| Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 15, Number 22, 2008
Contents
Structural Bases for Substrate and Inhibitor Recognition
by Matrix Metalloproteinases Pp. 2192-2222
Loretta Aureli, Magda Gioia, Ilaria Cerbara, Susanna Monaco,
Giovanni Francesco Fasciglione, Stefano Marini, Paolo Ascenzi,
Alessandra Topai and Massimo Coletta
[Abstract]
Similarities Between Pre-Eclampsia and Atherosclerosis:
A Protective Effect of Physical Exercise? Pp. 2223-2229
Luís Belo, Alice Santos-Silva, Alexandre Quintanilha
and Irene Rebelo
[Abstract]
Organophosphorus Compounds: Intervention in Mechanisms
of Signal Transduction Relevant to Proliferative, Immunological
and Circulatory Disorders Pp. 2230-2257
Nick J. Wardle, S.W. Annie Bligh and Harry R. Hudson
[Abstract]
Expression and Function of Cytochrome P450-Dependent
Enzymes in Human Skin Cells Pp. 2258-2264
J.M. Baron, T. Wiederholt, R. Heise, H.F. Merk and D.R.
Bickers
[Abstract]
High Density Lipoprotein Cholesterol and Statin
Trials Pp. 2265-2270
Anna Kakafika, Vasilios G. Athyros, Konstantinos Tziomalos,
Asterios Karagiannis and Dimitri P. Mikhailidis
[Abstract]
Nuclear Receptors as Potential Molecular Targets in
Cholesterol Accumulation Conditions: Insights from Evidence
on Hepatic Cholesterol Degradation and Gallstone Disease in
Humans Pp. 2271-2284
M. Bertolotti, C. Gabbi, C. Anzivino, L. Carulli, P. Loria
and N. Carulli
[Abstract]
Enzymes as Target Antigens of Liver-Specific
Autoimmunity: The Case of Cytochromes P450s Pp. 2285-2292
D.P. Bogdanos and G.N. Dalekos
[Abstract]
Metabolism and the Paradoxical Effects of Arsenic:
Carcinogenesis and Anticancer Pp. 2293-2304
Xing Cui, Yayoi Kobayashi, Makoto Akashi and Ryuichi Okayasu
[Abstract]
Abstracts
[Back to top]
Structural Bases for Substrate and Inhibitor Recognition by
Matrix Metalloproteinases
Loretta Aureli, Magda Gioia, Ilaria Cerbara, Susanna Monaco,
Giovanni Francesco Fasciglione, Stefano Marini, Paolo Ascenzi,
Alessandra Topai and Massimo Coletta
Matrix metalloproteinases (MMPs) are a family of zinc-dependent
endopeptidases which are involved in the proteolytic processing
of several components of the extracellular matrix. As a consequence,
MMPs are implicated in several physiological and pathological
processes, like skeletal growth and remodelling, wound healing,
cancer, arthritis, and multiple sclerosis, raising a very
widespread interest toward this class of enzymes as potential
therapeutic targets. Here, structure-function relationships
are discussed to highlight the role of different MMP domains
on substrate/inhibitor recognition and processing and to attempt
the formulation of advanced guidelines, based on natural substrates,
for the design of inhibitors more efficient in vivo.
[Back to top]
Similarities Between Pre-Eclampsia and Atherosclerosis: A
Protective Effect of Physical Exercise?
Luís Belo, Alice Santos-Silva, Alexandre Quintanilha
and Irene Rebelo
Pre-eclampsia (PE), a characteristic hypertensive disorder
of human pregnancy and a leading cause of maternal and fetal
mortality and morbidity worldwide, shares some similarities
with atherosclerosis, namely the involvement of oxidative
stress and of endothelial dysfunction in their pathophysiologies,
the presence of similar typical lesions and of common risk
factors. Although it is widely accepted that regular physical
exercise protects against cardiovascular events, few studies
have addressed the impact of physical activity in reducing
PE risk. In this paper, similarities between athero-sclerosis
and PE, involving pathogenic mechanisms, are described. This
paper also reviews the studies performed until now that evaluated
the impact of regular physical exercise (prenataly or during
pregnancy) in reducing risk of PE. The potential mechanisms
underlying physical activity as a prophylactic approach of
PE, as observed with cardiovascular dis-eases, are discussed.
