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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 27, 2007
Contents
Anti-Cancer Therapeutic Approaches Based on Intracellular
and Extracellular Heat Shock Proteins Pp. 2839-2847
Celine Didelot, David Lanneau, Mathilde Brunet, Anne-Laure
Joly, Aurelie De Thonel, Gabriela Chiosis and Carmen Garrido
[Abstract]
Role of the APP Non-Amyloidogenic Signaling Pathway
and Targeting α
-Secretase as an Alternative Drug Target for Treatment
of Alzheimer’s Disease Pp. 2848-2864
S. Bandyopadhyay, L.E. Goldstein, D.K. Lahiri and J.T.
Rogers
[Abstract]
Manipulation of Microglial Activation as a Therapeutic
Strategy in Alzheimer's Disease Pp. 2865-2871
Feng-Shiun Shie and Randall L. Woltjer
[Abstract]
Recent Progress in Rational Drug Design of Neuraminidase
Inhibitors Pp. 2872-2891
Yu Liu, Jie Zhang and Wenfang Xu
[Abstract]
Apoptotic Cell Clearance and Autoimmune Disorder
Pp. 2892-2897
Masato Tanaka and Yasunobu Miyake
[Abstract]
A Needle-Free Approach for Topical Immunization: Antigen
Delivery via Vesicular Carrier System(s)
Pp. 2898-2910
Sunil Mahor, Prem N. Gupta, Amit Rawat and Suresh P. Vyas
[Abstract]
Interaction of Proteins with Lipid Rafts Through Glycolipid-Binding
Domains: Biochemical Background and Potential Therapeutic
Applications Pp. 2911-2917
Jacques Fantini
[Abstract]
Estrogens and Glucocorticoid Hormones in Adipose Tissue
Metabolism Pp. 2918-2924
Cecilia Mattsson and Tommy Olsson
[Abstract]
Fibrinogen Signal Transduction as a Mediator and Therapeutic
Target in Inflammation: Lessons from Multiple Sclerosis
Pp. 2925-2936
R.A. Adams, C. Schachtrup, D. Davalos, I. Tsigelny and
K. Akassoglou
[Abstract]
Cochlear Stem Cells/Progenitors and Degenerative Hearing
Disorders Pp. 2937-2943
Jizhen Lin, Ling Feng, Shinji Fukudome, Yuki Hamajima,
Tina Huang and Samuel Levine
[Abstract]
Abstracts
[Back to top]
Anti-Cancer Therapeutic Approaches Based on Intracellular
and Extracellular Heat Shock Proteins
Celine Didelot, David Lanneau, Mathilde Brunet, Anne-Laure
Joly, Aurelie De Thonel, Gabriela Chiosis and Carmen Garrido
Stress or heat shock proteins (Hsps) Hsp90, Hsp70 and
Hsp27 are chaperones that assist the proteins in their folding,
stability, assembly into multi-protein complexes and transport
across cellular membranes. The expression of some of them
is highly induced in response to a wide variety of physiological
and environmental insults. Hsps have a dual function depending
on their intracellular or extracellular location. Intracellular
Hsps have a protective function. They allow the cells to survive
to lethal conditions. The cytoprotective functions of Hsps
can largely explain by their anti-apoptotic properties. Hsp90,
Hsp70 and Hsp27 can directly interact with different proteins
of the tightly regulated programmed cell death machinery and
thereby block the apoptotic process at distinct key points.
In cancer cells, where the expression of Hsp27, Hsp70 and/or
Hsp90 is frequently abnormally high, they participate in oncogenesis
and in resistance to chemotherapy. Therefore, the inhibition
of Hsps has become an interesting strategy in cancer therapy.
In contrast to intracellular Hsps, extracellular located or
membrane-bound Hsps mediate immunological functions. They
can elicit an immune response modulated either by the adaptive
or innate immune system. In cancer, most immunotherapeutical
approaches based on extracellular Hsps exploit their carrier
function for immunogenic peptides. This review will discuss
this different and often paradoxical approaches in cancer
therapy based on the dual role of Hsps, protective/tumorigenic
versus immunogenic.
