Tài liệu OXIDATIVE STRESS AND DISEASES pptx

OXIDATIVE STRESS
AND DISEASES
Edited by Volodymyr Lushchak
and Dmytro V. Gospodaryov

OXIDATIVE STRESS
AND DISEASES

Edited by Volodymyr Lushchak
and Dmytro V. Gospodaryov











Oxidative Stress and Diseases
Edited by Volodymyr Lushchak and Dmytro V. Gospodaryov


Published by InTech
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First published April, 2012
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Oxidative Stress and Diseases, Edited by Volodymyr Lushchak and Dmytro V. Gospodaryov

p. cm.
ISBN 978-953-51-0552-7







Contents

Preface IX
Section 1 Introduction 1
Chapter 1 Introductory Chapter 3
Volodymyr I. Lushchak and Dmytro V. Gospodaryov
Section 2 General Aspects 11
Chapter 2 Oxidative Stress:
Cause and Consequence of Diseases 13
Dmytro Gospodaryov and Volodymyr Lushchak
Section 3 Cardiovascular Diseases 39
Chapter 3 Reactive Oxygen Species and Cardiovascular Diseases 41
Vitor Engrácia Valenti, Luiz Carlos de Abreu,
Celso Ferreira and Paulo H. N. Saldiva
Chapter 4 Oxidative Stress in the Carotid Body:
Implications for the Cardioventilatory
Alterations Induced by Obstructive Sleep Apnea 71
Rodrigo Iturriaga and Rodrigo Del Rio
Chapter 5 Adipocytokines, Oxidative Stress
and Impaired Cardiovascular Functions 87
Ana Bertha Zavalza Gómez, María Cristina Islas Carbajal

and Ana Rosa Rincón Sánchez
Chapter 6 Role of Oxidized Lipids in Atherosclerosis 119
Mahdi Garelnabi, Srikanth Kakumanu

and Dmitry Litvinov
Chapter 7 Oxidative Damage in Cardiac Tissue from Normotensive
and Spontaneously Hypertensive Rats: Effect of Ageing 141
Juliana C. Fantinelli, Claudia Caldiz,
María Cecilia Álvarez, Carolina D. Garciarena,
Gladys E. Chiappe de Cingolani and Susana M. Mosca
VI Contents

Chapter 8 Oxidative Stress and Mitochondrial
Dysfunction in Cardiovascular Diseases 157
Sauri Hernández-Reséndiz, Mabel Buelna-Chontal,
Francisco Correa and Cecilia Zazueta
Chapter 9 Oxidatively Modified Biomolecules:
An Early Biomarker for Acute Coronary Artery Disease 189
Sarawut Kumphune
Section 4 Diabetes Mellitus 215
Chapter 10 Oxidative Stress in Diabetes Mellitus:
Is There a Role for Hypoglycemic
Drugs and/or Antioxidants? 217
Omotayo O. Erejuwa
Chapter 11 Oxidative Stress and Novel Antioxidant
Approaches to Reduce Diabetic Complications 247
Sih Min Tan, Arpeeta Sharma and Judy B. de Haan
Chapter 12 Evaluation of Oxidative Stress and the Efficacy
of Antioxidant Treatment in Diabetes Mellitus 281
Nemes-Nagy Enikő, V. Balogh-Sămărghiţan, Elena Cristina Crăciun,

R. Morar, Dana Liana Pusta, Fazakas Zita, Szőcs-Molnár Terézia,
Dunca Iulia, Sánta Dóra and Minodora Dobreanu
Chapter 13 Diabetes, Oxidative Stress,
Antioxidants and Saliva: A Review 303
Natheer H. Al-Rawi
Section 5 Systemic, Neuronal and Hormonal Pathologies 311
Chapter 14 The Role of Oxidative Stress
in Female Reproduction and Pregnancy 313
Levente Lázár
Chapter 15 Effects of Oxidative Stress on
the Electrophysiological Function
of Neuronal Membranes 337
Zorica Jovanović
Chapter 16 Circulating Advanced Oxidation Protein Products,
Nε-(Carboxymethyl) Lysine and Pro-Inflammatory
Cytokines in Patients with Liver Cirrhosis:
Correlations with Clinical Parameters 359
Jolanta Zuwala-Jagiello, Eugenia Murawska-Cialowicz
and Monika Pazgan-Simon
Contents VII

