Section 2 Antioxidants

#### **Chapter 9**

## Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria

*Bhavana Gangwar, Santosh Kumar and Mahendra P. Darokar*

#### **Abstract**

The antibiotic resistance in pathogenic bacteria is a major concern and the emergence of novel multidrug-resistant (MDR) strains are a growing threat worldwide. Bacterial resistance to antibiotics has become a serious problem of public health that concerns almost all antibacterial agents and that manifests in all fields of their application. Therefore, novel antimicrobial compounds against new bacterial targets and drug resistance mechanisms are urgently needed. Plants are well-known sources of structurally diverse phytochemicals such as alkaloids, flavonoids, phenolics, and terpenes, which plays important roles in human health. Plant-derived antimicrobial agents are an attractive and ongoing source of new therapeutics. Natural compounds that prevent and treat infections through dual action mechanisms such as oxidative stress against pathogens and antioxidant action in the host cell hold promising potential for developing novel therapeutics. Identification of detailed mechanisms of action of such phytomolecules with both antioxidant and antimicrobial activities may help to develop novel antimicrobial therapeutics and benefit overall human health. The purpose of this chapter is to summarize important antioxidant phytochemicals, and focusing on their potential role in the management of drug-resistant bacterial infections.

**Keywords:** antioxidant, drug resistance, oxidative stress, phytochemicals, drug-resistant bacteria

#### **1. Introduction**

Antimicrobial resistance has now become a serious public health issue worldwide. Resistance to antimicrobials is a growing challenge that limits treatment options against serious pathogens and therefore new effective treatment strategies are needed [1]. Infections caused by *Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis*, and Gram-negative bacteria such as *Escherichia coli, Klebsiella pneumonia, Salmonella typhi, Pseudomonas aeruginosa*, are among the most common bacteria that have developed drug-resistant to many antibiotics. According to the Centers for Disease Control and Prevention (CDC) 2019 AR threats report [2] penicillin-resistant *Pneumococcus*, drug-resistant *Campylobacter* sp., methicillin-resistant *Staphylococcus aureus* (MRSA), vancomycinresistant *Enterococcus faecalis* (VRE), multidrug-resistant of *Pseudomonas aeruginosa*, *Salmonella typhi*, *Shigella sp.*, and *Mycobacterium tuberculosis* (MDR-TB) are serious threat and major causes of worldwide outbreaks of both the community infections and hospitals [3]. While carbapenem-resistant *Enterobacterales,* drug-resistant *Gonorrhea* and *Clostridioides difficile* are grouped among urgent treats [3]. The spread of multidrug-resistant (MDR) strains of pathogenic bacteria necessitate the discovery and deployment of new classes of antibacterial and compounds that can combat resistant strains and the spread of drug resistance.

During infections in humans, immune cells produce reactive oxygen and nitrogen species (RONS) which is used as part of warfare activity against pathogens [4, 5]. Oxidative stress induced by intracellular bacterial infection or other metabolic processes can cause inflammation and cellular damage however RONS production helps to kill bacterial pathogens. Unfortunately, pathogens have evolved a number of adaptive mechanisms against host-mediated defense systems and RONS [6, 7]. Microorganisms' survival strategies against RONS include the expression of various enzymes catabolizing RONS such as catalase, peroxidases, and biofilm formation also helps pathogens overcome the immune defense system [8, 9]. Therefore, targeting bacterial redox systems could present an important tool to combat such infections. Indeed, significant progress has been made in identifying several natural source of antioxidants that may also cause oxidative stress as a part of the antibacterial mechanism of action [10–12]. This emerging field needs further focus on the redox biology of antioxidants with antimicrobial activity by oxidative stress to cure intracellular bacterial pathogens.

Plants have an exceptional ability to produce cytotoxic agents to protect themselves from pathogenic microbes in their environment. Plant-derived secondary metabolites with antibacterial properties can be a source for designing novel therapeutics [13–15]. Historically, traditional medicines based on plants have made a considerable amount of contributions to human health. Plants are rich in a wide variety of secondary metabolites such as terpenoids, alkaloids, polyphenols, and tannins with a diverse set of biological activities. During the last decades, there is increasing interest to explore ancient remedies. A significant number of works, e.g., biological screening, isolation as well as clinical trials have been done for a variety of plants to unlock the secrets of herbal remedies [15]. Antimicrobials with reuse potential, which can be used in combination with drug treatments against drug-resistant pathogens, are identified using this approach. For example, plants derived alkaloids such as tomatidine and berberine are reported to be highly effective against drug-resistant microbes and also show synergy with antibiotics against *S. aureus,* and *E. coli* [16]. Therefore, screening and identification of compounds responsible for antimicrobial activity can be the foundation of a novel class of drugs. In this chapter, we have summarized the importance of medicinal and aromatic plants in the management of drug-resistant bacterial pathogens.

#### **2. Role of oxidative stress and antioxidants mechanisms in health and infectious diseases**

The paradox of oxidative stress is that it plays a dual role in the disease and health of humans. The importance of oxidative stress mechanisms in living cells is based on a balance between oxidants and antioxidants [17]. During metabolic reactions and infection, various types of RONS are produced in human by enzymes like myeloperoxidase, oxidases, and nitric oxide synthase, however, excess of these RONS can also *Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria DOI: http://dx.doi.org/10.5772/intechopen.108220*

damage host tissues and thus are reduced by the human cellular antioxidative defense system that includes enzymes like peroxidases, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and others which eliminates the excess of reactive oxygen species (ROS) such as hydroxyl radicals (OH. ), superoxide anions (O2.−), alkoxyl radicals (RO. ), and peroxy radicals (ROO. ). As a result, we require antioxidant supplements like vitamin C, vitamin E, carotenoids, and polyphenols to avoid oxidative stress [18, 19]. Supplementing a low amount of oxidative stress may also help to signal processes to express enzymes that detoxify the RONS [20]. This means low level of physiological oxidative stress can be beneficial to counteract excess oxidants produced during stress and infections that may result in cellular damage.

During phagocytosis, NADH-dependent oxidase (NOX) mediated burst of superoxide anion (O2− ) causes bactericidal oxidative stress [8, 21, 22]. This free radical is converted to hydrogen peroxide (H2O2) by superoxide dismutases. Infection control requires the presence of the NOX protein and abnormalities in the genes that produce the NOX protein makes it more vulnerable to bacterial and fungal infections [8, 23, 24]. H2O2 produced during phagocytosis passes through bacterial membranes barrier and interacts with ferrous iron (Fe2+) and thiol groups (-SH) of the cysteine in proteins which can eventually inactivate the function of enzymes [25]. During the Fenton reaction, H2O2 oxidizes Fe2+ to Fe3+ and produces hydroxyl radicals (OH− ), which further damage bacterial DNA, proteins, and lipids [22, 26]. Myeloperoxidases expressed in macrophages and neutrophils produce hypochlorous acid (HClO) from the reaction between H2O2 and chloride ion (Cl− ) . HClO has a stronger antibacterial effect than H2O2 [21, 22]. Later phases of phagocytosis activate inducible nitric oxide synthases (iNOS). Nitric oxide (NO• ) is produced by these enzymes from L-arginine. Peroxynitrite is formed when nitric oxide reacts with the superoxide ion produced by NOX proteins. Peroxynitrite can directly oxidize the thiol groups of sulfur-containing amino acids, or it can break down into nitrogen dioxide and hydroxyl radicals, which can damage the sulfur-containing proteins in bacteria [26, 27].

#### **3. Bacterial antioxidant and redox pathway mechanisms**

As described above, during phagocytosis bacteria are exposed to several RONS but they can still be growing in the intracellular environment under these oxidative conditions [8, 22, 26, 28, 29]. It is important to note that microorganism also possesses several enzymes like catalase, peroxidases, and superoxide dismutase. These protect against oxidative stress with a complex set of enzymatic activities (**Figure 1**) that can be divided into two categories: (i) preventive mechanisms, which are based on protein scavengers to inactivate RONS, and (ii) the repair mechanism, which is based on the reduction of the thiol groups of oxidized protein to restore enzyme activity [8]

The expression of antioxidant enzymes is controlled by transcriptional regulators that can interact with RONS based on thiol switches or metal centers. For example, OxyR is redox regulator that is reported to act as transcriptional activators or repressors in several bacteria [30]. Homologs of the MarR-family, thiol-based transcriptional regulators e.g. the sodium hypochlorite sensor (HypS) are found in the genomes of a variety of pathogens. Oxidation the thiol groups by RONS causes conformational changes in transcriptional regulators and modulates their binding capacity to promoters of genes encoding scavenger enzymes such catalases (Kat), superoxide dismutases, glutathione peroxidases (GPx), and peroxiredoxins (Prx). Many pathogens such as *Mycobacterium tuberculosis* are known to use combination

#### **Figure 1.**

*Overview of oxidative stress and response mechanism in bacteria. Oxidative stress is caused by the accumulation of reactive oxygen species (ROS) caused by both exogenous and endogenous sources. Bacterial cells are damaged by ROS because it causes DNA degradation, protein inactivation, membrane degradation, etc. Bacteria use a variety of mechanisms such as repair mechanisms and protective enzyme synthesis, metal homeostasis, the SOS response, and efflux pumps to counteract oxidative stress. OxyR, PerR, OhrR, and SoxRS are transcriptional factors that control the expression of oxidative stress response in bacteria.*

of these enzymes to overcome RONS challenges. Loss of one or more of these genes directly affects resistance to RONS and survival of bacteria [31, 32]. Extracellular thioredoxins (Etrx) found on the bacterial surface, have been found in human pathogens such as *M. tuberculosis*, *S. pneumoniae*, *N. gonorrhoeae*, as well as in plantassociated bacteria such as *Agrobacterium tumefaciens*, and *Bradyrhizobium japonicum* [8, 33, 34]. Although the targets of Etrx proteins are unknown, deletion of the genes encoding Etrx proteins reduced the pathogenicity of *M. tuberculosis* and *S. pneumoniae* [33]. However, more research is needed to fully understand the role of such surfaceome-associated proteins and their involvement during infection.

