Oxidative stress: Insights into the Pathogenesis and Treatment of
Shweta Ramkar, Hemendra Kumar Sahu, Narayan Hemnani,
Ravi Parashar, Preeti K. Suresh*
University Institute of Pharmacy, Pt. Ravishankar
Shukla University, Raipur, Chhattisgarh, India.
are exposed to a host of endogenous and environmental stress by pollutants,
microbial assaults, UV radiation, oxidized scalp lipids, grooming practices and
cosmetic treatments which have diverse range of adverse consequences. The
exposure to these environmental and cosmetic substances, leads to generation of
free radicals, reactive oxygen species in particular, leading to oxidative
stress. Oxidative stress generates inflammation, and/or psycho-emotional
stress, and also influences the ageing process, including the hair follicle.
The term alopecia signifies loss of hair owing to several factors, ultimately
resulting in decreased hair density. Cell death on hair follicle (keratinocytes
and its distinctive mesenchyme of dermal papilla) have been attributed to
mechanisms of oxidative stress, including H2O2, nitric
oxide and derivatives, ultraviolet rays, ionizing radiations, endotoxin-induced
inflammation, photodynamic therapy and cigarette smoke. Persistent oxidative
activities in the body, may generate antioxidant defense systems, which can
prevent the attack of biological molecules. In case of androgenic alopecia,
copper and zinc was discovered in the disrupted metabolism form in serum, urine
and hair of the patients, and data suggests rise in oxidative stress. This
review is focused on the effects of the reactive oxygenated species in
disturbing the redox balance and inducing oxidative injury that leads to
Follicle, Oxidative Stress, Antioxidants, Reactive Oxygen Species, Redox
stress is caused by the imbalance between the production of free radicals and
ability of the body to counteract or detoxify their harmful effects through
neutralization by antioxidants, leading to tissue damage (Haslam
et al., 2016). Free radicals are the atom or the
group of atoms that contain unpaired electron and are formed during a number of
biochemical reactions (Suresh et al., 2013). They are highly reactive and may
cause damage to macromolecules like DNA, protein, lipid, enzymes, etc. They are
also known as reactive oxygen species (ROS). Antioxidants are one of the
defensive strategies that assist in controlling the level of free radical and
prevent the oxidation of biomolecules. Oxidative stress have been implicated in
a number of human pathologies including neuro-degenerative disorders, chronic
kidney disease, skin aging and common dermatoses such as psoriasis (Richter
et al., 2015; Wagener et al., 2013; Haslam et al., 2016, Suresh et al.,
2014). Oxidative stress is reported to be one of the key influences leading to
as it is linked with a number of factors that increase cellular oxidative
stress, including smoking, alcohol consumption, some metabolic syndrome, and UV
radiation (Upton et al., 2015; Gao and Dalton, 2007). Some of the common examples
of enzymatic antioxidants in alopecia include superoxide dismutase, catalase,
glutathione peroxidase, paroxone, nemoxigenase and thioredoxin
reductase. Non-enzymatic antioxidants include glutathione, vitamin E and
beta-carotene. In excess amount, the antioxidants may damage protein structure (Yasuko
et al. 1994). The reaction of human organs on
oxidative damage and how they control redox insult is of significant
physiological and clinical relevance.
alopecia (AGA) is a common hair loss dysfunction and is also referred to as hereditary/genetic
hair loss. Accordingly, there are two conditions viz., male pattern baldness
(MPB) and female pattern baldness (FPB). It may occur as early as in the late
teens or occasionally in early twenties. The phenotypical changes are produced
when 5-alpha reductase enzyme starts transforming the testosterone hormone into
its derivative, dihydrotestosterone (DHT) which induces the miniaturization of the
hair follicles and the hair cycle changes, and ultimately hair no more extrudes
through the skin (
et al., 2016). Mantel et. al. (2017) reported that
substantial levels of prostaglandin-D2 was present in the bald scalp of AGA
patients and it functionally inhibits the hair growth (Mantel
et al., 2017). Alopecia areata (AA) is an autoimmune
disorder with body's own immune system assaulting the healthy hair follicles
leading to patchy hair loss on the scalp. The actual explanation for generation
of AA remains unclear, however it is commonly assumed to be induced by stress
and stressful events. In certain situations, AA can advance throughout the
entire scalp, and this is termed as alopecia totalis (AT). In alopecia
universalis (AU), significant hair loss occurs across the entire body,
including eyebrows (Islam
et al., 2015). In cicatricial alopecia (CA) or
scarring alopecia hair follicles are damaged and replaced by scar tissue. In
case of primary CA, hair loss occurs owing to direct inflammation of the hair
follicles. Secondary CA usually refers to scarring hair loss (such as burns or
infections), and ensues as a result of an event or process unrelated to the
follicles. Traction alopecia (TA) is a distinct kind of alopecia and is
frequently produced directly by the action of the individual, which results in
excessive stress on the hair and breakdown (Price
and Colombe, 1996). It may be caused by traumatic hair
styles (e.g., braiding, tight ponytails and frequent hair treatment with
chemicals (e.g., hair coloring and bleaching). Exposure to allergens,
irritants, toxins, burns, injuries, and infection as well as certain medication
(especially antibiotics, testosterone), chronic kidney failure, radiation and
chemotherapy and malnutrition have also been attributed to the generation of
alopecia (Ramkar et al., 2020).