Chapter 17 Oxidative Stress in Parkinson’s Disease;
Parallels Between Current Animal Models,
Human Studies and Cells 387
Anwar Norazit, George Mellick and Adrian C. B. Meedeniya
Chapter 18 The Relationship Between Thyroid States,
Oxidative Stress and Cellular Damage 413
Cano-Europa, Blas-Valdivia Vanessa,
Franco-Colin Margarita and Ortiz-Butron Rocio
Chapter 19 Oxidative Stress in Human Autoimmune Joint Diseases 437

Martina Škurlová
Chapter 20 Oxidative Stress in Multiple Organ Damage
in Hypertension, Diabetes and CKD,
Mechanisms and New Therapeutic Possibilities 457
Tatsuo Shimosawa, Tomoyo Kaneko, Xu Qingyou,
Yusei Miyamoto, Mu Shengyu, Hong Wang, Sayoko Ogura,
Rika Jimbo, Bohumil Majtan, Yuzaburo Uetake,
Daigoro Hirohama, Fumiko Kawakami-Mori,
Toshiro Fujita and Yutaka Yatomi
Chapter 21 Retinal Vein Occlusion Induced by a MEK Inhibitor – Impact
of Oxidative Stress on the Blood-Retinal Barrier 469
Amy H. Yang and Wenhu Huang
Section 6 Cancer 495
Chapter 22 Oxidative Therapy Against Cancer 497
Manuel de Miguel and Mario D. Cordero
Chapter 23 Monensin Induced Oxidative Stress Reduces Prostate
Cancer Cell Migration and Cancer Stem Cell Population 521
Kirsi Ketola, Anu Vuoristo, Matej Orešič,
Olli Kallioniemi and Kristiina Iljin
Section 7 Antioxidants as Therapeutics 541
Chapter 24 Compounds with Antioxidant Capacity as Potential
Tools Against Several Oxidative Stress Related Disorders:
Fact or Artifact? 543
P. Pérez-Matute, A.B. Crujeiras,
M. Fernández-Galilea

and P. Prieto-Hontoria
Chapter 25 Microalgae of the Chlorophyceae Class:
Potential Nutraceuticals Reducing Oxidative
Stress Intensity and Cellular Damage 581

Blas-Valdivia Vanessa, Ortiz-Butron Rocio,
Rodriguez-Sanchez Ruth, Torres-Manzo Paola,
Hernandez-Garcia Adelaida and Cano-Europa Edgar







Preface

The increased level of reactive oxygen species (ROS) in living organisms over 60 years
ago was implicated in the development of diseases and aging (Harman, 1956; 1983).
This book is a collective scientific monograph presenting several important aspects
related to ROS role in human and animal pathologies. In 1985, German scientist
Helmut Sies first denoted oxidative stress concept, which immediately attracted
attention of researchers in diverse basic fields. Several discoveries substantially
stimulated the interest to ROS as ones related to many diseases. They were
descriptions of catalytic function of superoxide dismutase (erythrocuprein or
hemocuprein) by McCord and Fridovich (1969) and role of superoxide anion in host
defense against pathogens (Babior et al., 1973; McCord, 1974). The knowledge on ROS
roles in diverse biological processes in living organisms was summarized in an
excellent book by Halliwell and Gutteridge (1999). An obvious question arises during
the accumulation of data on the ROS involvement in diseases: is oxidative stress their
reason or consequence? In most cases, we cannot directly answer the question, but it is
absolutely clear that reactive species accompany many pathologies. And even more –
in some cases antioxidants were able to attenuate the symptoms, but in most cases the
expectations on antioxidants as a panacea for many diseases was not confirmed what
finally led to understanding that suppression of free radical processes also may have

negative consequences for the organisms. In 1980, Arthur Hailey described the miracle
drug saving many lives in a novel “Strong Medicine”. That was a rather efficient
antioxidant, but side effects were related to suppression of immune system and
weakening defense against infections, the effects well known now. More and more
recent data reflect the situation that ROS are involved in many living processes, and
organisms delicately control their levels. The question on low specificity of ROS effects
has also been clarified to some extent. Really, being chemically highly reactive, the
processes with ROS participation are determined first of all by their species and forms,
temporary-spatial generation and elimination, presence of available sensors and
targets. So we are really dealing with a complicated net that is an integral part of living
organisms and is usually under strict control, but if not properly controlled may result
in injuries of diverse nature. Our understanding of ROS role in biological systems has
evolved from recognizing of them as clearly damaging side-products of cellular
metabolism changing normal physiological processes, through appreciation of their
X Preface

