**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. Halyna M. Semchyshyn graduated from the the Yuriy Fedkovych Chernivtsi State University, Ukraine in 1990 with MSc degree in Analytical Chemistry. In 1993 she obtained Doctoral Scholarship at the Department of Biochemistry of Ivano-Frankivsk Medical State Academy (Ukraine). After defending her Ph.D. thesis in 2002, she started working as an Assistant Professor and and as an

Associate Professor at the Department of Biochemistry and Biotechnology of Vassyl Stefanyk Precarpathian University Ivano-Frankivsk, Ukraine. From 2006 to 2011 she worked as a visiting researcher and a visiting professor at the Jagiellonian University, Poland and at the Lund University, Sweden. Her current research is related to dual role of reactive oxygen and carbonyl species, interplay between different kinds of stresses, and organisms' adaptations to environmental challenges.

Contents

**Preface IX** 

Chapter 1 **Introductory Chapter 3** 

Chapter 3 **Oxidative and Nitrosative** 

Chapter 4 **Nitric Oxide Synthase** 

Chapter 6 **Heme Proteins, Heme** 

**and Oxidative Stress:** 

Chapter 5 **Iron, Oxidative Stress and Health 73** 

Chapter 7 **Assessment of the General Oxidant Status** 

**Section 2 General Aspects of Oxidative Stress 13** 

Chapter 2 **Interplay Between Oxidative and Carbonyl** 

**Stresses: Their Role in Health and Disease in Man and Birds 47**  Hillar Klandorf and Knox Van Dyke

Volodymyr I. Lushchak and Halyna M. Semchyshyn

**Stresses: Molecular Mechanisms, Biological** 

**Regulation of Nitric Oxide Synthase 61** 

**Oxygenase-1 and Oxidative Stress 109**  Hiroshi Morimatsu, Toru Takahashi, Hiroko Shimizu, Junya Matsumi, Junko Kosaka and Kiyoshi Morita

**of Individuals in Non-Invasive Samples 125** 

Rafael Ayala, Afrah Ismaiel and Antonio Ayala

Sandro Argüelles, Mercedes Cano, Mario F. Muñoz-Pinto,

Ehab M. M. Ali, Soha M. Hamdy and Tarek M. Mohamed

Shobha Udipi, Padmini Ghugre and Chanda Gokhale

**Effects and Therapeutic Strategies of Protection 15**  Halyna M. Semchyshyn and Volodymyr I. Lushchak

**Section 1 Introduction 1** 

### Contents

#### **Preface XIII**


X Contents


Contents VII

Chapter 17 **Complex Regulatory Interplay Between Multidrug**

Chapter 18 **ROS as Signaling Molecules and Enzymes of Plant** 

Dominika Boguszewska and Barbara Zagdańska

Miguel C. Teixeira

**Resistance and Oxidative Stress Response in Yeast: The** *FLR1* **Regulatory Network as a Systems Biology Case-Study 323** 

**Response to Unfavorable Environmental Conditions 341** 

Chapter 17 **Complex Regulatory Interplay Between Multidrug Resistance and Oxidative Stress Response in Yeast: The** *FLR1* **Regulatory Network as a Systems Biology Case-Study 323**  Miguel C. Teixeira

VI Contents

Chapter 8 **Hydrogen: From a Biologically** 

Chapter 9 **Paraoxonase: A New Biochemical** 

**Section 3 Cellular and Molecular Targets 155** 

Chapter 11 **Effects of Oxidative Stress and Antenatal**

Chapter 10 **Renal Redox Balance and Na<sup>+</sup>**

**Marker of Oxidant-Antioxidant Status in Atherosclerosis 145**

**Inert Gas to a Unique Antioxidant 135** Shulin Liu, Xuejun Sun and Hengyi Tao

Tünay Kontaş Aşkar and Olga Büyükleblebici

Elisabete Silva and Patrício Soares-da-Silva

Chapter 12 **Protection of Mouse Embryonic Stem Cells from** 

Yuanyuan Jia, Yuejin Li, Keith A. Webster, Xupei Huang, Michael Hanna, Mohan P. Achary, Sharon L. Lemanski and Herbert Weissbach

