Life Sciences 93 (2013) 863–869

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Cordycepin: A bioactive metabolite with therapeutic potential

Hardeep S. Tuli a, Anil K. Sharma a,⁎, Sardul S. Sandhu b, Dharambir Kashyap c
a
Department of Biotechnology, Maharishi Markandeshwar University, Mullana-Ambala 133203, Haryana, India
b
Department of Biological Sciences, R.D. University, Jabalpur 482001, MP, India
c
Department of Histopathology, PGIMER, Chandigarh, Punjab, India

a r t i c l e i n f o a b s t r a c t

Article history: Cytotoxic nucleoside analogues were the first chemotherapeutic agents for cancer treatment. Cordycepin, an
Received 11 July 2013 active ingredient of the insect fungus Cordyceps militaris, is a category of compounds that exhibit significant
Accepted 30 September 2013 therapeutic potential. Cordycepin has many intracellular targets, including nucleic acid (DNA/RNA), apoptosis
and cell cycle, etc. Investigations of the mechanism of anti-cancer drugs have yielded important information
Keywords:
for the design of novel drug targets in order to enhance anti-tumor activity with less toxicity to patients. This
Cordyceps
Metabolite
extensive review covers various molecular aspects of cordycepin interactions with its recognized cellular targets
Cordycepin and proposes the development of novel therapeutic strategies for cancer treatment.
Mechanism © 2013 Elsevier Inc. All rights reserved.
Therapeutic potential

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
Chemistry of cordycepin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
Inhibition of purine biosynthesis, DNA/RNA biosynthesis, and mTOR signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
Induction of apoptosis and cell cycle regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
Anti metastatic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
Anti-platelets aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
Derivatives of cordycepin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
Conclusions and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868

Introduction medicinal mushroom has been found naturally at an altitude of approxi-

The biometabolite cordycepin was first isolated from the fermented
broth of the medicinal mushroom Cordyceps militaris (Cunningham et al.,
1950), which is an entomopathogenic fungus that grows parasitically
on lepidopteron larvae and insect pupae. The genus Cordyceps is well-
known in traditional Chinese medicine and exhibits a variety of clinical
health effects including immunomodulatory, anticancer, antioxidant,
anti-inflammatory and anti-microbial activities (Tuli et al., 2013). This
⁎ Corresponding author at: Department of Biotechnology, M.M.E.C., M.M. University,
Mullana-Ambala 133203, India. Tel.: +91 8059777758; fax: +91 1731274375.
E-mail address: anibiotech18@gmail.com (A.K. Sharma).
mately 14,000 ft in the Himalayan lands including Nepal, China, Tibet
and India (Meena et al., 2010). This mushroom is also known as winter
worm summer grass in China where it is known locally as keeda ghas.
Because of the specific distribution and potent medicinal value of the
fungus, the market price of Cordyceps species is approximately US
$12,000 kg−1 (Paterson, 2008). In addition to cordycepin, Cordyceps
have been known to produce a variety of other pharmacologically active
compounds, such as adenosine, exo-polysaccharides and sterols
(Huang et al., 2009; Xie et al., 2010; Yan et al., 2008; Zhong et al., 2009).
Cordycepin is a type of nucleoside analogue that is structurally
similar to adenosine, except that it lacks a 3′ hydroxyl group, which
increases its potency, and it is known to interfere with a number of

