\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
At present, one of the most urgent topics in science is the creation of aerogels based on reduced graphene oxide. Their high porosity, characterized by low material density and high specific surface area, as well as the ability to conduct electric current attracts the attention of various groups of scientists. The work on the creation of such materials has been conducted for the past 20 years. A number of materials developed during this time and approaches to their production form a serious prospect for the use of these materials as supercapacitors, gas sensors, electric batteries, and actuators. The increased interest in graphene oxide as a precursor of such materials is due to its ability to form stable colloidal dispersions in polar solvents (such as water) and also to transform into a reduced electrically conductive graphene-like form under chemical or thermal treatment. In addition, the ability of such materials to multi-cyclic deformations, flexibility, and elasticity attracts special interest of researchers. The rapid growth of publication activity in this theme in recent years is partly due to the need for the development of portable electronic devices, in particular, energy storage devices that are included in the everyday life of each person. In the development of aerogels based on reduced graphene oxide, the authors are striving to increase the electrical conductivity, the specific surface area, the mechanical strength, elasticity, and durability of these materials. The part of the science effort was aimed at studying the methods of obtaining aerogels from reduced graphene oxide. It has been shown that the main and most effective methods for the formation of superporous ultralight structures are self-gelation of graphene oxide containing systems, hydrothermal-assisted formation of aerogels, cross-linking of a structure, followed by freeze drying or supercritical drying. Each of the described methods has its advantages and disadvantages, which are effectively being used to achieve the target parameters of synthesized materials. To improve the obtained structures and give them new properties, the surface of graphene-like sheets is being modified in various ways: various polymeric materials are being introduced into the structure, the surface is being decorated with metal particles, the materials are being doped with nitrogen, etc. The application of these approaches made it possible to significantly improve the mechanical, electrophysical, catalytic, and sorption properties of aerogels and allow obtaining materials with controlled architecture and unique morphology of the surface. The latest achievements in this area will be discussed in this chapter.
\nUnique structures and attractive properties of reduced graphene oxide (rGO)-based 3D materials were the reasons to establish a number of approaches for fabrication of those materials with controlled regular structure. The main methods of organization of such structures are self-gelation of graphene oxide (GO) containing systems, hydrothermal-assisted formation of aerogels, and cross-linking of a structure. Almost all these methods need a support of freeze drying or supercritical drying due to ability to prevent stacking of graphene oxide/reduced graphene oxide sheets during drying process. The absence of mobility of the GO/RGO layers and the fixation of the dispersion structure make it possible to obtain materials with a high porosity, a high specific surface area, and a high degree of exfoliation of the graphene-like sheets in the final material.
\nAs a rule, freeze drying of the samples leads to the formation of a large number of macropores. This is due to the fact that during the freezing of the sample, ice crystals are formed, which displace part of the material from its volume, which leads to local structural irregularities and the formation of macropores in place of the crystals after they are removed from the matrix during the drying process. It is clear that the size of the ice crystals is highly dependent on the freezing speed of the material, but even the use of liquid nitrogen for freezing does not avoid macroporosity due to the low thermal conductivity of nitrogen. Supercritical drying leads to the formation of a uniform microporous structure. Both approaches lead to the formation of ultralight porous structures with highly developed morphology, but each of them has its advantages. For example, the presence of macropores provides a large number of diffusion paths for various molecules and ions, which is an undoubted advantage for a number of applications.
\nVarious organic and inorganic reducing agents are used. Zhang et al. used L-ascorbic acid to obtain a mechanically strong and electrically conductive aerogel [1]. The authors showed that, in contrast to other reducing agents (NaBH4, LiAlH4, hydrazine), the reduction with L-ascorbic acid does not lead to the formation of reaction by-products that significantly affect the uniformity of the structure of the synthesized aerogel. NaHSO3, vitamin C, Na2S, ammonia boron trifluoride, sodium ascorbate, and hydroquinone have also been used by various investigators to form aerogels based on reduced graphene oxide [2, 3]. Aerogels based on reduced graphene oxide have also been obtained using a new inexpensive, environmentally friendly reducing medium that combines oxalic acid and sodium iodide [4]. The materials showed a low density, high porosity structure, and electrical conductivity. Yang et al. have developed a light, environmentally friendly, mild method of forming aerogel by thermal evaporation of a suspension of graphene oxide in the presence of NaHCO3 [5]. This approach is based on in-situ reduction to form an rGO aerogel. The aerogel based on the reduced graphene oxide was also synthesized using the hypophosphorous acid reduction process and I2 [6]. He showed a large surface area of 830 m2/g. Typically, the reduction with chemical agents is carried out in a liquid medium; however, in work [7], an interesting approach was first proposed for the reduction of the aerogel of graphite oxide with hydrazine vapor at room temperature after drying. The authors showed that the reduction has explosive character, and the resulting material practically does not differ from the material obtained by thermal shock reduction at 600°C (Figure 1). Also, various organic amines are used as reducing agents.
\nMicrographs of materials obtained by explosive reduction of graphite oxide aerogel by (a) thermal shock and (b) hydrazine vapor. (c) Gaseous products of explosive reduction of graphite oxide aerogel by thermal shock and by hydrazine vapor. (d) Comparison of the elemental compositions of materials obtained by explosive reduction of graphite oxide aerogel by thermal shock and by hydrazine vapor [7].
The simplest and most effective way to produce three-dimensional materials from graphene-like sheets is to obtain a hydrogel from graphene oxide, followed by removal of the solvent by drying. It is known that a stable dispersion of graphene oxide is formed at a certain concentration [8] due to the optimal ratio of the forces of electrostatic repulsion due to the huge number of oxygen-containing functional groups on the basal plane of the particles and the van der Waals interaction of monolayers. Gelation of suspensions occurs when the balance between these forces is violated and leads to the stratification of the particles of graphite oxide on the monolayers of graphene oxide (Figure 2).
\nScheme showing the chemical route to the synthesis of aqueous graphene dispersions. 1, Oxidation of graphite (black blocks) to graphite oxide (lighter colored blocks) with greater interlayer distance. 2, Exfoliation of graphite oxide in water by sonication to obtain GO colloids that are stabilized by electrostatic repulsion. 3, Controlled conversion of GO colloids to conducting graphene colloids through deoxygenation by hydrazine reduction [8].