Chapter 13 **Structural and Activity Changes in Renal Betaine** 

**Section 4 Reactive Species as Signaling Molecules 253**

Chapter 15 **Role of the Yap Family in the Transcriptional** 

and M. Esperanza Cerdán

and Elisa M. Valenzuela-Soto

**, K+**

**Regulation: Role in Physiology and Pathophysiology 157** 

**Corticosteroids on the Pulmonary Expression of Vascular Endothelial Growth Factor (VEGF) and Alveolarization 173** 

**Oxidative Stress by Methionine Sulfoxide Reductases 197**

Ana Remesal, Laura San Feliciano and Dolores Ludeña

Larry F. Lemanski, Chi Zhang, Andrei Kochegarov, Ashley Moses, William Lian, Jessica Meyer, Pingping Jia,

**Aldehyde Dehydrogenase Caused by Oxidants 231**  Jesús A. Rosas-Rodríguez, Hilda F. Flores-Mendoza, Ciria G. Figueroa-Soto, Edgar F. Morán-Palacio

Chapter 14 **Signalling Oxidative Stress in** *Saccharomyces cerevisiae* **255** Maria Angeles de la Torre-Ruiz, Luis Serrano, Mima I. Petkova and Nuria Pujol-Carrion

> **Response to Oxidative Stress in Yeasts 277** Christel Goudot, Frédéric Devaux and Gaëlle Lelandais

Ana García Leiro, Silvia Rodríguez Lombardero, Ángel Vizoso Vázquez, M. Isabel González Siso

**upon Enzymatic Activities Related to Oxidative Stress 297** 

Chapter 16 **The Yeast Genes** *ROX1, IXR1, SKY1* **and Their Effect**

**-ATPase** 

Chapter 18 **ROS as Signaling Molecules and Enzymes of Plant Response to Unfavorable Environmental Conditions 341**  Dominika Boguszewska and Barbara Zagdańska

Preface

This book contains some of the scientific contributions that resulted from the research activities undertaken mainly over the last 25 years, in the field of oxidative stress. Being first denoted by Helmut Sies (1985), the oxidative stress concept immediately attracted the attention of researchers in both, basic and applied fields. To a large extent, the formulation of oxidative stress concept resulted from more than three decades of investigations of homeostasis of free radicals in biological systems. It is necessary to underline that, once discovered in biological systems, free radicals were proposed to be related to diverse diseases and aging (Harman, 1956; 1985). Due to that, many efforts were applied to decipher the role of reactive oxygen species (ROS) in diverse biological processes (Halliwell & Gutteridge, 1999). The history of our understanding of ROS-related processes is very interesting. They were at first recognized as clearly damaging side-products of cellular metabolism changing normal physiological processes. It later became clear that they may be produced by specific systems in a highly controlled manner and used to defend organisms against diverse pathogens. Finally, their signaling role was disclosed at the beginning of 1990, initially in coordination of response to oxidative stress, and further involved in hormone

effects in plants and animals (Semchyshyn, 2009; Lushchak, 2011a, b ).

environmental pollution due to human activity.

On December 16, 2011, Google Scholar search for "oxidative stress" yielded about 1,430,000 publication hits, whereas in Scopus and Pubmed databases it yielded 135,381 and 94,195 hits, respectively. When the publishing project presented here was initiated, we suggested to publish one book on Oxidative Stress, but after the project was started we received over 90 propositions and decided to divide the materials into three volumes. Due to the diverse fields presented, it was very difficult to group the chapters in many cases, because the problem of free radicals is very complex. The above reflects enormous interest and intensive research in this field that prompted us to develop this book idea. In addition to interest in basic science, there is also a growing interest in medicine, agriculture and biotechnology. A great number of diseases include oxidative stress as a component, either causing pathologies or accompanying them. Global climate changes also provide additional stress for living organisms affecting them via temperature increase and fluctuations, along with

As stated before, the book contains a collection of diverse scientific areas related to oxidative stress, ranging from purely theoretical works to biomedical or even

### Preface

This book contains some of the scientific contributions that resulted from the research activities undertaken mainly over the last 25 years, in the field of oxidative stress. Being first denoted by Helmut Sies (1985), the oxidative stress concept immediately attracted the attention of researchers in both, basic and applied fields. To a large extent, the formulation of oxidative stress concept resulted from more than three decades of investigations of homeostasis of free radicals in biological systems. It is necessary to underline that, once discovered in biological systems, free radicals were proposed to be related to diverse diseases and aging (Harman, 1956; 1985). Due to that, many efforts were applied to decipher the role of reactive oxygen species (ROS) in diverse biological processes (Halliwell & Gutteridge, 1999). The history of our understanding of ROS-related processes is very interesting. They were at first recognized as clearly damaging side-products of cellular metabolism changing normal physiological processes. It later became clear that they may be produced by specific systems in a highly controlled manner and used to defend organisms against diverse pathogens. Finally, their signaling role was disclosed at the beginning of 1990, initially in coordination of response to oxidative stress, and further involved in hormone effects in plants and animals (Semchyshyn, 2009; Lushchak, 2011a, b ).

