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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 13, 2008
Contents
Of Stem Cells and Gametes: Similarities and Differences
Pp. 1249-1256
Bernard A.J. Roelen and Susana M. Chuva de Sousa
Lopes
[Abstract]
Phenotypic Variants of the Deafness-Associated
Mitochondrial DNA A7445G Mutation Pp. 1257-1262
Anita Maász, Katalin Komlósi, Kinga
Hadzsiev, Zsolt Szabó, Patrick J. Willems, Imre Gerlinger,
György Kosztolányi, Károly Méhes
and Béla Melegh
[Abstract]
Histone Deacetylase Inhibitors: Therapeutic Agents
and Research Tools for Deciphering Motor Neuron Diseases
Pp. 1263-1273
A. Echaniz-Laguna, O. Bousiges, J.-P. Loeffler and
A.-L. Boutillier
[Abstract]
Epigenetic Treatment of Myelodysplastic Syndromes
and Acute Myeloid Leukemias Pp. 1274-1287
Giuseppe Leone, Francesco D’Alò,
Giuseppe Zardo, Maria Teresa Voso and Clara Nervi
[Abstract]
New Biochemical Markers in Acute Coronary Syndromes
Pp. 1288-1296
Dimitris Tousoulis, Anna-Maria Kampoli, Elli
Stefanadi, Charalambo Antoniades, Gerasimos Siasos, Athanasios
G. Papavassiliou and Christodoulos Stefanadis
[Abstract]
Why Chemokines are Cytokines while their Receptors
are not Cytokine Ones? Pp. 1297-1304
Larisa B. Goncharova and Alexander O. Tarakanov
[Abstract]
Bis-Quinolinium Cyclophanes: Highly Potent
and Selective Non Peptidic Blockers of the Apamin-Sensitive
Ca2+-Activated K+
Channel Pp. 1305-1315
Ana Conejo-García and Joaquín
M. Campos
[Abstract]
How Insulin Receptor Substrate Proteins Regulate
the Metabolic Capacity of the Liver - Implications for Health
and Disease Pp. 1316-1329
Louise Fritsche, Cora Weigert, Hans-Ulrich Häring and
Rainer Lehmann
[Abstract]
A Medicinal Mushroom: Phellinus Linteus
Pp. 1330-1335
Tongbo Zhu, Sung-Hoon Kim and Chang-Yan Chen
[Abstract]
Recent Structural and Computational Insights into
Conformational Diseases Pp. 1336-1349
Xavier Fernàndez-Busquets, Natalia S.
de Groot, Daniel Fernandez and Salvador Ventura
[Abstract]
Abstracts
[Back to top]
Of Stem Cells and Gametes: Similarities and Differences
Bernard A.J. Roelen and Susana M. Chuva de Sousa
Lopes
Fusion of a mammalian sperm cell with an oocyte will
lead to the formation of a new organism. As this new organism
develops, the cells that construct the organism gradually
lose developmental competence and become differentiated, a
process which is in part mediated via epigenetic
modifications. These mechanisms include DNA methylation, histone
tail modifications and association with Polycomb and Trithorax
proteins. Several cells within the organism must however maintain
or regain developmental competence while they are highly specialized.
These are the primordial germ cells that form the gametes;
the oocytes and sperm cells. In this review different epigenetic
modifying mechanisms will be discussed as they occur in developing
embryos. In addition, aspects of nuclear reprogramming that
are likely to occur via removal of epigenetic modifications
are important, and several epigenetic removal mechanisms are
indeed also active in developing germ cells.
In vivo, a pluripotent cell has the capacity to form
gametes, but in vitro terminal gametogenesis has
proven to be difficult. Although development of pluripotent
cells to cells with the characteristics of early germ cells
has been unequivocally demonstrated, creating the correct
culture milieu that enables further maturation of these cells
has as yet been futile.
