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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 5, 2008
Contents
Advances in Heme Oxygenase Research as a Potential Therapeutic
Strategy
Executive Editor: M.J. Alcaraz
Editorial Pp. 411
Heme Oxygenase: A Target Gene for Anti-Diabetic
and Obesity Pp. 412-421
N.G. Abraham, P.L. Tsenovoy, J. McClung and G.S. Drummond
[Abstract]
Role of Heme Oxygenase-1 in Vascular Disease
Pp. 422-428
H-T. Chung, H-O. Pae and Y-N. Cha
[Abstract]
Heme Oxygenase-1 as a Therapeutic Target in Neurodegenerative
Diseases and Brain Infections Pp. 429-442
A. Cuadrado and A.I. Rojo
[Abstract]
Cerebroprotective Functions of HO-2
Pp. 443-453
H. Parfenova and C.W. Leffler
[Abstract]
The Role of Heme Oxygenase-1 in T Cell-Mediated Immunity:
The All Encompassing Enzyme Pp. 454-464
Z.W. Xia, W.W. Zhong, J.S. Meyrowitz and Z. Zhang
[Abstract]
Carbon Monoxide-Releasing Molecules: A Pharmacological
Expedient to Counteract Inflammation Pp. 465-472
M.J. Alcaraz, M.I. Guillen, M.L. Ferrandiz, J. Megías
and R. Motterlini
[Abstract]
Inducers of Heme Oxygenase-1 Pp. 473-486
M.L. Ferrándiz and I. Devesa
[Abstract]
General Articles
Receptor for Advanced Glycation End Products
(RAGE): A Novel Therapeutic Target for Diabetic Vascular Complication
Pp. 487-495
S-i. Yamagishi, K. Nakamura, T. Matsui, Y. Noda and T.
Imaizumi
[Abstract]
The Protective Role of Steroids in Ischemia-Reperfusion
Injury of the Liver Pp. 496-503
C. Pulitanò and L. Aldrighetti
[Abstract]
Abstracts
[Back to top]
Editorial: Advances in Heme Oxygenase Research
as a Potential Therapeutic Strategy
In 2003, the issue of Current Pharmaceutical Design
entitled "Modulation of heme oxygenase-1 as a therapeutic
target" presented six papers focused on the role and
interest of heme oxygenase(HO)-1 modulation in human disease.
This topic has generated significant interest in the last
years leading to a growing number of publications
The purpose of this issue of Current Pharmaceutical Design
is to highlight studies examining novel aspects of HO. These
are important observations and point to fruitful areas for
future research. All of these papers provide useful information
to consider when assessing treatment strategies in human disease.
By sharpening our current knowledge about the role of HO,
we can better target specific interventions to a number of
conditions. This issue opens with papers reporting research
on HO as a therapeutic target in relevant diseases affecting
metabolism, blood vessels and the central nervous system.
The first article by prof. Abraham [1] describes the protective
role of HO-1 in animal models of diabetes and obesity. Enhanced
HO-1 expression and activity may be considered the primary
defense against the deleterious effects of diabetes, metabolic
syndrome and obesity.
The second article by Dr. Chung [2] summarizes recent studies
on HO-1 and its possible utility as a treatment for vascular
diseases. Carbon monoxide is produced by HO activity and plays
a protective role in vascular homeostasis, including the regulation
of nitric oxide- and H2S-producing
enzymes that may be involved in either vascular protection
or vascular injury.
In the third article, Dr. Cuadrado [3] examines the role of
HO-1 in redox homeostasis in the brain and neuroprotection.
Pharmacological modulation of HO-1 has shown promising results
in models of Alzheimer’s, Parkinson’s and of infectious
diseases, such as malaria. This theme is continued by Prof.
Parfenova, [4] who focuses on the functions of the constitutive
isozyme, HO-2. Pharmacological inhibition or gene deletion
of this enzyme in the brain exacerbates oxidative stress induced
by seizures, glutamate, and inflammatory cytokines, and causes
cerebral vascular injury, whereas the end products of HO-catalyzed
heme degradation have cytoprotective functions.
Next, Dr. Xia and co-workers [5] review the potential of HO-1
as a modulator in T cell-mediated immune processes. As a consequence,
this enzyme may provide protection in asthma, organ transplantation
rejection, inflammatory bowel disease and experimental autoimmune
encephalomyelitis.