0024-3205/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.lfs.2013.09.030
864 H.S. Tuli et al. / Life Sciences 93 (2013) 863–869
biochemical and molecular processes, such as purine biosynthesis
(Overgaard, 1964; Rottman and Guarino, 1964), DNA/RNA synthesis
(Holbein et al., 2009) and mTOR (mammalian target of rapamycin)
signaling transduction (Wong et al., 2010). In addition to these classical
activities, other molecular targets of cordycepin include apoptosis,
cell cycle arrest, anti-metastasis, inhibition of platelets aggregation
and inflammation mediators' pathways (Fig. 1). However, the cure of
diseases such as cancer still remains elusive despite the availability
of a variety of chemotherapeutics agents that exhibit sophisticated
mechanisms of action. Therefore, in-depth knowledge of nucleoside
analogues, such as cordycepin, is essential not only to understand the
biology behind cancer but also to develop novel therapeutic strategies.
This review describes the variety of molecular mechanisms that
mediate the pharmacological effects of cordycepin and the use and
biological applications of cordycepin-based derivatives.
Chemistry of cordycepin
Cordycepin, or 3′-deoxyadenosine (9-(3-deoxy-β-D-ribofuranosyl)
adenine), is an adenosine analogue (Fig. 2), molecular formula
C10H13N5O3, molecular weight 251.24, alkaline, needle-like or flaky
crystal, melting point 228 °C–231 °C, with a maximum absorption
wavelength of 259.0nm. The structure of cordycepin comprises a purine
(adenine) nucleoside molecule attached to a ribose sugar (ribofuranose)
moiety via a β-N9-glycosidic bond. The chemical synthesis of cordycepin
is achieved mainly through the replacement of the OH group at the
3′ position in the ribofuranosyl moiety with H, generating a deoxy
analogue of adenosine. Cordycepin can behave as a bi, tri or tetra dentate
ligand because of the 5 nitrogen and 3 oxygen atoms through which
it binds with the transition metals.
Inhibition of purine biosynthesis, DNA/RNA biosynthesis, and mTOR
signaling pathway
Once inside the cell, cordycepin is converted into 5′ mono-, di- and
tri-phosphates that inhibit the activity of enzymes, such as ribose-
phosphate pyrophosphokinase and 5-phosphoribosyl-1-pyrophosphate
amidotransferase, which are used in the de novo biosynthesis of purines
(Klenow, 1963; Overgaard, 1964; Rottman and Guarino, 1964). Because
of its similarity with adenosine, cordycepin can participate in various
molecular processes in cells, such as the synthesis of DNA and/or
RNA. During the process of transcription (RNA synthesis), a number of
enzymes cannot distinguish between an adenosine and cordycepin,
which leads to the incorporation of 3′-deoxyadenosine or cordycepin,
Fig. 1. Illustration of the various interactions of cordycepin in biochemical processes, including nucleic acid synthesis, platelet aggregation, metastasis, inflammatory reactions, apoptosis
and cell cycle signaling.
Fig. 2. The chemical structure of the bioactive compound cordycepin produced by
Cordyceps militaris.
in place of the normal nucleoside, preventing further incorporation of
nitrogenous bases (A, U, G, and C), leading to the premature termination
of transcription (Chen et al., 2008; Holbein et al., 2009). Wong et al.
(2010) reported the role of cordycepin in the shortening of the poly-A
tail of mRNA, inhibition of cell attachment and reduction in focal
adhesion. Furthermore, the study suggested that cordycepin may shut
down the mTOR signaling pathway by activating the AMP activated
kinase (AMPK) through an unknown mechanism, which leads to the
inhibition of translation, cell proliferation and growth.
Induction of apoptosis and cell cycle regulation
Apoptosis, also referred to as programmed cell death, is charac-
terized mainly by a series of distinct changes in cell morphology, such
as blebbing, loss of cell attachment, cytoplasmic contraction, DNA
fragmentation and other biochemical changes including the activation
of caspases through extrinsic and/or intrinsic mitochondrial pathways.
Past research has demonstrated the role of cordycepin in the induction
of apoptosis through regulating the expression of various proteins.
This process involves programmed cell death, for example, the Bcl-2
family of proteins has both anti-apoptotic and pro-apoptotic members.
Cordycepin has also been known to induce apoptosis in human colorectal
cancer cell lines (SW480 and SW620) by enhancing the protein ex-
pression levels of JNK, p38 kinase and Bcl-2 pro-apoptotic molecules
(He et al., 2010). Similarly, cordycepin-mediated apoptosis has been
observed in the breast cancer cell line MDA-MB-231 by increasing the
mitochondrial translocation of Bax and the release of cytochrome C,
followed by the activation of caspases-9 and -3 (Choi et al., 2011). The
apoptotic effect of cordycepin has also been investigated in human
 H.S. Tuli et al. / Life Sciences 93 (2013) 863–869