[Back to top]
Phenotypic Variants of the Deafness-Associated Mitochondrial
DNA A7445G Mutation
Anita Maász, Katalin Komlósi, Kinga
Hadzsiev, Zsolt Szabó, Patrick J. Willems, Imre Gerlinger,
György Kosztolányi, Károly Méhes
and Béla Melegh
A number of nuclear and mitochondrial mutations have
been implicated in non-syndromic hearing loss. Among them,
various mutations of mitochondrial SerUCN-tRNA
and 12S rRNA genes have been found to be associated with deafness;
the A7445G mitochondrial DNA (mtDNA) in this group is unique,
simultaneously affecting two different mitochondrial genes,
encoding the SerUCN-tRNA
and the first subunit of cytochrome oxidase. Besides the hearing
loss, it is mainly associated with palmoplantar keratoderma,
though; different phenotypic associations have been reported.
The current paper reviews the available PubMed reports on
the A7445G mtDNA mutation, with special attention to the phenotypic
variations. Further, a Hungarian family with the A7445G mutation
is reported, in which analysis of both the affected and the
non-affected members revealed the mutation in both homo- and
heteroplasmic forms, independently of the hearing status of
the subjects, a phenomenon previously not reported in other
pedigrees. The female lineage represented a rare variant of
the U4b haplogroup.
[Back to top]
Histone Deacetylase Inhibitors: Therapeutic Agents
and Research Tools for Deciphering Motor Neuron Diseases
A. Echaniz-Laguna, O. Bousiges, J.-P. Loeffler and
A.-L. Boutillier
Histone deacetylase (HDAC) inhibition
as a therapeutic regimen in motor neuron diseases (MND) is
generating intense interest in both the scientific and medical
areas, with a number of potent compounds having demonstrated
good safety profiles and hints of clinical activity on animal
models. In this review, we discuss recent developments in
dissecting the mechanism of action of HDAC inhibitors (HDACi)
as a new group of mechanism-based drugs for motor neuron diseases,
together with current progress in understanding their clinical
application. We also discuss how the use of HDACi on animal
models with motor neuron defects has allowed critical advances
in the understanding of the pathophysiology of motor neuron
diseases.
The use of HDACi and possible mechanisms of action will be
reviewed in three MND, i.e. amyotrophic lateral sclerosis
(ALS), spinal muscular atrophy (SMA) and spinal and bulbar
muscular atrophy (SBMA), diseases among which clinical trials
with HDACi are currently perfomed (ALS, SMA).
[Back to top]
Epigenetic Treatment of Myelodysplastic Syndromes
and Acute Myeloid Leukemias
Giuseppe Leone, Francesco D’Alò,
Giuseppe Zardo, Maria Teresa Voso and Clara Nervi
Epigenetic mechanisms affecting chromatin structure contribute
to regulate gene expression and assure the inheritance of
information, which are essential for the proper expression
of key regulatory genes in healthy cells, tissues and organs.
In the medical field, an increasing body of evidence indicates
that altered gene expression or de-regulated gene function
lead to disease. Cancer cells also suffer a profound change
in the genomic methylation patterns and chromatin status.
Aberrant DNA methylation patterns, changes in chromatin structure
and in gene expression are common in all kind of tumor types.
However, studies on leukemias have provided paradigmatic examples
for the functional implications of the epigenetic alterations
in cancer development and progression as well as their relevance
for therapeutical targeting.
[Back to top]
New Biochemical Markers in Acute Coronary Syndromes
Dimitris Tousoulis, Anna-Maria Kampoli, Elli
Stefanadi, Charalambo Antoniades, Gerasimos Siasos, Athanasios
G. Papavassiliou and Christodoulos Stefanadis
This article comments on the role of the most important
biochemical markers that are already applied in clinical practice
or are still under research, in Acute Coronary Syndromes (ACS).