[Back to top]
Role of the APP Non-Amyloidogenic Signaling Pathway
and Targeting α
-Secretase as an Alternative Drug Target for Treatment
of Alzheimer’s Disease
S. Bandyopadhyay, L.E. Goldstein, D.K. Lahiri and J.T.
Rogers
Alzheimer’s disease (AD) is the most prevalent form
of dementia, and its effective disease modifying therapies
are desperately needed. Promotion of non-amyloidogenic alpha
(α)-secretase
cleavage of amyloid precursor protein (APP) to release soluble
sAPPα,
based on the most widely accepted “amyloid model”
as a plausible mechanism for AD treatment, is the focus of
this review. Modulation of α-secretase
or “a disintegrin and metalloprotease (ADAM)”s
activity via protein kinase C (PKC), calcium ion
(Ca2+), tyrosine kinase (TK),
MAP kinase (MAPK), and hormonal signaling, which regulate
catabolic processing of APP, are discussed. The inhibition
of amy-loidogenic processing of APP by the beta (β)-and
gamma (γ)-secretase
has been considered till now a promising strategy to treat
AD. But β-
and γ-secretase
inhibitors, along with the available therapeutic tools for
AD, have side effects. These challenges can be circumvented
to certain extent; but activation of sAPPα
release appears to be a potential alternative strategy to
reduce cerebral amyloidosis. Drug screens have been performed
to identify therapeutics for AD, but an effective screening
strategy to isolate activators of α-secretase
has been rarely reported. Novel reporter-based screens targeted
toward APP mRNA 5’ untranslated region (UTR), followed
by counter-screens to detect α-secretase
stimulators, could be important in detecting compounds to
promote sAPPα
release and reduce amyloid beta (Aβ)
buildup. The primary inflammatory cytokine interleukin-1,
which stimulates APP 5’UTR-directed translation of cell-associated
APP, enhances processing to sAPPα
in astrocytes and co-activates ADAM-10/ADAM-17 through MAPK
signaling; thus illustrating a novel pathway that could serve
as therapeutic model for AD.
[Back to top]
Manipulation of Microglial Activation as a Therapeutic
Strategy in Alzheimer's Disease
Feng-Shiun Shie and Randall L. Woltjer
Alzheimer’s disease (AD) is the leading cause of dementia.
Although the etiology of AD remains controversial, the amyloid
hypothesis suggests that β-amyloid
(Aβ)
peptides may contribute to brain dysfunction, and microglial
activation has become increasingly regarded as a potential
contributor to disease pathogenesis. Microglial activation
is characterized by morphological changes and by production
of various effectors, and activated neuroinflammation concurrent
with increased oxidative stress may contribute to damage to
neurons. However, recently there has been a recognition that
microglia may also play a neuroprotective role through their
release of neurotrophic factors and through phagocytosis of
Aβ.
Thus, there is growing consensus that a favorable combination
of diminished microglia-mediated neuroinflammation and enhanced
Aβ
clearance may be critical in AD therapy. In this review, we
will discuss the role of microglial activation in AD and how
pharmacologic manipulation of microglia might bear upon the
treatment of AD.
[Back to top]
Recent Progress in Rational Drug Design of Neuraminidase
Inhibitors
Yu Liu, Jie Zhang and Wenfang Xu
Neuraminidase is a major glycoprotein of influenza virus which
is essential for viral infection and offers a potential target
for antiviral drug development. Rational drug design of NA
inhibitors is now in the clinic and these molecules are effective
and safe for the treatment of influenza. Recently, research
of structure-based NA inhibitors is becoming an interesting
field, leading to a breakthrough in the control of influenza.
Here we review the progress in the rational drug design of
NA inhibitors in recent years.
