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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical
Design
Volume 15, Number 26, 2009
Contents
Oxidative Stress and Cellular Homeostasis
Executive Editor: Victor M. Victor
Editorial: Pp. 2986-2987
[PMID:
19754374 PubMed - indexed for MEDLINE]
Oxidative Stress, Endothelial Dysfunction and Atherosclerosis
Pp. 2988-3002
V. M. Victor, M. Rocha, E. Solá,
C. Bañuls, K. Garcia-Malpartida and A. Hernández-
Mijares
[Abstract] [Purchase
Article] [PMID:
19754375 PubMed - indexed for MEDLINE]
An Update of the Oxidation-Inflammation
Theory of Aging: The Involvement of the Immune System in Oxi-Inflamm-Aging
Pp. 3003-3026
M. De la Fuente and J. Miquel
[Abstract] [Purchase
Article]
[PMID:
19754376 PubMed - indexed for MEDLINE]
Cross-Talk between Oxidative Stress and
Pro-Inflammatory Cytokines in Acute Pancreatitis: A Key Role
for Protein Phosphatases Pp. 3027-3042
J. Escobar, J. Pereda, A. Arduini, J. Sandoval,
L. Sabater, L. Aparisi, G. López-Rodas and
J. Sastre
[Abstract] [Purchase
Article]
[PMID:
19754377 PubMed - indexed for MEDLINE]
Protein Pool Maintenance During Oxidative
Stress Pp. 3043-3051
B. Catalgol and T. Grune
[Abstract] [Purchase
Article]
[PMID:
19754378 PubMed - indexed for MEDLINE]
Mitochondrial-Targeted Antioxidants and
Oxidative Stress: A Proteomic Prospective Study Pp.
3052-3062
M. Rocha, J.V. Esplugues, A. Hernández-Mijares
and V.M. Víctor
[Abstract] [Purchase
Article]
[PMID:
19754379 PubMed - indexed for MEDLINE]
Antioxidant Effects of Natural Bioactive
Compounds Pp. 3063-3073
C. Balsano and A. Alisi
[Abstract] [Purchase
Article]
[PMID:
19754380 PubMed - indexed for MEDLINE]
General Articles
Mechanisms Involved in Metformin Action in
the Treatment of Polycystic Ovary Syndrome Pp.
3074-3077
A.B. Motta
[Abstract] [Purchase
Article]
[PMID:
19754381 PubMed - indexed for MEDLINE]
The Oxidative Stress Menace to Coronary
Vasculature: Any Place for Antioxidants? Pp.
3078-3090
A. Briasoulis, D. Tousoulis, C. Antoniades
and C. Stefanadis
[Abstract] [Purchase
Article]
[PMID:
19754382 PubMed - indexed for MEDLINE]
Abstracts
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[PMID:
19754374 PubMed - indexed for MEDLINE]
Editorial: Oxidative Stress and Cellular Homeostasis
When there is an imbalance between the production
of free radicals (ROS) and the ability of the cell to scavenge
them, they accumulate in the cytoplasm, leading to what is
known as “oxidative stress”. This situation occurs
as a host defence mechanism whose involvement in maintaining
homeostasis and/or inducing disease has been widely investigated
over the past decade. Cellular targets attacked by ROS include
DNA, proteins, membrane lipids, and mitochondria. In particular,
free radicals are by-products of aerobic metabolism, and most
cellular ROS are produced due to “leakage” of
electrons from the mitochondrial respiratory chain, resulting
in an incomplete reduction of molecular oxygen (O2)
during oxidative phosphorylation and a production of hydrogen
peroxide and the superoxide radical anion. It has been estimated
that at O2 physiological
levels, 1–3% of the reduced molecular O2
in mitochondria form superoxide. Approximately 85–90%
of O2 is used by mitochondria,
making the mitochondrion the major site of ROS production.
The remaining 10–15% of O2
is used by other cellular oxidative enzymes, including xanthine
oxidase in the cytoplasm, and by the cytochrome P450 system
in the endoplasmic reticulum, which can also yield ROS.
The review articles included in this issue of Current Pharmaceutical
Design summarize recent evidence in the field of physiology
and pharmacology.
