The health benefits of Cordyceps militaris - A review

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INTRODUCTION
Edible mushrooms are widely used for their high nutritional
and therapeutic value as a functional food. Additionally, they
have been highly appreciated for their medicinal and
therapeutic applications (Chang and Miles, 2004). Medicinal
mushrooms produce a vast diversity of bioactive compounds
such as polysaccharides, proteoglucans, terpenoids, phenolic
compounds, steroids, and lectins. These compounds have a
wide range of therapeutic effects and can act as immuno-
modulatory, anticarcinogenic, antiviral, antioxidant, and anti-
inflammatory agents (Badalyan, 2012; Villares et al., 2012).
Cordyceps is a highly valued fungus in this regard which
thrives at altitudes above 3,800 meters above MSL, in the
cold, grassy, alpine meadows on the mountainous Himalayan
plateau (Alessandro and Francesca, 2009; Sharma et al.,
2015a,b;2016). Because of the difficulties involved in
harvesting, it has been expensively priced. Despite its cost
and rarity, the unprecedented medicinal applications of
Cordyceps has made it a highly valued staple component of
the traditional Chinese and Tibetan medicine. This review
gives a general overview of the modern progress in C.
militaris research, with regard to evaluation of the active
chemical components, the pharmacological effects and the
research and development of products in recent years. C.
militaris is a parasitic fungus on Lepidoptera larvae which
has been used as a traditional medicine in China. It is well
known for its nucleoside, cordycepin (3'-de-oxyadenosine)
and its derivatives, ergosterol, polysaccharides, glycoprotein
an d pe p tides cont a i ning α-am i n oisobu t y ric acid.
Polysaccharides and cordycepin present in C militaris
account for the anti-inflammatory antioxidant, anti-tumor,
anti-metastatic, immunomodulatory (Das et al., 2010),
hypoglycaemic, steroidogenic and hypolipidaemic effects
(Wang et al., 2014). Its biological activity includes anti-
t u mo ur ( L ee e t a l . , 20 15 ) , a nt i -m e ta st a ti c,
immunomodulatory, antioxidant (Ma et al., 2012), anti-
inflammatory, insecticidal, antimicrobial, hypolipidaemic
(Mizuno et al., 1999), hypoglycaemic (Ma et al., 2015), anti-
ageing, neuroprotective, and renoprotective properties (Patel
et al., 2013).
1. INHIBITION OF CELL PROLIFERATION
Cancer is one of the leading causes of death, still needing an
effective medicine for its remedy. Cordycepin from C.
mi l itaris ha s pl a y ed an evoluti o nary c h a nge in
pharmacognosy, leading to establish as a viable base for the
treatment of emerging diseases like cancer, SARS, AIDS and
Swine flu. Electrophoresis analysis (SDS PAGE) and gel
filtration showed strong inhibition of the viability of human
cancer cells such as MCF-7 cells with an IC50 of 15.0
uM,5637 cells with an IC50 of 9.30 uM, A-549 cells with an
IC50 of 8.10 uM (Park et al., 2009). Zhang et al., (2010)
reported that MCMP strain (a water soluble polysaccharide)
isolated from mycelium induces anti-tumor activity after 48
hr incubation against Hep-G2 cells, Hela cells, and mesangial
cells. Wong et al. (2011) purified a protease known as
Cordymin from C. militaris which showed anti-proliferative
activity towards breast cancer cells (MCF-7). It is important
to understand that C. militaris, inhibits cell proliferation in
tumor cells in order to develop it as a new agent for the
prevention and treatment of cancer. The A3 adenosine
receptor (A AR) is a member of the AR family, it has utility in
3
the treatment of cancer. It is reported to be over expressed in
cancer and inflammatory cells, as compared to normal cells
where expression is low (Wong et al., 2011).
2. THROMBOLYTIC ACTIVITY
Thromboembolic disorders such as pulmonary emboli, deep
vein thrombosis, strokes and heart attacks are the main causes
of morbidity and mortality in developed countries (Dickneite
et al., 1995). Current clinical thrombolytic agents are reported
to be plasminogen activators that convert the proenzyme
plasminogen to the active enzyme plasmin, which degrades
fibrin (Collen and Lijnen, 2005). New thrombolytic agents
are developed for fibrin-specific property, acting on the
surface of thrombus that avoids excessive induction of
systemic fibrinolytic system. These agents are reported to
reduce bleeding tendency induced by tissue type plasminogen
activator (t-PA), single- chain urokinase-type PA (scu-PA)
and staphylokinase (Ueshima and Matsuo, 2006). Kim et al.
