Open access peer-reviewed chapter

# Antioxidant Categories and Mode of Action

Written By

Manal Azat Aziz, Abdulkareem Shehab Diab and Abeer Abdulrazak Mohammed

Submitted: September 21st, 2018Reviewed: December 14th, 2018Published: November 6th, 2019

DOI: 10.5772/intechopen.83544

From the Edited Volume

## Antioxidants

Chapter metrics overview

View Full Metrics

## Abstract

Oxidative stress has received a considerable scientific attention as a mediator in the etiology of many human diseases. Oxidative stress is the result of an imbalance between free radicals and antioxidants. Cells can be damaged by free radicals that are considered to play a main role in the aging process and diseases development. Antioxidants are the first line of defense against the detrimental effects of free radical damage, and it is essential to maintain optimal health via different mechanisms of action. Types of antioxidants range from those generated endogenously by the body cells, to exogenous agents such as dietary supplements. Antioxidant insufficiency can be developed as a result of decreased antioxidant intake, synthesis of endogenous enzymes, or increased antioxidant utilization. To maintain optimal body function, antioxidant supplementation has become an increasingly popular practice through improving free radical protection. In this chapter, we first elucidate the oxidative stress, and then define the antioxidant and its categories. Finally, introduce the antioxidants mode of actions for cell protection from free radicals.

### Keywords

• oxidative stress
• antioxidants
• reactive oxygen species
• antioxidant enzymes
• antioxidant mechanisms

## 1. Introduction

Oxidative stress refers to the imbalance between oxidants and antioxidants within the body due to antioxidant deficiency or increased reactive oxygen species (ROS), reactive nitrogen species (RNA), and reactive sulfur species (RSS) production, which lead to potential cellular damage [1, 2]. ROS is a collective term that encompasses all highly reactive forms of oxygen, including free radicals. ROS categories include hydroxyl radical (OH), perhydroxyl radical (HO2), hypochlorous acid (HOCl), superoxide anion radical (O2•¯), hydrogen peroxide (H2O2), singlet oxygen (1O2), nitric oxide radical (NO), hypochlorite radical (OCl), peroxynitrite (ONOO), and different lipid peroxides. RNS are derived from nitric oxide by the reaction with O2•¯ to form ONOO¯, while RSS are easily produced from thiols through a reaction with ROS [3, 4].

Due to unpaired electrons of free radicals, these free radicals show high activity to react with other molecules in order to be neutralized. The free radicals have important functions in cell signaling, apoptosis, ion transportation, and gene expression [4]. Chemical reactivity of inactivated free radicals can damage all cellular macromolecules including carbohydrates, proteins, lipids, and nucleic acids. In general, cells are able to protect themselves against ROS damage via intracellular enzymatic reactions, metal chelating, and free radical scavenging actions to keep the ROS homeostasis at a low level. In addition, dietary antioxidants can assist to keep an adequate antioxidant status in the body. Nevertheless, during environmental stress and cell dysfunction, levels of ROS can increase dramatically and cause significant cellular damage in the body. Consequently, oxidative stress significantly contributes to the pathogenesis of different diseases, such as heart disease, inflammatory disease, cancer, diabetes mellitus, Alzheimer’s disease, autism, and to the aging process (Figure 1) [3, 4, 5]. The chapter clarifies oxidative stress. Then classify the antioxidants and their applications. Finally, we describe antioxidants’ mode of action and how they prevent the cell damage.

## 2. Oxidative stress

### 2.1 Oxidative damage to proteins

Protein oxidation can lead to amino acid modification, fragmentation of the peptide chain, aggregation of cross-linked reaction products, and increased electrical charges. Oxidized proteins are more susceptible to proteolysis, and a raise in oxidized proteins may be responsible for the loss of selected physiological and biochemical roles. Free radical damage to proteins may play a role in the causation of cataracts and aging (Figure 2) [1, 6].

### 2.2 Oxidative damage to lipids

Lipids have an important structural and functional role in cell membranes. After cell death, membrane lipids are susceptible to peroxidation and this process can cause misinterpretation of some lipid peroxidation assays. In particular, polyunsaturated fatty acids are susceptible targets for ROS attack. The important reactive moiety and initiator for ROS chain reaction and lipoperoxidation of polyunsaturated is OH [7]. Because of lipid peroxidation, several compounds are produced, such as alkanes, malondialdehyde, and isoprostanes. These compounds are utilized as indicators in lipid peroxidation assay, and have been confirmed in diseases including neurogenerative diseases, heart disease, and diabetes (Figure 2) [1, 8].

### 2.3 Oxidative damage to DNA

Activated oxygen and agents that produce oxygen-free radicals, for example, ionizing radiations, promote damage in DNA that leads to deletion, mutations, and other fatal genetic effects. Through this DNA damage, both sugar and base moieties are susceptible to oxidation, leading to base degradation, single-strand breakage, and cross links to proteins. Free radical damage to DNA is associated in the causation of cancer and accelerated aging (Figure 2) [1, 5, 9].

### 2.4 Oxidative damage to carbohydrates

According to carbohydrates, the production of oxygen-free radicals during early glycation could contribute to glycoxidative damage. Through the primary stages of nonenzymatic glycosylation, fragmentation of sugar forms short-chain species like glycoaldehyde whose chain is too short to cyclize and is thus prone to autoxidation, producing the superoxide radical that can lead to the formation of β-dicarbonyls, which are well-known mutagens [10]. Carbohydrates free radical oxidation mechanisms are comparable to those of lipids. Low molecular carbohydrates, such as glucose, mannitol, and deoxyribose, are well known to interact with HO, forming oxidized intermediates, which does not affect food quality [11].

## 3. Antioxidants

Antioxidants are inhibitors of oxidation, even at small concentrations; therefore, antioxidants have different physiological functions in the body. In addition, antioxidants act as free radical scavengers, by reacting with the reactive radicals and demolishing them to become less active, less dangerous, and long-lived substance than those radicals that have been neutralized. Antioxidants may be able to neutralize free radicals via accepting or donating electron(s) to remove the unpaired status of the radical [4]. Also, antioxidants can be defined as compounds able to inhibit oxygen-mediated oxidation of different substances from simple molecule to polymer and complicated bio-system [8].

The US Food and Drug Administration (FDA) defined antioxidants as substances utilized to preserve food by retarding deterioration, rancidity, or discoloration owing to oxidation. Whereas antioxidants are important to the food industry to prevent rancidity, antioxidants are also important to biologists and clinicians as they may assist to protect the human body against diseases from ROS danger by regulating ROS-related enzymes [8]. Cellular level of free radicals may be decreased by antioxidants either via inhibiting the activities or expression of free radical generating enzymes such as NAD(P)H oxidase and xanthine oxidase (XO), or by promoting the activities and expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) [12, 13, 14].

Since 1990s, antioxidant research has increased dramatically due to its potential role in disease prevention and health promotion. In biological systems such as animal models and clinical trials, the antioxidant action of pure compounds, foods, and dietary supplements has been extensively examined [4, 15, 16]. Numerous study models have been determined in chemical and/or biological systems to examine the mechanism of action of antioxidants, as well as the identification and recognition of new antioxidants, particularly from natural substances. Further research in animal models and cell cultures has provided critical information on the bioavailability, metabolism, and toxicity issues of antioxidants, suggesting probable clinical applications of these substances. Nevertheless, animal models and human research are expensive and not suitable for early antioxidant screening of foods and dietary supplements. Therefore, cell culture models have been utilized for early screening and study proceeding to animal research and human clinical trials [4].

Antioxidants can protect the cells and organs of the body against the harmful effect of the oxidative stress through various defense mechanisms by both enzymatic and nonenzymatic reactions, which work synergistically and together with each other. To prevent lipid peroxidation in food, nonenzymatic antioxidants are often added. The use of antioxidants for food and therapeutic purposes must be characterized carefully, because several lipid antioxidants can exert a prooxidant effect to other molecules under particular circumstances [5, 7].

The feature of a perfect antioxidant is that it should be readily absorbed, eliminate free radicals, and chelate redox metals at physiologically suitable levels. In addition, it should work in both aqueous and membrane domains, and have a positive effect on gene expression [7].

## 4. Antioxidant categories

Antioxidants can be classified in several ways [17, 18].

1. Based on their activity, they can be classified as enzymatic and nonenzymatic antioxidants. Dangerous oxidative products can be converted to H2O2 and then to water by enzymatic antioxidants that are able to break down and get rid of free radicals in a multistep process in the presence of cofactors such as copper (Cu), zinc (Zn), manganese (Mn), selenium (Se), and iron (Fe).

2. Vitamin C, vitamin E, plant polyphenol, carotenoids, and glutathione are nonenzymatic antioxidants, which act by interrupting free radicals chain reactions.

3. Based on solubility, antioxidants can be classified as water-soluble or lipid-soluble antioxidants. Vitamin C is a type of water-soluble vitamin found in cellular fluids such as cytosol or cytoplasmic matrix.

4. According to size, antioxidants can be categorized as small or large-molecule antioxidants. The small molecule antioxidants neutralize the ROS in a process named radicals scavenging and carry them away. Vitamin C, vitamin E, carotenoids, and glutathione (GSH) are the main antioxidants in this category. Large molecule antioxidants include enzymes (SOD, CAT, and GPx) and sacrificial proteins (albumin) that absorb ROS and prevent them from attacking other essential proteins.

5. Kinetically antioxidants can be categorized as below:

1. Antioxidants that are able to break chains through reacting with peroxyl radicals containing weak O–H or N–H bonds, phenol, naphthol, hydroquinone, aromatic amines, and aminophenols.

2. Antioxidants with a capability to break chains by reacting with alkyl radicals: quinines, nitrones, and iminoquinones.

3. Antioxidants that terminate cyclic chain such as aromatic amines, nitroxyl radicals, and variable valence metal compounds.

4. Hydroperoxide decomposing antioxidants such as sulfide, phosphide, and thiophosphate.

5. Metal-deactivating antioxidants include diamines, hydroxyl acids, and bifunctional compounds.

6. Synergism action of a number of antioxidants including phenol sulfide in which the phenolic group reacts with the peroxylradical’s sulfide group with hydroperoxide.

6. Based on their occurrence, antioxidants are categorized as natural or synthetic [19, 20].

1. Natural antioxidants

They are classified as chain-breaking antioxidants, which react with radicals and convert them into more stable products. Generally, antioxidants of this group are phenolic in structure and include the following:

1. Antioxidant minerals: these are antioxidant enzymes cofactors like selenium, copper, iron, zinc, and manganese. Absence of the cofactors will definitely enhance many macromolecules metabolism such as carbohydrates.

2. Antioxidant vitamins: these are important and required for most body metabolism functions such as, vitamin C, E, and B.

3. Phytochemicals: these are phenolic compounds derivatives that are neither vitamins nor minerals. Examples include flavonoids, catechins, carotenoids, carotene, lycopene, and herbs and spices such as diterpene, rosmariquinone, thyme, nutmeg, clove, black pepper, ginger, garlic, curcumin, and derivatives.

2. Synthetic antioxidants

These are phenolic compounds that carry out the role of capturing free radicals and stopping the chain reaction. These compounds include butylated hydroxyl anisole (BHA), butylated hydroxyltoluene (BHT), propyl gallate (PG), metal chelating agent (EDTA), tertiary butyl hydroquinone (TBHQ), and nordihydroguaiaretic acid (NDGA).

### 4.1 Antioxidant enzymes

There are several enzymes that catalyze reactions to neutralize free radicals and ROS. These enzymes form the body’s endogenous defense mechanisms from free radicals to protect the cell. The enzyme antioxidants GPx, CAT, and SOD are the best-known substances of the antioxidant protection system, and they are responsible for the free radical change [21]. Enzymes are important components of the protection and defense mechanisms, by decreasing ROS generation via removing potential oxidants/transferring ROS/RNS into relatively stable compounds [5]. For optimum catalytic activity, these enzymes require micronutrient cofactors such as Se, Fe, Cu, Zn, and Mn [21].

#### 4.1.1 Superoxide dismutase (SOD)

Irwin Fridovitch of Duke University and Joe McCord discovered antioxidant enzyme (SOD) (EC 1.15.1.1) in 1967, which belongs to the group of oxidoreductases. SOD is an important cellular defense against free radical damage. Therefore, medical scientists have begun to look seriously at free radicals [3]. SOD antioxidant enzymes are metal-containing proteins that catalyze the dismutation of the highly reactive superoxide anion to O2 and to the less reactive species H2O2 (Eq. (1)). The result is that peroxide can be destroyed by reaction of CAT or GPX [22, 23].

$O2−+O2−+2H+→SODH2O2+O2$E1

In mammals, there are three forms of SOD; the active site of the enzyme contains one or two different atoms of a transition metal in a certain oxidation state. SODs are categorized by their metal cofactors into known forms: cytosolic SOD, extracellular SOD [CuZnSOD], and mitochondrial SOD [MnSOD]. Each form is produced by distinct genes and distinct subcellular localization, but catalyzes the same reaction. This distinct subcellular localization of the three SOD forms is especially significant for compartmentalized redox signaling [24].

CuZnSOD enzymes have two identical subunits of about 32 kDa, though a monomeric structure is found in a high concentration of protein from E. coli. Each subunit includes a metal cluster, an active site, and a Cu and a Zn atom bridged By a histamine residue. The Cu and Zn which are important for SOD enzymatic activity. Zn contributes in appropriate protein folding and stability. Cu is not replaceable with another metal, while Zn is replaceable with cobalt and Cu, and it is not essential for enzyme action at low pH. CuZnSOD plays a major function in the first line of antioxidant defense [25].

MnSOD is a homotetramer 96 kDa; each subunit contains one Mn atom, those cycles from Mn3+ to Mn2+ and back to Mn3+ during the two-step dismutation of superoxide. In mitochondria, the main source of oxygen radicals is the respiratory chain. It was shown that this enzyme is greatly stimulated and decreased by cytokines, while oxidants moderately influenced it [26, 27, 28].

Extracellular SOD (ECSOD) is a tetrameric protein, containing Cu and Zn having a high affinity for certain glycosaminoglycans such as heparin and heparin sulfate [7]. ECSOD is found primarily in the extracellular membrane and to a lesser extent, in the extracellular fluids. It protects against the inactivation of NO liberating from the endothelium by O2¯ through diffusion to smooth muscle, thus preserving endothelial function. Studies have shown that ECSOD plays an essential role in various oxidative stress-dependent pathophysiologies, such as hypertension, ischemia reperfusion injury, and lung injury. In addition, a number of lines of research propose a role for ECSOD in aging. ECSOD plasma levels decrease with aging, and in old rats, gene transfer of ECSOD improves endothelial function. However, it is still unknown whether ECSOD expression or activity in blood vessels is adjusted by aging and whether endogenous ECSOD is engaged in regulation of vascular functions during aging [29].

#### 4.1.1.1 Application

SOD enzymes enhance the rejuvenation and cellular repair, while decreasing the damage caused by free radicals. SOD is necessary to generate sufficient amounts of skin building cells named fibroblasts and plays an essential role in preventing the progress of amyotrophic lateral sclerosis (ALS), which causes death if it affects the nerve cells in the spinal cord and brain. In addition, this enzyme is also utilized for inflammatory diseases treatment, burn injuries, prostate problems, corneal ulcer, arthritis, and reversing the long-term consequences of radiation and smoke exposure. Furthermore, it prevents wrinkle formation if the skin lotion contains this enzyme. Also, it enhances wound healing, reduces scars, and lightens skin pigmentation caused by UV rays.

Moreover, SOD facilitates nitric oxide moving into hair follicles. This is beneficial for people with a genetic predisposition or free radicals for premature hair loss. SOD is a very potent antioxidant, in that it combats the effect of free radicals on the hair follicles. Because of nitric oxide’s ability as a blood vessel relaxant, allowing more blood to reach the hair follicle, and SOD ability to remove free radicals, hair loss can be prevented or reversed. Maintaining overall well-being and health, as well as free radical protection, can be achieved by taking dietary supplement that provides an adequate supply of SOD [3].