On December 16, 2011, Google Scholar search for "oxidative stress" yielded about 1,430,000 publication hits, whereas in Scopus and Pubmed databases it yielded 135,381 and 94,195 hits, respectively. When the publishing project presented here was initiated, we suggested to publish one book on Oxidative Stress, but after the project was started we received over 90 propositions and decided to divide the materials into three volumes. Due to the diverse fields presented, it was very difficult to group the chapters in many cases, because the problem of free radicals is very complex. The above reflects enormous interest and intensive research in this field that prompted us to develop this book idea. In addition to interest in basic science, there is also a growing interest in medicine, agriculture and biotechnology. A great number of diseases include oxidative stress as a component, either causing pathologies or accompanying them. Global climate changes also provide additional stress for living organisms affecting them via temperature increase and fluctuations, along with environmental pollution due to human activity.

As stated before, the book contains a collection of diverse scientific areas related to oxidative stress, ranging from purely theoretical works to biomedical or even environmental. This demonstrates a wide spectrum of interests within the area of ROS research.

Preface XI

aldehyde to glycine betaine – one of the major non-perturbing osmolytes – is in the focus of experimental studies with a special attention of ROS effects on structural and

In the last two decades, the discovery of signaling roles of ROS demonstrated their universal use in biological systems. The third section of this book, entitled "Reactive Species as Signaling Molecules" contains the chapters covering clear ROS-based signaling in yeasts and plants. It is not strange that many authors provide readers with the information gained from yeasts. This is a very popular classic eukaryotic model system to disclose molecular mechanisms of cellular responses to oxidative stress (Lushchak, 2010). In the first chapter of this book section, M. A. de la Torre-Ruiz et al. describe the involvement of ROS signalling via "classic" regulatory systems such as RAS/cAMP and TOR pathways along with specific ones like Yap1 and Skn7. Using power of modern bioinformatics, C. Goudot, F. Devaux and G. Lelandais analyse the operation of probably the most studied system coordinating antioxidant response in the yeast, *Saccharomyces cerevisiae* Yap1 and functional homologues in other yeasts such as *Candida albicans* and *C. glabrata.* The group of authors led by A. G. Leiro highlights the interconnections between the transcriptional regulatory factors Rox1 and Ixr1, as well as the kinase Sky1 on yeast response to oxidative stress caused by different factors, with special attention to antioxidant and related enzymes such as glucose-6-phosphate dehydrogenase, catalase, glutathione reductase and thioredoxin reductase. Since yeasts are very well studied eukaryotic organisms, it allowed M. C. Teixeira again to characterise and compare the complex regulatory interplay between multidrug resistance and oxidative stress response with the key roles of *FLR1* described in *S. cerevisiae*, as a model organism and further extended to pathogenic *C. glabrata* and *C. albicans,* using the bioinformatics tools extensively*.* Although plants are probably the least studied among all phylogenetic groups of living organisms from the point of view of signalling by reactive species (Lushchak, 2011a), D. Boguszewska and B. Zagdańska clearly demonstrate the accumulated knowledge in the regulation of activity of antioxidant and related enzymes

physiological features of the enzyme, provided by J. A. Rosas-Rodríguez et al.

at plant response to unfavourable environmental conditions.

It is expected that this book will be interesting to experts in the field of basic investigations of reactive oxygen species and oxidative stress, as well as to practical users in the diverse fields such as medicine, environmental sciences, and toxicology.