leukemia cells (U937 and THP-1) through the reactive oxygen species
(ROS)-mediated activation of caspases (-3,-8 and -9) and the cleavage
of the poly (ADB-ribose) polymerase protein (Jeong et al., 2011). Baik
et al. (2012) suggested the induction of active caspase-3 and cleavage
of poly (ADB-ribose) polymerase protein (PARP) by cordycepin, leading
to apoptotic cell death in human the neuroblastoma SK-NBE(2)-C (CRL-
2268) and human melanoma SK-Mel-2 (HTB-68) cell lines. Furthermore,
Lee et al. (2012) demonstrated the anti-proliferative effect of cordycepin
in human breast cancer cells through the induction of DNA damage, PARP
cleavage and the phosphorylation of ATM, ATR and histone γH2AX.
In addition to its involvement in apoptotic pathways, cordycepin is
also known to arrest cell cycle at certain check-points. The cell cycle is
regulated by cyclin-dependent kinases (CDKs), and cyclins and cyclin-
dependent kinase inhibitors (CDKIs) in turn, positively and negatively
control the CDKs. Studies of the cell cycle in a human oral squamous
cancer cell line (OEC-MI) demonstrated that cordycepin decreased
the percentage of G1 phase cells in a dose dependent manner, whereas
the percentage of G2M and sub-G1 phase cells was increased (Wu et al.,
2007). Another study reported the anti-cancer activity of cordycepin
in human bladder carcinoma cell lines (5637 and T-24) through
the activation of JNK and cell cycle arrest at G2/M transition via
the inhibition of the cyclin B/CDC-complex and the up-regulation of
P21WAF1 expression (Lee et al., 2009). Similar results were observed
in a study in which colon cancer HCT116 cells were treated with
cordycepin (E.J. Lee et al., 2010; S.J. Lee et al., 201). In 11z human
immortalized epithelial endometriotic cells (Imesch et al., 2011),
cordycepin demonstrated an anti-proliferative effect through the up-
regulation of p21 and the down-regulation of cyclin D1, followed
by the reduced phosphorylation of p38 MAPK and retinoblastoma
protein (pRb). Jung et al. (2012) demonstrated that cordycepin arrests
vascular smooth muscle cell (VSMC) growth at G1 phase by decreasing
cyclin/CDK complexes through the up-regulation of p27KIPI via the Ras/
ERK1 signaling pathway. Therefore, the induction of apoptosis (Fig. 3)
and cell cycle arrest (Fig. 4) comprises of an important mechanism in
many anti-cancer drugs, including cordycepin.
Fig. 3. Schematic representation of the various apoptotic pathways controlled by cordycepin in cancer cells. Cordycepin can induce biochemical changes, including the activation of
caspases through extrinsic and/or intrinsic mitochondrial pathways.
865
The first in vivo study to demonstrate the anticancer properties of
cordycepin was performed in mice and demonstrated that cordycepin
leads to increased survival time in mice bearing the Ehrlich mouse ascites
tumor (Jagger et al., 1961)). Furthermore, a phase 1 clinical trial was
completed (Dec 1997–Mar 2001) using cordycepin and pentostatin to
treat patients with refractory acute lymphocytic or chronic myelogenous
leukemia (NCT00003005). Phase 2 clinical trials are ongoing, and the last
update was in Jan 2009 (NCT00709215). Despite these promising results,
a number of limitations are associated with the application of cordycepin
in clinical settings because it requires the co-administration of ADA
inhibitors, such as cladribine/deoxycoformycin (dcf)/coformycin (cf).
However, research is ongoing to identify a less toxic, synergistic co-
drug for cordycepin that works via mechanisms other than adenosine
deaminase resistance (Janek et al., 2007; Cui et al., 2013).
Anti metastatic activity
The major cause of cancer mortality is the metastasis of the cancer
from the native site to other parts of the body. Metastasis typically
includes the detachment of tumor cells from the primary site, invasion
through the extracellular matrix (ECM), followed by intravasation,
survival and extravasation from the blood vessels and finally, invasion
of the ECM of distant target organs. The ECM is made up of type IV
collagen, laminin, heparan sulfate, proteoglycan, nidogen and fibronectin
(Nakajima et al., 1987). Metalloproteinases (MMPs) have been shown to
play a critical role in the degradation of the ECM. MMPs are a family of
zinc- and calcium-dependent endopeptidases that can be divided into
four subclasses based on their ECM specificity, including collagenases,
gelatinases, stromelysins and matrilysins. Among the MMP family,
MMP-2 and 9 are the two key enzymes known to degrade type IV
collagen, which is an essential component of the basement membrane.
The elevated expression of these MMPs has been functionally corre-
lated with elevated tumor invasion capacity in various cancers, in-
cluding brain, prostrate, bladder and breast cancer (Egeblad and Werb,
2002; Hunter et al., 2008). The activity of MMPs can be regulated by
866 H.S. Tuli et al. / Life Sciences 93 (2013) 863–869

