Free radicals and oxidative stress: Mechanisms and therapeutic targets

Abstract

BACKGROUND:

Free radicals are small extremely reactive species that have unpaired electrons. Free radicals include subgroups of reactive species, which are all a product of regular cellular metabolism. Oxidative stress happens when the free radicals production exceeds the capacity of the antioxidant system in the body’s cells.

OBJECTIVE:

The current review clarifies the prospective role of antioxidants in the inhibition and healing of diseases.

METHODS:

Information on oxidative stress, free radicals, reactive oxidant species, and natural and synthetic antioxidants was obtained by searching electronic databases like PubMed, Web of Science, and Science Direct, with articles published between 1987 and 2023 being included in this review.

RESULTS:

Free radicals exhibit a dual role in living systems. They are toxic byproducts of aerobic metabolism that lead to oxidative injury and tissue disorders and act as signals to activate appropriate stress responses. Endogenous and exogenous sources of reactive oxygen species are discussed in this review. Oxidative stress is a component of numerous diseases, including diabetes mellitus, atherosclerosis, cardiovascular disease, Alzheimer’s disease, Parkinson’s disease, and cancer. Although various small molecules assessed as antioxidants have shown therapeutic prospects in preclinical studies, clinical trial outcomes have been inadequate. Understanding the mechanisms through which antioxidants act, where, and when they are active may reveal a rational approach that leads to more tremendous pharmacological success. This review studies the associations between oxidative stress, redox signaling, and disease, the mechanisms through which oxidative stress can donate to pathology, the antioxidant defenses, the limits of their effectiveness, and antioxidant defenses that can be increased through physiological signaling, dietary constituents, and probable pharmaceutical interference. Prospective clinical applications of enzyme mimics and current progress in metal- and non-metal-based materials with enzyme-like activities and protection against chronic diseases have been discussed.

CONCLUSION:

This review discussed oxidative stress as one of the main causes of illnesses, as well as antioxidant systems and their defense mechanisms that can be useful in inhibiting these diseases. Thus, the positive and deleterious effects of antioxidant molecules used to lessen oxidative stress in numerous human diseases are discussed. The optimal level of vitamins and minerals is the amount that achieves the best feed benefit, best growth rate, and health, including immune efficiency, and provides sufficient amounts to the body.

Keywords

Free radicals reactive species oxidative stress enzymatic antioxidants non-enzymatic antioxidants

1. Introduction

Free radicals are vastly unstable and reactive (atoms, molecules, molecular fragments, or ions), that have one or more unpaired valence electrons in outer orbits and live for only a fraction of a second, but during that time they can damage DNA and sometimes cause mutations. They are created in the body as a result of metabolism, or by exposure to toxins, also they can lead to numerous illnesses including heart disease (HD) and cancer [1]. Free radicals have a vital importance in many biological processes due to their dominant role in numerous physiological situations, in addition to their association with numerous diseases [2].

Table 1
Reactive-oxygen and nitrogen species created during metabolism [4]

Radicals	Half-life	Non-radicals	Half-life
Superoxide anion (O₂ ^⋅-)	10⁶ S	Hydrogen peroxide (H₂O₂)	Stable
Hydroxyl (^⋅OH)	10^{- 10}S	Ozone (O₃)	S
Hydroperoxyl (HO₂)	S	Singlet oxygen (¹O₂Dg)	10^{- 6} S
Peroxyl (ROO)	17 S	Hypochlorous acid (HOCl)	Stable (min)
Alkoxyl (RO)	10^{- 6}S	Nitrous acid (HNO₂)	S
Organic hydroperoxide (ROOH)	Stable	Nitrosonium cation (NO⁺)	S
Nitric oxide (NO^⋅)	Stable	Nitroxyl anion (NO)	S
Nitrogen dioxide (NO₂)	Stable	Peroxynitrite (ONOO)	10^{- 3} S
Nitrate radical (NO ${}_{3})$	Stable	Dinitrogen trioxide (N₂O₃)	S
		Dinitrogen tetroxide (N₂O₄)	S
		Peroxynitrous acid (ONOOH)	Fair stable
		Nitryl chloride (NO₂Cl)	S

S: seconds; min: minutes.

Since oxygen (O₂) has a great affinity for electrons, it releases free energy when it is reduced to form water. Hence, cellular respiration, in which O₂ is converted to water, has higher energy than can be derived from anaerobic metabolism. This is due to its high oxidation potential which makes it an excellent oxidizing agent that enables electrons from reduced substances. This opposite influence of O₂ requires the development of an antioxidant system to protect against oxidants and reactive species [3]. These species are; oxygen and nitrogen (ROS and RNS) cooperatively form free radicals and other non-radical reactive species. ROS/RNS play a dual role as valuable and toxic compounds to the living system. The involvement of these reactive species in physiological signaling or pathological modifications depends on the intensity, frequency, and duration of their availability. Certainly, fluctuations in ROS/RNS levels are usually a product of improved synthesis or exposure to exogenous oxidants combined with reduced antioxidant defense. Also, ROS comprises species, i.e., hydroxyl radical (^∙OH), which have high reactivity, so they interact closely with the same and other species, i.e., hydrogen peroxide (H₂H₂) and superoxide (O₂ ^.-), which are less reactive. Also, RNS comprises nitric oxide (NO^∙), peroxynitrite (ONOO^-), and other species (Table 1) [4].

$\displaystyle\text{O}_{2}\to\text{O}_{2}^{{\bullet-}}\to\text{H}_{2}\text{O}_{% 2}\to{{}^{\bullet}}\text{OH}\to\text{H}_{2}\text{O}$ (1)

However, ROS has been considered one of the significant factors in tissue damage. When infection occurs in living organisms, the equilibrium between ROS formation and antioxidant defense favors ROS, which is denoted by oxidative stress (OS). It is interrelated with the progress of several pathological illnesses such as diabetes mellitus (DM), cardiovascular disease (CVD), rheumatoid arthritis (RA), cancer, neurodegenerative diseases, and the use of exogenous antioxidants has been recommended [5].

This review aims to provide a critical analysis of the formation, and role of reactive radical species in mitochondria, and the antioxidants role in protection from the disease.

2. Materials and methods

Mechanisms of OS, including particular damages that affect mitochondria, the injury induced by free radicals, and the protective influence of antioxidants have both been extensively discussed in reviews and meta-analyses with details of databases including Scopus, and Science Direct from which the articles were studied and the tenure of the published articles covered in this review from 1987 to 2023.

Figure 1.

Sources of free radicals generation [6].

2.1 Generation of free radicals

A free radical is an atom or molecule that consists of one or more electrons in its outer shell and is stable enough to exist independently. Their covalent bonds (C-C, C-H, or C-O) might be rigid to destroy, while the O–O bond in H₂O₂ can be destroyed using UV light, producing ^∙OH (Fig. 1) [6].