The process of gel formation depends on many factors: van der Waals interaction, n-n stacking, the formation of hydrogen bonds, and electrostatic interaction [9]. The most important factor is also the concentration of suspensions, but the data on the optimal concentration are quite different. It has been shown that the optimal concentrations of gelation when exposed to ultrasound in a suspension of GO are 30 mg/ml and 0.075–0.125 mg/ml in different cases [10], but the aerogel obtained in the second case had a weak mechanical strength. In the work of Bai et al. [11], the optimal concentration was 4 mg/ml. Such a strong difference in the results, in our opinion, is due to several factors. The first of these is the method for obtaining a dispersion of graphene oxide. In the case where the critical gelling concentration is high, the dispersion is typically prepared by redispersing the sample of graphite oxide (in the form of a film or powder) air dried at an elevated temperature (typically T = 60°C). As practice shows, this method leads to the staking of monolayers and their redispergation is greatly hampered, which leads to a significant decrease in the ability to form a spatial grid and to gel. On the contrary, if the dispersion is prepared bypassing the drying stage of the product under such conditions (for example, by purifying the product from acids by dialysis), the self-gelation of dispersion occurs at substantially lower concentrations, even in the absence of ultrasonic treatment. The second factor is the size of the basal plane of the particles of graphene oxide, which is rarely taken into account in the processes of self-gelation of GO dispersions. This is due to the fact that it is rather difficult to obtain particles of graphene oxide with a given basal plane size. It is clear that the interaction of particles of different sizes should be completely different, but there are no dependencies of this kind in the scientific literature. The third factor is, at times, quite a noticeable difference, including in the chemical composition, of the graphene oxide itself (Figure 3), obtained from different types of graphite [12].
\nStructural characterization of (a) GO-f, (b) GO-g, and (c) GO-p. TEM analysis (i), AFM height imaging (ii), lateral size distribution (iii), and thickness distribution (iv). The analysis in (iii) and (iv) was based on counting approximately 100 sheets captured in several AFM images. (d) Quantification of π▬π*, carboxylic groups (O▬C▬O), carbonyls (C▬O), epoxides (C▬O▬C), hydroxyls (C▬OH), and graphitic structure (C▬C and C▬C) by high resolution C1s XPS spectra for GO-f, GO-g, and GO-p [12]. Three different GO thin sheets were synthesized from three starting graphite material: flakes (GO-f), ground (GO-g), and powder (GO-p).
Hydrothermal synthesis is a method of obtaining various chemical compounds and materials using physicochemical processes in closed systems that occur in aqueous solutions at temperatures above 100°C and pressures above 1 atm. In graphene systems, this process is realized at temperatures close to the effective reduction temperature of graphene oxide (200°C), using various reagents that can influence the structure and chemical composition and target physical properties of aerogels.
\nOne stage hydrothermal synthesis of aerogel from reduced graphene oxide (Figure 4a–f) was first proposed by Xu et al. [13]. The work shows that the aerogel obtained by this method is mechanically strong (after 12 hours of hydrothermal treatment at T = 180°C, the sample demonstrated an elastic modulus of 290 ± 20 kPa), could support 100 g of weight with little deformation, and has good electrical conductivity (4.9 ± 0.2 mS/cm), thermal stability, and high specific capacity (160 ± 5 F/g). It should be noted that the initial concentration of hydrogel oxide graphene was only 0.5–2 mg/ml, which was enough to the self-gelation of GO dispersion. It is also shown that the concentration of dispersion of graphene oxide is an important factor affecting the process of aerogel structure formation and its final properties. A study of the dependence of rGO aerogel properties on the time of hydrothermal reaction showed that with increasing thermal treatment time both mechanical and electrophysical characteristics of aerogel are improved.
\n(a) Digital photographs of a homogeneous GO aqueous dispersion with a 2 mg/mL concentration before and after hydrothermal reduction at 180°C for 12 h; (b) photos of a strong self-assembled graphene hydrogel; (c–e) SEM images with different magnifications of the strong self-assembled graphene hydrogel interior microstructures; and (f) room temperature I-V curve of the strong self-assembled graphene hydrogel exhibiting Ohmic characteristic by the two-probe method for the conductivity measurements [13].
Using the features of a closed environment allows the in-situ modification of rGO aerogels [14]. In his work, a method for forming a three-dimensional structure of reduced graphene oxide with noble metals was developed by hydrothermal reaction of a suspension of graphene oxide containing noble metal salts and glucose. The obtained material, containing Pt in the structure (Figure 5d–f), demonstrated high catalytic activity. Other authors have shown that using a hydrothermal reduction process for graphene oxide in the presence of divalent metal ions (Ni2+, Ca2+, Co2+), an aerogel of rGO decorated with metallic nanoparticles (Figure 5a–c) can be obtained in-situ [15]. A lot of work is devoted to the processes of decorating the particles of reduced graphene oxide in aerogels with various metal oxides. In particular, the great attention of researchers is attracted to Fe3O4 [16, 17, 18]. Special attention is also paid to the process of doping rGO aerogels with nitrogen. Doping with nitrogen by introducing into the system organic amines, ammonia, amino acids, and other nitrogen-containing compounds, at the stage of hydrothermal treatment, leads to a significant increase in the electrophysical characteristics of aerogels from reduced graphene oxide [19, 20, 21], improves electrocatalytic properties [22], and also contributes to obtaining a more regular structure of the aerogel itself.
\n(a) Digital photographs of the GO before and after hydrothermal treatment: (1) GO, (2) rGO, and (3) rGO mixed with Ca2+ (mCa/mGO is 0.003) suspensions as well as the gel-like rGO cylinders assembled by Ca2+. Various mCa/mGO were used: (4) 0.005, (5) 0.010, (6) 0.050, and (7) 0.100. (b) Photographs of the gel-like rGO samples assembled by (8) Ni2+ and (9) Co2+ with metal-ion/GO weight ratio of 0.010 [15]. (c) Schematic illustration of gel formation of rGO with divalent ion (M2+) linkage. (d–f) TEM images of graphene oxide decorated with Pd nanoparticles [14].
Moon et al. developed highly elastic and conductive N-doped monolithic graphene aerogels, using hexamethylenetetramine as a reducing agent, a nitrogen source, and a dispersion stabilizer of reduced graphene oxide [23]. To produce this material, hydrothermal synthesis was used, followed by annealing at T = 1000°C. The developed material showed good mechanical properties (Figure 6b) and record electrical conductivity of 704 S/m for aerogels based on the reduced graphene oxide (Figure 6a). It has also been reported that ammonia is an effective agent for the production of nitrogen-doped aerogels [24]. The authors showed that when ammonia is introduced into the hydrothermal synthesis reactor, the degree of doping of the reduced graphene oxide is sufficiently high (8.4 atomic %) and the material has a high specific surface area of 830 m2/g.
\n(a) Electrical conductivity of rGOhydro (prepared by hydrothermal synthesis) and rGOthermal (prepared by thermal annealing) aerogels when compressed along the axial direction. (b) Maximum stress (left pointing arrows) and energy loss coefficient (right pointing arrows) of rGO thermal aerogel during 10 cycles [23].
Polymer-assisted aerogel formation with a cross-linking approach consists of the use of polymer components capable of binding to monolayers of graphene oxide, creating steric hindrances for stacking layers into stacks and reducing the available surface. The first version of this approach is the chemical bonding of polymer chains to graphene oxide particles. Reversibly deformable, highly elastic and strong aerogels based on reduced graphene oxide [25] have been developed using this method (Figure 7). Poly(vinyl alcohol) and glutaraldehyde were used as cross-linking components. The scheme of the processes is shown in the figure. Hypophosphorous acid and iodine were used as reducing agents. It is important to note that in addition to the high porosity of 92.16% and the low density of 10.6 mg/cm3, the combination of polymer chains and graphene oxide layers led to the mechanical strength of the material, whose structure was not fundamentally changed even after deformation by 60% (Figure 7c). Therefore, x-rGO aerogel exhibits 8.6 times higher compressive stress as compared with rGO aerogel (Figure 7d).
