Accepted Manuscript

Title: Research and development of Cordyceps in Taiwan

Author: Ching-Peng Chiu Tsong-Long Hwang You Chan

Mohamed El-Shazly Tung-Ying Wu I-Wen Lo Yu-Ming Hsu
Kuei-Hung Lai Ming-Feng Hou Shyng-Shiou Yuan
Fang-Rong Chang Yang-Chang Wu

PII: S2213-4530(16)30041-6
DOI: http://dx.doi.org/doi:10.1016/j.fshw.2016.08.001
Reference: FSHW 91

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Received date: 2-5-2016

Revised date: 24-8-2016
Accepted date: 30-8-2016

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Research and development of Cordyceps in Taiwan

Ching-Peng Chiu a,†, Tsong-Long Hwang b,c,d,†, You Chan e, Mohamed El-Shazly f, Tung-Ying Wu g,
I-Wen Lo a, Yu-Ming Hsu a, Kuei-Hung Lai a, Ming-Feng Hou h, Shyng-Shiou Yuan i, Fang-Rong
Chang a,h,j,k,l,*, Yang-Chang Wu a,g,m,n,o,*

a
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 80708, Taiwan
b
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan
33302, Taiwan
c
Research Center for Industry of Human Ecology and Graduate Institute of Health Industry
Technology, Chang Gung University of Science and Technology, Taoyuan 33302, Taiwan
d
Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan
e
Department of Microbiology and Immunology, and Institute of Microbiology and Immunology,
School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
f
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams
University, Cairo, Egypt
g
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung
40402, Taiwan
h
Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.
i
Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
j
Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung
80424, Taiwan
k
Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 80708,
Taiwan
l
Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung
80708, Taiwan
m
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung
40402, Taiwan
n
School of Pharmacy, College of Pharmacy, China Medical University, Taichung 40402, Taiwan
o
Center of Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan

∗Corresponding author at:

Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University,
Kaohsiung 80708, Taiwan; Tel: +886-7-3121101 ext.2162; Fax: +886-7-3114773; E-mail addresses:
aaronfrc@kmu.edu.tw (F. R. Chang); Chinese Medicine Research and Development Center, China
Medical University Hospital, Taichung 40402, Taiwan; Tel: +886-4-22057153, Fax: +886-4-
22060248; E-mail addresses: yachwu@mail.cmu.edu.tw (Y. C. Wu).

†
These authors contributed equally to this work.
1
Abstract

Cordyceps is treasured entomopathogenic fungi that have been used as antitumor,

immunomodulating, antioxidant, and pro-sexual agent. Cordyceps, also called DongChongXiaCao in
Chinese, Yartsa Gunbu (Tibetan), means winter worm-summer grass. Natural Cordyceps sinensis with
parasitic hosts is difficult to be collected and the recent findings on its potential pharmacological
functions, resulted in skyrocketing prices. Therefore, finding a mass-production method or an
alternative for C. sinensis products is a top-priority task. In this review, we describe current status of
Cordyceps research and its recent developments in Taiwan. The content and pharmacological activities
of four major industrial species of Cordyceps (C. sinensis, C. militaris, C. cicadae and C. sobolifera)
used in Taiwan, were reviewed. Moreover, we highlighted the effect of using different methods of
fermentation and production on the morphology and chemical content of Cordyceps sp. Finally, we
summarized the bottle-necks and challenges facing Cordyceps research as well as we proposed future
road map for Cordyceps industry in Taiwan.

Keywords: Entomopathogenic fungi; Biofunction; Cordyceps sp.; C. sinensis; C. militaris; C. cicadae;

C. sobolifera

1. Introduction

Studies on medicinal mushrooms become a very important topic because of their potent
pharmacological uses and huge global markets. Fungi form the second largest group after insects, and
it is believed that 1.5 million fungi exist in nature [1]. They have attracted researchers from different
disciplines owing to their fascinating nature and capability to survive in hostile environments and the
midst of decay at the harshest layer of the ecosystem [2]. Different mechanisms in producing
secondary metabolites have been developed in various fungi from ancient times till now. To human
beings, these secondary metabolites are not only hazardous materials but also biofunctional agents
which were evolved over centuries with amazing potential in improving health and preventing diseases
[3]. Currently, fungi materials can be obtained from two main sources, natural wild collection as well
as artificial culture mycelium/fruity bodies. Collection of fungi from the wild is difficult and it raises
serious concerns regarding environment sustainability; therefore, most industrial manufacturers and
academic research groups use artificial fermentation technologies to obtain fungi material.
Mushrooms have been used by humans since thousands of years as food, functional food and/or folk
medicine. More than 14,000 species of mushrooms are recognized, and among them, approximately
2000 are identified as edible [4]. Other studies have suggested that many potential anticancer
medicinal mushrooms need to be developed, such as Agaricus, Antrodia, Albatrellus, Calvatia,
Clitocybe, Cordyceps, Flammulina, Fomes, Funlia, Ganoderma, Inocybe, Inonotus, Lactarius,
Phellinus, Pleurotus, Russula, Schizophyllum, Suillus, Trametes and Xerocomus, etc. [5]. The research
evidences from various research groups all over the world demonstrated the beneficial therapeutic

