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Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1871-5303
Endocrine, Metabolic &
Immune Disorders - Drug Targets
Volume 7, Number 1, March 2007
Contents
Does Calprotectin Represent a Regulatory Factor in Host Defense
or a Drug Target in Inflammatory Disease? Pp. 1-5
M.E. Baldassarre, M.A. Altomare, M. Fanelli, D. Carbone, G.
Di Bitonto, A. Mautone and N. Laforgia
[Abstract] [Full
Text Article]
Chemokines as Drug Targets in Type 1 Diabetes
Pp. 7-12
U. Christen
[Abstract] [Full
Text Article]
Epigenetic Alterations of the Wnt/b-Catenin Pathway
in Human Disease Pp. 13-21
O. Aguilera, A. Muñoz, M. Esteller and M.F. Fraga
[Abstract] [Full
Text Article]
CD40L – A Multipotent Molecule for Tumor Therapy
Pp. 23-28
A. Loskog and T.H. Tötterman
[Abstract] [Full
Text Article]
Use of Systemic Proteasome Inhibition as an Immune
Modulating Agent in Disease Pp. 29-34
L.H. Mattingly, R.A. Gault and W.J. Murphy
[Abstract] [Full
Text Article]
Immunotherapeutic Approaches in MS: Update on Pathophysiology
and Emerging Agents or Strategies 2006 Pp. 35-63
C. Kleinschnitz, S.G. Meuth, B.C. Kieseier and H. Wiendl
[Abstract] [Full
Text Article]
Role of Insulin in the Pathogenesis of Free Fatty
Acid-Induced Insulin Resistance in Skeletal Muscle
Pp. 65-74
Jianping Ye
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Does Calprotectin Represent a Regulatory Factor in Host Defense
or a Drug Target in Inflammatory Disease?
M.E. Baldassarre, M.A. Altomare, M. Fanelli, D. Carbone, G.
Di Bitonto, A. Mautone and N. Laforgia
[Full
Text Article]
Calprotectin, a protein composed by two subunits of 8
and 14 kD respectively, is released by neutrophils in the
biological fluids under inflammatory states. For instance,
detection of calprotectin in faeces represents a diagnostic
tool in the case of inflammatory bowel disease. Quite interestingly,
calprotectin is increased in the stool of healthy newborns
from day three up to day thirty and, physiologically, this
increase may be interpreted as a defense mechanism against
yeast and fungi. Therapeutic attempts at inhibiting the deleterious
effect of calprotectin have been experimentally made by using
lycoricinidol. This natural compound is able to hamper the
calprotectin-induced apoptosis on the one hand. On the other
hand, the same compound plays a prophylactic role in the course
of experimental arthritis in rats.
[Back to top]
Chemokines as Drug Targets in Type 1 Diabetes
U. Christen
[Full
Text Article]
Acute or chronic inflammation is thought to play a major role
in the etiology and/or pathogenesis of autoimmune disease.
Often viral infections are the initial cause for a local inflammatory
reaction resulting in tissue infiltration by activated leukocytes.
The activation and trafficking of these leukocytes to the
site of inflammation is conducted by chemoattractant cytokines,
termed chemokines. Depending on the genetic background and
the history of previous infections, such infiltrating leukocytes
can potentially include autoaggressive lymphocytes with specificity
to tissue antigens. The number of specific precursor lymphocytes,
strength of activation and degree of counteracting immunoregulatory
measures determine whether such an autoimmune incident ultimately
results in autoimmune disease. Thus, by blocking the initial
inflammatory insult one could in theory prevent the excessive
attraction of autoaggressive lymphocytes to the inflammation
site and the subsequent formation of a pattern that leads
to autoimmune disease. This review focuses on blocking of
chemokines in animal models of type 1 diabetes and discusses
the possible applications of such treatments in human autoimmune
disease.
[Back to top]
Epigenetic Alterations of the Wnt/b-Catenin Pathway
in Human Disease
O. Aguilera, A. Muñoz, M. Esteller and M.F. Fraga
[Full
Text Article]
The Wnt/β-catenin
pathway plays critical roles in cell physiology, including
determination, proliferation, migration and differentiation
in embryonic development and adult homeostasis. Several components
of the Wnt/β-catenin
pathway, such as SFRPs, WIF-1, DKK-1, APC, AXIN2, ICAT, LEF1
and β-catenin,
are the target of mutations or epigenetic inactivation leading
to the deregulation or constitutive activation of the Wnt/β-catenin
pathway. Aberrant activation of the Wnt signalling pathway
abrogates controlled growth and impairs cell differentiation.
Alterations of the Wnt signalling pathway have been found
in cancer, osteoporosis, ischemic neuronal death and other
human diseases. Here we review the alterations of the Wnt/β-catenin
signalling cascade and discuss the biological significance
and relationship between mutation and/or epigenetic silencing
within the same pathway.