#### 4.1.2 Catalase (CAT)

Catalase (EC 1.11.1.6) is an enzyme responsible for H2O2 degradation that is generated by oxidases involved in β-oxidation of fatty acids, respiration, and purine catabolism [3]. It is present in nearly all animal cells as a protective enzyme. The highest levels of CAT activity are measured in the liver, kidney, and red blood cells.

Human CAT composes four identical subunits of 62 kDa, each subunit containing four distinct domains and one prosthetic heme group, and has a molecular mass of about 240 kDa [30]. CAT enzyme reacts with H2O2 to form water and molecular oxygen and with H donors such as methanol, ethanol, formic acid, or phenols with peroxidase activity. CAT protects cells from H2O2 generated within them. Therefore, it has an essential role in the acquisition of tolerance to oxidative stress in the adaptive response of cells. Various disease conditions and abnormalities are associated with the deficiency or mutation of CAT enzyme [30, 31].

#### 4.1.2.1 Application

In the food industry, CAT enzyme is used to remove H2O2 from milk prior to cheese production, and to prevent food from oxidizing in food wrappers. In addition, CAT enzyme is used in the textile industry for H2O2 removal from fabrics, to make sure the material is peroxide free. Recently, esthetics industries have begun to use CAT enzyme in facial masks, as the combination of CAT enzyme with H2O2 on the face can be used to increase cellular oxygenation in the upper layers of the epidermis [3].

#### 4.1.3 Glutathione perioxidases (GPx)

Glutathione peroxidase (EC 1.11.1.9) contains a single selenocysteine residue in each of the four identical subunits, which is important for enzyme activity. GPx (80 kDa) is an imperative intracellular enzyme that catalyzes H2O2 to water and lipid peroxides to their corresponding alcohols mainly in the mitochondria and sometimes in the cytosol. In mammals, there are five GPx isoenzymes. Though their expression is ubiquitous, the level of each isoform differs depending on their tissue type. Mitochondrial and cytosolic glutathione peroxidase (GPx1 or cGPx) reduces fatty acid hydroperoxides and H2O2 at the expense of glutathione [32].

GPx1 is the main ubiquitous selenoperoxidase present in most cells; found in the cytosolic, mitochondrial, and peroxisomal compartments. It is an important antioxidant enzyme required in the detoxification of H2O2 and lipid hydroperoxides and preventing DNA, protein and lipids damage by harmful accumulation of intracellular H2O2 [33]. GPx1 uses GHS as an obligate co-substrate in the reduction of H2O2 to water [32]. Phospholipid hydroperoxidase glutathione (PHGPX) is found in most tissues and can directly reduce the phospholipid hydroperoxides, fatty acid hydroperoxides, and cholesterol hydroperoxides that are produced in peroxidized membranes and oxidized lipoproteins [30].

GPx4 is found in both the cytosol and the membrane fraction, and is highly expressed in renal epithelial cells and tests. Cytosolic GPx2 or extracellular GPx3 is inadequately found in nearly all tissues except for the gastrointestinal tract and kidney. In recent, GPx5, a new kind, expressed particularly in mouse epididymis, is selenium independent [34].

Several studies underlined the clinical importance of GPx. In addition, GPx, especially GPx1, have been implicated in the progression and prevention of many frequent and complex diseases, including cancer and cardiovascular disease [34, 35].

#### 4.1.3.1 Application

GPx is an important antioxidant enzyme in the body. Glutathione (GHS), the master antioxidant, is important for GPx levels due to the closely linked relationship; GHS is a tripeptide that protects the cells against the negative effects of pollution and functions as the body’s immune system booster. GHS plays an essential role in red blood cells to remain intact and protects white blood cells, which are responsible for the immune system. An antioxidant’s role is specifically essential for the brain because it is sensitive to the presence of free radicals. To increase the body’s protection from free radicals, it is imperative to combine certain antioxidants such as glutathione, vitamin C and E, Se, and GPx [3].

### 4.2 Nonenzymatic antioxidants

In previous decades, there has been increasing evidence that large amounts of antioxidants present in our diet contribute to the antioxidant defense system by preventing oxidative stress and specific human diseases. Phytochemicals, the plant-derived compounds, are one of the classes of the dietary factors, which play an essential role in functions of the body. Food materials contain a number of natural compounds reported to have antioxidant characteristics due to the presence of hydroxyl groups in their structure. Synthetic and natural antioxidants prevent the oxidative damage to the most important macromolecules such as lipids, proteins, and nucleic acids found in human body through scavenging the free radicals formed in different biochemical processes [36]. These antioxidants consist of small molecules including vitamin C, E, and β-carotene or natural antioxidants such as flavonoids, tannins, coumarins, phenolics, and terpenoids [37]. Because of oxidative stress, the free radicals that have been produced react with lipids, proteins and nucleic acids and lead to stimulation of apoptosis, which causes various neurological, cardiovascular, and physiological disorders [38].

In addition to phytochemical antioxidants, which can protect the body from oxidative damage, there are other antioxidants for example polyphenols, lycopene, and lutein [39]. Even though there has been a considerable concentration on antioxidant function of phytochemicals for several years, it is distinguished that phytochemicals have nonantioxidant effects important for health such as cell signaling and gene expression [40].

#### 4.2.1 Glutathione

Glutathione (γ-glutamyl-cysteinyl-glycine; GSH) is a tripeptide and is the most abundant intracellular antioxidant protecting normal cells from oxidative injury due to its role as a substrate of ROS scavenging enzymes. Glutathione is primarily present in its reduced form (GSH) in normal conditions, with only a small amount being found in the fully oxidized state (GSSG) [41]. Glutathione functions as a nonenzymatic antioxidant through free radical scavenging in cells and serves as a cofactor for several enzymes, include GPx, glutathione reductase (GR), and glutathione transferase (GST) [42, 43].

#### 4.2.1.1 Application

Recently, there is a new era of therapeutic applications of glutathione through the association of decreased GSH levels with the common features of aging and a wide range of pathological conditions, including neurodegenerative disorders. Remarkably, depletion and alterations of GSH in its metabolism appear to be crucial in the onset of Parkinson’s disease [44].

#### 4.2.2 Vitamin E

Vitamin E, C, and β-carotene are the main antioxidant vitamins for tissues against free radical damage. Vitamin E, a major lipid soluble antioxidant, functions as the most important membrane-bound antioxidant, neutralizing free radicals, and preventing oxidation of lipids within membranes [45]. Vitamin E is the free radical scavenger in the prevention of chronic diseases [46]. α-Tocopherol is the main form of vitamin E with antioxidant and immune functions. α-tocopherol has been revealed to be a more effective inhibitor of peroxynitrite-induced lipid peroxidation and inflammatory reactions [47]. In vitrotocotrienols have excellent antioxidant activity and have been proposed to restrain ROS more effectively than tocopherols [48].

#### 4.2.2.1 Application

The main function of vitamin E is to protect against lipid peroxidation through evidence suggesting that α-tocopherol and vitamin C function together in a cyclic type of process. It has been reported that vitamin E supplementation in hypercholesterolemic patients has shown to increase autoantibody levels against oxidized LDL, and prevent ischemic heart disease [49].

#### 4.2.3 Vitamin C

In extracellular fluids, vitamin C, a water-soluble vitamin, is the most important antioxidant and can protect biomembranes against lipid peroxidation injury through eliminating peroxyl radicals in the aqueous phase before peroxidation initiation. Vitamin C is an effective antioxidant located in the aqueous phase of cells; it simply loses electrons to give stability to reactive species such as ROS [45]. In addition to vitamin C’s biological functions as a superoxide and hydroxyl radicals’ scavenger, it also functions as an enzyme cofactor [42].

#### 4.2.3.1 Application

Vitamin C plays an essential function in the defense against oxidative damage particularly in leukocytes, as well as the possible effect it may have on the treatment of chronic degenerative diseases, autoimmune diseases, and cancer [42, 45].

#### 4.2.4 Carotenoids

Carotenoids are structurally and functionally different natural pigments found in many fruits and vegetables. A combination of carotenoids and tocopherols antioxidants in the lipid phase of biological membranes may enhance better antioxidant protection than tocopherols alone. Antioxidant characteristics of carotenoids include scavenging single oxygen and peroxyl radicals, thiyl, sulfonyl, sulfur, and NO2 radicals and giving protection to lipids from superoxide and hydroxyl radical attack [49].

#### 4.2.4.1 Application

Carotenoids and some of their metabolites are proposed to play a protective function in several ROS-mediated disorders, include cardiovascular, cancer, and myocardial infarction among smokers. Carotenoid-rich food and supplementation decrease morbidity in nonsmokers and reduce the risk of prostate cancer [42].

#### 4.2.5 Vitamin A

Vitamin A, a lipid soluble vitamin, is important for human health and has free radicals scavenging features that aid it to act as a physiological antioxidant in protecting a number of chronic diseases such as cardiovascular disease and cancer. All transretinol, the parent compound, are the most abundant dietary form of vitamin A that occurs naturally in the form of fatty acid esters such as retinyl palmitate, while retinal and retinoic acid are the minor natural dietary components of vitamin A [45]. Vitamin A was first labeled as an inhibitor of the effect of linoleic acid on the oxidation processes. At present, vitamin A and carotenoids are known for their antioxidant actions depending on their capability to interact with radicals and prohibit cell lipid peroxidation [9].

#### 4.2.5.1 Application

Vitamin A is important for life in mammals; it cannot be synthesized in body and has to be supplied by food. Due to its role as antioxidant, vitamin A has a new role in preventive nutrition against neurodegenerative diseases. Recently, vitamin A has increased the interest in supplementation via food [50].

#### 4.2.6 Uric acid

Uric acid, hyperuricemia, is a potent free radical scavenger and estimated ~60% of free radical scavenging capacity in plasma [51]. Uric acid is a physiological antioxidant and an effective preventer of the production of ROS species during the action of xanthine oxidase (XO) in catalysis reaction of xanthine and hypoxanthine [42]. A study illustrated the urate ability to scavenge oxygen radicals and protect the erythrocyte membrane from lipid oxidation, characterized further by Ames et al. through the effect of uric acid in protection of cells from oxidants, which related to a variety of physiological situation [51]. Nevertheless, it is probable that the increase in serum level of uric acid is a response to protect against the detrimental effects of extreme free radicals and oxidative stress [52].

#### 4.2.6.1 Application

Studies showed that serum uric acid levels are highly predictive of mortality in patients with coronary artery disease, heart failure, or diabetes. In addition, high uric acid level is associated with deleterious effect on vascular function. Recently, it has been found that patients with high serum uric acid level had impaired flow-mediated dilation, which was normalized by therapy for 3 months with the xo inhibitor allopurinol [53].

#### 4.2.7 Lipoic acid

Lipoic acid is a strong antioxidant, and it reveals a great capability of antioxidant when given natural or as a synthetic drug. Lipoic acid is a short-chain fatty acid, composed of sulfur in their structure that is known for its contribution in the reaction that catalyzes the oxidation decarboxylation of α-keto acids, for example pyruvate and α-ketoglutarate, in the citric acid cycle. Lipoic acid and its reduced form, dihydrolipoic acid (DHLA), are capable of quenching free radicals in both lipid and aqueous domains. Lipoic acid and DHLA have been revealed to have antioxidant, cardiovascular, antiaging, detoxifying, anti-inflammatory, anticancer, and neuroprotective pharmacological properties [40, 54].

#### 4.2.7.1 Application

Regarding the pathology of diabetes, there are many potential applications for lipoic acid. In type I diabetes, destruction of pancreatic β-cells leads to loss secretion of insulin, while the major problem in type II diabetes is insulin resistance of peripheral tissues. Lipoic acid has potential preventive or ameliorative effect in both type I and type II diabetes [54].

#### 4.2.8 Flavonoids

Flavonoids are low in molecular weight and are the main type of phenolic compounds in plants. They are structured by 15 carbon atoms, organized in a C6-C3-C6 configuration. Due to their high redox potential, flavonoids are, in particular, important antioxidants that allow them to function as reducing agents, hydrogen donors, and singlet oxygen quenchers. In addition, they include a metal chelating potential [55].

#### 4.2.8.1 Application

Flavonoids are generally found in many fruits and vegetables. When human increasingly consumed it, flavonoids have been linked with a decrease in the incidence of diseases such as prostate [56, 57] or breast cancer [58, 59].

#### 4.2.9 Tannins

Tannins are relatively high-molecular compounds, which comprise the third essential group of phenolics and can be divided into condensed and hydrolysable tannins. Condensed tannins are produced by the polymerization of flavonoid units. The mainly studied condensed tannins are based on flavan-3-ols: (−)-epicatechin and (+)-catechin. Hydrolysable tannins are heterogeneous polymers containing phenolic acids, in particular, gallic acid (3,4,5 trihydroxyl benzoic acid) and simple sugar [42, 55].

#### 4.2.9.1 Application

Because of tannin features, such as being the potential metal ion chelators, protein-precipitating agents, and biological antioxidants, tannins have different effects on biological systems. As a consequence of the diverse tannins biological roles and structural variation, it has been difficult to modify models that would let a precise prediction of their effects in any system. Therefore, the tannin structure modification and activity relationship are important to predict their biological effect [42].

## 5. Antioxidants: mechanisms of action

Generally, the antioxidants defend against free-radicals-induced oxidative damage by various mechanisms as discussed in below sections.

### 5.1 Preventive antioxidants

ROS such as H2O2, O2, and OH are produced irreversibly during metabolism. Therefore, methods have been extensively studied to reduce the damage enhanced by oxidative stress. Intracellular antioxidant enzymes produced in the cell are an essential protective mechanism against free radicals formation. SOD, CAT, GPx, GR, GST, thioredoxin reductase, and hemeoxygenase are the most important antioxidants enzymes. SODs convert O2 into H2O2, which is then converted into water by CAT, GPx, and Fenton reaction. Thus, two toxic species are converted into a harmless product (Figure 3) [5].

During metabolism, peroxides are formed and then eliminated via both GST and GPX. GRd regulates the equivalent of GSH and oxidized glutathione (GSSG), and the ratio of GSH/GSSG is a known index of oxidative stress [60]. The action of GRd plays an imperative role in increasing GSH concentration, which maintains the oxido-redox condition in the organism [14]. Consequently, the oxidative stress role has been reported in the progress and clinical symptom of autism. Recently, a comparison study between autism and control individuals showed decrease in GSH/GSSG ratio and increase in free radical generation in autism compared to control cells [60]. In addition, GPx is presented throughout the cell, while CAT is frequently limited to peroxisomes. In the brain, which is very sensitive to free radical damage, it has seven times more GPx activity than CAT activity. Moreover, CAT’s highest levels are found in the liver, kidney, and erythrocytes, where it decomposes the most of H2O2 [61].

#### 5.2.1 Scavenging superoxide and other ROS

Superoxide (O2•¯), a predominant cellular free radical, is contributed in a huge number of deleterious alterations often linked to a low concentration of antioxidants and associated with a raise in peroxidative processes. Though O2•¯ itself is not reactive to biomolecules, it assists in production of stronger OH•, and ONOO¯.O2•¯ is formed in large quantities, in phagocytes via NADPH oxidase enzyme during pathogen-killing process. In addition, it is a byproduct of mitochondrial respiration [3].

#### 5.2.2 Scavenging hydroxyl radical and other ROS

Hydroxyl radical (OH) is an extremely active and more toxic radical on biologic molecules such as DNA, lipids, and proteins than other radical species. In general, OH is considered to be formed from the Fe2+ or Cu+/H2O2 Fenton reaction system, through incubation FeSO4 and H2O2 in aqueous solution. Therefore, antioxidants activity as OH scavenger can be accomplished by direct scavenging or prohibiting of OH generation by the chelation of free metal ions or altering H2O2 to other nontoxic compounds [3].

