| |

Received: 24 July 2019    Revised: 25 November 2019    Accepted: 28 December 2019

DOI: 10.1111/jfbc.13145

REVIEW

Understanding oxidants and antioxidants: Classical team with

new players

Syed Saqib Ali1 | Haseeb Ahsan2  | Mohammad Khalid Zia1 | Tooba Siddiqui1 |

Fahim Halim Khan1

1
Faculty of Life Sciences, Department of
Biochemistry, Aligarh Muslim University, Abstract
Aligarh, India The free radical oxidants such as reactive oxygen species, reactive nitrogen species, and
2
Faculty of Dentistry, Department of
reactive sulfur species are produced inside cells through various metabolic processes.
Biochemistry, Jamia Millia Islamia, New
Delhi, India The body is equipped with an antioxidant defense system that guards against oxidative
damage caused by these reactive oxidants and plays a major role in protecting cells from
Correspondence
Fahim Halim Khan, Department of oxidative stress and damage. Antioxidants such as glutathione (GSH), thioredoxin, ascor-
Biochemistry, Faculty of Life Sciences,
bic acid and enzymes, for example, superoxide dismutase (SOD), glutathione peroxidase
Aligarh Muslim University, Aligarh (202002),
India. (GPx), catalase (CAT) counter the oxidative stress and protect lipids, proteins, and DNA.
Email: fahimhkhan@rediffmail.com;
Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids, amino acids are
fahimhalimkhan@hotmail.com
also natural antioxidants present in foods. There is increasing demand and availability
of designer foods fortified with antioxidants and probiotics that may be important in
human health. The review article presents a brief overview of oxidants and antioxidant
systems inside the human body including the role of probiotics and inflammation.
Practical applications
Antioxidants such as GSH, thioredoxin, ascorbic acid, etc. and protective enzymes,
for example, SOD, GPx, CAT, etc. counter oxidative stress and protect cellular bio-
molecules. Antioxidants such as tocopherols, ascorbic acid, carotenoids, flavonoids,
amino acids, phospholipids, and sterols are natural antioxidants found in consumed
foods. They play a major role in scavenging free radical and non-radical oxidants, and
protect cells from oxidative stress and damage. The importance of antioxidants can
be understood from the fact that oxidative damage is now associated with a variety
of diseases including cancer, neurodegeneration, diabetes, etc. Several approaches
to improve human health and achieve longevity use dietary antioxidants as formula-
tion in diet and fortified foods. Antioxidants also maintain freshness and prolonging
the shelf life of food products. The fortified or designer foods that are added with
antioxidant nutrients and the use of microorganisms as probiotics are increasingly
available in the market as health foods and supplements.

KEYWORDS

antioxidants, enzymatic antioxidants, free radicals, functional foods, natural antioxidants,

oxidants, probiotics

−⋅
Abbreviations: CAT, catalase; GPx, glutathione peroxidase; H2O2, hydrogen peroxide; HO2, perhydroxyl radical; HOCl, hypochlorous acid; O2 , superoxide anion; OH, hydroxyl radical;
ONOO, peroxynitrite; R·, lipid alkyl radical; RH, lipid; ROO·, lipid peroxyl radical; ROOH, lipid hydroperoxide; SOD, superoxide dismutase.

J Food Biochem. 2020;44:e13145. wileyonlinelibrary.com/journal/jfbc |

© 2020 Wiley Periodicals, Inc.     1 of 13
https://doi.org/10.1111/jfbc.13145
 |
2 of 13       ALI et al.

1 |  I NTRO D U C TI O N prevent the body from acute or chronic diseases and/or repair the
cellular/tissue damage already sustained. However, a considerable
Reactive species of oxygen, nitrogen, and the recently identi- number of antioxidant molecules have been found to have a pro-
fied reactive sulfur species (RSS) are well known to induce oxida- oxidant potential and promote oxidative reactions. It has also be-
tive damage to lipids, proteins, and DNA (Pallavi, Ambuj, Rama, & come obvious that free radicals are not only involved in pathological
Mohammad, 2012). These reactive species could be free radicals processes, but their existence is also necessary for many physiolog-
or non-radical oxidants. Free radicals can be defined as potentially ical functions of living organisms, including “healthy aging.” It is now
damaging chemical species containing an unpaired electron. Free widely known that these biologically hyperactive molecules act as
radicals are generally electrically charged and they tend to neutralize signaling agents in various cellular pathways known as “redox sig-
themselves by reacting with other substances thereby causing oxi- naling.” H2O2 and ONOO, in particular, have been implicated in a
dation (Cheeseman & Slater, 1993). Reactive oxygen species (ROS), considerable number of cellular signaling cascades and due to their
reactive nitrogen species (RNS), and RSS are the three main classes non-radical structure these molecules have a relative longer half-life
of oxidants that are formed inside the body. Among ROS, the major than almost all other oxidants allowing them to migrate away from
players are free radicals such as superoxide radicals (O2 ), hydroxyl their production sites and to diffuse through membranes. Moreover,
−⋅

radicals (· OH), and non-radical oxidant such as hydrogen peroxide the transcription factors such as AP-1, NF-κB, and/or Nrf2 have
(H2O2) and hypochlorous acid (HOCl). Major RNS are nitric oxide been reported to be involved in these redox-modulated signaling
(NO) and peroxynitrite (ONOO−) apart from others (Lu, Lin, Yao, & pathways (Oter, Jin, Cucullo, & Dorman, 2012).
Chen, 2010). RSS include thiyl radical (RS) and RSS formed by the Antioxidant in food sciences are compounds that block oxida-
reaction of ROS with thiols. The main target of these oxidants are tive reactions, thereby maintaining freshness and prolonging the
nucleic acids, sugars, lipids, and proteins (Carocho & Ferreira, 2013; shelf lives of food products. Dietary antioxidants and antioxidant
Craft, Kerrihard, Amarowicz, & Pegg, 2002; Lu et al., 2010) (Figure 1). supplements quench ROS and may prevent different chronic dis-
The deleterious effects of these ROS and RNS free radicals such eases. In addition to the essential antioxidant nutrients such as
as O2 , · OH, H2O2, and ONOO− occurs as a result of the alterations vitamins E and C, there are several well-designed antioxidant and
−⋅

of organic biomolecules such as the polyunsaturated fatty acids in cytoprotective enzyme systems in the human body, which are
membrane lipids, oxidation of proteins, DNA strand breakage, RNA more important than dietary non-nutrient antioxidants. At high
oxidation, mitochondrial depolarization, and apoptosis. Under nor- concentrations, many antioxidants could act as prooxidants, in-
mal conditions, reactive species are cleared by the antioxidants creasing oxidative stress, and inducing toxicity (Yang et al., 2018).
which are able to react directly with oxidants to reduce their oxida- In recent years, the consumption of natural products or functional
tion capacity, for example, scavenging enzymes such as superoxide foods has increased and the food industry has expanded expo-
dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), etc., nentially. Therefore, the functional foods or nutraceuticals are de-
or chemicals inhibiting the activities of oxidant generating enzymes fined as a foods or ingredients that improve health. They contain
such as xanthine oxidase, for example, polyphenols (Figure 1). These dietary supplements like proteins, vitamins, minerals, and phyto-
molecules can be either natural or synthetic, either hydrophilic such chemicals (Inan, 2019).
as ascorbic acid or hydrophobic such as α-tocopherol. The antioxi-
dants can prevent the generation of oxidizing species or reduce the
effects of dangerous metabolic or xenobiotic oxidants and hence 1.1 | Oxidants

ROS, RNS, and RSS include a variety of reactive molecules including

free radicals and non-radical derivatives of oxygen, nitrogen, and sulfur
that are capable of oxidizing substrates under appropriate conditions.

1.1.1 | Reactive oxygen species

The sequential one-electron reduction of molecular oxygen pro-

duces three ROS such as superoxide (O2 ), hydrogen peroxide (H2O2),
−⋅

and hydroxyl radical (·OH) before terminating as water;

⋅− ⋅− ⋅ ⋅ ⋅
O2 − e− → O2 , O2 − e− → H2 O2 , H2 O2 − e− → HO , HO − e− → H2 O

In addition to their toxicity, H2O2, and arguably O2 , are considered to

−⋅

F I G U R E 1   The type of ROS and action of antioxidants (adapted be important regulatory molecules necessitating careful regulation
with permission from Lu et al., 2010) of their titers. SOD and CAT are well known antioxidant enzymes,
ALI et al. |
      3 of 13

the former catalyzes the dismutation of superoxide to oxygen and anion, nitrogen derivatives, as well as transition metals. NO can also
peroxide while the latter catalyzes peroxide dismutation to oxygen be converted into nitrogen dioxide, nitrogen trioxide, nitrate, and sev-
and water (Olson et al., 2018). eral other RNS  (Lamattina et al., 2003). NO can also react with thi-
ols and generate RSS. NO can rapidly react with superoxide radical
(rate  ~  6.7  ×  109  M.s−1) to form highly reactive ONOO. This RNS is
⋅−
2 O2 + 2H+ → O2 + H2 O2 ,
a stronger oxidant and more stable as compared to O2 and NO, and
⋅ −⋅
2 H2 O2 → O2 + H2 O
hence can attack and damage many more biological targets. ONOO
The production of superoxide radical begins with the consumption formed is known to modify zinc finger motifs, thiols, iron-sulfur clus-
of oxygen and activation of nicotinamide adenine dinucleotide phos- ters, and is reported to be involved in etiology of number of diseases.
phate (NADPH) oxidase located on the surface of phagocytes and At neutral pH the pernitrous acid can undergo hemolysis to generate
non-phagocytes (John, 2008). The lifetime of O2 in the water cellular nitrogen dioxide radical and ·OH which in turn can elicit more damage
−⋅

