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Current
Medicinal Chemistry
ISSN: 0929-8673
Current Medicinal Chemistry
Volume 14, Number 15, 2007
Contents
COX-2 Expression in Atherosclerosis: The Good, the Bad or
the Ugly? Pp. 1595-1605
C. Cuccurullo, M.L. Fazia, A. Mezzetti and F. Cipollone
[Abstract]
New Biological Approaches in Asthma: DNA-Based Therapy
Pp. 1607-1618
Li-Chieh Wang, Jyh-Hong Lee, Yao-Hsu Yang, Yu-Tsan Lin
and Bor-Luen Chiang
[Abstract]
Biochemical Basis of Ischemic Heart Injury and
of Cardioprotective Interventions Pp. 1619-1637
R. Zucchi, S. Ghelardoni and S. Evangelista
[Abstract]
Diseases Originating from Altered Protein Quality
Control in the Endoplasmic Reticulum Pp. 1639-1652
Mieko Otsu and Roberto Sitia
[Abstract]
The Road to Advanced Glycation End Products: A Mechanistic
Perspective Pp. 1653-1671
S.-J. Cho, G. Roman, F. Yeboah and Y. Konishi
[Abstract]
Phthalocyanines Covalently Bound to Biomolecules for
a Targeted Photodynamic Therapy Pp. 1673-1687
Jean-philippe Taquet, Céline Frochot, Vincent Manneville
and Muriel Barberi-Heyob
[Abstract]
Adrenomedullin in the Kidney–Renal Physiological
and Pathophysiological Roles Pp. 1689-1699
Toshio Nishikimi
[Abstract]
Abstracts
[Back to top]
COX-2 Expression in Atherosclerosis: The Good, the Bad or
the Ugly?
C. Cuccurullo, M.L. Fazia, A. Mezzetti and F. Cipollone
Cyclooxygenase (COX) is the rate limiting enzyme catalyzing
the conversion of arachidonic acid into prostanoids, lipid
mediators critically implicated in a variety of physiological
and pathophysiological processes, including inflammation,
vascular and renal homeostasis, and immune responses. Since
the early 1990s it has been appreciated that two isoforms
of COX exist, referred to as COX-1 and COX-2. Although structurally
homologous, COX-1 and COX-2 are regulated by two independent
and quite different systems and have different functional
roles. In the setting of acute ischemic syndromes it has been
recognized that COX pathway plays an important role; however,
whereas the function of platelet COX-1 in acute ischemic diseases
is firmly established, the role of COX-2 in atherothrombosis
remains controversial. The complex role of COX-2 in this setting
is also confirmed by the unexpected cardiovascular side effects
of long-term treatment with COX-2 inhibitors. In this article,
we review the pattern of expression of COX-2 in the cellular
players of atherothrombosis, its role as a determinant of
plaque vulnerability, the effects of the variable expression
of upstream and downstream enzymes in the prostanoid biosynthesis
on COX-2 expression and inhibition.
[Back to top]
New Biological Approaches in Asthma: DNA-Based Therapy
Li-Chieh Wang, Jyh-Hong Lee, Yao-Hsu Yang, Yu-Tsan Lin
and Bor-Luen Chiang
Asthma is characterized by airway inflammation, bronchial
hyper-responsiveness, and reversible airway obstruction. Medications
for asthma include corticosteroids, β2-adrenergic
receptor agonists, chromones, methylxanthines, and leukotriene
modifiers. Despite these advances in therapy, many symptoms
are not well controlled. Since asthma is a chronic airway
inflammation with a bias towards a type 2 T helper (Th2) cell
response, some new approaches are targeted towards the Th2
inflammation pathway. These include anti-IgE therapy, anti-Th2
cytokine therapy, and therapies aiming at increasing Th1 cytokines.
This article will focus on DNA-based therapy, a novel therapeutic
strategy for asthma. Immunostimulatory gene therapy using
CpG oligodeoxynucleotides with central deoxycytidyl-deoxyguanosine
(CpG) dinucleotide, in which the cytosine nucleobase is unmethylated,
can stimulate the innate immunity and augment Th1 response.