3. ANTIOXIDANT AND ITS ACTION
are the substances that prevent or inhibit the factors that lead to oxidative
injury in the cell. When an antioxidant reacts with a free radical, antioxidant
itself becomes oxidized. Therefore, the antioxidant resources must be regularly
stored in the body. Antioxidants perform diverse roles in different systems,
for instance an antioxidant effective against free radicals in one particular
system may be ineffective in other systems. Also, in certain situations, these
antioxidants may even act as a pro-oxidant as it can generate toxic ROS/RNS (Abdel
et al., 2011). The antioxidant process can
function in one of the two ways, viz., it can break or prevent the chain
reaction or assist in disintegrating into a harmless product. In the
chain-breaking process, when a radical is released or steals an electron, a
second radical is formed. In this continuous process, the last one exerts the
same action on another molecule until the free radical does not form a stable
compound by a chain-breaking antioxidant, or it is simply converted into an
innocuous product (Ryter
et al., 2007). The classic example of such a chain
reaction is lipid peroxidation. An antioxidant enzyme like superoxide
dismutase, catalase and glutathione peroxidase can prevent oxidation by
reducing the rate of chain initiation, e.g., either by scavenging initiating
free radicals or by stabilizing transition metal radicals such as copper and
et al., 2002).
4. OXIDATIVE STRESS AND PATHOPHYSIOLOGY
of pluripotent stem cells are responsible for regulation of hair follicle
development as well as hair growth and are present in dermal papilla (DP). In
DP cells (DPCs), attachment of androgen in androgenic receptors is believed to
be action on hair growth regulation. Studies indicate that in greying
follicles, ROS was produced by the melanocytes and it might be a reason for
creating an oxidative environment in the surrounding follicular area that could
affect DPCs especially in balding scalp (Driskell
et al., 2013; Hunt and McHale, 2005). As depicted in Fig.1
free radical causes the oxidative damage to hair follicle stem cells or dermal
papilla cells in epithelial bulge, which are responsible for the repetitive
growth of hair follicle during hair cycle (Arck
et al., 2006).
1: Sequential events in pathogenesis of alopecia
(mainly UV-B) radiation attacks the keratin (hair protein fractions) and
melanin pigments. On the surface of the cuticle and inside the hair fibre,
disulfide bonds are present that are broken by UV-B radiation leading to denaturation
of the hair structure. On the other hand, UV-A radiation generally produces ROS
via interaction with endogenous photo sensitizers (Fernández
et al. 2012). Fig. 2 demonstrates the cellular
damage in hair follicle.
2: Schematic illustration of the UV-induced alopecia
may be a fall out of radiation therapy, chemotherapy, stem cell
transplantation, and targeted therapy. These therapies can cause hair loss by
damaging the cells that promote hair growth. Hair loss may occur throughout the
body, including the head, face, arms, legs, underarms, and pubic area (Ramkar et
al.,2022). Hair may come out entirely, slowly, or in parts. Or, hair will
simply become thin, sometimes unnoticeably and may become duller or dryer. Hair
loss associated with cancer therapy is usually transitory. Most of the time,
hair will grow back, however infrequently, it may remain thin (Gilhar
et al., 2016; Harman, 2002). Some of the
drugs likely to cause hair loss or thinning are listed in Table 1.