Cardiac troponin (cTn) is established as the ‘gold standard’
in the diagnosis of ACS. C-reactive protein (CRP) and especially
high-sensitivity CRP (hs-CRP) are considered to be the most
useful inflammatory markers for clinical practice in the setting
of acute coronary syndrome. Brain-type natriuretic peptide
(BNP) and the amino terminal fragment of the prohormone BNP
(NT-proBNP) appear to provide prognostic information in individuals
admitted for acute coronary syndromes. Microalbuminuria in
nondiabetics appears to be a signal from the kidney that the
vasculature, particularly the endothelium, is not functioning
properly. Increased plasma levels of cystatin C, neopterin,
myeloperoxidase, and pregnancy associated protein are associated
with adverse cardiovascular outcomes, cardiovascular and noncardiovascular
death, and possibly cerebrovascular disease. Furthermore,
recent evidence suggests that serum levels of CD40-CD40L pathway
exert important roles in progression, and outcome of acute
coronary syndrome. In the future further, studies are necessary
to elucidate the exact role of the new biochemical markers
in ACS.
[Back to top]
Why Chemokines are Cytokines while their Receptors
are not Cytokine Ones?
Larisa B. Goncharova and Alexander O. Tarakanov
Chemotactic cytokines, or chemokines, are a large family
of small proteins, which are distinguished from other cytokines
in that they are the only members of the cytokine family that
act on G-protein coupled receptor superfamily. This minireview
tries to answer the title question by structure/function analysis
of chemokines, cytokines, and their receptors. We also consider
secretion of chemokines/cytokines in health and disease as
well as expression of their receptors both in immune system
and brain. Our analysis suggests that cytokine and chemokine
receptors may share similar architecture with Toll-like receptors.
Such similarity hints a similar way of their functioning as
molecular switches controlled by protein-protein interactions.
Hence, we pay attention to the related receptor-receptor associations
and evolutionary conserved leucine-rich motifs.
[Back to top]
Bis-Quinolinium Cyclophanes: Highly Potent
and Selective Non Peptidic Blockers of the Apamin-Sensitive
Ca2+-Activated K+
Channel
Ana Conejo-García and Joaquín
M. Campos
Small conductance Ca2+-activated
K+ (SKCa)
channels comprise an important subclass of K+ channels.
Selective blockade of SKCa
channels may find application in the therapy of myotonic muscular
dystrophy, gastrointestinal dysmotilities, memory disorders,
narcolepsy, and alcohol abuse. In the cyclophanes described
herein the two 4-aminoquinolinium groups are joined at the
ring N atoms (linker L) and at the exocyclic N atoms (linker
A). When both the spacer A and L have only one benzene ring,
the blocking potency changes dramatically with simple structural
variations in the linkers. One of these smaller cyclophanes
having A = benzene-1,4-diylbis(methylene) and L = benzene-1,3-diylbis(methylene)
shows activity in the low nanomolar range. Furthermore, the
results with the present series add significantly to the structure-activity
knowledge in the field, since they incorporate the first example
of molecules in which the activity depends critically on the
nature of the linkers joining the two quinolinium (Q) groups.
Later on, a novel series of bis-quinolinium bis-alkylene
cyclophanes was described. The biological results of the present
series add support to the suggestion that the linkers of the
two Q groups do not form direct interactions with the channel
protein but comprise a molecular support for the two Q groups.
Two important structural features of the pharmacophore for
SKCa channel blockade have
been identified. These are (1) an optimum distance of ca.
5.8 Å
between the centroids of the pyridinium rings of the two quinolinium
groups, and (2) a preference for conformations having the
Q groups in a synperiplanar orientation.
[Back to top]
How Insulin Receptor Substrate Proteins Regulate the
Metabolic Capacity of the Liver - Implications for Health
and Disease
Louise Fritsche, Cora Weigert, Hans-Ulrich Häring and
Rainer Lehmann
The liver plays a key role in glucose homeostasis, lipid
and energy metabolism. Its function is primarily controlled
by the anabolic hormone insulin and its counterparts glucagon,
catecholamines and glucocorticoids. Dysregulation of this
homeostatic system is a major cause for development of the
metabolic syndrome and type 2 diabetes mellitus. The features
of the underlying dynamic molecular network that coordinates
systemic nutrient homeostasis are less clear. But recently,
considerable progress has been made in elucidating molecular
pathways and potential factors involved in the regulation
of energy and lipid metabolism and affected in diabetic states.