\n(a) Illustration of the different steps for fabricating the rGO (chemically converted reduced GO) aerogel and x-rGO (cross-linked rGO) aerogel. Insets at center: Digital photographs depict the as-prepared chemically converted rGO wet-gel and x-rGO wet-gel (top and bottom, respectively) after the self-assembly process. (b) A possible cross-linking mechanism between PVA-wrapped rGO sheets and Glutaraldehyde. PVA-bonded rGO sheets were covalently cross-linked by an acetal oxygen bridge through esterification reaction. (c) Digital photographs and SEM images (from left to right) of rGO and x-rGO aerogels after compression with 60% strain. Arrows indicate the material areas of deformed and recovered after the compression for rGO and x-rGO aerogels, respectively. (d) Compressive stress-strain curves were plotted with 60% strain for rGO and x-rGO [25].
The second cross-linking option is the use of sol-gel technology, which is the preparation of a sol followed by its conversion to a gel-colloid system consisting of a liquid dispersion medium enclosed in a spatial grid formed by the connected particles of the dispersed phase. For the first time to produce aerogels based on reduced graphene oxide, this technology was applied by Worsley et al. [26]. The authors proposed the use of polymerization of resorcinol and formaldehyde in the presence of sodium carbonate in an aqueous dispersion of graphene oxide. The obtained material showed an increased electrical conductivity (~102 S/m) compared to the reduced graphene oxide (~0.5 S/m), as well as a high specific surface area of 584 m2/g. Later Sui et al. also obtained an rGO aerogel with a high degree of nitrogen doping (5.8 atomic %), having a surface area of 1170 m2/g [27] by sol-gel technology (Figure 8). The material was synthesized by freeze-drying an rGO/melamine-formaldehyde hydrogel and subsequent thermal treatment.
\n(a) XPS full spectrum of NPGM (nitrogen-doped porous graphene material) and PGM (porous graphene material). (b) N1s spectrum of NPGM. TEM images of NPGM (c) and PGM (d) [27].
A third option for the formation of cross-linked aerogels is the polymerization of monomers in-situ in the presence of a dispersion of graphene oxide. Various polymers such as pyrrole [28] and aniline [29] have been used for this approach. Zhao et al. proposed a unique approach to the production of aerogel by hydrothermal reaction of graphene oxide with pyrrole, followed by electrochemical pyrrol polymerization [30]. The material showed excellent resistance to high loads without significant structural deformation and loss of elasticity. Qin et al. have developed a unique superelastic aerogel consisting of reduced graphene oxide and polyimide [30]. For its preparation, the introduction of a water-soluble polyamido acid into a dispersion of graphene oxide followed by lyophilization and thermal annealing was used. This aerogel showed extremely low density, excellent flexibility, the possibility of multiple reversible deformations (even after 2000 cycles), and good electrical conductivity (Figure 9). Li et al. proposed a utilization of in-situ polymerization of acrylamide to create rigid 3D structures based on reduced graphene oxide [31].
\n(a–c) SEM image of rGO aerogel, PI monolith, and rGO/PI nanocomposite, respectively. (d, e) Digital images show the high-level deformation of bend and torsion of rGO/PI nanocomposite. (f) Retention of maximum stress at 50% strain and total loss during 2000 cycles. (g) Tensile σ-ε curve for the rGO/PI [30].
The first and the most developing direction of applications is the use of such aerogels as active electrode materials for supercapacitors. The supercapacitor is an electrochemical device for storage of electric energy on the surface of highly porous materials with an organic or inorganic electrolyte. At the heart of the work of supercapacitors, there are two processes—the formation of a double electrical layer at the material/electrolyte boundaries and electrochemical reactions on the surface of the electrode material, leading to the appearance of pseudocapacitance [32]. Both processes occur on the surface of the material during the charge/discharge of the device, so the energy capacitance of these devices is highly dependent on the surface area of the aerogels used. The combination of an electrically conductive three-dimensionally connected structure and good electrical conductivity of graphene-like materials makes them extremely attractive for this application. The high specific surface area of aerogels based on the reduced graphene oxide provides high capacity on a double electrical layer. To introduce a pseudocapacitive component, the aerogel surface is ordinarily decorated with transition metal oxides (Mn, V, etc.) capable of participating in redox reactions during charge/discharge of the device, making a significant contribution to the overall capacitance value [33, 34, 35, 36]. Also interesting is the direction in the creation of flexible supercapacitors. In the framework of this direction, in addition to the reduced graphene oxide, various polymers are introduced into the aerogel, such as glucose [37], polyvinyl alcohol [25], polyaniline [38], etc.
\nThe second, but not less interesting and intensively developing, direction is the use of aerogels based on reduced graphene oxide for rechargeable lithium-ion batteries. Graphene-like materials are the most widespread anode materials in commercial Li-ion batteries [39, 40]. The main role of rGO aerogel is to facilitate the multidimensional electronic transport routes and to reduce transport spaces between the electrode and the electrolyte. The consequence of this is an increase in the performance of the batteries and their cyclic stability. Sometimes, rGO aerogels containing metal, metal oxide, and metal sulfide are used as hybrid materials for the cathode of Li-ion batteries [41]. Similar structures containing Fe3O4 [42, 43] and Fe2O3 [39] show promising capacities (900–1100 mA*h*g−1) with good cyclicality. SnO2 is also used as an integral part of the FOG aerogel for this application [44]. Batteries with this material also show high performance (600–1200 mA*h*g−1) [45].
\nThree-dimensional electroconductive structures of rGO aerogels are an excellent platform for creating electrochemical sensors, strain gauge sensor, and biosensors. Introduction to the structure of metals, oxides, and hydroxides of metals provides high sensitivity and electrochemical stability [46]. Ultraelastic aerogels based on rGO and carbon nanotubes were fabricated for use in a strain gauge sensor with adjustable voltage/pressure measurement [47]. The sensitivity is adjusted by changing the aerogel density. In the compression test, the measurement coefficient was 230 and 125% for deformations of 30 and 60%, respectively. The aerogel containing gold nanoparticles in its structure was used for the electrochemical determination of hydroquinone and o-dihydroxybenzene [48]. The detection limit is 1.5 × 10−8 M for hydroquinone and 3.3 × 10−9 M for o-dihydroxybenzene.
\nIn the technique, actuators are transducers that convert an input signal (electrical, optical, mechanical, pneumatic, etc.) into an output signal (usually in motion) that acts on the control object. Devices of this type include electric motors; electric, pneumatic, or hydraulic actuators; relay devices; comb drives; DMD mirrors; electroactive polymers; robotic grasping mechanisms, drives for their moving parts, including solenoid actuators and voice coils; and many others. Recently, the actuators have been intensively studied as potential devices in flexible displays, soft robotics, and haptic devices. rGO-based aerogels are ideal candidates for such devices, because they have high porosity, are ultra-light, flexible, and resilient. To be able to act on the aerogel with magnetic forces, magnetic nanoparticles of Fe3O4 were introduced into it [49]. This material demonstrated great magnetic field-induced actuations of 52 and 35% along the radial and axial directions, respectively. Also, several works on actuators based on materials with shape memory are known. Li et al. developed an actuator based on an aerogel from rGO and trans-1,4-polyisoprene, which showed a strain of 80% at 10 V [31].
