| Endocrine,
Metabolic & Immune Disorders - Drug Targets
ISSN: 1568-0044
Current Drug Targets - Immunology,
Endocrine and Metabolic Disorders
Volume 5, Number 1, March 2005
Contents
Effects of Endocrine Disruptors on Developmental
and Reproductive Functions Pp.1-10
Tiziana A.L. Brevini, Simona Bertola Zanetto and Fabiana
Cillo
[Abstract] [Full
text article]
Therapeutic Strategies To Prevent Neurodegeneration
And Promote Regeneration In Multiple Sclerosis Pp.11-26
T. Chitnis, J. Imitola and S.J. Khoury
[Abstract] [Full
text article]
Mitochondrial Trifunctional Protein Defects: Molecular
Basis and Novel Therapeutic Approaches Pp.27-40
J. Angdisen, V.D.G. Moore, J.M. Cline, R.M. Payne and
J.A. Ibdah
[Abstract] [Full
text article]
Signal Transduction by IL-2 and its Receptors
as Target in Treatment of Rheumatoid Arthritis Pp.41-50
V. I. Kozanidou, A. D. Theocharis, A. Georgiadis, P. V.
Voulgari, A. A. Drosos and N. K. Karamanos
[Abstract] [Full
text article]
Reduction of Hepatic Glucose Production as a Therapeutic
Target in the Treatment of Diabetes Pp.51-59
Chaodong Wu, David A. Okar, Johnthomas Kang and Alex J.
Lange
[Abstract] [Full
text article]
Determination of Binding Constant of DNA-binding
Drug to Target DNA by Surface Plasmon Resonance Biosensor
Technology Pp.61-72
Liang-Ping Lin, Long-Sun Huang, Chii-Wann Lin, Chi-Kung
Lee, Ji-Liang Chen, Su-Ming Hsu, Shiming Lin
[Abstract] [Full
text article]
New Approach to Immunotherapy Against Organ-specific
Autoimmune Diseases with T Cell Receptor and Chemokine Receptor
DNA Vaccines Pp.73-77
Yoh Matsumoto
[Abstract] [Full
text article]
Signaling Mechanism for the Insulin-like Effects
of Growth Hormone -Another Example of a Classical Hormonal
Negative Feedback Loop Pp.79-92
Martin Ridderstrale
[Abstract] [Full
text article]
Regulation of the Steroidogenic Acute Regulatory
Protein Expression: Functional and Physiological Consequences
Pp.93-108
P.R. Manna and D.M. Stocco
[Abstract] [Full
text article]
CXCR3-binding Chemokines: Novel Multifunctional
Therapeutic Targets Pp.109-118
E. Lazzeri and P. Romagnani
[Abstract] [Full
text article]
Abstracts
[Back to top]
Effects of Endocrine Disruptors on Developmental and Reproductive
Functions
Tiziana A.L. Brevini, Simona Bertola Zanetto
and Fabiana Cillo
[Full
text article]
Endocrine disruptors (EDs) are exogenous environmental molecules
that may affect the synthesis, secretion, transport, metabolism,
binding, action, and catabolism of natural hormones in the
body. EDs may thus interact with the endocrine system of animals
and humans and can exert this effect even when present in
minute amounts. EDs have adverse impacts on a number of developmental
functions in wildlife and humans. Critical periods of urogenital
tract and nervous system development in-utero and during early
post-natal life are especially sensitive to hormonal disruption.
Furthermore a wide range of hormone-dependent organs (pituitary
gland, hypothalamus, reproductive tract) are targets of EDs
disrupting effects in adult subjects, possibly resulting in
cell transformation and cancer.
At present about 60 chemicals have been identified and characterized
as EDs and belong to three main groups: (a) synthetic compounds
utilized in industry, agriculture and consumer products; (b)
synthetic molecules used as pharmaceutical drugs and (c) natural
chemicals found in human and animal food (phytoestrogens).