The last two papers that are included in this issue make a
contribution to the current knowledge about pharmacological
interventions in the HO pathway. With the collaboration of
Dr. Motterlini [6], we have discussed our own research on
inflammation, HO-1 and carbon monoxide-releasing molecules
including in vitro and in vivo studies.
Finally, Dr. Ferrándiz [7] has summarised a number
of pharmacological approaches to induce HO-1.
Perhaps one result of this issue will be to stimulate future
studies that address not only basic knowledge, but also therapeutic
applications. The heme oxygenase pathway provides exciting
areas for future intervention-oriented research.
References
[1] Abraham NG, Tsenovoy PL, McClung J, Drummond GS. Heme
Oxygenase: A Target Gene for Anti-Diabetic and Obesity. Curr
Pharm Des 2008; 14(5): 412-421.
[2] Chung H-T, Pae H-O, Cha Y-N. Role of Heme Oxygenase-1
in Vascular Disease. Curr Pharm Des 2008; 14(5): 422-428.
[3] Cuadrado A, Rojo AI. Heme Oxygenase-1 As A Therapeutic
Target in Neurodegenerative Diseases and Brain Infections.
Curr Pharm Des 2008; 14(5): 429-442.
[4] Parfenova H, Leffler CW. Cerebroprotective Functions of
HO-2. Curr Pharm Des 2008; 14(5): 443-453.
[5] Xia ZW, Zhong WW, Meyrowitz JS, Zhang Z. The Role of Heme
Oxygenase-1 in T Cell-Mediated Immunity: The All Encompassing
Enzyme. Curr Pharm Des 2008; 14(5): 454-464.
[6] Alcaraz MJ, Guillen MI, Ferrandiz ML, Megías J,
Motterlini R. Carbon Monoxide-Releasing Molecules: A Pharmacological
Expedient to Counteract Inflammation. Curr Pharm Des 2008;
14(5): 465-472.
[7] Ferrándiz ML, Devesa I. Inducers of Heme Oxygenase-1.
Curr Pharm Des 2008; 14(5): 473-486.
M.J. Alcaraz
Department of Pharmacology
University of Valencia
Av. Vicent Andres Estelles s/n
46100 Burjasot, Valencia
Spain
maria.j.alcaraz@uv.es
[Back to top]
Heme Oxygenase: A Target Gene for Anti-Diabetic and Obesity
N.G. Abraham, P.L. Tsenovoy, J. McClung and G.S. Drummond
Heme oxygenase-1 (HO-1) is central to the regulation
of oxidative injury. The role of increased HO-1 expression
and Heme oxygenase (HO) activity in mitigating the detrimental
side effect of diabetes is examined. A review of the mechanism(s)
of action is included. This may lead to the development of
pharmacological and genetic approaches to mitigate the clinical
complications associated with the progression of diabetes
and obesity.
[Back to top]
Role of Heme Oxygenase-1 in Vascular Disease
H-T. Chung, H-O. Pae and Y-N. Cha
Great attention has been placed on the protective role
of heme oxygenase-1 (HO-1) for several vascular diseases such
as athe-rosclerosis. HO-1, by exerting anti-inflammatory,
antiproliferative, anti-apoptotic and anti-oxidant effects
on the vasculature, protects against atherosclerosis. The
precise underlying mechanisms for HO-1-based protection are
not yet completely understood, but appear to involve the protective
effects of HO-1 by-products, carbon monoxide (CO), biliverdin/bilirubin
and free iron. Among the HO-1 by-products, CO has been shown
to mimic some protective actions of HO-1, specifically, in
vascular system. There is evidence supporting that HO-1-derived
CO also interacts with other gaseous molecules, such as nitric
oxide (NO) and hydrogen sulfide (H2S)
that may relate to either vascular protection or injury. CO,
NO and H2S not only exert
comparable biological actions but also compete with and are
antagonists with each other for maintaining vascular homeostasis.
This review will highlight the protective roles of HO-1/CO
in vascular injury/disease, and emphasize the potential roles
of CO in possible interplay among three gaseous molecules,
which may be important to explore the overall protective roles
of HO-1/CO system in the pathogenesis of human vascular disease.
[Back to top]
Heme Oxygenase-1 as a Therapeutic Target in Neurodegenerative
Diseases and Brain Infections
A. Cuadrado and A.I. Rojo
Heme oxygenase-1 (HO-1) catalyzes the degradation of
heme to generate carbon monoxide, biliverdin and free iron.