\nAerogels based on reduced graphene oxide are promising materials and attracting the interest of many researchers due to unique physicochemical properties. High specific surface area, extremely low density, high porosity, uniqueness of structure, and good electrical conductivity make these materials indispensable in many applications. Main researches are carried out in the direction of surface modification with various materials in order to improve the mechanical, electrophysical, and structural properties of these materials, and the variety and number of articles in this field testify to the incredible promise of materials based on graphene-like particles. However, there are a number of problems that need to be overcome in order to bring most of the developments beyond the scope of laboratory research. First, it is necessary to develop simple methods for obtaining regular structures based on reduced graphene oxide, suitable for real use. Secondly, special attention needs to be given to a detailed study of the mechanisms of the structure formation of such materials, since at the moment many of the processes are only described, but not explained theoretically. Third, one of the main factors is the high cost of graphene-like materials, which means that efforts should be made to develop cheaper methods for the synthesis of GO and rGO. However, despite the fact that in the near future the researchers will have to solve a number of the problems described above, one can say unambiguously that materials based on graphene-like particles are among the most promising for revolutionary changes in technology, science, and the life of all mankind.
\nThis work was partially supported by Russian Foundation for Basic Research (project 16-29-06440).
\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Erythrocytes are the most abundant cells in human blood, with unique morphology and metabolic characteristics and are highly important for body homeostasis. Erythrocytes come from a hematopoietic process—erythropoiesis—by which hematopoietic stem cells from the bone marrow proliferate and differentiate into mature red blood cells (RBCs) [1, 2, 3]. Erythrocytes are enucleated cells with a cytoplasm without organelles and rich in hemoglobin (Hb), which represents about 95% of total erythrocyte’s cytoplasmic proteins [4, 5].
\nMembrane structure and composition are responsible for the biconcave disc shape and for the high deformability of the cell. These features are essential for oxygen transport, since RBCs have to undergo repeated shape changes without fragmentation, to assure their passage and oxygen perfusion through all vascular networks, namely, through capillary blood vessels with smaller lumen diameter than that of RBCs [6, 7]. Modifications in RBC membrane protein structure, by decreasing membrane flexibility and stability, may lead to premature removal of the cell reducing RBC’s life span [1, 8].
\nThe erythrocyte membrane is a complex structure composed by a lipid bilayer and a protein-based cytoskeleton tethered together by transmembrane proteins, such as protein band 3 and glycophorins. When under oxidative stress (OS) conditions, Hb is oxidized, it binds to the cytoplasmic domain of membrane protein band 3, triggering the formation of aggregates and the covalent linkage of natural anti-band 3 antibodies that may lead to premature RBC removal by splenic macrophages [1, 9].
\nHb, the main cytoplasmic protein in RBC, is extremely important for erythrocyte’s primary function, as a gas exchanger and for performing oxygen (O2) distribution to body tissues. Erythrocytes carry O2 from the lungs to the tissues and mediate carbon dioxide removal from the tissues to the lungs. In the lungs, O2 binds to the heme group in Hb; in the tissues, O2 is unloaded from Hb that undergoes a spatial rearrangement of the globin chains, allowing the entry of 2,3-diphosphoglycerate (2,3-DPG) which diminishes O2 affinity [1, 2]. Oxyhemoglobin suffers autoxidation daily (2–3%), with oxidation of heme ferrous iron into ferric iron [10], leading to the formation of methemoglobin (metHb), which is not capable of O2 transport, and the release of superoxide anion that is converted to H2O2, with a lower oxidant capacity [11]. The erythrocytes are capable of reducing metHb to functional Hb through methemoglobin reductases and of detoxifying the cell from H2O2 through the glutathione metabolism [2].
\nTo prevent or reverse the harmful effects of OS, leading to oxidative changes in the erythrocyte constituents, RBCs are equipped with a powerful antioxidant system that is able to protect not only themselves, but also other cells and tissues while circulating throughout the vascular network. The protective antioxidant mechanisms of RBCs include enzymatic and non-enzymatic antioxidant systems that work together to detoxify the cell from reactive oxygen species (ROS) produced within or outside the cell.
\nIn this chapter, we will focus on the importance of the RBC enzymatic antioxidant systems, namely on the peroxidases catalase (CAT), glutathione peroxidase (GPx) and peroxiredoxin 2 (Prx2). These peroxidases have a major role in the RBC’s defense against OS, although the interplay between them is still a topic of discussion, as well as the potential role of their binding to the membrane, which may provide a protective mechanism for the cell.
\nErythrocytes have a limited metabolic capacity since they lack a nucleus and organelles, like mitochondria, for oxidative metabolism [1, 11]. Therefore, energy is generated by the anaerobic glycolytic Embden-Meyerhof pathway, through which the breakdown of glucose to lactate generates two ATP molecules (Figure 1). This energy is essential for the maintenance of RBC’s shape, membrane deformability and regulation of sodium-potassium pump [1, 2]. This pathway also provides NADH, which is important as a cofactor of methemoglobin reductase to regenerate oxidized Hb to its reduced functional state. The Luebering-Rapoport shunt, a side arm of Embden-Meyerhof pathway, produces 2,3-DPG (Figure 1), essential for the regulation of O2 affinity [1, 2]. Around 80–90% of glucose that enters the cell follows the Embden-Meyerhof pathway, while about 10% is metabolized through the pentose phosphate pathway [12] to ribose-5-phosphate concomitantly generating NADPH (Figure 1). NADPH is essential for glutathione (GSH) metabolism that assures the detoxification of RBCs from ROS, being, therefore, an important erythrocyte antioxidant defense mechanism [11].
\nErythrocyte metabolic pathways synopsis. 2,3 DPG, 2,3-diphosphoglycerate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; G-6-P, glucose 6-phosphate; GPx, glutathione peroxidase; GR, glutathione reductase; GSSG, oxidized glutathione; GSH, glutathione; Hb, hemoglobin; metHb, methemoglobin; NAD, NADH, nicotinamide adenine dinucleotide; NADP, NADPH, nicotinamide adenine dinucleotide phosphate.
GSH is a tripeptide constituted by the three amino acids L-glutamate, L-cysteine and L-glycine [13, 14], existing in the cell in two different forms, the reduced form (GSH) and the oxidized form (GSSG). The reduced form is the predominant one and GSSG is maintained at low levels, less than 1% mainly by the action of NADPH-dependent glutathione reductase [13], which converts GSSG into the reduced GSH (Figure 1). Despite the limited biosynthesis capability of the RBC, some endogenous GSH is still synthetized in the cytosol through two ATP-dependent reactions catalyzed by two different enzymes, glutamate cysteine ligase and glutathione synthase [13].