roles as critically important elements of host defense against pathogens, to recognition
of their role as regulators of many physiological processes.
On December 16, 2011, a Google Scholar search for “oxidative stress” and “disease”
yielded about 1,430,000 publication hits, whereas in Scopus and Pubmed databases it
yielded 135,381 and 94,195 hits, respectively. Enormous interest to the ROS roles has
been indirectly confirmed by the project by InTech Publisher, with the book on
oxidative stress. We initially planned to publish one book, but when the project was
started, more than 90 propositions were received. Therefore, recognizing the
popularity of the field and interest of many scientists to share their knowledge with a
broad auditory, we decided to divide the propositions and publish three books.
The Introduction section (V. I. Lushchak & D.V. Gospodaryov), that briefly covers the
general aspects of oxidative stress theory, shows the potential cellular targets for ROS
attacks, and via understanding of key aspects along with the details of ROS roles in
biological systems, describes potential benefits from this understanding and its use to

prevent or cure certain diseases. The detailed knowledge of the mechanisms with
participation of reactive species may provide interesting targets for general and
directed therapy or prophylactics of many diseases.
The book is divided into six sections. The first section, entitled “General Aspects” is
the smallest one and contains only one chapter “Oxidative stress: cause and
consequence of diseases” by D. V. Gospodaryov & V. I. Lushchak, It provides the
readers with information on genetic polymorphism or deficiency of antioxidant and
related enzymes which, not always, but in some cases may realize predisposition to
develop certain pathologies. The enzymes analyzed in this chapter include antioxidant
and associated ones such as glucose-6-phosphate dehydrogenase, catalase, cytosolic
(Cu,Zn-containing), mitochondrial (Mn-containing) and extracellular superoxide
dismutases, glutathione peroxidase, reparation and detoxification enzymes 8-hydroxy-
2′-deoxyguanosine glycosylase, glutathione-S-transferases, etc. The last parts of the
chapter are devoted to model organisms used to reveal the role of oxidative
modifications of antioxidant and related enzymes in disease progression and model
organisms, such as mice, fish, fruit flies, nematodes, plants, cell cultures, budding
yeast, or even bacteria, broadly used to study different aspects concerning
relationships between oxidative stress and diseases.
Cardiovascular diseases (CVD) are the number one killer in developed countries.
Therefore, the second part of the book, entitled “Cardiovascular Diseases” and
containing seven chapters, is supposed to disclose the relationships between ROS and
these pathologies. The first chapter of this section “Reactive Oxygen Species and
Cardiovascular Diseases” by V. E. Valenti describes animal models to study ROS-
induced cardiovascular diseases, sources of ROS in cells with particular interest to
heart, oxidative damage to vessels and kidney and is finalized by the role of nervous
system in ROS-induced CVD. R. Iturriaga and R. Del Rio cover the role of carotid body
in cardioventilatory alterations induced by obstructive sleep apnea. The factors of risk
Preface XI

of CVD, including metabolic complications of obesity, frequently referred as a

metabolic syndrome, and diabetes are connected with adipocytokine homeostasis and
may lead to cardiovascular pathologies, are covered in the chapter authored by A. B.
Z. Gómez et al. The team from the USA, M. Garelnabi, S. Kakumanu, and D. Litvinov,
demonstrates the role of oxidized lipids in development of atherosclerosis, one of the
most common CVDs. There is no doubt that animal models may help to identify key
aspects of disease development, and therefore the chapter by J. C. Fantinelli et al.
clearly shows some peculiarities of oxidative damage to cardiac tissue in normotensive
and spontaneously hypertensive rats, with substantial attention to aging, which is one
of the risk factors of CVD. Mitochondria are well known to be the main cellular ROS
source and physiological processes in this organella are tightly related to ROS
production, elimination, and their involvement in apoptosis and necrosis in
connection with CVD, which is highlighted by S. Hernández-Reséndiz et al. Early
diagnostics of CVD is the key to successful and proper treatment, and their
identification is a very attractive aspect of all studies in the field. S. Kumphune
compares different products of oxidative modification of biomolecules such as lipids,
proteins and nucleic acids with the focus on ones related to CVD to some extent.
In the next section, entitled “Diabetes Mellitus”, we present different aspects of
relationships between diabetes and ROS. In most cases, diabetes is not a directly
damaging fast killer, but affects patients via diverse complications such as
cardiovascular, nephrological and neurological diseases, etc. O. O. Erejuwa from
Malaysia systematically describes the relationships between operation of ROS
generation and elimination systems, development of oxidative stress and diabetes
mellitus. That led the author to the conclusion that if antioxidants alone may not be
useful to reduce diabetes-induced damages to cellular components, they may be
efficient when combined with hypoglicemic drugs. However, even then they cannot
prevent the development of certain diabetic complications. S. M. Tan et al. extend the
previous chapter underlining that antioxidants may reduce diabetic complications
such as diabetes-associated atherosclerosis, cardiomyopathy, nephropathy with the
use of endogenic and externally added antioxidants like ebselen (mimetic of
glutathione peroxidase), different mimetics of superoxide dismutase, inhibitors of