In the present review we will give special attention to the
family of Polychlorinated biphenyls (also indicated as PCBs)
because of their persistence in the environment, ability to
concentrate up the food chain, continued detection in environmental
matrices, and ability to be stored in the adipose tissue of
animals as well as humans. The detrimental effects of these
compounds, and of EDs more in general, on health and reproduction
will be discussed, presenting experimental data aimed at understanding
the molecular mechanisms involved in their action.
[Back to top]
Therapeutic Strategies To Prevent Neurodegeneration And Promote
Regeneration In Multiple Sclerosis
T. Chitnis, J. Imitola and S.J. Khoury
[Full
text article]
Multiple sclerosis (MS) is an immune-mediated demyelinating
and degenerative disease of the central nervous system (CNS),
with lesions predominantly occurring in the CNS white matter.
The current treatment for MS relies on therapies that primarily
target the peripheral immune response. However, it is clear
that these strategies alone are insufficient for treating
the chronic progressive disability that is the ultimate outcome
of the disease. Axonal degeneration may be the primary determinant
of fixed neurological deficits in MS. Here, we will discuss
the contribution of axonal damage to MS pathogenesis, and
potential cellular and molecular targets in the prevention
of neurodegeneration. In addition, we will discuss potential
molecular approaches to promote repair of CNS components in
multiple sclerosis.
[Back to top]
Mitochondrial Trifunctional Protein Defects: Molecular
Basis and Novel Therapeutic Approaches
J. Angdisen, V.D.G. Moore, J.M. Cline, R.M. Payne
and J.A. Ibdah
[Full
text article]
Mitochondrial trifunctional protein (MTP) is a complex protein
that catalyzes the last three steps of long chain fatty acid
oxidation. MTP defects have emerged recently as important
inborn errors of metabolism because of their clinical implications.
These disorders are recessively inherited and display a spectrum
of clinical phenotypes in affected children including hepatic
dysfunction, cardiomyopathy, neuro-myopathy, and may cause
sudden unexpected infant death if undiagnosed and untreated.
Interestingly, mothers who carry fetuses with MTP defects
develop life-threatening complications during pregnancy. Recently,
we delineated disease-causing mutations in MTP and reported
the molecular basis for the pediatric and fetal-maternal genotype-phenotype
correlations.
Current management of patients with MTP defects include long-term
dietary therapy of fasting avoidance, low fat diet with the
restriction of long chain fatty acid intake and substitution
with medium chain fatty acids. The long-term outcome of patients
treated by dietary modifications remains unknown. Thus, treatment
that aims at correcting the metabolic defect remains the therapy
of choice for this disorder. Currently, we are exploring the
potential use of protein transfection domains (PTD) for treatment
of these disorders. We have shown that the transactivator
of transcription (TAT) peptide from the human immunodeficiency
virus can deliver proteins to mitochondria. We have further
developed methods to localize these proteins to mitochondria
by including a mitochondrial targeting in the fusion protein
construct. Finally, we have shown that the fusion protein
can cross the placenta and was detectable in the fetus and
newborn pups. The practical therapeutic implications of this
novel approach will be discussed.
[Back to top]
Signal Transduction by IL-2 and its Receptors as Target
in Treatment of Rheumatoid Arthritis
V. I. Kozanidou, A. D. Theocharis, A. Georgiadis,
P. V. Voulgari, A. A. Drosos and N. K. Karamanos
[Full
text article]
Rheumatoid arthritis (RA) is a chronic and destructive arthropathy
with systemic features, the etiopathogenesis of which remains
unclear. It is characterized by relapsing and remitting inflammation
and hyperplasia of synovial cells. Proinflammatory cytokines,
such as interleukin-2 (IL-2), play an important role in maintaining
cartilage damage and severe destruction of the joints due
to an uncontrolled activation of cellular immunity. An imbalance
between proinflammatory and anti-inflammatory mediators is
likely to contribute to the chronicity of the disease. Therefore,
insight into the activation state of T-cells in different
stages of the disease may be important to understand pathogenetic
mechanisms underlying RA and could be a lead for the design
of future therapeutic strategies. Because of the central role
of the IL-2/IL-2 receptor (IL-2R) system in mediation of the
immune system, monitoring and manipulation of this system
has important diagnostic and therapeutic implications. New
approaches in RA therapy with anticytokine agents, which block
cytokines and their receptors, are now used as antirheumatic
drugs in clinical practice.