6
environment is about 10 s (Pryor, 1986). The superoxide anion that is (Pacher, Beckman, & Liaudet, 2007).
produced is quite reactive and unstable and is spontaneously converted
to H2O2 and molecular oxygen (Alugoju, Dinesh, & Latha, 2015). When
protonated, superoxide radicals exhibit much higher reactivity as com- 1.1.3 | Reactive sulfur species
pared to superoxide anion though physiologically it is unprotonated form
that predominates (Aikens & Dix, 1991). Hydoxyl radicals constitute an RSS is a  newly classified broad group of sulfur containing reactive
important reactive ROS as they can react with most of the molecules species that includes both radical and non-radical sulfur based moie-
present inside the cell (Esra, Umit, Cansin, Serpil, & Omer, 2012). They ties. This broad group includes radical species such RS, glutathionyl
have very short life span of about 10−6 and short radius of action, that is, radical (GSSG ·), as well as non-radical reactive sulfane species, reac-
about 30Å from where they are produced (Devasagayam, Tilak, & Boloor, tive sulfur substances, etc. (Giles, Nasim, Ali, & Jacob, 2017) (Table 1).
2004). The main source of hydroxyls are metal catalyzed Fenton/Haber– Unlike other reactive oxygen and nitrogen species, RSS are capable
Weiess reactions. H2O2 is one of the most stable oxidant. Though less of both oxidation and reduction (Dhawan, 2014). It has now become
reactive than superoxide anion it is more damaging as it can move too apparent that molecules with sulfur-containing functional groups can
far off places from where it is produced as well as easily pass through the also be stressors in their own right, with pivotal roles in cellular func-
membranes (Alugoju et al., 2015). It can also easily convert into highly tion and homeostasis. A key distinction for RSS is that, unlike oxygen
reactive ·OH under appropriate conditions such as presence metal ions or nitrogen, sulfur not only forms a plethora of specific reactive spe-
(Jonah, 2013). Hypochlorite is a highly reactive non-radical ROS which cies, but sulfur also targets itself, as sulfur containing molecules, that
can cause oxidative damage to cellular machinery of the organism is, peptides, proteins, and enzymes, preferentially react with RSS.
(Marnett, Riggins, & West, 2003). Hypochlorite is generated under phys- RSS are omnipresent and sometimes even considered as important
iological conditions by activated neutrophils during respiratory burst in a as ROS and RNS which for decades have dominated the redox field
reaction catalyzed by myeloperoxidases (Siddiqui et al., 2016). It reacts (Giles et al., 2017).
with a wide variety of biological molecules including DNA and proteins.
Hypochlorite is a major oxidant which undergoes oxidation reactions
(Winterbourn, 2002) and is a potent inactivator of anti-proteinases in- 2 | OX I DATI V E S TR E S S A N D C H RO N I C
cluding α-2-macroglobulin (Siddiqui, Zia, Ali, Ahsan, & Khan, 2018; Wu & I N FL A M M ATI O N
Pizzo, 2011). Hypochlorite modified proteins can be detected in diseases
like atherosclerosis (Van der Veen, de Winther, & Heeringa, 2009) and Oxidative stress has been implicated in the pathogenesis of many
are implicated in the pathology of human diseases such as Alzheimer's chronic diseases including the inflammatory process. Oxidative stress
disease and arthritis (Wyatt et al., 2014). and inflammation are closely related pathophysiological processes and
both processes are simultaneously found in many pathological con-
ditions (Biswas, 2016). During inflammatory process the activated
1.1.2 | Reactive nitrogen species phagocytic cells like neutrophils and macrophages produce large

One of the most important RNS is NO. It can be produced enzymati-

cally via nitric oxide synthase (NOS) from arginine as shown in reac- TA B L E 1   Reactive Sulfur species (adapted from Giles et al.,
tion 6 or nonenzymatically (Andrew, 1999). It is a free radical lipophilic 2017)

diatomic gas, with small stokes’ radius and neutral charge which al- Radicals Non-radicals
lows its rapid diffusion across the membrane (Lamattina, García-Mata,
Thiyl radical Reactive sulfane species (RSR)
Graziano, & Pagnussat, 2003). NO at a low concentration of 10 nmol/L
GSSG · Reducing sulfur species (H2S, GSH)
is a signaling molecule while at higher concentrations is detrimental for
RSR· Reactive sulfur substances (SO2, SO3)
health (Chen, Chen, Xu, & Shen, 2013). NO being free radical has an
  Sulfur secondary metabolites (Allicin)
unpaired electron which allows high reactivity with oxygen, superoxide
 |
4 of 13       ALI et al.

amounts of ROS, RNS, etc. superoxide, H2O2, hydroxyl free radical, stress, including nutritional starvation and excess nutrient stress. The
NO, ONOO, and HOCl to kill the invading agents. Under pathologi- homeostasis of nutrient metabolism is vital for the maintenance of cell
cal inflammatory conditions there may be exaggerated generation of survival and normal physiological functions (He et al., 2018).
reactive species and some of those reactive species diffuse out of the
phagocytic cells and thus they can induce localized oxidative stress
and tissue injury. However, apart from the direct production of reac- 3 | A NTI OX I DA NT S
tive species by the professional phagocytic cells, the nonphagocytic
cells can also produce reactive species in response to pro-inflamma- Antioxidants are those molecules that inhibit, decrease, delay, or
tory cytokines (Li et al., 2015; Wu, Lu, & Antony, 2013). Recent find- completely scavenge the action of free radicals and oxidants, and
ing also showed that the costimulation of Toll-like receptor produces protect the body from oxidative damage (Lobo, Patil, Phatak, &
oxidative stress with unbalance of pro-inflammatory and anti-inflam- Chandra, 2010). The antioxidant defense is a universal mechanism
matory cytokine production. The NOX4 overexpression has also been that is present inside the cells and tissues of both plants and animals
found to enhance IL-6 production, and a positive reciprocal feedback though their types and concentration vary. Halliwell and Gutteridge
loop has been found between IL-6 and NOX4, the two mediators of in- (1995) defined antioxidants as “any substance that, when present
flammation and oxidative stress, respectively (Wu et al., 2013). As the at low concentrations compared with that of oxidizable substrates,
inflammatory process can induce oxidative stress, the oxidative stress significantly delays or inhibits oxidation of that substrate.” This defi-
can also induce inflammation through activation of multiple pathways. nition however was later modified as “any substance that delays,
The reactive species, H2O2 can induce inflammation through activa- prevents or removes oxidative damage to a target molecule” to in-
tion of transcription factor NF-κB. Furthermore, oxidative stress plays clude the molecules that repair the oxidative damage to the system
an important role in the activation of NOD-like receptor protein 3 (Halliwell, 1995a, 1995b; Halliwell & Gutteridge, 1995). Thus, ef-
(NLRP3) inflammasome. The NLRP3 inflammasome is an oligomeric fective antioxidants have the ability to delay oxidation reaction or
molecular complex that triggers innate immune defenses through the obstruct the development of free radicals or break the generation
maturation of pro-inflammatory cytokines like IL-1β and IL-18. The of the autoxidation chain reaction that generates free radicals/oxi-
ROS released from damaged mitochondria has been shown to activate dants. They also act as reducing agents and metal chelators which
NLRP3 inflammasomes leading to IL-1β secretion and localized inflam- convert hydroperoxides into stable compounds. Some antioxidants
mation. Oxidized mitochondrial DNA has also been found to activate act as metal chelators that transform metal prooxidants into stable
NLRP3 inflammasomes during apoptosis. Furthermore, in conditions form. Oxidative/nitrosative stress results from disequilibrium in ox-
of oxidative stress the ROS causes the thioredoxin-interacting pro- idant-antioxidant balance in the favor of reactive species with the
tein, an inhibitor of endogenous antioxidant thioredoxin, to dissoci- increase of reactive oxygen and/or RNS production, respectively
ate from thioredoxin and to bind with NLRP3 leading to activation of (Kurutas, 2015). The body’s defense mechanisms against oxidative
NLRP3 inflammasome. Therefore, inflammation and oxidative stress damage are operative in two main systems. The first one includes
are closely related and tightly linked interdependent pathophysiologi- removal of free radicals and reactive species by enzymes such as
cal processes (Biswas, 2016). superoxide-dismutase, CAT, GPx, etc. and second one is scavenging
ROS accumulation may trigger oxidative stress involving many of free radicals by electron donors, such as glutathione (GSH), toco-
biological processes including apoptosis, necrosis, and autophagy. pherols, ascorbic acid, thioredoxin, etc. (Devasagayam et al., 2004)
Autophagy may be induced by oxidative stress and lipid peroxidation. (Figure 2). Other mechanisms include binding pro-oxidant metal
Autophagy is a highly conserved degradation pathway which can re- ions, such as iron and copper by specific metal binding proteins such
cycle nutrients and organelles to enable cells to adapt to undesirable as transferrin, metallothionein, haptoglobin, ceruloplasmin (Table 2).
surroundings. When cells sense nutritional stress, autophagy will The antioxidants in foods help to prevent oxidative reactions
be induced very quickly. One study revealed that oxidative stress is that decrease their quality. Many dietary supplements have been
an essential element of autophagy induced by nutrient deficiency. promoted as antioxidants, but only a few, few antioxidant dietary
However, nutrient excess will also induce autophagy mainly through supplements have been shown to promote health. The health ef-
ROS or endoplasmic reticulum (ER) stress (He et al., 2018). Moreover, fect of an antioxidant depends on the systemic bioavailability, the
autophagy protects cells against environmental stress through recy- concentration of the compound that can be delivered to specific
cling limited nutrients or degrading damaged organelles. ROS derived organ sites, and whether this antioxidant can perform the expected
from mitochondria can oxidize membrane lipids leading to damage function. With the exception of antioxidant nutrients, many dietary
of the mitochondrial membrane structure causing cell death. Studies antioxidants are generally less effective in combating ROS compared
have also reported that the induction of autophagy in tumor necrosis with the antioxidant and cytoprotective enzyme systems. Therefore,
factor-alpha-treated cells via the NF-κB pathway requires the accumu- a non-pro-oxidative activator of Nrf2 may be more useful and less
lation of ROS. The p38 mitogen-activated protein kinases (MAPK) are problematic, because antioxidant enzyme systems are better regu-
also involved in the generation of ROS. Studies have shown that oxida- lated in the body. Many studies have shown that taking antioxidants,
tive stress can be elevated by the inhibition of p53 targeted gene ex- especially at high doses, can lead to toxicity because of prooxida-
pression inducing autophagy. Autophagy can be induced by nutritional tive activities. It would also be interesting to consider the issue of
ALI et al. |
      5 of 13