NADPH oxidase, mitochondrially-targeted antioxidants and augmentation, enhancers
of activities of antioxidant enzymes via activation of transcription factor Nrf2. Since it
is widely believed that antioxidants may reduce diabetes-induced damage to
organisms, one more chapter, written by N N. Enikő, presents data on effectiveness of
antioxidants, especially of natural origin from fruits and vegetables, in treatment of
diabetes and its complications. This book section is finalized by the chapter of N. H.
Al-Rawi, describing a rather unusual approach to evaluate certain saliva parameters
for diagnostics of diabetes.
The section “Systemic, Neuronal and Hormonal Pathologies” includes chapters related
to relationship between ROS metabolism and diverse systems. The section is opened
by the L. Lázár review on the role of oxidative stress in female reproduction and
XII Preface

pregnancy, where the author highlights the information on the ROS role in normal and
pathological pregnancies, embryo and fetal malformation, pregnancy-related
pathologies and potential of supplementation with antioxidants. An experimental
work presented by Z. Jovanović describes the effects of oxidants, cumene
hydroperoxide and hydrogen peroxide on electrophysiological parameters such as
spontaneous spike potential and Ca
2+
-activated K
+
current in leech Retzius nerve cells
and clearly demonstrates the regulatory ROS role and potential benefits of glutathione
in maintaining of cell functions, which can be used to understand fundamental
pathogenic mechanisms in the mammalian brain during normal aging, as well as in
neurodegenerative diseases such as Alzheimer's and Parkinson's. The Polish team led
by J. Zuwala-Jagiello presents an experimental material on circulation of advanced
oxidation protein products, Nε-(carboxymethyl) lysine and pro-inflammatory
cytokines in patients with liver cirrhosis and postulate that the advanced oxidation

protein products such as modified albumin can be used as a marker of oxidative stress
in healthy people and liver cirrhosis patients. The relationship between oxidative
stress and neurodegenerative diseases attracted the attention of not only basic
scientists, but also clinicians, and the chapter written by A. Norazit et al. provides
readers with the information on this aspect in the case of Parkinson’s disease and
compares the model studies with cell cultures, experimental animal models and
humans. E. Cano-Europa wt al. describe the operation of the system of thyroid
hormones under normal conditions, at hypo- and hyperthyroidism in detail, followed
by the relationship between alterations of thyroid hormone status and ROS-steady
state levels, with special interest to the role of glutathione in operation of the system.
M. Škurlová presents interesting materials on the ROS role in functioning of joints and
after general introduction discloses potential ROS roles in the development of human
autoimmune joint diseases, particularly rheumatoid arthritis and systemic lupus
erythematosus, which was logically finalized by the question if antioxidants can be
beneficial at autoimmune joint diseases. T. Shimosawa et al. logically state that
supplementation with vitamins C and E, either alone or in combination with each
other or with other antioxidant vitamins, does not appear to be efficient in treatment of
cardiovascular diseases and they therefore investigated a role of oxidative stress in
consequences of multiple organ damages in mice and possible new therapeutic agents
such as adrenomedullin (a 52-amino-acid peptide), platinum nanoparticles and
bardoxolone methyl. A. H. Yang and W. Huang nicely cover a topic connected to the
operation of our eyes and its relationship with ROS. They described the functioning of
blood-retinal barrier in detail, how it is impacted by ROS and retinal vein occlusion
induced by the inhibitor of a mitogen-activated protein kinase kinase.
The section entitled “Cancer” consists of only two chapters, what does not reflect an
enormous attention of basic and clinic scientists to the problem. This attention to the
problem is related to clearly enhanced level of ROS in transformed cells due to which
antioxidants are expected to be beneficial in this case (Steinbrenner & Sies, 2009).
Probably, survival of cancer cells possessing higher steady-state ROS levels than
normal cells is provided by efficient antioxidant systems. At least two approaches may