\nAs an antioxidant defense, GSH has several roles: it can directly scavenge hydroxyl radicals and peroxynitrites [14, 15]; it is involved in lipid peroxide detoxification [16]; it can reduce H2O2 in the presence of GPx by the reduction of its thiol group and keeps thiol groups from Hb, enzymes and membrane proteins in the reduced form [13], which is very important for the preservation of their functions, once oxidation of these groups can lead to functional and structural cellular modifications. Therefore, the GSH/GSSG ratio is an important indicator of the cell redox state [15].
\nIn OS conditions, the capacity of RBCs to reduce GSSG to GSH decreases, leading to GSSG accumulation and, consequently, to GSH depletion [14]. Diminished GSH concentrations have been described in physiological events, as aging, and in pathologic conditions associated with OS, such as Alzheimer’s disease, Parkinson’s disease [15], sickle cell anemia and asthma [17, 18].
\nAscorbic acid (vitamin C) and α-tocopherol (vitamin E) obtained mostly from diet are also important non-enzymatic erythrocyte antioxidants [19]. α-Tocopherol has a protective effect on RBC membranes against lipid peroxidation [11, 19]. Ascorbic acid can reduce O2− levels and it is an important regenerator of α-tocopherol. Uric acid can also act as an antioxidant and is able to directly scavenge OH− [12].
\nDuring their life span, the erythrocytes are continuously exposed to high O2 tension, due to their primary function as gas carriers, and are unable to synthesize new or repair damaged proteins, due to the lack of nucleus and other organelles. Therefore, RBCs are more vulnerable to ROS action than other cells of the human body [12].
\nROS are chemically reactive species containing oxygen with one or more unpaired electrons that are formed by the reduction of an O2 molecule (Figure 2) [12, 20, 21]. The transfer of one electron to an O2 molecule produces superoxide anion (O2−), the precursor of other ROS [22]. Spontaneous O2− dismutation or catalysis by superoxide dismutase (SOD) action produces hydrogen peroxide (H2O2) [22]. This molecule is not a free radical and is more stable than O2−, but it can easily cross cell membranes and cause damage in other cells and tissues [12]. The RBC needs to be detoxified from H2O2, as its accumulation leads to the production of other more potent ROS. This molecule can be decomposed into water and O2 by CAT, GPx or Prx2. In case of failure of these antioxidant enzymes, H2O2 can also be reduced to hydroxyl radical (OH−), the most harmful free radical for biological systems, due to its high reactivity. With a short half-life, OH− does not travel far, but has a much higher oxidant potential than all the other ROS [12, 20].
\nOxidative stress in erythrocytes. (1) Production of reactive oxygen species resulting from hemoglobin autoxidation. (2) Linkage of denatured Hb to erythrocyte membrane band 3 protein. (3) Peroxidation of erythrocyte membrane lipids. CAT, catalase; e−, electron; GPx, glutathione peroxidase; H+, hydrogen; H2O, water; H2O2, hydrogen peroxide; Hb, hemoglobin; HO−, hydroxyl radical; LPO, lipid peroxidation; metHb, methemoglobin; O2, oxygen; O2−, superoxide anion; Prx2, peroxiredoxin 2; SOD, superoxide dismutase.
OS arises when an imbalance between free-radical formation and antioxidant defenses occurs, that is, when ROS concentration overwhelms the antioxidant capacity within the RBC [19]. The endogenous source of ROS in erythrocytes is the autoxidation of Hb [11, 12]; occasionally oxyhemoglobin loses one electron (2–3% per day) leading to the production of O2− and oxidized Hb (metHb) (Figure 2) which is not able to bind and carry O2. Erythrocytes can also develop OS due to exogenous ROS that are able to diffuse and cross the RBC membrane. The enhanced production and release of ROS by activated inflammatory cells, macrophages, neutrophils and endothelial cells [23], are the main source of exogenous ROS. The continuous exposure of RBCs to ROS can cause cell damage, including lipid and protein oxidation, causing damages in enzymes and ion transport proteins [19, 24].
\nConsidering the major role of Hb, its oxidation may trigger important structural and functional changes in RBCs [11, 12]. Thus, as oxidation of Hb occurs, even under normal physiological conditions, the antioxidant defenses have a crucial role in the regeneration of functional Hb and maintenance of low metHb levels [11]. When oxidized, the primary structure of Hb is altered by the establishment of disulfide cross-links between globin chains that make the molecule unstable, leading to the formation of Heinz bodies and, eventually, to a premature RBC removal [11]. Indeed, oxidized Hb binds to the cytoplasmic domain of band 3 protein in the RBC membrane (Figure 2), triggering band 3 clustering, marking the erythrocyte for removal by splenic macrophages [23, 25]. Clustering of band 3 as a result of enhanced metHb formation and linkage to the membrane has been reported in several erythrocyte disorders such as, hereditary spherocytosis [26], beta-thalassemia [27], sickle cell anemia [28] and glucose-6-phosphate dehydrogenase deficiency [29]. An increase in metHb levels and in its linkage to the RBC membrane, accompanied by ROS formation, was also found in stored RBCs for blood transfusion [30] and in exogenous H2O2-induced OS upon healthy erythrocytes [31, 32]. Hb oxidation also occurs as a natural process, resulting from RBC aging [33], that is associated with metabolic degradation due to reduction in enzyme activity.
\nRBC membrane is an important target for both endogenous and exogenous ROS that may induce oxidative changes in membrane proteins and lipids. Changes in RBC membrane proteins have been reported in some diseases in which OS is involved, such as chronic kidney disease [34, 35] or chronic obstructive pulmonary disease [36]. ROS can affect erythrocyte proteins through oxidation of the protein backbone, cross-linking or amino acid oxidation [19, 24]. The polyunsaturated fatty acids (PUFAs) of the RBC cell membranes are highly vulnerable to oxidation (about half of the RBC membrane fatty acids are unsaturated [12]). ROS are able to break the double bonds of PUFA, producing malondialdehyde (MDA) [24], the main end-product of membrane lipid peroxidation (LPO). MDA is a highly reactive molecule that can further react with lipids and proteins of the membrane. These changes in membrane proteins and lipids contribute to functional and structural alterations that decrease erythrocyte membrane stability and deformability and trigger premature RBC removal [12, 24]. LPO has also been described following metHb binding to the membrane, suggesting that this linkage favors LPO [37]. Increased LPO and MDA levels have been reported in different conditions associated to OS, including physiological events, such as aging [38], and pathological conditions like schizophrenia [39], Alzheimer’s disease [40], inflammatory associated diseases [41], atherosclerosis [42] and chronic kidney disease [43]. Considering the reduced biosynthetic capacity of erythrocytes, they accumulate oxidative changes along their life span and, therefore, the OS-induced changes in RBCs could be used as useful biomarkers in several pathological and physiological conditions.
\nTo cope with oxidative injuries, the erythrocytes have several enzymes that neutralize ROS or transform them into less reactive species. SOD provides the first line of protection against free radicals. It is a cytosolic copper-zinc containing enzyme that converts O2− into the less reactive H2O2 (Eq. (1)), through the alternate reduction and re-oxidation of Cu2+ [44].