Endogenous sources include free radicals formed during normal metabolism in peroxisomes, mitochondria, endoplasmic reticulum, fatty acid (FA) metabolism, and phagocytic cells. Production of ROS within cells in physiological situations is dependent on nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), uncoupled nitric oxide synthase (NOS), lipoxygenase, and xanthine oxidoreductase (XOR). Effective XO inhibitors, such as allopurinol and its active metabolite oxypurinol, are utilized in the clinical treatment of hyperuricemia-related disorders such as gout. Furthermore, the neuroprotective effects of allopurinol are supported by the inhibition of ROS production, which is the cause of apoptosis. Elevation in ROS levels and its products through cellular components with defective antioxidant systems can initiate the progress of several chronic degenerative diseases, leading to severe injury for macromolecules [7].

Radiation, chemicals, high temperatures, toxins in the environment, microbial diseases, medications, and their metabolites are examples of exogenous sources. Secondary radicals are created when water molecules are broken down by ionizing radiation. Radiation damage to mitochondria is very likely to occur, which leads to an increase in ROS production. It has been demonstrated that radiation increases the production of NO and calcium (Ca^{+ 2}) while suppressing the activity of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT), using both in vivo and in vitro trials. Among the ROS that can be produced by UV light are ¹O₂, OH, H₂O₂, and other ROS. The generated ROS interact with the cellular constituents of the skin and have the potential to harm antioxidant enzymes, particularly CAT, and mitochondrial DNA [8]. Additionally, it has been observed that UV radiation increases 8-hydroxyguanine (8-OHG), a sensitive marker of oxidative damage, most likely by a process involving ¹O₂. The reduction of protein kinase C (PKC) expression and increase in NOS production are lead to an increase in ROS formation; PKC regulates numerous cellular roles, i.e., cell proliferation, gene transcription and translation, cell shape alterations, migration, cell-cell contact regulation, secretion, apoptosis, and regulation of ion channels and receptors, which is complicated in numerous diseases, i.e., DM, CVD, RA, neurodegenerative diseases, autoimmune diseases, and cancer. Furthermore, ROS triggers PKC by formation of lipid cofactors and regulation of Ca^{+ 2} levels. Also, modification of cysteine residues in PKCs and phosphorylation of tyrosine in PCK $\delta$ by OS, lead to PKC activation [9]. Cigarette smoke encompasses greater than 6000 materials, such as nitrosamines, CO, NO, polycyclic hydrocarbons, H₂O₂, and ^∙OH. In addition to the inhibited formation of endogenous antioxidants and enzymatic antioxidant, which is trigger nuclear factor kappa B (NF- $\kappa$ B) and stimulate pro-inflammatory signaling activity [10].

Non-steroidal anti-inflammatory medications, anti-cancer therapeutic factors, analgesics, and antiviral medicines are identified to have harmful effects and yield ROS. These medications interact via electron transfer reactions, and this lead to numerous illnesses, i.e., cardiotoxicity, liver toxicity, and nephrotoxicity. The exact mechanism is not known. It may be due to direct scavenging of the peroxyl radicals or by donating reducing equivalents to the peroxyl radicals. In oral administration of aspirin, it is converted to salicylic acid, which can lessening OS and pro-inflammatory and possibly neoplastic prostaglandins associated with rise in glutathione peroxidase (GPx) activity. Salicylic acid may have anti-cancer effect for aspirin against colon cancer [11].

Many of these metals, including; cobalt (Co), cadmium (Cd), iron (Fe^{+ 2}), copper (Cu^{+ 2}), nickel (Ni), arsenic (As), and lead (Pb) and other redox or non-redox metals, can produce redox-active metals directly by Fenton or Haber-Weiss reaction or indirectly under certain circumstances by lipid peroxidation (LP), which can lead to the creation of toxic molecules like hydroxynonenal or malondialdehyde (MDA). Additionally, some of these metals, i.e., Cd, can block several cellular membrane channels and transporters that are complicated in LP, glutathione (GSH) depletion, and changes in the blood-brain barrier’s (BBB) permeability. Antioxidant enzyme activity loss or suppression is a common denominator of metal poisoning. Free radicals mechanisms can be initiated by converting ^∙OH, O₂ ^∙- and organic radicals into H₂O₂ and hydroperoxides (LOOH) [12].

It has been proposed that ^∙OH causes biomolecule injuries through catalyzing specific reactions, comprising H abstraction, addition reactions, and oxidation reactions in numerous diseases.

$\displaystyle\text{H}_{2}\text{O}_{2}+\text{Fe}^{2+}\to{{}^{\bullet}\text{OH}}% +\text{HO}+\text{Fe}^{3+}$ (2) $\displaystyle\text{Fe}^{3+}/\text{Cu}^{2+}+\text{O}_{2}\to\text{Fe}^{2+}/\text% {Cu}^{+}+\text{O}_{2}\text{Fe}^{3+}/$ $\displaystyle\text{Cu}^{2+}+\text{O}_{2}\to\text{Fe}^{2+}/\text{Cu}^{+}+\text{% O}_{2}$ (3) $\displaystyle\text{Fe}^{2+}/\text{Cu}^{+}+\text{H}_{2}\text{O}_{2}\to\text{Fe}% ^{3+}/\text{Cu}^{2+}+\bullet\text{OH}+$ $\displaystyle\text{OH}-\text{Fe}^{2+}/\text{Cu}^{+}+\text{H}_{2}\text{O}_{2}% \to\text{Fe}^{3+}/\text{Cu}^{2+}$ $\displaystyle+\bullet\text{OH}+\text{OH}$ (4) $\displaystyle\text{O}_{2}^{{\bullet-}}\to\text{H}_{2}\text{O}_{2}\to\text{O}_{% 2}+{\bullet}\text{OH}+\text{OH}-\text{O}_{2\bullet}+$ $\displaystyle\text{H}_{2}\text{O}_{2}\to\text{O}_{2}+\bullet\text{OH}+\text{OH}$ (5)

Moreover, Pb activates LP and GPx levels in the brain. Arsenic prompts the formation of H₂O₂, O₂ ^.-, NO and constrains antioxidant enzymes, i.e., glutathione S-transferase (GST), GPx, and glutathione-reductase (GR) via binding to the -SH group. These created radicals can disturb DNA and some of the DNA bases [13].

The electron transfer chain (ETC) in mitochondria is deliberated to be the main endogenous source of ROS but others also exist. When the O₂ level rises, the rate of mitochondrial O_2- ^∙ yields rises linearly. Nevertheless, the release of H₂O₂ from mitochondria is increasing at a faster rate exceeding 60% O₂. In addition to microsomes and peroxisomes as the main source of H₂O₂, also macrophages and neutrophils can produce ROS. Moreover, unregulated ROS signaling may donate to a host of illnesses. All these forms of ROS have destructive roles to cells, they can oxidize and then inactivate numerous roles of cell constituents. All these processes may lead to apoptosis and irreversible necrosis [14].