1- Drugs with oxidant properties
Multiple brand names
5. NUTRIENT ANTIOXIDANTS
nutrient antioxidant deficiency is one of the major factors, which can cause
numerous chronic and degenerative pathologies. Hair growth can be maintained by
the combination of nutrients delivered to the hair roots and good health. It is
also affected by the androgens enzyme blockers without the possibility of side
effects from the use of hair loss medications (
Sinbad et al., 2019). Right choice of antioxidants,
minerals, vitamins, and amino acids may promote hair growth. However, excess
use of antioxidants, vitamin A, vitamin E, omega 3 can cause hair loss instead
of hair growth (Rutkowski
and Grzegorczyk, 2012; Timbo et al., 2006; Rajput, 2017). There are number
of nutrients present in the body that have unique structure and antioxidant
et al., 2004).
2- Mechanism of action of various nutrients
The role of vitamin
B5 in hair loss is not clear, but it might
assist in improvement of
cellular metabolism and can provide benefits to hair. Vitamin B6 is
also critical in skin building and growth, and also contributes in cysteine
incorporation within hair cells. Thiamine
(B1), riboflavin (B2) and vitamin B12 also play a role in maintaining healthy
(D’Agostini et al., 2007; Rushton, 2002)
An important cofactor in the normal function of enzymes in
carboxylation. Deficiency of biotin may lead to conjunctivitis, skin rashes
Has a significant enzymatic role in the
formulation of collagen fibers and crosslinks in elastin, in the production
of di-sulfide bonds between cysteine molecules in cytoskeletal proteins of
cortical and cuticle proteins in post-translational phase. Hence, it may have
some role in hair biology, which is not clearly understood.
Cysteine and Methionine
The use of cysteine along with methionine promotes
the repair of structural graze of hair as well slows down the hair loss. They
contribute to the evasion of oxidative stress that can stop the hair loss,
and favor the formation of natural antioxidants like glutathione.
(Clementeet al., 2018; Trüeb, 2009)
Folate is a water-soluble vitamin (vitamin B6), and comprises of
naturally occurring dietary folate and folic acid. Folate is a coenzyme that
aids in the production of nucleic acids and in amino acid metabolism.
(Almohanna et al., 2019)
Niacin (vitamin B3) is a vital component for the body, aids in
the generation of ATP and thus an energy support for the cells. Its
insufficiency leads to pellagra, as well as diarrhea, weakness, dermatitis,
hyper pigmentation and hair loss.
(Guo and Katta, 2017)
Selenium is an essential trace element;
it plays a functional role to protection to the hair from oxidative damage as
well as it provides hair follicle morphogenesis.
Taurine, a beta-amino acid, is found to have an important
character to provide a proper function and maintenance of nervous system and
muscle structure. Hence, it can be used as a counter androgenetic alopecia, by limiting the
process of follicular weakening.
(Collin et al., 2006)
Vitamin C is a water-soluble
antioxidant, helpful to decrease the oxidative stress responsible for the
hair follicle degeneration. In the formation of collagen and as supporting
element in the cross-linking of keratin fibers by enzymatic reaction, vitamin
C plays a crucial role as a cofactor.
(Finner, 2013; Padayatty et al., 2003)
Zinc plays an essential role in several metabolic
pathways and cellular functions. Additionally, it helps in the production of
keratin, which is the main component (about 95%) of the hair structure. Zinc
accelerates hair follicle recovery and is inhibitor of hair follicle
(Kilet al., 2013)
E is a fat-soluble vitamin with high antioxidant potency. It is a chiral
compound with eight stereoisomers: α, β, γ, δ tocopherol and α, β, γ, δ tocotrienol.
In humans, only α-tocopherol is the bioactive form. α-tocopherol safeguards the
membranes around the cell from damage by free radicals owing to its fat-soluble
et al., 2005; Sinbad et al., 2019). Studies have
indicated that vitamin E may have preventive action against breast, prostate
and colon cancers, ischemia, some cardiovascular diseases, arthritis, cataract
and certain neurological disorders. Cooking and storage may destroy the natural
d-α-tocopherol in foods (Devasagayam
et al., 2004).