#### 5.2.3 Metal ion (Fe2+, Fe 3+, Cu2+, and Cu+) chelating

Even though trace minerals are essential dietary components, they can function as prooxidants (through enhancing formation of free radicals). Fe2+ and Cu+ react with H2O2, which is a product produced by the dismutation of the O2•¯ via SOD, to form extremely reactive OH (Eq. (2)). Dissimilarly, iron and copper’s reaction with H2O2 forms more singlet oxygen than OH. Fe2+ and Cu+ are oxidized to Fe3+ and Cu2+, respectively. Cellular reductant such as NADH and oxidized metal ions Fe3+, and Cu2+ are reduced and permit the recycling to react with another molecule of H2O2 to produce OH radical in the presence of vitamin C (Eq. (3)). OH is strongly reactive and can directly react with proteins and lipids to produce carbonyls (aldehydes and ketones), cross linking, and lipid peroxidation. Chelating metal ions are able to decrease their action, thus reducing the ROS formation.

$Fe2+orCu++H2O2Fe3+orCu2++OH•+OH−$E2
$Fe3+orCu2++vitCH−Fe2+orCu++vitaminC−•+H+$E3

Studies showed that Se antioxidant is able to chelate Cu+ (formed in situ with Cu2+/ascorbic acid) extremely efficiently and prevent the damage of DNA by OH radical (formed via Cu+/H2O2) [3].

### 5.4 Prevention of lipid peroxidation

Lipid peroxidation is defined as oxidative deterioration of lipids composed of C-C double bonds such as unsaturated fatty acids, glycolipids, cholesterol, cholesterol ester, phospholipids. ROS damage the unsaturated fatty acids, which include numerous double bonds and the methylene-CH2-groups with particularly reactive hydrogen atoms, and begin the radical peroxidation chain reactions [65]. Antioxidants are able to directly react and quench peroxide radicals to stop the chain reaction. Lipid peroxidation and DNA damage are related to different chronic diseases, such as cancer, and atherosclerosis. Antioxidants can scavenge ROS and peroxide radicals, therefore prohibiting or treating certain pathogenic situations. Scientific attention has been concentrated in lipid peroxidation for recognizing natural antioxidants and studying their mechanism of action. Researches on antioxidants such as vitamins, polyphenols and flavones against free radical enhanced lipid peroxidation have been assumed in many systems such as lipid, red blood cells and LDL. The antioxidant activity of these polyphenols depends considerably on molecules structure, the initiation conditions and the microenvironment of the reaction medium [3].

### 5.5 Prevention of DNA damage

In vivo, the OH and ONOO¯ radicals produced from nitric oxide and O2•¯ are able to react directly with plasmid DNA macromolecules to cleave one DNA strand, leading to oxidative DNA damage. Cell death and mutation as a result of DNA damage are associated with neurodegenerative and heart diseases, cancer and aging. Consequently, DNA or plasmid damage has received attention and been utilized as models for the study and identification of antioxidants [66]. A study has been progressed include DNA damage caused by Cu+ induced OH, through metal-free plasmid DNA mixed with Cu2+, ascorbic acid and H2O2 at pH 7. The reaction includes reduction of Cu2+ to Cu+ in situ with ascorbic acid. The OH radical formed via Cu+/H2O2 cleaves one DNA strand, causing the ordinarily supercoiled plasmid DNA to unwind [3].

### 5.6 Prevention of protein modification

Besides lipid peroxidation and DNA damage, protein modification through nitration or chloration of amino acids also is caused by ROS. In vivo, peroxynitrite, O═N─O─O¯, is a powerful oxidant and nitrating agent formed through the reaction of O2•¯ with free radical nitric oxide via a diffusion-controlled reaction. In cells, ONOO¯ is a much stronger oxidizing agent than O2•¯ and is able to damage a wide range of different molecules such as DNA and proteins. ONOO¯ and its protonated form peroxynitrous acids (ONOOH) are capable of exerting direct oxidative modifications during one or two electron oxidation processes [67]. In vivo, ONOO¯ reacts nucleophically with CO2 to produce nitrosoperoxy carbonate, which is the predominant pathway for ONOO¯. These modifications often cause the alteration of protein function or structure, in addition to enzyme activities inhibition. Proteins containing nitrotyrosine residues have been detected in various pathogenic conditions, such as diabetes, hypertension, and atherosclerosis, all linked with promoted oxidative stress, including increased formation of ONOO¯. Antioxidants and antioxidant enzyme are utilized to prevent the protein modification of ONOO¯. Antioxidants or enzyme such as CAT is able to remove H2O2 and also inhibit HOCl formation; similarly, SOD or antioxidants, like polyphenols, may scavenge O2•¯ and inhibit ONOO¯ formation [3].

## 6. Conclusion

This chapter briefly summarized types of antioxidants, and their mode of action. The harmful products formed during normal cellular functions are oxygen radical derivatives that are the most important free radical in the biological system. For normal physiological functioning, it is important to maintain a tolerated antioxidant status by increasing intake of natural antioxidants. Studies have shown that different types of antioxidants, including natural and synthetic antioxidants, can help in disease prevention. The antioxidant compounds may directly react with the reactive radicals to destroy them via accepting or donating electron(s) to directly remove the unpaired status of the radical. Moreover, they may indirectly reduce the production of free radicals by inhibiting the efficacy or expressions of free radical creating enzymes or by stimulating the activities and expressions of other antioxidant enzymes. Thus, it is essential to know the antioxidant mechanisms of action with the free radicals.

## Conflict of interest

The authors declare they have no financial or other conflict of interests related to this chapter.

## References

1. 1.Law BMH, Waye MMY, So WKW, Chair SY. Hypotheses on the potential of rice bran intake to prevent gastrointestinal cancer through the modulation of oxidative stress. International Journal of Molecular Sciences. 2017;18:1-20
2. 2.Aziz MA, Ghanim HM, Diab KS, Al-Tamimi RJ. The association of oxidant-antioxidant status in patients with chronic renal failure. Renal Failure. 2016;38(1):20-26
3. 3.Krishnamurthy P, Wadhwani A. Antioxidant enzymes and human health. In: El-Missiry MA, editor. Antioxidant Enzyme. Croatia: In Tech; 2012. pp. 3-18. DOI: 10.3109/0886022X.2015.1103654
4. 4.Lü JM, Lin PH, Yao Q , Chen C. Chemical and molecular mechanisms of antioxidants: Experimental approaches and model systems. Journal of Cellular and Molecular Medicine. 2009;14(4):840-860
5. 5.Pandey KB, Rizvi SI. Markers of oxidative stress in erythrocytes and plasma during aging in humans. Oxidative Medicine and Cellular Longevity. 2010;3(1):2-12
6. 6.Kumar S. Free radicals and antioxidants: Human and food system. Advanced in Applied Science Research. 2011;2(1):129-135
7. 7.KurutasEB. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Kurutas Nutrition Journal. 2016;15:71-93
8. 8.Bagchi K, Puri S. Free radicals and antioxidants in health and disease: A review. Eastern Mediterranean Health Journal. 1998;4(2):350-360
9. 9.Zadák Z et al. Antioxidants and vitamins in clinical conditions. Physiological Research. 2009;58(1):S13-S17
10. 10.Benov L, Beema AF. Superoxide-dependence of the short chain sugars-induced mutagenesis. Free Radical Biology and Medicine. 2003;34:429-433
11. 11.Polumbryk M, Ivanov S, Polumbryk O. Antioxidants in food systems. Mechanism of action. Ukrainian Journal of Food Science. 2013;1(1):15-40
12. 12.Shebis Y et al. Natural antioxidants: Function and sources. Food and Nutrition Sciences. 2013;4:643-649
13. 13.Panchatcharam M et al. Curcumin improves wound healing by modulating collagen and decreasing reactive oxygen species. Molecular and Cellular Biochemistry. 2006;290:87-96
14. 14.Shih PH, Yeh CT, Yen GC. Anthocyanins induce the activation of phase II enzymes through the antioxidant response element pathway against oxidative stress-induced apoptosis. Journal of Agricultural and Food Chemistry. 2007;55:9427-9435
15. 15.Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies. American Journal of Clinical Nutrition. 2005;81:243S-2255S
16. 16.Lotito SB, Frei B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: Cause, consequence, or epiphenomenon? Free Radical Biology and Medicine. 2006;41:1727-1746
17. 17.Shahidi F, Zhong Y. Novel antioxidants in food quality preservation and health promotion. European Journal of Lipid Science Technology. 2010;112:930-940
18. 18.Nimse SB, Pal D. Free radicals, natural antioxidants, antheir reaction mechanisms. Royal Society of Chemistry Advances. 2015;5:27986-28006
19. 19.Mathew BB, Tiwari A, Jatawa SK. Free radicals and antioxidants: A review. Journal of Pharmacy Research. 2011;4(12):4340-4343
20. 20.Hurrell RF. Influences of vegetable protein sources on trace element and mineral bioavailability. Journal of Nutrition. 2003;133(9):2973S-2977S
21. 21.Butnariu M, Grozea I. Antioxidant (antiradical) compounds. Journal of Bioequivalence and Bioavailability. 2012;4(6):4-6
22. 22.Vitale M, Di Matola T, Ďascoli F. Iodide excess induces apoptosis in thyroid cells trough a p53-independent mechanism involving oxidative stress. Endrocriology Scoeity. 2000;141:598-605
23. 23.Fernandez V, Barrientos X, Kiperos K, Valenzuela A, Videla LA. Superoxide radical generation, NADPH oxidase activity and cytochrome P-450 content of rat liver microsomal fractions in an experimental hyperthyroid state: Relation to lipid peroxidation. Endocrinology. 1985;117:496-501
24. 24.Fukai T, Ushio-Fukai M. Role in redox signaling, vascular function, and diseases. Antioxidants and Redox Signaling. 2011;15(6):1583-1606
25. 25.Ghafourifar P, Cadenas E. Mitochondrial nitric oxide synthase. Trends in Pharmacological Sciences. 2005;26(4):190-195
26. 26.Maggi-Capeyron MF, Cases J, Badia E, et al. A diet high in cholesterol and deficient in vitamin E induces lipid peroxidation but does not enhance antioxidantenzyme expression in rat liver. Journal of Nutritional Biochemistry. 2002;13:296-301
27. 27.Ighodaro OM, Akinloye OA. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): Their fundamental role in the enrire antioxidant defence grid. Alexandria Journal of Medicine. 2017;54(4):287-293.https://doi.org/10.1016/j.ajme.2017.09.001
28. 28.MacMillan-Crow LA, Crow JP, Thompson JA. Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry. 1998;37:1613-1622
29. 29.Fukai T. Extracellular SOD and aged blood vessels. American Journal of Physiology—Heart and Circulatory Physiology. 2009;297(1):H10-H12
30. 30.Buschfort C, Muller MR, Seeber S, et al. DNA excision repair profiles of normal and leukemic human lymphocytes: Functional analysis at the single cell level. Cancer Research. 1997;57:651-658
31. 31.Góth L, Rass P, Pȧy A. Catalase enzyme mutations and their association with diseases. Molecular Diagnostics. 2004;8:141-149
32. 32.Esworthy RS, Ho YS, Chu FF. The GPx1 gene encodes mitochondrial glutathione peroxidase in the mouse liver. Archives Biochemistry Biophysics. 1997;340:59-63
33. 33.JB DH et al. Lack of the antioxidant enzyme glutathione peroxidase-1 (GPx1) does not increase atherosclerosis in C57BL/J6 mice fed a high fat diet. Journal of Lipid Research. 2006;47(6):1157-1167
34. 34.Imai H, Narashima K, Arai M, Sakamoto H, Chiba N, Nakagawa Y. Suppression of leukotriene formation in RBL-2H3 cells that overexpressed phospholipid hydroperoxide glutathione peroxidase. Journal of Biological Chemistry. 1998;273:1990-1997
35. 35.Rayman MP. Selenium in cancer prevention: A review of the evidence and mechanism of action. Proceedings of the Nutrition Scoiety. 2005;64:527-542
36. 36.Shui GH, Leong LP. Analysis of polyphenolic antioxidants in star fruit using liquid chromatography and mass spectrometry. Journal of Chromatography A. 2004;1022:67-75
37. 37.Perumalla VS, Hettiarachchy NS. Green tea and grape seed extracts potential applications in food safety and quality. Food Research International. 2011;44(4):827-839
38. 38.Uttara B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options. Current Neuropharmacology. 2009;7(1):65-74
39. 39.Moon JK, Shibamoto T. Antioxidant assays for plant and food components. Journal of Agricultural and Food Chemistry. 2009;57(5):1655-1666
40. 40.El Barky AR, Hussein SA, Mohamed TM. The potent antioxidant alpha lipoic acid. Journal of Plant Chemistry and Ecophysiology. 2017;2(1):1-5
41. 41.Pocsi I, Prade RA, Penninckx MJ. Glutathione, altruistic metabolite in fungi. Advances in Microbial Physiology. 2004;49:1-76
42. 42.Skowyra M. Antioxidant properties of extracts from selected plant materials (Caesalpinia spinosa,Perilla frutescens,Artemisia annuaand Viola wittrockiana) in vitro and in model food systems [thesis]. Department of Chemical Engineering, Universitat Politècnica de Catalunya; 2014
43. 43.Sun SY. N-acetylcysteine, reactive oxygen species and beyond. Cancer Biology & Therapy. 2010;9(2):109-110
44. 44.Homma T, Fujii J. Application of glutathione as anti-oxidative and anti-aging drugs. Current Drug Metabolism. 2015;16(7):560-571
45. 45.Arredondo ML. Relationship between vitamin intake and total antioxidant capacity in elderly adults. Universitas Scientiarum. 2016;21(2):167-177
46. 46.Herrera E, Barbas C. Vitamin E: Action, metabolism and perspective. Journal of Physiology and Biochemistry. 2001;57:43-56
47. 47.McCormick CC, Parker RS. The cytotoxicity of vitamin E is both vitamer and cell specific and involves a selectable trait. Journal of Nutrition. 2004;134:3335
48. 48.Schaffer S, MullerbWE, Eckert GP. Tocotrienols: Constitutional effects in aging and disease. Journal of Nutrition.2005;135:151
49. 49.Rahman K. Studies on free eadicals, antioxidants, and co-factors. Clinical Interventions in Aging. 2007;2(2):219-236
50. 50.Sauvant P, Cansell M, Hadj A, Atgie C. Vitamin a enrichment: Caution with encapsulation strategies used for food applications. Food Research International. 2012;46(2):469-479
51. 51.Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant-and radical-caused aging and cancer: A hypothesis. Proceedings of the National Academy Sciences of the United States of America. 1981;78:6858-6862
52. 52.Johnson RJ. Essential hypertension, progressive renal disease, and uric acid: A pathogenetic link? Journal of Anerican Nephrology. 2005;16:1909-1919
53. 53.Mercuro G et al. Effect of hyperuricemia upon endothelial function in patients at increased cardiovascular risk. The American Journal of Cardiology. 2004;94:93293-93295
54. 54.Packer L, Witt EH, Tritschler HJ. Alpha lipoic acid as a biological antioxidant. Free Radical Biology and Medicine. 1995;19(2):227-250
55. 55.Walter M, Marchesan E. Phenolic compounds and antioxidant activity of rice. Brazilizn Archives of Biology and Technology. 2011;54(1):371-377
56. 56.Tsao R, Yang R. Optimization of a new mobile phase to know the complex and real polyphenolic composition: Towards a total phenolic index using high performance liquid chromatography. Journal of Chromatography. 2003;1018(1):29-40
57. 57.Jaganathan SK et al. Role of pomegranate and citrus fruit juices in colon cancer prevention. World Journal Gastroenterology. 2014;20(16):4618-4625
58. 58.Sharmila G et al. Chemopreventive effect of quercetin, a natural dietary flavonoid on prostate cancer in in vivo model. Clinical Nutrition (Edinburgh, Scotland). 2014;33(4):718-726
59. 59.Yiannakopoulou EC. Effect of green tea catechins on breast carcinogenesis: A systematic review of in-vitro and in-vivo experimental studies. European Journal of Cancer Prevention: The official Journal of the European Cancer Prevention Organisation. 2014;23(2):84-89
60. 60.James SJ, Rose S, Melnyk S, et al. Cellular and mitochondrial glutathione redox imbalance in lymphoblastoid cells derived from children with autism. Federation of American Societies For Experimental Biology Journal. 2009;23:237-283
61. 61.Marklund SL, Westman NG, Lundgren E, et al. Copper and zinc containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues. Cancer Research. 1982;42:1955-1961
62. 62.Lin HC, Tsal SH, Chen CS, et al. Structure-activity relationship of coumarin derivatives on xanthine oxidase-inhibiting and free radical-scavenging activities. Biocmeical Pharmacology. 2008;75:1416-1425
63. 63.Schroder K, Vecchione C, Jung O, et al. Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. Free Radical Biology and Medicine. 2006;41:1353-1360
64. 64.Castilla P, Davalos A, Teruel JL, et al. Comparative effects of dietary supplementation with red grape juice and vitamin E on production of superoxide by circulating neutrophil NADPH oxidase in hemodialysis patients. American Journal of Clinical Nutrition. 2008;87:1053-1561
65. 65.Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids. 1995;30:277-290
66. 66.Zhao F, Tang YZ, Liu ZQ. Protective effect of icariin on DNA against induced oxidative damage. Journal of Pharmacy and Pharmacology. 2007;59:1729-1732
67. 67.Pacher P, Beckman JB, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiolagical Review. 2007;87:315-424

Written By

Manal Azat Aziz, Abdulkareem Shehab Diab and Abeer Abdulrazak Mohammed

Submitted: September 21st, 2018Reviewed: December 14th, 2018Published: November 6th, 2019

## 2. Oxidative stress

### 2.1 Oxidative damage to proteins

Protein oxidation can lead to amino acid modification, fragmentation of the peptide chain, aggregation of cross-linked reaction products, and increased electrical charges. Oxidized proteins are more susceptible to proteolysis, and a raise in oxidized proteins may be responsible for the loss of selected physiological and biochemical roles. Free radical damage to proteins may play a role in the causation of cataracts and aging (Figure 2) [1, 6].