\nAfterward, H2O2 can be decomposed into O2 and water by three distinct erythrocyte peroxidases: CAT, GPx and Prx2 [45, 46, 47].
\nCatalase (H2O2:H2O2 oxidoreductase, EC 1.11.1.6) is an intracellular enzyme found at high concentrations in erythrocytes and liver peroxisomes in mammals [48, 49, 50, 51]. CAT is a very important enzyme, as it is able to protect cells and tissues from the toxic effects of H2O2 [19, 51]. As referred, the decomposition of H2O2 is particularly important in erythrocytes, to prevent oxidation of Hb and of other RBC constituents. CAT is one of the most efficient enzymes, since it exhibits one of the fastest turnover rates with a capacity to convert millions of H2O2 molecules per second (kcat = 4 × 107 s−1) [45, 48].
\nMore than 300 catalase sequences are available, divided among several groups [45, 50, 52]. Human erythrocyte catalase, a tetrameric protein of 244 kDa [53], belongs to the monofunctional heme-containing catalases. Each monomer is formed by a single polypeptide chain that has a molecular weight of approximately 60 kDa [54]. Each subunit also has one heme group at the catalytic center, with iron (III) linked to protoporphyrin IX [53]. Some studies [55, 56, 57] showed that each catalase tetramer has four tightly bound NADPH molecules that appear to be important only to protect the enzyme against inactivation by its own substrate (H2O2), and are not essential for its catalytic activity. It is thought that NADPH prevents the formation of the inactive form of catalase (Compound II) and that it increases the rate of removal of this inactive form [45, 53, 55, 56].
\nThe overall reaction catalyzed by CAT involves the degradation of two molecules of H2O2 to two molecules of water and one of O2 (Eq. (2)).
\nThe H2O2 decomposition is believed to occur in two steps (Figure 3, steps 1 and 2) [45, 50, 52]. The first involves the interaction between one molecule of H2O2 and CAT which leads to the production of Compound I, in which the heme group is oxidized to oxyferryl species [45, 50, 52]. Compound I is an enzymatic active form of catalase but spectroscopically different [58]. At the second step, a second H2O2 molecule acts, as a reducing agent, on Compound I, producing one molecule of water, one of O2 and the enzyme in the resting state [45, 50, 52].
\nHydrogen peroxide removal by catalase. (1) Interaction between H2O2 and catalase leading to the production of Compound I. (2) Interaction of a second H2O2 molecule with Compound I producing one molecule of H2O, O2 and the enzyme at the resting state. (3) Catalase peroxidatic activity. H2O, water; H2O2, hydrogen peroxide; O2, oxygen.
In addition to their catalytic activity, catalases can also function peroxidatively (Figure 3, step 3) to eliminate H2O2 [45, 49]. In this case, the enzyme uses peroxidation to eliminate H2O2 molecules by oxidizing substances like alcohols. The peroxidatic activity of CAT is, usually, minor, weak and restricted to smaller substrates, as compared to other peroxidases [45].
\nWhen compared with the other H2O2 scavenger enzymes, CAT seems to be the key enzyme to remove high intracellular concentrations of H2O2 [32, 53, 59, 60]. Moreover, CAT is highly specific for its substrate, H2O2, and it is not able to eliminate organic peroxides, unlike other peroxidases [59].
\nCatalase has also been studied in a number of different diseases in which OS is implicated, such as, diabetes mellitus where patients presented lower CAT values [61]; in some type of cancers, CAT activity was lower in patients, especially in lymphomas, when compared with CAT activity in the normal population [62] and, in bipolar disorder, subjects with bipolar depression presented a significant increase in CAT levels [63].
\nGPx (GSH2:H2O2 oxidoreductase, EC 1.11.1.9) is an intracellular antioxidant enzyme that contributes to prevent H2O2 accumulation in cells. In mammals, eight GPxs have been identified [47] at different locations and cellular compartments, differing at their catalytic center. GPx-1 is one of the most abundant type of GPx and the only type present in RBC’s cytosol [60]. GPx-1 is a tetramer of four identical subunits of 21 kDa [64], each with one selenocysteine (Sec) [65]. The catalytic tetrad formed by Sec, glutamine, tryptophan and asparagine is essential for GPx activity, since these residues are crucial for enzyme-substrate interaction and stabilization of the GSH-GPx interaction [47, 65, 66].
\nGPx-1 catalyzes the reduction of H2O2 [47, 66], lipid hydroperoxides and other low molecular hydroperoxides [64] into water, or into the corresponding alcohols, using GSH as a reducing agent; thus, GPx-1 prevents both lipid peroxidation [65, 67] and H2O2 accumulation.
\nThe overall catalytic reaction of GPx-1 is given by Eq. (3).
\nThe catalytic cycle of GPx includes a peroxidatic part that is followed by a reductive step (Figure 4) [47]. In the peroxidatic part, one molecule of H2O2 reacts with the selenol group from Sec in GPx, producing a selenenic acid at the active site [47, 66]. In the reductive part, one GSH molecule forms a selenadisulfide bond with the selenic acid forming the glutathiolated selenol intermediate [47]. As a second GSH molecule reduces the glutathiolated selenol bond, GSSG is released and GPx is regenerated. The restoration of GSH involves the action of the NADPH-dependent enzyme, glutathione reductase. The recycling of NADPH associates the GSH system to the pentose-phosphate pathway [66].
\nCatalytic cycle of glutathione peroxidase 1. (1) Peroxidatic part of GPx-1 catalytic cycle. (2) and (3) Reductive part of GPx-1 catalytic cycle (4) Regeneration of GSH by NADPH-dependent GR. (5) NADP+/NADPH recycling by G6PD. 6PG, 6-phosphogluconolactone; G6P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; GPx-SeH, glutathione peroxidase selenol; GPx-SeOH, glutathione peroxidase selenic acid; GPx-Se-SG, glutathiolated selenol intermediate; GR, glutathione reductase; GSH, glutathione; GSSG, oxidized glutathione; H2O, water; H2O2, hydrogen peroxide; NADPH/NADP+, nicotinamide adenine dinucleotide phosphate.
CAT was considered as the only enzyme involved in erythrocyte antioxidant defense by performing H2O2 removal [68]. Nowadays, it is known that GPx also has a major role in RBC antioxidant protection, being essential for the detoxification of low H2O2 concentrations and hydroperoxides [59, 69, 70], with a constant rate superior to 107 M−1 s−1 [47, 71].
\nPeroxiredoxins (Prxs; SH:H2O2 oxidoreductases, EC 1.11.1.15) are a family of homodimeric peroxidases with an antioxidant role in living organisms. Six different mammalian Prx isoforms are known (Prx 1–6). Prx 1 and Prx 6 can be found in erythrocytes, although in much lower amounts than Prx2, which is the third most abundant protein in the RBC cytosol (after Hb and carbonic anhydrase) [5].