#### **4. Plant as potential source of preventative and therapeutic agents of oxidative stress and disease**

Medicinal plants and their extracted phytochemicals are widely used in the treatment of a variety of diseases, including bacterial, fungal, viral and cancer, as well as oxidative stress-related problems [35–37]. Due to the anti-oxidative, antiinflammatory, anti-microbial, and wound-healing characteristics natural phytochemicals (**Figure 2**) reduce the risk of diseases [9]. These substances have been studied extensively to facilitate their application as phytomedicine in the pharmaceutical field. Several phytomolecules such as quercetin prevents oxidative damage in human

*Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria DOI: http://dx.doi.org/10.5772/intechopen.108220*

#### **Figure 2.**

*Schematic representation of the potential roles of antioxidant phytochemicals.*

by influencing glutathione levels, enzymes, signal transduction pathways, and ROS production as well as show antibiofilm activity and bacteriostatic properties against several pathogens like *E. coli, S. aureus* and *P. aeruginosa* by means of promoting oxidative cellular stress targeting a wide range of cellular component [12, 38, 39]

Natural products have shown to be a never-ending source of novel medicines. Medicinal plants have been used in drug development since ancient times, and they continue to provide novel and important roles against a variety of medicinal targets, including infections, cancer, HIV/AIDS, Alzheimer's disease, and malaria [40]. Ayurveda and Charaka Samhita have contributed significantly to the discovery of new drugs and chemical entities due to India's abundant biodiversity and traditional medicinal herbs [41]. Ancient Chinese and African traditional medicine has a long history of medicinal plants for several physiological conditions [42]. Early pharmaceuticals such as cocaine, codeine, digitoxin, and quinine, as well as morphine, were discovered from medicinal plants, and are still used today [43]. Natural compounds or chemicals inspired by nature provide more than 80% of all medicines used today [44]. On the other hand, drug discovery from natural plants is a time-consuming and laborious process.

To date, several bioactive chemicals have been identified and described from medicinal plants that have been successfully exploited for biomedical purposes. There are more than 100 natural product-derived compounds already in clinical studies [44]. Traditional medicinal systems have a long history, dating back more than 60,000 years [45, 46]. Herbal remedies are used in all developed countries, and the WHO estimates that approximately 75% of the world's population uses medicinal items as an alternative to allopathic medicines [47]. It is interesting to note that medicinal plants provide 35% of all drugs recommended and prescribed today [47, 48]. Natural source phytomedicine in pure is either used directly or converted using appropriate chemical or microbiological processes until used as medicine [37]. Alkaloids, phenolics, and terpenes are examples of natural chemicals that have been demonstrated to be effective against many pathogens. Pomolic acid, oleanolic acid [49], gallic acid, chebulagic acid, and other galloyl glucose [50] have also been reported to inhibit HIV integrase. Researchers continue to uncover phytochemicals in many plants that are important for drug development; Their actions may offer new hope in treating various infections or diseases as well as reducing toxicity.

### **5. Classification of phytochemicals**

Natural bioactive compounds or phytochemicals have significant physiological effects on human health. They are a major source of diver's chemicals, making them a potential source of new drugs. Phytochemicals are classified as primary and secondary constituents according to their importance in plant metabolism (**Figure 3**). Generally, primary metabolite includes carbohydrates, proteins, lipid, and chlorophyll; the secondary metabolite has been classified into six major categories (i.e., phenolic, coumarins, glycoside, chalcones, terpenes, and alkaloid) based on chemical structures and characteristics.

#### **5.1 Alkaloids**

Alkaloids are produced by plants as protective agents against attack by predators. Alkaloids are basic compounds that contain heterocyclic nitrogen atoms that react with acids to produce salts. Most of all alkaloids are sour in taste. Morphine, the first alkaloid discovered in *Papaver somniferum*, has antibacterial properties [51]. Antimicrobial activities were discovered in diterpene alkaloids from Ranunculaceae plants [52]. Berberine is an isoquinoline alkaloid isolated from berberine species that has antibacterial and antiviral properties [53] Quinine, an alkaloid, was the first successful antimalarial drug extracted from the Cinchona tree. Atropine, codeine, coniine, caffeine, hyoscyamine, scopolamine, sanguinarine, etc., are the other examples of alkaloid found in nature. Alkaloids have diverse physiological effects and have been reported to possess antibacterial, anesthetic, antiinflammatory, antimitotic, analgesic, hypnotic, psychotropic, and antitumor activity, and many others.

#### **5.2 Flavonoids**

Flavonoids are polyphenolic chemicals found in vascular plants that come in the form of aglycones, glucosides, and methylated derivatives. Tomatoes, grapes, berries, apples, onions, kale, and lettuce are rich sources of flavonoids. Flavonoids are divided into two groups: flavone and isoflavone depending on the position of the benzenoid substituent. The majority of flavonoids are found in the conjugated form

#### **Figure 3.**

*Phytochemical classification demonstrating the link between primary and secondary metabolism in plants.*

#### *Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria DOI: http://dx.doi.org/10.5772/intechopen.108220*

in nature and can be classified as monoglycosidic, diglycosidic, or polyglycosidic within each class. The carbohydrate unit might be L-rhamnose, D-glucose, galactose, or arabinose, and the glycosidic linkage is usually found at position 3 or 7 [37]. Plants, animals, human, and microorganisms all use flavonoids for a range of biological functions. Flavonoids have been linked to improved human health, and they are currently being studied for antibacterial activity and chemoprevention [54, 55]. Apigenin, quercetin, kaempferol, fisetin, glabridin, and myricetin are most studied flavonoids. Flavonoids act as antioxidants and also insilico modeling and docking studies suggest potential as an antibiocbial activity. Apigenin, and quercetin are known to show antibacterial activity [55]. Quercetin and its analog penta-O-ethylquercetin were found to be potential inhibitors of New Delhi metallo-β-lactamase-1 (NDM-1). Several researches have reported synergy between flavonoids and antibiotics against resistant strains of bacteria [55, 56].

#### **5.3 Phenolics and polyphenols**

Phenolic acids contain carboxylic acid functional group. The hydroxycinnamic and hydroxybenzoic structures are found in naturally occurring phenolic acids [57]. Phenolic compounds possess strong anti-inflammatory, antioxidant, and antimicrobial activities [57]. Plant phenolic compounds and phenolic compound-rich herbal extracts control cell proliferation, survival, and apoptosis via modulating the amounts of reactive oxygen species (ROS) in cells. Recent research has also shown that phenolic compounds undergo change in the gut microbiota, gaining new characteristics that enhance their biological activity [57]. Tennins are polyphenolic chemicals that can form complexes with nucleic acids, proteins, and polysaccharides among other elements [37]. Phenolic compounds such as catechins, epigallocatechin gallate, galangin are reviewed for their antibacterial activity [58]. Ferulic acid, coumaric acid, chlorogenic acid, and caffeic acid have shown efficacy against *S. aureus* [59, 60].

#### **5.4 Terpenes**

Terpenes are natural occurring chemicals found in plants and are known for the aromas and flavors. Terpene contains isoprene units made up of five carbons atoms. Terpene chemical formula is (C5H8)n and their hydrocarbons are characterized by number of isoprene units [61]. Terpenes are important for plant growth and development, physiological processes, and response to the environment. Cannabis is important terpenes known for several uses such as aroma and taste. Terpenoids are essential oils and volatile chemicals found in higher medicinal plants. Terpenoids also show antimicrobial activity [61]. Monoterpenes such as menthol, sabinene, limonene, and carvone have shown strong antibacterial activity against *S. aureus* [61, 62]. Sesquiterpene (Patchouli alcohol), Diterpene (Artemisinin and Andrographolide), and Triterpene (Oleanolic acid) also show antibacterial activity in bacterial strains [61, 63–65].