C or ascorbic acid is a water-soluble vitamin, and have been implicated in the
formation of carnitine collagen and neurotransmitters biosynthesis. They are
antioxidant, anti-atherogenic, anti-carcinogenic and immunomodulator (Yadav
et al., 2016). It has also demonstrated reduction
in the incidence of stomach cancer, colorectal and lung cancer. Vitamin C and
vitamin E act synergistically to reduce free radicals and also regenerates the
reduced form of vitamin E. However, the intake of high doses of vitamin C (2000
mg or more/day) has been the subject of debate for its eventual pro-oxidant or
carcinogen property (Hatem
et al., 2018; Labrozzi, 2020).
is a pro-vitamin and converts into the active form i.e. vitamin A, a fat
soluble member of the carotenoids. Beta-carotene is converted to retinol, which
is essential for vision. It acts as antioxidant by quenching of singlet oxygen (Yadav
et al., 2016).
is a trace mineral found in vegetables, liver, meat, water, sea food, soil, and
yeast. It helps to form the active site of several antioxidant enzymes like
glutathione peroxidase (Finner,
At low dose, it acts as an antioxidant, anti-carcinogenic and immunomodulator.
But at higher doses it produces selenosis which is a selenium poisoning
characterized by gastrointestinal disorders, hair and nail loss, cirrhosis,
pulmonary edema and death (Heyland
et al., 2005).
are polyphenolic compounds present in most of the plants. Based on the chemical
structure, more than 4000 flavonoids have been acknowledged and categorized
into flavanols, flavanones, flavones, isoflavones, catechins, anthocyanins,
proanthocyanidins. Because of their potent antioxidant activity, they are
reported to prevent or delay a number of chronic and degenerative disorder such
as cardiovascular diseases, cancer, memory loss, arthritis, cataract, aging,
stroke, inflammation, Alzheimer’s disease, infection. Every plant contains a
distinctive amalgamation of flavonoids and every plant shows very different
effects on the body. The natural sources of flavonoids include green tea,
grapes, apple, cocoa, ginkgo biloba, soybean, curcuma, berries, onion,
broccoli, etc. For example, green tea is a rich source of flavonoids,
especially flavanols (catechins) and quercetin. Catechin levels are 4-6 times
greater in green tea than in black tea. Many health benefits of green tea
reside in its antioxidant, anticarcinogenic, antihypercholesterolemic,
antibacterial (dental caries), anti-inflammatory activities (Sathishkumar
et al., 2016; Kaushik et al., 2011).
6. GENERATION OF ROS DURING DRUG METABOLISM
involved in Reactive Oxygen Species (ROS) generation during phase-I of drug
et al., 2012). Substrate binding to CYP-450 occurs
via the combination of one molecule of oxygen to the enzyme leading to the
formation of an oxy complex (Thiboutot
et al., 2003). The oxy complex thus formed is
again reduced to peroxy complex that accepts two protons and produce water
through intermediate reactions. Since ROS is generated during the intermediate
stages of CYP-mediated biotransformation of drugs, their continuous production
results in NADPH consumption by the CYP molecules (Abdel
et al., 2011; Ogun, 2015). Although it was
mentioned earlier that ROS is generated during the reaction of CYP-450 with its
substrate, the electron-transfer chain of microsome continues to oxidize NADPH and
produce ROS even in the absence of any substrate (Maxson
and Mitchell, 2016). This excessive ROS generation leads
to repression of CYP gene expression (Fig. 3) (specifically CYP-1A1 gene
expression) is through the inactivation of the transcription factor, nuclear
factor-1. Enzymes like ipoxygenase, cyclooxygenase and xanthine oxidase can
also contribute to ROS production (Held,
2015; Snezhkina et al., 2020).
generated during biotransformation of drugs consists of hydrogen peroxide,
hydroxyl and superoxide radical. The hydroxyl radical is very reactive and can
modify nitrogenous bases of DNA leading to DNA strand breakage. These ROS,
particularly superoxide radical, gets protonated to form perhydroxyl radical.
This radical plays a significant role in lipid peroxidation and membrane
et al., 2011). These reactive species also reacts
with nitric oxide (NO) forming peroxynitrite ion (ONOO) and exerting
deleterious effect on DNA, protein and lipid molecule (Koca
et al., 2005; Wolf et al., 2003). Peroxisome is
also a source of hydrogen peroxide but catalase present in this organelle
decomposes it into water and oxygen creating a fine balance at physiological
3: Flow chart depicting CYP mediated ROS generation and transcriptional
repression of CYP
7. GENERATION OF OXIDATIVE STRESS BY DRUG METABOLITES
of the drugs and xenobiotics, to which human beings are exposed, generate
quinone metabolites. Quinones are involved in electron transport.