\nFor a long time, CAT and GPx were considered the major erythrocyte players for H2O2 detoxification [68]. However, several studies [72, 73, 74, 75] have shown the significant role of Prx2 as an efficient H2O2 scavenger in the erythrocyte antioxidant system. Studies using Prx2 knock-out mice showed that these animal models developed hemolytic anemia and their erythrocytes displayed a significantly shorter life span, when compared to wild-type mice [72]. In contrast, CAT and GPx knock-out mice showed a normal hematologic profile and normal development [72, 76]. Another important study reported that Prx2 reacts with H2O2 at a constant rate (1.3 × 107 M−1 s−1) comparable with that of CAT and GPx [75].
\nUnder its physiological functional state, Prx2 appears as a monomer (active form) of about 20–30 kDa and when interacting with H2O2, Prx2 is oxidized and a disulfide-linked dimmer is formed (inactive form) [73, 77]. This oxidized form is reversed by thioredoxin (Trx)/Trx reductase/NADPH system, although, in RBCs, it is a very slow regeneration due to the low concentrations of Trx reductase [73]. Besides H2O2, Prx2 can also remove peroxynitrites [5] and hydroperoxides in the RBC membrane [73, 75].
\nSince Prx2 is a thiol-dependent peroxidase, it uses redox-active cysteines to reduce peroxides. According to the number and location of the catalytic cysteines, Prxs are divided into three classes: the typical 2-Cys, the atypical 2-Cys and the 1-Cys [46]. Prx2 is a typical 2-Cys peroxiredoxin, with two redox-active cysteines: the peroxidatic cysteine near residue 50 in one subunit and the resolving cysteine near residue 170 in the other subunit [46]. The overall peroxidase reaction is given by Eq. (4).
\nThe catalytic cycle of Prx2 is composed by two steps (Figure 5). The first step is the oxidation of peroxidatic cysteine to peroxidatic cysteine-sulfenic acid by interaction with H2O2. In the second step, the resolving cysteine of one Prx subunit attacks the peroxidatic cysteine-sulfenic acid of the other subunit generating an inter-subunit disulfide bond [46, 75]. This dimeric form of Prx2 is non-functional, but the disulfide bridge between the subunits can be broken by Trx, regenerating Prx2, and completing the catalytic cycle [73]. In turn, Trx can be reduced by the NADPH-dependent Trx reductase. Reduction of the disulfide bond by Trx is the rate-limiting step in the Prx2 catalytic cycle [73].
\nPeroxiredoxin 2 catalytic cycle. (1) Oxidation of SPH to SPOH by interaction with H2O2. (2) Attack of SRH of one subunit to SPOH of the other subunit and formation of the intersubunit disulfide bond. (3) Reduction of the disulfide bond by Trx. (4) Regeneration of reduced Trx by NADPH-dependent Trx reductase. 2-Cys Prx, 2-cys peroxiredoxin 2; H2O, water; H2O2, hydrogen peroxide; NADPH/NADP+, nicotinamide adenine dinucleotide phosphate; SPH, peroxidatic cysteine; SPOH, peroxidatic cysteine sulfenic acid; SRH, resolving cysteine; Trx, thioredoxin; TrxR, thioredoxin reductase.
In the presence of high peroxide levels, 2-Cys Prxs can become over-oxidized to their sulfinic acid form. In RBCs, this hyperoxidation of Prx2 does not occur, as it is counteracted by sulfiredoxin [60, 73].
\nAs part of the erythrocyte antioxidant system, Prx2 is responsible for the removal of low H2O2 concentrations, since the Trx system has a limited capacity for Prx2 regeneration into its reduced active form [32, 59, 60, 73]. Recently, it was found that Prx2 can have a dual function according to H2O2 levels, as an antioxidant enzyme or as a chaperone, due to changes in its structure [59, 73, 78]. In RBCs, Prx2 can bind to Hb under OS conditions to stabilize its structure and prevent Hb aggregation [79]. A recent work by our group [80] showed that under steady-state conditions, Prx2 acts as a typical peroxidase, protecting the erythrocytes from low endogenous levels of ROS. However, when RBCs are saturated with carbon monoxide, Prx2 was observed only in the active form in the cytosol and none in the oxidized form, suggesting that Prx2 is acting specifically to protect Hb, shifting its function from peroxidase to chaperone. Prx2, initially called calpromotin, is also required to regulate the calcium-dependent potassium channel in the erythrocyte membrane [81].
\nThe use of Prx2 as a potential therapeutic drug target has gained growing interest; so far, it has already been reported as a possible target for malaria treatment [82]. Changes in human Prx2 expression or oxidation state have been associated with several diseases: alterations in Prx2 expression have been reported in different types of cancer [83, 84]; oxidatively modified Prx2 has been found in Alzheimer’s disease patients [85]; hyperoxidized forms of Prx2 were also found in asthmatic patients [86] and linkage of cytosolic Prx2 to the RBC membrane was found in hereditary spherocytosis patients [26]. Thus, there has been an increasing interest in Prx2 as a biomarker for different conditions where OS plays a crucial role. For example, a novel HPLC method to monitor the levels of reduced Prx2 form was developed [87], which could prove useful for future clinical practice.
\nThe individual contribution of CAT, GPx and Prx2 to erythrocyte protection against H2O2 damage has been a controversial issue for many years. It is clear that all three enzymes are involved in the prevention of H2O2 accumulation in the RBC through H2O2 conversion into water and O2 (Figure 6); however, the relative importance of the three enzymes is still a topic of discussion.
\nInterplay between erythrocyte’s peroxidases. (1) Methemoglobin formation and release of O2−. (2) Formation of band 3 protein aggregates triggered by methemoglobin linkage to the integral membrane protein band 3. (3) O2− removal by SOD with H2O2 formation. (4) H2O2 removal by CAT. (5) H2O2 removal by GPx. (6) H2O2 removal by Prx2. (7) Linkage of CAT, GPx and Prx2 to the RBC membrane imposed by oxidative stress. CAT, catalase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; GSSG, oxidized glutathione; H2O, water; H2O2, hydrogen peroxide; Hb, hemoglobin; metHb, methemoglobin; Hb-O2, oxyhemoglobin; NADPH/NADP+, nicotinamide adenine dinucleotide phosphate; O2, oxygen; O2−, superoxide anion; Prx2, peroxiredoxin 2; SOD, superoxide dismutase; Trx, thioredoxin; TrxR, thioredoxin reductase.
CAT was considered the main erythrocyte defense against OS, for many years [68, 88], but several studies [59, 69, 89] showed that GPx has also an important role in H2O2 decomposition. In fact, a study by Johnson et al. [59] showed that CAT and GPx-deficient RBCs were more sensitive to H2O2-induced OS than cells with only CAT deficiency, suggesting that GPx has an important role in erythrocyte defense. The same authors also showed [59, 70] that the action of both CAT and GPx was insufficient to explain the erythrocyte oxidative catabolism, and proposed [70] a model including Prx2 that, in accordance with their experimental data, could better explain the erythrocyte antioxidant defense system. Furthermore, the development of hemolytic anemia in Prx2 knock-out mice [72, 73, 74] and the high turnover rate of Prx2 with H2O2 [5, 75] strengthened the importance of the role of Prx2 in RBC antioxidant protection.