#### **6. Antioxidant phytochemicals: mechanism of action**

Antioxidants are a type of defense mechanism that protects the human body from oxidative damage caused by free radicals. There are many different types of naturally occurring antioxidants with different physical and chemical properties, processes,

and mechanisms of action. Antioxidant activity has been reported in medicinal plants rich in vitamins, carotenoids, flavonoids, polyphenols, and anthocyanins. The antioxidant mechanism of phytochemicals has been reviewed in detail [66]. Briefly, phytochemicals exert antioxidant activity by the following means; 1. Free radical scavenging activity; antioxidants are known to chelate free radicals, transition metals, and remove electrons or hydrogen from substance. 2. Inhibition of the expressions of free radical creating enzymes or induce the expressions of other antioxidant enzymes, e.g., modulation of host nuclear factor erythroid 2 (Nrf2), a master regulator of antioxidant defense system, that controls over a dozen of enzymes such as glutathione S-transferases (GSTs) and NAD(P)H: quinone oxidoreductase 1 (NQO1) [66]. Resveratrol, anthocyanins, and curcumin are phytochemicals that modulate prostaglandin formation and Nrf2 activity, inhibit enzymes, and increase cytokine production, all of which may help reduce inflammation [67, 68]. 3. Prevents lipid peroxidation, DNA damage, and protein modification caused by ROS [66].

#### **7. Anti-microbial phytochemicals: mechanism of action**

The use of medicinal plants and their extracts for the treatment of all infectious ailments was widespread. In recent years, many research works have been conducted on the efficacy of plant phytochemicals as antibacterial agents *in vitro* and *in vivo* [16, 69]. Some of the important phytochemicals found active against Gram-negative and Gram-positive bacteria with their mode of action are listed in **Table 1**. Different antioxidant phytochemicals show various modes of action against pathogens such as inhibition of: (1) efflux pump, (2) DNA gyrase, (3) protein synthesis, (4) cell division and metabolic enzyme, (5) cell wall and cell membrane, (6) energy production, and (7) Biofilm. Here we focus more on oxidative stress as a new therapeutic strategy with the goal of unbalancing the redox defenses of bacterial pathogens. The intervention of redox homeostasis is becoming a potential target for combating drug resistance in bacteria. RONS-generating plant-derived antimicrobials have received a lot of attention in recent years [8]. Because of their ability to generate dose-dependent oxidative shifts in the bacteria, some plant-derived chemicals have been shown to have antibacterial activity. Several pathways have been discovered using system biology approaches to disrupt the antioxidant systems of bacterial pathogens [70]. Ebselen (also known as PZ 51, DR3305, and SPI-1005) is reported for antioxidant activity in humans, however, in bacteria such as *M. tuberculosis* or *S. aureus,* it can inhibit growth by causing oxidative stress [71]. Allicin, a defensive molecule, produced by garlic (*Allium sativum*) is the most investigated. Allicin can oxidize proteins' thiol groups in a dose-dependent manner. In *S. aureus* and *Bacillus subtilis*, allicin's antibacterial efficacy and oxidative role have both been proven. Allicin causes high disulfide stress in these bacteria, lowering their viability considerably. Curcumin, a strong antioxidant substance found in turmeric is reported as an antibacterial compound which disrupts bacterial quorum sensing system, cell wall and cell membrane, biofilm and virulence gene expression, and also shows synergy with antibiotics [72]. Recent published work on glabridin also showed dose-dependent activity as antioxidant, antibacterial as well as anti-biofilm against multidrug-resistant *S. aureus* [73, 74].

Some conventional antibiotics such as Norfloxacin, Kanamycin, Rifampicin, and Quinones can also generate RONS as part of their mechanism of action [8, 75]. Combining RONS-generating antimicrobials with antibiotics may have a synergistic effect against specific bacterial infections. Similarly, combining antimicrobials with


*Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria DOI: http://dx.doi.org/10.5772/intechopen.108220*


#### *Importance of Oxidative Stress and Antioxidant System in Health and Disease*


 *List of antioxidant phytochemicals summarized for their antimicrobial properties, chemical class, source, and major mode of action against pathogenic bacterial strains.*

#### *Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria DOI: http://dx.doi.org/10.5772/intechopen.108220*

silver nanoparticles may improve RONS production and, as a result, can improve the treatment's efficacy. These unique therapeutic techniques have the potential to improve the antibacterial activity of some repurposable medicines. Antimicrobials that have been clinically approved to treat common infections could even be employed in combination therapy against novel multidrug-resistant bacteria. Natural compounds can not only provide novel antimicrobial treatment options but can also lower the cost of antibiotics treatments in combination, reduce the dose of antibiotics, and therefore can slow the resistance development. Phytochemicals causing oxidative stress with multitarget mode of action further warrant less chance of developing resistance in pathogens. However, the majority of this information is currently based on *in vitro* trials, and further study is needed to show that these innovative medicines are effective against harmful bacteria *in-vivo*.

#### **8. Conclusion and future perspectives**

Medicinal and aromatic plants are an appealing source for novel therapeutics in the era of antibiotic-resistant "superbugs." Plants frequently produce phytochemicals as pathogen-defeating compounds. Many phytochemicals derived from various plants, showed promising antibacterial, antifungal, and antiviral action against a variety of human diseases to date. Phytochemicals offer a lot of potentials when it comes to managing and treating microbial infections and wounds. Antibacterial mechanism of action of several phytochemicals is well-known, and knowledge of these bioactive substances has exploded in recent years. In general, phytochemicals disrupt the bacterial membrane, reduce certain virulence factors such as enzymes and toxins, and prevent the formation of bacterial biofilms, etc. Antimicrobial, antioxidant, and wound-healing phytochemicals promote blood coagulation, infection prevention, and wound healing. Phytochemicals, with dual potential of antioxidants and antimicrobial activity, in alone or combined with antibiotics can not only boost the human immune response to fight infection but can also present newer treatment strategies to combat drug-resistant microbes. Natural compounds such as curcumin, and carotenoids are antioxidants themselves but are also known to modulate Nrf2. Thus, identification, evaluation, and formulation of such natural antimicrobials with dual oxidative stress and antioxidant actions can play an important role to cure infectious diseases while at the same time can repair ROS-induced stress damage and inflammation in the host. It is critical to research and evaluate all accessible solutions that can combat infections, and antimicrobial resistance, and simultaneously improve human lives. Phytochemicals are not only less expensive and more accessible, but they are also safer, less toxic, and have wider acceptance than allopathic pharmaceuticals. However, before suggesting phytochemicals for medicinal purposes, standardization, safety, and scientific evaluation are required.

#### **Acknowledgements**

The authors are thankful for the support and encouragement of the Director, CSIR-Central Institute of Medicinal and Aromatic Plants in Lucknow, India, and Dr. Bhavana Gangwar, also acknowledge the Indian Council of Medical Research (ICMR) in New Delhi, India.

*Antioxidant Phytochemicals as Novel Therapeutic Strategies against Drug-Resistant Bacteria DOI: http://dx.doi.org/10.5772/intechopen.108220*

#### **Author details**

Bhavana Gangwar1 \*, Santosh Kumar2 and Mahendra P. Darokar1

1 Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India

2 Metabolic Engineering and Fermentation Science Group, Department of Food Science, University of Wisconsin-Madison, Madison, WI, USA

\*Address all correspondence to: bhavanagangwar1@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 10**

## Involvement of Antioxidant in the Prevention of Cellular Damage

*Olalekan Bukunmi Ogunro, Aderonke Elizabeth Fakayode and Gaber El-Saber Batiha*

#### **Abstract**

Oxidative stress occurs when the body's enzymatic or non-enzymatic antioxidants are outweighed by endogenous or exogenous free radicals. Oxidative radicals, reactive oxygen species, and other biomolecule-damaging free radicals can be generated during normal cellular metabolism and react with proteins, lipids, and DNA. In the domains of biology and medicine, free radicals have become increasingly important. They can accumulate in a variety of ways, both endogenously and exogenously. Mitochondria are the primary source of cell-level endogenous reactive oxygen species. In several chronic and degenerative disorders, this results in tissue destruction. In addition to being produced endogenously, antioxidants can also be delivered exogenously to the biological system, most frequently through nutrition. Antioxidants are generally used to counteract the effects of free radicals produced by metabolic processes. In this chapter, the crucial function of reactive oxygen species in human health, as well as exploring the functioning of antioxidative defense systems in reducing toxicity caused by excess reactive oxygen species were discussed.

**Keywords:** cellular damage, free radicals, human diseases, cell signaling, antioxidant milieu

#### **1. Introduction**

Defending cells against the harm produced by free radicals is the goal of antioxidants. Taking antioxidants may help to counteract some of the damage that free radicals can inflict. Carotenoids and other nutrients like beta carotene and lycopene have been shown to be effective antioxidants [1]. Free radicals can be generated during oxidation reactions, which can set off a cascade of events that damage cells. By eliminating free radical intermediates, antioxidants put an end to these chain events and block further oxidation reactions. They participate in processes that maintain cell health and repair DNA. Because of this, oxidizing substances like thiols or ascorbic acid frequently serve as antioxidants. Plants and animals utilize a wide variety of antioxidants, such as glutathione and vitamins C and E, as well as enzymes such as catalase, superoxide dismutase, glutathione peroxidase to mitigate

the deleterious effects of oxidation reactions [2]. If a cell's antioxidant levels are low or its antioxidant enzymes are blocked, oxidative stress can cause the cell to become damaged [3, 4].