F I G U R E 2   Different classes of antioxidants (Adapted with permission from Carocho & Ferreira, 2013)

TA B L E 2   Major antioxidants and their functions (adapted from Zhang et al., 2019)

Antioxidants Target Presence Functions

SOD1 (Cu/Zn) Ubiquitous Cytosolic and mitochondrial O2  dismutation

−⋅ −⋅
O2
SOD2 (Mn) Ubiquitous Mitochondrial O2  dismutation,
⋅ −⋅
O2
SOD3 (Cu/Zn) Vessel, lung, kidney Extracellular space O2  dismutation
⋅ −⋅
O2
CAT H 2 O2 Liver, erythrocyte H2O2 detoxification, Ethanol metabolism
GRx GSSG Ubiquitous Reducing GSSG to GSH
GSH GPX, PRDX1/4 Ubiquitous GPX and PRDX1/4 reduction xenobiotic detoxification
Uric acid OH·, HOCl, ROO · Plasma Major plasma ROS scavenger, Within the cell as prooxidant
Vitamin E OH·, LOO · Plasma Membrane lipid peroxidation termination
·
Vitamin C TO Plasma Vitamin E reduction
Bilirubin O2, H2O2,, ONOO ·- Plasma, spleen Protect lipids from oxidation
⋅

homeostasis in the redox states of tissues. ROS are also known to GPx, and glutathione reductase (GRx). The activity of SOD, CAT, and
play physiological functions, such as being involved in killing infec- GPx constitute the first line of antioxidant defense which plays a key
tious bacteria in monocytes. There are also suggestions that ROS role in the total defense mechanisms of the host biological system
play roles in the signal transductions of many physiological func- (Ighodaro & Akinloye, 2018).
tions. The physiological health requires a proper balance between
ROS generation and the antioxidant systems and when ROS over-
comes the antioxidant-defense systems in the body resulting in oxi- 3.1.1 | Superoxide dismutase
dative stress (Yang et al., 2018). The effects of food on physiological
antioxidant capacities and its measurement have limitations in pre- SOD was discovered by Irvin Fridovich in 1968. This enzyme cata-
dicting the health effects directly in animal models and in humans. A lyzes the transition O2 into H2O2 (McCord & Fridovich, 1968, 1969).
−⋅

few methods and techniques employed to measure the oxidative and SODs are located in cytosol and mitochondria and belong to the fam-
antioxidative properties have been shown in Table 3. ily of multimeric metalloenzymes. They are categorized into different
families: Cu-SOD, Mn-SOD, Cu-Zn-SOD, Fe-SOD, and Ni-SOD. These
enzymes are found at different places, for example, Cu-Zn-SOD is
3.1 | Enzymatic antioxidants predominantly present in the chloroplast and cytosol of eukaryoic
cells, while MnSOD is mostly present in the matrix of mitochondria
Human system possesses a battery of enzymes that neutralize the and cytosol of bacteria, and FeSOD is found in prokaryotes and some
reactive species formed. The important ones include CAT, SOD, plants (Duke & Salin, 1985). Among these enzymes, Cu-Zn-SOD is
 |
6 of 13       ALI et al.

TA B L E 3   Some methods and techniques for the analysis of

oxidation and antioxidant activity (adapted from Carocho &
Ferreira, 2013)

Assay mechanism/
Method detection

ABTS (2,20-azinobis(3- Scavenging activity

ethylbenzothiazoline-6-sulfonic acid)
ACA (aldehyde/carboxylic acid) Oxidation
Conjugated diene Lipid peroxidation
DPPH (2,2-diphenyl-1-picrylhydrazyl) Scavenging activity
ESR (electron spin resonance Free radicals quantification
spectrometry)
Fluorescence assay Total aldehydes
FOX (ferrous oxidation-xylenol) Lipid peroxidation
FRAP (ferric reducing antioxidant Reducing power
power)
FTC (ferric thiocyanate) Lipid peroxidation
Gas chromatography (GC) Lipid peroxides, Aldehydes,
Sterols, Phenolic acids,
Flavonoids
High performance liquid Flavonoids, Aldehydes,
chromatography (HPLC) Phenolic acids
Light emission Excited-state carbonyls
and singlet O2
Spin trapping Alkoxyl and peroxyl
radicals
TBARS (thiobarbituric reactive Lipid peroxidation
substances)
TEAC assay (Trolox equivalent Antioxidant activity F I G U R E 3   (a) Proposed catalytic mechanism of Glutathione
antioxidant capacity) (GSH). (b) Superoxide and hydroperoxide generation from NAD(P)
TRAP (total radical-trapping antioxidant Antioxidant activity H, oxidase (NOX), and XO (adapted with permission from Lu et al.,
parameter) 2010)
   
the decomposition of H2O2 to H2O and O2 (Aslani & Ghobadi, 2016).
CAT has two enzymatic activities depending on the concentration
known to provide a strong defense against oxygen toxicity inside the of H2O2. If the concentration of H2O2 is high, CAT acts catalytically,
cell, and according to studies it is accepted that Cu-Zn-SOD is an im- that is, removes H2O2 by forming H2O and O2. However, at a low
portant enzyme for aerobic life and is irreplaceable (Peskin, Koen, & concentration of H2O2 and in the presence of a suitable hydrogen
Zbarsky, 1977). Studies have shown that SODs play a role in protect- donor, for example, ethanol, methanol, phenol, and others, it acts
ing enzymes and proteins against oxygen toxicity in both prokary- peroxidically, removing H2O2, but oxidizing its substrate (peroxidatic
otes and eukaryotes including higher plants (Fridovich, 1986; Bowler, reaction).
Montagu, & Inzé, 1992; Gralla & Kosman, 1992; Hassan & Scandalios,
1990; Scandalios, 1990; Scandalios, 1992).
3.1.3 | Glutathione peroxidase and
glutathione reductase
3.1.2 | Catalase
GPx is a family of enzymes that require reduced GSH as a sub-
CAT is present in most cells and is considered as a major antioxidant strate. They provide a second line of defense against oxidative
enzyme. CAT (EC 1.11.1.6) is an enzyme which is present mainly in stress. It is made up of four identical subunits of 21 kDa and each
the peroxisomes of mammalian cells. Though found in mitochon- subunit contains a selenocysteine (Sec) residue (Lubos, Loscalzo,
dria, animal CAT is largely localized in peroxisomes. It is a tetrameric & Handy, 2011). GPx catalyzes the reduction of organic and in-
enzyme consisting of four identical, tetrahedrally arranged subu- organic H2O2 to H2O and corresponding alcohols, using GSH as
nits of 60 kDa each containing an active heme group and NADPH a cofactor (Birben, Sahiner, Sackesen, Erzurum, & Kalayci, 2012)
(Kirkman & Gaetani, 1984; Martfnez-Cayuela, 1995). CAT catalyzes (Figure 3a). It plays an important role in the protection of cell
ALI et al. |
      7 of 13

membrane polyunsaturated fatty acids, where it functions as a 4 | N O N E NZ Y M ATI C A NTI OX I DA NT S