In this review we will focus on important stations in the
complex network of molecules that control the balance between
glucose production, glucose utilization and regulation of
lipid metabolism. Special attention will be paid to the insulin
receptor substrate (IRS) proteins with the two major isoforms
IRS-1 and IRS-2 as a critical node in hepatic insulin signalling.
IRS proteins act as docking molecules to connect tyrosine
kinase receptor activation to essential downstream kinase
cascades, including activation of the PI-3 kinase or MAPK
cascade. IRS-1 and IRS-2 are complementary key players in
the regulation of hepatic insulin signalling and expression
of genes involved in gluconeogenesis, glycogen synthesis and
lipid metabolism. The function of IRS proteins is regulated
by their expression levels and posttranslational modifications.
This regulation within the dynamic molecular network that
coordinates systemic nutrient homeostasis will be outlined
in detail under the following conditions: after feeding, during
fasting and during exercise. Dysfunction of IRS proteins initially
leads to post-prandial hyperglycemia, increased hepatic glucose
production, and dysregulated lipid synthesis and is discussed
as major pathophysiological mechanism for the development
of insulin resistance and type 2 diabetes mellitus.
Understanding the molecular regulation and the pathophysiological
modifications of IRS proteins is crucial in order to identify
new sites for potential intervention to treat or prevent hepatic
insulin resistance and type 2 diabetes mellitus.
[Back to top]
A Medicinal Mushroom: Phellinus Linteus
Tongbo Zhu, Sung-Hoon Kim and Chang-Yan Chen
Phellinus Linteus (Berkeley & M. A. Curtis) Teng
(PL) is a medicinal mushroom that has been practiced in oriental
countries for centuries to prevent ailments as diverse as
gastroenteric dysfunction, diarrhea, haemorrhage and cancers.
In an effort to translate the Asian traditional medicines
into western-accepted therapies, scientists have demonstrated
that the extracts from fruit-bodies or mycelium of PL not
only stimulate the hormonal and cell-mediated immune function
and quench the inflammatory reactions caused by a variety
of stimuli, but also suppress the tumor growth and metastasis.
Mounting evidence from different research groups has shown
that PL induces apoptosis in a host of murine and human carcinomas
without causing any measurable toxic effects to their normal
counterparts. Recently, research has been focused on the anti-tumor
effect of PL, and in particular, on its ability to enhance
some conventional chemotherapeutic drugs. These studies suggest
PL to be a promising candidate as an alternative anticancer
agent or a synergizer for existing antitumor drugs. Hereinafter,
we summarize the present progress in elucidating the mechanisms
underlying the potency of PL and its anti-tumor function.
The fractionation and identification of the biologically active
components from PL are also briefly introduced.
[Back to top]
Recent Structural and Computational Insights into
Conformational Diseases
Xavier Fernàndez-Busquets, Natalia S.
de Groot, Daniel Fernandez and Salvador Ventura
Protein aggregation correlates with the development of
several deleterious human disorders such as Alzheimer's disease,
Parkinson's disease, prion-associated transmissible spongiform
encephalopathies and type II diabetes. The polypeptides involved
in these disorders may be globular proteins with a defined
3D-structure or natively unfolded proteins in their soluble
conformations. In either case, proteins associated with these
pathogeneses all aggregate into amyloid fibrils sharing a
common structure, in which β-strands
of polypeptide chains are perpendicular to the fibril axis.
Because of the prominence of amyloid deposits in many of these
diseases, much effort has gone into elucidating the structural
basis of protein aggregation. A number of recent experimental
and theoretical studies have significantly increased our understanding
of the process. On the one hand, solid-state NMR, X-ray crystallography
and single molecule methods have provided us with the first
high-resolution 3D structures of amyloids, showing that they
exhibit conformational plasticity and are able to adopt different
stable tertiary folds. On the other hand, several computational
approaches have identified regions prone to aggregation in
disease-linked polypeptides, predicted the differential aggregation
propensities of their genetic variants and simulated the early,
crucial steps in protein self-assembly. This review summarizes
these findings and their therapeutic relevance, as by uncovering
specific structural or sequential targets they may provide
us with a means to tackle the debilitating diseases linked
to protein aggregation.
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