### 2.2 Oxidative damage to lipids

Lipids have an important structural and functional role in cell membranes. After cell death, membrane lipids are susceptible to peroxidation and this process can cause misinterpretation of some lipid peroxidation assays. In particular, polyunsaturated fatty acids are susceptible targets for ROS attack. The important reactive moiety and initiator for ROS chain reaction and lipoperoxidation of polyunsaturated is OH [7]. Because of lipid peroxidation, several compounds are produced, such as alkanes, malondialdehyde, and isoprostanes. These compounds are utilized as indicators in lipid peroxidation assay, and have been confirmed in diseases including neurogenerative diseases, heart disease, and diabetes (Figure 2) [1, 8].

### 2.3 Oxidative damage to DNA

Activated oxygen and agents that produce oxygen-free radicals, for example, ionizing radiations, promote damage in DNA that leads to deletion, mutations, and other fatal genetic effects. Through this DNA damage, both sugar and base moieties are susceptible to oxidation, leading to base degradation, single-strand breakage, and cross links to proteins. Free radical damage to DNA is associated in the causation of cancer and accelerated aging (Figure 2) [1, 5, 9].

### 2.4 Oxidative damage to carbohydrates

According to carbohydrates, the production of oxygen-free radicals during early glycation could contribute to glycoxidative damage. Through the primary stages of nonenzymatic glycosylation, fragmentation of sugar forms short-chain species like glycoaldehyde whose chain is too short to cyclize and is thus prone to autoxidation, producing the superoxide radical that can lead to the formation of β-dicarbonyls, which are well-known mutagens [10]. Carbohydrates free radical oxidation mechanisms are comparable to those of lipids. Low molecular carbohydrates, such as glucose, mannitol, and deoxyribose, are well known to interact with HO, forming oxidized intermediates, which does not affect food quality [11].

## 3. Antioxidants

Antioxidants are inhibitors of oxidation, even at small concentrations; therefore, antioxidants have different physiological functions in the body. In addition, antioxidants act as free radical scavengers, by reacting with the reactive radicals and demolishing them to become less active, less dangerous, and long-lived substance than those radicals that have been neutralized. Antioxidants may be able to neutralize free radicals via accepting or donating electron(s) to remove the unpaired status of the radical [4]. Also, antioxidants can be defined as compounds able to inhibit oxygen-mediated oxidation of different substances from simple molecule to polymer and complicated bio-system [8].

The US Food and Drug Administration (FDA) defined antioxidants as substances utilized to preserve food by retarding deterioration, rancidity, or discoloration owing to oxidation. Whereas antioxidants are important to the food industry to prevent rancidity, antioxidants are also important to biologists and clinicians as they may assist to protect the human body against diseases from ROS danger by regulating ROS-related enzymes [8]. Cellular level of free radicals may be decreased by antioxidants either via inhibiting the activities or expression of free radical generating enzymes such as NAD(P)H oxidase and xanthine oxidase (XO), or by promoting the activities and expression of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) [12, 13, 14].

Since 1990s, antioxidant research has increased dramatically due to its potential role in disease prevention and health promotion. In biological systems such as animal models and clinical trials, the antioxidant action of pure compounds, foods, and dietary supplements has been extensively examined [4, 15, 16]. Numerous study models have been determined in chemical and/or biological systems to examine the mechanism of action of antioxidants, as well as the identification and recognition of new antioxidants, particularly from natural substances. Further research in animal models and cell cultures has provided critical information on the bioavailability, metabolism, and toxicity issues of antioxidants, suggesting probable clinical applications of these substances. Nevertheless, animal models and human research are expensive and not suitable for early antioxidant screening of foods and dietary supplements. Therefore, cell culture models have been utilized for early screening and study proceeding to animal research and human clinical trials [4].

Antioxidants can protect the cells and organs of the body against the harmful effect of the oxidative stress through various defense mechanisms by both enzymatic and nonenzymatic reactions, which work synergistically and together with each other. To prevent lipid peroxidation in food, nonenzymatic antioxidants are often added. The use of antioxidants for food and therapeutic purposes must be characterized carefully, because several lipid antioxidants can exert a prooxidant effect to other molecules under particular circumstances [5, 7].

The feature of a perfect antioxidant is that it should be readily absorbed, eliminate free radicals, and chelate redox metals at physiologically suitable levels. In addition, it should work in both aqueous and membrane domains, and have a positive effect on gene expression [7].

## 4. Antioxidant categories

Antioxidants can be classified in several ways [17, 18].

1. Based on their activity, they can be classified as enzymatic and nonenzymatic antioxidants. Dangerous oxidative products can be converted to H2O2 and then to water by enzymatic antioxidants that are able to break down and get rid of free radicals in a multistep process in the presence of cofactors such as copper (Cu), zinc (Zn), manganese (Mn), selenium (Se), and iron (Fe).

2. Vitamin C, vitamin E, plant polyphenol, carotenoids, and glutathione are nonenzymatic antioxidants, which act by interrupting free radicals chain reactions.

3. Based on solubility, antioxidants can be classified as water-soluble or lipid-soluble antioxidants. Vitamin C is a type of water-soluble vitamin found in cellular fluids such as cytosol or cytoplasmic matrix.

4. According to size, antioxidants can be categorized as small or large-molecule antioxidants. The small molecule antioxidants neutralize the ROS in a process named radicals scavenging and carry them away. Vitamin C, vitamin E, carotenoids, and glutathione (GSH) are the main antioxidants in this category. Large molecule antioxidants include enzymes (SOD, CAT, and GPx) and sacrificial proteins (albumin) that absorb ROS and prevent them from attacking other essential proteins.

5. Kinetically antioxidants can be categorized as below:

1. Antioxidants that are able to break chains through reacting with peroxyl radicals containing weak O–H or N–H bonds, phenol, naphthol, hydroquinone, aromatic amines, and aminophenols.

2. Antioxidants with a capability to break chains by reacting with alkyl radicals: quinines, nitrones, and iminoquinones.

3. Antioxidants that terminate cyclic chain such as aromatic amines, nitroxyl radicals, and variable valence metal compounds.

4. Hydroperoxide decomposing antioxidants such as sulfide, phosphide, and thiophosphate.

5. Metal-deactivating antioxidants include diamines, hydroxyl acids, and bifunctional compounds.

6. Synergism action of a number of antioxidants including phenol sulfide in which the phenolic group reacts with the peroxylradical’s sulfide group with hydroperoxide.

6. Based on their occurrence, antioxidants are categorized as natural or synthetic [19, 20].

1. Natural antioxidants

They are classified as chain-breaking antioxidants, which react with radicals and convert them into more stable products. Generally, antioxidants of this group are phenolic in structure and include the following:

1. Antioxidant minerals: these are antioxidant enzymes cofactors like selenium, copper, iron, zinc, and manganese. Absence of the cofactors will definitely enhance many macromolecules metabolism such as carbohydrates.

2. Antioxidant vitamins: these are important and required for most body metabolism functions such as, vitamin C, E, and B.

3. Phytochemicals: these are phenolic compounds derivatives that are neither vitamins nor minerals. Examples include flavonoids, catechins, carotenoids, carotene, lycopene, and herbs and spices such as diterpene, rosmariquinone, thyme, nutmeg, clove, black pepper, ginger, garlic, curcumin, and derivatives.

2. Synthetic antioxidants

These are phenolic compounds that carry out the role of capturing free radicals and stopping the chain reaction. These compounds include butylated hydroxyl anisole (BHA), butylated hydroxyltoluene (BHT), propyl gallate (PG), metal chelating agent (EDTA), tertiary butyl hydroquinone (TBHQ), and nordihydroguaiaretic acid (NDGA).

### 4.1 Antioxidant enzymes

There are several enzymes that catalyze reactions to neutralize free radicals and ROS. These enzymes form the body’s endogenous defense mechanisms from free radicals to protect the cell. The enzyme antioxidants GPx, CAT, and SOD are the best-known substances of the antioxidant protection system, and they are responsible for the free radical change [21]. Enzymes are important components of the protection and defense mechanisms, by decreasing ROS generation via removing potential oxidants/transferring ROS/RNS into relatively stable compounds [5]. For optimum catalytic activity, these enzymes require micronutrient cofactors such as Se, Fe, Cu, Zn, and Mn [21].

#### 4.1.1 Superoxide dismutase (SOD)

Irwin Fridovitch of Duke University and Joe McCord discovered antioxidant enzyme (SOD) (EC 1.15.1.1) in 1967, which belongs to the group of oxidoreductases. SOD is an important cellular defense against free radical damage. Therefore, medical scientists have begun to look seriously at free radicals [3]. SOD antioxidant enzymes are metal-containing proteins that catalyze the dismutation of the highly reactive superoxide anion to O2 and to the less reactive species H2O2 (Eq. (1)). The result is that peroxide can be destroyed by reaction of CAT or GPX [22, 23].

$O2−+O2−+2H+→SODH2O2+O2$E1

In mammals, there are three forms of SOD; the active site of the enzyme contains one or two different atoms of a transition metal in a certain oxidation state. SODs are categorized by their metal cofactors into known forms: cytosolic SOD, extracellular SOD [CuZnSOD], and mitochondrial SOD [MnSOD]. Each form is produced by distinct genes and distinct subcellular localization, but catalyzes the same reaction. This distinct subcellular localization of the three SOD forms is especially significant for compartmentalized redox signaling [24].

CuZnSOD enzymes have two identical subunits of about 32 kDa, though a monomeric structure is found in a high concentration of protein from E. coli. Each subunit includes a metal cluster, an active site, and a Cu and a Zn atom bridged By a histamine residue. The Cu and Zn which are important for SOD enzymatic activity. Zn contributes in appropriate protein folding and stability. Cu is not replaceable with another metal, while Zn is replaceable with cobalt and Cu, and it is not essential for enzyme action at low pH. CuZnSOD plays a major function in the first line of antioxidant defense [25].

MnSOD is a homotetramer 96 kDa; each subunit contains one Mn atom, those cycles from Mn3+ to Mn2+ and back to Mn3+ during the two-step dismutation of superoxide. In mitochondria, the main source of oxygen radicals is the respiratory chain. It was shown that this enzyme is greatly stimulated and decreased by cytokines, while oxidants moderately influenced it [26, 27, 28].

Extracellular SOD (ECSOD) is a tetrameric protein, containing Cu and Zn having a high affinity for certain glycosaminoglycans such as heparin and heparin sulfate [7]. ECSOD is found primarily in the extracellular membrane and to a lesser extent, in the extracellular fluids. It protects against the inactivation of NO liberating from the endothelium by O2¯ through diffusion to smooth muscle, thus preserving endothelial function. Studies have shown that ECSOD plays an essential role in various oxidative stress-dependent pathophysiologies, such as hypertension, ischemia reperfusion injury, and lung injury. In addition, a number of lines of research propose a role for ECSOD in aging. ECSOD plasma levels decrease with aging, and in old rats, gene transfer of ECSOD improves endothelial function. However, it is still unknown whether ECSOD expression or activity in blood vessels is adjusted by aging and whether endogenous ECSOD is engaged in regulation of vascular functions during aging [29].

#### 4.1.1.1 Application

SOD enzymes enhance the rejuvenation and cellular repair, while decreasing the damage caused by free radicals. SOD is necessary to generate sufficient amounts of skin building cells named fibroblasts and plays an essential role in preventing the progress of amyotrophic lateral sclerosis (ALS), which causes death if it affects the nerve cells in the spinal cord and brain. In addition, this enzyme is also utilized for inflammatory diseases treatment, burn injuries, prostate problems, corneal ulcer, arthritis, and reversing the long-term consequences of radiation and smoke exposure. Furthermore, it prevents wrinkle formation if the skin lotion contains this enzyme. Also, it enhances wound healing, reduces scars, and lightens skin pigmentation caused by UV rays.

Moreover, SOD facilitates nitric oxide moving into hair follicles. This is beneficial for people with a genetic predisposition or free radicals for premature hair loss. SOD is a very potent antioxidant, in that it combats the effect of free radicals on the hair follicles. Because of nitric oxide’s ability as a blood vessel relaxant, allowing more blood to reach the hair follicle, and SOD ability to remove free radicals, hair loss can be prevented or reversed. Maintaining overall well-being and health, as well as free radical protection, can be achieved by taking dietary supplement that provides an adequate supply of SOD [3].

#### 4.1.2 Catalase (CAT)

Catalase (EC 1.11.1.6) is an enzyme responsible for H2O2 degradation that is generated by oxidases involved in β-oxidation of fatty acids, respiration, and purine catabolism [3]. It is present in nearly all animal cells as a protective enzyme. The highest levels of CAT activity are measured in the liver, kidney, and red blood cells.

Human CAT composes four identical subunits of 62 kDa, each subunit containing four distinct domains and one prosthetic heme group, and has a molecular mass of about 240 kDa [30]. CAT enzyme reacts with H2O2 to form water and molecular oxygen and with H donors such as methanol, ethanol, formic acid, or phenols with peroxidase activity. CAT protects cells from H2O2 generated within them. Therefore, it has an essential role in the acquisition of tolerance to oxidative stress in the adaptive response of cells. Various disease conditions and abnormalities are associated with the deficiency or mutation of CAT enzyme [30, 31].

#### 4.1.2.1 Application

In the food industry, CAT enzyme is used to remove H2O2 from milk prior to cheese production, and to prevent food from oxidizing in food wrappers. In addition, CAT enzyme is used in the textile industry for H2O2 removal from fabrics, to make sure the material is peroxide free. Recently, esthetics industries have begun to use CAT enzyme in facial masks, as the combination of CAT enzyme with H2O2 on the face can be used to increase cellular oxygenation in the upper layers of the epidermis [3].

#### 4.1.3 Glutathione perioxidases (GPx)

Glutathione peroxidase (EC 1.11.1.9) contains a single selenocysteine residue in each of the four identical subunits, which is important for enzyme activity. GPx (80 kDa) is an imperative intracellular enzyme that catalyzes H2O2 to water and lipid peroxides to their corresponding alcohols mainly in the mitochondria and sometimes in the cytosol. In mammals, there are five GPx isoenzymes. Though their expression is ubiquitous, the level of each isoform differs depending on their tissue type. Mitochondrial and cytosolic glutathione peroxidase (GPx1 or cGPx) reduces fatty acid hydroperoxides and H2O2 at the expense of glutathione [32].