multicomponent antioxidant defense system. GPx has a higher af-
finity for substrate than CAT and is known to reduce fatty acid Dietary micronutrients constitute many water and lipid soluble
hydroperoxides (Gathwala & Aggarwal, 2016). Most animal cells nonenzymatic antioxidants founds in the mammalian system.
have both CAT and GPx (Sharma, Jha, Dubey, & Pessarkli, 2012). Important antioxidants include vitamin A (retinol and β-carotene
The GPx can be classified into two forms––selenium dependent as provitamin A), vitamin C (ascorbic acid), and vitamin E (tocoph-
and selenium independent. They are found in both cytosol and erol and tocotrienol). These antioxidants work as defense barrier
mitochondria. In mammalian tissues, four major types’ selenium against free radicals and non-radical oxidants and prevent the
dependent GPx isozymes are present: (a) classical GPx (GPx1), assault to DNA, proteins, lipids, and other molecules which are
(b) gastrointestinal GPx (GPx2), (c) plasma GPx (GPx3), and (d) induced by oxidants. The most abundant cellular antioxidant is
phospholipid GPx (PHGPx4 or GPx4). GPx1 are mostly found in tripeptide GSH which prevents oxidation of thiols groups inside
red blood cells (RBC), liver, lung, and kidney. GPx2 and GPx3 are the cell. Another endogenous protein called thioredoxin which is
ubiquitous but are mostly present in organs such as kidney, lung, involved in antioxidative reactions inside the cell is also discussed
epididymis, vas deferens, placenta, seminal vesicle, heart, and here.
muscle. GPx4 are broadly dispersed in various tissues (Margis,
Dunand, Teixeira, & Margis-Pinheiro, 2008). GPxs also play an im-
portant role in the detoxification of ROS and it was found to be 4.1 | Ascorbic acid
first enzyme activated under high levels of ROS (Duggett et al.,
2016; Halliwell & Gutteridge, 2015). Vitamin C is commonly called as ascorbic acid and it is mainly di-
Glutathione reductase is a cytosolic protein that shows a similar vided into two compounds, L-ascorbic acid and L-dehydroascorbic.
distribution pattern as GPx in cells. It reduces oxidized glutathione Both possess antioxidant activity and can be enzymatically con-
(GSSG) by utilizing NADPH (Figure 3b). One of the important func- verted in vivo and may be absorbed through the gastrointestinal
tions of GRx is to maintain the ratio of GSH/GSSG. When the con- tract. Ascorbic acid is readily oxidized to dehydroascorbic acid
centration of GSSG (oxidized glutathione) increases inside the cell it (Figure 4). It is a vital water-soluble antioxidant found in bio-
often leads to DNA breakage, protein denaturation, and lipid perox- logical fluids and required for normal metabolic functions of the
idation (Zitka et al., 2012). body (Jaffe, 1984). It is a very potent free radical scavenger and
conserves the integrity of low density lipoprotein (LDL) and also
maintains the level of vitamin E in cell membranes (Harats et al.,
3.1.4 | Glutathione 1998; Niki, 1987). It prevents the macromolecules such as DNA,
lipids, and proteins from oxidative damage by scavenging reactive
Glutathione or γ-glutamylcysteinylglycine is the major nonen- oxygen and nitrogen species (Noctor & Foyer, 1998). Ascorbic acid
zymatic antioxidant, involved in many cellular functions. It is a mainly scavenges ONOO −, NO, and HOCl but also quenches O2 ,
−⋅

ubiquitous tripeptide that regulates intracellular redox homeo- ·OH, and O2 , and reduces H2O2 to H2O via ascorbate peroxidase
stasis and is present either in reduced (GSH) or oxidized form reaction (Noctor & Foyer, 1998). In addition to scavenging free
(GSSG) (Figure 3). GSH is a tripeptide (cysteine, glycine, and glu- radicals, ascorbic acid also helps to restore small molecules such as
tamic acid) found in relatively high concentrations in many bod- α-tocopherol, GSH, urate, and β-carotene so that they too can act
ily tissues. It is found in almost all types of cell compartments: as an antioxidant. It is an effective antioxidant that prevents lipid
cytosol, ER, mitochondria, and vacuoles at millimolar concentra- peroxidation and can reduce or prevent H2O2-induced lipid peroxi-
tion (Jimenez, Hernandez, Pastori, Rio, & Sevilla, 1998; Meister & dation and formation of 8-hydroxydeoxyguanosine (8-OHdG) in
Anderson, 1983). GSH scavenges many ROS such as H2O2, O2 and nucleic acids (Bayani, Singh, Zamboni, & Mahajan, 2009). Ascorbic
−⋅

·
OH (Misak et al., 2018). One of the basic role of GSH as an anti- acid is not synthesized inside the body because the glucuronic
oxidant is its ability to restore ascorbic acid via the ascorbate-GSH pathway required for the biosynthesis of vitamin C is defective
cycle (Noctor & Foyer, 1998). GSH is a potent detoxifier of xeno- due to mutation in the gene coding for L-gulonolactone oxidase
biotics and acts as a barrier against hydroperoxide induced oxida- (Woodall & Ames, 1997).
tion. It plays a pivotal role in reducing oxidative stress, maintaining
redox balance, enhancing metabolic detoxification, and regulating
the immune system. Various chronic, age-related diseases such as 4.1.1 | Tocopherols
those related to neurodegeneration, mitochondrial dysfunction,
and even cancer, have been related to suboptimal or deficient GSH Naturally occurring four tocopherols are designated as alpha (α),
level. There is increasing awareness of its ability in mitigating toxin beta (β), gamma (γ), and delta (δ)-tocopherols and out of these iso-
load through its ability to enhance hepatic conversion and excre- forms α-tocopherol (αT) being the most abundant is also called vita-
tion of compounds such as mercury and persistent organic pollut- min E. All the isoforms of tocopherols are composed of a chromanol
ants (Minich & Brown, 2019). ring and a 16-carbon phytyl like side chains (Jiang, 2014). While
 |
8 of 13       ALI et al.

F I G U R E 4   Radical scavenging mechanism of ascorbic acid (vitamin C). Direct reactions of vitamin E (TOH) with ·OH (a) and vitamin C
(AscH) with ROO·(b) and regeneration of vitamin E from vitamin C (adapted with permission from Lu et al., 2010)

saturated while tocotrienols possess three double bonds. αT is not

an endogenous antioxidant and is taken by diet in human body.
Major source of vitamin E are nuts, seeds, whole grain, vegetable
oil, etc. Vitamin E is an effective lipid soluble antioxidant found in
plasma membrane where it works as chain breaker in lipid peroxi-
dation of cell membranes (Bayani et al., 2009). It can directly scav-
enge lipoperoxyl radicals and protect cell membranes against lipid
peroxidation by donating a hydrogen atom to the radical (Martfnez-
Cayuela, 1995). The oxidized tocopheryl radical is then reconverted
back via ascorbic acid facilitated pathway to tocopherol (Traber &
Stevens, 2011). Though αT is the most abundant and the predomi-
nantly investigated form, the other isoforms such as γ-tocopherol,
δ-tocopherol, and γ-tocotrienol also have antioxidative and anti-in-
flammatory activity and play a vital role in the pathophysiology of a
number of diseases (Mathur, Ding, Saldeen, & Mehta, 2015).

F I G U R E 5   Natural forms vitamin E (tocopherols, tocotrienols)

4.1.2 | β-carotene
α-tocopherol was the first vitamin E analoge to be recognized, eight
chemically distinct analoges are now known, consisting of α, β, γ, and Since, β-Carotene has numerous biological functions in body but
δ-tocopherols (T) and α, β, γ, and δ-tocotrienols (T3), all of them are humans are not able to synthesize it, hence, it is necessary to sup-
now referred to as vitamin E. The tocopherols are saturated forms of ply these compounds with food or pharmaceuticals. Originally
vitamin E, whereas the tocotrienols are unsaturated and possess an β-carotene was recovered from plants by physicochemical extrac-
isoprenoid side chain (Ahsan, Ahad, Iqbal, & Siddiqui, 2014, Ahsan, tion mainly from carrots but nowadays β-carotene is mainly pro-
Ahad, & Siddiqui, 2015). As shown in Figure 5, the tocopherols are duced through chemical synthesis (Bogacz-Radomska & Harasym,
ALI et al. |
      9 of 13