A wide variety of dietary supplements contain antioxidants which help people stay healthy while also reducing their risk of developing ailments like cancer and heart disease. In later, more extensive clinical tests, researchers were unable to demonstrate any benefit to taking antioxidant supplements; instead, they discovered that taking an excessive amount may be harmful [5]. Natural antioxidants have a variety of applications in industry, in addition to their usage in medicine. Some of these applications include acting as preservatives in food and cosmetics [6, 7].

#### **2. Oxidants and free radicals**

Any molecular species that has an unpaired electron in an atomic orbital and is capable of independent existence is referred to as a free radical. When an electron is missing from a pair, it causes the resulting species to be extremely reactive. Free radicals are capable of a diverse set of reactions, the most common of which are electron transfer and addition processes that lead to the creation of covalent bonds [8, 9]. Reducing free radicals are those that give up an electron to an acceptor, while oxidizing free radicals are those that take in electrons (accepting an electron from a donor). There is a thermodynamic hierarchy, often known as a pecking order, for the many types of electron transfer reactions. This is because radicals can have a wide variety of reactivities [1, 9].

#### **2.1 Generation of free radicals and oxidants**

Non-radicals can be converted into radicals through a variety of methods, including the addition of a single electron to the molecule. A covalent bond (C–H, C–O or C–C) can be broken via homolytic fission, in which one electron from the bonding pair remains on each atom. While disulfide links can readily be broken, the O–O bond in H2O2 can be broken by exposing it to UV light, resulting in the formation of • OH, these covalent bonds are extremely difficult to dissociate. Exogenous and endogenous sources of free radicals exist [10, 11]. Different cell organelles, such as mitochondria, peroxisomes, and endoplasmic reticulum, as well as various enzyme activity, fatty acid metabolism, and phagocytic cells, are examples of endogenous sources. High temperatures and environmental pollutants, such as those produced by cooking (smoked meat or used cooking oil), H2O2, N2O2, deoxyosones, and ketamine, are examples of exogenous sources of radiation. Other exogenous sources include X-ray and beta-ray light, ultraviolet A light in the presence of a sensitizer and chemical reagents such as these (aromatic hydrocarbons, pesticides, polychlorinated biphenyls, dioxins, and many others), microbial infections, drugs, and their metabolites [9, 11]. To combat bacteria and other invaders, activated immune cells (eosinophils, neutrophils, etc.) produce endogenous free radicals, as does the mitochondrial respiratory chain, enzymatic activity (xanthin oxidase, NADPH oxidase, lipo-oxygenase, NO synthase, etc.), and various pathological conditions and diseases [12, 13]. Air and water pollution, cigarette smoke, heavy metals or transition and other medications and chemicals, radiation and extreme temperatures produce exogenous free radicals.

#### **3. Oxidative damage to cellular molecules**

#### **3.1 Oxidative damage to protein**

Free radicals, amino acid modification, cross-linkage formation due to lipid peroxidation, and protein fragmentation are all methods by which proteins can be damaged. Methionine, cysteine, arginine, and histidine are the most susceptible to oxidation in proteins. Proteins that have already been damaged by free radicals are more vulnerable to enzyme proteolysis. The oxidation of protein products can influence enzymes, receptors, and the transport of molecules across membranes [13].

Since oxidatively damaged protein products contain highly reactive groups, membrane damage and other cellular activities may be impaired because of their existence. Peroxyl radicals, a type of free radical, are hypothesized to be responsible for protein oxidation. Carbonyls and other amino acid modifications can be created because of ROS damaging proteins and causing carbonyl and other amino acid alterations, such as the production of methionine sulfoxide and protein peroxide. From signaling pathways to enzyme activity to heat stability to proteolysis susceptibility, many elements of protein oxidation are affected [4, 9].

#### **3.2 Lipid peroxidation**

In a variety of physiological and pathological processes, Including aging, arterial hardening, inflammation, and cancer development and progression, oxidative stress play an important role to increase biochemical lesions by reacting with other biomolecules [14]. Cell membrane-bound polysaturated fatty acids are subjected to lipid peroxidation, which progresses via radical chain reaction. ROS is hypothesized to be triggered by hydroxyl radicals, which remove hydrogen atoms, resulting in the formation of lipid radicals and diene conjugates. In addition, it generates a peroxyl radical when oxygen is added; this extremely reactive radical then attacks a different fatty acid, resulting in lipid hydroperoxide (LOOH) and a brand-new radical. As a result, lipid peroxidation grows. Several chemicals are generated because of lipid peroxidation, including alkanes, malonaldehyde, and isoprotanes. Researchers have shown these chemicals to be biomarkers for lipid peroxidation in a variety of conditions including diabetes, ischemia reperfusion injury and neurodegenerative disorders [4, 15].

#### **3.3 Oxidative damage to DNA**

Oxidative DNA damage is an inevitable consequence of cellular metabolism. While guanine typically pairs with cytosine, the most common form of oxidative base damage, 8-oxo-7,8-dihydroguanine (8-oxoG), can lead to adenine mispairing through a conformational change. DNA and RNA can be damaged by oxidative stress, as numerous studies have demonstrated beyond reasonable doubt. Many diseases, including aging and cancer, have been linked to mutations in DNA. When free radicals or ultraviolet radiation cause oxidative damage to DNA, the levels of oxidative nucleotides including glycol, dTG, and 8-hydroxy-2-deoxyguanosine rise [16]. One of the many illnesses linked to oxidative damage is cancer, and mitochondrial DNA has been found to be particularly vulnerable. The use of 8-hydroxy-2-deoxyguanosine as a biomarker for oxidative stress is well adopted. Oxidatively stressed cells have high levels of this marker [17].

#### **4. Biological activities of free radicals and oxidants**

It is necessary for the maturation of cellular structures that both reactive oxygen species (ROS) and reactive nitrogen species (RNS) are present in low to moderate concentrations since they can operate as weapons for the host defense system. It is true that phagocytes (which include neutrophils, macrophages, and monocytes) create free radicals as a part of the body's immune system's fight against sickness. Reactive oxygen species (ROS) production by the immune system is clearly demonstrated in patients with granulomatous illness (ROS) [18]. The membrane-bound NADPH oxidase machinery is faulty in these individuals; therefore, they are unable to create the superoxide anion radical (O2 • ). The effect is that people get sick and become infected with numerous diseases that endure for a long time.

Several cellular signaling systems benefit from the physiological functions ROS and RNS play in their operation, as well (ROS and RNS). Nonphagocytic NADPH oxidase isoforms are crucial for the control of intracellular signaling cascades in fibroblasts, endothelial cells, vascular smooth muscle cells, cardiac myocytes, and thyroid tissue. Blood flow, clotting, and cognitive function are all affected by nitric oxide (NO), an intercellular messenger [18, 19].

In addition to its role in nonspecific host defense, NO is essential for the eradication of intracellular infections and malignancies. A mitogenic reaction is one of the many good effects of free radicals. At low to moderate levels of intensity, ROS and RNS are required for human health.

#### **5. Mechanism of cell signaling mediated by RNS/ROS**

Oxidation can take place in any of these macromolecules: DNA, proteins, and lipids when ROS are present. Oxidative stress is primarily caused by reactive oxygen species (ROS) in cells. Signaling molecules such as ROS are critical to the proper operation of the body's physiological systems. In a physical sense, this is what is going on. Autophagy, apoptosis, necrosis, and other mechanisms that lead to cell death are activated when ROS levels are too high.

#### **5.1 ROS induce autophagy**

Lysosomes of the cell remove damaged organelles, protein aggregates, and foreign invaders via autophagy, a cellular breakdown process. Several human diseases, including as cancer, neurological disorders, infectious diseases, metabolic disorders, and the aging process, may be caused in part by problems with autophagy. Autophagy can be triggered in response to a variety of stresses, including starvation, ER stress, organelle breakdown, and pathogen infection. Activation of autophagy has been linked to reactive oxygen species (ROS). H2O2 will eventually cause oxidative stress because of its buildup in the cell. The autophagic process relies heavily on the autophagy gene ATG4. There is evidence to suggest that H2O2 oxidizes this gene specifically in the absence of food. If H2O2 builds up, the ATG4's activity can be oxidized. The lipidation of LC3/ATG8 is essential for the initiation of autophagy, which is facilitated by oxidized ATG4. For the buildup of LC3-PE on autophagosome membranes and the subsequent stimulation of autophagosome formation, ROS is necessary [20, 21].

