A Review of the Bioactive Compound and Medicinal Value of Cordyceps Militaris

Abstract

For centuries, traditional Chinese medicine has relied on medicinal fungi as a panacea for strengthening the immune system and revitalizing the human body based on the belief that fungi have diverse biological functions. Modernly, Cordyceps militaris has also been a source of several bioactive components in pharmacology and medicine, such as cordycepin, ergosterol and polysaccharide. Cordyceps militaris has been the topic of numerous reviews; however, many of them have not focused on the bioactive compound and medicinal value of this fungus. In this mini-review, we compile recent data on, the latest molecular research, its bioactive compounds and medicinal value.

Full text

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A Review of the Bioactive Compound and Medicinal Value of Cordyceps militaris
Abdulhakim Bawadekji*1, Khalil Al Ali 2, Mouhanad Al Ali 3
(Received 12/02/2016; accepted 26/03/2016)
Abstract: For centuries, traditional Chinese medicine has relied on medicinal fungi as a panacea for strengthening the
immune system and revitalizing the human body based on the belief that fungi have diverse biological functions. Modernly,
Cordyceps militaris has also been a source of several bioactive components in pharmacology and medicine, such as
cordycepin, ergosterol and polysaccharide. Cordyceps militaris has been the topic of numerous reviews; however, many of
them have not focused on the bioactive compound and medicinal value of this fungus. In this mini-review, we compile recent
data on, the latest molecular research, its bioactive compounds and medicinal value.
Keywords: Cordyceps militaris, Bioactive compound, Entomopathogenic fungus, Medicinal value.
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   Cordyceps militaris           

    

Cordyceps militaris 

Cordyceps militaris
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Journal of the North for Basic and Applied Sciences (JNBAS)
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
 )
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* Corresponding Author:
(1) Deanship of Scientific Research, Northern
Border University, P.O.Box 1321, Arar 91431,
Kingdom of Saudi Arabia.
DOI: 10.12816/0021378
e-mail: hakimbawadekji@gmail.com & bawadekji@nbu.edu.sa
    
  
(2) Medical Technology Laboratory, College of
Applied Medical Sciences, Taibah University,
P.O.Box 30001, Almadina Almanwra 41411,
Saudi Arabia.
(3) Institut Supérieur de la Santé et des Bioproduits
d‟Angers, Université d‟Angers, 16 Boulevard
Daviers, 49045 Angers Cedex, France.