In the first article [1], the author discusses the role of
oxidative processes in atherosclerosis and the cardiovascular
diseases (CVD) that can arise as a result. Atherosclerosis
represents a state of heightened oxidative stress characterized
by lipid and protein oxidation in the vascular wall. As an
expert in the field, the author describes an overproduction
of ROS under pathophysiologic conditions, and these ROS form
an integral part of the development of CVD, and in particular
atherosclerosis. Endothelial dysfunction, characterized by
a diminution of nitric oxide (NO) bioactivity, occurs early
on in the development of atherosclerosis, and determines future
vascular complications. Although the molecular mechanisms
responsible for mitochondria-mediated disease processes are
not clear, oxidative stress seems to play an important role.
This review provides a summary of the cellular metabolism
of ROS and its role in pathophysiological processes such as
atherosclerosis. In addition, the author describes currently
available antioxidants and possible reasons for their efficacy
and inefficacy in ameliorating oxidative stress-mediated diseases.
The outstanding review by De la Fuente et al. [2]
focuses on the aging process as one of the best examples of
the effects of deterioration of homeostasis, describing how
aging is accompanied by an impairment of physiological systems
such as the immune system. The authors propose an integrative
theory of aging. In accordance with this oxidation-mitochondrial
theory, they have observed that the age-related changes of
immune functions are based on a situation of oxidative and
inflammatory stress among whose intracellular mechanisms is
the activation of the NFkB in the immune cells. The authors
present a clear argument for why several functions of the
immune cells are good markers of biological age and predictors
of longevity. Based on the above, they propose a theory of
oxidation-inflammation as the main cause of aging. Accordingly,
the chronic oxidative stress that appears with age affects
all cells, and especially those of the regulatory systems,
such as the nervous, endocrine and immune systems, and the
communication between them. This prevents an adequate homeostasis,
and therefore is an obstacle to the preservation of health.
The authors also propose a key involvement of the immune system
in the aging process of the organism, specifically in the
rate of aging, based on the relation between the redox state
and functional capacity of the immune cells and the longevity
of individuals. Finally, they affirm that adequate amounts
of antioxidants in the diet improve immune functions, thereby
decreasing oxidative stress, and consequently increasing the
longevity of subjects.
The review by Escobar et al. [3] describes the key
role of phosphatases in the cross talk between oxidative stress
and proinflammatory cytokines in acute pancreatitis. They
highlight the pivotal role of proinflammatory cytokines and
oxidative stress in the early pathophysiological events of
the disease. Other important points stated are that the depletion
of pancreatic glutathione is an early hallmark of acute pancreatitis,
and that ROS are associated with the inflammatory process.
Changes in thiol homestasis and redox signalling decisively
contribute to the amplification of the inflammatory cascade
through mitogen-activated protein kinase (MAP kinase) pathways.
The authors discuss the relationship between oxidative stress,
pro-inflammatory cytokines and MAP kinase/protein phosphatase
pathways as major modulators of the inflammatory response
in acute pancreatitis.
The changes of protein pool maintenance during oxidative stress
is discussed by Catalgol et al. [4]. The authors
focus on available data about protein modifications following
oxidative stress, the cellular responses to this stress and
the role of proteasome in the process. The authors also affirm
that the production of ROS causes oxidative modifications
of proteins accompanied by a loss of protein function, and
that this can result in a defective cellular homeostasis.
In this sense, the degradation of non-functional, oxidized
proteins is an essential function of the proteolytic branch
of the antioxidant defence machinery. The major proteolytic
system responsible for the removal of oxidized proteins is
the proteasomal system. Whereas moderately oxidized proteins
are more sensitive to proteolytic attack, severely oxidized
ones are often poor substrates and can inhibit the proteasome.
The review by Rocha et al. [5] provides an overview
of the role of the mitochondrial proteome/genome interplay
that is currently believed to be implicated in a range of
human diseases. The authors propose that mitochondria produce
large amounts of free radicals and play an important role
in the life and death of the cell by regulating the signalling,
metabolism and energy production of cellular function. Interestingly,
they describe the contribution of mitochondrial oxidative
damage and dysfunction to a number of cell pathologies that
are manifested through a range of conditions that include
cardiovascular diseases (CVD). Recent developments in proteomics
have allowed the oxidative stress response to be studied in
more depth. The authors give special attention to current
knowledge of the role of mitochondria in the development of
oxidative-stress-based diseases. Finally, they discuss the
insight provided by recent proteomic research and the effects
of mitochondrial-antioxidants on possible interventions.