#### *Involvement of Antioxidant in the Prevention of Cellular Damage DOI: http://dx.doi.org/10.5772/intechopen.108732*

Reactive oxygen species (ROS) have the potential to regulate autophagy via activating the mitogen-activated protein kinase [MAPK] family. JNK1c-Jun-Nterminal kinase (JNK), p38, and extracellular signal-regulated kinase are all members of this family (ERK). In the three-tier kinase cascade that activates the members of the MAPK family, MAPK kinase (MAPKK), MAPK kinase (MAPKK), and MAPK all participate. When JNK is activated for an extended period, the cell's production of reactive oxygen species (ROS) increases significantly, increasing the risk of DNA damage. The identification of cellular redox stress is the final step in the activation of the p53 pathway. Many autophagy-inducing genes can be activated by p53 as a transcription factor. As a result, JNK and Sestrin2 may be activated, resulting in the phosphorylation and activation of TSC2 and the resulting autophagy [22].

Additional signaling pathways that participate in ROS-mediated autophagy and contribute to the process include Akt/mTOR (mechanistic target of rapamycin), as well as AMPK The well-known kinase Akt/mTOR, which in turn oxidizes the phosphatase and tensin homolog, is controlled by reactive oxygen species (ROS) (PTEN). Inhibition of mTOR and activation of AMPK are required for autophagy activation, and these two processes are controlled by the VPS34 complex [23].

#### **5.2 ROS trigger apoptosis**

Death receptors and mitochondrial pathways initiate cell apoptosis in response to both external and internal stimuli. Because an increase in oxidative stress disturbs the homeostatic equilibrium within cells and causes long-term oxidative changes to fat, protein, or DNA, ROS levels rise. TRAIL and nuclear factor kappa B (NF-kB) are activated by reactive oxygen species (ROS) and result in the death of cancer cells. Apoptosis can be induced by ROS-driven activation of JNK, a MAPK family member like JNK. Mitochondrial malfunction and apoptosis are becoming more obvious roles for JNK [24]. Several studies have shown that Shikonin, a naturally occurring naphthoquinone derivative, can kill cancer cells. Shikonin boosted ROS production and apoptosis, as well as the production of JNK and p38 in K562 cells, which were then treated. Programed cell death in cancer cells increases because of ROS/JNK activation [25]. The redox sensitive MAPK kinase and Apoptosis Signal Regulation Kinase 1 (ASK1) are positioned upstream of ROS/JNK. The antioxidant protein ASK1 is prevented from conducting its work by Grx and Trx1, which are antioxidant proteins. Components associated with the tumor necrosis factor receptor are recruited to the complex when ROS cause Trx1 to dissociate from the ASK1-Trx1. Activated ASK1 signals can activate AP-1-dependent proapoptotic genes and mitochondrial signaling. By altering the mitochondrial ASK1/ASK2/Trx2 complex, ROS can also lead to the release of cytochrome C. Increase ROS levels in the ER and stimulate mitochondria to do this. Antioxidant flavone can protect against myocardial ischemia/reperfusion injury, which can lead to apoptosis [26, 27].

#### **5.3 Necrosis induced by ROS**

In contrast to apoptosis, necrosis is a unique form of cell death. The receptorinteracting serine/threonine 3-like (RIP3) protein kinase has the potential to destroy cells because it is highly expressed in so many different cell lines. The RIP1 and RIP3 serine/threonine kinases both regulate necrosis in a similar manner. To activate the transmission of the pro-necrotic signal, RIP1 and RIP3 must be phosphorylated to

form necrosome, an amyloid-like complex. Depletion of RIP3 in necrosis-inducing cells reduces ROS concentration, but RIP3 overexpression raises ROS levels. The involvement of RIP3 in necrosis induction is performed via increasing ROS production associated to energy metabolism [28, 29]. When RIP1 and RIP3 are phosphorylated, the pronecrotic kinase activity is triggered, and ROS are generated. According to this study, the phosphorylation of pronecrotic complexes stabilizes their interactions. A link between STAT3 and the mitochondrial electron transport chain complex I component GRIM-19 governs enhanced ROS production from RIP1 phosphorylation-dependent activation of the mitochondrial electron transport chain. In the mitochondria, STAT3 and GRIM-19 accumulate and increase ROS production and necroptosis, the process by which cells die, because of this interplay [30]. They all work together to increase energy consumption and mitochondrial ROS generation by enhancing the interaction between RIP3 and the enzymes glutamate dehydrogenase 1 [GDH], glutamate ligase (GLUL), and PYGL. During necrosis induction, there may be an interaction between the TNF receptor and the necrosis-inducing ROS generated by the NADPH oxidase NOX enzyme complex. As an important RIP3 downstream component of TNF-induced necrosis in ROS-induced necrosis, MLKL has been found to be an important player in the process. In the last phases of necrosis caused by TNF, MLKL also plays a role in ROS production and JNK activation [31].

#### **6. Oxidative stress and human diseases**

An organ or tissue is said to be under oxidative stress when the endogenous antioxidant defense system is overwhelmed by the production of highly reactive molecules like ROS, RNS and RSS, resulting in cellular damage and malfunction and a wide spectrum of illnesses. As a result of normal metabolic activities, the reactive species are created in low concentrations within the cells themselves. Radiation (X-rays and UV), pollution, cigarette smoke, bacteria, viruses, and drugs can also cause them, as can acute or chronic cellular stress (acute or chronic) [24]. They include free radicals and nonradical oxidants. Free radicals are unstable because of the presence of unpaired electrons in their outer electron orbit. Free radicals tend to neutralize themselves by reacting with other molecules and triggering their oxidation because they are so unstable and reactive. Thus, they have the potential to disrupt a wide spectrum of biological components, such as DNA, lipids, and proteins. Proteins are a common target for free radicals because of their critical role in cellular activity. Although free radicals have been shown to cause some protein modifications, such as protein unfolding or structural alteration, the majority are absolutely harmless. It is possible for protein inactivation and long-term cellular damage to be caused by irreversible protein alterations, even if reversible oxidative changes govern protein activity [1].

#### **6.1 Oxidative stress in atherosclerosis**

Atherosclerosis is a chronic inflammatory disease of the vascular system that is marked by chronic inflammation. There is a strong correlation between cardiovascular disease and atherosclerosis in most developed countries (CVD). The endothelium is injured because of inflammation and oxidative stress, resulting in arterial lesions and plaque deposition [32]. It is easier for plaque, which is mostly composed of blood cells and foam cells as well as lipids and proteins to impede the vascular system and prevent blood flow. Infarctions and strokes resulting from coronary artery disease

#### *Involvement of Antioxidant in the Prevention of Cellular Damage DOI: http://dx.doi.org/10.5772/intechopen.108732*

characterize cardiovascular disease (CVD). Diabetes, high blood pressure, smoking, cholesterol difficulties, obesity, and other metabolic illnesses are linked to endothelial degradation. In the early phases of atherosclerosis, oxidative stress has a negative impact on endothelial function. Endothelial function, inflammation, bleeding, and oxidative damages are all influenced by the endocrine system (RAS) [33, 34]. As a result of activating NADPH oxidase in the cardiovascular system, reactive oxygen species (ROS) are produced that damage the endothelium, resulting in endothelial dysfunction (ROS).

#### **6.2 Oxidative stress in hypertension**

The most common cause of cardiovascular disease and death around the world is high blood pressure. About 90% of instances of hypertension are categorized as essential hypertension, when the exact reason is unknown. Hypertensive stimuli, such as salt and the hyperactive RAS and OS systems as well as endogenous hormones such as Ang II and aldosterone, produce protein modification that results in a rise in blood pressure. Neoantigens are proteins that have been altered so that they are no longer identified by activated T cells as being their own. Macrophages in the blood and kidneys are stimulated to release proinflammatory cytokines by T cell-derived signals. Activated T cells in the vasculature enhance renal salt and water retention, as well as renal vasoconstriction and remodeling. Chronic inflammation can lead to high blood pressure, which is a risk factor for OS. In the presence of Ang II-induced hypertension, T cells show substantial amounts of p47phox, p22phox, and NOX2 oxidase components. To put it another way, the transfer of faulty T cells results in arterial hypertension and a decreased generation of oxygen. Angiotensin II (Ang II) is one of the most major ROS generators, while NADPH oxidase is one of the most prominent ROS producers [35, 36]. The production of Ang II reaches its peak under hypertensive conditions. In addition, increased angiotensin II levels can promote necrosis and apoptosis in renal tissue during the period of reperfusion. Ang II inhibits the SR-BI HDL receptor in proximal tubular cells. Statins were intended to inhibit HMG-CoA reductase to lower cholesterol production. However, these medications have antiinflammatory properties as well as the potential to reduce systolic blood pressure in people with high cholesterol as part of their pleiotropic effects. Patients with elevated blood pressure feel the effects more intensely [37].

