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Current Drug Discovery Technologies
ISSN: 1570-1638
Current Drug Discovery Technologies
Volume 4, Number 1, June 2007
Contents
Activity-Based Proteomics of Lipolytic Enzymes
Pp. 1-11
Ruth Birner-Gruenberger and Albin Hermetter
[Abstract] [Full
Text Article]
Microarray Analysis Reveals CCL24/Eotaxin-2 as
an Effector of the Pathogenetic Effects Induced by HIV-1 Nef
Pp. 12-23
Gianna Fiorucci, Eleonora Olivetta, Maria Vincenza Chiantore
and Maurizio Federico
[Abstract] [Full
Text Article]
Transcription Factor Profiling Shows New Ways Towards
New Treatment Options of Cutaneous T Cell Lymphomas
Pp. 24-30
Udo Döbbeling
[Abstract] [Full
Text Article]
Controlled Release of the Pineal Hormone Melatonin
from Hydroxypropylmethylcellulose/Sodium Alginate Matrices
in Aqueous Media Containing Dioctyl Sulfosuccinate
Pp. 31-38
Marilena Vlachou, Athanasia Tsiakoulia and Aphrodite Eikosipentaki
[Abstract] [Full
Text Article]
Diabetes Beyond Insulin; Review of New Drugs for Treatment
of Diabetes Mellitus Pp. 39-47
Pankaj Modi
[Abstract] [Full
Text Article]
Targetability of Human Disease Genes Pp.
48-58
Meena K. Sakharkar and Kishore R. Sakharkar
[Abstract] [Full
Text Article]
Pharmacogenomics of Sex Difference in Chemotherapeutic
Toxicity Pp. 59-68
Jeffrey Wang and Ying Huang
[Abstract] [Full
Text Article]
Abstracts
[Back to top]
Activity-Based Proteomics of Lipolytic Enzymes
Ruth Birner-Gruenberger and Albin Hermetter
[Full
Text Article]
Lipases play fundamental roles in biological processes
since hydrolysis of triacylglycerols and cholesteryl esters
is a key event in energy homeostasis of animals. Perturbations
in the metabolism and the cellular retention of lipids result
in common diseases such as obesity, type 2 diabetes, and atherosclerosis.
The introduction of active site-directed chemical probes for
enzymatic activity profiling in complex mixtures, known as
activity-based proteomics, has greatly facilitated and accelerated
global analysis and functional annotation of lipolytic proteins.
Here we review probe design and application for discovery
and discrimination of lipolytic and esterolytic enzymes. These
probes are usually detected by their fluorescent or affinity
tags and their protein targets are analyzed using established
proteomics techniques. Moreover, microarray technologies can
be applied for higher throughput screenings of enzyme or probe
specificity.
[Back to top]
Microarray Analysis Reveals CCL24/Eotaxin-2 as
an Effector of the Pathogenetic Effects Induced by HIV-1 Nef
Gianna Fiorucci, Eleonora Olivetta, Maria Vincenza Chiantore
and Maurizio Federico
[Full
Text Article]
Human immunodeficiency virus (HIV)-1 Nef is a regulatory protein
critically involved in AIDS pathogenesis. We previously demonstrated
that extracellular Nef is efficiently internalized by human
primary monocyte-derived macro-phages (MDMs), thereby activating
a number of transcription factors including STATs, MAPKs,
IRF-3, and NF-κB.
Such an activation state leads to the release of inflammatory
factors whose paracrine effects deserve deep consideration.
Here, we demonstrate that quiescent CD4 lymphocytes undergo
cell activation when cultivated in supernatants from autologous
MDMs treated with extracellular wt Nef but not with its counterpart
mutated in the 72PxxP75
polyproline domain. Of a pathogenetic relevance, this effect
coupled with the sensitization of quiescent CD4 lymphocytes
to HIV-1 infection. By microarray assay, we found that the
CCL24/eotaxin-2 gene was up-regulated in MDMs treated with
wt Nef but not with the 72AxxA75
mutant. In addition, the higher transcription activity correlated
with a significant increase of the CCL24/Eotaxin-2 release.
Finally, we observed that anti-CCL24/eotaxin-2 antibodies
efficiently neutralized the stimulatory effect on CD4 lymphocytes
of supernatants from MDMs treated with extracellular Nef.
Overall, these data support the idea that CCL24/eotaxin-2
is part of the mechanism of CD4 lymphocyte activation paracrinally
induced by Nef.
[Back to top]
Transcription Factor Profiling Shows New Ways Towards
New Treatment Options of Cutaneous T Cell Lymphomas
Udo Döbbeling
[Full
Text Article]
Most oncogenes encode activators of transcription factors
or transcription factors themselves. Transcription factors
that are induced by growth stimuli are, in contrast to transcription
factors that regulate house keeping genes, tightly regulated
and only active, when a stimulus (e.g. cytokines or other
growth factors) is given. Examples of such transcription factors
are members of the jun, fos, myc, NFκB
and STAT gene families. In cancer cells this regulation is
interrupted, resulting in constitutive activities of transcription
factors that are normally silent. This in turn results in
the increased expression of target genes that are necessary
for growth and protection from apoptosis. Since inducible
transcription factors are activated by specific pathways,
the identification of unusual constitutively active transcription
factors also identifies the involved signal transduction pathway.