[Back to top]
Reduction of Hepatic Glucose Production as a Therapeutic Target
in the Treatment of Diabetes
Chaodong Wu, David A. Okar, Johnthomas Kang and
Alex J. Lange
[Full
text article]
There has been an alarming increase in the population diagnosed
with diabetes worldwide. Although there is an ongoing debate
as to the role of liver in the pathogenesis of diabetes, reduction
of hepatic glucose production has been targeted as a strategy
for diabetes treatment. Indeed, reduction of hepatic glucose
production can be achieved through modulation of both hepatic
and extra-hepatic targets. This review describes the role
of the liver in the control of glucose homeostasis. Gluconeogenesis
and glycogenolysis are pathways for glucose production, whereas
glycolysis and glycogenesis are pathways for glucose utilization/storage.
At the biochemical and molecular level, the metabolic and
regulatory enzymes integrate hormonal and nutritional signals
and regulate glucose flux in the liver. Modulating either
activities of or gene expression of these metabolic enzymes
can control hepatic glucose production. Dysfunction of one
or several enzyme(s) due to insulin deficiency or resistance
results in increases in fluxes of glycogenolysis and gluconeogenesis
and/or decreases in fluxes of glycolysis and glycogenesis,
which thereby lead to glucose generation exceeding glucose
consumption/disposal, as well as dysregulation of lipid metabolism.
Activation of enzymes that promote glucose utilization/storage
and/or inhibition of enzymes that reduce glucose generation
achieve reduction of hepatic glucose production, and hence
lower levels of plasma glucose in diabetes. This is also beneficial
for the correction of dyslipidemia. Therefore, many enzymes
are viable therapeutic targets for diabetes.
[Back to top]
Determination of Binding Constant of DNA-binding Drug to Target
DNA by Surface Plasmon Resonance Biosensor Technology
Liang-Ping Lin, Long-Sun Huang, Chii-Wann Lin,
Chi-Kung Lee, Ji-Liang Chen, Su-Ming Hsu, Shiming Lin
[Full
text article]
The experimental determination of the binding constant of
a drug for its target molecule is of considerable importance.
It is a basic experimental parameter in a variety of studies,
such as the prediction of drug efficiency, or in the pharmacokinetic
drug interaction. DNA-binding drugs have been reported to
be able to interfere in a sequence dependent manner with biological
functions such as topoisomerase activity, restriction of enzyme
cleavage of DNA, protein-DNA interactions and the activity
of transcription factors, leading to alteration of gene expression.
This effect could have important practical application in
the experimental therapy of human pathologies, including neoplastic
diseases and viral, or microbial infections. The assessment
of the biological activity of DNA-binding drugs by polymerase
chain reaction, footprinting, gel retardation and in vitro
transcription studies was recently reported. However, most
of these techniques are steady-state methodologies and therefore
are not suitable for an easy determination of the binding
activity of DNAbinding drugs to target DNA and the stability
of drugs-DNA complexes. Direct real-time observation and measurement
of the interaction between DNA-binding drug and target DNA
sequence is a subject of interest for drug discovery and development.
The recent development of biosensors, based on surface plasmon
resonance (SPR) technology, enables monitoring of a variety
of biospecific interactions of DNA-binding drugs with target
DNA elements in real-time. The present review is designed
to indicate the theoretical background of SPR-based biosensor
technology as well as to present the great variety of measurements
and modes of interaction kinetics that can be performed with
these techniques. In addition, some of the most recent studies
in determining the binding constant and stoichiometry of DNA-binding
drugs to target DNA with SPR technology are reviewed and the
available theoretical aspects necessary for the comprehension
of the experiments are provided.