A Review of the Bioactive Compound and Medicinal Value of Cordyceps militaris.
70
1. INTRODUCTION
For centuries, traditional Chinese medicine has
turned to medicinal fungi as a panacea for
strengthening the immune system and revitalizing
the human body, qualities that have usually been
attributed to their diverse biological activities, the
two most commonly used fungal species being
Cordyceps sinensis and Cordyceps militaris (Liu,
1994; Liang, 2007), of which
C. sinensis is more famous. Many active
compounds found in the two varieties have positive
effects not only on the human immune and
respiratory systems but in the treatment of several
diseases, such as renal, hyperglycemic and hepatic
dysfunctions (Song, Jeon, Yang, Ra, & Sung,
1998; Mizuno, 1999; Yun, Han, Lee, Ko, Lee, Ha,
& Kim, 2003; Choi, Par, Choi, Jun, & Park, 2004;
Yu, Wang, Zhang, Zhou, & Zhou, 2004). Although
C. sinensis and C. militaris have identical
medicinal properties, C. militaris is more easily
cultured (Zheng, Huang, Cao, Xie, & Han, 2011;
Dong, Lei, Ai, & Wang, 2012). It is a great source
of biomedical products (Ng & Wang, 2005) and a
more dependable fungus for extracting bioactive
components, such as cordycepin, ergosterol and
polysaccharides, that are used in pharmacology and
modern medicine (Das, Masuda, Hatashita,
Sakurai, & Sakakibara, 2010; Reis, Barros,
Calhelha, Ćirić, Van Griensven, Soković, &
Ferreira, 2013). Moreover, research has shown that
C. militaris also possesses the ability to infect and
parasitize lepidopteran insects, such as butterflies,
at different stages, infecting their pupae (or larvae),
living and developing there until finally killing and
mummifying them. Thereafter, C. militaris
produces fruiting bodies of 2 to 8 cm in length of
and a width of 0.5 cm (Han, Liu, Cao, & Chen,
2006; Hong, Kang, Kim, Nam, Lee, Choi, Kim,
Kim, Lee, & Humber, 2010).
C. militaris has been the topic of numerous
reviews, many of which have not focused on both
the bioactive compound and medicinal value
aspects of the fungus. Consequently, this mini
review will expand the bibliographic research into
those aspects to focus on the biological activities of
Coryceps militaris, and to reveal the importance of
this entomopathogenic fungus as valuable source
of medicinal compounds. In addition, to highlight
the need for further, molecular research to refine
the taxonomical position of Cordyceps spp. and the
necessity to better understand biochemical
synthetic pathway of its bioactive compounds.
2. TAXONOMY OF Cordyceps militaris
RELATED TO MOLECULAR
RESEARCH
C. militaris
(L.: Fr.)Link classified in the
subphylum Ascomycotina, Clavicipitales and
Clavicipitaceae. In previous studies, the
classification of this fungus based on
morphological characters, such as asci, ascospore
fragmentation, thickened ascus apices, part-spores,
and the arrangement of perithecia (Kobayasi, 1941,
1982; Mains, 1957, 1958). However, since that
system proved difficult to apply and inefficient in
differentiating between any two close species of
fungi, which the research attributed to various
factors, such as the environment and the effects of
diverse ecological habitat conditions on
morphological characters, there have been attempts
to offer alternate classifications using molecular
methods. For instance, Sung, Hywel-Jones, Sung,
Luangsa-ard, Shrestha, & Spatafora, (2007) used
molecular markers to refine the classification of
Clavicipitaceae that utilized seven loci: nuclear
ribosomal small subunits (nrSSU), nuclear
ribosomal large subunits (nrLSU), elongation
factor 1α (tef1), the largest subunits of RNA
polymerase II (rpb1), the second largest subunits
of RNA polymerase II (rpb2), β-tubulin (tub), and
mitochondrial ATP6 (atp6) (ibid). The results
indicated that most of the morphological characters
used in earlier classifications of Cordyceps spp.,
such as the arrangement of perithecia, ascospore
fragmentation, ornamentation, etc., were not
adequate to study phylogenetic relationships; they
did not provide phylogenetic information, whereas,
the pigmentation, texture and shape of the stromata
were principally phylogenetically informative
(ibid).