[Back to top]
Apoptotic Cell Clearance and Autoimmune Disorder
Masato Tanaka and Yasunobu Miyake
In multicellular organisms, unnecessary or harmful cells,
such as those that are cancerous or infected with a virus,
are eliminated by apoptosis. After apoptosis, cell corpses
are rapidly recognized and phagocytosed by professional phagocytes,
such as macrophages and dendritic cells. The rapid removal
of cell corpses by phagocytes prevents the release of potentially
toxic or immunogenic materials from dying cells. Although
a number of molecules on phagocytes have been found to be
involved in apoptotic cell clearance in vitro, only
a few have been proved to be involved in apoptotic cell clearance
in vivo by analyses of knockout animals. These knockout
mice commonly suffer from autoimmunity, indicating that the
complete removal of apoptotic cells is essential for the maintenance
of self-tolerance. In this review, we present an overview
of the molecular mechanisms of apoptotic cell clearance by
phagocytes and the pathological relevance of the failure of
apoptotic cell clearance to autoimmune disorder.
[Back to top]
A Needle-Free Approach for Topical Immunization: Antigen
Delivery via Vesicular Carrier System(s)
Sunil Mahor, Prem N. Gupta, Amit Rawat and Suresh P. Vyas
Topical immunization (TI) is novel and needle free strategy
involving vaccine delivery through topical application of
antigen and adjuvant(s) directly or via a suitable
carrier system on intact skin. Anatomy and physiology of skin
attracts scientists in developing topical carrier system(s)
for enhanced delivery of bioactive(s). Numerous techniques
i.e. physical, chemical and vesicular carrier systems
have been exploited for topical immunization. The present
review discuss various vesicular systems i.e. liposomes,
nio-somes, transfersomes, vesosomes etc. for the efficient
topical delivery of various immunogens along with comparative
points of their merit(s) in TI. The mechanism of permeation
of bioactive(s) through skin route via these carriers
to the immune system for development of both cellular and
humeral immunity has also been discussed. Moreover, the effect
of composition and type of carrier system on type of immunity
induced has also been focused to develop new effective carrier
system(s) for topical immunization.
[Back to top]
Interaction of Proteins with Lipid Rafts Through Glycolipid-Binding
Domains: Biochemical Background and Potential Therapeutic
Applications
Jacques Fantini
The wide biochemical diversity of glycolipids in membranes
explains why these molecules are often selected by pathogens
(viruses, bacteria, prions) as primary sites of interactions
with the cell surface. Moreover, glycolipids concentrate into
cholesterol/glycolipid-rich microdomains where they can reach
high local concentrations consistent with the multivalent
attachment of pathogens on the cell surface. Finally, recent
studies have shown that glycolipids could also modulate protein
conformation. This chaperone activity of glycolipids has been
associated with various pathogenic processes including HIV
infection, prion propagation, and amyloid aggregation in Alzheimer’s
and Creutzfeldt-Jakob’s diseases. Despite the potential
interest for drugs mimicking glycolipid structure and function,
the physicochemical properties of authentic glycolipids suggested
that it might be difficult to obtain synthetic glycolipid
analogues able to neutralise those pathogens before they could
reach the cell surface. Recent data obtained with mono-, di-,
and tri-hexosylceramide (GalCer, LacCer and Gb3)
have proven that this was absolutely not the case and that
highly active inhibitors could be designed through slight
modifications of glycolipid structure. Biochemical studies
of glycolipid-protein interactions have highlighted the importance
of CH-π
stacking interactions between galactosyl head groups of the
glycolipid and aromatic amino acids of the protein. The discovery
of this unique mechanism of interaction may allow a rational
strategy for the design and synthesis of glycolipid-based
molecules as new anti-infectious and/or anti-amyloidogenesis
compounds. This strategy, which takes into account the hierarchical
organisation of glycolipids into discrete membrane microdomains
as well as their association with cholesterol, is discussed
in the present review.
[Back to top]
Estrogens and Glucocorticoid Hormones in Adipose Tissue
Metabolism
Cecilia Mattsson and Tommy Olsson
Women have a higher percentage of body fat than men, and there
is a gender-specific difference in fat distribution: Females
tend to accumulate fat around the hips, buttocks, and thighs
while men have a larger intra-abdominal (visceral) fat mass.
