immunological properties in addition to
their direct anesthetic activity. Because local anesthetics are often used
together with blood vessel contraction drugs, such as epinephrine and
felypressin in the clinical setting, we have examined possible abilities of
both local anesthetic alone including lidocaine, mepivacaine, procaine,
prilocaine and tetracaine, and local anesthetics with blood vessel contraction
drugs including lidocaine with epinephrine and prilocaine with felypressin on
the functions related to natural immunity in neutrophils and macrophages. In
contrast, lidocaine, mepivacaine, procaine, prilocaine and tetracaine all inhibited adhesion, chemotaxis,
phagocytosis, and the production of superoxide anion and hydrogen peroxide by
neutrophils and macrophages. Lidocaine with epinephrine and prilocaine with
felypressin were effective in significantly inhibiting adhesion, chemotaxis,
phagocytosis, and the production of hydrogen peroxide by neutrophils and
macrophages. Interestingly, lidocaine with epinephrine potentiated the
production of superoxide anion, whereas prilocaine with felypressine inhibited
the production, irrespective of cells. In addition, epinephrine potentiated the
production of superoxide anion, whereas epinephrine inhibited the production of
hydrogen peroxide as well as lidocaine with epinephrine. This potentiation by
epinephrine was not prevented by adrenergic antagonists. Furthermore,
superoxide dismutase potentiated the production of hydrogen peroxide, which was
in part prevented by epinephrine. These results suggest that local anesthetics
may inhibit the functions related to natural immunity in neutrophils and
macrophages. In addition, lidocaine with epinephrine evidently differs from
prilocaine with felypressine regarding the molecular mechanisms underlying the
modulation of superoxide anion production by neutrophils and macrophages.
[Back to top] DI-2-Ethylhexyl Phthalate and Endocrine
Disruption: A Review
Giuseppe
Latini, Alberto Verrotti and Claudio De Felice
Esters of o-phthalic
acid are widely distributed in the ecosystem. The phthalate acid esters (PAE's)
are used as plasticizers in enormous quantities for a variety of industrial
uses in the formulation of plastics. They are also used as solvents in certain
industrial processes and as vehicles for pesticides and have been described as
being among the most abundant man-made environmental pollutants. Plasticizers
have been shown to
elute at a
constant rate from plastic products to the environment. Increasing chemical
use needs a better understanding of how these pollutants may affect human
health. In particular, certain members of this chemical class, such as
di-[2-ethylhexyl]-phthalate (DEHP), have been shown to cause reproductive and
developmental toxicity and are suspected to be endocrine disruptors.
[Back to top] The Utility of Proteomic Patterns for the
Diagnosis of Cancer
Thomas P. Conrads and Timothy D. Veenstra
The advent of
proteomics has brought with it the hope of discovering novel biomarkers that
can be used to diagnose diseases, predict susceptibility, and monitor
progression. Much of this effort has focused on the mass spectral
identification of the thousands of proteins that populate complex biosystems
such as serum and tissues. A revolutionary approach termed proteomic pattern
analysis has emerged as an effective method for the early diagnosis of diseases
such as ovarian, breast, and prostate cancer. Proteomic pattern analysis relies
on the pattern of proteins observed and does not rely on the identification of
a traceable biomarker. Utilizing this technology, hundreds of clinical samples
per day can be analyzed with the potential to be a novel, highly sensitive
diagnostic tool for the early detection of diseases or as a predictor of
response to therapy.