Journal of the North for Basic and Applied Sciences, Vol. 1, Number (1), Northern Border University, (2016 /1437H.)
71
3. BIOACTIVE COMPOUND AND
MEDICINAL VALUE OF Cordyceps
militaris
3.1. Cordycepin
In recent years, several bioactive compounds have
been extracted and examined. The first, and
primary, bio-active compound extracted was
cordycepin (3-deoxyadenosine), which is a
nucleoside analogue synthesized by C. militaris,
that possesses several pharmaceutical proprieties,
and is widely used in modern medicine (Zongqi,
2002; Tuli, Sandhu, & Sharma, 2014). It has also
been shown that cordycepin (3-deoxyadenosine)
displays antimicrobial, immunomodulatory and
anticancer effects (Ohta, Lee, Hayashi, Fujita,
Park, & Hayashi, 2007; Vitali, Petrelli,
Lambertucci, Prenna, Volpini, & Cristalli, 2012),
and that it is intracellularly transformed into its 5′
mono-, di- and triphosphates, which inhibits the
activities of several enzymes in the purine
biosynthetic pathway (Masuda, Urabe, Sakurai, &
Sakakibara, 2006).
3.2. Ergosterol peroxide
Several previous studies conducted to determine
the effect of ergosterol peroxide (CAS Number:
2061-64-5) extracted from C. militaris
demonstrated that ergosterol peroxide has a
significant activity against gastric cancer cell line
(Kim, Kim, Cai, Nam, Lee, An, Jeong, Yun, Sung,
Lee, & Hyun, 2001). Another also catalogued the
anti-inflammatory, anticancer effects of ergosterol
peroxide, that found that it suppresses
inflammatory responses through the inhibition of
the transcriptional activity of NF-kB and C/EBPb
and the phosphorylation of MAPKs. This study
also confirmed that ergosterol peroxide is one of
the most important antitumor sterols to be
produced by medicinal mushrooms -- although its
molecular mechanism still remains a mystery
(Kobori, Yoshida, Ohnishi-Kameyama, &
Shinmoto, 2007).
3.3. Adenosine
It is well documented in the literature that
adenosine is considered as the main nucleoside in
Cordyceps spp. (Yang, Li, Li, & Wang, 2007b).
Yang, Guan, & Li, (2007a) discovered a large
number of C. militaris adenosines although the
figure is low when compared to that discovered for
C. sinensis (Yang et al., 2007b). Other studies have
also documented that adenosine has an essential
role in the biochemical process and that it
possesses several pharmaceutical properties, such
as anti-inflammatory and anticonvulsant activities,
and that it can also be used to treat chronic heart
failure and, perhaps, even prevent tissue damage
(Ontyd and Schrader, 1984; Katakaze & Hori,
2000).
3.4. Fibrinolytic enzyme
A new bioactive compound similar to subtilisin-
like serine protease was extracted from Korean C.
militaris by Choi, Cha, Park, Kim, Lee, Park, &
Park, (2011), which was a fibrinolytic enzyme that
had a molecular mass of 34 kDa, with a sequence
alignment that indicated that the enzyme shared the
highest (68%) sequence identity with subtilisin
PR1J (Gene bank, CAC95048), that was isolated
from Metarhizium acridum. It is worthy of note
that the N-terminal sequence of the enzyme
contains 15 amino acids, different from those of
fibrinolytic enzymes found in other mushrooms.
Results obtained from research conducted to
investigate the effect of fibrinolytic enzyme
purified from C. militaris, also indicated that the
fibrinolytic enzyme has fibrin binding activity and
that it contributes to fibrin pathway degradation
(Kim, Sapkota, Park, Choi, Kim, Hiep, & Park,
2006; Choi, Par, Choi, Jun, & Park, 2011).
3.5. Xanthophylls
Recently, studies have reported that C. militaris
fruit-bodies contain essential bioactive
components. Research has also documented that
Cordyceps carotenoids are considered as some of
the most important active components present in C.