(2006) extracted and purified an enzyme which showed
fibrinolytic activity from C. militaris, this enzyme has been
reported to result in rapid hydrolysis of the fibrin alpha chain
followed by the gamma-gamma chains, and the reaction is
2+ 2+
enhanced by Ca and Mg ions. It was concluded that this
enzyme exhibited a high specificity for the chymotrypsin
substrate S-2586 indicating it to be a chymotrypsin like serine
protease which has a fibrin binding activity which allows for
local activation of the fibrin degradation pathway. Patel and
Ingalhalli (2013) also witnessed the fibrin binding activity
KAVAKA 48(1):27-32 (2017)
The health benefits of Cordyceps militaris - a review
Aarti Mehra, Kamal U.Zaidi*, Abin Mani and Vijay Thawani
Biotechnology Pharmacology Laboratory, Center for Scientific Research and Development, People's University, Bhopal-462037, India
*Corresponding author Email: zaidi.kamal92@gmail.com
(Submitted in November, 2016; Accepted on June 22, 2017)
ABSTRACT
Cordyceps militaris, a macro fungus is medicinally important for having potential therapeutic applications. Its medicinal properties are due to
variety of therapeutically important constituents including cordycepin, cordymin, ergosterol, glycoprotein, polysaccharides, as a part of its
composition. This review focuses on the pharmacological properties of Cordyceps militaris explored by different workers from time to time.
Key words: Cordyceps militaris, Bioactive compound, Cancer, Cordymin, Polysaccharides

from the fibrinolytic enyme isolated from C. militaris which
allowed the fibrin degradation pathway, which might be used
in thrombolytic therapy. This property provides an alternative
to the other costly fibrinolytic enzymes which are used in
humans' age related heart diseases.
3. ANTI-OXIDATIVE PROPERTY
Mushrooms accumulate a variety of secondary metabolites,
including phenolic compounds, polyketides, terpenes and
steroids. Among the antioxidant compounds, polyphenols
have gained importance due to their large array of biological
actions that include free radical scavenging, metal chelation,
enzyme modulation activities and inhibition of LDL
oxidation, among others (Rodrigo and Bosco, 2006). Li and
Xu (1997) explained the anti-oxidant property of fruiting
bodies of C. militaris cultivated artificially under optimized
conditions. The effects of C. militaris on the activities of
catalase (CAT), surperoxide dismutase (SOD), glutathione
peroxidase (GPx) and anti-hydroxyl radicals when assayed
in vivo. It has been documented to show that C. militaris could
2
inhibit mitochondrial injury and swelling induced by Fe (+)-
L-Cysteine in a concentration dependent manner along with
a significant superoxide anion scavenging effect. Moreover,
the activities of CAT, SOD, GPx and anti-hydroxyl radicals in
mice liver have been documented to increase significantly by
C. militaris. These results indicated that C.militaris protected
mitochondria by scavenging reactive oxygen species
inhibiting mitochondrial swelling, and increasing the activity
of antioxidases. C. militaris have been reported to have
pharmaceutical value for mitochondrial protection and anti-
aging. Dong et al. (2010) showed that the extract of C.
militaris possessed anti-oxidative property with capability to
normalize superoxide dismutase and glutathione peroxide
level.
4. ANTI-INFLAMMATORY PROPERTY
Inflammations represent a complex set of interactions among
soluble factors and cells that can arise in any tissue in
response to trauma, infections, or postischaemic, toxic, or
autoimmune injury (Nathan, 2002). In normal cases, the
body's response to inflammation has been reported to be self-
limiting through the down regulation of proinflammatory
protein expression, the increased expression of anti-
inflammatory proteins, and a reversal in the vascular changes
that facilitated the initial immune cell recruitment process
(Cook et al., 2005). This beneficial host response to foreign
challenge or tissue injury has been reported to result in the
restoration of normal tissue structure and function. Wol et al.