The work by Balsano et al. [6] discusses the numerous
epidemiological studies that indicate that a reduced risk
of various lifestyle diseases - in particular CVD and cancer
- and other disorders, is associated with a diet rich in fruit
and vegetables and their products. The authors discuss a very
interesting concept concerning how to enhance consumption
of fruit and vegetables within the human diet related to the
positive effects of beneficial antioxidants on health.
They provide an outline of the main roles of ROS in biological
processes and diseases, and discuss how natural bioactive
compounds of fruits and vegetables determine their health-promoting
properties.
References
[1] Victor VM, Rocha M, Sola E, Bañuls C, Garcia-Malpartida
K, Hernández- Mijares A. Oxidative stress, endothelial
dysfunction and atherosclerosis. Curr Pharm Des 2009; 15(26):
2988-3002.
[2] De la Fuente M, Miquel J. An update of the oxidation-inflammation
theory of aging. The involvement of the immune system in oxi-inflamm-aging.
Curr Pharm Des 2009; 15(26): 3003-3026.
[3] Escobar J, Pereda J, Arduini A, Sandoval J, Sabater L,
Aparisi L, López-Rodas G, Sastre J. Cross-talk between
oxidative stress and pro-inflammatory cytokines in acute pancreatitis:
a key role for protein phosphatises. Curr Pharm Des 2009;
15(26): 3027-3042.
[4] Catalgol B, Grune T. Protein pool maintenance during oxidative
stress. Curr Pharm Des 2009; 15(26): 3043-3051.
[5] Rocha M, Esplugues JV, Hernandez-Mijares A, Victor VM.
Mitochondrial-targeted antioxidants and oxidative stress:
a proteomic prospective study. Curr Pharm Des 2009; 15(26):
3052-3062.
[6] Balsano C, Alisi A. Antioxidant effects of natural bioactive
compounds. Curr Pharm Des 2009; 15(26): 3063-3073.
Victor M. Victor
Fundación Hospital Universitario Doctor Peset
Endocrinology Service
Avda Gaspar Aguilar 90
46017, Valencia
Spain
E-mail: Victor.Victor@uv.es
[Back to top]
[Purchase
Article] [PMID:
19754375 PubMed - indexed for MEDLINE]
Oxidative Stress, Endothelial Dysfunction and Atherosclerosis
V. M. Victor, M. Rocha, E. Solá,
C. Bañuls, K. Garcia-Malpartida and A. Hernández-
Mijares
This review focuses on the role of oxidative processes
in atherosclerosis and the cardiovascular diseases (CVD) that
can arise as a result. Atherosclerosis represents a state
of heightened oxidative stress characterized by lipid and
protein oxidation in the vascular wall. Overproduction of
reactive oxygen species (ROS) under pathophysiologic conditions
forms an integral part of the development of CVD, and in particular
atherosclerosis. Endothelial dysfunction, characterized by
a loss of nitric oxide (NO) bioactivity, occurs early on in
the development of atherosclerosis, and determines future
vascular complications. Although the molecular mechanisms
responsible for mitochondria-mediated disease processes are
not clear, oxidative stress seems to play an important role.
In general, ROS are essential to the functions of cells, but
adequate levels of antioxidant defenses are required in order
to avoid the harmful effects of excessive ROS production.
In this review, we will provide a summary of the cellular
metabolism of reactive oxygen species (ROS) and its role in
pathophysiological processes such as atherosclerosis; and
currently available antioxidants and possible reasons for
their efficacy and inefficacy in ameliorating oxidative stress-mediated
diseases.
[Back to top]
[Purchase
Article] [PMID:
19754376 PubMed - indexed for MEDLINE]
An Update of the Oxidation-Inflammation Theory of Aging: The
Involvement of the Immune System in Oxi-Inflamm-Aging
M. De la Fuente and J. Miquel
The aging process is one of the best examples of the
effects of a deterioration of homeostasis, since aging is
accompanied by an impairment of the physiological systems
including the homeostatic systems such as the immune system.
