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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 12, 2007
Contents
Interferon: Cellular Executioner or White Knight?
Pp. 1279-1289
S.G. Maher, A.L. Romero-Weaver, A.J. Scarzello and A.M. Gamero
[Abstract]
Pyridoxal 5’-Phosphate Enzymes as Targets for
Therapeutic Agents Pp. 1291-1324
Alessio Amadasi, Mariarita Bertoldi, Roberto Contestabile,
Stefano Bettati, Barbara Cellini, Martino Luigi di Salvo,
Carla Borri Voltattorni, Francesco Bossa and Andrea Mozzarelli
[Abstract]
Genetic Polymorphisms in the Chemokine and Chemokine
Receptors: Impact on Clinical Course and Therapy of the Human
Immunodeficiency Virus Type 1 Infection (HIV-1) Pp.
1325-1334
E.M.V. Reiche, A. M. Bonametti, J.C. Voltarelli, H.K.Morimoto
and M.A.E. Watanabe
[Abstract]
Inhaled Insulin and the Lung Pp. 1335-1347
Leonello Fuso, Dario Pitocco and Raffaele Antonelli Incalzi
[Abstract]
A Review on Synthetic and Natural Steroid Dimers:
1997-2006 Pp. 1349-1370
L. Nahar, S. D. Sarker and A. B. Turner
[Abstract]
Angiomodulatory and Neurological Effects of Ginsenosides
Pp. 1371-1380
K.W. Leung, K.K.L. Yung, N.K. Mak, P.Y.K. Yue, H.-B. Luo,
Y.-K. Cheng, T.P.D. Fan, H.W. Yeung, T.B. Ng and R.N.S. Wong
[Abstract]
Abstracts
[Back to top]
Interferon: Cellular Executioner or White Knight?
S.G. Maher, A.L. Romero-Weaver, A.J. Scarzello and A.M. Gamero
Interferons (IFNs) are a family of pleiotropic cytokines
that typically exhibit antiviral, antiproliferative, antitumor,
and immunomodulatory properties. While their complex mechanisms
of action remain unclear, IFNs are used clinically in the
treatment of viral infections, such as hepatitis B and hepatitis
C, and remain the primary treatment for a limited number of
malignancies, such as melanoma, hairy cell leukemia, and non-Hodgkin’s
lymphoma and in autoimmune diseases such as multiple sclerosis.
IFNs not only regulate somatic cell growth and division but
also influence cell survival through the modulation of apoptosis.
Paradoxically, IFNs are described to be both pro- and anti-apoptotic
in nature. The biological effects of IFNs are primarily mediated
via activation of the JAK/STAT pathway, formation
of the ISGF3 and STAT1:STAT1 protein complexes, and the subsequent
induction of IFN-stimulated genes. However, the activation
of JAK/STAT-independent signal transduction pathways also
contribute to IFN-mediated responses. To further demonstrate
the complexity of the downstream events following stimulation,
oligonucleotide microarray studies have shown that in excess
of 300 genes are induced following treatment with IFN, some
of which are crucial to the induction of apoptosis and cell
growth control. In this review we describe the recent advances
made in elucidating the various signaling pathways that are
activated by IFNs and how these diverse signals contribute
to the regulation of cell growth and apoptosis and inhibition
of viral replication. Furthermore, we highlight the role of
specific signaling molecules and the function(s) of particular
IFN-stimulated genes that have been implicated in determining
cell fate in response to IFN, as well as the clinical experience
of IFN immunotherapy.
[Back to top]
Pyridoxal 5’-Phosphate Enzymes as Targets for
Therapeutic Agents
Alessio Amadasi, Mariarita Bertoldi, Roberto Contestabile,
Stefano Bettati, Barbara Cellini, Martino Luigi di Salvo,
Carla Borri Voltattorni, Francesco Bossa and Andrea Mozzarelli
The vitamin B6-derived
pyridoxal 5’-phosphate (PLP) is the cofactor of enzymes
catalyzing a large variety of chemical reactions mainly involved
in amino acid metabolism. These enzymes have been divided
in five families and fold types on the basis of evolutionary
relationships and protein structural organization. Almost
1.5% of all genes in prokaryotes code for PLP-dependent enzymes,
whereas the percentage is substantially lower in eukaryotes.
Although about 4% of enzyme-catalyzed reactions catalogued
by the Enzyme Commission are PLP-dependent, only a few enzymes
are targets of approved drugs and about twenty are recognised
as potential targets for drugs or herbicides. PLP-dependent
enzymes for which there are already commercially available
drugs are DOPA decarboxylase (involved in the Parkinson disease),
GABA aminotransferase (epilepsy), serine hydroxymethyltransferase
(tumors and malaria), ornithine decarboxylase (African sleeping
sickness and, potentially, tumors), alanine racemase (antibacterial
agents), and human cytosolic branched-chain aminotransferase
(pathological states associated to the GABA/glutamate equilibrium
concentrations). Within each family or metabolic pathway,
the enzymes for which drugs have been already approved for
clinical use are discussed first, reporting the enzyme structure,
the catalytic mechanism, the mechanism of enzyme inactivation
or modulation by substrate-like or transition state-like drugs,
and on-going research for increasing specificity and decreasing
side-effects. Then, PLP-dependent enzymes that have been recently
characterized and proposed as drug targets are reported. Finally,
the relevance of recent genomic analysis of PLP-dependent
enzymes for the selection of drug targets is discussed.