Fig. 4. Cordycepin has been shown to arrest cell cycle, which is regulated by cyclin dependent kinases (CDKs). Cyclins and cyclin-dependent kinase inhibitors (CDKIs), in turns, positively
and negatively control the CDKs. Cordycepin clearly exhibits an anti-proliferative effect through the up-regulation of p21 and p27 and the down-regulation of cyclin D, E and B, followed by
a reduction in retinoblastoma protein (pRb) phosphorylation.

several mechanisms (Woessner, 1991), such as transcription inhibition, Anti-platelets aggregation

pro-enzyme activation or MMP inhibitors, i.e., tissue inhibitors of
metalloproteinases (TIMPs). Cytokines and TPA have been known to
induce MMP-9 synthesis and secretion via the activation of transcription
factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1)
during tumor invasion (Chung et al., 2004; Hong et al., 2005; Woo et al.,
2005). Cordycepin has been known to inhibit MMP expressions levels
(Fig. 5) through the deactivation of AP-1 via the MAPK signaling pathway
(Noh et al., 2010). A study demonstrated that cordycepin blocks TNF-α-
induced MMP-9 expression by decreasing the DNA-binding activity
of transcription factors, such as NF-κB and AP-1 (E.J. Lee et al., 2010;
S.J. Lee et al., 201). Yet another study concluded that the combination
of cisplatin and cordycepin might act as a potent inhibitor of peri-
toneal tumor dissemination and VEGF expression (Cai et al., 2011).
Furthermore, it has been suggested that cordycepin inhibits the migra-
tion and invasion of LNCaP (human prostate carcinoma) cells by down
regulating the activity of TJs (tight junctions) and MMPs, possibly in
association with the suppression of Akt activation (Jeong et al., 2012).
Platelets are known to regulate tumor angiogenesis, growth and
metastasis. Earlier evidence suggested that cancer cells have the ability
to activate platelets, which facilitate their survival in the blood cir-
culation during hematogenous metastasis by preventing tumor cell
lysis by natural killer (NK) cells and cytotoxic lymphocytes (Tsuruo
and Fujita, 2008; Goubran and Burnouf, 2012). A variety of molecular
mechanisms (Fig. 6), such as GPIIb/IIIa, GP Ib-IX-V, P2Y receptors, and
PAR receptors, have been proposed to describe tumor cell-induced
platelet aggregation (TCIPA) (Jackson, 2007; Bambace and Holmes,
2011). Cho et al. (2006, 2007a) reported that cordycepin inhibits
collagen-induced platelet aggregation by lowering [Ca2+]i and throm-
boxane A2 [TXA2] and through the up-regulation of intracellular
levels of cAMP and cGMP. Furthermore, the study demonstrated that
500 μM cordycepin blocked the up-regulation of [Ca2+]i and TXA2 by
74% and 46%, respectively. Another study demonstrated that cordycepin
exerted a potent inhibitory effect on thapsigargin and U46619-elevated