Figure 2.

Reactive oxygen species generated by endogenous and exogenous sources[16].

Higher ROS production can be clarified by the mechanism known as ROS-induced ROS release (RIRR). It is generated by circuits requiring mitochondrial membrane channels, comprising nonspecific mitochondrial channels termed the mitochondrial permeability transition (MPT) pores and the inner membrane anion channel (IMAC) [15]. In OS resulting from higher levels of ROS leads to RIRR, which reaches a threshold level that causes the MPT pore opening. Also, mitochondrial Ca^{+ 2} overload occurs, which reduces mitochondrial function and initiates numerous processes, comprising MPT pore opening. This leads to the collapse of mitochondrial membrane potential and a temporary rise in ROS generation. Additionally, the ROS release into the cytosol, which appears to happen via IMAC can lead to activation of RIRR in the neighboring mitochondria. Also, ROS trafficking between mitochondria might initiate a positive feedback mechanism to enhance ROS formation, which could lead to major mitochondrial and cellular damage. The generation of ROS is explained in Fig. 2. Metabolic processes increase different types of ROS capable, if present in insufficient levels, of oxidizing DNA and causing various damages, which are often found in human tumors [16]. Moreover, it is created in hypoxic states in the ETC reaction and ROS may cause the production of numerous species, i.e., acrolein, 4-hydroxy-2-nonenal, prostates, hydroxy octadecanoic acid, and MDA [17].

In physiological situations, most of the mitochondrial influences of NO are utilized on the ETC. First, NO^∙ competes with O₂ for the binding site of cytochrome c oxidase (complex IV), resulting in an inhibition of this enzyme activity. Second, NO^∙ interacts with respiratory complex III, prevents electron transfer, and increases O₂ creation. Also, NO^∙ leads to protein nitrosation, reacts with the thiol protein residues, and inhibition of complex I [18].

Reactive nitrogen species, particularly ONOO^-, can lead to DNA damage. It is resulting from the reaction of NO^∙ with O₂ ^∙- [19]. Fast protonation of ONOO in vivo gives peroxynitrous acid (ONOOH), which is an electrophilic nitrating agent for tyrosine and tryptophan side chains in proteins. When ONOOH is fragmented can produce ^∙OH, which can then impair DNA. Subsequently, NO^∙ can also react with ^∙OH to yield HNO₂ which leads to diazotization of the primary amino groups of nucleic acid bases. Also, ONOOH can react with deoxyribose in DNA causing single- and double-strand breaks. Accumulated hypoxanthine is a prospective producer of ROS via endogenous enzymatic reactions, i.e., the formation of xanthine and uric acid from hypoxanthine by XO [20].

2.2 Oxidative stress

The harmful possessions of ROS on cellular molecu- les, i.e., lipids, proteins, carbohydrates, and DNA cause changes in these components. Reports showed that OS is complicated by the progress of metabolic or chronic illnesses, and is capable of disturbing signaling pathways [21].

Oxidative stress is a disturbance in oxidant and antioxidant systems that may injure biological systems. Nevertheless, in extracellular (EC) fluids where enzymatic antioxidants are lacking, O₂ ^∙- and H₂O₂ (but not ^∙OH) can be purified using SOD and CAT. The ^∙OH is an unusually strong oxidizing agent that rapidly oxidizes any molecule.

$\displaystyle\text{LH}+^{\bullet}\text{OH}\to\text{L}^{\bullet}+\text{H}_{2}% \text{O}$ (6) $\displaystyle\text{L}^{\bullet}+\text{O}_{2}\to\text{LOO}^{\bullet}$ (7) $\displaystyle\text{LOO}^{\bullet}+\text{LH}\to\text{LOOH}+\text{L}^{\bullet}$ (8)

Where LH is a lipid with an allyl hydrogen from polyunsaturated FAs (PUFAs) comprising arachidonic acid.

$\displaystyle\text{O}_{2}^{\bullet-}+^{\bullet}\text{NO}\to\text{ONOO}^{-}$ (9) $\displaystyle\text{HNOO}^{-}\longleftrightarrow{{}^{\bullet}}\text{NO}_{2}+{{}% ^{\bullet}}\text{OH}\to\text{NO}_{3}^{-}+\text{H}^{+}$ (10) $\displaystyle\text{H}_{2}\text{O}_{2}+\text{X}^{-}+\text{H}^{+}% \longleftrightarrow\text{HOX}+\text{H}_{2}\text{O}$ (11)

$\displaystyle\text{X}^{-}:\text{Cl}^{-},\text{Br}^{-}\ \text{or}\ \text{SCN}^{-}$

Three isoforms for SOD were found as follows: SOD1 (Cu/Zn SOD) is the main form of SOD scavenger and is found in the cytoplasm, nucleus, and mitochondrial intermembrane space; SOD2 (Mn SOD) and SOD3 (Cu/Zn SOD) are found in the mitochondria. Cytosolic SOD1 and mitochondrial matrix SOD2 are examples of intracellular defenses that eliminate O₂ ^-, whereas CAT in peroxisomes and cardiac mitochondria, GPxs, and peroxiredoxins (PRDXs) eliminate H₂O₂. A few GPxs and PRDXs are also capable of lowering LP; PRDX6 and GPx4, can even lower phospholipid peroxidation. The rate at which endogenous SODs remove O₂ ^∙- from cells is far higher than that of most other reactions involving the gas ( $\sim$ 2 $\times$ 10⁹ M^{- 1} s^{- 1}). Scavenging of O₂ ^∙- by tiny molecules within cells is insignificant. However, SOD mimics are functional in EC environments that lack significant EC-SOD. The SOD yields H₂O₂, which appears to be not a significant gain in terms of antioxidant defense; However, removal of O₂ ^∙- prevents the formation of the more serious ONOO while at the same time preserving the physiologically important NO. While a variety of diseases are associated with altered SOD1 activity, the following two genetic diseases have attracted much attention. Since Down syndrome is caused by trisomy 21 and SOD1 is located in the region of the proposed causative gene, it has been assumed to be caused by elevated SOD1 activity [22]. Pathological defects in the neuromuscular junctions of the tongue are typically detected in transgenic mice that overexpress SOD1 [23]. This assumption suggests that an increase in SOD1 may cause higher levels of H₂O₂, which in turn creates ^∙OH radicals through the Fenton reaction, hence leads to neuronal damage. However, SOD family enzymes consume the two O₂ ^∙- radicals very quickly, hence, the O₂ ^∙- will be the electron source for eventual Fe^{+ 2} creation. They denote tissue injury related to phagocytosis during inflammation. The LP process disturbs the fluidity of the membrane in addition to the integrity of the membrane-bound biomolecules.