Preface XIII

be used to kill cancer cells – increase in ROS steady-state levels and the use of
antioxidants to prevent progression of diseases, which is covered by M. de Miguel and
M. D. Cordero in their chapter on oxidative therapy against cancer. The authors
describe the use of amitriptyline, a commonly prescribed tricyclic antidepressant drug
that is well known to death investigators, forensic pathologists, and toxicologists, but
in cancer cases it causes mitochondrial dysfunction, increasing mitochondrial ROS
production. An experimental chapter submitted by a Finnish group led by K. Ketola
clearly shows that monensin, an ionophore related to the crown ethers, induces
oxidative stress and reduces prostate cancer cell migration and cancer stem cell
population probably via decrease of NF-κB pathway activity.
The final section, “Antioxidants as Therapeutics” includes two chapters devoted to
analysis of potential benefits of antioxidants. Immediately after the discovery of free
radicals in biological systems and their harmful effects, it was logically predicted that
antioxidants could be beneficial to health protecting cellular structures against ROS-
induced modifications. However, the problem was not so straightforward – in many
cases antioxidants were found to be non-effective, and in some cases they were even
harmful. The issue is described in detail by P. Pérez-Matute et al. They list diets
containing antioxidants with recognized benefits to health, but further show that not
everything with antioxidants is positive and provide examples of side effects of
antioxidants, their neutral or even deleterious effects and propose some explanations.
V. Blas-Valdivia and colleagues provide the information on health benefits of diverse
nutraceuticals such as polyphenols, terpenes, chlorophylls, polyunsaturated fatty acids
and vitamins, and other vitamins with the focus on the micro-algal sources of these
compounds. The Chlorophyceae class is rich in these nutraceuticals and genus
Chlorella, Chlamydomonas, Haematococcus, and Dunaliella are extensively studied
from this point of view.
The book is expected to be interesting to researchers in the field of basic investigations
interested in the involvement of reactive oxygen species and oxidative stress in diverse

pathologies, medical scientists and practical physicians wishing to perform first of all
prophilactics and further cure different pathologies.

Prof. Dr. Volodymyr I. Lushchak
PhD, DSc, Department of Biochemistry and Biotechnology,
Vassyl Stefanyk Precarpathian National University, Ivano-Frankivsk,
Ukraine
Dr. Dmytro V. Gospodaryov
Senior Research Fellow, Ph.D., Department of Biochemistry,
Vassyl Stefanyk Precarpathian National University, Postdoctoral Fellow,
Institute of Biomedical Technology, University of Tampere, Tampere,
Finland

Section 1
Introduction

1
Introductory Chapter
Volodymyr I. Lushchak and Dmytro V. Gospodaryov
Precarpathian National University, Ivano-Frankivsk,
Ukraine
1. Introduction
The term “oxidative stress” was first defined by Helmut Sies (1985) as “Oxidative stress”
came to denote a disturbance in the prooxidant-antioxidant balance in favor of the former”.
In order to reflect the findings of last 25 years in the field, such as plural ROS roles and
dynamics of their levels we recently proposed one more definition such as “Oxidative stress
is a situation when steady-state ROS concentration is transiently or chronically enhanced,
disturbing cellular metabolism and its regulation and damaging cellular constituents”
(Lushchak, 2011b). Understanding of mechanisms of reactive oxygen species (ROS)
formation and operation of the systems responsible for ROS elimination were necessary