\nThe relative importance of the three enzymes appears to be related to the H2O2 levels in the RBC [59]. CAT is able to scavenge exogenous and high endogenous peroxide levels [59, 60, 70], while GPx and Prx2 appear to scavenge endogenous and low peroxide levels [59, 70, 73]. Thus, the elimination of the basal flux and low H2O2 levels is performed by GPx and Prx2, since CAT does not work efficiently at low H2O2 levels [60]. Whenever RBCs are exposed to higher H2O2 levels, CAT becomes essential for its rapid removal since this enzyme has a high turnover rate, unlike GPx and Prx2 that become less efficient (or even inactive), due to their slow GSH reductase and Trx recycling systems, respectively [59, 60, 73].
\nThe enzymes GPx and Prx2 seem to have other functions in RBC antioxidant defense, beyond H2O2 scavenging. In fact, GPx and Prx2 are also able to detoxify organic peroxides [5, 59, 75], while CAT does not show this function [59]. As shown by Johnson et al. [59, 90], GPx-deficient RBCs are more susceptible to oxidation by organic peroxides than wild type cells [90]; and when CAT deficiency was added to GPx deficiency, no increased sensitivity to oxidation by organic peroxides occurred in these cells [59]. Thus, when erythrocytes are exposed to high H2O2 levels, organic peroxides will accumulate, since GPx and Prx2 become less efficient and CAT is not able to detoxify these organic peroxides [60].
\nRecently, it was reported that Prx2 can have multiple functions, as a peroxidase or as a chaperone, through the formation of high-molecular-weight complexes [78, 91]. It was shown that Prx2 acts as a chaperone in RBCs, by interacting directly with Hb to maintain its stability [79]. A study by our group [80] showed that when erythrocytes were saturated with CO, the enzyme Prx2 was present in the cytosol only in the monomeric form, suggesting that Prx2 was not acting as a peroxidase but, instead, exclusively as a chaperone for Hb’s protection. Several authors have suggested [59, 92] that Prx2 can also have an important role in erythropoiesis. Johnson et al. [59] believe that the role of Prx2 as Hb chaperone is especially important in the different stages of erythropoiesis. According to Matte et al., Prx2 appears to be a regulator of iron homeostasis during erythropoiesis [92].
\nCAT, GPx and Prx2 are essentially cytosolic enzymes; however, the association of these enzymes to the erythrocyte membrane has been reported in different in vivo and in vitro studies [26, 31, 32, 93, 94, 95, 96, 97]. Erythrocytes from patients with hereditary spherocytosis showed CAT [95] and Prx2 bound to their membranes [26]. The association of CAT to the membrane appears to be a consequence of the metabolic stress triggered by the destabilization of membrane structure, due to an altered RBC membrane composition; the linkage of Prx2 might be involved in the protection of the RBC membrane against LPO [26, 31]. This linkage of Prx2 to the membrane appears to be through the N-terminal cytoplasmic domain of band 3, which is also the site of linkage of other cytoplasmic proteins, including metHb [98]. In recent in vitro assays performed by our group [32], we showed that H2O2-induced oxidative stress triggered the binding of Prx2 and GPx to RBC membrane. A recent study by Bayer et al. [96] about the interaction of Prx2 with the RBC membrane reported that the linkage of Prx2 to the membrane is independent of its redox state and that Prx2 competes with Hb for the same binding site in the RBC membrane. Thus, they demonstrated that Prx2 prevents metHb aggregation, and, probably acts as a chaperone for the denatured Hb [96]. Contrary to what was previously observed [26, 31, 32], Bayer et al. [96] found a decrease in Prx2 membrane binding, with increasing concentrations of H2O2. A decrease in Prx2 linkage to the RBC membrane with OS conditions was also observed in beta-thalassemic mice RBCs, probably due to the increase in metHb that binds to the membrane, reducing the access of Prx2 to the same site [99].
\nThe linkage of GPx to the RBC membrane was first described by van Gestel et al., using proteome analysis [94]. Later on, Rocha et al. showed the linkage of GPx to the RBC membrane in response to in vitro H2O2-induced OS [32].
\nStudies of stored RBCs in blood bank conditions also reported the recruitment of Prx2, CAT and GPx to the RBC membrane due to OS modifications resulting from the metabolic stress of long-term erythrocyte storage [93, 97].
\nData in literature suggest that the linkage of these RBC cytosolic enzymes to the membrane is triggered by metabolic stress, possibly, to protect the erythrocyte membrane and counteract the effects of OS.
\nErythrocytes, as oxygen carrier cells, are highly exposed to oxidative injury; to face this challenge, RBCs are well equipped with an efficient antioxidant system, important to maintain erythrocyte homeostasis during its life span. The antioxidant system includes non-enzymatic and enzymatic agents such as peroxidases, namely Prx2, GPx and CAT. The role and interplay between these enzymes that prevent H2O2 accumulation in the erythrocyte has been a topic of discussion over the years. So far, it appears that their role depends on the H2O2 levels within RBC: CAT is crucial for scavenging high exogenous and endogenous peroxide levels, GPx and Prx2 are important for scavenging low endogenous and low peroxide levels. GPx and Prx2 are also able to detoxify the cell from organic peroxides, unlike CAT that does not show this function. Therefore, GPx and Prx2 can have a direct role on RBC membrane antioxidant defense.
\nSeveral authors have already reported the linkage of CAT, GPx and Prx2 to the erythrocyte membrane in case of metabolic stress and/or OS. In fact, the recruitment of the three peroxidases to the RBC membrane has been described in OS-associated conditions, by in vitro assays and by studies with stored RBCs under blood bank conditions.
\nStudies about Prx2 reveal a dual function in RBC defense, as a peroxidase and as an Hb chaperone preventing metHb aggregation. Some authors have also proposed that Prx2 may have a major role in erythropoiesis.
\nErythrocytes are the ultimate antioxidant defense against the harmful effects of OS in humans; so, the knowledge about the RBC antioxidant system has evolved over time, and should continue to grow, focusing on the importance of CAT, GPx and Prx2 working together in ROS detoxification and also their potential role in the erythrocyte membrane.
\nFinancial support from FCT/MCTES through national funds UID/MULTI/04378/2019 and Norte Portugal Regional Coordination and Development Commission (CCDR-N)/NORTE2020/Portugal 2020 (Norte-01-0145-FEDER-000024) and a PhD grant (SRRH/BD/139622/2018) attributed to D. Melo.
\nThe authors report no conflict of interest.
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\\n\\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
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\\n\\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\\n\\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\\n\\n5. TERMINATION
\\n\\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\\n\\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\\n\\n6. INTECHOPEN’S DUTIES AND RIGHTS
\\n\\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\\n\\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\\n\\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\\n\\n7. MISCELLANEOUS
\\n\\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\\n\\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\\n\\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\\n\\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\\n\\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\\n\\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\\n\\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\\n\\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\\n\\nLast updated: 2020-11-27
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
\n\nLast updated: 2020-11-27
\n\n\n\n
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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