Fig. 5. The inhibitory effect of cordycepin on tumor metastasis through the MAPK signaling pathway. MAPK is known to activate the AP-1 molecule, which in turn positively controls the
expression of matrix metalloproteinases.
 H.S. Tuli et al. / Life Sciences 93 (2013) 863–869
Fig. 6. Schematic representation of cordycepin as an anti-platelet aggregation agent. The figure highlights the molecular mechanisms through which cordycepin inhibits platelet
aggregation molecules, including Ca2+, cAMP, ADP and TXA2.
intracellular Ca2+, which is known to induce a wide variety of ligands
that further facilitate platelet aggregation (Cho et al., 2007b). In addition
to [Ca2+]i and TXA2, cordycepin has been known to reduce the
hematogenic metastasis of cancer cells via the inhibition of adenosine
diphosphate (ADP), which is a potent inducer of platelet aggregation
during TCIPA (Yoshikawa et al., 2009).
Anti-inflammatory activity
It is understood that inflammatory activities are related to cancer
progression. Cancer cells are known to express variety of cytokines,
chemokines and their receptors, which play an important role in
mediating inflammatory responses (Arias et al., 2007; Nelson et al.,
2004; Farrow et al., 2004). Many anti-cancer compounds can also be
used to treat inflammatory diseases (Rayburn et al., 2009). Previous
studies have reported that the expression of cytokines, such as IL-6,
IL-8, G-CSF, IFN-γ, and MIP-1β, is up-regulated in carcinoma (Chavey
et al., 2007; Wang et al., 2009). Therefore, to develop a potent strategy
to tackle and prevent cancer, it is essential to inhibit inflammatory
mediators. Kim et al. (2006) evaluated the anti-inflammatory effect of
cordycepin in LPS-stimulated macrophages by inhibiting nitric oxide
(NO) production. The study suggested that cordycepin downregulates
iNOS, COX-2 and TNF-α gene expression via the suppression of NF-κB
activation and Akt and p38 phosphorylation. Similar studies have
shown that cordycepin significantly attenuated the release of inflam-
matory mediators, such as NO, PGE2, TNF-α, and IL-1β in LPS-induced
microglia cells by inactivating NF-κB through the inhibition of IκB-α
degradation (Jeong et al., 2010). In lipo-polysaccharide-stimulated
macrophages (Shin et al., 2009), cordycepin suppressed the gene
expression of M1 cytokines (IL-1β and TNF-α) and chemokines
(CX3CR1 and RANTES), whereas the expression of M2 cytokines (IL-10,
IL-1ra, TGF-β) was increased. Furthermore, cordycepin has been shown
to increase the expression of the interleukin-10 protein in human
peripheral blood mononuclear cells, which is known to inhibit the
secretion of proinflammatory and inflammatory cytokines (Moore
et al., 1993; Armstrong et al., 1996; Cunha et al., 1992; Mertz et al.,
1994; Dokka et al., 2001; Zhou et al., 2002). Rao et al. (2010)
demonstrated that cordycepin is a potent inhibitor of free radical
867
NO and cytokine (TNF-and IL-12) production. The study suggested
that cordycepin might be useful for the prevention of cancer by acting
as an anti-inflammatory agent. Kim and colleagues demonstrated
in a mouse model that cordycepin blocks acute lung inflammatory
(ALI) responses and the expression of related genes, including adhe-
sion molecules (ICAM and VCAM), cytokines/chemokines and the
chemokine receptor CXCR2. The study suggested that cordycepin blocks
LPS-induced VCAM expression in A549 cells through a remarkable
reduction in p65-NF-kB, which is directly linked to PARP inhibition
(Kim et al., 2011).
Derivatives of cordycepin
The intrinsic resistance of adenosine deaminase (ADA) to cordycepin
has become a serious issue for the scientific community. ADA is an
important enzyme involved in purine metabolism and deaminates
adenosine to the inactive metabolite inosine (Saboury et al., 2002).
Because of the similarity between cordycepin and adenosine, cordycepin