2
effects of mushroom extracts, and thus unarguably makes it a popular research area with mass
attention. Certainly, studying the rare and medicinally active mushroom, Cordyceps sp., is included in
this wave of research.
The entomogenous habit likely arose and spread concomitantly with the diversification of
phytophagous insects that took place during the Cretaceous period [6]. Entomopathogenic fungi
produce a wide range of secondary metabolites during their infection and proliferation in insects [7].
Most entomopathogenic fungi belong to the orders Entomophthorales and Hypocreales. Currently, 51
entomopathogenic fungi genera were identified with over 9000 isolates belonging to different species.
These isolates are important and promising bio-control agents for controlling arthropod pests [8].
Among the entomopathogenic fungi is the caterpillar fungus “DongChongXiaCao”, which is an
important Traditional Chinese Medicine (TCM).
The genus Cordyceps belongs to the Ascomycota, Pyrenomycetes, Hypocreales, Clavicipitaceae.
Cordyceps sp. are interesting macrofungi because of their characteristic parasitic habitat on larvae and
pupae of insects, and even on perfect insects [9]. Many natural Cordyceps sp. are used in traditional
Chinese medicines in China, Japan, Korea, Taiwan and other eastern Asian countries. In 2006, the
imbalance between supply and demand of wild C. sinensis increased the price of the mushroom up to
$32,000/kg justifying its name as “soft gold” in China [10]. Cordyceps capsules in functional foods
reached an average price of $5.8 per gram [11].
Due to collection difficulties, most researchers invested in developing fermentation technologies to
harvest large amounts of biomass for functional foods [12]. Functional foods can offer health benefits
and nutrition especially to an intended population. In developed countries, chronic and age-related
diseases have turned into major causes of death. These kinds of foods, which can protect or delay the
onset of diseases such as cancer, diabetes mellitus, cardiovascular and obesity diseases, become a
necessity rather than luxury [13].
In Taiwan, the origin of functional foods began in 1970 with Taiwan Sugar Corporation, and has
been developing over the last 40 years. People generally use functional foods to improve their stamina
as well as to protect them from diseases. The total global market value of functional food reached 896
billion NTD (approximately 27 billion USD) in 2011 [14]. The most popular functional foods sold in
Taiwan are herbal products, functional drinks, and medicinal mushroom such as Agaricus blazei,
Antrodia cinnamomea, Cordyceps sp., and Ganoderma lucidum. Additionally, dietary supplements
such as multiple vitamins, calcium tablets and glucosamine are widely used [15].
One of the most important features of functional foods economy is its resilience to economic
recession. During 2008-2009 economic collapse, the sales of functional foods did not drop down but
they increased due to high consumers’ satisfaction and loyalty. Taiwanese consumers are interested in
functional foods targeting metabolic, liver, sexual, and bone/joint disorders [15]. In this review, we
focus on the Cordyceos sp. functional foods in Taiwan, including origins, chemistry, and biofunctions.
This review aims to guide researchers for a better utilization of Cordyceos sp. in the development of
new drugs and therapeutics targeting various ailments.