[Back to top]
Organophosphorus Compounds: Intervention in Mechanisms of
Signal Transduction Relevant to Proliferative, Immunological
and Circulatory Disorders
Nick J. Wardle, S.W. Annie Bligh and Harry R. Hudson
Literature publications reporting the development of
organophosphorus compounds, targeting aspects of signal transduction
to the titled therapeutic ends, are reviewed. With respect
to extracellular targets, the development of ligands to purinergic
(P2), and endothelial differentiation-gene receptors (of S1P-
and LPA-receptor subtypes) is charted, along with inhibitors
of the production and release of tumour necrosis factor-α
(TNF-α).
Reported also are inhibitors of the ectoenzymes aminopeptidase
N, aminopeptidase A and dipeptidyl peptidase IV, the proteolytic
enzyme thrombin, ligands to “apoptosis-receptors”
and γδ
T-cell activators. In addition, disruption of intracellular
signalling chains mediated through reversible coupling of
proteins via phosphorylation of Tyr residues and docking of
pTyr residues in SH2-binding domains is covered. In particular,
the development of ligands to SH2-binding domains in tyrosine
kinases Src and lck, adaptor protein Grb2, and also ZAP70
protein are reported along with inhibitors to relevant phosphatases.
SAR studies of ligands to Ins(1,4,5)-P3-
and ryanodine-type receptors of intracellular Ca2+
-storage organelles are described including analogues to secondary
messengers cyclic-ADP-ribose (cADPR) and myo-inositol-1,4,5-triphosphate.
Inhibitors of phosphatidyl inositol 3-kinase (PI3K) and sphingomyelinase
are also reported, as are inhibitors of farnesyl transferase,
the enzyme involved in protein-prenylation.
[Back to top]
Expression and Function of Cytochrome P450-Dependent Enzymes
in Human Skin Cells
J.M. Baron, T. Wiederholt, R. Heise, H.F. Merk and D.R.
Bickers
Scientific interest in defining the human body’s
ability to limit the effects of administered drugs and xenobiotics
dates from the mid-19th century when developing knowledge
and techniques in the field of organic chemistry first made
such studies possible. The first experimental evidence documenting
the existence of cytochrome p450 (CYP) dates to the year 1955,
when an enzyme system capable of oxidizing xenobiotic compounds
was identified in the endoplasmic reticulum of liver homogenates.
From these days on several studies analyzed the expression
and function of metabolizing phase I enzymes in liver cells.
Due to the unique structural features of human skin, little
was known about the expression and function of CYP enzymes
in this tissue and their role in uptake, metabolism and elimination
of xenobiotics as well as endogenous substrates. Lasting recent
years it has become clear that human skin cells express various
CYP enzymes, including CYP26AI which is responsible for the
metabolism of retinoic acid in skin cells. It has been also
shown that CYP enzyme expression patterns are cell type and
tissue specific and that in skin cells this differs significantly
from its expression in other environmental interfaces such
as the liver, lung and gastrointestinal tract. Therefore knowledge
of skin-specific CYP expression and function is a prerequisite
for pharmacological studies of the skin.
[Back to top]
High Density Lipoprotein Cholesterol and Statin Trials
Anna Kakafika, Vasilios G. Athyros, Konstantinos Tziomalos,
Asterios Karagiannis and Dimitri P. Mikhailidis
Epidemiological studies show that high density lipoprotein
cholesterol (HDL-C) levels are inversely related to the risk
of vascular events. Statins are the most widely prescribed
drugs for the treatment of dyslipidaemias and their use for
the prevention of vascular events is evidence based. Statins
raise HDL-C but this effect seems to vary considerably between
studies.
We searched the literature to assess the relationship between
statin-induced increases in HDL-C levels and surrogate and/or
clinical endpoints. Based on the existing evidence, it is
difficult to determine how much reduction, if any, in vascu-lar
risk is attributable to a statin-induced increment in HDL-C
levels.
Whether a statin that beyond its LDL-C lowering effect also
raises HDL-C has additional benefits in the prevention of
vascular events remains to be established.
[Back to top]
Nuclear Receptors as Potential Molecular Targets in Cholesterol
Accumulation Conditions: Insights from Evidence on Hepatic
Cholesterol Degradation and Gallstone Disease in Humans
M. Bertolotti, C. Gabbi, C. Anzivino, L. Carulli, P. Loria
and N. Carulli
The liver plays a central role in the regulation of cholesterol
homeostasis. Hepatic cholesterol content is maintained by
a complex interplay between input and output pathways; alterations
in the balance among these processes may lead to accumulation
of excess cholesterol in body compartments with potentially
deleterious consequences at the level of blood vessels (atherosclerosis)
and biliary tract (gallstone disease).