[Back to top]
New Approach to Immunotherapy Against Organ-specific Autoimmune
Diseases with T Cell Receptor and Chemokine Receptor DNA Vaccines
Yoh Matsumoto
[Full
text article]
Organ-specific autoimmune diseases are characterized by the
presence of relapse and remittance of the clinical signs,
and last for a long period of time in most cases without an
appropriate treatment. Immunopathologically, T cells that
respond to organ-specific autoantigens play an important role
in the development of inflammatory lesions in the target organ.
These pathogenic T cells that had been activated by various
stimuli including preceding infection infiltrate the target
organ in an antigen-specific manner and break the homeostasis
of the organ. Furthermore, they secrete a large number of
pro-inflammatory cytokines and chemokines, which recruit by-stander
inflammatory cells in the lesion. Although general immunosuppressive
drugs such as corticosteroid and cyclosporine are effective
in suppressing clinical signs and inflammation, immunospecific
therapy is essential for the establishment of long-lasting
remission or complete cure. In order to achieve effective
immunospecific therapy, several groups have focused on two
key molecules that are deeply involved in pathogenesis of
autoimmune diseases. One is the T cell receptor (TCR) expressed
on pathogenic T cells and the other is the cytokine and chemokine
receptor expressed in the target organ. Another important
aspect of this issue is the reagent that is used for the suppression
of the function of the key molecules. So far, monoclonal antibodies,
peptide vaccines and DNA vaccines are the major reagents used
for immunosuppressive therapies.
In the present review, I introduce the results of immunotherapy
obtained in my laboratory using TCR-based and chemokine receptor
(chemoR)-based DNA in experimental autoimmune encephalomyelitis
(EAE) and myocarditis (EAC) and discuss its effectiveness
and pathomechanisms of immunosuppression. First, we administered
DNA vaccines encoding pathogenic TCR Vβ8.2, 10 (to Lewis rats)
and 15 (to DA rats) and observed that these vaccinations protected
animals from the development of EAE [1]. Similar results were
obtained in EAC [2]. Second, DNAs encoding several chemoRs
were prepared and administered after the challenge to neutralize
the function of chemokines that are highly upregulated in
the lesions. It was demonstrated that these chemoR DNAs suppress
the relapse of chronic relapsing EAE and block the progression
of EAC to dilated cardiomyopathy (manuscripts submitted for
publication). These findings clearly indicate that DNA vaccination
can be a powerful tool for treatment of organ-specific autoimmune
diseases.
[Back to top]
Signaling Mechanism for the Insulin-like Effects of Growth
Hormone -Another Example of a Classical Hormonal Negative
Feedback Loop
Martin Ridderstrale
[Full
text article]
Growth hormone (GH) exerts many effects in addition to its
ability to stimulate growth. The metabolic effects are either
chronic diabetogenic or acute insulin-like. The latter effects
are only seen in cells that have been deprived of the hormone
for a few hours. After exposure to GH the ability of the cells
to respond with insulin-like effects disappears within a couple
of hours, a negative feedback loop, which is a part of the
chronic effects of the hormone. The insulin-like effects are
mediated by the cytosolic tyrosine kinase Janus kinase 2 (JAK2)
upon GH-GH receptor interaction, resulting in tyrosine phosphorylation
of downstream targets including the GH receptor itself and
insulin receptor substrate-1 (IRS-1) and IRS-2. Analogous
to the post-receptor events for insulin this results in recruitment
of phosphatidylinositol-3 kinase (PI3-kinase) to the IRS-proteins.
Downstream PI3-kinase protein kinase B/Akt participates in
the activation of glucose transporters (GLUT4) and increased
glucose uptake as well as activation of phosphodiesterase
3B and hydrolysis of cAMP leading to a net dephosphorylation
of the hormone sensitive lipase and inhibition of lipolysis.