(2010) showed the anti-inflammatory effects of hot water
extract of C. militaris in traditional herbals, and the effect on
the production of NO, IL-6, TNF and LPS stimulated RAW
264.7 cells and concluded that hot extract of C. militaris
inhibited t he production o f macrop hag es derived
inflammatory mediators in a dose dependent manner. Fung
and Ko (2012) concluded that C. mililtaris extract
(p o l y s accharid e ) and cord y c e p in ex h ibited a n t i -
inflammatory effects in the in-vitro and in-vivo models of
inflammation (mice), possibly through suppression of
humoral immunity. It has also been reported that by
decreasing the level of pro- inflammatory cytokine mediator
(TNF-alpha) with the help of C. militaris extract, there is a
suppression in intestinal inflammation in an acute colitis
mouse model. When various concentrations of hot C.
militaris were examined, the fall was seen in LPS-induced
production, TNF-alpha, NO and IL-6 secretion, which
showed the potential inhibitory effect on the production of
inflammatory mediators (Patel and Ingalhalli, 2013). In
addition to the bioactive compounds, anti-inflammatory
peptides of different molecular weights have also been
isolated from mushrooms. Cordymin, a low molecular weight
peptide (10,906 Da), has been purified from C. militaris
(Wong et al., 2011). This peptide has been evaluated to
significantly inhibit the infiltration of poly morphonuclear
cells and IR-induced upregulation of C3 protein produced in
the brain, interleukin- 1β, and tumour necrosis factor-α,
which had a neuro protective effect on the ischemic brain, due
to the inhibition of inflammation.
5. ANTI- MICROBIAL AGENT
The development of antibiotics has been one of the most
important scientific achievements of the last seventy years.
These compounds are reported to act in several ways, by
interfering in metabolic processes or in the organism
structures (Fuchs, 2004). The mechanism of action is mostly
related with interferences in the synthesis of the cell wall,
modification of plasmatic membrane permeability,
interferences in chromosome replication, or in protein
synthesis(Tenover, 2006). Park et al. (2009) showed that the
C. militaris protease extract inhibited the growth of Fusarium
oxysporum in a controlled concentration manner. The purified
cytotoxic antifungal protease form C.militaris fruiting bodies
has been documented to show strong antifungal effect against
Fusarium oxysporum, Bipolaris maydis, Mycosphaerella
arachidicola, Rhizoctonia solani and Candida albicans
(Wong et al., 2011). Patel and Ingalhalli (2013) suggested that
an acidic polysaccharide from C. militaris showed
therapeutic effects against influenza virus infection when
grown on germinated soybeans. Wong et al. (2011) reported
that cordymin, a protease extracted from C. militaris also
inhibited HIV-1 reverse transcriptase.
6. FERTILITY ENHANCER
Infertility is a common problem, affecting many peoples, the
majority of whom now seek medical care (Glazener et al.,
1987). The use of herbal extracts as fertility enhancer in
animals is now on the rise because of the shifting of attention
from synthetic drugs to natural herbal products (Dada and
Ajilore, 2009). Chang et al. (2008) explained the effect of role
of cordycepin from C. militaris in increasing the sperm
quality and quantity. The C. militaris supplementation has
been reported to result in an increase of serum cordycepin
concent rat ion whic h simult ane ous ly en han ced the
testosterone and estradiol-17, increasing the percentage of
motile sperm cells. Patel and Ingalhalli (2013) suggested that
cordycepin might be responsible for the increased semen
production and sperm quality in boars. Hong et al. (2011)
documented the stimulatory effect of C. militaris on
testosterone production in male mouse rats. Results
illustrated that changes of the body weight, food and water
intake of the rats were not observed in this study but the
The health benefits of Cordyceps militaris - a review
28

concentration of testosterone in the serum of the rats was
significantly increased by C. militaris (p<0.05). Therefore
fruiting bodies of C. militaris grown on the drone bee medium
can serve as an integrative medicine for the treatment of
reproductive problems caused by insufficient testosterone
levels in human males.
7. ANTI CHOLESTEROL AGENT
Hypercholesterolemia is a major socioeconomic problem in
common individuals as well as health professionals due to the
strong correlation between cardiovascular diseases and lipid
a b n o rm al it ie s ( M o r sy a n d F o ua d, 2 0 08 ). I n
hypercholesterolemia, high levels of low- density lipoprotein
(LDL) cholesterol accumulate in the extracellular sub
endothelial space of arteries which are highly atherogenic
and toxic to vascular cells, leading to atherosclerosis,
hypertension, obesity, diabetes and functional depression in
organs such as the liver, heart and kidneys (Jain et al., 2010).