2018). Monaghan and Schmitt (1932) first described β-carotene already present in them or other complementary nutrient. These
as a fat-soluble vitamin A. This antioxidant protects lipids against are designed to have some health benefits other than its traditional
rancidity and is known as the most efficient singlet oxygen radical nutritional value. The term was introduced in Japan in 1980s for re-
scavenger. ferring processed food containing nutrient conferring of some addi-
tional health benefits apart from its own nutritional value, whereas
in China, designer food (or health foods) is used in their traditional
4.1.3 | Thioredoxin medicine. “A functional food is similar in appearance to, or may be,
a conventional food that is consumed as part of a usual diet, and
Thioredoxin is a pervasive cellular protein disulfide reductase which is demonstrated to have physiological benefits and/or reduce the
serves as an electron donor for several enzymes including ribonu- risk of chronic disease beyond basic nutritional functions, i.e. they
cleotide reductase, thioredoxin peroxidase, and methionine sul- may contain bioactive compounds” (Health Canada, 1998). The
foxide reductase (Arner & Holmgren, 2000). Thioredoxin is a small Institute of Medicine's Food and Nutrition Board (IOM/NAS, 1994)
(12  kDa) multifunctional protein (Haendeler et al., 2002) consist- defined functional foods as “any food or food ingredient that may
ing of 105 amino acid residues and acts as a powerful antioxidant provide a health benefit beyond the traditional nutrients it contains”
(Kaimul, Nakamura, Masutani, & Yodoi, 2007). It is responsible for (Rajasekaran & Kalaivani, 2013). Designer foods are normal foods
maintaining proteins in the reduced state thus regulating redox re- that are enriched with one or more health promoting or disease pre-
actions in signal transduction pathways. It functions as an intracel- venting substances. Most of the time the processed food are fortified
lular reductase through a dithiol–disulfide exchange reaction using with health benefiting nutrients which are already present in them in
two cysteine residues (Holmgren, 1985). Reduced thioredoxin forms small amounts or added with complementary nutrients. A variety of
dithiols and the oxidized form incorporates disulfide bonds in the foods are now available in the market (Table 4) that are fortified with
active site. Reduced thioredoxin transfers a hydrogen ion (H+) to various health promoting nutrients and antioxidants that help in the
the disulfide in the targeted oxidized protein to reduce it and it- maintenance of various aspects of health ranging from the immune,
self becomes oxidized. Thioredoxin is also susceptible to nitrosyla- visual, inflammation systems, etc. (Rajasekaran & Kalaivani, 2013).
tion (Engelman, Ziv, Arnér, & Benhar, 2016). Thioredoxin levels are Functional foods include a wide variety of foods and food compo-
high in some cancers such as hepatocelluler (Miyazaki et al., 1998), nents believed to improve the overall health and wellbeing, reduce
lung (Kim et al., 2003), and cervical cancers (Nishiyama, Masutani, the risk of specific diseases, or minimize the effects of other health
Nakamura, Nishinaka, & Yodoi, 2001). Plasma concentrations of concerns (IFIC, 2011). It can be produced by fortification or nutrifi-
thioredoxin is a biomarker for oxidative stress-related disorders cation of conventional food. Genetically engineered foods contain-
and metabolic syndrome. It stimulates hypoxia-inducible factor-1α ing higher than normal amounts of health promoting nutrients and
(HIF-1α), which increases the production of vascular endothelial fermented foods with live cultures are considered functional foods.
growth factor (VEGF) promoting tumor angiogenesis and drug re- Infant formula may be the first designer food as it contains nutrients
sistance (Welsh, Bellamy, Briehl, & Powis, 2009). Thioredoxin is said for the development of brain and immune system. The addition of
to be a “moonlighting protein” (Jeffery, 1999) with several new func- docosahexaenoic acid to health drinks for improving brain and visual
tions being discovered. development, the alteration or reduction of allergenic components
in food, the use of probiotics and nucleotides to enhance immune
response and sports nutrition are important examples of designer
5 | D E S I G N E R FO O DS foods. Traditional and complementary medicine in various countries
like China, Japan, and India has the tradition of using fermented food
The designer foods, also known as “functional food” and “fortified for its health benefits, which includes red wine, yogurt, tofu, cheese,
food,” refers to the food fortified or enriched with nutrient content etc. (Rajasekaran & Kalaivani, 2013).

TA B L E 4   Designer food and their fortified contents

Food Contents fortified/added References

Chicken/meat Selenium Bennett & Cheng, 2010

Eggs α-linolenic acid/vitamin E, vitamin D, omega-3 fatty acid Bourre, 2006
Grains Folic acid Al-Hooti, Sidhu, Al-Sager, & Al-Othman, 2002
Milk Linoleic acid, polyphenols Axten, Wohlers, & Wegrzyn, 2008
Oil (vegetable, fish, nuts) Omega-3 fatty acids, omega-6 fatty acids, polyphenols, Riediger, Othman, Suh, & Moghadasian, 2009
tocopherols
Rice Vitamin A, iron Kalaivani & Mathew, 2010
Yogurt Probiotic microbes, vitamin D, vitamin B1, vitamin B2 Sleator, 2010
 |
10 of 13       ALI et al.

Probiotics are organisms or substances that contribute to in- in women. In addition to the beneficial effects, studies have shed
testinal microbial balance, in contrast to antibiotics that counteract new light on the antioxidant capacity of probiotics. Further, the
microbial activity. However, a currently widely accepted definition oxidative stress in patients with type 2 diabetes can be amelio-
is that “probiotics are live microorganisms which when adminis- rated by multispecies probiotics. It has been found that LAB can
trated in adequate amounts confer a health benefit on the host.” suppress oxidative stress and in humans, Lactobacillus rhamnosus
Humans have always ingested bacteria unintentionally together exerted strong antioxidant activity in physical stress. Athletes ex-
with food which could be adverse, but they could also be harm- posed to oxidative stress might benefit from the ability of L. rham-
less “dietary bacteria” when fermented foods were consumed. In nosus to increase antioxidant levels and neutralize the effects of
particular, lactic acid fermented foods such as yoghurt, cheese, ROS (Wang et al., 2017).
olives may contain high concentration of live bacteria often of
Lactobacillus species that are now used for probiotics. In search of
strains with better resistance to pH of the stomach and digestive 7 | CO N C LU S I O N
juices of intestine,  Lactobacillus acidophilus  was launched in USA
and Lactobacillus casei (L. paracasei) in Japan in the 1930s as pro- The antioxidants play a major role in scavenging free radical
biotics (Hakansson & Molin, 2011). The human gut microbiota has and non-radical oxidants and protecting the cells from oxidative
been the interest of research in recent years and the knowledge stress. Antioxidants both small molecules such as GSH, thiore-
about their potential capacity is growing rapidly. Microorganisms doxin, ascorbic acid as well as enzymes, for example, SOD, GPx,
have colonized throughout the gastrointestinal tract of human CAT counter the stress caused by the reactive radicals and protect
through a symbiotic relationship and influence physiology, metab- cellular biomolecules. The tocopherols, ascorbic acid, carotenoids,
olism,  nutrition,  and immune functions of an individual. The gut flavonoids, amino acids, phospholipids, and sterols are natu-
microbes are directly involved in conferring protection against rally occurring antioxidants. They inhibit the oxidation of foods
pathogen colonization by inducing direct killing, competing with by scavenging free radicals, chelating pro-oxidant metal ions,
nutrients, and enhancing the response of gut-associated immune quenching photosensitizers, and inactivating non-heme contain-
system. Damage to the microbiome (dysbiosis) is linked with ing lipoxygenase preventing lipid peroxidation. Antioxidant in food
several life-threatening pathophysiological conditions, that is, sciences describes compounds that block oxidative reactions,
inflammatory bowel disease, cancer, obesity, allergy, and auto-im- thus maintaining freshness and prolonging the shelf lives of food
munity (Sokol et al., 2018; Viennois et al., 2019; Vitetta, Coulson, products. In addition to the essential antioxidant nutrients such
Thomsen, Nguyen, & Hall, 2017). Therefore, the manipulation of as vitamins E and C, there are several well-designed antioxidant
human gut microbiota is a potential target for therapeutic inter- and cytoprotective enzyme systems in the human body, which are
vention in several human diseases (Mamantopoulos et al., 2017; more important than dietary non-nutrient antioxidants. At high
Mamantopoulos, Ronchi, McCoy, & Wullaert, 2018; Mukherjee, concentrations, many antioxidants could act as prooxidants, in-
Joardar, Sengupta, & Sinha Babu, 2018; Richard & Sokol, 2019). creasing oxidative stress and inducing toxicity. Newer approaches
of designer foods that are fortified with antioxidants and nutri-
ents are currently available in that may be important in human
6 |  D E S I G N E R FO O DS A N D health including the use of different types of probiotics, which
A NTI OX I DA NT S are live microorganisms and confer health benefit on the host. In
particular, lactic acid fermented foods such as yoghurt, cheese,
Due to growing interest in functional foods with antioxidative olives may contain live bacteria of the same Lactobacillus species
attributes, probiotics are known as potential sources of antioxi- that is now used in probiotics. Microorganisms have colonized the
dants (Mishra et al., 2015). The probiotic fermented milk prepared gastrointestinal tract of humans through a symbiotic relationship
from cows, goats, and camels milk supplemented with bacteria and influence the physiology, metabolism, nutrition, and immune
Pediococcus pentosus showed radical scavenging antioxidant ac- functions of an individual.
tivity. Moreover, it has also been reported that different protein
peptides present in fermented milk are responsible for increased AC K N OW L E D G M E N T S
radical scavenging activity. Some researchers worked on the ef- The authors are grateful to the Department of Biochemistry, AMU,
fect of prebiotics (inulin, lactulose, raffinose) on multiplication of Aligarh for the facilities provided. The UGC is also acknowledged for
some probiotic strains of Lactobacillus and Bifidobacterium, to ob- financial support and UGC-MANF for providing fellowship to MKZ
tain a bread-like product (Mishra et al., 2015). Lactic acid bacteria and Department of Biotechnology (DBT), Government of India for
(LAB) strains are the major representatives of probiotics both in providing fellowship to TS.
the food and pharmaceutical industries. Probiotic Bifidobacterium
is also a very commonly used probiotic bacterium and is able to C O N FL I C T O F I N T E R E S T
promote antitumor immunity and relieve irritable bowel syndrome The authors declare that they have no competing financial interests.
ALI et al. |
      11 of 13