Simultaneously, JAK2 phosphorylates STAT-family transcription
factors that move into the nucleus and activate the transcription
of, among others, genes coding for negatively regulatory proteins
called Suppressors of cytokine signalling (SOCS). The turnover
of SOCS is rapid and in their presence JAK2 will still activate
STAT-proteins (and the diabetogenic effects), but no longer
phosphorylate the IRS-proteins (and induce insulin-like effects),
closing the loop of yet another classical hormonal negative
feedback loop.
[Back to top]
Regulation of the Steroidogenic Acute Regulatory Protein
Expression: Functional and Physiological Consequences
P.R. Manna and D.M. Stocco
[Full
text article]
Steroid hormones are synthesized in steroidogenic cells of
the adrenal, ovary, testis, placenta and brain and are essential
for normal reproductive function and bodily homeostasis. The
rate-limiting and regulated step in steroid biosynthesis is
the intramitochondrial transport of cholesterol, a process
that is mediated by the steroidogenic acute regulatory (StAR)
protein. The importance of StAR has been illustrated by analyses
of patients with lipoid congenital adrenal hyperplasia (lipoid
CAH), an autosomal recessive disorder that markedly disrupts
the synthesis of all gonadal and adrenal steroids. Molecular
and physio-pathological analyses have demonstrated that alterations
in the StAR gene are the only known cause of lipoid CAH. Furthermore,
StAR knockout mice have been generated and display a phenotype
that is essentially identical to the human condition. Recent
advances in tissue-specific and hormone-induced expression
of the StAR protein provide insights into a number of human
endocrinological health issues including developmental and
reproductive abnormalities. Several factors and processes
have been demonstrated to influence StAR expression in steroidogenic
cells and there is increasing evidence that a transcription
factor-binding site-rich region present in the proximal region
of the StAR promoter is highly instrumental in StAR gene expression.
In this review we focus on the significant findings that have
been made with regards to the regulation of StAR expression
and also on the clinical and endocrinological consequences
of a non-functioning StAR gene.
[Back to top]
CXCR3-binding Chemokines: Novel Multifunctional Therapeutic
Targets
E. Lazzeri and P. Romagnani
[Full
text article]
The goal to attenuate inflammation without inducing generalized
immunosuppression has focused the attention on chemokines,
a family of chemotactic peptides that regulate the leukocyte
traffick into tissues. However, the development of drugs that
block ckemokine activity may be hampered by the observation
that some chemokines display pleiotropic biologic functions.
For example, the chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC
exhibit the ability to recruit different leukocytes subsets,
the capacity to induce the proliferation of vascular pericytes
as well as powerful anti-tumor effects, which are mediated
by a common receptor, named CXCR3. Because of their pleiotropic
biologic effects, these chemokines have been proposed as possible
therapeutic targets in cancer, allograft rejection, glomerulonephritis,
diabetes, multiple sclerosis, and autoimmune disorders of
the thyroid. The chemokine CXCL4/PF4 shares several activities
with CXCL9, CXCL10, and CXCL11, including angiostatic effects,
although its specific receptor has remained unknown for a
long time. Recently, we provided evidence that the different
functions of CXCL9, CXCL10, and CXCL11 on distinct cell types
can be at least partly explained by the interaction of these
chemokines with two distinct receptors. Indeed, in addition
to the classic form of CXCR3 receptor, which we have renamed
as CXCR3-A, a novel CXCR3 receptor variant (CXCR3-B) was identified,
that not only mediates the angiostatic activity of CXCR3 ligands,
but also acts as functional receptor for CXCL4.
In this review, we focus on the accumulating evidence demonstrating
the pivotal role of CXCR3-binding chemokines inseveral human
diseases. Studies based on CXCR3 targeting have shown its
importance in different pathologic conditions and orally active
small molecules capable of inhibiting this receptor are now
being developed in order to be tested for their activity in
humans.
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