GPx1 is the main ubiquitous selenoperoxidase present in most cells; found in the cytosolic, mitochondrial, and peroxisomal compartments. It is an important antioxidant enzyme required in the detoxification of H2O2 and lipid hydroperoxides and preventing DNA, protein and lipids damage by harmful accumulation of intracellular H2O2 [33]. GPx1 uses GHS as an obligate co-substrate in the reduction of H2O2 to water [32]. Phospholipid hydroperoxidase glutathione (PHGPX) is found in most tissues and can directly reduce the phospholipid hydroperoxides, fatty acid hydroperoxides, and cholesterol hydroperoxides that are produced in peroxidized membranes and oxidized lipoproteins [30].

GPx4 is found in both the cytosol and the membrane fraction, and is highly expressed in renal epithelial cells and tests. Cytosolic GPx2 or extracellular GPx3 is inadequately found in nearly all tissues except for the gastrointestinal tract and kidney. In recent, GPx5, a new kind, expressed particularly in mouse epididymis, is selenium independent [34].

Several studies underlined the clinical importance of GPx. In addition, GPx, especially GPx1, have been implicated in the progression and prevention of many frequent and complex diseases, including cancer and cardiovascular disease [34, 35].

#### 4.1.3.1 Application

GPx is an important antioxidant enzyme in the body. Glutathione (GHS), the master antioxidant, is important for GPx levels due to the closely linked relationship; GHS is a tripeptide that protects the cells against the negative effects of pollution and functions as the body’s immune system booster. GHS plays an essential role in red blood cells to remain intact and protects white blood cells, which are responsible for the immune system. An antioxidant’s role is specifically essential for the brain because it is sensitive to the presence of free radicals. To increase the body’s protection from free radicals, it is imperative to combine certain antioxidants such as glutathione, vitamin C and E, Se, and GPx [3].

### 4.2 Nonenzymatic antioxidants

In previous decades, there has been increasing evidence that large amounts of antioxidants present in our diet contribute to the antioxidant defense system by preventing oxidative stress and specific human diseases. Phytochemicals, the plant-derived compounds, are one of the classes of the dietary factors, which play an essential role in functions of the body. Food materials contain a number of natural compounds reported to have antioxidant characteristics due to the presence of hydroxyl groups in their structure. Synthetic and natural antioxidants prevent the oxidative damage to the most important macromolecules such as lipids, proteins, and nucleic acids found in human body through scavenging the free radicals formed in different biochemical processes [36]. These antioxidants consist of small molecules including vitamin C, E, and β-carotene or natural antioxidants such as flavonoids, tannins, coumarins, phenolics, and terpenoids [37]. Because of oxidative stress, the free radicals that have been produced react with lipids, proteins and nucleic acids and lead to stimulation of apoptosis, which causes various neurological, cardiovascular, and physiological disorders [38].

In addition to phytochemical antioxidants, which can protect the body from oxidative damage, there are other antioxidants for example polyphenols, lycopene, and lutein [39]. Even though there has been a considerable concentration on antioxidant function of phytochemicals for several years, it is distinguished that phytochemicals have nonantioxidant effects important for health such as cell signaling and gene expression [40].

#### 4.2.1 Glutathione

Glutathione (γ-glutamyl-cysteinyl-glycine; GSH) is a tripeptide and is the most abundant intracellular antioxidant protecting normal cells from oxidative injury due to its role as a substrate of ROS scavenging enzymes. Glutathione is primarily present in its reduced form (GSH) in normal conditions, with only a small amount being found in the fully oxidized state (GSSG) [41]. Glutathione functions as a nonenzymatic antioxidant through free radical scavenging in cells and serves as a cofactor for several enzymes, include GPx, glutathione reductase (GR), and glutathione transferase (GST) [42, 43].

#### 4.2.1.1 Application

Recently, there is a new era of therapeutic applications of glutathione through the association of decreased GSH levels with the common features of aging and a wide range of pathological conditions, including neurodegenerative disorders. Remarkably, depletion and alterations of GSH in its metabolism appear to be crucial in the onset of Parkinson’s disease [44].

#### 4.2.2 Vitamin E

Vitamin E, C, and β-carotene are the main antioxidant vitamins for tissues against free radical damage. Vitamin E, a major lipid soluble antioxidant, functions as the most important membrane-bound antioxidant, neutralizing free radicals, and preventing oxidation of lipids within membranes [45]. Vitamin E is the free radical scavenger in the prevention of chronic diseases [46]. α-Tocopherol is the main form of vitamin E with antioxidant and immune functions. α-tocopherol has been revealed to be a more effective inhibitor of peroxynitrite-induced lipid peroxidation and inflammatory reactions [47]. In vitro tocotrienols have excellent antioxidant activity and have been proposed to restrain ROS more effectively than tocopherols [48].

#### 4.2.2.1 Application

The main function of vitamin E is to protect against lipid peroxidation through evidence suggesting that α-tocopherol and vitamin C function together in a cyclic type of process. It has been reported that vitamin E supplementation in hypercholesterolemic patients has shown to increase autoantibody levels against oxidized LDL, and prevent ischemic heart disease [49].

#### 4.2.3 Vitamin C

In extracellular fluids, vitamin C, a water-soluble vitamin, is the most important antioxidant and can protect biomembranes against lipid peroxidation injury through eliminating peroxyl radicals in the aqueous phase before peroxidation initiation. Vitamin C is an effective antioxidant located in the aqueous phase of cells; it simply loses electrons to give stability to reactive species such as ROS [45]. In addition to vitamin C’s biological functions as a superoxide and hydroxyl radicals’ scavenger, it also functions as an enzyme cofactor [42].

#### 4.2.3.1 Application

Vitamin C plays an essential function in the defense against oxidative damage particularly in leukocytes, as well as the possible effect it may have on the treatment of chronic degenerative diseases, autoimmune diseases, and cancer [42, 45].

#### 4.2.4 Carotenoids

Carotenoids are structurally and functionally different natural pigments found in many fruits and vegetables. A combination of carotenoids and tocopherols antioxidants in the lipid phase of biological membranes may enhance better antioxidant protection than tocopherols alone. Antioxidant characteristics of carotenoids include scavenging single oxygen and peroxyl radicals, thiyl, sulfonyl, sulfur, and NO2 radicals and giving protection to lipids from superoxide and hydroxyl radical attack [49].

#### 4.2.4.1 Application

Carotenoids and some of their metabolites are proposed to play a protective function in several ROS-mediated disorders, include cardiovascular, cancer, and myocardial infarction among smokers. Carotenoid-rich food and supplementation decrease morbidity in nonsmokers and reduce the risk of prostate cancer [42].

#### 4.2.5 Vitamin A

Vitamin A, a lipid soluble vitamin, is important for human health and has free radicals scavenging features that aid it to act as a physiological antioxidant in protecting a number of chronic diseases such as cardiovascular disease and cancer. All transretinol, the parent compound, are the most abundant dietary form of vitamin A that occurs naturally in the form of fatty acid esters such as retinyl palmitate, while retinal and retinoic acid are the minor natural dietary components of vitamin A [45]. Vitamin A was first labeled as an inhibitor of the effect of linoleic acid on the oxidation processes. At present, vitamin A and carotenoids are known for their antioxidant actions depending on their capability to interact with radicals and prohibit cell lipid peroxidation [9].

#### 4.2.5.1 Application

Vitamin A is important for life in mammals; it cannot be synthesized in body and has to be supplied by food. Due to its role as antioxidant, vitamin A has a new role in preventive nutrition against neurodegenerative diseases. Recently, vitamin A has increased the interest in supplementation via food [50].

#### 4.2.6 Uric acid

Uric acid, hyperuricemia, is a potent free radical scavenger and estimated ~60% of free radical scavenging capacity in plasma [51]. Uric acid is a physiological antioxidant and an effective preventer of the production of ROS species during the action of xanthine oxidase (XO) in catalysis reaction of xanthine and hypoxanthine [42]. A study illustrated the urate ability to scavenge oxygen radicals and protect the erythrocyte membrane from lipid oxidation, characterized further by Ames et al. through the effect of uric acid in protection of cells from oxidants, which related to a variety of physiological situation [51]. Nevertheless, it is probable that the increase in serum level of uric acid is a response to protect against the detrimental effects of extreme free radicals and oxidative stress [52].

#### 4.2.6.1 Application

Studies showed that serum uric acid levels are highly predictive of mortality in patients with coronary artery disease, heart failure, or diabetes. In addition, high uric acid level is associated with deleterious effect on vascular function. Recently, it has been found that patients with high serum uric acid level had impaired flow-mediated dilation, which was normalized by therapy for 3 months with the xo inhibitor allopurinol [53].

#### 4.2.7 Lipoic acid

Lipoic acid is a strong antioxidant, and it reveals a great capability of antioxidant when given natural or as a synthetic drug. Lipoic acid is a short-chain fatty acid, composed of sulfur in their structure that is known for its contribution in the reaction that catalyzes the oxidation decarboxylation of α-keto acids, for example pyruvate and α-ketoglutarate, in the citric acid cycle. Lipoic acid and its reduced form, dihydrolipoic acid (DHLA), are capable of quenching free radicals in both lipid and aqueous domains. Lipoic acid and DHLA have been revealed to have antioxidant, cardiovascular, antiaging, detoxifying, anti-inflammatory, anticancer, and neuroprotective pharmacological properties [40, 54].

#### 4.2.7.1 Application

Regarding the pathology of diabetes, there are many potential applications for lipoic acid. In type I diabetes, destruction of pancreatic β-cells leads to loss secretion of insulin, while the major problem in type II diabetes is insulin resistance of peripheral tissues. Lipoic acid has potential preventive or ameliorative effect in both type I and type II diabetes [54].

#### 4.2.8 Flavonoids

Flavonoids are low in molecular weight and are the main type of phenolic compounds in plants. They are structured by 15 carbon atoms, organized in a C6-C3-C6 configuration. Due to their high redox potential, flavonoids are, in particular, important antioxidants that allow them to function as reducing agents, hydrogen donors, and singlet oxygen quenchers. In addition, they include a metal chelating potential [55].

#### 4.2.8.1 Application

Flavonoids are generally found in many fruits and vegetables. When human increasingly consumed it, flavonoids have been linked with a decrease in the incidence of diseases such as prostate [56, 57] or breast cancer [58, 59].

#### 4.2.9 Tannins

Tannins are relatively high-molecular compounds, which comprise the third essential group of phenolics and can be divided into condensed and hydrolysable tannins. Condensed tannins are produced by the polymerization of flavonoid units. The mainly studied condensed tannins are based on flavan-3-ols: (−)-epicatechin and (+)-catechin. Hydrolysable tannins are heterogeneous polymers containing phenolic acids, in particular, gallic acid (3,4,5 trihydroxyl benzoic acid) and simple sugar [42, 55].

#### 4.2.9.1 Application

Because of tannin features, such as being the potential metal ion chelators, protein-precipitating agents, and biological antioxidants, tannins have different effects on biological systems. As a consequence of the diverse tannins biological roles and structural variation, it has been difficult to modify models that would let a precise prediction of their effects in any system. Therefore, the tannin structure modification and activity relationship are important to predict their biological effect [42].

## 5. Antioxidants: mechanisms of action

Generally, the antioxidants defend against free-radicals-induced oxidative damage by various mechanisms as discussed in below sections.

### 5.1 Preventive antioxidants

ROS such as H2O2, O2, and OH are produced irreversibly during metabolism. Therefore, methods have been extensively studied to reduce the damage enhanced by oxidative stress. Intracellular antioxidant enzymes produced in the cell are an essential protective mechanism against free radicals formation. SOD, CAT, GPx, GR, GST, thioredoxin reductase, and hemeoxygenase are the most important antioxidants enzymes. SODs convert O2 into H2O2, which is then converted into water by CAT, GPx, and Fenton reaction. Thus, two toxic species are converted into a harmless product (Figure 3) [5].

During metabolism, peroxides are formed and then eliminated via both GST and GPX. GRd regulates the equivalent of GSH and oxidized glutathione (GSSG), and the ratio of GSH/GSSG is a known index of oxidative stress [60]. The action of GRd plays an imperative role in increasing GSH concentration, which maintains the oxido-redox condition in the organism [14]. Consequently, the oxidative stress role has been reported in the progress and clinical symptom of autism. Recently, a comparison study between autism and control individuals showed decrease in GSH/GSSG ratio and increase in free radical generation in autism compared to control cells [60]. In addition, GPx is presented throughout the cell, while CAT is frequently limited to peroxisomes. In the brain, which is very sensitive to free radical damage, it has seven times more GPx activity than CAT activity. Moreover, CAT’s highest levels are found in the liver, kidney, and erythrocytes, where it decomposes the most of H2O2 [61].

#### 5.2.1 Scavenging superoxide and other ROS

Superoxide (O2•¯), a predominant cellular free radical, is contributed in a huge number of deleterious alterations often linked to a low concentration of antioxidants and associated with a raise in peroxidative processes. Though O2•¯ itself is not reactive to biomolecules, it assists in production of stronger OH•, and ONOO¯.O2•¯ is formed in large quantities, in phagocytes via NADPH oxidase enzyme during pathogen-killing process. In addition, it is a byproduct of mitochondrial respiration [3].

#### 5.2.2 Scavenging hydroxyl radical and other ROS

Hydroxyl radical (OH) is an extremely active and more toxic radical on biologic molecules such as DNA, lipids, and proteins than other radical species. In general, OH is considered to be formed from the Fe2+ or Cu+/H2O2 Fenton reaction system, through incubation FeSO4 and H2O2 in aqueous solution. Therefore, antioxidants activity as OH scavenger can be accomplished by direct scavenging or prohibiting of OH generation by the chelation of free metal ions or altering H2O2 to other nontoxic compounds [3].

#### 5.2.3 Metal ion (Fe2+, Fe 3+, Cu2+, and Cu+) chelating

Even though trace minerals are essential dietary components, they can function as prooxidants (through enhancing formation of free radicals). Fe2+ and Cu+ react with H2O2, which is a product produced by the dismutation of the O2•¯ via SOD, to form extremely reactive OH (Eq. (2)). Dissimilarly, iron and copper’s reaction with H2O2 forms more singlet oxygen than OH. Fe2+ and Cu+ are oxidized to Fe3+ and Cu2+, respectively. Cellular reductant such as NADH and oxidized metal ions Fe3+, and Cu2+ are reduced and permit the recycling to react with another molecule of H2O2 to produce OH radical in the presence of vitamin C (Eq. (3)). OH is strongly reactive and can directly react with proteins and lipids to produce carbonyls (aldehydes and ketones), cross linking, and lipid peroxidation. Chelating metal ions are able to decrease their action, thus reducing the ROS formation.

$Fe2+orCu++H2O2Fe3+orCu2++OH•+OH−$E2
$Fe3+orCu2++vitCH−Fe2+orCu++vitaminC−•+H+$E3

Studies showed that Se antioxidant is able to chelate Cu+ (formed in situ with Cu2+/ascorbic acid) extremely efficiently and prevent the damage of DNA by OH radical (formed via Cu+/H2O2) [3].

### 5.4 Prevention of lipid peroxidation

Lipid peroxidation is defined as oxidative deterioration of lipids composed of C-C double bonds such as unsaturated fatty acids, glycolipids, cholesterol, cholesterol ester, phospholipids. ROS damage the unsaturated fatty acids, which include numerous double bonds and the methylene-CH2-groups with particularly reactive hydrogen atoms, and begin the radical peroxidation chain reactions [65]. Antioxidants are able to directly react and quench peroxide radicals to stop the chain reaction. Lipid peroxidation and DNA damage are related to different chronic diseases, such as cancer, and atherosclerosis. Antioxidants can scavenge ROS and peroxide radicals, therefore prohibiting or treating certain pathogenic situations. Scientific attention has been concentrated in lipid peroxidation for recognizing natural antioxidants and studying their mechanism of action. Researches on antioxidants such as vitamins, polyphenols and flavones against free radical enhanced lipid peroxidation have been assumed in many systems such as lipid, red blood cells and LDL. The antioxidant activity of these polyphenols depends considerably on molecules structure, the initiation conditions and the microenvironment of the reaction medium [3].