ORCID Carocho, M., & Ferreira, I. C. F. R. (2013). A review on antioxidants, pro-

oxidants and related controversy: Natural and synthetic compounds,
Haseeb Ahsan  https://orcid.org/0000-0002-5313-5959
screening and analysis methodologies and future perspective. Food
Fahim Halim Khan  https://orcid.org/0000-0001-9004-7993 and Chemical Toxicology, 50, 15–25.
Cheeseman, K. H., & Slater, T. F. (1993). An introduction to free radical
REFERENCES biochemistry. British Medical Bulletin, 49(3), 481–493.
Chen, X. M., Chen, H. S., Xu, M. J., & Shen, J. G. (2013). Targeting reactive
Ahsan, H., Ahad, A., Iqbal, J., & Siddiqui, W. A. (2014). Pharmacological
nitrogen species: A promising therapeutic strategy for cerebral isch-
potential of tocotrienols: A review. Nutrition & Metabolism, 11(1), 52.
emia-reperfusion injury. Acta Pharmacologica Sinica, 34, 67–77.
https​://doi.org/10.1186/1743-7075-11-52
Craft, B. D., Kerrihard, A. L., Amarowicz, Z. R., & Pegg, R. B. (2002).
Ahsan, H., Ahad, A., & Siddiqui, W. A. (2015). A review of characteri-
Phenol-based antioxidants and the in vitro methods used for their
zation of tocotrienols from plant oils and foods. Journal of Chemical
assessment. Comprehensive Reviews in Food Science and Food Safety,
Biology, 8(2), 45–59. https​://doi.org/10.1007/s12154-014-0127-8
11(2), 148–173.
Aikens, J., & Dix, T. A. (1991). Perhydroxyl radical (HOO.) initiated lipid
Devasagayam, T. P. A., Tilak, J. C., Boloor, K. K., Sane, K. S., Ghaskadbi,
peroxidation. The role of fatty acid hydroperoxides. Journal of
S. S., & Lele, R. D. (2004). Free radicals and antioxidants in human
Biological Chemistry, 266, 15091–15098.
health: Current status and future prospects. JAPI, 52, 794–804.
Al-Hooti, S. N., Sidhu, J. S., Al-Sager, J. M., & Al-Othman, A. (2002).
Dhawan, V. (2014). Reactive oxygen and nitrogen species: General consider-
Effect of raw wheat germ addition on the physical texture and ob-
ations. In N. K. Ganguly, S. K. Jindal, S. Biswal, P. J. Barnes, & R. Pawankar
jective color of a designer food (pan bread). Nahrung, 46(2), 68–72.
(Eds.), Studies on respiratory disorders, oxidative stress in applied basic
https​://doi.org/10.1002/1521-3803(20020​3 01)46:2%3C68:AID-
research and clinical practice. New York, NY: Springer Science+Business
FOOD6​8%3E3.0.CO;2-W
Media. https​://doi.org/10.1007/978-1-4939-0497-6_2
Alugoju, P., Dinesh, B. J., & Latha, P. (2015). Free radicals: Properties,
Duggett, N. A., Griffiths, L. A., McKenna, O. E., De Santis, V.,
sources, targets, and their implication in various diseases. Indian
Yongsanguanchai, N., Mokori, E. B., & Flatters, S. J. (2016). Oxidative
Journal of Clinical Biochemistry, 30, 11–26. https​://doi.org/10.1007/
stress in the development, maintenance and resolution of pacli-
s12291-014-0446-0
taxel-induced painful neuropathy. Neuroscience, 333, 13–26. https​://
Andrew, P. J., & Mayer, B. (1999). Enzymatic function of nitric oxide
doi.org/10.1016/j.neuro​scien​ce.2016.06.050
synthases. Cardiovascular Research, 43, 521–531. https​://doi.
Duke, M. V., & Salin M. L. (1985). Purification and characterization of
org/10.1016/S0008-6363(99)00115-7
an iron-containing superoxide dismutase from a eukaryote Ginkgo
Arner, E. S., & Holmgren, A. (2000). Physiological functions of thiore-
biloba. Archives of Biochemistry and Biophysics, 243(1), 305–314.
doxin and thioredoxin reductase. European Journal of Biochemistry,
Engelman, R., Ziv, T., Arnér, E. S. J., & Benhar, M. (2016). Inhibitory ni-
267, 6102–6109.
trosylation of mammalian thioredoxin reductase 1: Molecular char-
Aslani, B. A., & Ghobadi, S. (2016). Studies on oxidants and antioxidants
acterization and evidence for its functional role in cellular nitroso-
with a brief glance at their relevance to the immune system. Life
redox imbalance. Free Radical Biology and Medicine, 97, 375–385.
Sciences, 146, 163–173. https​://doi.org/10.1016/j.lfs.2016.01.014
https​://doi.org/10.1016/j.freer​adbio​med.2016.06.032
Axten, L. G., Wohlers, M. W., & Wegrzyn, T. (2008). Using phytochem-
Fridovich, L. (1986). Superoxide dismutases. Advances in Enzymology and
icals to enhance health benefits of milk: Impact of polyphenols on
Related Areas of Molecular Biology, 58, 61–97.
flavor profile. Journal of Food Science, 73(6), 122–126. https​://doi.
Gathwala, G., & Aggarwal, R. (2016). Selenium supplementation for the
org/10.1111/j.1750-3841.2008.00808.x
preterm Indian neonate. Indian Journal of Public Health, 60(2), 142–
Bayani, U., Singh, A. V., Zamboni, P., & Mahajan, R. T. (2009).
144. https​://doi.org/10.4103/0019-557X.184571
Oxidative stress and neurodegenerative diseases: A review of up-
Giles, G. I., Nasim, M. J., Ali, W., & Jacob, C. (2017). The reactive sul-
stream and downstream antioxidant therapeutic options. Current
fur species concept: 15 years on. Antioxidants, 6(2), E38. https​://doi.
Neuropharmacology, 7(1), 65–74.
org/10.3390/antio​x6020038
Bennett, D. C., & Cheng, K. M. (2010). Selenium enrichment of table
Gralla, E. B., & Kosman, D. J. (1992). Molecular genetics of superoxide dis-
eggs. Poultry Science, 89, 2166–2172. https​://doi.org/10.3382/
mutases in yeasts and related fungi. Advances in Genetics, 30, 251–319.
ps.2009-00571​
Haendeler, J., Hoffmann, J., Tischler, V., Berk, B. C., Zeiher, A. M., &
Birben, E., Sahiner, U. M., Sackesen, C., Erzurum, S., & Kalayci, O. (2012).
Dimmeler, S. (2002). Redox regulatory and anti-apoptotic functions
Oxidative stress and antioxidant defense. World Allergy Organization
of thioredoxin depend on S-nitrosylation at cysteine 69. Nature Cell
Journal, 5(1), 9–19. https​://doi.org/10.1097/WOX.0b013​e3182​439613
Biology, 4, 743–749. https​://doi.org/10.1038/ncb851
Biswas, S. K. (2016). Does the Interdependence between oxidative
Hakansson, A., & Molin, G. (2011). Gut microbiota and inflammation.
stress and inflammation explain the antioxidant paradox? Oxidative
Nutrients, 3(6), 637–682. https​://doi.org/10.3390/nu306​0637
Medicine and Cellular Longevity, 2016, 5698931. https​://doi.
Halliwell, B. (1995a). How to characterize an antioxidant: An update.
org/10.1155/2016/5698931
Biochemical Society Symposia, 61, 73–101. https​://doi.org/10.1042/
Bogacz-Radomska, L., & Harasym, J. (2018). β-Carotene—Properties and
bss06​10073​
production methods. Food Quality Safety, 2(2), 69–74. https​://doi.
Halliwell, B. (1995b). Antioxidant characterization: methodology and
org/10.1093/fqsaf​e/fyy004
mechanism. Biochemical Pharmacology, 49(10), 1341–1348. https​://
Bourre, J. M. (2006). Effects of nutrients (in food) on the structure and
doi.org/10.1016/0006-2952(95)00088-H
function of the nervous system: Update on dietary requirements for
Halliwell, B., & Gutteridge, J. M. (1995). The definition and measurement
brain. Part 1: Micronutrients. Journal of Nutrition Health and Aging,
of antioxidants in biological systems. Free Radical Biology and Medicine,
10(5), 377–385.
18(1), 125–126. https​://doi.org/10.1016/0891-5849(95)91457-3
Bowler, C., Van Montagu, M., & Inzé, D. (1992). Superoxide dismutase
Halliwell, B., & Gutteridge, J. M. (2015). Free radicals in biology and medi-
and stress tolerance. Annual Review of Plant Physiology and Plant
cine (5th ed.). New York: Oxford University Press.
Molecular Biology, 43, 83–116. https​://doi.org/10.1146/annur​
Harats, D., Chevion, S., Nahir, M., Norman, Y., Sagee, O., & Berry, E. M.
ev.pp.43.060192.000503
(1998). Citrus fruit supplementation reduces lipoprotein oxidation
Health Canada. (1998) Health Canada policy paper. Retrieved from
in young men ingesting a diet high in saturated fat: Presumptive
http://www.hcsc.gc.ca
 |
12 of 13       ALI et al.