2. Studies on origins, chemistry and biofunctions

3
2.1. Cordyceps sinensis

Cordyceps sinensis (Berk.) Sacc. is an entomopathogenic fungus that has long been used as a
Chinese medicine and tonic foods. The natural C. sinensis herbal product is composed of the fruiting
body and its host larva. This species endophytically parasitizes on dead caterpillars of the moth
Hepilus spp. Spores of C. sinensis geminate inside the caterpillars, filling the caterpillars with hyphae,
and produce a stalked fruiting body [16]. C. sinensis exists in two stages: sexual stage (teleomorph)
and asexual stage (anamorph). Generally, C. sinensis is similar to the sexual stage (teleomorph) with a
caterpillar and fruiting body. In the past few years, due to the high demand on C. sinensis, the
collection of the fungus from its natural habitat has been insufficient, and so culturing C. sinensis as a
conidial form (anamorphic stage) has been used as a substitute for the natural fruiting bodies [17].
However, culturing C. sinensis does not produce a uniform mycelium and the produced anamorphic
type was named Hirsutella sinensis [18]. Genetic analysis of H. sinensis and C. sinensis proved that
both fungi are the same species but H. sinensis is the asexual phase of the C. sinensis.
Many compounds were purified from C. sinensis and their structures were elucidated using different
spectroscopic techniques. The isolated major compounds (Figure 1) were cordycepin (3'-
deoxyadenosine, C10H13N5O3), adenosine (C10H13N5O4), ergosterol (C28H44O), nucleosides and
nucleobases [19–21]. Adenosine containing extract from C. sinensis contributes to the fungus
hypotensive and vasorelaxant activities [22]. In order to explore chemical components and biofunction
of C. sinensis mycelia, the crude extract and partially purified fractions were examined for their
inhibition ability of superoxide anion generation and elastase release. Furthermore, five new
compound, cordysinins A–E were reported [23]. The sterol type compounds are important group in C.
sinensis. Sterols H1-A from C. sinensis were isolated and purified by silica gel column
chromatography and high-performance liquid chromatography. They were found to suppress the active
HMC (human mesangial cell) and alleviate IgAN (Berger’s disease) with clinical and histologic
improvement [24]. The study revealed that the pure compound H1-A may be potentially useful for
treating systemic lupus erythematosus in patients [25]. It was suggested that H1-A might be effective
in the management of autoimmune disorders, apoptosis, and modulation of signal transduction
proteins, Bcl-2 and Bcl-XL [26]. C. sinensis contains a large amount of polysaccharides, which can be
in the range of 3–8% of the total weight and usually comes from the fruiting bodies, the mycelium of
solid fermentation submerged cultures and the broth [27]. Polysaccharides CME-1 exhibited highly
potent antiplatelet activity that might involve in the activation of adenylate cyclase/cyclic AMP and
subsequently the inhibition of intracellular signals such as Akt and MAPK resulting in the inhibition of
platelet activation [28].
The ancient herbal pharmacopoeia (Ben Cao Cong Xin) recorded the activity of the mushroom in
protecting “lung-kidney, resolving phlegm, hemostasis and improve erectile dysfunction”. According
to the theory of TCM, the main effect of C. sinensis is enriching the lung yin and yang, which includes
treating chronic lower back pain, sensitivity to cold, overabundance of mucus and tears, chronic cough
and wheezing, blood in phlegm from consumption of kidney yang (shenyangxu) [27]. C. sinensis also
exhibited antibacterial function, reduced asthma, lowered blood pressure, and strengthened the
heartbeat [27]. As highlighted in relevant citations, most reported bioactivities were

4
immunomodulatory, antiinflammatory, apoptotic (antitumor), and organ protective (lung and kidney)
effects (Table. 1). In most studies, the treatment with C. sinensis water extracts brought
immunomodulatory effect. On the other hand, organic solvent extracts of C. sinensis, containing
nucleosides, sterols, fatty acids, etc., showed apoptotic and organ protective functions.