Quinone-quinol cycle leads to oxidative stress leading to devastating effect.
Many drugs are converted to quinone metabolites during biotransformation (Deavall
et al., 2012). These quinone metabolites are
reactive molecular species which forms adducts with macromolecules,
anti-oxidant molecules like GSH and deplete the pool of antioxidant molecule
like GSH thereby generating more ROS (Fig. 4). Excessive ROS generation and
sequestration of endogenous antioxidant species lead to oxidative stress. Prolonged
persistence of cellular stress causes sustained activation of stress responsive
MAPKs ultimately manifesting into cell death (Schiffer
et al., 2018).
Fig. 4: Flow chart depicting mechanism of drug
metabolism induced cellular stress
3- Oxidative stress producing drug metabolites
Drug of SERM is a well-known anticancer agent, undergoes
hydroxylation to 4-Hydroxytamoxifen catalyzed by CYP2D6. This
4-Hydroxytamoxifen gets oxidized via P450 mediated oxidation to para-quinone
methide that forms stable adducts with nitrogen bases of DNA.
(Garg et al., 2016; Bhise et al., 2017)
This is a
frequently prescribed antipsychotic drug, oxidative bioactivation of this
drug by CYP450 families generates reactive nitrite ion, clozapine-N-oxide.
These reactive intermediates generated during metabolism, cause ROS formation
and impose oxidative stress.
2005; Microglial et al., 2011)
Berberine is the most abundant protoberberine alkaloid. CYP
enzymes, namely CYP2D6, CYP1A2 and CYP3A4, contribute to oxidative metabolism
of this alkaloid and play a major role in the generation of berberine
metabolites like demethyleneberberine, thalifendine.
(Park et al., 2015)
is a widely used anticancer drug. It can also generate free radical formation
which generates oxidative stress in cancer cell. The cycling process between
quinone and semiquinone forms generates a huge amount of superoxide radical
(O2-). This in turn produces a variety of active ROS/RNS species,
including H2O2, •OH, and ONOO-.
(Kim et al., 2006; Cappetta et al., 2017)
This is the most popularly used 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase inhibitor. The oxidative metabolism of
atorvastatin and generation of reactive metabolites must be considered for a
reliable prediction of drug disposition.
(Najah et al., 2008; Wassmann et al., 2002)
follicle comprises of the epithelium of keratinocytes and a group of specified
mesenchymal cells called dermal papilla. Developmental morphogenesis and
postnatal growth of hair follicles are build-up with characteristic structure
of epithelial-mesenchymal interaction (EMI) of these two groups of cells (Huang
et al., 2017). Elevated levels of prostaglandin D2
(PGD2) have been shown to be present in the bald scalp of androgenic alopecia
(AGA) patients and to functionally inhibit hair growth.
stress was supposed to be one of the important causative agents of androgenic
alopecia, which is characterized by excessive scalp hair thinning. Hence, it
can be suggested that the utilization of antioxidant molecules with some
functional excipients can stop the progression of this disease (Hatem
et al., 2018). Hair loss rarely needs to be
treated. Many people seek treatment for cosmetic reasons, but there is no cure
for alopecia and no universally proven therapy to induce hair growth. Although
there are some drugs useful in alopecia and these include finasteride,
minoxidil, and corticosteroids.
and dutasteride are the drugs available in the market as tablet. A synthetic
type II-5α reductase inhibitor can reduce the conversion of testosterone to DHT
as demonstrated in Fig. 5. If it is taken for over 6 months to 1 year, at a
dose of 1 mg daily, it can improve the hair count and thickness, with enhanced
response. The efficacy of dutasteride 2.5 mg/day was superior to that of
finasteride 5 mg/day (McElwee
and Shapiro, 2012; Kaufman et al., 1998). Finasteride is
reported to exhibit some side effects related to sexual functions. On
continuous oral administration for long term, there can be loss of hairs, which
was gained within 12 months. It is also reported to be less effective on large
bald spots (Guo
et al., 2017; Yu et al., 2006).