Ph.D. in Biochemistry, Department of Biochemistry, Natural Sciences Institute,

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

**Assoc. Prof. Dr. Halyna Semchyshyn**

Ivano-Frankivsk,

Ukraine

Ukraine

PhD, DSc, Department of Biochemistry and Biotechnology,

Vassyl Stefanyk Precarpathian National University,

Vassyl Stefanyk Precarpathian National University, Ministry of Education and Science of Ukraine,

The book starts with the Introduction section (V. I. Lushchak & H. M. Semchyshyn) that covers general aspects of oxidative stress theory starting from discovery of free radicals in biological systems, their appreciation as damaging ones, through discovery of superoxide dismutase by McCord and Fridovich (1969), to recognizing of their defensive and signaling roles.

The book is divided into three sections. The first section, entitled "General aspects of oxidative stress" provides readers with some common aspects of oxidative stress theory. In this section, H. M. Semchyshyn and V. I. Lushchak describe the relationship between oxidative and carbonyl stresses, taking place at enhanced levels of either reactive oxygen or carbonyl species, with a focus on molecular mechanisms, biological effects and therapeutic strategies of protection. Similarly to previous chapter, H. Klandorf and K. Van Dyke describe the interplay, but in this case between oxidative and nitrosative stresses with some general attention to diseases in humans and birds. The next chapter, authored by E. M. M. Ali and colleagues is logically connected to the previous one, going deeper into the role and involvement of nitric oxide in oxidative stress development with the special attention to regulation of nitric oxide synthase. In the next chapter, S. Udipi and coauthors provide information on the relationship between oxidative stress and iron metabolism, the involvement of iron ions in generation and metabolism of free radicals and their potential roles in diverse pathologies. The Japanese team led by H. Morimatsu provides the most up-to-date knowledge on operation of heme proteins, heme oxygenase and roles of products of heme degradation in the induction of oxidative stress and the defence against it; interesting potential use of exhaled carbon monoxide (CO) for non-invasive evaluation of heme degradation under normal and pathological conditions is also presented. The fundamental question on types and dynamics of oxidative stress biomarkers in noninvasive samples and involvement of oxidative stress in diseases and aging is covered by S. Argüelles and colleagues. The complicated way of our understanding of hydrogen roles in biological systems – from inert gas to unique antioxidant with potential therapeutic use is described by S. Liu et al. The relatively unknown enzyme paraoxonase as a new biochemical marker of prooxidant-antioxidant status in atherosclerosis is described by T. Kontaş Aşkar and O. Büyükleblebici.

The second section of the book, entitled "Cellular and Molecular Targets" is devoted to specific systems and enzymes, which are affected under oxidative stress and possible ways of its induction. The overview written by E. Silva and P. Soares-da-Silva describes in details the structure and operation of renal Na+,K+-ATPase and its direct or non-direct regulation particularly by ROS under normal conditions and pathology. The pulmonary expression of vascular endothelial growth factor (VEGF) and alveolarization under oxidative stress and effects of antenatal corticosteroids are covered by A. Remesal and colleagues. The role of methionine sulfoxide reductases in protection of mouse embryonic stem cells against oxidative stress is highlighted by L. F. Lemanski et al. Betaine aldehyde dehydrogenase catalyzing the oxidation of betaine

aldehyde to glycine betaine – one of the major non-perturbing osmolytes – is in the focus of experimental studies with a special attention of ROS effects on structural and physiological features of the enzyme, provided by J. A. Rosas-Rodríguez et al.

X Preface

research.

defensive and signaling roles.

environmental. This demonstrates a wide spectrum of interests within the area of ROS

The book starts with the Introduction section (V. I. Lushchak & H. M. Semchyshyn) that covers general aspects of oxidative stress theory starting from discovery of free radicals in biological systems, their appreciation as damaging ones, through discovery of superoxide dismutase by McCord and Fridovich (1969), to recognizing of their