With DNA gene therapy, genes can be introduced to target Th1
cytokines or other mediators in the airway in order to counteract
Th2 inflammation in asthma. Also, antisense oligonucleotides
can target mRNA species of interest in asthma. Through these
therapies, we can expect long-lasting effects, better control
of symptoms, and reducing medication in the future.
[Back to top]
Biochemical Basis of Ischemic Heart Injury and
of Cardioprotective Interventions
R. Zucchi, S. Ghelardoni and S. Evangelista
Cardioprotective interventions are defined as interventions
able to increase myocardial resistance to ischemia. The authors
approach the issue of cardioprotection on the basis of the
present knowledge about the biochemical mechanisms responsible
for the injury produced by myocardial ischemia or ischemia-reperfusion.
Reversible and irreversible injury are distinguished. The
former is largely accounted for by the direct consequences
of reduced ATP synthesis, which causes decreased ATP phosphorylation
potential, acidosis and phosphate accumulation. The biochemical
mechanisms leading to irreversible injury include osmotic
overload, production of toxic lipid metabolites, cytosolic
calcium overload, and generation of reactive oxygen species,
which lead to membrane disruption, mitochondrial dysfunction
and possibly to the activation of apoptotic pathways. The
major effect of the classical cardioprotective agents (nitrates,
beta adrenergic antagonists, calcium channel blockers) consists
in affecting ATP demand/supply ratio in such a way as to delay
the decrease in ATP phosphorylation potential. Other drugs
have been introduced, which allegedly interfere directly with
the mechanisms responsible for irreversible ischemic injury.
These include 3-ketoacyl-CoA tiolase inhibitors, modulators
of intracellular calcium channels, ionic exchanger inhibitors,
free radical scavengers, caspase inhibitors, purinergic agonists,
K+ATP channel openers, and
modulators of mitochondrial permeability transition. The results
obtained with these substances in experimental models and
in the clinical setting are discussed. Special attention is
devoted to angiotensin converting enzyme inhibitors, whose
direct cardioprotective properties has recently been demonstrated.
[Back to top]
Diseases Originating from Altered Protein Quality
Control in the Endoplasmic Reticulum
Mieko Otsu and Roberto Sitia
A challenging question in biology is how cells control their
shape and volume. The relative abundance of organelles can
be radically modified to comply with a new task, an example
being the massive development of the endoplasmic reticulum
(ER) in Ig-secreting plasma cells. The ER is the site where
secretory proteins are made and folded. Remarkably, it can
discriminate between native and non-native proteins, restricting
transport to the former, whilst retaining and eventually degrading
the latter (quality control). Recent studies revealed that
certain components of the unfolded protein response (UPR),
a multidimensional signalling pathway originally discovered
in cells exposed to severe ER stress, are crucial for the
normal development of secretory cells. According to the cell
types, different arms of the UPR are required: the IRE1-XBP1
pathway is essential for plasma cell differentiation, whilst
the PERK-eIF2α
pathway is essential for pancreatic β
cells survival. Therefore, the UPR is far from being a monolithic
response. Disturbances in the signalling pathways that allow
the ER to satisfy the changing demand of protein synthesis
can occur at various levels and often cause diseases. Here
we summarize the molecular mechanisms underlying this variegated
and constantly growing class of pathological conditions, focusing
on diseases that are linked to alterations in the quality
control functions that the ER exerts over its protein products.
[Back to top]
The Road to Advanced Glycation End Products: A Mechanistic
Perspective
S.-J. Cho, G. Roman, F. Yeboah and Y. Konishi
Protein glycation is a slow natural process involving the
chemical modification of the reactive amino and guanidine
functions in amino acids by sugars and carbohydrates-derived
reactive carbonyls. Its deleterious consequences are obvious
in the case of long-lived proteins in aged people and are
exacerbated by the high blood concentration of sugars in diabetic
patients. The non-enzymatic glycation of proteins occurs through
a wide range of concurrent processes comprising condensation,
rearrangement, fragmentation, and oxidation reactions. Using
a few well established intermediates such as Schiff base,
Amadori product and reactive α-dicarbonyls
as milestones and the results of in vitro glycation
investigations, an overall detailed mechanistic analysis of
protein glycation is presented for the first time. The pathways
leading to several advanced glycation end products (AGEs)
such as (carboxymethyl)lysine, pentosidine, and glucosepane
are outlined, whereas other AGEs useful as potential biomarkers
of glycation are only briefly mentioned. The current stage
of the development of glycation inhibitors has been reviewed
with an emphasis on their mechanism of action.