2.2.1 Biomarkers of oxidative stress in clinical trials

Additionally, ROS leads to oxidative damage at amino acid residues, i.e., arginine, threonine, lysine, and proline, creating carbonyl (C $=$ O) derivatives. The oxidation of diverse amino acids leads to denaturation of proteins and loss of function. These C $=$ O groups were deliberated markers of oxidation proteins, i.e., $O$ -tyrosine and 3-nitrotyrosine. An elevated serum protein carbonyl and lipoprotein (a) level are detected in numerous illnesses, i.e., Parkinson’s disease, muscle dystrophy, RA hypertension (HTN) atherosclerosis, and aging [24].

It has been hypothesized that an elevation in protein carbonylation levels is associated with age, greater than 180 proteins that are carbonylated through age-related illnesses, which is related to insufficiencies in the mitochondrial DNA repair system and does not involve histones, hence is less threatened against OS than the nuclear DNA. Consequently, it displays a 10-20-fold rise in 8-hydroxylamine, resulting from guanine oxidation [25].

The sex-related variances in lifespan, with females typically living longer than males, also interrelate with variances in antioxidant defenses. This variation seems to be related to the production of estrogens, as it is not detected in ovariectomized models. These mechanisms are related to raised mitochondrial GSH levels and GPx activity [26].

2.2.2 Roles of oxidative stress in disease

The role of OS can be demonstrated in various diseases by two mechanisms

The ROS and RNS production in OS – in particular, ^∙OH, ONOO^-, and hypochlorous acid (HOCl) – that causes abnormal cell function and death. HOCl belongs to the reactive species group of small molecules that can be synthesized by neutrophils and macrophage cells. It functions as both a bactericidal agent against infection and a damaging agent for the host’s molecular structures and cells. It is a dominant antimicrobial oxidant, capable of altering lipids lipoproteins, and DNA, and reacts with the sulfur atom existent in thioethersand thiols compounds. The development of various diseases, such as atherosclerosis, chronic inflammation, and some cancers, is believed to be influenced by the excessive production of HOCl, which can cause tissue damage. Myeloperoxidase (MPO) is the most dominant protein in neutrophils and is the only peroxidase enzyme that catalyzes the conversion of H₂O₂ and chloride (Cl^-) to HOCl.

$\displaystyle\text{Cl}^{-}+\text{H}_{2}\text{O}_{2}\longrightarrow^{\hskip-15.% 933543pt\text{MPO}}\text{HOCl}+\text{H}_{2}\text{O}$ (12)

The development of atherosclerotic plaques and coronary artery disease is linked to the importance of MPO in inflammation and tissue damage. Higher MPO levels have been suggested as a sensitive prognostic marker for myocardial infarction (MI) [27].

A typical OS signal. The ROS, especially H₂O₂ produced in cells during the physiological state, can act as second messengers. The two mechanisms may occur in the same disease, as in DM, where both the accumulation of advanced glycation end products and irregular triggering of signaling pathways lead to DM complications. Hence, it can be categorized according to its involvement in the etiology of different diseases as the following:

The main reason for pathology such as radia-tion-induced toxicity and atherosclerosis.

A minor trigger for disease progression i.e., chronic obstructive pulmonary disease, Alzhei-mer’s disease, and coronavirus disease-19 (COVID-19) [28].

Figure 3.

Oxidative stress and disease [29].

Under a variety of investigational situations clearly showed a main role for free radicals in numerous illnesses. These highly oxidized lipids are related to a diversity of chronic health complications (Fig. 3). An increase in the formation of reactive species as endogenous or exogenous origin leads to OS and this can increase cell inflammation, necrosis, damage to DNA, lipid membrane and collagen structure, mitochondrial dysfunction, and apoptosis. Oxidative stress is known to play a role in numerous diseases including cancers [29].

2.3 Reactive oxygen species signal transduction during inflammations

Inflammation is a result of H₂O₂ interacting with lipids, proteins, nucleic acids, and other cellular constituents, resulting in significant molecular damage and apoptosis, which has an important role in host antimicrobial defense. Inflammation, predominantly induced by stimulated macrophages and microglia, it is a vital factor in numerous diseases. In pathological circumstances, ROS in cells may transmit redox signals via the reversible oxidation of signaling molecules, causing permanent modifications in inflammatory gene expression. It has been revealed that ROS disturb numerous inflammatory signaling pathways, comprising the nod like receptor pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and NF- $\kappa$ B signaling pathway [30].

The possible mechanism as follows: (a) H₂O₂ is produced in response to a proinflammatory association, for example, by NADPH oxidase and (b) H₂O₂ diffuses across cell membranes to adjacent target cells. Both H₂O₂ and tumor necrosis factor alpha (TNF- $\alpha$ ), are formed during inflammation, but H₂O₂ can activate NF- $\kappa$ B, which is a protein complex that controls DNA transcription, so H₂O₂ modulates TNF- $\alpha$ and this stimulates NF- $\kappa$ B activation, that is complicated in inflammation, innate and adaptive immune responses to viral infection, cell proliferation, and apoptosis. In the presence of an H₂O₂ gradient, it regulated at the enzymatic level to inhibit extreme tissue injury. Continued H₂O₂ formation diminishes NADPH stores, which may automatically lead to cessation of H₂O₂ production [31].

Moreover, creation of ROS, LP and MDA yields is increased in type 2 DM (T2DM), insulin resistance, and obese subjects. Chronic inflammation, hyperglycemia, and hyperlipidemia improved OS in obesity. It has been found that there is greater mitochondrial ROS activity in smooth muscle and lower antioxidant levels in asthma [32]. In HTN, MI, ischemia, and atherosclerosis, there is an imbalance between ROS secretion and endogenous antioxidant levels. The link between many metabolic and chronic disorders is OS and redox imbalance resulting from persistent chronic inflammation. Certain doses of H₂O₂ and O₂ ^.- stimulate cell proliferation in a diversity of cancer cell types, especially in breast cancer (BC) cells, where H₂O₂ is increased through estrogen transport to mitochondria. An increase in mitochondrial OS triggers the release of cytochrome C, which is an irreversible step, leading to caspase activation and apoptosis. All human cancer cell types, except human kidney cancer, showed low levels of CAT and GPx. In general, the concentration of CAT is low in cancer cells, but its activity appears to vary significantly between diverse cancer cell lines [33]. The typical biological roles of hematopoietic cells may be seriously disrupted if antioxidant defense systems are defective, leading to an increase in intracellular OS accumulation, this can progress of leukemia. Insufficient of redox signaling in normal and cancer steam cells limits the effectiveness of all managements. Oxidizing drugs can cause drug resistance and side effects, which are still an urgent and challenging problem in treating leukemia [34].

