**Meet the editors**

Dr. Volodymyr I. Lushchak graduated from the Lomonosov Moscow State University (Soviet Union) in 1982. In 1986 he defended his Ph.D. Theisis and in 2002 his D.Sc. Dissertation. He obtained his full professor title in 2004. From 1987 to 1998 he worked in Southern Seas Biology Institute of Academy of Sciences of Ukraine. In 1998 Dr. Lushchak joined Vassyl Stefanyk Precarpathian Nation-

al University in Ivano-Frankivsk,Ukraine) where he currently works as the head of the Department of Biochemistry and Biotechnology. He also worked at Universities of Canada, Brazil, United Kingdom, Finland, Poland, Sweden and Germany. Dr. Lushchak's scientific interests are related to effects of environmental conditions and molecular aspects of adaptive responses in bacteria, fungi, plants and animals. Although interested in general aspects of metabolism regulation, his interests are mainly focused on the homeostasis of reactive species of oxygen, nitrogen and carbon.

Dr. Dmytro V. Gospodaryov graduated from the Chernivtsi National University named after Yuriy Fedkovych (Ukraine) in 2001. In 2005, he defended Ph.D. thesis "Protein And Lipid Oxidation In The Yeast Saccharomyces Cerevisiae And The Role Of Catalases In Its Prevention" supervised by Prof. V. Lushchak. Since 2004, Dmytro Gospodaryov has been working as an Assistant

Professor at Department of Biochemistry and Biotechnology of Stefanyk Precarpathian National University in Ivano-Frankivsk. Dr. Gospodaryov's scientific interests of are related to metabolic conditions which can induce and aggravate oxidative stress (e.g., deficiencies in antioxidant or related enzymes). He is also interested in oxidative stress induced by abnormalities in transition metal metabolism or by influence of high concentrations of transition metals.

Contents

**Preface IX** 

Chapter 1 **Introductory Chapter 3** 

**Section 3 Cardiovascular Diseases 39** 

Chapter 4 **Oxidative Stress in the Carotid Body:** 

Chapter 5 **Adipocytokines, Oxidative Stress** 

and Ana Rosa Rincón Sánchez

**Section 2 General Aspects 11** 

Chapter 2 **Oxidative Stress:** 

Volodymyr I. Lushchak and Dmytro V. Gospodaryov

**Cause and Consequence of Diseases 13**  Dmytro Gospodaryov and Volodymyr Lushchak

**Implications for the Cardioventilatory** 

**and Impaired Cardiovascular Functions 87** 

Chapter 7 **Oxidative Damage in Cardiac Tissue from Normotensive** 

María Cecilia Álvarez, Carolina D. Garciarena,

Gladys E. Chiappe de Cingolani and Susana M. Mosca

Rodrigo Iturriaga and Rodrigo Del Rio

Chapter 6 **Role of Oxidized Lipids in Atherosclerosis 119** 

Juliana C. Fantinelli, Claudia Caldiz,

Chapter 3 **Reactive Oxygen Species and Cardiovascular Diseases 41**  Vitor Engrácia Valenti, Luiz Carlos de Abreu, Celso Ferreira and Paulo H. N. Saldiva

**Alterations Induced by Obstructive Sleep Apnea 71** 

Ana Bertha Zavalza Gómez, María Cristina Islas Carbajal

Mahdi Garelnabi, Srikanth Kakumanu and Dmitry Litvinov

**and Spontaneously Hypertensive Rats: Effect of Ageing 141** 

**Section 1 Introduction 1** 

### Contents

#### **Preface XIII**

#### **Section 1 Introduction 1**


X Contents


Contents VII

Chapter 17 **Oxidative Stress in Parkinson's Disease;** 

**Human Studies and Cells 387** 

Chapter 18 **The Relationship Between Thyroid States,** 

Martina Škurlová

**Section 6 Cancer 495**

Cano-Europa, Blas-Valdivia Vanessa,

Chapter 20 **Oxidative Stress in Multiple Organ Damage in Hypertension, Diabetes and CKD,**