prerequisites for such formulation. Fenton reaction, enzymatic systems like cytochromes
P450, xanthine oxidase or respiratory chains were identified as ROS producers. Studies on
catalase and peroxidase since the beginning of 20
th
century (Loew, 1900; Popov &
Zvyagilskaya, 2007), and discovery of superoxide dismutase by McCord and Fridovich
(1969), lead to suggestion, that cells have specialized systems for conversion of ROS to less
reactive compounds. After introduction, the term “oxidative stress” has been accreting with
medical issues. Today, one could find in literature connection of oxidative stress to almost
all of well-known diseases. The most important of them are cardiovascular and
neurodegenerative ones, diabetes, cancer, viral and bacterial infections, taking millions of
lives every year.
In the simplest case, pathology originates from the perturbations in either reactive species
formation, their elimination or in both simultaneously. Many of real situations are much
more complicated, that is difficult to determine the crucial event for disease origin. In some
cases, gene mutations can be responsible for the imbalance in ROS metabolism. In other
ones, a range of environmental influences would produce metabolic changes. Antioxidant
therapy seems to be useful in both cases. It is often important to know, if oxidative stress
was a primary event leading to the disease or it was developed during the disease.
Diseases caused by gene polymorphism are curable hard, and here only really emerging
gene therapy could be the best solution. In addition, environment can be changed easier. We
need to understand how environmental changes may induce oxidative stress and perturb
redox processes. This field is rather broad. Food toxins or even some of usual meals
supposed to be safe, cigarette smoke or polluted air, car exhaust fumes or pesticides can be
prerequisites for enhanced oxidant formation or impairment in antioxidant defence system.

Oxidative Stress and Diseases

4
Evidences for connection of oxidative stress with the stresses induced by other factors are

promptly gained. The potency of transition metals, some herbicides and carbohydrates to
promote oxidative stress was recently showed (Lushchak et al., 2009a; Lushchak et al.,
2009b; Lushchak, 2011; Semchyshyn et al., 2011). The same thing is concerned to many
physical factors like heat, sound or ionizing irradiations. After all, inflammation induced by
traumatic event or pathogenic agent like viral, bacterial or protist infections can result in
oxidative stress. Disturbances in ROS metabolism, caused by multiple external factors or by
DNA mutations, lead, eventually, to progressive tissue damage and subsequent
degeneration.
Identification of specific targets for ROS is one more thing important for the development of
appropriate therapy. Moreover, place of ROS formation and their targets determine often
particular connection with certain pathology. Proteins, nucleic acids and lipids are the most
critical targets for ROS and their derivatives. Important enzymes, standing on crossroads of
metabolic pathways, are frequently inactivated at excessive ROS formation not
counterbalanced by antioxidants. Glyceraldehyde-3-phosphate dehydrogenase, aconitase,
glucose-6-phosphate dehydrogenase and superoxide dismutase are the most studied
examples (Bagnyukova et al., 2005; Lushchak, 2007; Grant, 2008; Di Domenico et al., 2010;
Avery, 2011). The list is indeed much longer including representatives for almost all
metabolic pathways in different tissues, as well as ion transporters (Unlap et al., 2002),
receptors (Anzai et al., 2000), and other proteins. Polyunsaturated fatty acid residues of
diverse lipids are mainly subjected to oxidation by ROS in this class of compounds. Protein
oxidation results in formation of carbonylated or glutathionylated derivates, whilst non-
enzymatic lipid oxidation yields 4-hydroxy-2-nonenal, isoprostanes, malondialdehyde and
diene conjugates (Hermes-Lima, 2004b). Reactive species, particularly hydroxyl radical, are
also involved in carbohydrate oxidation, what is especially harmful for nucleic acid pentose
backbones (Gutteridge & Halliwell, 1988; Hermes-Lima, 2004b). Nucleotides are not any
exception. Mutagenesis resulted from guanosine oxidation is widely described (reviewed in
Hermes-Lima, 2004b). Cells may possess even special receptors for some products of
oxidation, e.g. receptors for F
2
-isoprostanes and advanced glycation end products

(Fukunaga et al., 1997) or scavenger receptors for oxidized low-density lipoproteins (Ashraf
& Gupta, 2011). Increase in ROS production was found to be also regulated via specific
receptors (Thannickal & Fanburg, 2000). Production of ROS driven by transforming growth
factor-β1, by receptors for endothelial or platelet-derived growth factors, as well as for
angiotensin II or advanced glycation end-products (Thannickal & Fanburg, 2000) are among
the most discussed examples. These facts suggest robust cellular control for ROS
metabolism.
Oxidized derivatives of proteins and lipids may also damage other molecules exacerbating
consequences of oxidative stress. For instance, 4-hydroxy-2-nonenal was shown to modify
proteins through the interaction with amino group of lysine, cysteine or histidine residues.
That results in the formation of Michael adducts. The formed adducts can impair
considerable number of metabolically important proteins like transporters of glucose and
glutamate, GTP-binding proteins, ion-motive ATPases and so forth (reviewed in (Mattson,
2009)). Ability to initiate protein carbonylation was also demonstrated for MDA (Burcham &
Kuhan, 1996).