The normal value of H₂O₂ in the blood is 1–5 $\mu$ M, and the value at which cytotoxicity seems $\approx$ 30 $\mu$ M. However, values up to 558 $\mu$ M are detected in the blood of patients with sepsis and septic shock [35]. In sepsis, hypermetabolism is characterized by higher metabolic activity provided by ATP resulting from oxidative phosphorylation, generating H₂O₂ as a byproduct of the ETC. The ETC’s bioenergetic reactions can lead to an increase in H₂O₂ production, which can lead to apoptosis if they are not removed under normal conditions. Cytotoxic levels of H₂O₂ are a metabolic toxic that can lead to chronic bioenergetic imbalance and cellular injury if a regulatory mechanism is not occur. Long exposure may lead to failure of redox balance, organ failure, microvascular dysfunction, and fatal septic shock. H₂O₂ inhibits the action of Krebs cycle enzymes, i.e., aconitase $\alpha$ -ketoglutarate dehydrogenase and succinate dehydrogenase, reducing the production of the reductases nicotinic adenine dinucleotide NADH and flavin adenine dinucleotide FADH2, which are complicated in cellular redox reactions. The mitochondrial proton gradient may collapse and impact the proton motive force necessary for the pyruvate enzyme to locate in the inner mitochondrial membrane and transport pyruvate into the mitochondria. Hereditary $\alpha$ -ketoglutarate dehydrogenase deficiency, which is associated with severe congenital hyperlactatemia, has a dysfunctional Krebs cycle that affects serum lactate level [36]. Additionally, it has been detected that altered bases appear in Parkinson’s disease, while protein nitration and carbonylation in T2DM and Alzheimer’s disease [37]; LP, DNA and RNA oxidation are shown among patients with amyotrophic lateral sclerosis; mitochondrial dysfunction in Huntington’s disease, and dermatitis. An imbalance in intra-and EC GSH levels and low antioxidant levels were observed among children with autism, as signs of enhanced OS. It has been determined that excessive production of ROS and RNS may lead to infertility [38]. Higher MDA, SOD, XO levels and low GSH levels in patients with polycystic ovary syndrome, chronic kidney disease, COVID-19, and acromegaly reveal the damage resulting from OS as a consequence of high redox reactions in mitochondria and low antioxidant levels [39]. Moreover, ROS production induces the expression of matrix-degrading proteases in osteoarthritis disease. Consequently, cartilage EC matrix synthesis reduces and may cause joint dysfunction. Moderate ROS donate to mutation, whereas oxidative alterations in proteins and lipids reveal tumor initiation and the development of numerous diseases [40].

2.4 Antioxidants

Antioxidants break the chain of radical reactions and prevent damage from OS. They are classified as enzymatic and non-enzymatic, but from a nutritional insight, a more useful classification can be completed between them. Consequently, all enzymatic antioxidants are endogenous, and the non-enzymatic antioxidants such as thiol antioxidants and coenzyme Q10. As conflicting, exogenous antioxidants must be taken up from the diet. Additionally, antioxidants can be categorized according to their solubility to water- and fat-soluble [41].

2.4.1 Enzymatic antioxidants and their actions

Many enzymatic systems that catalyze antioxidant reactions such as CAT, SOD, and GPx, all of which have important roles in maintaining cellular homeostasis. Deficiency or absence of these enzymes leads to OS and may cause cell damage. Protection by antioxidants can achieved through the following mechanisms:

i) Blocking the creation of free radicals. ii) Oxidative scavenging. iii) Preventing the creation of inflammation mediators. iv) Preventing the chain of proliferation of minor oxidants. v) Repairing damaged molecules, initiation, and strengthening the intrinsic antioxidant defense system.

The SOD converts O₂ ^∙- radicals to H₂O₂, while GPx reduces H₂O₂, lipid LOOH, and other organic derivatives. The GST also represents a main group in the defense of tissues from oxidation. In addition, these enzymes detoxify organisms from drugs or toxins in humans and animals and catalyze the reduction of hydrolyzed organic oxides to alcohol analogs. Cancer, CV, and neurodegenerative disorders are some of the chronic diseases that have been linked to changes in SOD expression and/or activity [42].

Catalase (EC 1.11.1.6) consists of 4 polypeptide chains, each one consisting of more than 500 amino acids, and containing 4 heme (iron) porphyrin groups that allow the enzyme to interact with H₂O₂. The turnover rate of CAT is the maximum among other enzymatic antioxidant systems. Most of CAT is found in the oxidoreduction in the mammalian cells excluding red blood cells. Since H₂O₂ is a substrate for a particular reaction that increases in ^∙OH, $\beta$ -lactase diminishes H₂O₂ accumulation. The stabilization of glucose oxidase activity is dependent on the H₂O₂ hydrolysis activity of pure CAT. Consequently, after 30 hours of drying with enzymatic treatment, a 2% drop in alcohol was detected. Glucose oxidase catalyzes the conversion of $\beta$ -d-glucose to gluconic acid, supplying H₂O₂ concurrently by acting as an electron acceptor through molecular O₂. The fungus Penicillium and Aspergillus generate this enzyme. It is used in the food industry to preserve food, which includes removing free O₂, inactivating microbes, preserving flavor and color, and altering ethanol fermentation or other desired modifications in specific food products, as well as to make desirable changes in some food products, such as in bakery products or modifying ethanol fermentation [43].

Patients with CAT deficiency, expect an improved tendency to develop progressive tissue damage from H₂O₂ produced by bacteria such as pneumococcus and streptococcus, in addition to phagocytic cells [44].

Figure 4.

The main endogenous enzymatic systems of aerobic cells [45].

The GR catalysis is the conversion of the oxidized form (GSSG) to GSH. This enzyme maintains sufficient GSH levels in the cell. Its kinetic mechanism is identified to be a consecutively arranged pattern. The GR is a flavoprotein containing two molecules as a prosthetic group, that can be reduced by NADPH as in Fig. 4 [45].

Although cytochrome P450 (CYP450) activation helps with xenobiotic detoxification, it can also be thought of as an adaptive reaction that increases the organism’s chances of survival. CYP450 first converts unreactive substances into hazardous chemically reactive intermediates. Since CYP450 induction is larger than that of the conjugating form, there is likely an imbalance between the rate of reactive intermediate formation and the rate of their inactivation and elimination. Proteins, membrane components, or nucleic acids may be attacked by unconjugated reactive metabolites and ROS produced by P450, which can result in cytotoxicity, mutagenicity, and cancer [46]. Stressful conditions demand greater energy generation and expenditure of the cell. This is fulfilled by increased catabolism which generates H₂O₂. CAT removes the H₂O₂ in an energy efficient way.