The book is divided into three sections. The first section, entitled "General aspects of oxidative stress" provides readers with some common aspects of oxidative stress theory. In this section, H. M. Semchyshyn and V. I. Lushchak describe the relationship between oxidative and carbonyl stresses, taking place at enhanced levels of either reactive oxygen or carbonyl species, with a focus on molecular mechanisms, biological effects and therapeutic strategies of protection. Similarly to previous chapter, H. Klandorf and K. Van Dyke describe the interplay, but in this case between oxidative and nitrosative stresses with some general attention to diseases in humans and birds. The next chapter, authored by E. M. M. Ali and colleagues is logically connected to the previous one, going deeper into the role and involvement of nitric oxide in oxidative stress development with the special attention to regulation of nitric oxide synthase. In the next chapter, S. Udipi and coauthors provide information on the relationship between oxidative stress and iron metabolism, the involvement of iron ions in generation and metabolism of free radicals and their potential roles in diverse pathologies. The Japanese team led by H. Morimatsu provides the most up-to-date knowledge on operation of heme proteins, heme oxygenase and roles of products of heme degradation in the induction of oxidative stress and the defence against it; interesting potential use of exhaled carbon monoxide (CO) for non-invasive evaluation of heme degradation under normal and pathological conditions is also presented. The fundamental question on types and dynamics of oxidative stress biomarkers in noninvasive samples and involvement of oxidative stress in diseases and aging is covered by S. Argüelles and colleagues. The complicated way of our understanding of hydrogen roles in biological systems – from inert gas to unique antioxidant with potential therapeutic use is described by S. Liu et al. The relatively unknown enzyme paraoxonase as a new biochemical marker of prooxidant-antioxidant status in

atherosclerosis is described by T. Kontaş Aşkar and O. Büyükleblebici.

The second section of the book, entitled "Cellular and Molecular Targets" is devoted to specific systems and enzymes, which are affected under oxidative stress and possible ways of its induction. The overview written by E. Silva and P. Soares-da-Silva describes in details the structure and operation of renal Na+,K+-ATPase and its direct or non-direct regulation particularly by ROS under normal conditions and pathology. The pulmonary expression of vascular endothelial growth factor (VEGF) and alveolarization under oxidative stress and effects of antenatal corticosteroids are covered by A. Remesal and colleagues. The role of methionine sulfoxide reductases in protection of mouse embryonic stem cells against oxidative stress is highlighted by L. F. Lemanski et al. Betaine aldehyde dehydrogenase catalyzing the oxidation of betaine

In the last two decades, the discovery of signaling roles of ROS demonstrated their universal use in biological systems. The third section of this book, entitled "Reactive Species as Signaling Molecules" contains the chapters covering clear ROS-based signaling in yeasts and plants. It is not strange that many authors provide readers with the information gained from yeasts. This is a very popular classic eukaryotic model system to disclose molecular mechanisms of cellular responses to oxidative stress (Lushchak, 2010). In the first chapter of this book section, M. A. de la Torre-Ruiz et al. describe the involvement of ROS signalling via "classic" regulatory systems such as RAS/cAMP and TOR pathways along with specific ones like Yap1 and Skn7. Using power of modern bioinformatics, C. Goudot, F. Devaux and G. Lelandais analyse the operation of probably the most studied system coordinating antioxidant response in the yeast, *Saccharomyces cerevisiae* Yap1 and functional homologues in other yeasts such as *Candida albicans* and *C. glabrata.* The group of authors led by A. G. Leiro highlights the interconnections between the transcriptional regulatory factors Rox1 and Ixr1, as well as the kinase Sky1 on yeast response to oxidative stress caused by different factors, with special attention to antioxidant and related enzymes such as glucose-6-phosphate dehydrogenase, catalase, glutathione reductase and thioredoxin reductase. Since yeasts are very well studied eukaryotic organisms, it allowed M. C. Teixeira again to characterise and compare the complex regulatory interplay between multidrug resistance and oxidative stress response with the key roles of *FLR1* described in *S. cerevisiae*, as a model organism and further extended to pathogenic *C. glabrata* and *C. albicans,* using the bioinformatics tools extensively*.* Although plants are probably the least studied among all phylogenetic groups of living organisms from the point of view of signalling by reactive species (Lushchak, 2011a), D. Boguszewska and B. Zagdańska clearly demonstrate the accumulated knowledge in the regulation of activity of antioxidant and related enzymes at plant response to unfavourable environmental conditions.

It is expected that this book will be interesting to experts in the field of basic investigations of reactive oxygen species and oxidative stress, as well as to practical users in the diverse fields such as medicine, environmental sciences, and toxicology.

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

PhD, DSc, Department of Biochemistry and Biotechnology, Vassyl Stefanyk Precarpathian National University, Ivano-Frankivsk, Ukraine

#### **Assoc. Prof. Dr. Halyna Semchyshyn**

Ph.D. in Biochemistry, Department of Biochemistry, Natural Sciences Institute, Vassyl Stefanyk Precarpathian National University, Ministry of Education and Science of Ukraine, Ukraine

**Section 1** 

**Introduction** 