Introductory Chapter

5
Nowadays, the knowledge about important signalling role for some ROS has gained in
addition to their known deleterious roles (Thannickal & Fanburg, 2000; Dröge, 2002). It is
known that ROS, namely hydrogen peroxide, can regulate c-Jun N-terminal kinase pathway,
apoptosis initiation, tumour suppression by means of p53, ion channels and G-protein-
coupled receptors (Thannickal & Fanburg, 2000; Dröge, 2002; Ushio-Fukai, 2009).
The term “reactive oxygen species” has itself seems become insufficient. It would be difficult
to speak today about oxidant metabolism considering only ROS. In many contemporary
studies, ROS are examined along with reactive nitrogen species (RNS), reactive carbon
species (RCS), reactive chlorine species (RChS), and reactive sulphur species (RSS) (Hermes-
Lima, 2004b; Ferreri et al., 2005). Formation for most of them is driven by specialized
systems and is finely controlled (Dröge, 2002). It suggests a bunch of important roles for

these highly reactive molecules. Some of these roles may even not be discovered. More and
more interactions between ROS, RNS, RCS and RSS are found from study to study. The
formation of peroxinitrite, a powerful oxidant and RNS, in reaction between nitric oxide and
superoxide anion radical is a commonly known example in this case. Similarly, thiyl
radicals, which are considered to be RSS, can be formed under the interaction of peroxyl or
hydroxyl radical with thiol-containing compounds (Ferreri et al., 2005). Thus, once the
formation of ROS has overwhelmed cellular detoxifying capacity, there is a big potential for
generation of other highly reactive molecules with different properties and targets.
Ischemia, atherosclerosis, stroke and different types of inflammation were, probably, the
first recognized pathological states closely connected with oxidative stress. The strong
association between ROS and pathological states were disclosed here. At all these states,
probability of ROS formation is much higher than in normal physiological state. For
instance, mitochondria of ischemic cells increase the steady-state level of electrons which
may escape electron carriers under reperfusion leading to one-electron reduction of oxygen
(Hermes-Lima, 2004a). During inflammatory processes, ROS are produced purposely by
NADPH oxidases (Lassègue & Griendling, 2010). In both these cases ROS seem to
accompany disease flow, but are not the cause. A relation between oxidative stress and
commonly known neurodegenerative disorders and diabetes was also found. These diseases
are believed to be caused by ROS. It is known that alloxan, a compound broadly used for
experimental diabetes induction, is a redox-cycling compound damaging insulin-producing
pancreatic -cells (Lenzen, 2008). Alzheimer’s and Parkinson’s diseases are connected with
impairment of mitochondrial function resulting in enhanced ROS generation (Henchcliffe &
Beal, 2008). The key proteins composing protein aggregates in Parkinson’s and Alzheimer’s
diseases, -synuclein and β-amyloid, respectively, were found to be capable to produce ROS
themselves (Atwood et al., 2003; Wang et al., 2010). Diabetic complications are found to be
induced by the formation of advanced glycation end products which interact with
specialized receptors and promote ROS production (Forbes et al., 2008).
The term “human disease” has been defined as a condition worsening usual human being
and working capacity, and in some cases leading to death. Illness state is also a disorder of
homeostasis connected with impairment of important parts of either whole organism, or

specific proteins, whole cells, and even whole tissues and organs. In this context, ROS role as
damaging agents would seem to be evident in disease origin. Despite that ROS in many