A Review of the Bioactive Compound and Medicinal Value of Cordyceps militaris.
72
militaris fruit-bodies (Dong, Wang, Ai, Yao, Sun,
Lei, & Wang, 2013).
Substantial research has also been conducted to
study the Cordyceps carotenoids that are isolated
from C. militaris fruit-bodies. For example, Dong
et al. (2013) identified and classified four new
xanthophylls: cordyxanthin-I, cordyxanthin-II,
cordyxanthin-III and cordyxanthin-IV, although
the chemical compositions and pharmaceutical
properties of these carotenoids are still to be
determined
3.6. Polysaccharides
Studies have reported that polysaccharide extracted
from the fruiting bodies of C. militaris has an
important medicinal value. Ohta et al. (2007)
isolated an acidic polysaccharide (APS) that
consisted of D-galactose (CAS number: 59-23-4),
L-arabinose (CAS number: 5328-37-0), L-
rhamnose (CAS number: 3615-41-6), D-xylose
(CAS number: 58-86-6) and D-galacturonic acid
(CAS number: 6556-12-3). In their study, Ohta et
al. (2007) examined the effect of acidic
polysaccharide (APS) on mice infected with the
influenza A virus. Interestingly, the results
demonstrated that when the polysaccharide was
administered, the virus titers decreased in the mice
and their survival rate increased. Moreover, the
study indicated that acidic polysaccharide (APS)
increased TNF-alpha and IFN-gamma levels in the
treated mice while also enhancing nitric oxide
(NO) production. Furthermore, the study also
noted that there was an induction of iNOS mRNA
and protein expressions in RAW 264.7 murine
macrophage cells. The study concluded that its
results proved that APS had anti-viral effects on
the influenza A virus through the modulation of the
immune function of macrophages (Ohta et al.,
2007).
In a subsequent, it was discovered that
polysaccharide (cordlan) extracted from C.
militaris has an antitumor activity (Kim, Kim,
Kang, Kim, Kim, Hong, Lee, Hong, Kim, & Han,
2010). The study examined the effects of
polysaccharide (cordlan) on the defect of dendritic
cells (DC), and established that polysaccharide
(cordlan) increased allogenic T cell stimulation but
that it decreased endocytosis. The study further
indicated that cordlan increased the
phosphorylation of the main signaling molecules
down-stream from TLR4. The study concluded that
its results demonstrated that cordlan induces DC
maturation via TLR4 signaling pathways (Kim et
al., 2010). In a corresponding study (Li, Li, Li,
Douz, & Gao, 2010), to examine the effects of
polysaccharides isolated from cultivated fruiting
bodies of C. militaris (CMP), it was observed that
CMP can inhibit mitochondrial injury and
mitochondrial swelling through scavenging
reactive oxygen species (ROS) and increasing anti-
oxidase activities, which the study concluded
indicated that CMP has both anti-aging activity and
pharmaceutical properties.
The investigation of Lin, Liu, Wu, Pang, Jia, Fan,
Jia, & Jia (2012) on the antioxidant effect of the
exopolysaccharide (EPS) isolated C. militaris SU5-
08, (which had been extracted from a strain of C.
militaris SU5), revealed that the EPS of C.
militaris SU5-08 had an antioxidant activity that
reinforced adaptive immune responses.
3.7. Antibacterial effect of Cordyceps militaris
Research recently undertaken to evaluate the
antibacterial activity of C. militaris against human
bacteria includes one in Korea to investigate the
antibacterial effect of the fungus on nine human
intestinal bacteria (Che, 2003). The results
indicated that the liquid culture of
C. militaris has growth-inhibiting activity against
several bacteria, such as Clostridium perfringens
and Clostridium paraputrificum, which the
research attributed to an active compound present
in the liquid culture of C. militaris, that the
research identified as cordycepin (3„-
deoxyadenosine). It is noteworthy from the study
that cordycepin did not reveal any adverse effects
against Bifidobacterium bifidum, Bifidobacterium
longum, Bifidobacterium breve, Bifidobacterium
adolescentis, Lactobacillus casei, or Lactobacillus
acidophilus. This outcome suggests that C.
militaris has at least one pharmacological action;
moreover, that cordycepin could be a valuable
antibacterial agent against various diseases caused
by Clostridium spp. (Ahn, Park, Lee, Shin, & Choi,
2000).