### 5.5 Prevention of DNA damage

In vivo, the OH and ONOO¯ radicals produced from nitric oxide and O2•¯ are able to react directly with plasmid DNA macromolecules to cleave one DNA strand, leading to oxidative DNA damage. Cell death and mutation as a result of DNA damage are associated with neurodegenerative and heart diseases, cancer and aging. Consequently, DNA or plasmid damage has received attention and been utilized as models for the study and identification of antioxidants [66]. A study has been progressed include DNA damage caused by Cu+ induced OH, through metal-free plasmid DNA mixed with Cu2+, ascorbic acid and H2O2 at pH 7. The reaction includes reduction of Cu2+ to Cu+ in situ with ascorbic acid. The OH radical formed via Cu+/H2O2 cleaves one DNA strand, causing the ordinarily supercoiled plasmid DNA to unwind [3].

### 5.6 Prevention of protein modification

Besides lipid peroxidation and DNA damage, protein modification through nitration or chloration of amino acids also is caused by ROS. In vivo, peroxynitrite, O═N─O─O¯, is a powerful oxidant and nitrating agent formed through the reaction of O2•¯ with free radical nitric oxide via a diffusion-controlled reaction. In cells, ONOO¯ is a much stronger oxidizing agent than O2•¯ and is able to damage a wide range of different molecules such as DNA and proteins. ONOO¯ and its protonated form peroxynitrous acids (ONOOH) are capable of exerting direct oxidative modifications during one or two electron oxidation processes [67]. In vivo, ONOO¯ reacts nucleophically with CO2 to produce nitrosoperoxy carbonate, which is the predominant pathway for ONOO¯. These modifications often cause the alteration of protein function or structure, in addition to enzyme activities inhibition. Proteins containing nitrotyrosine residues have been detected in various pathogenic conditions, such as diabetes, hypertension, and atherosclerosis, all linked with promoted oxidative stress, including increased formation of ONOO¯. Antioxidants and antioxidant enzyme are utilized to prevent the protein modification of ONOO¯. Antioxidants or enzyme such as CAT is able to remove H2O2 and also inhibit HOCl formation; similarly, SOD or antioxidants, like polyphenols, may scavenge O2•¯ and inhibit ONOO¯ formation [3].

## 6. Conclusion

This chapter briefly summarized types of antioxidants, and their mode of action. The harmful products formed during normal cellular functions are oxygen radical derivatives that are the most important free radical in the biological system. For normal physiological functioning, it is important to maintain a tolerated antioxidant status by increasing intake of natural antioxidants. Studies have shown that different types of antioxidants, including natural and synthetic antioxidants, can help in disease prevention. The antioxidant compounds may directly react with the reactive radicals to destroy them via accepting or donating electron(s) to directly remove the unpaired status of the radical. Moreover, they may indirectly reduce the production of free radicals by inhibiting the efficacy or expressions of free radical creating enzymes or by stimulating the activities and expressions of other antioxidant enzymes. Thus, it is essential to know the antioxidant mechanisms of action with the free radicals.

## Conflict of interest

The authors declare they have no financial or other conflict of interests related to this chapter.

• Department of Medical Laboratories, Al Mansour Institute of Medical Technology, Middle Technical University, Iraq
• Department of Physiotherapy, College of Health and Medical Technology, Middle Technical University, Iraq
• Department of Chemistry, College of Sciences, University of Mustanseriya, Iraq

## 1. Introduction

Mg-alloys are being considered as one of the most versatile material choices among the structural materials that exhibit both energy efficiency and environmental benefits. Mg-based materials (alloys and composites) have enormous and unlimited potential to replace aluminum, steel, and structural plastics in diverse industrial and commercial sectors such as automotive, aviation, defense, biomedical, sporting equipment, consumer electronics, etc. These applications result from the need to use magnesium and its alloys as a material with favorable physical properties, especially high relative strength (Rm/ρ). Due to the good casting properties of magnesium, it was used primarily in cast structural elements. Wrought alloys have been used on a smaller scale so far, but material research and plastic formability processes to produce semi-finished products from magnesium alloys are currently under intensive development. The development is caused by the possibility of using various types of light structures in the construction, including vehicles made of magnesium-based materials, for which, for example, thin sheets are the basic initial material. This is mainly due to the attempt to reduce the weight of the structure and ensure adequate strength.

The interest in magnesium alloys for various structural elements, e.g., for the aviation industry, dates back to the 1940s. Examples of applications concerned, for example, the Northrop XP-56 plane, in which virtually all parts exposed to elevated temperature were made of magnesium and its alloys [1], B-36 bomber or [2], the S55 helicopter by Westland Aircraft Ltd. (1950 r.) [1, 3].

In later years, the use of magnesium alloys for aircraft structural elements was significantly limited, which was mainly due to the rapid corrosion of alloys (the main disadvantage), opinions about the flammability of magnesium, low metallurgical purity, low strength, high processing costs through plastic formability and poor machinability [4, 5, 6, 7].

Since the beginning of the twenty-first century, there has been a renewed, significant increase in interest in magnesium alloys for applications in the aerospace industry. It results from the development of new coatings that can protect alloys against corrosion, new alloys, new technologies of obtaining semi-finished products by casting methods, and the improvement of various plastic forming technologies, which significantly improves the properties of the product and allows the use of these alloys wherever engineers look for very light construction elements, relatively durable and with anticorrosion protection at the same time [8, 9, 10].

The main problem in the development of techniques for processing magnesium alloys with metal forming methods is low formability [4, 11]. Low deformability at room temperature as well as temperature increased to 200°C of magnesium alloys result from a limited number of hexagonal lattice slip systems. The test results show that the microstructure of Al-Mg-Zn alloys deformed at temperatures up to 200°C shows bands slip and deformation twins [11]. In the range from 200 to 300°C, limited dynamic recovery and the formation of nuclei of dynamic recrystallization are observed. Continuous dynamic recrystallization takes place above 300°C, which results in an almost twofold increase in formability.

Metal forming of magnesium and its alloys is carried out, depending on the content of alloying elements, only in a narrow temperature range. Grains with an average diameter of up to 10 μm were obtained in magnesium alloys by thermo-plastic treatment. The fragmentation of the grains below 10 μm is only achieved by introducing large deformations. The use of unconventional methods of deformation allows for obtaining the grinding of magnesium alloys to sub-micrometric or nanometric sizes. Therefore, these deformation methods constitute a very significant support for conventional forming methods [12, 13, 14].

In magnesium alloys, deformation processes are carried out at an elevated temperature. Therefore, it is practically impossible to obtain nanometric grain sizes obtained by the development of shear bands. The most common methods of large deformation, leading to the grinding of the grains of magnesium alloys, are equal channel angular pressing (ECAP) [15, 16] or hydrostatic extrusion [14, 17].

Basic magnesium alloys for metal forming contain up to 8% Al and the addition of Mn (up to 2%), Zn (usually up to 1.5%), Si (about 0.1%), and traces of Cu, Ni, Fe. There are three basic groups of magnesium alloys for metal forming. The first group includes mainly alloys with the addition of aluminum, zinc, and manganese. The second group includes alloys containing mainly the elements Zn, RE, Y, Zr, Th, and the third group, which is in the phase of intensive research, consists of new ultralight alloys containing lithium.

Magnesium alloys for metal forming are still used to a relatively small extent, which results from technological difficulties in metal forming and high production costs [13, 18, 19]. The main disadvantage of magnesium and its alloys is low deformability at ambient temperature, which results from the type of crystal lattice. At ambient temperature, only one in-plane glide system (0001) is active. In addition to low temperature slip, a significant amount of twinning is observed in magnesium alloys.

Hot forming of magnesium alloys, depending on the chemical composition and deformability, is performed using the following methods [20, 21]:

• rolling (mainly grades from the group of Mg Al-Zn and Mg-Zn-Mn alloys, as well as new alloys of the Mg-Th- (Mn or Zr) and Mg-Li-Al alloys,

• open die and die forging,

• extrusion (alloys AZ31 (Mg-Al-Zn), AZ61 (Mg-Al-Zn), ZM21 (Mg-Zn-Mn),

• KOBO extrusion (AZ31, AZ 61 Az80, WE43)

• sheet metal stamping after the rolling process in heated dies.

The formability effect of magnesium alloys has been recently also used in a relatively new solid-state joining process, under the influence of frictional heat, i.e., Friction Stir Welding (FSW). There is no melting involved in the process unlike conventional Fusion welding processes. This method gives very good results in the creation of strong joints, competitive to other joining techniques that require additional joining materials (e.g., riveting, bolted connections, welding, and others). Joining elements (e.g., sheets) made of magnesium alloys with this technique are very effective and require careful selection of process parameters, taking into account the special features of the plasticization of magnesium alloys and the stirring effect in the joint area [4, 22, 23, 24].

## 2. Evaluation of plastic formability of Mg alloys

Various magnesium alloys for plastic deformation have difficulties in carrying out metal forming processes. The evaluation of the plastic formability of magnesium alloys can be conducted by determining the mechanical behavior of samples of tested materials in compression, torsion, and tensile tests. These tests reflect relatively well essential features of the state of stress or deformation in technological processes of metal forming, including extrusion, forging, and rolling, respectively.

To evaluate mechanical behavior of the material in extrusion process, the upsetting test was used to realize plastic deformation under various conditions and to look for adequate their choice for real deformation process. The grades AZ31, AZ61, AZ80, WE43, and magnesium alloys with lithium, as casted ingots and extruded preforms, were used in the research work. In order to study feasibility of these magnesium alloys in extrusion process, the upsetting test of cylindrical specimens was carried out and let to determine flow stress–strain relationships [25, 26, 27, 28, 29, 30]. Before upsetting, the specimens were heated in a furnace to established temperature (Figure 1).

On the example of AZ31, AZ61, AZ80, WE43 alloys, and magnesium and lithium alloys, the determined flow stress–strain relationships between flow stress and strain for different values of temperature and strain rate allow for adequate adjustment of plastic deformation parameters based on specific relationships between the structure and deformation under conditions of hot compression test. Documented occurrence of two deformation mechanisms: slip and twinning in the presented relationships between plasticity characteristics such as: maximum yield stress and strain corresponding to the maximum, and the Zener-Hollomon parameter allows for an appropriate interpretation of the effects of microstructure transformation [31]. In order to prepare technological process, it is necessary to define precisely the plastic properties and microstructure changes of those alloys. Comparison of the plasticity and microstructure of magnesium alloys with from 3 to 8% aluminum content from group Mg-Al-Zn-Mn let to choose proper parameters of the process. On the basis of tensile tests, the plasticity changes were determined at temperature from 150 to 450°C. Conducted compression test at temperature from 250 to 450°C and deformation speed from 0.01 to 10 s–1 provided important data concerning the influence of process parameters on flow stress and microstructure changes connected with recrystallization process.

The characteristics of the relationships obtained in the compression test: flow stress σp- strain ε for the tested alloys AZ31, AZ61, AZ80, WE43 (Figure 2), and magnesium alloys with lithium (Figure 3) show the influence of temperature on their course, which allows for an adequate choice of technological parameters for plastic deformation methods with the dominant state of compressive stress (e.g., forging, extrusion).

Tests of magnesium and lithium alloys [32] with lithium content of 2.5, 4.5, 7.5, and 15% of the mass showed very different flow stress–strain relationship characteristics plasticizing from deformation, which results from the fact that alloys with 2.5 and 4.5% lithium form a lithium solid solution in magnesium and have a hexagonal structure. The 7.5% lithium alloy has an.

α + two-phase structure β., where the α-phase with the hexagonal structure is a solid solution of lithium in magnesium and the β phase has a wall structure centered is a solution of magnesium in lithium. The 15% lithium alloy is a solution of magnesium in lithium and has a wall-centered structure. An example of the flow stress–strain relationship for Mg-7,5 Li alloy is shown in Figure 3.

Alloys that contain more lithium, which is 7.5%, have good formability at temperature of 150°C. The alloy content of 15% lithium demonstrates very good deformability. The shape of flow curves and microstructure of alloys after deformation at elevated temperatures show significant influence of dynamic recrystallization process.

Determination of the plastic formability can be made on the basis of the results of torsion test too [30].

Flow curves for the magnesium alloy AZ31, most commonly used so far, were determined using torsion test at 300, 400, and 450°C at the speed 1 s−1 (Figure 4), while in the compression test at the temperature of 200, 300, 400, and 450°C at a strain rate of 0.01 and 1 s−1, respectively (Figure 5). AZ31 magnesium alloy exhibits an increase in deformability with an increase in the torsional temperature from 1.2 at 300°C to 5 at 450°C (Figure 4).

Axial-symmetric compression tests carried out on the Gleeble 3800 simulator with simultaneous “freezing” of the microstructure after deformation by rapid cooling with water, in the temperature range from 200 to 450° C with the strain rateέ = 0.1 s−1 and 1,0 s−1, until the deformation ε = 1, 2 (Figure 5) allows the assessment of the influence of these factors on the course of the characteristic and its use in the design of plastic forming processes.

The flow curves obtained in the compression test indicate a similar level of the value of flow stress of the alloy for comparable conditions of its deformation in relation to the torsion curves.

Performing plastometric tests for a magnesium alloy allows the identification of two types of flow curves. Classical curve—where the dominant mechanism in the microstructure is slip (e.g., Figure 6a) and the characteristic curve, where the dominant mechanism in the microstructure is twinning (Figure 6b).

The relationship of the maximum yield stress σpp and strain εp as a function of ln Z, where: Z – Zener-Hollomon parameter, $Z=ε̇expQRT$is shown in Figures 7 and 8.

Currently, plastic forming of magnesium alloys is limited to a few basic grades from the group of Mg Al-Zn (AZ21, AZ31, AZ61) and Mg-Zn-Mn (ZM21) alloys. AZ31 magnesium alloy as the most widely used for rolling metal sheets shows good formability under hot-forming conditions. The obtained flow curves depending on the deformation parameters show two different types of the deformation process. For higher temperatures and lower strain rates, the curve follows the classical course of changes in the yield stress. At lower temperatures and higher strain rates, the course of stress changes is different and characteristic for the process based on the twinning mechanism, which was confirmed in structural studies. It has been shown that there is a relationship between the maximum yield stress σpp and the corresponding strain εp, and the Zener-Hollomon parameter (Figures 7 and 8). A worse fit occurs for curves where twinning dominates, which changes the shape of the curve [30]. Flow stress–strain curves of alloy AZ31 are characteristic for alloy in which during deformation a mechanism of plastic strain called twinning occurs [33].

The microstructure of AZ31 alloy after deformation by hot compression at the temperature of 200, 300, 400, and 450°C with strain rate of 0.01 s−1 and 1 s−1, respectively, was examined, and an example is shown in Figure 9. It was observed after the compression test at 200°C for strain =1.2, for both the strain rates used, the microstructure of the primary elongated grains and the ultrafine grains dynamically recrystallized (Figure 9). Samples deformed at a lower strain rate are characterized by a greater advancement of the recrystallization process. Recrystallized grains are observed both at the boundaries and within the primary grains.

The microstructure of AZ31 alloy, after deformation at the temperature of 300°C with the speed of 0.01 s−1, consists of fine grains that are dynamically recrystallized. For a higher strain rate, chains of recrystallized grains at the boundaries of the deformed primary grains are observed. Increasing the temperature to 400 and 450°C intensifies the recrystallization processes and grain growth. Few deformation twins are also observed (Figure 10).

The presented results of plasticity tests of AZ31 magnesium alloy indicate its good formability during hot deformation. The fine-grained recrystallized microstructure was obtained at the temperature of 300°C for a low strain rate. Increasing the temperature leads to the growth of recrystallized grains. Consequently, the average grain diameter after deformation at 450°C is much higher than before deformation.