After menopause, there is a redistribution of fat depots,
and post-menopausal women develop increased amounts of visceral
fat. The risk of developing obesity-related diseases is significantly
lower in pre-menopausal women compared to men, a difference
that is abolished after menopause, suggesting that the female
sex steroid estrogen influences adipogenesis and adipose metabolism.
Experimentally, estrogen increases the size and number of
subcutaneous adipocytes and attenuates lipolysis. Post-menopausal
women also develop a more atherogenic lipid pattern and decreased
levels of the prothrombotic protein plasminogen activator
inhibitor-1, which attenuates fibrinolysis. Pathologically
increased circulating cortisol concentration is associated
with dysmetabolic features e.g., central obesity, elevated
blood pressure, insulin resistance, and dyslipidemia. In “simple
obesity,” glucocorticoid production is elevated. Peak
levels of circulating cortisol are however low or normal,
possibly because of increased clearance and/or tissue-specific
changes in cortisol production. In addition to the adrenal
production of cortisol, cortisol is also generated in adipose
tissue by the enzyme 11β-hydroxysteroid
dehydrogenase type 1 (11βHSD1)
which converts inactive cortisone to active cortisol. The
enzyme activity in subcutaneous fat increases with increasing
body weight. Estrogen seems to have a tissue-specific influence
on 11βHSD1
enzyme activity, attenuating it in liver, kidney, and testis
but upregulating 11βHSD1
mRNA expression in preadipocytes from women. In the present
review, we summarize and discuss the interaction between glucocorticoids
and sex steroids and their influence on adipocyte metabolism.
[Back to top]
Fibrinogen Signal Transduction as a Mediator and Therapeutic
Target in Inflammation: Lessons from Multiple Sclerosis
R.A. Adams, C. Schachtrup, D. Davalos, I. Tsigelny and
K. Akassoglou
The blood protein fibrinogen as a ligand for integrin and
non-integrin receptors functions as the molecular nexus of
coagulation, inflammation and immunity. Studies in animal
models and in human disease have demonstrated that extravascular
fibrinogen that is deposited in tissues upon vascular rupture
is not merely a marker, but a mediator of diseases with an
inflammatory component, such as rheumatoid arthritis, multiple
sclerosis, sepsis, myocardial infarction and bacterial infection.
The present article focuses on the recent discoveries of specific
cellular targets and receptors for fibrinogen within tissues
that have extended the role of fibrinogen from a coagulation
factor to a regulator of inflammation and immunity. Fibrinogen
has the potential for selective drug targeting that would
target its proinflammatory properties without affecting its
beneficial effects in hemostasis, since it interacts with
different receptors to mediate blood coagulation and inflammation.
Strategies to target receptors for fibrinogen and fibrin within
the tissue microenvironment could reveal selective and disease-specific
agents for therapeutic intervention in a variety of human
diseases associated with fibrin deposition.
[Back to top]
Cochlear Stem Cells/Progenitors and Degenerative Hearing
Disorders
Jizhen Lin, Ling Feng, Shinji Fukudome, Yuki Hamajima,
Tina Huang and Samuel Levine
Hearing loss (deafness) affects approximately 250 million
people globally. The major cause of deafness is loss of hair
cells and spiral ganglion neurons due to aging, antibiotic
use, noise exposure, and genetic defects. At the present time,
there is no effective method for restoration of hearing biologically.
Cochlear stem cells/progenitors (CSCs), quiescent in the organ
of Corti, are excellent candidates for restoration of cell
types in the organ of Corti biologically. However, little
is known about the biology of CSCs and developmental cues
for CSCs to differentiate into hair cells and neurons at the
present time. In this article, we briefly reviewed the isolation
of CSCs from the postnatal organ of Corti in mice and their
capability to differentiate into hair cells and neurons in
vitro under the guidance of a group of growth factors:
sonic hedgehog (SHH), epidermal growth factor (EGF), retinoic
acid (RA), and brain-derived neurotrophic factor (BDNF), herein
termed SERB. The identification of CSCs and their differentiation
signals is potentially of clinical importance.
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