is rapidly metabolized by ADA; therefore, a high therapeutic dose might
be required, which could be therapeutically unacceptable. An approach
to tackle this problem is to generate structurally different derivatives
of cordycepin, which not only enhance the potency but also provide
resistance towards ADA. Researchers have reported the production
of a cordycepin 2-5A (2-5 linked oligoadenylate) analogue, namely
ppp5′(3′dA) 2′p5′- (3′dA)2′p5′(3′dA), in lysed rabbit reticulocytes and
determined the analogue to be a more potent inhibitor of protein
synthesis than the 2-5A trimer triphosphate. It has also been reported
that the “core” of the cordycepin analogue, i.e., (3′dA)2′–5′(3′dA)2′–
5′(3′dA), similar to the core of 2-5A itself, could prevent the trans-
formation of human lymphocytes infected with Epstein–Barr virus
(Doetsch et al., 1981a,b) and could be used to supplement the
treatment of cells with interferon. Sawai et al. (1983) prepared
dicyclohexylcarbodiimide-induced cordycepin 5′-monophosphate and
demonstrated the importance of the 3′-hydroxyl groups in 2-5A for
the activation of the 2-5A-dependent endonuclease. The cordycepin
analogue and its 5′-monophosphate derivative were shown to ex-
hibit pronounced anti-human immunodeficiency virus type 1 activity
in vitro (Muller et al., 1991). Wei et al. (2009) synthesized four
868 H.S. Tuli et al. / Life Sciences 93 (2013) 863–869
N-acyl-cordycepin derivatives containing a normal alkyl chain, which
not only protected its primary amine from rapid oxidation but also
improved its bioavailability and pharmacological activity.
Conclusions and future perspective
Cordyceps are an excellent source of bioactive metabolites that
exhibit many clinically approved benefits for human health. Because
people have an inclination towards natural/herbal therapies, the
use of Cordyceps as a natural medicinal mushroom is inevitable. The
challenge is to understand in depth the key factors influencing the
growth and cultivation of this fungus. Rigorous efforts will be required
to produce this mushroom in enough bulk to obtain sufficient amounts
of bioactive compounds, including cordycepin, from its fruiting bodies
or mycelial extracts. Modern biotechnological tools will be needed to
enhance further the bioactive potential of the metabolite.
Looking at the structure of cordycepin, one can imagine that it has a
strong tendency to form transition metal complexes in the form of di, tri
and tetra dentate ligands; metals can accommodate a donor atom's lone
pair of electrons into their empty d orbital and cordycepin has five N
and three O atoms (Tuli et al., 2013). These complexes can be analyzed
further using modern spectroscopic tools, which in turn may improve
the bioactivity of the compound. Future studies should focus on the
synergistic association of cordycepin with metal-containing anti-cancer
drugs (Cai et al., 2011). Additionally, drug delivery strategies using
nano-particles containing cordycepin are promising tools for assessing
the therapeutic potential of this bio metabolite.
To counter anti-cordycepin resistance, there is a strong need to
generate structurally different derivatives of cordycepin that will
not only enhance the potency but also provide resistance towards
ADA. More sincere efforts will be required to identify most of the
pharmacologically active compounds in Cordyceps and to understand
their structure-function relationship as well to realize the full poten-
tial of this wonderful mushroom for commercialization and ethno-
pharmacological use.
Conflict of interest statement
There are no potential conflicts of interest among the authors regarding the
publication of this manuscript.
Acknowledgments
The authors would like to acknowledge M.M. University Mullana
(Ambala) for providing the requisite facilities to perform this study.
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