Increased HO-1 levels constitute an anatomopathological feature
of many neurological diseases, such as neurodegenerative disorders
and brain infections, which correlate with exacerbated oxidative
stress and inflammation. It is generally accepted that the
elevated HO-1 levels represent an attempt to restore redox
homeostasis and to down-modulate inflammation. However, experimental
observations indicate that the extent of HO-1 induction may
be critical because excessive heme degradation may result
in toxic levels of CO, bilirubin and, more importantly, iron.
Pharmacological modulation of HO-1 levels in the brain, within
therapeutic limits, shows promising results in models of Alzheimer’s
(AD), Parkinson’s (PD) and of infectious diseases, such
as malaria. A more complete understanding on how HO-1 is involved
in the pathogenesis of neurological diseases will be essential
to develop therapeutic approaches. In the next coming years
we will witness the description of chemicals, drugs or dietary
products that cross the blood brain barrier efficiently, activate
HO-1 expression, and achieve neuroprotective and anti-inflammatory
effects in vivo.
[Back to top]
Cerebroprotective Functions of HO-2
H. Parfenova and C.W. Leffler
The constitutive isoform of heme oxygenase, HO-2, is
highly expressed in the brain and in cerebral vessels. HO-2
functions in the brain have been evaluated using pharmacological
inhibitors of the enzyme and HO-2 gene deletion in in
vivo animal models and in cultured cells (neurons, astrocytes,
cerebral vascular endothelial cells). Rapid activation of
HO-2 via post-translational modifications without
upregulation of HO-2 expression or HO-1 induction coincides
with the increase in cerebral blood flow aimed at maintaining
brain homeostasis and neuronal survival during seizures, hypoxia,
and hypotension. Pharmacological inhibition or gene deletion
of brain HO-2 exacerbates oxidative stress induced by seizures,
glutamate, and inflammatory cytokines, and causes cerebral
vascular injury. Carbon monoxide (CO) and bilirubin, the end
products of HO-catalyzed heme degradation, have distinct cytoprotective
functions. CO, by binding to a heme prosthetic group, regulates
the key components of cell signaling, including BKCa
channels, guanylyl cyclase, NADPH oxidase, and
the mitochondria respiratory chain. Cerebral vasodilator effects
of CO are mediated via activation of BKCa
channels and guanylyl cyclase. CO, by inhibiting
the major components of endogenous oxidant-generating machinery,
NADPH oxidase and the cytochrome C oxidase of the mitochondrial
respiratory chain, blocks formation of reactive oxygen species.
Bilirubin, via redox cycling with biliverdin, is
a potent oxidant scavenger that removes preformed oxidants.
Overall, HO-2 has dual housekeeping cerebroprotective functions
by maintaining autoregulation of cerebral blood flow aimed
at improving neuronal survival in a changing environment,
and by providing an effective defense mechanism that blocks
oxidant formation and prevents cell death caused by oxidative
stress.
[Back to top]
The Role of Heme Oxygenase-1 in T Cell-Mediated Immunity:
The All Encompassing Enzyme
Z.W. Xia, W.W. Zhong, J.S. Meyrowitz and Z. Zhang
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of
ferroheme metabolic pathway, which has the functions of anti-oxidation,
anti-inflammatory, anti-apoptosis and anti-smooth muscle hyperplasia.
Furthermore, HO-1 exerts a protective action in the diseases
mediated by effector T lymphocytes such as T helper (Th) 1,
Th2 and Th17. In addition, regulatory T cells (Treg) control
the activity of CD4+CD25
-effector cells in a suppressive manner. Numerous studies
indicate that the protective action of HO-1 in diseases is
through CD4+CD25+
Treg. This paper will review the current research and understanding
of HO-1’s role in T cells-mediated immunoregulation.
[Back to top]
Carbon Monoxide-Releasing Molecules: A Pharmacological Expedient
to Counteract Inflammation
M.J. Alcaraz, M.I. Guillen, M.L. Ferrandiz, J. Megías
and R. Motterlini
Carbon monoxide (CO) mediates many of the biological
effects that are attributed to heme oxygenase (HO), the enzyme
responsible for CO production in mammals. Antioxidant and
anti-inflammatory activities of HO-1, the inducible isoform
of heme oxygenase, have been demonstrated in a variety of
disease models and a therapeutic exploitation of this pathway
is currently under scrutiny. In this context, the liberation
of CO from CO-releasing molecules (CO-RMs) is extremely attractive
as these compounds may form the basis of a new class of pharmaceuticals.