Oxidative Stress and Diseases

6
works are described in their halo of harmfulness, especially in concern with diseases, there
is also a complementary view on beneficial role of ROS in adaptation to stress (Ristow &
Schmeisser, 2011; Lushchak, 2011a). Protein oxidation may also not always be harmful.
Particularly, reversible oxidation of some key enzymes may respond to metabolic
reorganization promoting to some extent cell adaptation to enhanced ROS production
(Grant, 2008). Even protein carbonylation may have signalling role in vascular system
(Wong et al., 2010) and in some examples activates proteins (Lee & Helmann, 2006). These
findings should also be taken into account at analysis of association between oxidative stress
and particular diseases. Participation of ROS in signaling, their roles in regulation of
apoptosis and cell adaptation significantly complicate our view on them as a cause of
diseases. Consequently, the view on oxidative stress should also be altered. Now, it is
emerging impression that oxidative stress is not only the state when oxidation prevails. It is
more resemble to the state of disturbance redox control mechanisms when “harmful” and
undesirable for cell survival oxidation is prevailing, and physiological functions of ROS are
altered or reprogrammed to promot cell death (Jones, 2006). Using this approach, one can
suggest that cell death may result not only from several dozens of oxidized proteins and
lipids. If we would not have any oxidation events, disturbance of physiological ROS
metabolism might turn several dozens of processes in wrong direction. It may have more
systemic effects, spread on whole organism, rather than causing cell death in particular
tissue.
In the current book, the most topical issues of connection between oxidative stress and
broadly known pathologies are examined. They include presumably cardiovascular
diseases, hypertension and diabetes. Some attention is paid to well-known neurological
diseases and cancer. Issues like reproduction, immunity, hormonal disorders are also

affected. Some chapters are devoted to discussion on antioxidant therapy, though
antioxidant clue goes through all other chapters as well. It is worth noting, knowledge
highlighted in this book is collected all over the world. It implies the topic is long ago out of
particular laboratories and elaborated by medical scientists in many countries. In some
points concerns of the authors coincide, in other ones they are unique. Thus, the book
mirrors many different aspects of pathological roles of ROS. We did not aim to make it
comprehensive as much as possible. It is rather impossible taking into account that oxidative
stress today has many faces. If someone would like to get specific knowledge on this topic
from the beginning, the best advice would be to choose firstly the branch among
incomprehensive canopy of oxidative stress studies. The book aimed to show how the field
is studied in different countries and what is common for all investigations.
The connection between oxidative stress and diseases is mentioned in introduction of almost
every article in the field. However, there is a difference between in vitro studies, studies on
cell cultures, laboratory animals and clinical studies with humans. The last ones are most
complicated for perception, but they provide a picture of reality. In this context, it is a
pleasure to realize that some of the authors of this book are physicians whose studies are
conducted on patients. The results from these studies are always more difficult for
interpretation than those from model experiments carried out at cultivated cells.
Nevertheless, clinical studies are highly complicated for understanding of ROS contribution
in illness state. Once the implication of ROS in particular disease found, it suggests

Introductory Chapter

7
possibility of antioxidant therapy. However, how it is mentioned in one of the chapters,
under some conditions antioxidants may act also as pro-oxidants. Following redox pioneers,
John Gutteridge and Barry Halliwell, here one could say “pro-oxidants can be better for you
in some circumstances” (Gutteridge & Halliwell, 2010). Moreover, modulation of signalling
pathways linked with ROS may be more effective than simple antioxidant therapy. Most of
known antioxidants can act also as signalling molecules, but there are also many

compounds important for signaling that are not antioxidants. Other crucial thing is
prophylactics. Cardiovascular diseases, diabetes, obesity, metabolic syndrome, neurological
and hormonal disorders, impairment in kidney and liver functioning, mentioned in the
book and described in terms of free radical biology, are not always strictly genetically
conditioned. They are lifestyle and life condition pathologies often with onset in late age. So,
they can be prevented. It is, probably, the most important conclusion that can be drawn
from the generalized data. Even genetically caused pathologies could be attenuated by
wisely arranged prophylactics if the defect is not too serious. That is also the reason for the
accumulation, generalization and systematization knowledge obtained at different levels,
with different models and clinical studies. We hope that this book will disclose, at least
partially, the state of the problem worldwide and the current directions of laboratories
focused on studies for implication of ROS in different pathologies. We also believe that it
will help researchers to find weak places in current understanding and advise them quite
novel and non-standard approaches to find and decipher mechanisms of diseases.
Finally, we would like to thank all authors for their contributions and hard work to match
and unify the “philosophy” of this book. We also thank to our colleagues from
Precarpathian National University and University of Tampere who supported us and
helped us in preparation and edition of the chapters, especially to those who raised complex
questions and promoted us to answer them. We are also grateful to the “In-Tech” Publisher
personnel, especially Ms. Sasa Leporic, who assisted us in the arrangement of the book and
scheduling our activities.
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Section 2
General Aspects