We propose an integrative theory of aging providing answers
to the how (oxidation), where first (mitochondria
of differentiated cells) and why (pleiotropic genes)
this process occurs. In agreement with this oxidation-mitochondrial
theory of aging, we have observed that the age-related changes
of immune functions have as their basis an oxidative and inflammatory
stress situation, which has among its intracellular mechanisms
the activation of NFκB
in immune cells. Moreover, we have also observed that several
functions of immune cells are good markers of biological age
and predictors of longevity. Based on the above we have proposed
the theory of oxidation-inflammation as the main cause of
aging. Accordingly, the chronic oxidative stress that appears
with age affects all cells and especially those of the regulatory
systems, such as the nervous, endocrine and immune systems
and the communication between them. This fact prevents an
adequate homeostasis and, therefore, the preservation of health.
We have also proposed a key involvement of the immune system
in the aging process of the organism, concretely in the rate
of aging, since there is a relation between the redox state
and functional capacity of the immune cells and the longevity
of individuals. Moreover, the role of the immune system in
senescence could be of universal application. A confirmation
of the central role of the immune system in oxi-inflamm-aging
is that the administration of adequate amounts of antioxidants
in the diet, improves the immune functions, decreasing their
oxidative stress, and consequently increases the longevity
of the subjects.
[Back to top]
[Purchase
Article] [PMID:
19754377 PubMed - indexed for MEDLINE]
Cross-Talk between Oxidative Stress and Pro-Inflammatory Cytokines
in Acute Pancreatitis: A Key Role for Protein Phosphatases
J. Escobar, J. Pereda, A. Arduini, J. Sandoval,
L. Sabater, L. Aparisi, G. López-Rodas and
J. Sastre
Acute pancreatitis is an acute inflammatory process localized
in the pancreatic gland that frequently involves peripancreatic
tissues. It is still under investigation why an episode of
acute pancreatitis remains mild affecting only the pancreas
or progresses to a severe form leading to multiple organ failure
and death. Proinflammatory cytokines and oxidative stress
play a pivotal role in the early pathophysiological events
of the disease. Cytokines such as interleukin 1beta and tumor
necrosis factor alpha initiate and propagate almost all consequences
of the systemic inflammatory response syndrome. On the other
hand, depletion of pancreatic glutathione is an early hallmark
of acute pancreatitis and reactive oxygen species are also
associated with the inflammatory process. Changes in thiol
homestasis and redox signaling decisively contribute to amplification
of the inflammatory cascade through mitogen activated protein
kinase (MAP kinase) pathways. This review focuses on the relationship
between oxidative stress, pro-inflammatory cytokines and MAP
kinase/protein phosphatase pathways as major modulators of
the inflammatory response in acute pancreatitis. Redox sensitive
signal transduction mediated by inactivation of protein phosphatases,
particularly protein tyrosin phosphatases, is highlighted.
[Back to top]
[Purchase
Article] [PMID:
19754378 PubMed - indexed for MEDLINE]
Protein Pool Maintenance During Oxidative Stress
B. Catalgol and T. Grune
The production of reactive species causes oxidative modifications
of proteins accompanied by a loss of protein function. By
protein oxidation all cellular compartments and any amino
acid are effected. This might result in a defect of cellular
homeostasis. Therefore, the degradation of non-functional,
oxidized proteins is an essential function of the proteolytic
branch of the antioxidant defense machinery. The major proteolytic
system responsible for the removal of oxidized proteins is
the proteasomal system. Whereas moderately oxidized proteins
are more sensitive to proteolytic attack, severely oxidized
ones are often poor substrates and might, however, inhibit
the proteasome.
This paper reviews the data available on protein modifications
following oxidative stress, the cellular responses and the
role of proteasome in this process.