#### **6.3 Oxidative stress in diabetes mellitus**

The body's ability to neutralize free radicals and produce antioxidants is out of whack, resulting in diabetes mellitus (DM). Diabetes can be triggered by changes in blood glucose levels. OS has a significant impact on the emergence of DM problems. A high blood sugar level can have a significant impact on a person's overall health [38]. As a result, chronic hyperglycemia has a lower OS than any other kind of glucose oscillation. Long-term and severe chronic hyperglycemia, as well as frequent blood glucose fluctuations, are hallmarks of many glycemic disorders. Hyperglycemia triggers ROS production in the body. Even if the cells of persons with type 2 diabetes are still functioning and intact, ROS produces OS because of the existence of ROS. Insulin production is reduced as a result. Diabetes mellitus has been linked to an increase in the radical O2 - in both animal and vitro investigations. Many mechanisms, such as enzymatic, nonenzymatic, and mitochondrial processes, exist in DM for the generation of oxidative stress. There are numerous

reasons for the rise in OS in DM. The most major oxidizing activity, glucose autooxidation, generates free radicals [38, 39]. Reduced antioxidant defenses (lower levels of cellular antioxidants and decreased enzyme activity against free radicals) and unbalanced reduction/oxidation are also contributing factors. High blood glucose levels activate numerous pathways when O2 - is generated, for the same reasons the hexosamine route is more active and the protein kinase C isoform is activated in DM. When studying DM in mitochondria, researchers look at how much energy is produced, ROS are produced, signals are transmitted, and cells die. The processes of mitochondrial fusion and fission are essential for the preservation of homeostasis. The expansion of the mitochondrial network via mitochondrial fusion appears to be beneficial. Excessive mitochondrial fission, which results in a buildup of mitochondrial fragments and a shortened electron transport chain, can aggravate cellular mitochondrial ROS generation [40].

#### **6.4 Oxidative stress in neurodegenerative diseases**

Alzheimer's, Parkinson's, and depression are all linked to OS. The emergence of neurological diseases like Alzheimer's and Parkinson's, both of which are intimately linked to aging, is a key risk factor for OS. Oxidative stress and mitochondrial dysfunction are two of OS's long-term side effects. The hippocampus of Alzheimer's disease animal models shows decreased activation of mitochondrial complex IV. As well as causing mitochondrial oxidative damage, increased OS also generates harmful byproducts for the brain [41, 42]. Alzheimer's disease neurodegeneration is linked to the production of a potentially hazardous peptide known as -amyloid by ROS. Neocortical neurons produce more H2O2 when -amyloid is present. Activation of NADPH by microglia cells in Parkinson's disease mice is also linked to the progression of dopaminergic neurodegeneration. Multiple sclerosis (MS) and depressive and autoimmune illnesses are all connected to OS. Multiple sclerosis patients have lower GPx enzyme activity and higher levels of oxidative damage to DNA (8-OHdG). Patients with unipolar depression have been shown to have low levels of SOD, ascorbic acid, and MDA [43].

#### **6.5 Oxidative stress in cancer**

Cancerous cells can proliferate more quickly when ROS is present. OH, the major ROS that damages mitochondrial and nuclear DNA, hydrolyzes bases to form 8-OHdG and 8-oxodG, two examples of hydrolyzed base products. Various enzymatic pathways can be used by cells to repair damaged DNA. However, mutations caused by base change or deletion can cause cancer if DNA damage is too severe to repair. Insufficient DNA repair is more likely when there are twice as many DNA oxidative damages [44]. As we age, the bodies' ability to repair oxidative damage and other forms of DNA damage decreases. Cytotoxicity and chromosomal disorders can result from DNA oxidation. Genetic mutations may be generated through free radical interactions with other biological components, in addition to DNA damage. The carcinogen LPO is a known carcinogen. In the presence of guanine bases, MDA may create adducts, which are toxic. It's yet unclear how OS-induced carcinogenesis affects the human body. The ability of OS to alter gene and protein expression that signals cell growth and proliferation has been demonstrated through new techniques [1, 24].

#### **7. Classification of antioxidants**

In order to protect cells from oxidative stress, antioxidant enzymes network together to create a protective barrier. Oxidative phosphorylation and other cellular processes generate H2O2, which is then reduced to water. The initial stage in this detoxification pathway is initiated by superoxide dismutase, and hydrogen peroxide is eliminated by catalases and other peroxidases [2, 45].

#### **7.1 Enzymatic antioxidants**

#### *7.1.1 Superoxide dismutase*

A set of enzymes known as superoxide dismutases (SODs) breaks down the superoxide anion to produce oxygen and hydrogen peroxide. SOD enzymes are found in almost all aerobic cells and fluids. It is possible to categorize superoxide dismutases into three main types based on their ability to bind iron or manganese as cofactors: the Cu/Zn, Fe, and Mn, and finally the Ni subtypes [46]. It has been discovered that SOD isozymes are present in several cell compartments in higher plants. Mn-SOD is found in both mitochondria and peroxisomes. CuZn-SOD was found in all four chloroplasts, peroxisomes, and apoplasts using fluorescent microscopy. Fe-SOD was also found in these organelles, albeit at lower concentrations [47].

Superoxide dismutase enzymes are found in all mammals and most chordates, including humans. SOD1 and SOD2 can be found in the cytoplasm, mitochondria, and extracellular space. In comparison, the other three are tetramers (four units) in structure (four subunits). SOD1 and SOD3 include copper and zinc, while SOD2 contains manganese in the reactive core [48, 49].

#### *7.1.2 Catalase*

Catalase is an antioxidant enzyme that also plays the role of a catalyst in the process of converting hydrogen peroxide into oxygen and water. It does this by nullifying the effect that the hydrogen peroxide that is present inside the cell would otherwise have. It is not possible to determine the exact quantity of catalase that is present in the cytoplasm due to the fact that the majority of it is destroyed whenever the tissue is handled. The interaction of reactive oxygen species and antioxidants can lead to an imbalance, which in turn can lead to oxidative stress. Oxidative stress is both a disease-causing and disease-aggravating factor, and it plays a role in the development of many different diseases [1, 50].

#### *7.1.3 Glutathione systems*

The glutathione system includes glutathione, glutathione reductase, glutathione peroxidases, and glutathione S-transferases. This system can be found in all living things, including bacteria, plants, and mammals. Hydroperoxides and hydrogen peroxide can be broken down by glutathione peroxidase, an enzyme found in the body. The enzyme Glutathione peroxidase possesses all four of the necessary selenium cofactors for this procedure. There are at least four unique isozymes of glutathione peroxidase reported in different species of animals. As far as scavenging hydrogen peroxide is concerned, glutathione peroxidase 1 is more

common and more effective than glutathione peroxidase 4 when it comes to lipid hydroperoxides. S-transferase activity increases when lipid peroxides are present. These enzymes are particularly abundant in the liver, where they contribute to the metabolic process of detoxification [1].

#### **7.2 Non-enzymatic antioxidants**

#### *7.2.1 Ascorbic acid*

Both plants and animals contain ascorbic acid, a monosaccharide antioxidant. For this reason, the nutrient is categorized as a vitamin and must be ingested through food. Most other animals can produce this chemical on their own and do not need it in their diets because of that. Cells can continue to function effectively because glutathione is kept in a reduced state by protein disulfide isomerase and glutaredoxins. Ascorbic acid, for example, can neutralize ROS such as hydrogen peroxide (H2O2). In addition to being a direct antioxidant, ascorbic acid also provides a substrate for an enzyme called ascorbate peroxidase. Because of this function, plants are better equipped to deal with a wide range of stresses [51, 52].

#### *7.2.2 Glutathione*

In all aerobic living forms, the cysteine-containing peptide known as glutathione can be detected. It can be made in the cells of the body from the amino acids that make up its components, therefore getting it in one's food is not necessary for getting it. Because the thiol group in the cysteine that makes up glutathione is a reducing agent, glutathione could both oxidize and reduce itself in a reversible fashion, giving it antioxidant properties [53, 54]. Within cells, the enzyme glutathione reductase is responsible for maintaining the reduced form of glutathione. Glutathione, in this state, can reduce the levels of other metabolites and enzyme systems, as well as react directly with oxygen. A key antioxidant in cells, glutathione has an extremely high concentration and plays a critical role in maintaining the redox balance within cells. Mycothiol and trypanothione, two additional thiols can be substituted for glutathione in some organisms, such as actinomycetes and Kinetoplastids [55].

#### *7.2.2.1 Thiols*

The group of organic compounds with a sulfhydryl group includes thiols (-SH). They are made up of a carbon atom joined to a hydrogen atom and a sulfur atom. In the organism, extra electrons pass to thiols during the oxidation caused by ROS, resulting in the formation of disulphide bonds. These reversible bonds allow electrons to transfer back to thiols due to the oxidative balance. In enzymatic reactions, signal transduction, detoxification, transcription, regulation of enzymatic activation, cellular signaling mechanisms, and apoptosis reaction, thiol-disulphide homeostasis' antioxidant capacity plays a crucial role [55].