evidence for an interaction between vitamins C and E in vivo. Lamattina, L., García-Mata, C., Graziano, M., & Pagnussat, G. (2003).
American Journal of Clinical Nutrition, 67, 240–245. https​://doi. Nitric oxide: The versatility of an extensive signal molecule. Annual
org/10.1093/ajcn/67.2.240 Review of Plant Biology, 54, 109–136.
Hassan, H. M., & Scandalios, J. G. (1990). Superoxide dismutases in aer- Li, J., Lan, T., Zhang, C., Zeng, C., Hou, J., Yang, Z., … Liu, B. (2015). Reciprocal
obic organisms. In R. Alscher, & J. Cumming (Eds.), Stress responses in activation between IL-6/STAT3 and NOX4/Akt signalings promotes
plants: Adaptation to acclimation mechanisms (pp. 175–179). New York, proliferation and survival of non-small cell lung cancer cells. Oncotarget,
NY: Wiley-Liss. 6(2), 1031–1048. https​://doi.org/10.18632/​oncot​arget.2671
He, L., Zhang, J., Zhao, J., Ma, N., Kim, S. W., Qiao, S., & Ma, X. (2018). Lobo, V., Patil, A., Phatak, A., & Chandra, N. (2010). Free radicals, antioxi-
Autophagy: The last defense against cellular nutritional stress. dants and functional foods: Impact on human health. Pharmacognosy
Advances in Nutrition, 9(4), 493–504. https​://doi.org/10.1093/advan​ Reviews, 4(8), 118–126. https​://doi.org/10.4103/0973-7847.70902​
ces/nmy011 Lu, J., Lin, P. H., Yao, Q., & Chen, C. (2010). Chemical and molecular
Holmgren, A. (1985). Thioredoxin. Annual Review of Biochemistry, 54, mechanisms of antioxidants: Experimental approaches and model
237–271. https​://doi.org/10.1146/annur​ev.bi.54.070185.001321 systems. Journal of Cellular and Molecular Medicine, 14(4), 840–860.
IFIC. (2011). Background on functional foods. Retrieved from https​:// Lubos, E., Loscalzo, J., & Handy, D. E. (2011). Glutathione peroxidase-1 in
www.foodi​nsight.org health and disease: From molecular mechanisms to therapeutic op-
Ighodaro, O. M., & Akinloye, O. A. (2018). First line defence antioxi- portunities. Antioxidants & Redox Signaling, 15(7), 1957–1997. https​://
dants-superoxide dismutase (SOD), catalase (CAT) and glutathione doi.org/10.1089/ars.2010.3586
peroxidase (GPX): Their fundamental role in the entire antioxidant Mamantopoulos, M., Ronchi, F., McCoy, K. D., & Wullaert, A. (2018).
defence grid. Alexandria Journal of Medicine, 54(4), 287–293. https​:// Inflammasomes make the case for littermate-controlled experimen-
doi.org/10.1016/j.ajme.2017.09.001 tal design in studying host-microbiota interactions. Gut Microbes,
Inan, S. (2019). The potential role of nutraceuticals in inflammation 9(4), 374–381. https​://doi.org/10.1080/19490​976.2017.1421888
and oxidative stress. IntechOpen, https​://doi.org/10.5772/intec​ Mamantopoulos, M., Ronchi, F., Van Hauwermeiren, F., Vieira-Silva,
hopen.83797​. Retrieved from https​://www.intec​hopen.com/on- S., Yilmaz, B., Martens, L., … Wullaert, A. (2017). Nlrp6- and ASC-
line-first/​the-poten​tial-role-of-nutra​ceuti​c als-in-infla​mmati​on-and- dependent inflammasomes do not shape the commensal gut mi-
oxida​tive-stress crobiota composition. Immunity, 47(2), 339–348.e4. https​://doi.
IOM/NAS. (1994). Opportunities in the nutrition and food sciences: org/10.1016/j.immuni.2017.07.011
Research challenges and the next generation of investigators. In P. R. Margis, R., Dunand, C., Teixeira, F. K., & Margis-Pinheiro, M. (2008).
Thomas, & R. Earl (Eds.), Food and nutrition board. Washington, DC: Glutathione peroxidase family—An evolutionary overview. FEBS
National Academy Press. Journal, 275(15), 3959–3970.
Jaffe, G. M. (1984). Vitamin C.In L. Machlin (Ed.), Hand book of vitamins. Marnett, L. J., Riggins, J. N., & West, J. D. (2003). Endogenous gen-
New York, NY: Marcel Dekker Inc. eration of reactive oxidants and electrophiles and their reaction
Jeffery, C. J. (1999). Moonlighting proteins. Trends in Biochemical Sciences, with DNA and proteins. The Journal of Clinical Investigation, 111,
24, 8–11. 583–593.
Jiang, Q. (2014). Natural forms of vitamin E: Metabolism, antioxidant, and Martfnez-Cayuela, M. (1995). Oxygen free radicals and human disease.
anti-inflammatory activities and their role in disease prevention and Biochimie, 77(3), 147–216. https​://doi.org/10.1016/0300-9084(96)
therapy. Free Radical Biology and Medicine, 72, 76–90. 88119-3
Jimenez, A., Hernandez, J. A., Pastori, G., de Rio, L. A., & Sevilla, F. (1998). Mathur, P., Ding, Z., Saldeen, T., & Mehta, J. L. (2015). Tocopherol in
Role of the ascorbate-glutathione cycle of mitochondria and peroxi- the prevention and treatment of atherosclerosis and related car-
somes in the senescence of pea leaves. Plant Physiology, 118, 1327– diovascular disease. Clinical Cardiology, 38(9), 570–576. https​://doi.
1335. https​://doi.org/10.1104/pp.118.4.1327 org/10.1002/clc.22422​
John, M. R. (2008). Reactive oxygen species in phagocytic leukocytes. McCord, J. M. & Fridovich, I. (1968). The reduction of cytochrome c by
Histochemistry and Cell Biology, 130, 281. https​://doi.org/10.1007/ milk xanthine oxidase. The Biochemical Journal, 243, 5753–5760.
s00418-008-0461-4 Mccord, J. M., & Fridovich, I. (1969). Superoxide dismutase: An enzy-
Jonah, S. A. (2013). Pharmacology of free radicals and the impact of reac- mic function for erythrocuprein (hemocuprein). Journal of Biological
tive oxygen species on the testis. Journal of reproduction & infertility, Chemistry, 244, 6049–6055.
14(4), 158–172. Meister, A., & Anderson, M. E. (1983). Glutathione. Annual Review
Kaimul, A. M., Nakamura, H., Masutani, H., & Yodoi, J. (2007). Thioredoxin of Biochemistry, 52, 711–760. https​://doi.org/10.1146/annur​
and thioredoxin-binding protein-2 in cancer and metabolic syn- ev.bi.52.070183.003431
drome. Free Radical Biology and Medicine, 43(6), 861–868. https​://doi. Minich, D. M., & Brown, B. I. (2019). A review of dietary (Phyto) nutri-
org/10.1016/j.freer​adbio​med.2007.05.032 ents for glutathione support. Nutrients, 11(9), E2073. https​://doi.
Kalaivani, T., & Mathew, L. (2010). Free radical scavenging activity org/10.3390/nu110​92073​
from leaves of Acacia nilotica (L.) Wild. ex Delile, an Indian medic- Misak, A., Grman, M., Bacova, Z., Rezuchova, I., Hudecova, S.,
inal tree. Food and Chemical Toxicology, 48(1), 298–305. https​://doi. Ondriasova, E., … Ondrias, K. (2018). Polysulfides and products of
org/10.1016/j.fct.2009.10.013 H2S/S-nitrosoglutathione in comparison to H2S, glutathione and an-
Kim, H. J., Chae, H. Z., Kim, Y. J., Kim, Y. H., Hwangs, T. S., Park, E. M., & tioxidant Trolox are potent scavengers of superoxide anion radical
Park, Y. M. (2003). Preferential elevation of Prx I and Trx expression and produce hydroxyl radical by decomposition of H2O2. Nitric Oxide,
in lung cancer cells following hypoxia and in human lung cancer tis- 76, 136–151. https​://doi.org/10.1016/j.niox.2017.09.006
sues. Cell Biology and Toxicology, 19, 285–298. Mishra, V., Shah, C., Mokashe, N., Chavan, R., Yadav, H., & Prajapati, J.
Kirkman, H. N., & Gaetani, G. F. (1984). Catalase: A tetrameric en- (2015). Probiotics as potential antioxidants: A systematic review.
zyme with four tightly bound molecules of NADPH. Proceedings of Journal of agricultural and food chemistry, 63, 3615–3626.
the National Academy of Sciences, 81(14), 4343–4347. https​://doi. Miyazaki, K., Noda, N., Okada, S., Hagiwara, Y., Miyata, M., Sakurabayashi,
org/10.1073/pnas.81.14.4343 I., … Wakasugi, H. (1998). Elevated serum level of thioredoxin in pa-
Kurutas, E. B. (2015). The importance of antioxidants which play tients with hepatocellular carcinoma. Biotherapy, 11, 277–288.
the role in cellular response against oxidative/nitrosative stress: Monaghan, B. R., & Schmitt, F. O. (1932). The effects of carotene and
Current state. Nutrition Journal, 15(1), 71. https​://doi.org/10.1186/ vitamin A on the oxidation of linoleic acid. Journal of Biological
s12937-016-0186-5 Chemistry, 96, 387–395.
ALI et al. |
      13 of 13