[Back to top]
[Purchase
Article] [PMID:
19754379 PubMed - indexed for MEDLINE]
Mitochondrial-Targeted Antioxidants and Oxidative Stress:
A Proteomic Prospective Study
M. Rocha, J.V. Esplugues, A. Hernández-Mijares
and V.M. Víctor
Mitochondria produce large amounts of free radicals and
play an important role in the life and death of a cell, regulating
the signalling, metabolism, and energy production needed for
cellular function. In this way, mitochondrial oxidative damage
and dysfunction contribute to a number of cell pathologies
that are manifested through a range of conditions that include
cardiovascular diseases (CVD). Although the molecular mechanisms
responsible for mitochondria-mediated disease processes are
not yet completely understood, oxidative stress definitely
seems to play an important role. When examined at the protein
level, both expression levels and protein modifications are
altered by oxidative stress. While these effects have been
studied in the past by classic biochemical methods, recent
developments in proteomics have allowed the oxidative stress
response to be studied in more depth. The focus of this work
is the mitochondrial proteome/genome interplay that is currently
believed to be implicated in a range of human diseases. Particular
attention is given to the current knowledge of the role of
mitochondria in the development of oxidative-stress-based
diseases; e.g. CVD is highlighted together with the prospective
proteomics perspective as an alternative prognostic and diagnostic
tool for interpreting many mitochondria-related anomalies.
Accordingly, strategies for the targeted delivery of antioxidants
to mitochondria are being developed. The insight provided
by recent proteomic research and the effects of mitochondrial-antioxidants
on possible interventions are also discussed.
[Back to top]
[Purchase
Article] [PMID:
19754380 PubMed - indexed for MEDLINE]
Antioxidant Effects of Natural Bioactive Compounds
C. Balsano and A. Alisi
Reactive oxygen species (ROS), as well as reactive nitrogen
species (RNS) play either harmful or beneficial role in biological
systems. Beneficial effects of ROS include physiological roles
in cellular responses against infectious agents and in several
cellular signalling pathways. Harmful effects are due to high
concentrations of ROS, which can damage biomolecules, including
lipids, proteins and nucleic acids. The harmful effects of
ROS are counterbalanced by the antioxidant action of both
antioxidant enzymes and non-enzymatic antioxidants; however,
despite the presence of the cell’s antioxidant system,
oxidative damage accumulates during the life cycle and has
been proposed to play a pivotal role in the development of
age-dependent diseases such as atherosclerosis, arthritis,
neurodegenerative disorders and cancer.
Numerous epidemiological studies indicate that a reduced risk
of various lifestyle diseases, mainly cardiovascular diseases
and cancer, as well as other disorders, is associated to a
diet rich in fruits, vegetables and their products. The drive
to enhance the consumption of fruits and vegetables in the
human diet is linked with positive effects of beneficial antioxidants
impacting on health promotion.
In this review we present an outline of main roles of ROS
in biological processes and diseases and how natural bioactive
compounds of fruits and vegetables determine their health-promoting
properties.
[Back to top]
[Purchase
Article] [PMID:
19754381 PubMed - indexed for MEDLINE]
Mechanisms Involved in Metformin Action in the Treatment of
Polycystic Ovary Syndrome
A.B. Motta
The N, N´ dimethyl-biguanide : Metformin is an
antidiabetic drug that increases glucose utilization in insulin-sensitive
tissues. As Polycystic Ovary Syndrome (PCOS) and diabetes
share some altered parameters-such as abnormal glucose: insulin
ratio, altered lipidic metabolism and insulin-resistance syndrome-
the use of metformin has become increasingly accepted and
widespread in the treatment of PCOS. Currently, metformin
is used to induce ovulation and during early pregnancy in
PCOS patients, however, a complete knowledge of the metformin
action has not been achieved yet. This review describes beyond
the classical reproductive action of metformin and explores
other benefits of the drug. In addition, the present work
discusses the molecular mechanisms involved further than the
classical pathway that involves the AMP-activated protein
kinase.
[Back to top]
[Purchase
Article] [PMID:
19754382 PubMed - indexed for MEDLINE]
The Oxidative Stress Menace to Coronary Vasculature: Any Place
for Antioxidants?
A. Briasoulis, D. Tousoulis, C. Antoniades
and C. Stefanadis
Oxidative stress is involved in the pathogenesis of atherosclerosis.
A variety of antioxidants has been used in clinical studies,
during the past few years, for the prevention and treatment
of atherosclerosis. In small clinical studies it was found
that both vitamins C and E may improve endothelial function
in high risk patients. However, interventional trials have
been controversial, with some positive findings, many null
findings, and some suggestion of harm in certain high-risk
populations. Therefore, treatment with antioxidant vitamins
C and E should not be recommended for the prevention or treatment
of coronary atherosclerosis. New antioxidant strategies are
needed to clarify the exact role of antioxidant treatment
in coronary atherosclerosis.
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