In human as well as animal studies, administration of
Cordyceps has been associated with reduction in cholesterol
and triglyceride and an increase in the ratio of high density
lipoprotein to LDL cholesterol. Whether the causative
mechanism for this lipid balancing effect is through blood
sugar stabilization, enhancing liver function, or any other as
hitherto unknown cause, remains to be seen (Patel and
Ingalhalli, 2013). This has nurtured research interest in
evaluating traditional remedies and alternative medicines as
potentially efficacious cholesterol- lowering therapies which
have few or no, side- effects.
8. ANTI DIABETIC PROPERTY
Diabetes mellitus (DM) is a chronic metabolic disorder in the
endocrine system resulting from defects of insulin secretion
(type 1), increased cellular resistance to insulin (type 2), or
both. The consequence of this is characterized by an
abnormally high level of blood glucose, also known as
hyperglycemia, that leads to serious damage of the body
organs (Wong et al., 2011).Currently, several DM therapeutic
drugs are available in the market. This includes various oral
antidiabetic agents such as sulfonylureas, biguanides,
glinides, tolbutamide, phenformin, rosiglitazone and
repaglinide. Even though there are many drugs available,
most of them are too toxic and costly and promote negative
effects on the patient. Thus, they fail to alter the course of
diabetic complications. Some of these drugs may potentially
increase the incidence of renal tumors, hepatic injury and
acute hepatitis. (Singh et al., 2008). Currently, most
antidiabetic researches are focused highly on the
development of antihyperglycemic agents that are safe and
free of adverse effects such as nausea, diarrhoea, liver
problems and weight gain. (Malviya et al., 2010). Zhang et
al. (2006) compared the anti-diabetic effects of crude extract
obtained from fruiting bodies and mycelia of many medicinal
fungi including C. militaris, C. sinensis, Omphalia
lapidescens and Tricholoma mongolicum. Dong et al. (2010)
induced a water extract or alcohol extract of Cordyceps
militaris on diabetic Sprague- Dawley rats and concluded that
this extract caused significant reduction in blood glucose
levels by promoting glucose metabolism and strongly
suppressed total cholesterol and triglycerides concentration.
Silva et al. (2012)showed the anti- diabetic effect of various
fractions of C. militaris in streptozotocin induced diabetic
mice which exhibited reduced blood glucose levels. They
concluded that water extract of C. militaris contained a
compound that acted as an insulin sensitizer (insulin
resistance and improved insulin secretion in type II diabetic
rats). Patel and Ingalhalli (2013) suggested that cordycepin
extracted from C. militaris suppressed expression of diabetes
regulating genes through the inactivation of NF-Kb
dependent inflammatory responses. Diabetes mellitus is
reported to be accompanied by hormonal and neurochemical
changes that can be associated with anxiety and depression. It
has been hypothesized that vanadium complex of vanadium-
enriched C. militaris (VECM), is beneficial in preventing
depression in diabetes, and influences the action of insulin,
and mimic further favourable effects on the level of treatment
satisfaction and mood. C. militaris has been reported to
demonstrate an antidepressant- like activity, which attenuates
the diabetes induced increase in blood glucose concentrations
(Ji et al., 2009).
9. MELANOGENASIS
Melanogenesis is reported to be regulated by three specific
enzymes viz. tyrosinase, tyrosinase-related protein-1 (TRP-
1), and tyrosinase- related protein-2 (TRp-2). Tyrosinase, a
copper- containing glycoprotein, is a key enzyme in melanin
synthesis and a rate-limiting enzyme in this pathway, and can
catalyze three different reactions viz. the hydroxylation of
tyrosine to 3, 4- dihydroxyphenylalanine (DOPA), the
oxidation of DOPA to DOPA-quinone changes to DOPA-
chrome, and then to dihydro- indolizine (DHI) or indole 5,6-
quinone2-carboxylic acid (DHICA) (Lee et al., 2010; Zaidi et
al., 2015 a,b). During this biosynthetic pathway, TRP-1 has
been documented to catalyze the oxidation of DHICA, and
TRP-2 (DOPA chrome tautomerase) catalyzes the conversion
of DOPA-chrome to DHICA (Ando et al., 2007; Zaidi et al,
2014a, b). Additionally, the two enzymes are reported to be
regulated by a specific transcription factor, microphthalmia-
associated transcription factor (MITF) (Shimoda et al., 2010;
Hasegawa, 2010). Cordyceps is traditionally used in Korea,
China and Japan, for the ethno pharmacological treatment of
anti-aging activities from various extracts of Cordyceps
exhibited a wide range of bioactivity in vivo, as well as in vitro
(Ji et al., 2009; Shi et al., 2009; Ko et al., 2010). Chien et al.