2.2. Cordyceps militaris

C. militaris (bei-chong-cao, northern worm grass) is a valuable source of a useful natural

components possessing diverse biological activities. Despite some similarities between C. militaris and
C. sinensis they differ in their color and host. The host of C. militaris is Lepidopteran pupa and the
color of its fruiting bodies is yellow or orange, while C. sinensis host is Hepialu larva, and the color of
its fruiting bodies is dark brown. Scientists used electron microscopic tools such as TEM and SEM to
elucidate anamorph-teleomorph relationships of C. militaris [29]. The examination indicated that
providing a distinct taxonomic name for the anamorph of C. militaris was unnecessary for the practical
purposes because this fungus is normally dominant in nature as a teleomorph [30]. The fruiting bodies
of wild C. militaris are extremely expensive because of host specificity and rarity in nature. Also, they
grow extremely slowly, their growth is restricted to specific areas and their sizes are very small.
Consequently, the solid culture of C. militaris takes a long time to provide fruiting bodies. Many
attempts have been made to extract useful substances from the submerged mycelial cultures to be
incorporated in nutraceuticals and functional foods [31]. Therefore, the collection of this fungus in
large and sufficient quantities for the use as a drug remedy and in scientific research is an urgent
priority. Many researchers tuned conditions to culture this fungus, such as culture chemical
components[32], illumination[33], gene expression[34] and traditional culture condition[35]. Batch to
batch variations in fruiting bodies cultured products obtained under optimized conditions can be
monitored by a simple and rapid method using capillary electrophoresis (CE) and high-performance
liquid chromatography (HPLC) [36]. Deep ocean water (DOW) was applied to cultivate C. militaris in
submerged and solid culture, and the effect of DOW on the production of C. militaris fermentative
products was investigated. The results showed that it could significantly increase the production of
cordycepin [37]. In addition, the solid waste medium of C. militaris had been used for the preparation
of cordycepin with high extraction efficiency and minimum solvent usage [38]. The cultured and
amplified fruiting bodies technologies applied to cultivate C. militaris were extremely investigated and
developed. The results of these investigations are summarized in Table 2 showing their different
morphological characteristics.
Different chemical constituents from C. militaris were isolated including polysaccharides, sugars,
cerebroside derivatives, sterols, nucleotides, nucleosides, proteins (cyclic dipeptides and amino acid)
and essential oils. In one report, authors demonstrated the isolation of ten pure compounds from C.
militaris along with the evaluation of their biological activities by determining their effect on free
radical NO and cytokines (TNF-α and IL-12) production [39]. Among the isolated compounds
cordycepin, ergosterol, 3,4-O-isopropylidene-D-mannitol, D-mannitol and ergosterol peroxide showed
the most potent activity through inhibiting inflammatory mediators production and human cancer cell
proliferation. Our group reported the purification of cerebroside, nucleotides and sterols from C.
militaris fruiting bodies [40]. The antiinflammatory activity of the isolated compounds was
5
demonstrated by their inhibitory effect on the accumulation of pro-inflammatory iNOS protein and the
reduction of COX-2 protein expression in LPS-stimulated RAW264.7 cells. This was the first study
reporting the isolation of cerebrosides with antiinflammatory activity from this TCM. Another study
reported the identification of nonvolatile components of C. militaris fruiting bodies and mycelia [41].
The concentrations of the free amino acids in C. militaris fruiting bodies differed from mycelia. In a
descending order, glutamic acid, cysteine, lysine, arginine and tyrosine were the major amino acids in
the fruiting bodies. The order differed in mycelia with tyrosine as the major amino acid followed by
lysine, cysteine and arginine. In general, these previous reports revealed that the chemical content and
biological activities of C. militaris cultured products differed with the culture conditions suggesting
that uniform conditions are essential for stable products profile.
C. sinensis was used more extensively than C. militaris, nevertheless their clinical applications were
similar. A number of valuable biological activities have been collected for C. militaris by several teams
(Table. 3). It was revealed that C. militaris biological activities focused on antitumor, antidiabetic,
antiinflammatory and improving sperm effects. These biological activities are similar to those of C.
sinensis rendering C. militaris as interesting alternative for the expensive and rare C. sinensis.

2.3. Cordyceps cicadae and Cordyceps sobolifera (Chan-hua)

C. cicadae and C. sobolifera are other examples of entomogenous fungi belonging to the family
Clavicipitaceae and the genus Cordyceps. They are considered two treasured traditional Chinese
medicinal mushrooms known as Chan-hua, Sandwhe, and cicadae flower. They are rigorously parasitic
on wingless Cicada nymphs or larva [42,43]. The mushrooms absorb nutrition from larva and become
a clover larva of mycelium. The few fruiting bodies come out from the head, mouth and bottom of the
larva.
An ergosterol proxide, 3β-hydroxy-5,8-epidioxyergosta-6,22-diene (C28H44O3), from the Chan-hua
exhibited suppressant effects on T-cell proliferation, activated by PHA.[44] Cordycepin was also
reported to suppress NF-κB through Akt and p38 inhibition in RAW264.7 macrophage cells. A similar
cordycepin derivative, N6-(2-hydroxyethyl)adenosine, demonstrated antiinflammatory activity by
suppressing TLR4-mediated NF-κB signaling pathways [45]. In one previous report, myriocin,
adenosine, cordycepin, N6-(2-hydroxyethyl) adenosine, ergosterol, ergosterol peroxides, cyclic
heptapeptides and polysaccharides were isolated from Chan-hua [43]. Based on Chan-hua literature,
the mushroom is easy to be cultured and its chemical constituents are similar to those of C. sinensis.
Therefore, it became another interesting alternative for C. sinensis.
The ancient herbal pharmacopoeia (Ben Cao Gang Mu) stated that Chan-hua can be used to treat
“infantile convulsions and morbid night crying of babies, palpitation and malaria”. The compendium
of Materia Medica showed that C. cicadae relieved convulsion, dispelled wind and heat, promoted
eruption and improved eyesight, and removed eye. It also mentioned that C. cicadae was primarily
used in the treatment of infantile convulsions and morbid night crying of babies, palpitation and
malaria [43]. Literature had indicated that the two different species of Cordyceps, C. sobolifera and C.
cicadae, possess similar bioactivity. It is worth noting that three species (C. sinensis, C. sobolifera and
C. cicadae) have a common characteristic in renal protection effects [46]. Three different Cordyceps
sp. were listed in the articles indicating the extent of the possible diversity involved in the biology and
6
activity. According to relevant references, the bioactivities of Chan-hua were described as
antiinflammatory and renal protective effects (Table. 4). In one recent report, the possible health
hazards arising from repeated exposure to submerged mycelial culture of C. cicadae over 90 days was
investigated [47]. In general, Chan-hua possesses multiple pharmacological activities that provide
featured advantages including low toxicity and the availability of inexpensive raw materials from
artificial cultivation.