#### *7.2.3 Tocopherols and tocotrienols (vitamin E)*

Tocopherols and tocotrienols make form a set of eight different fat-soluble vitamins with antioxidant properties. These vitamins are closely connected to one another. The umbrella term "vitamin E" is used to refer to all these different

#### *Involvement of Antioxidant in the Prevention of Cellular Damage DOI: http://dx.doi.org/10.5772/intechopen.108732*

vitamins. The most research has been done on beta-tocopherol because of its high bioavailability compared to the other tocopherols [56]. This demonstrates that the body can absorb beta-tocopherol and metabolize it more efficiently than it does the other forms. It has been hypothesized that the form of tocopherol known as gamma-tocopherol is the most effective lipid-soluble antioxidant, and that it shields membranes from oxidation by engaging in a chain reaction with lipid radicals that are generated during the process of lipid peroxidation [57]. In other words, gammatocopherol protects membranes from oxidation by reacting with lipid radicals. There are no free radical intermediates left after this process and the reaction comes to a complete and total stop. Oxidized-tocopheroxyl radicals are generated because of this procedure. Activated radicals can be regenerated back into the reduced form by other antioxidants as ascorbate, retinol, or ubiquinol [58, 59].

#### **7.3 Exogenous antioxidants**

Several pharmacological properties are attributed to flavonoids, a class of polyphenolic chemicals with a benzo—pyrone structure that is abundantly found in plants. Researchers have been looking into the antioxidant properties of these compounds because of the free radical scavenging and metal ion chelating abilities of their functional hydroxyl groups. Functional groups play a critical role in determining activities such as ROS/RNS-scavenging and metal chelation, which are dependent on functional groups' configuration and substitution. Flavonoid suppresses ROS creation, inhibits enzymes, or chelates trace elements that generate free radicals; Flavonoid scavenges ROS; and Flavonoid increases antioxidant protection [60].

Due to Genistein's wide range of pharmacological properties, it is perhaps the most interesting and thoroughly researched flavonoid component in soy. An abundance of research has shown that genistein can scavenge ROS and RNS with great efficiency. Through gene and protein regulation, this flavonoid molecule can increase a cell's antioxidant defenses, hence preventing apoptosis. Many plant-based foods (fruits, oils, seeds, etc.) include flavonoids, a class of naturally occurring substances that have been proved to be beneficial to human health. However, there are certain possible hazards to human health and well-being when these foods are included in the diet (as food enrichment or as nutraceuticals) [61]. Flavonoids, a group of polyphenolic compounds with a benzo—pyrone structural arrangement that is abundant in plants, are known to have several pharmacological characteristics. Because of their functional hydroxyl groups' ability to scavenge free radicals and chelate metal ions, these compounds have been investigated for their antioxidant capabilities [62].

It is important to note that the methods of antioxidant activity such as ROS/RNS removal and metal chelation are all dependent on a variety of factors. The conformational disposition of functional groups in these compounds determines their antioxidant activity. Increased antioxidant defenses and suppression of ROS generation are both caused by flavonoid-induced ROS scavenging, as are enzyme inhibition and trace element chelation [61].

In terms of pharmacological effects, genistein is perhaps the most fascinating and well-studied flavonoid molecule. It is an isoflavone found in soy. Antioxidant genistein has been used widely in a wide range of investigations, indicating its ability to scavenge ROS and RNS. Antioxidant defenses of a cell can be improved by this flavonoid molecule, which modulates numerous genes and proteins. Flavonoids are a class of naturally occurring compounds found in a wide variety of plant-based foods (fruits, oils, seeds, etc.) that have been shown to be beneficial to human health,

#### **Figure 1.** *Classes of antioxidants. Source: [24, 26].*

both as antioxidant molecules and for their other, less obvious but no less intriguing, pharmacological qualities. It's still important to take precautions when using these supplements, and there may be some negative effects on human health and well-being if they are used in this way (as dietary supplements or nutraceuticals). Lipid soluble vitamins acts as an antioxidant, blocking free radicals from causing damage to cell membranes through a process known as lipid peroxidation (**Figure 1**) [8, 61].

### **8. Diets rich in antioxidants**

#### **8.1 Fruits**

A lot of different fruits have a lot of health benefits, like being high in antioxidants, filled with vitamins, and having a lot of different vitamin content. Cranberries, red grapes, peaches, raspberries, strawberries, red currants, figs, cherries, pears, guava, oranges, apricots, mango, red grapes, cantaloupe, watermelon, papaya, and tomatoes are some of the fruits that fall into this category [63].

### **8.2 Dried fruits**

Dried fruits have a greater antioxidant ratio than fresh fruits since the water have been removed during drying. They are convenient to carry around in a handbag, briefcase, or car because they can be eaten on the go and are high in nutritional value.

#### **8.3 Vegetables**

In addition to broccoli, spinach, carrots, and potatoes, other vegetables and fruits that are high in antioxidants include artichokes, cabbage, asparagus, avocados, beetroot, radish, lettuce, sweet potatoes, squash, pumpkin, collard greens, and kale. Broccoli, spinach, carrots, and potatoes are all high in antioxidants.

#### **8.4 Herbs and other seasonings**

Antioxidants can be found in a variety of spices, including cinnamon, cardamom, paprika, oregano, and turmeric. Curry powder and mustard seed powder are also rich in antioxidants. In addition to spices like sage and tarragon and herbs like peppermint and oregano and basil, herbs also include dill weed and marjoram. Dill weed is one of several herbs that can be found. They are a fantastic source of antioxidants, as well as taste and complexity to your meals.

Grains and nuts can be found in a wide variety of cuisines. Everything from cereal to nuts to a peanut butter and jelly sandwich contains nutritional powerhouses including peanut butter and jelly, granola bars, corn flakes, and granola.

#### **8.5 Beverages**

In contrast to popular belief, the great majority of our body's antioxidants can be found in beverages rather than in food. Apple juice, cider, tomato juice, pomegranate juice, and pink grapefruit juice are among the most common sources. In addition to green tea, black tea and ordinary tea contain a significant number of antioxidants. Coffee aficionados, welcome! Coffee is heavy in calories; however, it should be used in moderation because it can boost blood pressure and heart rate, which is why it is important to drink it in moderation. The antioxidants in coffee or tea are inhibited from being released when milk is added. While red wine and beer [which are both brewed from grains] provide a large amount of alcohol in moderation, the health benefits of moderate alcohol use have been extensively studied. Colorful fruits and vegetables are vital to have in your diet. Consider all selections, not just the most popular ones. More antioxidants can be found in foods that are deeper and brighter in color, such as oranges and yellows. With so many options, you'll never get bored or run out of tasty and nutritious dishes to pick from. Variety, it is claimed, is the flavor of life [64].

#### **9. Mechanism of action of antioxidants**

It has been found that antioxidants can have two primary effects. The primary antioxidant breaks the chain by supplying an electron to the system's free radical. To eliminate ROS/reactive nitrogen species initiators, the second procedure involves quenching the chain-initiating catalyst (secondary antioxidants). Co-antioxidants, electron donation, and gene expression control are some of the ways antioxidants can alter biological systems.

#### **9.1 Preventive antioxidants**

The production of ROS, such as H2O2 and O2 • , cannot be prevented during metabolism. To decrease the harm caused by oxidative stress, numerous techniques have

been developed. One of the finest defenses against the creation of free radicals is the cell's own synthesis of antioxidant enzymes. SOD, CAT, GPx, GR, GST, thioredoxin reductase, and hemeoxygenase are some of the most significant antioxidant enzymes in the body. Using the Fenton reaction, the CAT, GPx, and CAT reactions, SOD decomposes O2 • into water [65].

GST and GPX work together to help the body get rid of peroxides. The GSH/GSSG ratio is a well-established biomarker of oxidative stress since GRd controls it. GRd plays a vital role in boosting GSH concentration to maintain a steady oxido-redox state. As a result, researchers have discovered a link between oxidative stress and autism. Free radical generation and GSH/GSSG ratio in autistic cells were shown to be lower in comparison to those in control cells in an experiment.

Thus, GPx is widely distributed in cells, as opposed to CAT, which is typically restricted to the peroxisomes. Seven times more GPx activity in the brain than CAT activity, which is more susceptible to free radical damage, is found in the brain. Catalase (CAT) can breakdown H2O2 in the liver, kidneys, and erythrocytes at high doses [66].

#### **9.2 Free radical scavengers**

#### *9.2.1 Scavenging superoxide and other ROS*

The most prevalent kind of cellular free radical, which is referred to as superoxide (O2 • ), is accountable for a wide array of damaging modifications. Alterations in peroxidative processes and low antioxidant concentrations are commonly related with these changes. As a means of generating more powerful OH• and ONOO even when it itself is not reactive with biomolecules, O2• is nevertheless beneficial. The phagocyte enzyme known as NADPH oxidase is responsible for the production of massive volumes of oxygen dioxide (O2) during the process of phagocytes eliminating microorganisms. In addition to this, it is a direct result of the respiration that takes place in the mitochondria of the cell [2, 14].