[Back to top]
CD40L – A Multipotent Molecule for Tumor Therapy
A. Loskog and T.H. Tötterman
[Full
Text Article]
CD40L-based therapy is currently under intensive investigation
for its potent anti-tumor effects in experimental animal models
of cancer as well as in Phase I clinical trials. CD40L is
one of the strongest inducers of Th1 responses although it
stimulates both innate and adaptive immunity. The molecule
is normally expressed by activated immune cells such as T
helper cells that act on dendritic cells to induce their maturation
and capability of activating tumor-reactive T cells. Moreover,
recent findings implicate that CD40L stimulation abrogates
the suppressive effect of T regulatory cells. Interestingly,
while being an activator of immune cells, CD40L has been shown
to directly induce apoptosis in tumor cells by mechanisms
only beginning to emerge. These two major effector mechanisms
synergize to combat tumor growth. Op-timal use of this multipotent
molecule might therefore result in effective immunotherapy
of cancer. CD40L can be administered to patients as soluble
protein trimers. To achieve membrane-bound expression, viral
vectors can be used to transfer CD40L cDNA into 1) tumor cells
ex vivo for creating CD40L-expressing tumor vaccines,
2) ex vivo cultured dendritic cells for cell therapy,
and 3) tumor nodules in situ. CD40L substitutes such
as CD40-directed agonistic antibodies have been evaluated
with interesting results in experimental models. In this survey,
different types and mechanisms of CD40L-based therapy will
be discussed from bench to bedside.
[Back to top]
Use of Systemic Proteasome Inhibition as an Immune
Modulating Agent in Disease
L.H. Mattingly, R.A. Gault and W.J. Murphy
[Full
Text Article]
Bortezomib is the first proteasome inhibitor to be used clinically
for the treatment of multiple myeloma and has been suggested
as a possible treatment for a wide variety of hematologic
and solid malignancies. Recent data suggests that potent immunomodulatory
effects can also occur with systemic proteasome inhibition.
This has been recently shown to occur in a graft-versus host
disease model following bone marrow transplantation in mice.
The suggested direct immunological effects of bortezomib treatment
to include a decrease in anti-apoptotic protein levels, an
increase in expression of TNF-family receptors (specifically
Apo2L/TRAIL), induction of apoptosis, and inhibition of the
transcription factor NF-κB.
The NF-κB
pathway has been associated with the regulation of numerous
immune and inflammatory response mediators. In this review,
we will present recent information concerning the potential
therapeutic implications of bortezomib for a range of immune
disorders. These findings would suggest that bortezomib treatment
may be of clinical significance to suppress solid organ transplant
rejection, autoreactive T cell responses, pro-inflammatory
cytokine production, and consequently disease progression
and pathology in autoimmunity.
[Back to top]
Immunotherapeutic Approaches in MS: Update on Pathophysiology
and Emerging Agents or Strategies 2006
C. Kleinschnitz, S.G. Meuth, B.C. Kieseier and H. Wiendl
[Full
Text Article]
Multiple sclerosis (MS) is a chronic disabling disease with
significant implications for patients and society. The individual
disease course is difficult to predict due to the heterogeneity
of clinical presentation as well as radiological and pathological
findings. Although its etiology still remains unknown, the
last decade has generated considerable success in understanding
the underlying pathophysiology of MS. In addition to its view
as a prototypic inflammatory autoimmune disorder, recent data
support the importance of primary and secondary neurodegenerative
mechanisms such as oligodendrocyte death, axonal loss and
ion channel dysfunction. The deepened understanding of the
immunopathogenesis as well as the limited effectiveness of
the currently approved disease modifying therapies have led
to a tremendous number of trials investigating potentially
new drug targets. Emerging treatments take into account the
different immunopathological mechanisms as well as strategies
to protect against axonal damage or to promote remyelination.
This review provides a compilation of novel immunotherapeutic
strategies or new aspects of known immunotherapeutic agents
which have evolved recently. The pathogenetic rationale of
these novel drug targets for the treatment of MS as well as
accompanying preclinical and clinical data are highlighted.
[Back to top]
Role of Insulin in the Pathogenesis of Free Fatty
Acid-Induced Insulin Resistance in Skeletal Muscle
Jianping Ye
[Full
Text Article]
Insulin resistance is a pathophysiological link of obesity
to type 2 diabetes. The initial cause of insulin resistance
is critical for prevention and treatment of type 2 diabetes.
Lipotoxicity is a well-known concept in the explanation of
initiation of insulin resistance. Although there are several
prevailing hypotheses about the cellular/molecular mechanisms
of lipotoxicity, such as inflammation, oxidative stress, hyperinsulinemia,
and ER stress, the relative importance of these hypothesized
events remains to be determined. The role of hyperinsulinemia
is relatively under documented in the literature for the initiation
of insulin resistance. In this review, an interaction of fatty
acid and beta-cells, and a synergy between free fatty acids
(FFAs) and insulin are emphasized for the role of hyperinsulinemia.
This article presents the evidence about FFA-induced insulin
secretion in vitro and in vivo, recent advances in
the molecular mechanism of FFA action in beta-cells, a role
of GPR40 in the development of insulin resistance, and the
negative feedback loop of the insulin receptor signal pathway.
The negative feedback loop is discussed in detail with a focus
on IRS-1 serine kinases. This article provides a substantial
support for the role of insulin in the early stages of FFA-associated
insulin resistance. The hypothesis of insulin’s role
in lipotoxicity is referred to as the “insulin
hypothesis” in this review. According to this
hypothesis, prevention of increased beta-cell response to
glucose may be a potential approach for early intervention
of metabolic syndrome.
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