Traditionally, the compression test specimens are circular in cross section. Taking into account the geometrical profiles of plastically formed products, e.g., in the process of forging or extrusion, the cross-sectional geometries are usually more complex. The analysis of the influence of the geometry of the deformed sample in the non-standard compression test when the cross sections of the deformed sample are not circular (Figure 11) shows that the differences are significant in the mechanical behavior of the material (the level and course of the forming force, the change in the geometry of the upset sample).

Taking into account the different geometry of the initial material in the evaluation of the impact of the strain rate and temperature on the forging (upsetting) effect of magnesium alloy specimens (as a material test before designing the forging process) allows for determining the appropriate process parameters.

The results of modeling the upsetting process of magnesium alloys obtained in the form of temperature distributions, stress and strain distribution as well as strain rates provide the basis for determining the conditions of the actual process leading to a product without defects and with high-quality requirements.

The analysis of force courses as a function of displacement during the upsetting process of magnesium alloys showed that the value of the force required for deformation decreases with increasing temperature. The value of the force is strongly influenced by the shape of the upset specimen, including the geometrical parameters (number of corners, the measure of angles, axes of symmetry, and planes of symmetry) (Figure 12).

Both in numerical simulation of upsetting and in experimental tests, the values of the force needed to deform individual specimens are convergent. The more complicated the cross-sectional shape, the greater the force needed to deform a given specimen of metallic material.

The results of upsetting test for the forging process demonstrate different mechanical behavior of various Mg alloys: e.g., AZ31 and WE 43, and they are useful to determine plastic formability (Figure 13a and b).

On the basis of their analysis, it is possible to assess ability to deformation of magnesium alloys on the basis of determining:

• limit deformations, deformations leading to cracking, and force parameters during the process of metal forming.

## 3. Processes of metal forming: forging, extrusion, KOBO extrusion, rolling, and joining: friction stir welding. Mechanical properties, microstructure, and quality of the final product. Examples of applications

The analysis of magnesium alloys and their possibilities of deformation by plastic forming shows that they are prospective due to the development of a number of new technologies. The purposefulness of work on the development of the plastic forming technique [34] is primarily determined by the better mechanical properties of plastically processed magnesium alloys compared with the cast ones. Now, there are main groups of magnesium alloys available for plastic deformation:

• Mg-Al-Zn alloys—The magnesium alloys Mg-Al-Zn are the most popular ones. Four basic alloys AZ31, AZ61, and AZ80 are distinguished. The alloy AZ31 shows relatively low mechanical properties, but it is weldable and perfectly suitable for rolling, stamping, and extrusion. This grade is used to produce sheet metal designed mainly for drawpieces. The alloys AZ61 and AZ80 are characterized by a larger content of alloyed components, and they show more advantageous mechanical properties. The alloy AZ61 is weldable, plastically worked by extrusion and forging methods. The alloy AZ80 demonstrates the best mechanical properties in the group of plastically worked alloys; however, its susceptibility to plastic working is relatively low. It is suitable for making only simple forgings.

• Mg-Zn alloys—Two alloys ZM21 and ZC71 are distinguished in this group. The alloy ZM21 includes zinc up to 2% and manganese in the amount of about 1%; it is susceptible to rolling and stamping and characterized by good weldability. A fine-grained structure of average grain size of about 15 μm can be obtained after extrusion. ZC71 is a new magnesium alloy with zinc, copper, and manganese that is characterized by high strength of up to 360 MPa. It can be formed by extrusion and forging methods, and this alloy is weldable.

• Mg-Zn-Zr alloys—This group comprises the alloys ZK30, ZK40, and ZK60 that includes 3–6% Zn and 0.4–0.6% Zr. An addition of zirconium leads to an intensive grain refinement. These alloys are characterized by high strength, and they are formed in forging and extrusion processes.

• Mg-Y-Re-Zr alloys—The alloys of such a type are formed by the plastic working methods, most often via extrusion. It can be mentioned that the alloy WE43 that, as main component, includes yttrium in the amount of 4.0% and rare earth elements RE, i.e., about 3.5%. After extrusion and heat treatment, the alloy WE43 shows tensile strength Rm equal to 420 MPa, yield point Re = 340 MPa, and elongation A = 15%. This alloy is characterized by good creep resistance at the increased temperatures

• Mg-Li alloys—Magnesium-lithium (Mg-Li) alloys thus have distinct advantages over conventional magnesium alloys. However, Mg-Li alloys possess relatively low strength and oxidation resistance. Alloying is well known to be an effective method to improve mechanical and chemical properties. Small editions to Mg-Li system, e.g., aluminum may improve mechanical properties. Mg-Li-Al (LA 143) alloys with high strength and plastic deformability were prepared through a combination of heat treatment and multidirectional forging in a channel die (MDFC). The maximum specific yield strength of the Mg-Li-Al alloy in this study is 263 kN·m·kg−1. The limit of reduction during cold rolling of all MDFCed LA143 samples exceeded 99%. The high specific yield strength could be attributed to severe plastic deformation. LA143 alloys with excellent mechanical properties can be prepared by heat treatment and severe plastic deformation [35].

Designing the processes of metal forming of structural elements made of magnesium alloys requires precise determination of the influence of process parameters on the microstructure and consequently on the mechanical properties of the manufactured elements. This is of particular importance when designing products in aviation [36, 37], automotive, medical, and other applications. Plastic forming tests carried out under laboratory and industrial conditions indicate that selected magnesium alloys can be formed especially in the process of rolling, forging, and extrusion. When forming AZ61, AZ80, and WE43 alloys, the temperature range is significantly limited, both at the beginning and the end of the deformation process. Therefore, to carry out plastic forming, especially forging, it is necessary to have devices that enable the process to be carried out in isothermal conditions. For AZ31 alloy, the range of temperatures of good formability is greater due to the greater tendency of this alloy to the recrystallization process.

The beneficial properties of magnesium alloys are obtained thanks to thermo-plastic treatment. In magnesium alloys, an intensive process of dynamic recrystallization takes place during plastic deformation, which promotes grain refinement and improvement of mechanical properties. Plastic forming of magnesium and its alloys can be carried out, depending on the content of alloying elements, only in a narrow temperature range.

Examples of the use of magnesium alloys in the formation of products/semi-finished products in the processes of plastic forming and joining processes involving plastic deformation (friction stir welding) show the enormous potential of these materials and the clear benefits of using these technologies in the forming of various types of products.

### 3.1 Particularities of metal forming processes of Mg alloys

#### 3.1.1 Rolling

Rolling of magnesium alloys is currently limited to a few basic grades from the group of Mg Al-Zn and Mg-Zn-Mn alloys. The new alloys Mg-Th- (Mn or Zr) and Mg-Li-Al are also susceptible to rolling [30, 32, 35, 38, 39].

The process of rolling magnesium alloy products is very expensive and time-consuming. This is due to the necessity to carry out annealing between successive operations. As a result of the current growing interest in sheets of magnesium alloys, the so-called “twin rolls casting” technology has been developed, which reduces the number of rolling and heating operations by casting between rolls and subsequent rolling [32].

Rolling AZ31 alloy with heating the billet in a chamber furnace to the temperature of 470°C for 30 minutes and cooling it in the air to the rolling temperature, in the range from 200 to 450°C, allows for obtaining a product with the required mechanical properties at the level of Rm = 220–265 MPa and A50 = 10–12%.

Examples of the microstructure of AZ31 alloy bands after the hot rolling process are shown in Figures 14 and 15. In the microstructure of the specimens rolled with a total draft of 44%, it shows a partially recrystallized structure (Figure 14a). The presence of primary grains and recrystallized grains was found (Figure 14b) fully recrystallized structure with fine grains. The analysis of the microstructure of the AZ31 alloy bands shows that it is precisely the application of large creases (here 82%) that allows obtaining a fine-grained structure without visible areas of primary grains.

The existing industrial application of magnesium alloys is currently focused on the utilization of semi-finished products such as sheets. The effects of processing parameters and special aspects of the rolling process on the mechanical properties and sheet formability is examined, and recent developments is presented in [37, 40].

#### 3.1.2 Forging

Among the most common forming processes, forging is a promising candidate for the industrial production of magnesium wrought products. The basics of magnesium forging practice are described, and possible problems as well as material properties are presented and discussed in many papers. Several alloy systems containing aluminum, zinc, or rare earth elements as well as biodegradable alloys are evaluated to focus on the process control and processing parameters, from stock material to finished parts including mechanical properties and analysis of microstructure [37, 40, 41].

The final properties of the forgings made of Mg alloys depend on the type of alloy and the string technological process leading to the final product. Most often feet cast magnesium is plastically deformed into semi-finished products, mainly by extrusion or rolling. Usually, forgings are made of semi-finished products in the form of extruded bars or rolled plates, which can be supplied in various conditions depending on the type of heat treatment applied. Forgings after being forged are subjected to precipitation hardening, recrystallization annealing, or stress relief annealing or leaving heat untreated. Each stage of the production line affects the structure and final properties of the product.

Forging as a process of forming the material through multistage deformation for magnesium alloys is a typical process based on hot forming at a narrow temperature range. An example of multistage forging of the airplane wheel hub and the AZ31 magnesium alloy control system lever of the helicopter is shown in Figure 16 [42, 43, 44].

Forging should be carried out on hydraulic or low-speed hydraulic presses. In specialist literature, it is not recommended to use die hammers and high-speed presses due to the cracking of the material during forging. When designing the transverse flow tendency of the magnesium alloys, the rod axis as well as difficult flow in the longitudinal direction should be taken into consideration. Die blanks should be polished to facilitate material flow and avoid surface defects. Free removal of the forging from the blank is possible thanks to forging inclinations equal to 3°, and in some cases even smaller [45, 46].

A very important process parameter is the temperature of the charge and tools. Magnesium alloys are good heat conductors and quickly cool down in contact with the tools, the more so that during forging, the material deformed over a relatively long time is in contact with a large surface with the die shape. For this reason, the temperature of the tools should be kept slightly below the load. Too much cooling of the billet leads to the formation of cracks. Conversely, too high a temperature also causes cracking due to the occurrence of hot brittleness. Lubrication is applied during the forging operation. Greases based on graphite or molybdenum disulfide are recommended for the forging temperature range of magnesium alloys.

Magnesium alloys are highly strain rate sensitive and exhibit good workability at a narrow forging temperature range. Consequently, parts made of these materials are usually forged with low-speed hydraulic presses, using specially designed tool heating systems in order to ensure near isothermal conditions. This study investigates whether popular magnesium alloys such as Mg-Al-Zn can be forged in forging machines equipped with high-speed forming tools.

Results presented in work [47] have demonstrated that AZ80A is not suitable for forging with either the screw press or the die forging hammer, that AZ61A can be press- and hammer-forged but to a limited extent, and that AZ31B can be subjected to forging in both forging machines analyzed in the study.

Examples of the application of magnesium alloys in aviation structures obtained by forging indicate the effective use of the possibilities of this technology (Examples shown in Figures 1722).

The forging process was carried out on a drop forging hammer. The initial material was ingots heated to the initial forging temperature equal to 350°C and 410°C, followed by upsetting, forging, forging in a die blank. The correct forging was obtained for the alloy annealed at 410°C [41, 42, 43, 44].

The results of the research on the forging process in industrial conditions of two selected parts of aircraft structures: i.e., the aircraft wheel hub and the helicopter control system levers showed that the appropriate geometric parameters of these magnesium alloy elements and the determination of the conditions of the hammer forging process allowed for obtaining final products without defects with the required final properties (geometric and mechanical properties).

#### 3.1.3 Extrusion

The conventional process of extrusion of magnesium alloys is carried out at a temperature range from 320 to 450°C, at a speed of 1–25 m/min. The developing method of hydrostatic extrusion allows for plastic deformation at lower temperatures and to obtain greater grain grinding of magnesium alloys [28, 43, 48, 49]. The extrusion process was carried out on a counter-press with a heated container. AZ31, AZ61, AZ80, and WE43 magnesium alloy ingots with a diameter of 100 mm, heated to a temperature of 400°C, were extruded at various speeds from 0.04 to 0.16 m/s and with a different extrusion ratio of 6,25–25. The most favorable effect on the microstructure was observed after billet extrusion with an extrusion ratio of λ = 25 (Figure 20ad). As a result of plastic deformation and recrystallization, fine recrystallized grains were obtained, although in the case of AZ61 and AZ80 alloys, a banded microstructure was observed (Figure 20b and c).

Different shapes of cross section of profiles for aviation application were obtained in the way of backward hot extrusion process. Some results of final products are presented in Figure 21. It is possible to obtain profiles of complex shape with elements of varied wall thickness and with thin walls. Microstructure of tested alloys in initial condition after extrusion is shown in Figure 20. Before deformation the tested alloys AZ31 and AZ61 were characterized by single-phase microstructure of solution α-Mg, whereas in microstructure of alloy AZ80 the presence of intermetallic phase γ-(Mg17Al12) was found and which was confirmed by prior X-ray tests. The extrusion of profiles with a complex cross-sectional shape and large differences in wall thicknesses (Figures 21 and 22) allowed the assessment of high plastic deformation possibilities of these alloys, favorable microstructure, and obtaining very good mechanical properties [28, 49, 50, 51].

The measurements of the grain size (acc. to ASTM E 112) and the microhardness HV0.1 of the magnesium alloy on the cross section of the extruded profile in the characteristic areas A, B, C (Figure 22) show different values of microhardness and grain size (Table 1), which proves the influence of the cross-sectional geometry on the microstructure and properties of the magnesium alloy.

Alloy Cross section zone Grain size—G, Plate I, ASTM E 112 Microhardness HV0.1
AZ31 Billet– Ø 100 mm 7.5 65
Square 7.5 58
Isosceles triangle 8.5 65
7.5 56
Profile 1 A
B
C
10.5
10.5
10
Profile 2 A
B
10
9.5
Profile 3 A
B
C
10
9.5
10
AZ61 Billet– Ø 100 mm 8.5 65
Square 9 56
Isosceles triangle 9.5 62
9.5 63
Profile 1 A
B
C
9
10.5
9,5
Profile 2 A
B
9
10
Profile 3 A
B
C
9
9
9
AZ80 Billet– Ø 100 mm 7.5 60
Square 9.5 58
Isosceles triangle 9.5 60
9.5 59
Profile 1 A
B
C
9.5
9.5
9.5
Profile 2 A
B
9
10
Profile 3 A
B
C
9
9
9

### Table 1.

Grain size and hardness HV0.1 of magnesium alloys profiles after extrusion.

Parameters of the direct and hydrostatic extrusions are presented in Table 2. In the field of extrusion of magnesium alloys, the method of hydrostatic extrusion has been developed quite intensively in recent years. Due to favorable thermo-mechanical conditions, the hydrostatic extrusion process can be carried out at lower-temperatures and a greater grain grinding of magnesium alloys [52, 53].

The comparison of microstructures of various magnesium alloys after plastic forming during extrusion with the same extrusion ratio λ = 25 for alloys: AZ31, AZ61, AZ80 WE43 (Figure 23) indicates diametrical differences in the final plastic deformation effect and let to choose adequate alloy for requirements of given possible application.

Mg alloy Direct extrusion Direct extrusion Hydrostatic extrusion Hydrostatic extrusion
temperature [°C] Speed [m/min] temperature [°C] speed [m/min]
AZ31 (Mg-Al-Zn) 320–380 8–15 190 45
AZ61 (Mg-Al-Zn) 320–380 2–4 200 10
ZM21(Mg-Zn-Mn) 320–380 3÷5 200 30

### Table 2.

Parameters of the direct and hydrostatic extrusion.

Research work using magnesium alloys AZ31, AZ61, AZ80, WE 43, and Mg alloy with Li for production of thin-walled profiles showed the potential of the backward extrusion process of magnesium alloys and KOBO extrusion process to apply them for aeronautical applications. It gives the possibility for indicating the best materials and parameters of the process to use, e.g., bridge dies to produce different types of complex shape of cross sections, which are the interest of aviation industry in light extruded products in order to save energy, costs, etc., by reducing aircraft weight.