[Back to top] HDL and Inflammation in Atherosclerosis
Lukas
E. Spieker, Frank Ruschitzka, Thomas F. Luscher and Georg Noll
Atherosclerotic
vascular disease is among the most frequent causes of death worldwide. Current
therapeutic strategies concentrate mainly on lowering of low-density
lipoprotein (LDL) cholesterol and an impressive reduction in the risk for
cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms
are more and more recognized to play an important role in vascular disease as
inflammatory markers correlate with prognosis in acute and chronic coronary
artery disease. HDL cholesterol exerts anti-inflammatory effects on the
vasculature. Moreover, HDL is an antioxidant, inhibits thrombogenesis, and has
pro-fibrinolytic properties. Last but not least, HDL mediates reverse
cholesterol transport. These pleiotropic effects make HDL an ideal therapeutic
target for novel therapeutic strategies specifically aiming at HDL elevation
for the prevention and treatment of atherosclerotic vascular disease.
[Back to top] Evidence for a Putative Relationship Between Type 2 Diabetes and Neoplasia with Particular
Reference to Breast Cancer: Role of Hormones, Growth Factors and Specific
Receptors
E.
Guastamacchia, F. Resta, V. Triggiani, A. Liso, B. Licchelli, S. Ghiyasaldin,
C. Sabba and E. Tafaro
The issue of a
possible relationship between type 2 diabetes and
cancer is still debated. Such chronic diseases show a high incidence in the
general population. In their pathophysiology both genetic and environmental
factors are involved, inducing important modifications of metabolism.
Diabetes is associated
to profound metabolic alterations, such as hyperinsulinemia and insulin
resistance, which are common in various diseases, i.e. obesity, hypertension,
dyslipidemia and hyperuricemia. Those illnesses form the so-called metabolic
syndrome.
Insulin resistance,
hyperestrinism and the associated hyperandrogenism may play a role in the onset
of some malignancies, such as endometrium cancer, breast cancer and prostate
cancer.
Low plasma levels of
IGF-1 are able to reduce the risk of cancer in type 2 diabetes patients. This
goal can be obtained with preventive measures, as physical activity, diet and
drugs that can reduce insulin resistance (metformin and thiazolidinediones).
[Back to top] The Paracrine Role Played by Interleukin-1a in the Testis
K.
Svechnikov, C. Petersen, T. Sultana, A. Wahlgren, C. Zetterstrom, E. Colon, C.
Bornestaf and O. Soder
Interleukin-1a(IL-1aplays an important role(s) in the regulation of immune and inflammatory responses. The testis is
an immunologically privileged organ and the variety of effects
exerted by IL-1a on this
organ have yet to be explored in
detail. The aim of the present review is to describe our current view of the
paracrine role played by IL-1an testicular physiology.
Testicular IL-1a
is expressed during development, primarily in Sertoli
cells, appearing in rats for the first time 20 days after birth. This cytokine
is microheterogeneous, consis- ting of three molecular species with molecular
weights of 45, 24 and 17 KDa. The 17KDa form represents mature IL-1a,while
the 24-KDa IL-1a has been shown by our research group to be an
alternately spliced form of the 45-KDa
pro-IL-1a.IL-1a was observed to stimulate
the proliferation of immature Sertoli cells with higher efficacy than FSH.
IL-1a was also found to exert mitogenic effects both on isolated
peritubular cells and germ cells.
Furthermore,
isoforms of IL-1a were seen to stimulate basal
testosterone production in immature Leydig cells, but not in the corresponding
adult cells. This effect
involved induction of the steroidogenic acute regulatory (StAR) protein and
positively regulation by p38 MAPK. Recently, we have observed positive
interactions between IL-1a and hormones of the GH/IGF-I system
that lead to enhanced androgen production by the Leydig cell.
In conclusion, our
findings suggest that isoforms of IL-1a may serve as paracrine
mediators, alone or in concert with other factors, that support proper
testicular cell functioning and, thereby, reproduction and fertility.
[Back to top] Participation of Maternal and Fetal CRH in
Early Phases of Human Implantation: The Role of Antalarmin
A.
Makrigiannakis, E. Zoumakis, S. Kalantaridou, G. Chrousos and A. Gravanis
The hypothalamic
neuropeptide corticotropin-releasing hormone (CRH) is produced by several
tissues of the female reproductive system. It is also secreted at