[Back to top]
Phthalocyanines Covalently Bound to Biomolecules for
a Targeted Photodynamic Therapy
Jean-philippe Taquet, Céline Frochot, Vincent Manneville
and Muriel Barberi-Heyob
Photodynamic therapy (PDT) is a relatively new cytotoxic treatment,
predominantly used in anticancer approaches, that depends
on the retention of photosensitizers in tumor and their activation
after light exposure. This technology is based on the light
excitation of a photosensitizer which induces very localized
oxidative damages within the cells by formation of highly
reactive oxygen species, the most important being singlet
oxygen. Many photo-activable molecules have been synthesized
such as porphyrins, chlorins and more recently phthalocyanines
which present a strong light absorption at wavelengths around
670 nm and are therefore well-adapted to the optical window
required for PDT application.
However, the lack of selective accumulation of these photo-activable
molecules within tumor tissue is a major problem in PDT, and
one research area of importance is developing targeted photosensitizers.
Indeed, targeted photodynamic therapy offers the advantage
to enhance photodynamic efficiency by directly targeting diseased
cells or tissues.
Many attempts have been made to either increase the uptake
of the dye by the target cells and tissues or to improve subcellular
localization so as to deliver the dye to photosensitive sites
within the cells. The aim of this review is to present the
actual state of the development of phthalocyanines covalently
conjugated with biomolecules that possess a marked selectivity
towards cancer cells; for some of them their photophysical
properties and photodynamic activity will be presented.
[Back to top]
Adrenomedullin in the Kidney–Renal Physiological
and Pathophysiological Roles
Toshio Nishikimi
Adrenomedullin (AM) is a potent vasodilatory peptide
originally discovered in human pheochromocytoma tissue. AM
and AM gene expression are widely distributed in the cardiovascular
system, including the kidney. The co-localization of AM and
its receptor components such as calcitonin receptor-like receptor
(CRLR), receptor activity modifying protein (RAMP)2 and RAMP3
in the kidney, heart, and vasculature suggests an important
role for the peptide as a regulator of renal, cardiac, and
vascular function. Indeed, in addition to its cardiovascular
effects, AM has renal vasodilatory, natriuretic, and diuretic
actions. Consistent with these observations, immunohistochemical
studies revealed that AM is stained in the collecting duct,
distal convoluted tubules, vessels, and glomerular mesangial
cells, endothelial cells and podocytes. Plasma AM levels are
increased in patients with renal impairment in proportion
to the severity of the disease. Previously we and other investigators
showed that two molecular forms of AM, AM-glycine, an inactive
form, and AM-mature, an active form, circulate in human plasma.
Urine also contains both forms of AM; however, the AM-mature/AM-glycine
ratio is higher in urine than in plasma. Interestingly, plasma
AM-glycine and AM-mature levels are increased in renal failure,
whereas urinary AM-glycine and AM-mature are decreased in
this condition. These results indicate that the origin of
urinary AM is different from that of plasma AM. Experimental
studies showed that the renal tissue AM-mature/AM-glycine
ratio is higher than that in plasma and urine. In addition,
renal tissue concentrations of AM are increased in severely
hypertensive rats. Considering that AM has antiapoptotic,
antifibrotic, and antiproliferative effects, the increase
of AM in renal disease may be a protective mechanism. In fact,
AM gene delivery or long-term AM infusion significantly improved
glomerular sclerosis, interstitial fibrosis, and renal arteriosclerosis
in several malignant hypertensive models.
This review describes the biochemistry, physiology, and circulating
levels of AM and also discusses what is known about the pathophysiological
role of AM in renal disease.
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