Potential therapeutic applications of antioxidants

Raising SOD levels can aid in redox balance restoration, which is one possible therapeutic strategy for addressing illnesses brought on by OS. However, there are a number of important problems with administering SOD externally. These comprise insufficient bioavailability, low pharmacokinetics, and enhance renal clearance. Improving the pharmacokinetics of SOD can be effectively achieved by applying metal-based SOD. However, the antioxidant activity of enzyme mimicking is mainly limited to the extracellular area since antioxidant enzyme abundance is restricted to this location. The most stable and effective mineral complexes that can break down H₂O₂ include mineral salines, mineral porphyrins, and mineral complexes. Many of these metalomimetics react well with a wide range of substances and have a poor specificity for H₂O₂. Typical physiological quantities for these kinds of chemicals are nanomolar ( $\sim$ nM), although many in vitro research are carried out with high concentrations of H₂O₂ ( $\sim$ mM) under non-physiological circumstances [47]. Synthetic porphyrins are replaced for the mineral porphyrins used as CAT mimetics. Metal porphyrins have been shown to scavenge O₂ ^∙-, H₂O₂, ONOO^-, and LOOH. They comprise Mn or Fe metals, one electron can be transferred to the metal center of CAT-like metal metalloporphyrins, and an extended conjugated ring structure can likewise undergo this process. Regarding radical scavenging activity, there are two classes of metalporphyrins according to their possesses; SOD-like and CAT-like activities. Manganese (Mn)-porphyrins that possess both SOD and CAT activities are comprised of pyridine and imidazole-containing porphyrins. A half-life for metalporphyrins between several hours to two days in serum and are removed from the body in the urine. In vitro and animal models have shown that these compounds can effectively suppress OS and inflammation. Mn-contained nanozymes primarily comprise MnO, MnO₂, Mn₂O₃, Mn₃O₄, and other Mn oxide nanozymes reveal SOD- and CAT-mimetic activities, probably due to their diverse oxidation states [48].

2.4.2 Non-enzymatic antioxidants and their actions

Protein- and non-protein-bound thiols act as cellular reducing agents and defensive elements against most inorganic contaminants, through the -SH group. Thus, thiols are the first line of protection against oxidants. The concentrations of thiols can be elevated in OS as an adaptation mechanism. Nevertheless, severe oxidative damage may reduce the concentrations of thiols due to the defeat of the adaptive mechanisms. Low-molecular weight ROS scavengers can activate antioxidant enzymes or terminate oxidative chain reactions. Vitamin D, for example, counteracts the activity of NOX and increases the activity of antioxidant enzymes to accelerate ROS elimination Some of natural biomaterials, i.e., apocynin, can inhibit ROS production by inhibiting NOX activity or NOX-mediated ROS production, hence achieving anti-inflammatory possessions and inhibits ROS production by inhibiting NOX-2 As it is nontoxic and can lessen the OS markers, the compound is commonly used in animal models of inflammasome diseases, comprising collagen-induced arthritis, and it has significant defensive possessions. Also, apocynin has a major role as inflammatory inhibition among ulcerative colitis and asthma models [49].

Vitamin C has been an important antioxidant against oxidative damage by scavenging ROS and RNS and binding to fatty radicals, that are formed in cell metabolism. Vitamin C ionizes mainly in the form of a monovalent anion, called ascorbate, whose enodiol structure permits the donation of electrons that, after losing 2 electrons, yields the last oxidized product, dehydroascorbic acid. The water-soluble antioxidant ascorbate has the ability to scavenge radicals. It enters cells through two vitamin C transporters that are dependent on sodium, SVCT1 and SVCT2, which are responsible for the regulation of vitamin C absorption from plasma in tissues; SVCT1 is mainly confined to the surface of epithelial cells and participates in the transport of vitamin C in the intestine, kidney, liver, lung, and other tissues. It regulates gastrointestinal absorption and renal reabsorption and maintaining a plasma vitamin C levels $\approx$ 50 $\mu$ M. whereas SVCT2 is mostly present in specific tissues, such as the muscle, brain, lymphoid tissue, bone, adrenal and pituitary glands [50].

The recommended amount of ascorbate for adults is 75 mg/day for women and 90 mg/day for men. Studies have shown that excessively high amounts of ascorbate can have prooxidant impact. It has been proposed ascorbate as a common chemotherapy mediator. The cytotoxic impacts of ascorbate, a commonly used chemotherapeutic agent, are clarified by several mechanisms. One underlying mechanism includes the exact association between administered ascorbate, extracellular H₂O₂, and traces of redox minerals, especially iron. H₂O₂ is a cell-permeable molecule that acts inside and outside the cell and can be hydrolyzed by traces of iron into harmful ^∙OH (Fenton reaction). The PRDX-2 is a redox protein that neutralizes H₂O₂. The deleterious effect of H₂O₂ on cancer cell death is clarified by the oxidation of PRDX-2 by ascorbate. Oxidized PRDX-2 has a considerably lessen ability to neutralize H₂O₂, which is hydrolyzed by the effects of redox-active Fe^{+ 2} to ^∙OH [51]. Moreover, CAT, which converts H₂O₂, is usually upregulated in cancer cells. Eight diverse types of vitamin E ( $\alpha$ -, $\beta$ -, $\gamma$ -, and $\delta$ -tocopherol, and $\alpha$ -, $\beta$ -, $\gamma$ -, and $\delta$ -tocotrienol) were documented. The $\alpha$ -tocopherol has the maximum antioxidant activity, particularly in cell membranes. Vitamin E is recommended for adults to take 15 mg/day and act as antioxidant agent to protect PUFAs from oxidation [52].

Figure 5.

Structures of $\alpha$ -tocopherol and $\gamma$ -tocopherol [53].

An $-$ OH group on the chromanol ring is responsible for vitamin E’s antioxidant activity, and the mechanism of ROS scavenging involves donating a H atom from the -OH group in the chromanol ring of vitamin E (T-OH) to lipid radicals with subsequent tocopheroxyl radical (T^∙) formation, resulting the vitamin E radical (tocopheryl radical, T-O^∙) and the cells terminate to produce (RH), as shown in Fig. 5 [53]. The delocalization occurs above the aromatic ring for the unpaired electron of the vitamin E radical (T-O^∙), resulting in decreased T-O reactivity. The hydrophobic core of the phospholipid cell membrane has an anchored $\alpha$ -tocopherol, with the -OH group allied towards a hydrophilic environment, $\alpha$ -tocopherols are inhibition the LP [54].