Toshiro Fujita and Yutaka Yatomi

Amy H. Yang and Wenhu Huang

Chapter 22 **Oxidative Therapy Against Cancer 497**

Olli Kallioniemi and Kristiina Iljin

P. Pérez-Matute, A.B. Crujeiras,

Chapter 25 **Microalgae of the Chlorophyceae Class:**

**Section 7 Antioxidants as Therapeutics 541** 

**Fact or Artifact? 543**

Manuel de Miguel and Mario D. Cordero

Kirsi Ketola, Anu Vuoristo, Matej Orešič,

Chapter 24 **Compounds with Antioxidant Capacity as Potential** 

M. Fernández-Galilea and P. Prieto-Hontoria

**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

Chapter 23 **Monensin Induced Oxidative Stress Reduces Prostate** 

**Cancer Cell Migration and Cancer Stem Cell Population 521** 

**Tools Against Several Oxidative Stress Related Disorders:**

**Parallels Between Current Animal Models,**

**Oxidative Stress and Cellular Damage 413** 

Franco-Colin Margarita and Ortiz-Butron Rocio

Rika Jimbo, Bohumil Majtan, Yuzaburo Uetake, Daigoro Hirohama, Fumiko Kawakami-Mori,

Chapter 21 **Retinal Vein Occlusion Induced by a MEK Inhibitor – Impact of Oxidative Stress on the Blood-Retinal Barrier 469** 

Chapter 19 **Oxidative Stress in Human Autoimmune Joint Diseases 437**

**Mechanisms and New Therapeutic Possibilities 457** Tatsuo Shimosawa, Tomoyo Kaneko, Xu Qingyou,

Yusei Miyamoto, Mu Shengyu, Hong Wang, Sayoko Ogura,

Anwar Norazit, George Mellick and Adrian C. B. Meedeniya


VI Contents

Chapter 8 **Oxidative Stress and Mitochondrial**

Chapter 9 **Oxidatively Modified Biomolecules:**

Chapter 10 **Oxidative Stress in Diabetes Mellitus:** 

Chapter 11 **Oxidative Stress and Novel Antioxidant**

Omotayo O. Erejuwa

Chapter 13 **Diabetes, Oxidative Stress,**

Natheer H. Al-Rawi

Chapter 14 **The Role of Oxidative Stress**

Chapter 15 **Effects of Oxidative Stress on** 

Zorica Jovanović

Levente Lázár

**Is There a Role for Hypoglycemic Drugs and/or Antioxidants? 217** 

Chapter 12 **Evaluation of Oxidative Stress and the Efficacy**

Sarawut Kumphune

**Section 4 Diabetes Mellitus 215** 

**Dysfunction in Cardiovascular Diseases 157** Sauri Hernández-Reséndiz, Mabel Buelna-Chontal,

**An Early Biomarker for Acute Coronary Artery Disease 189**

**Approaches to Reduce Diabetic Complications 247**  Sih Min Tan, Arpeeta Sharma and Judy B. de Haan

**of Antioxidant Treatment in Diabetes Mellitus 281** 

Dunca Iulia, Sánta Dóra and Minodora Dobreanu

**Antioxidants and Saliva: A Review 303**

**Section 5 Systemic, Neuronal and Hormonal Pathologies 311** 

**the Electrophysiological Function of Neuronal Membranes 337** 

Chapter 16 **Circulating Advanced Oxidation Protein Products,**

and Monika Pazgan-Simon

**Cytokines in Patients with Liver Cirrhosis: Correlations with Clinical Parameters 359** Jolanta Zuwala-Jagiello, Eugenia Murawska-Cialowicz

**in Female Reproduction and Pregnancy 313** 

**Nε-(Carboxymethyl) Lysine and Pro-Inflammatory** 

Nemes-Nagy Enikő, V. Balogh-Sămărghiţan, Elena Cristina Crăciun, R. Morar, Dana Liana Pusta, Fazakas Zita, Szőcs-Molnár Terézia,

Francisco Correa and Cecilia Zazueta


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

### 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

#### XIV Preface

roles as critically important elements of host defense against pathogens, to recognition of their role as regulators of many physiological processes.

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

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

for diagnostics of diabetes.

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 ROSinduced 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 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.

X Preface

roles as critically important elements of host defense against pathogens, to recognition

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

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

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 ROSinduced 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

of their role as regulators of many physiological processes.

directed therapy or prophylactics of many diseases.

relationships between oxidative stress and diseases.

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 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 Ca2+**-**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.

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

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 ROSinduced 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

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

**Prof. Dr. Volodymyr I. Lushchak** 

**Dr. Dmytro V. Gospodaryov** 

Ukraine

Finland

PhD, DSc, Department of Biochemistry and Biotechnology,

Senior Research Fellow, Ph.D., Department of Biochemistry,

Vassyl Stefanyk Precarpathian National University, Ivano-Frankivsk,

Vassyl Stefanyk Precarpathian National University, Postdoctoral Fellow, Institute of Biomedical Technology, University of Tampere, Tampere,

population probably via decrease of NF-κB pathway activity.

from this point of view.

prophilactics and further cure different pathologies.

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 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.

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 Ca2+**-**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

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 ROSinduced 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** 