Mukherjee, S., Joardar, N., Sengupta, S., & Sinha Babu, S. P. (2018). Gut mi- Sokol, H., Jegou, S., McQuitty, C., Straub, M., Leducq, V., Landman, C.,
crobes as future therapeutics in treating inflammatory and infectious dis- … Beaugerie, L. (2018). Specificities of the intestinal microbiota in
eases: Lessons from recent findings. Journal of Nutritional Biochemistry, patients with inflammatory bowel disease and Clostridium difficile
61, 111–128. https​://doi.org/10.1016/j.jnutb​io.2018.07.010 infection. Gut Microbes, 9(1), 55–60.
Niki, E. (1987). Interaction of ascorbate and alphatocopherol. Annals of Traber, M. G., & Stevens, J. F. (2011). Vitamins C and E: Beneficial ef-
the New York Academy of Sciences, 498, 186–199. fects from a mechanistic perspective. Free Radical Biology and
Nishiyama, A., Masutani, H., Nakamura, H., Nishinaka, Y., & Yodoi, J. Medicine, 51(5), 1000–1013. https​://doi.org/10.1016/j.freer​adbio​
(2001). Redox regulation by thioredoxin and thioredoxin-binding med.2011.05.017
proteins. IUBMB Life, 52, 29–33. https​://doi.org/10.1080/15216​ Van der Veen, B. S., de Winther, M. P., & Heeringa, P. (2009). Myeloperoxidase:
54025​2774739 Molecular mechanism of action and their relevance to human health
Noctor, G., & Foyer, C. H. (1998). Asorbate and glutathione: Keeping active and disease. Antioxidants & Redox Signaling, 11, 2899–2937.
oxygen under control. Annual Review of Plant Biology, 49, 249–279. Viennois, E., Chassaing, B., Tahsin, A., Pujada, A., Wang, L., Gewirtz,
Olson, K. R., Gao, Y., Arif, F., Arora, K., Patel, S., DeLeon, E. R., … Straub, A. T., & Merlin, D. (2019). Host-derived fecal microRNAs can indi-
K. D. (2018). Metabolism of hydrogen sulfide (H(2)S) and produc- cate gut microbiota healthiness and ability to induce inflammation.
tion of reactive sulfur species (RSS) by superoxide dismutase. Redox Theranostics, 9(15), 4542–4557. https​://doi.org/10.7150/thno.35282​
Biology, 15, 74–85. https​://doi.org/10.1016/j.redox.2017.11.009 Vitetta, L., Coulson, S., Thomsen, M., Nguyen, T., & Hall, S. (2017).
Oter, S., Jin, S., Cucullo, L., & Dorman, H. J. (2012). Oxidants and antiox- Probiotics, D-Lactic acidosis, oxidative stress and strain specific-
idants: Friends or foes? Oxidants and Antioxidants in Medical Science, ity. Gut Microbes, 8(4), 311–322. https​://doi.org/10.1080/19490​
1(1), 1–4. https​://doi.org/10.5455/oams.080612.ed.001 976.2017.1279379
Pacher, P., Beckman, J. S., & Liaudet, L. (2007). Nitric oxide and peroxyni- Wang, Y., Wu, Y., Wang, Y., Xu, H., Mei, X., Yu, D., … & Li, W. (2017).
trite in health and disease. Physiological Reviews, 87(1), 315–424. Antioxidant properties of probiotic bacteria. Nutrients, 9(5), 521.
https​://doi.org/10.1152/physr​ev.00029.2006 Welsh, S. J., Bellamy, W. T., Briehl, M. M., & Powis, G. (2009). The redox
Pallavi, S., Ambuj, B. J., Rama, S. D., & Mohammad, P. (2012). Reactive protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor
oxygen species, oxidative damage, and antioxidative defense mecha- 1alpha protein expression: Trx-1 overexpression results in increased
nism in plants under stressful. Journal of Botany, 2012, 1–26. https​:// vascular endothelial growth factor production and enhanced tumor
doi.org/10.1155/2012/217037 angiogenesis. Cancer Research, 62, 5089–5095.
Peskin, A. V., Koen, Y. M., & Zbarsky, I. B. (1977). Superoxide dismutase Winterbourn, C. C. (2002). Biological activity and biomarkers of the neu-
and glutathione peroxidase activities in tumors. FEBS Letters, 78, 41– trophil oxidant hypochlorous acid. Toxicology, 181–2, 223–227.
45. https​://doi.org/10.1016/0014-5793(77)80268-8 Woodall, A. A., & Ames, B. N. (1997). Diet and oxidative damage to
Pryor, W. A. (1986). Oxy-radicals and related species, their formation, DNA: The importance of ascorbate as an antioxidant. In L. Packer, &
lifetimes, and reaction. Annual review of Physiology, 48, 657–667. J. Fuchs (Eds.), Vitamin C in health and disease (pp. 193–203).
Rajasekaran, A., & Kalaivani, M. J. (2013). Designer foods and their ben- New York, NY: Marcel Dekker Inc.
efits: A review. Journal of Food Science and Technology, 50(1), 1–16. Wu, S. M., & Pizzo, S. V. (2011). Alpha 2-macroglobulin from rheumatoid ar-
https​://doi.org/10.1007/s13197-012-0726-8 thritis of synovial fluid: Functional analysis defines a role for oxidation
Richard, M. L., & Sokol, H. (2019). The gut mycobiota: Insights into anal- in inflammation. Archives of Biochemistry and Biophysics, 391, 119–126.
ysis, environmental interactions and role in gastrointestinal dis- Wu, Y., Lu, J., Antony, S., Juhasz, A., Liu, H., Jiang, G., …Roy, K. (2013). Acti-
eases. Nature Reviews Gastroenterology & Hepatology, 16(6), 331–345. vation of TLR4 is required for the synergistic induction of dual oxidase
https​://doi.org/10.1038/s41575-019-0121-2 2 and dual oxidase A2 by IFN-γ and lipopolysaccharide in human pan-
Riediger, N. D., Othman, R. A., Suh, M., & Moghadasian, M. H. (2009). A creatic cancer cell lines. The Journal of Immunology, 190(4), 1859–1872.
systemic review of the roles of n-3 fatty acids in health and disease. Wyatt, A. R., Kumita, J. R., Mifsud, R. W., Gooden, C. A., Wilson, M. R., &
Journal of the American Dietetic Association, 109(4), 668–679. https​:// Dobson, C. M. (2014). Hypochlorite-induced structural modifications
doi.org/10.1016/j.jada.2008.12.022 enhance the chaperone activity of human α2-macroglobulin. PNAS,
Scandalios, J. G. (1990). Response of plant antioxidant defense genes to 111, 2081–2090.
environmental stress. Advances in Genetics, 28, 1–41. Yang, C. S., Ho, C. T., Zhang, J., Wan, X., Zhang, K., & Lim, J. (2018).
Scandalios, J. G. (1992). Molecular biology of free radical scavenging Antioxidants: Differing meanings in food science and health sci-
systems. Cold Spring Harbor, New York, NY: Cold Spring Harbor ence. Journal of Agriculture and Food Chemistry, 66(12), 3063–3068.
Laboratory Press. https​://doi.org/10.1021/acs.jafc.7b05830
Sharma, P., Jha, A. B., Dubey, R. S., & Pessarkli, M. (2012). Reactive oxy- Zhang, L., Wang, X., Cueto, R., Effi, C., Zhang, Y., Tan, H., … Wang, H. (2019).
gen species, oxidative damage, and antioxidative defense mechanism Biochemical basis and metabolic interplay of redox regulation. Redox
in plants under stressful conditions. Journal of Botany, 26. https​://doi. Biology, 26, 101284. https​://doi.org/10.1016/j.redox.2019.101284
org/10.1155/2012/217037 Zitka, O., Skalickova, S., Gumulec, J., Masarik, M., Adam, V., Hubalek, J.,
Siddiqui, T., Zia, M. K., Ali, S. S., Ahsan, H., & Khan, F. H. (2018). Insight … Kruseova, J. (2012). Redox status expressed as GSH: GSSG ratio as
into the interactions of proteinase inhibitor-alpha-2-macroglobulin a marker for oxidative stress in paediatric tumour pateints, Oncology
with hypochlorite. International Journal of Biological Macromolecules, Letters, 4(6), 1247–1253.
117, 401–406. https​://doi.org/10.1016/j.ijbio​mac.2018.05.112
Siddiqui, T., Zia, M. K., Ali, S. S., Rehman, A. A., Ahsan, H., & Khan, F.
H. (2016). Reactive oxygen species and antiproteinases. Archives of How to cite this article: Ali SS, Ahsan H, Zia MK, Siddiqui T,
Physiology and Biochemistry, 122, 1–7. https​://doi.org/10.3109/13813​
Khan FH. Understanding oxidants and antioxidants: Classical
455.2015.1115525
team with new players. J Food Biochem. 2020;44:e13145.
Sleator, R. D. (2010). The human super organism of microbes and men.
Medical Hypotheses, 74(2), 214–215. https​://doi.org/10.1016/j. https​://doi.org/10.1111/jfbc.13145​
mehy.2009.08.047