Recent investigations indicate that HO-1 and CO modulate important
processes in chronic inflammation; these include the control
of immune responses, the production of inflammatory mediators
and the mitigation of cartilage or bone destruction. As HO-1
is highly expressed in the joint tissues of patients affected
by arthritic diseases, it is plausible to suggest that this
pathway may play a protective role against joint degenerative
diseases. Studies aimed at identifying the signaling pathways
responsive to endogenous CO and CO-RMs in rheumatoid arthritis
and other inflammatory states are currently in progress. This
research will help to elucidate the molecular mechanisms underlying
the pharmacological effects of CO-RMs and may lead to the
development of novel therapeutic strategies for the treatment
of acute and chronic inflammatory conditions.
[Back to top]
Inducers of Heme Oxygenase-1
M.L. Ferrándiz and I. Devesa
Heme oxygenase-1 (HO-1) is an inducible rate-limiting
enzyme which catalyzes group heme into carbon monoxide, iron
and bilirubin. In the recent years, HO-1 expression has been
reported as an important protective endogenous mechanism against
physical, chemical and biological stress. In this regard,
induction of this enzyme has shown beneficial effects in several
pathologic conditions, such as inflammatory processes, atherosclerosis,
carcinogenesis, ischemia-reperfusion systems or degenerative
diseases.
Complex intracellular signalling cascades mediate the expression
of HO-1 in response to external stimuli, Transcription factors,
as nuclear factor E2–related factor-2, activator protein-1,
and nuclear factor-kappa B, and some of their upstream kinases,
mitogen-activated protein kinases, phosphatidylinositol 3-kinase,
or protein kinases A, C are responsible of the HO1 gene expression.
The purpose of this article is to review the increasing number
of natural and synthetic molecules reported to induce HO-1
as additive mechanism responsible for their therapeutic effects;
experimental and pathological conditions as well as possible
signalling mechanism involved in HO-1 expression by this compounds
are described. Controlled upregulation of this enzyme, or
its catalytic activity, has shown antioxidant, anti-proliferative,
anti-apoptotic and anti-inflammatory properties. For this
reason, pharmacologic modulation of HO-1 system may represent
an effective and cooperative strategy to intervene in several
pathologic conditions.
[Back to top]
Receptor for Advanced Glycation End Products (RAGE): A Novel
Therapeutic Target for Diabetic Vascular Complication
S-i. Yamagishi, K. Nakamura, T. Matsui, Y. Noda and T.
Imaizumi
Diabetic vascular complication is a leading cause of
acquired blindness, end-stage renal failure, a variety of
neuropathies and accelerated atherosclerosis, which could
account for disabilities and high mortality rates in patients
with diabetes. Although several hyperglycemia-elicited metabolic
and hemodynamic derangements have been implicated in the pathogenesis
of diabetic vascular complication, the process of formation
and accumulation of advanced glycation end products (AGEs)
and their mode of action are most compatible with the theory
‘hyperglycemic memory’. Further, there is a growing
body of evidence that AGEs and their receptor (RAGE) axis
is involved in the pathogenesis of diabetic vascular complication.
Indeed, the engagement of RAGE with AGEs is shown to elicit
oxidative stress generation and subsequently evoke inflammatory
responses in various types of cells, thus playing an important
role in the development and progression of diabetic micro-
and macroangiopathy. These observations suggest that down-regulation
of RAGE expression or blockade of the RAGE downstream signaling
may be a promising target for therapeutic intervention in
diabetic vascular complication. In this review, we discuss
several types of agents that could potentially inhibit RAGE
expression or its downstream pathways and their therapeutic
implications in diabetic vascular complication.
[Back to top]
The Protective Role of Steroids in Ischemia-Reperfusion Injury
of the Liver
C. Pulitanò and L. Aldrighetti
Liver ischemia-reperfusion injury occurs in a number
of clinical settings, including liver surgery, transplantation,
and circulatory shock, leading to significant morbidity and
mortality. There is a substantial evidence that hepatic ischemia-reperfusion
injury results from an intense inflammatory response initiated
by oxidative stress in the liver parenchyma during reperfusion.
The anti-inflammatory effects of glucocorticosteroids (GCs)
have been known for decades and have found extensive therapeutic
use in a wide range of clinical situations associated with
organ ischemia. Based on their biological effects, routine
perioperative GCs administration has been advocated to reduce
hepatic ischemic injury. However, the use of GCs in hepatic
surgery remains controversial and clinical benefits are still
uncertain. The aim of this review is to present the experimental
and clinical evidence about the role of GCs in modulating
hepatic ischemia-reperfusion injury.
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