Inhibitors of the components of these pathways may be effective
anti-cancer agents, as they interrupt the abnormal signalling
and in cancer cells. We applied this strategy for two forms
of cutaneous T cell lymphomas and identified several groups
of agents that may be the prototypes of new drugs to fight
these diseases.
[Back to top]
Controlled Release of the Pineal Hormone Melatonin
from Hydroxypropylmethylcellulose/Sodium Alginate Matrices
in Aqueous Media Containing Dioctyl Sulfosuccinate
Marilena Vlachou, Athanasia Tsiakoulia and Aphrodite Eikosipentaki
[Full
Text Article]
An investigation of the controlled release profile of mono-layered
formulations of the hormone melatonin in modified aqueous
media is described. The tablets used were comprised of hydroxypropylmethylcellulose
(HPMC K15M) and sodium alginate with melatonin (fully soluble
in the dioctyl sulfosuccinate (DSS) containing simulated intestinal
solution). Three different sets of tablets (diameters 7.5,
10.0 and 13.0 mm) were tested with respect to the influence
of their sizes on the hormone’s release; the general
trend observed was that tablets with larger surface area values
had lower % release. A decrease in the value of Wo,
obtained from the ratio [H2O]/[DSS],
results to the predominance of DSS conformers in the aqueous
media, which are less likely to solubilize melatonin effectively.
[Back to top]
Diabetes Beyond Insulin; Review of New Drugs for Treatment
of Diabetes Mellitus
Pankaj Modi
[Full
Text Article]
Diabetes mellitus (DM) is a progressive disease characterized
by insulin deficiency and insulin resistance or both. The
fasting and post-prandial blood glucose is elevated, exposing
the patient to acute and chronic complications (micro- and
macro-vascular) leading to blindness, kidney failure, heart
disease, stroke and amputations. Improving glycemic control
has been demonstrated to lower the risk of these complications.
Owing to the progressive nature of the disease, an evolving
treatment strategy is necessary to maintain glycemic control.
Varieties of new pharmacologic interventions are developed
in past 5 years to treat people with diabetes. Several studies
have been carried out covering different aspects of pharmacological
interventions (newer and old drugs) along with the effects
of weight loss, diet and exercise. Two categories of drugs
have been used for the treatment of Diabetes Mellitus: the
insulin and oral agents. Insulin analogues are molecules that
differ from human insulin in amino acid sequence but bind
to the insulin receptors and act similarly in function.
This article provides an update of pharmacologic interventions
for diabetes with practical overview of the new drug options,
new insulin analogues, pharmacology, clinical efficacy, safety,
dosing, cost, with specific examples of each and their background
and side effects used to achieve tight glucose control. These
agents have distinct characteristics that help in their selection
for the treatment of type 1 and type 2 diabetes.
[Back to top]
Targetability of Human Disease Genes
Meena K. Sakharkar and Kishore R. Sakharkar
[Full
Text Article]
The availability of complete genome sequences and the wealth
of large-scale biological datasets provide an unprecedented
opportunity to elucidate the genetic basis of human diseases.
Therapeutically relevant targets should be both ‘druggable’
and ‘disease modifying’. In this review we examine
the application of computational biology towards the exploration
of druggability, targetability and evolutionary conservation
of human disease genes. These analyses could have a tremendous
potential for systematic in silico drug target identification
in the post-genomic era.
[Back to top]
Pharmacogenomics of Sex Difference in Chemotherapeutic
Toxicity
Jeffrey Wang and Ying Huang
[Full
Text Article]
Except for few cases, chemotherapeutic toxicity is in
general influenced by multiple genetic factors and non-genetic
factors including age, sex and drug-drug interactions. The
manifestations of adverse drug reactions differ between men
and women. In particular, women experience greater toxicity
from certain chemotherapeutic drugs than men. Sex-related
factors are likely to play an increasing role in drug development
and therapeutic decision-making in the future. The sex-selective
toxicity could be attributed to sex-related differences in
pharmacokinetic and pharmacodynamic properties of these drugs.
Systematic pharmacogenomic investigation into sex difference
in chemotherapeutic toxicity potentially presents an opportunity
to assess the effects of multiple genetic factors or gene
networks on sex-related differences in the toxicity of anti-cancer
drugs. A thorough understanding of the interactions between
sex, drug and gene will provide valuable insights in assessing
the susceptibility of an individual to chemotherapy-induced
toxicity, predicting the sex-related effects for any anticancer
drug and ultimately achieving the goal of personalized cancer
therapy.
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