$\displaystyle\text{T}-\text{OH}+\text{R}^{\bullet}\to\text{T}-\text{O}^{% \bullet}+\text{RH}$

Vitamin E has excellent antioxidant and anti-inflam- matory possessions that definitely control the immune system. It has been demonstrated that vitamin E could inhibit the secretion of inflammation-mediating molecules such as eicosanoids and cyclooxygenase-2 (COX-2). The COX has two isoforms, COX1 and COX2. The COX2 is regulated by cytokines, growth factor, tumor promoters, glucocorticoids, and lipopolysaccharides. The COX is responsible for the conversion of arachidonic to prostaglandin E2. High levels of COX2 are associated with the inhibition of cell death and overexpression of COX2 are implicated in pathogenesis of numerous tumors, i.e., colo-rectal cancer. Hence, alterations in arachidonic acid metabolism stimulate cell profilation via PKC that is considered as a primry signaling pathway, which tumor is initiated. It has been reported both $\alpha$ - and $\gamma$ -tocopherol inhibit oxidative activation of PKC $\alpha$ , that proposing an antioxidant role for tocopherols. Nevertheless, $\alpha$ -tocopherol considerably lessened peroxide activation of PKC $\alpha$ at a 10-fold lower dose compared to $\gamma$ -tocopherol. Therefore, tocopherol isoforms differ in their antioxidant capacity towards PKC $\alpha$ [55]. Vitamin E also suppresses pro-inflammatory signalling pathways, such as nuclear factor kappa beta (NF-k $\beta$ ) and signal transducer and activator of transcription 3 (STAT-3)-mediated pathways. Supplementation with 200 mg/day of vitamin E was reported to decrease the level of DNA damage, reduce fasting blood glucose, preventing metabolic disoredr and CVD, and increase mitogen-induced lymphocyte proliferation. Additionally, the activities of GPx4 is similar to the role of vitamin E in LP prevention. Vitamin E is essential for stimulating bone remodeling, osteoclast differentiation, healing wounds and skin burns [56].

Figure 6.

A schematic interaction between ROO, CAR, a reduced form of vitamin C (AscH-) and vitamin E ( $\alpha$ -T-OH) [59].

Individuals with fat malabsorption are at a higher risk of severe vitamin E deficiency, which is relatively rare, which leads to a diversity of neurological symptoms, i.e., imbalance, retinopathy, and myopathy. As vitamin E is an effective antioxidant in scavenging ROS, it is assumed that it could prevent chronic diseases. While, higher doses of this vitamin lead to toicit and cause adverse effects. This has been explained by the interfering of vitamin E with CYP450 and CYP4F2 metabolism, which have significant roles in cellular metabolism and drug detoxification. Vitamin E has the ability to modulate CYP450’s activities, which could lead to improved degradation of drugs used for treating cancer, HD, metabolic diseases, and other chronic illnesses [57]. Vitamin E supplementation with 400 IU/day for 1 month improved the level of vitamin E in sera of patients with Alzheimer disease by approximately 150%. Clinical outcomes propose that supplementation with vitamin E is essential against LP in the CSF. Damage of DNA caused by ROS may lead to mutations, which may contribute to cancer. Moreover, studies have failed to find an association between vitamin E intake and the occurrence of lung disease or BC. Moreover, it has been found that people who were taking vitamin E, the CV complications were enhanced among them. Vitamin E has been shown to reduce the level of oxidative damage associated with DM in animal studies. Male smokers who took 50 mg/day of synthetic vitamin E were studied in an tocopherol/carotene trial, but it was found to have no impact on deaths or macrovascular complications among T2DM patients. Vitamin E metabolism appears to interfere with vitamin K metabolism. Daily adult supplementation of 670 mg of vitamin E supplementation for 3 months has been shown to inhibit a “vitamin K-dependent factor,” which is essential in the coagulation cascade. Therefore, vitamin supplements should not be taken by patients who are regularly taking anticoagulants because of the risk of bleeding [58].

Carotenoids (CAR) are a widely form of tetraterpenes, dispersed in plants and separated into deoxygenated. $\beta$ -carotenes, the precursor of vitamin A found in vegetables, have a dominant antioxidant property by scavenging single O₂ thus protecting against free radical attack. CAR interact with ROS via numerous mechanisms The mechanism of radical addition reactions to CAR comprises the addition of fatty peroxyl radicals (ROO^∙) to the polyene CAR chain, leading to the produce of a carbon-centered radical of a CAR molecule (ROO-CAR^∙) [59], as illustrated in Fig. 6.

$\displaystyle\text{ROO}^{\bullet}+\text{CAR}\to\text{ROO}-\text{CAR}^{\bullet}% (\text{radical addition}).$

In lungs as highly oxygenated tissues, carbon-centered radicals can react with molecular O₂ to yield ROO-CAR-OO^∙

$\displaystyle\text{ROO}-\text{CAR}^{\bullet}+\text{O}_{2}\to\text{ROO }-\text{% CAR}-\text{OO}^{\bullet}$

CAR have redox mechanisms that raise ROS levels in the reaction system through oxygen-mediated reactions. Additional mechanism by which CAR can react with radicals is through an electron transfer mechanism, which leads to the formation of a cation (CAR⁺), anion (CAR^-), or an alkyl radical (CAR^∙).

$\displaystyle\text{CAR}+\text{R}^{\bullet}\to\text{CAR}^{\bullet}++\text{R}^{-% }(\text{electron transfer}).$ $\displaystyle\text{CAR}+\text{ROO}^{\bullet}\to\text{CAR}^{\bullet}+\text{ROOH}$ $\displaystyle\quad(\text{hydrogenabstraction}).$

These oxidation yields increase the catabolism of retinoic acid by stimulating CYP450 enzyme activity. Low retinoic acid levels lead to increased phosphorylation of MAPKs while decreasing the expression of the anti-inflammatory MAPK-1, which triggers lung cancer. The clinical data showed a contrary correlation between total CAR levels, $\alpha$ -carotene, $\beta$ -carotene, and lutein in the blood and the risk of cancer. The supplementation with 5 mg/day of $\beta$ -carotene reduces cancer risk by 5% [60].

Organic compounds containing sulfur have also been proposed as effective antioxidants, i.e., metabolites found in garlic. Their antioxidant activity comprises scavenging ROS and preventing LP. Additionally, microbiotas can inhibit cell proliferation and differentiation of intestinal epithelium by providing an energy source, i.e., butyrate and short-chain FA to the epithelium. The intestinal microbiota also has a role in the conversion of steroids and FA in addition to the fermentation of dietary fiber and ions. Furthermore, the intestinal microorganisms synthesize vitamins B and K [61].

Melatonin is an influential antioxidant that can simply cross cell membranes and the BBB. In contrast to other antioxidants, melatonin does not have redox recycling. So, once oxidized cannot be reduced because it forms numerous stable end products when it reacts with free radicals [62]. Also, uric acid is assumed to have substituted ascorbate in evolution. It is capable to production of free radical species [63].