#### *9.2.2 Scavenging hydroxyl radical and other ROS*

When compared to other radical species, the hydroxyl radical, which is represented by the symbol OH• and has the chemical formula OH, is a very active radical that can cause significant damage to biological components such as DNA, lipids, and proteins. Usually, it is believed that the synthesis of OH• originates from the Fenton reaction system. This reaction system involves the interaction of FeSO4 and H2O2 and is then carried out in an aqueous medium. Because of this, the activity of antioxidants as OH• scavengers can be achieved through direct scavenging, the restriction of OH• generation through the chelation of free metal ions, or the transformation of H2O2 into other molecules that are not harmful to the body [9].

#### *9.2.3 Metal ion (Fe2+, Fe3+, cu2+, and Cu+ ) chelating*

Even though trace minerals are essential for human nutrition, they are also capable of performing the function of antioxidants (through enhancing formation of free radicals). During the process of dismutation of SOD, H2O2 is produced as a byproduct. This H2O2 combines with the ions Fe2+ and Cu+ to produce the highly reactive OH• . Although this is not the case with OH• , the reaction of iron and copper

#### *Involvement of Antioxidant in the Prevention of Cellular Damage DOI: http://dx.doi.org/10.5772/intechopen.108732*

with H2O2 results in the generation of more singlet oxygen than OH• . Oxidation has occurred for both the Fe2+ and the Cu+1 ions. When vitamin C is available, it is feasible to recycle the cellular reductants, such as NADH as well as Fe3+ and Cu2+, to produce OH• radicals [1]. This can be accomplished when vitamin C is present. OH, is one of the most reactive elements in the body. It may react directly with proteins and fats to generate carbonyls [aldehydes and ketones], as well as cause lipid peroxidation and cross-linking. Chelating metal ions can lower their activity, which in turn lowers the formation of reactive oxygen species (ROS). Cu2+ and ascorbic acid are responsible for the generation of Cu<sup>+</sup> . This Cu<sup>+</sup> is then chelated by the Se antioxidant, which prevents DNA damage caused by the OH• radical that is generated when Cu<sup>+</sup> is combined with H2O2 [67].

#### **9.3 Free radical generating enzyme inhibitors**

The production of free radicals by specific enzymes has been shown to occur in a wide range of physiological and pathological situations. The plasma membrane is home to a group of enzymes known as NADPH oxidases. A cytosolic donor NADPH is transferred to an extracellular oxygen molecule by these electron transporters. Hypoxanthine and hypoxanthin are converted into uric acid in the organism when catalysts for the oxidation of these compounds are present [2]. Hydrogen peroxide and oxygen radicals are formed because of this process. Aside from mitochondrial respiration, additional enzymes produce oxygen dioxide as a waste product, including NADH oxidase, monooxygenases, and cyclooxygenases. The enzyme NADPH oxidase produces a large amount of oxygen that is poisonous to all living things to fight infections in a way that is dependent on oxygen. The dying mechanism then makes use of this oxygen. Regulating the generation of reactive oxygen derivatives is critical during a respiratory burst to prevent tissue damage. This is done so that an organism can defend itself against invading pathogens [68]. On the other side, excessive ROS can cause oxidative stress, which can lead to processes like the oxidation of low-density lipoprotein (LDL). An increase in the amount of oxidized LDL that is circulating in the blood of patients who have metabolic syndrome has been linked to increased phagocytic NADPH oxidase activity. To lessen the negative consequences of oxidative stress, several studies have demonstrated that hemodialysis patients can gain advantages from inhibiting NADPH oxidase and taking antioxidants. In recent years, a great number of naturally occurring antioxidants have demonstrated the potential to inhibit enzymes that enhance O2 generation, which has led to the development of new therapy agents for illnesses related to oxidative stress [61].

#### **9.4 Prevention of lipid peroxidation**

Some of the most frequent C-C double bonds can be found in unsaturated fatty acids, glycolipids, cholesterol, the cholesterol ester, and phospholipids, although there are many others. Lipid peroxidation is the process by which these compounds are oxidized. As a result of this chain reaction, ROS begin to damage unsaturated fats. There are several double bonds and methylene-CH2-group groups in unsaturated fatty acids, which are very reactive hydrogens. Antioxidants can quench peroxide radicals directly, stopping the chain reaction and preventing further damage [1]. Chronic diseases such as cancer and atherosclerosis, which can cause early death, have been related to lipid peroxidation. It is possible for antioxidant compounds to neutralize or inhibit the generation of ROS and peroxide radicals, respectively. Lipid peroxidation

is an important method for discovering naturally occurring antioxidants and figuring out the mechanism by which they work. Lipoproteins and red blood cells as well as low density lipoprotein (LDL) have been studied for their ability to protect against lipid peroxidation due to free radicals. An important aspect influencing the antioxidant activity of these polyphenols is their structure and starting circumstances. The microenvironment in which this reaction occurs also has a substantial impact [61].

#### **9.5 Prevention of DNA damage**

Direct interactions between nitric oxide radicals (OH• ) and O2 • radicals (OO• ) in living cells can sever a single strand of DNA. This causes damage to the DNA that is not repairable in any way. DNA damage, which results in cell death and mutation, has been linked to degenerative diseases such as Alzheimer's. As a result of this, DNA or plasmid damage has evolved into a model for the investigation and characterization of antioxidants. On the other hand, a study that used metal-free plasmid DNA found that the reaction of Cu2+ with ascorbic acid and hydrogen peroxide at pH 7 caused DNA damage. This was observed in the study. During the process, which takes place in the presence of Cu2+, ascorbic acid is utilized to bring about the reduction of Cu2+ to Cu+ . Cu+ and H2O2 react to produce an OH• radical, which then cleaves one strand of DNA. This results in the typically supercoiled plasmid DNA unraveling and becoming more helical [69].

#### **10. Conclusion**

Oxidative stress occurs in cells as a result of normal physiological processes and interactions with the environment, and cells are protected from oxidative damage by a sophisticated network of antioxidant defense systems. In general, our body's innate antioxidant defense system or antioxidants added to our diet counteract the creation of reactive species. Oxidative stress arises when this balance is disrupted. Oxidative stress plays a role in the development of a wide range of diseases, including those of the gastrointestinal system. The development of antioxidant therapies is a viable route for the treatment of gastrointestinal illnesses, as data suggests that using antioxidants can improve the progression of many diseases. As a result, understanding the unique oxidative route implicated in each disease may help to identify disease signs as well as design preventive and curative therapy techniques. Inhibiting radical generation, scavenging radicals, or stimulating their breakdown are some of the ways antioxidants protect tissue against free radical harm. In the last few years, synthetic antioxidants have been connected to human health issues. As a result, the search for natural antioxidative compounds that are safe and effective has intensified in recent years. Dietary and plant-derived antioxidants may offer a feasible alternative to the body's own antioxidant defenses. A wide variety of plant and food-derived antioxidants can be found.

#### **Conflict of interest**

The authors do not have any conflict of interest to declare.

*Involvement of Antioxidant in the Prevention of Cellular Damage DOI: http://dx.doi.org/10.5772/intechopen.108732*

### **Author details**

Olalekan Bukunmi Ogunro1 \*, Aderonke Elizabeth Fakayode2 and Gaber El-Saber Batiha3

1 Reproductive and Endocrinology, Toxicology, and Bioinformatics Research Laboratory, Department of Biological Sciences, KolaDaisi University, Ibadan, Nigeria

2 Department of Biochemistry, Federal University of Technology, Akure, Nigeria

3 Faculty of Veterinary Medicine, Department of Pharmacology and Therapeutics, Damanhour University, AlBeheira, Egypt

\*Address all correspondence to: olalekanbukunmi@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Suna Sabuncuoğlu and Ahmet Yalcinkaya*

Oxidative stress is a major contributor to the etiology of chronic disorders like cancer, diabetes, neurodegenerative diseases, and cardiovascular diseases. Long-term exposure to elevated levels of pro-oxidant substances can lead to structural damage in mitochondrial DNA as well as functional changes in a number of enzymes and cellular components, which can lead to abnormalities in gene expression. Modern lifestyles, which include eating processed food, exposure to a variety of chemicals, and not exercising, are significant factors in the development of oxidative stress. However, the ability of medicinal plants with antioxidant capabilities to cure or prevent a number of human illnesses in which oxidative stress appears to be a contributing factor has been demonstrated. A growing body of research links free radicals to the etiology of many diseases, supporting the use of antioxidants as a promising therapeutic strategy for the management of pathologies caused by free radicals. Despite these remarkable advances, there is still much to learn about the relationship between free radicals and antioxidants. Understanding the principles behind pathological and physiological disorders caused by free radicals is crucial. *Importance of Oxidative Stress and Antioxidant System in Health and Disease* contributes to understanding the fundamental principles of oxidative stress and the effects of antioxidants on disease and health.

### *Miroslav Blumenberg, Biochemistry Series Editor*

Published in London, UK © 2023 IntechOpen

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Importance of Oxidative Stress and Antioxidant System in Health and Disease

IntechOpen Series

Biochemistry, Volume 43

Importance of Oxidative

Stress and Antioxidant

System in Health and Disease

*Edited by Suna Sabuncuoğlu and Ahmet Yalcinkaya*