[Back to top]
Genetic Polymorphisms in the Chemokine and Chemokine
Receptors: Impact on Clinical Course and Therapy of the Human
Immunodeficiency Virus Type 1 Infection (HIV-1)
E.M.V. Reiche, A. M. Bonametti, J.C. Voltarelli, H.K.Morimoto
and M.A.E. Watanabe
The natural history and pathogenic processes of infection
by the human immunodeficiency virus type 1 (HIV-1) are complex,
variable, and dependent upon a multitude of viral and host
factors and their interactions. The CCR5-Δ32 allele remains
the most important genetic factor known to be associated with
host resistance to the HIV-1 infection. However, other mutations
in the CCR5, CCR2, CX3CR1, CXCL12 (SDF1), and CCL5
(RANTES) genes have been identified and associated with host
resistance and/or susceptibility to HIV-1 infection and disease
progression. Some studies have also suggested that chemokine
receptor gene polymorphisms may affect response to potent
antiretroviral therapy. This article reviews the polymorphisms
already described in the mutant chemokine receptors or ligands
and their impact on the host susceptibility to HIV-1 infection
and on the clinical course of the disease, as well as the
development of new anti-HIV therapies that takes into account
these potential targets in the host. These genetic polymorphisms
could be used as genetic markers to detect individuals at
higher risk of developing either a faster disease progression
or therapeutic failure. Once these individuals are identified,
therapeutic strategies based on either different, more aggressive
drugs or combinations of drugs can be used, either alone or
in combination with shorter intervals for therapeutic monitoring.
Pharmacogenetics is very likely to underlie future therapies
for HIV-1 infection, and current patients with multi-resistance
to the existing antiretroviral agents could also benefit from
this approach. These developments also underscore the importance
of continuing the investigation of new therapies targeted
to the host in order to inhibit the HIV-1 entry into the host
cells.
[Back to top]
Inhaled Insulin and the Lung
Leonello Fuso, Dario Pitocco and Raffaele Antonelli Incalzi
Pulmonary delivery of insulin is more than a promise in the
treatment of diabetes mellitus. Inhaled insulin seems at least
as efficacious as the conventional regimen of subcutaneous
insulin and/or oral glucose-lowering agents in both type 1
and type 2 diabetes mellitus. Improved metabolic control and
the use of a non-invasive route of administration represent
the main benefits of this new treatment. Several physico-chemical
factors could reduce the bioavailability of inhaled insulin.
Indeed, both deep-lung deposition and adsorption of insulin
variously depend on the type of propellants used, speed of
air flow, particle size and velocity, drug deposition into
the throat and larger bronchial tree. These factors, in turn,
depend on the pulmonary delivery systems used and on respiratory
mechanics and flows. Furthermore, the pharmacokinetics of
inhaled insulin is affected by smoke, which increases its
absorption, and by lung diseases, which decrease the available
alveolar-capillary surface. Selected abnormalities of respiratory
function complicate both type 1 and type 2 diabetes mellitus
and a mild depression of carbon monoxide lung transfer after
a 6-month period of treatment with inhaled insulin has been
reported. Finally, results from some longitudinal studies
suggest that diabetes might speed up the age-related decline
of lung volumes and probably alter the pharmacokinetics of
inhaled insulin, particularly in the elderly. Clarifying these
issues is mandatory in order to define the indications and
safety of inhaled insulin.
[Back to top]
A Review on Synthetic and Natural Steroid Dimers:
1997-2006
L. Nahar, S. D. Sarker and A. B. Turner
Since the publication of the review by Li and Dias in 1997,
which covered almost all steroid dimers known to us until
the early part of 1997, there have been significant amounts
of work carried out on steroid dimers, and another review
on this topic has long been overdue. Thus, this review presents
a comprehensive review of literature published over the last
decade on various aspects of steroid dimers, including synthesis
and applications. Steroid dimers that were published before
1997 but were not covered within the previous review have
also been included.
[Back to top]
Angiomodulatory and Neurological Effects of Ginsenosides
K.W. Leung, K.K.L. Yung, N.K. Mak, P.Y.K. Yue, H.-B. Luo,
Y.-K. Cheng, T.P.D. Fan, H.W. Yeung, T.B. Ng and R.N.S. Wong
Panax ginseng C.A. Meyer, one of the most popular
and valued herbs, has been used extensively in traditional
Chinese medicine for thousands of years. More than thirty
ginsenosides, the pharmacologically active ingredients in
ginseng, have been identified with various sugar moieties
attached at the C-3, C-6 and C-20 positions of the steroidal
skeleton. We herein review the current literature on the pharmacological
effects of ginsenosides on the modulation of angiogenesis,
dysregulations of which contribute towards many pathological
conditions. Regarding the adaptogenic property of ginseng,
the effects of ginsenosides on central nervous system are
also discussed. Recent researches have pointed to the steroid
hormone receptors as the target molecules to elicit the diverse
cellular and physiological activities of ginseng. We believe
that understanding the interaction between ginsenosides and
various steroid hormone receptors may provide clues to unravel
the secret of ginseng.
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