2.4.3 Natural antioxidants

The protecting possessions of natural antioxidants have initiated further interest in toxins caused by free radicals. Flavonoids have a substantial role in defending against oxidative injury and are widely found in vegetables, fruit, cocoa, and tea. Flavonoids are found in drinks and foods that have a varied series of biological activities. Natural antioxidants support the intrinsic antioxidant resistances of ROS and return optimum stability by counteracting reactive species. The antioxidant actions of phenols are associated with several various mechanisms. The nephroprotective influence could be due to its role in the inhibition of LP in tissues and the improvement of antioxidant action. Consequently, it has been proposed that this antioxidant may be beneficial for people exposed to nephrotoxic agents and patients with kidney disease. Protective possessions might be due to the existence of glycosides, alkaloids, benzoquinones, catechols, terpenoids, CAR, terpenes derivatives, flavonoids, saponins, and polyphenols [64].

3. Results and discussion

This review approves the indication from numerous meta-analyses covering the physiological influence of antioxidants on common chronic illnesses. The leading importance was that the data were not extracted from distinct studies, and this can be deliberated as a benefit because meta-analysis has the highest grade of indication.

Free radicals and antioxidants have favorable influences on the body. Degradation of major cellular components leads to an extreme level of free radicals. This degradation is responsible for excessive free radicals generations, which may lead to pollution, ionizing radiation, excessive consumption of PUFAs, infections, and subsequently OS, which causes numerous diseases [65]. On the other hand, antioxidants are considered to balance these effects. It denotes a chemical possession of a material to give electrons. Some materials have antioxidants and pro-oxidant effects, reliant on the chemical conformation of the environment in which they are. The antioxidant level, i.e., polyphenols is sometimes so little in the blood that no considerable outcome is detected. Vegetables and fruits have bioactive constituents that in numerous situations do not act as antioxidants outside of the body. But when they are in the body, they act as antioxidants, because they activate their antioxidant mechanisms [66].

Antioxidant supplements, also have diverse health effects. Some materials probably have helpful possessions on health by the synergistic influence of numerous materials. Also, the chemical structure of antioxidants in food is frequently unlike that recognized in supplements. Antioxidants can help definite patients in whom there is recognized inequity, but it may not lead to extra benefits for persons who have an adequate quantity of nutrients from their diet [67].

Recent approaches that utilize new technology and combined data with traditional conservative health applications can be used shortly for the enhancement of health status, particularly among people who cannot obtain expensive therapeutic medications.

There are several possible reasons for the ineffectiveness of antioxidants in clinical trials including (i) The integrated BBB is a main obstacle to the delivery of desired substances, i.e., antioxidants, to the nervous system, resulting in insufficient levels of antioxidants in the target organ; (ii) The specificity of antioxidants in protecting certain target structures from specific forms of ROS may be another reason for this problem (i.e., vitamin E is a dominant chain-breaking antioxidant and resides principally in biologic membranes, keeping membrane phospholipids from peroxidation); (iii) the significance of initiating antioxidant administration; the preventive or therapeutic influence of a particular antioxidant; and (iv) dose size, when higher levels of antioxidants, i.e., ascorbate are recognized as a powerful antioxidant, particularly in certain tissues, (i.e., lungs or the existence of redox metals, such as Cu or Fe). Higher vitamin C levels reveal prooxidative action considered as a common chemotherapeutic factor that donates to the damage of cancer cells. The cytotoxicity of vitamin C can be illuminated by increased levels of H₂O₂ in vitamin C and the yield of OH via Fe- Fenton reaction. Additionally, the helpful health influence for regular intake of flavonoids-rich foods has been recognized in several clinical outcomes. Minor oxidants effects of flavonoids enhance the antioxidant system, supported by the stimulated synthesis of enzymes and low molecular weight endogenous antioxidants, such as GSH [68].

Effective healing application of antioxidants with low molecular weight needs a complex method. There are numerous influences associated with specific OS biomarkers for different illness, the nature, the levels of radicals formation, the location of their creation, the appropriate choice of the antioxidant and their levels, also the age and disease state of the individual whom treated must be taken into account. To determine the type of radical predeterminants for the effectiveness of antioxidant treatment, it is necessary to determine the origin of ROS involved in each specific disease. Also, there are variances in pathogens and their distinct biomarkers, i.e., cancer and Parkinson’s disease have diverse causes, but they have the similar type of oxidative damage to DNA that typically affects guanine. Both Parkinson’s and Alzheimer’s are neurodegenerative diseases, but the types of oxidative damage that they cause are distinct.

4. Conclusions

Oxidative stress occurs in case the free radicals levels exceed the ability of the antioxidant system in the body’s cells. The stress that generates free radical can be categorized as nutritional, environmental, and endogenous. Antioxidant nutrients have significant roles in animal health by disrupting destructive free radicals caused by normal cellular activity and numerous stress factors. These composites have an interest in the area of biomedical investigation as they have shown an enhanced degree of effectiveness in the treatment and inhibition of numerous illnesses. Synthetic antioxidants are injurious to the organism’s health. So, it has been increased the search for a natural and non-toxic compound with higher antioxidant activity for clinical applications and managements. Regarding this review, it can be concluded that OS might be used as a treatment tool to comprehend this phenomenon in vivo Understanding small molecules’ mechanisms of action, their specific dose and action sites needed to achieve the health outcome, and the optimal time to initiate antioxidant rehabilitation for therapeutic consequences might supply a rational strategy that may produce more significant pharmacological and management effects by using low-molecular-weight compounds in antioxidant therapy.

Author contributions

Conception: Huda A. Hassan, Hind Sh. Ahmed, Dheefaf F. Hassan.

Methodology: Huda A. Hassan, Hind Sh. Ahmed.

Data collection: Huda A. Hassan, Dheefaf F. Hassan.

Interpretation or analysis of data: Huda A. Hassan, Hind Sh. Ahmed, Dheefaf F. Hassan.

Preparation of the manuscript: Huda A. Hassan, Hind Sh. Ahmed, Dheefaf F. Hassan.

Revisions: Huda A. Hassan, Hind Sh. Ahmed, Dheefaf F. Hassan.

Ethical approval

Required approval was achieved by the institute according to the Helsinki Declaration.

Datasets/data availability statement

The data supporting the findings of this study are available within the article and/or its supplementary material.

Funding

There were no financial support.

Footnotes

Acknowledgments

Authors express their gratitude to the College of Education for Pure Science (Ibn Al-Haitham)/ University of Baghdad, Baghdad, Iraq for consent of this study.

Conflict of interest

None.

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Free radicals and oxidative stress: Mechanisms and therapeutic targets

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Introduction

Table 1 Reactive-oxygen and nitrogen species created during metabolism [4]

2.2.2 Roles of oxidative stress in disease

2.4 Antioxidants

2.4.1 Enzymatic antioxidants and their actions

3. Results and discussion

4. Conclusions

Author contributions

Ethical approval

Datasets/data availability statement

Funding

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Reactive-oxygen and nitrogen species created during metabolism [4]