Molecular biology has brought new insights into this field.
Nuclear receptors have been shown to play a key role in the
“sensing” of intracellular cholesterol levels
and in the triggering of metabolic responses via the sterol
regulatory element binding protein (SREBP) cascade.
A nuclear receptor for bile acids, farnesoid X receptor (FXR),
has been identified and the molecular pathways underlying
feedback inhibition of bile acid synthesis, the main mechanism
of irreversible degradation of cholesterol, have been clarified.
Such regulation involves a number of additional coactivators/corepressors
of the transcription of the limiting enzyme of bile acid synthesis,
cholesterol 7α-hydroxylase.
Finally, the main transporters of biliary lipids (bile acids,
phospholipids and cholesterol) have been described; most of
them undergo transcriptional control by nuclear receptors,
allowing regulation of biliary lipid efflux in conditions
of different intracellular availability.
Despite a body of evidence coming from experimental models
the intimate mechanisms of regulation have not been clearly
defined and direct evidence in humans is rather limited.
This review will focus on the role of nuclear receptors in
the regulation of hepatic cholesterol degradation and biliary
lipid secretion, and on the theoretical applications from
a pharmacotherapeutic perspective.
[Back to top]
Enzymes as Target Antigens of Liver-Specific Autoimmunity:
The Case of Cytochromes P450s
D.P. Bogdanos and G.N. Dalekos
Characterization of liver-specific autoantigens has given
a fresh impetus to research in the pathogenesis of autoimmune
liver diseases, viral-triggered and drug-induced autoimmunity
affecting the liver. Intriguing is the fact that most of the
liver-specific autoantigens are enzymes of key importance
for cell’s homeostasis. Detection of autoantibodies
against the respective antigens is carried out for diagnostic
and research purposes using indirect immunofluorescence, immunoblotting,
enzyme-linked immunosorbent assays, radioimmunoassay, immunoprecipitation
or assays determining inhibition of enzyme activity. In patients
with autoimmune hepatitis, a liver disorder of unknown etiology
and pathogene-sis, disease-specific autoantibodies are frequently
directed against drug metabolizing enzymes of phase 1, namely
cyto-chrome P450 2D6 (CYP2D6). The same and other members
of these families of enzymes (CYPs) have also been de-scribed
as targets of liver-specific autoimmunity in chronic hepatitis
C virus (HCV)-infected patients, patients with auto-immune
hepatitis as part of the autoimmune polyglandular syndrome
type-1 (APS-1) and drug-induced autoimmunity. How these enzymes
become ‘self targets’ is not yet established.
An antigen release following hepatocyte injury could provide
the stimulus for an immune response towards epitopes on these
enzymes but the highly-specific, antigen-restricted initiation
of the observed autoimmune response is against such an explanation.
Accordingly, in this review we will focus on the pathogenic
role -if any- of autoimmune responses against liver-related
CYPs in autoimmune hepatitis, HCV infection, APS-1 and drug-induced
autoimmunity. Learning more about the specificity of antibody
responses against these enzymes may help us better understand
the mechanisms underlying liver autoimmunity and may facilitate
the development of therapeutic and preventive interventions.
[Back to top]
Metabolism and the Paradoxical Effects of Arsenic: Carcinogenesis
and Anticancer
Xing Cui, Yayoi Kobayashi, Makoto Akashi and Ryuichi Okayasu
Arsenic, a known human carcinogen, can induce tumors
of the skin, urinary bladder, liver and lung etc.. On the
other hand, arsenic is also a novel promising anticancer agent,
and can be used effectively to treat acute promyelocytic leukemia
(APL) and some other tumors. These paradoxical effects of
arsenic not only result from direct or indirect influences
on the genetic and epigenetic levels, but are also closely
correlated with unique arsenic metabolism. This article reviews
our recent studies as well as other reports on arsenic metabolism
and epigenetic changes of DNA methylation during its metabolism.
We also summarize the clinical use of arsenic trioxide (As2
O3 ) to date and discuss
new therapeutic strategies such as concurrent arsenic-radiation
therapy to achieve local tumor control and enhance the radiosensitivity
of solid tumors.
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