(2008) and Ji et al. (2009) reported that Cordyceps spp.
Extract exhibited suppressing effect on the melanin
production by tyrosinase- inhibitory activities. The water
extract of C. militaris has been reported to give 71%
inhibitory activity against tyrosinase, 40% L-DOPA (L-3,4-
dihydroxyphenylalanine) oxidation and over 50% melanin
biosynthesis in B16 mouse melanoma cells (Nam et al.,
2010). Jin et al. (2012) explored the inhibitory effect of
cordycepin on melanogenesis and the relative molecular
mechanisms. It has been documented that cordycepin
inhibited melanin synthesis related enzymes, such as
tyrosinase, tyrosinase related protein-1 (TRP-1) and
tyrosinase related protein -2 (TRP -2. α-MSH and IBMX were
reported as melanin synthesis enhancers. Aramwit et al.
(2014) reported that cordycepin isolated from mycelia of C.
-4
militaris has anti- tyrosinase activity of 13× 10 unity/µl. It
Aarti Mehra, Kamal U.Zaidi, Abin Mani and Vijay Thawani 29

was also shown that, the highest anti tyrosinase activity was
of the cordycepin extracted from the Cordyceps mycelia. The
inhibitory effect of C. militaris on melanogenesis was
attributed to enhancement of tyrosinase degradation.
A tabulated description of health benefits of Cordyceps
militaris are listed in the table (Table 1).
List of Abbreviations used
C. militaris Cordyceps militaris
MSL Mean Sea Level
SDS PAGE Sodium Dodecyl Sulfate Polyacrylamide
Gel Electrophoresis
MCMP Multi-Component Multiphase
AIDS Acquired Immune Deficiency Syndrome
AR Family Adenosine Receptor Family
LDL Low-Density Lipoprotein
CAT Activities of Catalase
SOD Surperoxide Dismutase
GPx Glutathione Peroxidase
NO Nitric Oxide
IL-6 Interleukin-6
LPS Lipopolysaccharide
DM Diabetes Mellitus
NF-kB Nuclear Factor- kB
VECM Vanadium- Enriched C. militaris
L-DOPA L-3, 4- Dihydroxyphenylalanine
TRP-1 Tyrosinase-Related Protein-1
MSH Melanocyte Stimulating Hormones
CONCLUSION
Cordyceps militaris has been widely used since antiquity for
pharmacological purposes like immuno-modulation, anti-
inflammatory, anti-cancer, anti-diabetic, anti-oxidative and
radical scavenging and anti- aging effects. In the recent past
more scientific information about it has become available, to
support these claims. The potency of C. militaris depends
chiefly on its chemical constituents, viz. the cordycepin and
polysaccharides that make up the fruiting body, mycelium or
spores. Its anti-cancer properties have been demonstrated in
various human and murine cancer cell lines. However, the
mechanisms responsible for the anti-cancer effects of C.
militaris on cancer cells remain inconclusive. C. militaris
offers a promising role in cancer prevention and treatment.
However, further experimental, epidemiological and clinical
studies are needed to identify other molecular targets, resolve
the relationships between C. militaris intake and cancer risks,
and explore the optimum dosing, efficacy and safety-alone
and in combination with chemotherapy/ radiotherapy. In
addition to the anti-cancer activity, C. militaris is being used
for the general promotion of health and longevity. The anti-
inflammatory and immune- promoting effects described can
potentially facilitate the treatments of other diseases such as
arthritis, HIV and Crohn's disease. Since this fungi is edible
and thus can be a food additive or supplement will play a key
role in the prevention and cure of various ailments caused by
metabolic disorder or infections.
ACKNOWLEDGMENT
The authors are thankful to People's University, People's
Group, Bhopal, for laboratory facilities, granting financial
assistance to carry out the present research work.
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The health benefits of Cordyceps militaris - a review
30
Disease Fruitbody/Mycelial
Extract
Effect References
Breast Cancer Fruiting bodies and
mycelia
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breast cancer cells (MCF-7)
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Diabeties Fruiting bodies and
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Table 1: Health benefits of Cordyceps militaris

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