5: Mechanism of action of finasteride
was originally employed as antihypertensive therapy and improved the blood circulation
in particular area of hair follicles and has been consequently used as a
topical treatment for hair loss and is available as 2% and 5% solutions.
Minoxidil use is associated with angiogenesis, vasodilation, and enhanced cell
proliferation, probably mediated via potassium channel opening. Minoxidil
produces some side effects when it comes in contact to skin with dermatitis and
a transitory shedding with starting first 4 months of use. It helps to increase
blood flow to hair follicles by dilating the blood vessels via increasing K+
channel (Fig. 6). Hence, it provides more nutrients to the hair follicle and
promotes growth (Kumar
et al., 2018; Sheikh et al., 2015; Bilandi et al., 2017).
6: Mechanism action of minoxidil
act by suppressing immune system. This is useful in androgenic alopecia because
the condition is thought to be caused by the immune system damaging the hair
is used in the treatment of hair loss and stimulation of hair growth. It also
inhibits phosphodiesterase (PDE) that is responsible for degradation of cAMP.
This increases intracellular levels of cAMP and stimulates cellular metabolism.
Furthermore, caffeine causes vasodilation and, thereby, increases blood supply
to the follicles (Ramezani
et al., 2018). Cyclosporin's main effect is to
lower the activity of T-cells;
it does so by calcineurin–phosphatase pathway and preventing the mitochondrial
permeability transition pore from opening (López-Ongil
et al., 1998). Cyclosporin binds to the cytosolic protein cyclophilin (immunophilin)
of lymphocytes, especially of T cells. This
cyclosporin—cyclophilin complex inhibits calcineurin,
normally responsible for activation of transcription of interleukin-2.
In T-cells, activation of the T-cell receptor normally increases intracellular
calcium, which acts via calmodulin to
activate calcineurin. Calcineurin then dephosphorylates the transcription
factor NF-AT (nuclear
factor of activated T-cells), which moves to the T-cell nucleus and increases
the transcription of genes for IL-2 and related cytokines. Cyclosporin, by
preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell
function; it does not affect cytostatic activity
et al., 2002; López-Ongil et al., 1998; Pérez de Hornedo et al., 2007). In case of
sulfasalazine, sulfapyridine splits off in colon by bacterial action and active
compound (5-ASA is active in ulcerative colitis) absorbed systemically and
generation of superoxide radicals and cytokine liberation is suppressed (Kim
et al., 2009; Couto et al., 2010). Methotrexate is
a folate antagonist and is a potent immunosuppressant which markedly depresses
cytokine production and cellular immunity, and has anti-inflammatory property.
Azathioprene is a prodrug and is converted to 6-mercaptopurine (Elelaimy
et al., 2012), that inhibit de novo purine
synthesis and causes DNA damage that inhibit proliferation of T cell (Bhandaru
et al., 2012).
issues related to the hair including reduction in hair production (alopecia)
and decreases in hair coloration (greying) have been focal in human culture since
prehistoric times. Hair has been associated with youth, beauty and health, and
conditions leading to hair loss prove to be a cause of immense psychological
distress. Intake of food supplements and nutraceuticals including vitamins,
minerals, omega fatty acids and antioxidants have been reported to play a vital
role in appropriate hair follicle production as well as in immune cell
function. Oxidative stress is one of the important components that plays a
function in the ageing as well diminution of the hair follicle. ROS are formed
by a large array of endogenous and environmental sources. The body endogenously
generates defensive mechanisms, such as antioxidative enzymes and non-enzymatic
antioxidative chemicals, which protect against free radicals by lowering their concentration
and neutralizing them. On one side the production of free radicals escalates with
age and on the other side the endogenous defense mechanisms are reduced. This
imbalance causes a steady degradation of cellular and molecular structures,
most definitely culminating in the ageing phenotype. The therapeutic utility of
antioxidants in the treatment of androgenic alopecia has been proven
scientifically and expanded in the recent years. This review presents the new
approaches for prevention of oxidative stress-based alopecia.
authors are thankful to the University Institute of Pharmacy, Pandit
Ravishankar Shukla University, Raipur for the infrastructural facilities.
The authors extend special thanks to the Librarian, Pt. Sundarlal Sharma
Library of the University for e-resources available through
UGC-INFLIBNET. This work was supported by Pt. Ravishankar Shukla
University Research Scholarship [797/Fin./Sch./ 2021].
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