#### 3.1.4 KOBO extrusion

Processes of severe plastic deformation (SPD) are defined as metal forming processes in which a very large plastic strain is imposed on a bulk process in order to make an ultrafine-grained metal [54]. Possibility to influence on the microstructure and the mechanical properties by heat treatment is also important to plan an SPD process [52, 55]. The KOBO extrusion process as SPD process is an unconventional extrusion method based on the idea of cyclical deformation path change during the process and localized plastic flow [53, 56]. The deformation path change is carried out by setting the die into an oscillating rotary motion around its axis. The method combines the extrusion of the material with an additional plastic deformation caused by reversible torsion of die. Being induced this way super plastic mode of deformation makes possible to deform metals with very high deformation (SPD process) at low temperature (room temperature). Hence, despite very low load capacity of the press, the methods allow for the variety of metallic products to be extruded at room temperature from the billet, with size and dimensions with value of extrusion ratio λ up to several hundreds. The example for KOBO extrusion of MgLi4 is presented in Figure 24.

Superplastic behavior of a metals under such deformation conditions is proven also in exact filling of a die opening, regardless how complicated it is and mode of extrusion forward or sideway. The most important advantage of the KOBO method is the ability to deform metals with a very high λ coefficient (extrusion ratio) [53, 57, 58, 59] in the “cold” process (without preheating the billet or tooling), regardless of the hardening state of the initial material. The use of the KOBO method allows for reducing the work of deformation, so the extrusion forces are incomparably lower than in conventional extrusion processes. The examples of measured parameters of KOBO process for magnesium alloys AZ31 and WE43 are shown in Figure 25.

KOBO extrusion is a process carried out in a system of concurrent extrusion with an oscillating matrix. In turn, the possibility of forming the products of a specific cross-sectional shape, as in conventional extrusion processes, makes it possible to obtain products, not only specimens, with very fine grains and favorable mechanical properties, which qualify the KOBO method for potential industrial implementations. The significant reduction of the extrusion load and the lack of the need for preheating make the method very economically attractive. Another, extremely attractive feature of the KOBO method is the possibility of low-temperature consolidation of postprocessing chips [28, 53, 57, 58, 59, 60, 61, 62, 63, 64] and obtaining a solid product as a result of plastic deformation in the process. The deformation effects of magnesium alloys, both in the form of a solid billet and in the form of consolidated postprocessing chips, are shown in Figure 26.

Low temperature—above 200°C in KOBO extrusion technology of magnesium alloys, possibility to control the final properties of the extruded profiles let to maintain a fine grain structure of the alloys [65]. It comes from the number of KOBO process parameters, such as amplitude and frequency of die oscillations. It is possible to use the backward extrusion and KOBO processes for bulk metals and chips. To determine proper parameters of extrusion process, it is necessary to know exact information on initial features of given magnesium alloy—its macro and microstructure, mechanical properties, and final results of transformation of the internal structure under conditions of plastic deformation.

#### 3.1.5 Joining. Friction Stir Welding

Joining. Friction Stir Welding FSW is solid-state joining process under the influence of frictional heat. There is no melting involved in the process unlike conventional fusion welding process. The FSW process was originally invented in institute TWI in the United Kingdom in 1991 [65, 66, 67]. The principle of utilizing the frictional heat between a rotating tool and the two joining metal interfaces is shown in Figure 27.

The rotating tool serves two basic purposes: heating of the workpiece materials due to friction and plastic deformation and stir movement and containment of materials to produce joint. Rotating tool with a specially designed pin and shoulder is inserted into the abutting edges of sheets or plates to be joined and subsequently traversed along the joint line. Advancing and retreating side orientations require knowledge of the tool rotation and travel directions. It is especially important when FSW process is designed for given metallic material. Magnesium alloys require special attention from the point of view of adequate parameters choice, especially for joining very thin sheets, because FSW process is very sensitive to the technological parameters of welding. From the point of view of plasticization of metals, the FSW process is very complex. The rotating tool in the first phase of the process supplies more and more heat, then the welded material is strongly deformed plastically. The material, in contact with the pin of the moving tool, experiences a state of stress and deformation comparable to that in extrusion and forging. The last stage is cooling of the weld [67]. It is important to know the influence of the selected technological and geometrical parameters of the process on the plasticization of the materials to be joined. Assessment of joint quality on the basis of tests of the mechanical properties of the obtained joints (static strength, fatigue strength, microhardness), microstructure tests in the area of weld, and parent material as well as the measurement of forces acting on the tool as a material response to the load resulting from the adopted process conditions. As a result of the conducted research on linear, FSW stir-mixed butt welding of thin sheets with a thickness of 0.5 mm made of AZ31B magnesium alloy, the basic goal was achieved, which was to obtain a solid, durable, free from defects connection of elements. When welding 0.5 mm thick sheets, the variable parameters were the rotational speed and the tool feed. The friction stir welding process was carried out with the use of magnesium alloy sheets, including AZ31B, 0.5 mm thick. The FSW joining process was carried out as a butt joint. An example of a connection is shown in Figure 28.

Due to the difficult conditions for the implementation of the process, an important issue is the selection of an appropriate tool with the appropriate geometry and kind of material of the tool. During FSW welding of magnesium sheets a cemented carbide tool was used. Taking into account the interdependence of mechanical and structural effects in the FSW process, special attention should also be paid to the analysis of the microstructure in the joint area, identification of characteristic zones as a result of the transformation of the microstructure resulting from the plasticization of the joined materials and the generated heat due to friction and plastic deformation, heat dissipation, among others in contact with the tool and tooling and the overall heat balance resulting in the final state of the joint. These are issues for thin sheets, especially for light metals (aluminum alloys, magnesium alloys) [68, 69]. Figure 29 shows the FSW weld microstructure of a sheet with a thickness of 0.5 mm of AZ31B alloy. The presented sample was made with the welding speed of 80 mm/min and the tool rotation speed of 2000 rpm. It is difficult to identify the zones characteristic for the FSW joint in the case of welding very thin sheets. In this case, the locations of areas such as the heat affected zone, the thermomechanical interaction zone, and the weld core were estimated based on the dimensions of the tool. The area of direct contact of the rim of the tool resistance is characterized by fragmented grain due to high plastic deformation. Equal-axis grain was also observed in the HAZ (heat-affected zone) and TMAZ (thermomechanical-affected zone) as shown in Figure 28.

The presence of equiaxed grains in the HAZ and TMAZ zone indicates that the material has fully recrystallized during the FSW process. The dynamics of recrystallization affects the grain size. Magnesium alloys are more prone to dynamic recrystallization than aluminum alloys because the Mg recrystallization temperature is approximately 523 K—lower than that for aluminum alloys. The factor that inhibits grain growth as a result of high temperature is also the cooling rate. In ultrathin materials (sheet thickness equal to or less than 0.5 mm), it is relatively high—the material cools down quickly, which is noticeable already during the process. The joint shown in Figure 30 does not contain any crater defects or discontinuities.

The obtained results of the FSW joining process of magnesium alloys showed that the process of linear friction stir welding (FSW) is a favorable method of joining difficult-to-weld magnesium alloys [70, 71, 72, 73]. Appropriate selection of parameters allows for obtaining joints free from defects. The assessment of the quality of the joints made on the basis of: the results of the joint microstructure analysis, measurements of the microhardness of the joint and the base material as well as the static tensile test of the weld material allowed for an unambiguous determination of the joint effectiveness. Proper selection of technological and geometric parameters allows for obtaining a connection with approximately 90% efficiency in relation to the parent material, determined on the basis of a static tensile test. During the tensile test, all joints broke in the thermomechanical impact zone on the retreating side. This is due to the resulting structural notch at the boundary of the weld nucleus and the thermomechanical influence zone. When welding 0.5 mm thick sheets of Mg AZ31B alloy, the maximum force acting on the tool in the Z axis was 4.5 kN. The values of the forces acting on the tool in the radial direction range from 40 to 100 N. After making a total of approximately 20 m of linear FSW weld, the tungsten carbide tool was not worn according to visual assessment. The FSW process is an excellent alternative to riveting or conventional welding. It does not require the use of an additional connector, which contributes to reduce the weight of the structure. Friction stir welding of the FSW joint allows for the creation of a high-quality, durable, defect-free joint with high mechanical properties (static and dynamic tests) and favorable internal structure of the AZ31B alloy sheet material.

The average obtained connection efficiency with appropriately selected input parameters of the process ranges from 85 to 95% compared with the parent material. These values are fully acceptable to the aviation (min. 80%) and automotive (min. 70%) industries. The analysis of the variability of forces generated during the FSW process requires knowledge of material properties and process conditions. It is necessary to adequately select the process parameters to the type of alloy and thickness of the joined elements (Figure 31).

The estimated value of the FSW process temperature should be approximately 0.8 solidus temperature. In this case, for alloy AZ31B, solidus temperature is 605°C, so temperature for FSW process is 430°C. AZ31 alloy with aluminum as the main alloy additive is very brittle at room temperature (only one slip plane (0001)). Only when the temperature of 200°C is exceeded, other slip planes are activated, which facilitates further plastic deformation. Reaching the temperature of 200°C is associated with the phenomenon of recrystallization. Achieving these conditions during welding is possible while providing the rotating and plunging tool with a sufficiently long time stoppage. This treatment is necessary to heat the material due to the pressure and friction of the rotating tool (dwell time). The recorded force courses may indicate the most favorable time to achieve the plasticizing effect and achieve the appropriate plasticization conditions of the material over 450 MPa, which exceeds the value of the yield stress for AZ31B alloy. A sudden increase in radial forces acting on the tool was noticed. Then the welding stage begins, where the stabilization of both axial and radial forces was observed. Very good results of joining thin sheets of the AZ31 B alloy [64, 65, 66, 67, 68, 69, 74, 75] prove the purposeful use of friction stir welding to join sheets of various thicknesses. Butt joints with smooth surface, without voids and flash, can be obtained by cylindrical flat shoulder and pin tool made from tungsten carbide. Tensile tests revealed a durability increase up to 90% compared with BM, which is thought to be mainly attributed to the preferred basal orientation and the activation of the extension twins. The SZ and TMAZ experienced full dynamic recrystallization and thus consisted predominantly of equiaxed grains. The grain size in SZ increased with increasing heat input.

During the FSW, the process must be carried out at the temperature preferably higher than the recrystallization temperature of the base material BM to be joined for the dynamic recrystallization to take place in the SZ. With increasing tool rotational speed or decreasing welding speed supplied more heat energy and generated a higher temperature in stir zone SZ. This led to a weaker or more random texture stemming from the occurrence of more complete dynamic recrystallization. After the FSW of AZ31B alloy of 0.5 mm in thickness, the lowest hardness occurred at the center of SZ through the HAZ and TMAZ of the welded joints; however, the differences are minor.

The welding speed and rotational speed had a strong effect on the UTS (ultimate tensile strength). When choosing the technological parameters for the process, tool feed rate played an important role compared with a tool rotation speed. The plastic flow in the welded regions is also observed with uniform grain orientation.

## 4. Summary

The development of plastic forming processes as well as joining processes, such as FSW, is primarily determined by better mechanical properties of plastically processed magnesium alloys compared with castings. Designing the technology of plastic forming of structural elements made of magnesium alloys requires precise determination of the influence of the process parameters on the microstructure and consequently on the mechanical properties of the manufactured elements. This is of particular importance when designing products made of magnesium alloys for structural elements for the aviation industry. The selected results of plastic forming research carried out in material tests and technological processes, under laboratory or industrial conditions presented in this chapter, indicate that selected magnesium alloys can be formed by plastic forming methods, especially by rolling, extrusion, and KOBO extrusion and forging. When forming AZ61, AZ80, and WE43 alloys, the temperature range is significantly limited, both at the beginning and the end of the deformation process. Therefore, to carry out plastic forming, especially forging, it is necessary to have devices that enable the process to be carried out in isothermal conditions. For AZ31 alloy, the range of temperatures of good formability is greater due to the greater tendency of this alloy to the recrystallization process. Thus, it is possible to manufacture AZ31 alloy products on conventional devices, but the obtained mechanical properties are less favorable than other magnesium alloys.

Magnesium-lithium alloys deserve attention due to their plastic formability, mechanical properties, and low specific weight, which makes them very attractive wherever lightweight and durable structures are desired. Elements manufactured by plastic processing of magnesium alloys and new technologies involving plastic deformation, including joint friction welding (FSW) technologies, are currently successfully implemented in various sectors of the economy.

Magnesium and its alloys are mainly used as a construction material (most often in the form of castings from magnesium alloys, but also plastically formed products), as an alloy additive to aluminum alloys, and for desulfurization of iron and steel. Due to the low specific mass and high relative strength, magnesium alloys in the form of castings or plastically formed products are used in such industries such as: aviation and aerospace, for the production of aircraft and rocket parts, including engine parts, gearbox components, hinges, fuel tanks, wing elements; automotive, for the production of, among others car rims, various types of housings, engine blocks, steering wheels, seat frames, windows and doors, body parts; sports and recreational, for bicycle parts and elements of various sports equipment articles; electronic, mainly for the production of various types of electronic equipment housings; medical, for strengthening elements in bone fractures. Examples of applications of magnesium alloys in the aviation industry include: Rolls Royce gear housing made of ZRE1 alloy Pratt & Whitney Canada PW535 engine housing made of ZE41 alloy, helicopter parts. In the automotive sector, the examples are steering wheel, boot lid; manufacturer GM, BMW engine block; cross section of the outer layer made of Mg alloy revealing the inner layer of Al alloy.

Now it is time for the successful application of magnesium-based materials. It is particularly important to promote exchange of information and discussion in which development trends and application potential in different fields such as the automotive industry and communication technology in an interdisciplinary framework [37, 72, 73].

## Acknowledgments

The author gratefully acknowledges the collaboration and discussions with.

Prof. Eugeniusz. Hadasik and Prof. Andrzej Gontarz, who provided support and information on magnesium research and application.

Financial support of Structural Funds in the Operational Program–Innovative Economy (IE OP) financed from the European Regional Development Fund–Project “Modern material technologies in aerospace industry,” Nr POIG.01.01.02-00-015/08-00 is gratefully acknowledged.

• Rzeszow University of Technology, Rzeszów, Poland

\\n\\n

\\n\\n

\\n\\n

Formats

\\n\\n

Based on your preferences and the stage of your scientific projects, you have multiple options for publishing your scientific research with IntechOpen:

\\n\\n
\\n\\t
• Chapters in Edited Volumes
• \\n\\t
• Monographs – Long Form
• \\n\\t
• IntechOpen Compacts Monograph – Short Form
• \\n\\t
• IntechOpen Journals - Articles
• \\n
\\n\\n

\\n\\n

Peer Review Policies

\\n\\n

All scientific Works are subject to Peer Review prior to publishing.

\\n\\n

\\n\\n

Costs

\\n\\n

The Open Access publishing model followed by IntechOpen eliminates subscription charges and pay-per-view fees, thus enabling readers to access research at no cost to themselves. In order to sustain these operations, and keep our publications freely accessible, we levy an Open Access Publishing Fee on all manuscripts accepted for publication to help cover the costs of editorial work and the production of books.

\\n\\n

\\n\\n

Digital Archiving Policy

\\n\\n

IntechOpen is dedicated to ensuring the long-term preservation and availability of the scholarly research it publishes.

\\n"}]'},components:[{type:"htmlEditorComponent",content:'

\n\n

\n\n

\n\n

Formats

\n\n

Based on your preferences and the stage of your scientific projects, you have multiple options for publishing your scientific research with IntechOpen:

\n\n
\n\t
• Chapters in Edited Volumes
• \n\t
• Monographs – Long Form
• \n\t
• IntechOpen Compacts Monograph – Short Form
• \n\t
• IntechOpen Journals - Articles
• \n
\n\n

\n\n

Peer Review Policies

\n\n

All scientific Works are subject to Peer Review prior to publishing.

\n\n

\n\n

Costs

\n\n

The Open Access publishing model followed by IntechOpen eliminates subscription charges and pay-per-view fees, thus enabling readers to access research at no cost to themselves. In order to sustain these operations, and keep our publications freely accessible, we levy an Open Access Publishing Fee on all manuscripts accepted for publication to help cover the costs of editorial work and the production of books.

\n\n