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3.8. Effect of Cordyceps militaris on fertility
C. militaris is prevalently used in traditional
medicine to improve sperm production and
enhance sexual activity; but no evidence to
corroborate the effects on humans. However, a
study on boars by Lin, Tsai, Chen, Hou, Hung, Li,
& Jeng (2007) conducted in Taiwan had surprising
results. Two groups of boars, one fed on a normal
diet (control group) and another on a C. militaris
mycelium supplemented diet (treated group).The
results revealed that sperm production was
considerably enhanced in the treated group;
moreover that sperm motility and morphology
were also significantly enhanced in the group.
3.9. Uses and health benefits of Cordyceps
militaris
C. militaris is widely used as food in Southeast
Asia, especially in China, Taiwan and Hong Kong
(Li, Guan, & Li, 2015). The fruiting bodies of C.
militaris are used to make traditional foods and
drinks, such as stewed chicken, duck, tea, and a lot
of other traditional staples (ibid). The fruiting
bodies are considered safe when consumed at less
than 2.5 g/kg of body weight. Li et al., 2015
examined the effects of cooking on the C. militaris
compounds, adenosine and cordycepin, and found
that the former compound decreased dramatically
when the fungus is steamed while the later
remained relatively stable.
Nowadays, the health benefits of the fruiting
bodies and mycelia of C. militaris are found in
pharmaceutical products and drugs. Cultures of C.
militaris have showed interesting properties, such
as utility in producing drugs for various diseases,
example, chronic bronchitis, kidney ailments and
pulmonary diseases, etc. (Dai, Fan, Wu, Xiao, &
Tian, 2007; Wang & Yang, 2006). Over 30
varieties of pharmaceutical products are now
available commercially (Huang, Lin, & Chen,
2010).
4. DISCUSSION
Some researchers have discovered that the
chemical components of the wild C. militaris and
the cultured C. militaris are similar (Tong, Kuang,
Wu, Zhang, & Ren, 1997; Jiang & Sun, 1999;
Wang, Lee, Chen, Yu, & Duh, 2012). For many
years, solid cultures were used to produce
industrial enzymes (Marques de Souza, Zilly, &
Peralta, 2002; Fenice, Giovannozzi, Federici, &
D‟Annibale, 2003) and nutrient enriched feeds
(Aguilar, Aguilera-Carbo, Robledo, Ventura,
Belmares, Martinez, Rodriguez-Herrara, &
Contreras, 2008; Vintila, Dragomirescu, Jurcoane,
Vintila, Caprita, & Maniu, 2009; Soltani, Al-Ali,
Othman, Malik, Elmarzugi, Aziz, & Al Enshasy,
2015). However, the process was found to be more
cost-effective than liquid and two-stage cultures.
At present, due to various reasons, such as host
specificity and scarcity, the fruiting bodies and
mycelia of wild C. militaris are expensive to
obtain. Consequently, current attempts to find and
develop alternative methods to extract its bioactive
components involve artificial cultivation, that
involves solid, liquid (including submerged and
surface liquid), and two-stage cultures (Junjun,
2007). Many researchers produce the fruit-body of
the fungus in vitro; some successfully grow C.
militaris and obtain fruiting bodies on brown rice
medium (Sung, Choi, Lee, Kim, Kim, & Sung,
1999; Sung, Choi, Shrestha, & Park, 2002). Other
scientists have also developed methods to
successfully grow fruiting bodies on insect pupae
(Harada, Akiyama, Yamamoto, & Shirota, 1995;
Sato & Shimazu, 2002). However, although solid
culture is cost-effective and appears to be a
promising culture technology, it takes considerable
time to yield fruiting bodies; the quality of the final
product is also not easy to manage, and solid
culture is not appropriate for large-scale industrial
production (Dong, 2013).
In recent years also, the liquid culture of
C. militaris has been widely studied to enhance the
production of valuable metabolites. This method
has many advantages, the main ones being those of
producing a high quantity of mycelia in a short
time and the reduction in the risk of contamination
(Hsieh, Tsai, & Shih, 2007; Kim, Hwang, Park,
Cho, Song, & Yun, 2002; Park, Kim, Hwang, &
Yun, 2004).

A Review of the Bioactive Compound and Medicinal Value of Cordyceps militaris.
74
A substantial amount of research has also been
conducted to shed light on the genetic and
molecular biology of C. militaris. Scientists have
identified several genes involved in the formation
of fruiting bodies, which is significant in
improving the production of bioactive compound
(Tuli et al., 2014). In order to enhance the
production of this valuable compound, scientists
have successfully obtained a C. militaris mutant
using different techniques, such as ion beam
irradiation (Das et al., 2010).
To our knowledge, there has been no report of any
toxicity in humans, and a recent study also
indicated that C. militaris can be used as a fresh
health food (Zhu, Pan, Yang, & Zhou, 2015).
5. CONCLUSION
As mentioned previously, the research paper study
has shown that the biological activities of the
Cordyceps militaris fungus are valuable sources of
medicinal compounds; however, further molecular
research is necessary to refine the taxonomical
position of Cordyceps spp. and in order to improve
the production of the medicinal compounds and
facilitate a better understanding of their
biochemical synthetic pathway.
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