3. Conclusion

In this review, we selected four species of Cordyceps including C. sinensis, C. militaris, C.

sobolifera and C. cicadae (Chan-hua), which possess potent pharmacological activities and marketing
potential. Literature indicated that these species exhibited potent antitumor, antiinflammatory, lung-
kidney protective effects. Interestingly, the major drive behind the use of these species is to improve
stamina.
Literature reported approximately 500 species of medicinal mushrooms in use. Among the most
important genera are Antrodia, Cordyceps Ganoderma and Phellinus, which are popular in the
Taiwanese markets. Currently, four Cordyceps sp., C. sinensis, C. militaris, C. sobolifera and C.
cicadae (Chan-hua), have been developed as functional foods with profitable economic value. Major
active compounds of Cordyceps sp. were cordycepin and adenosine; however, the rest of potential
compounds need to be further investigated. Recently, we identified cerebrosides as key components
with potent anti-inflammatory activity [40]. So far, nucleosides, sterols, sugars, fatty acids and
polysaccharides were more often to be analyzed as quality markers of Cordyceps. Among nucleosides,
cordycepin and adenosine were considered as important indicators in the chemical profiling of
Cordyceps sp. Furthermore, the Taiwanese traditional Chinese medicine of pharmacopoeia indicated
that adenosine was used in quality control protocols.
Moreover, different morphological or strain materials of Cordyceps genus are worthy of further
development. Studies on Cordyceps sp. should focus on developing this mushroom as functional food
and potential drug. Researchers should adopt regulations, standards, and practices from Western and
Eastern medicine that have proven to be the most valuable in the quest for health benefits.

Acknowledgments
This work was supported by grants from ministry of science and technology of Taiwan (NSC 102-
2628-B-037-003-MY3, MOST 103-2320-B-037-005-MY2, awarded to F.-R.C.). This study is also
supported partially by Kaohsiung Medical University (Aim for the Top Universities Grant, grant No.
KMU-TP104E39, KMU-TP104A26) Ministry of Health and Welfare of Taiwan (MOHW105-TDU-B-
212-134007), and Health and welfare surcharge of tobacco products. This work was supported by
grants from the Ministry of Science and Technology of Taiwan (MOST 105-2911-I-002-302, 103-
2911-I-002-303, 103-2325-B-039-008, 103-2325-B-039-007-CC1, and 102-2320-B-037-012-MY2,
awarded to Y.-C.W.), the National Health Research Institutes (NHRI-EX103-10241BI), and in part by
a grant from the Chinese Medicine Research Center, China Medical University (Ministry of Education,
Aim for the Top University Plan). Chang Gung Memorial Hospital (CMRPD1B0481~3,
CMRPD1D0281~3, and BMRP450 to H-L Hwang)
7
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15
Figure legends
Figure 1. Major chemical structures purified from Cordyceps sinensis. (A)
Cordycepin, (B) Adenosine and (C) Ergosterol.

16
Figure 1.

17
Table legends

Table 1 Biological activities of C. sinensis extracts.

Table 2 Compare different characteristics of C. militaris and C. sinensis.

Table 3 Biological activities of C. militaris extracts.

Table 4 Biological activities of C. sobolifera and C. cicadae (Chan-hua) extracts.

18
Table 1
Biological activities of C. sinensis extracts.
No. Extract or compound Material Source Biological activity Mechanism pathway Reference
1 Bailing capsule C. sinensis mycelium Renal protective Influenced SDF-1α, CXCR4, CXCL12 [48]
2 Extract C. sinensis mycelium Hepatoprotective Reduced AST, TNF-α,NO then increased [49]
IL-10 and SOD
3 Water extract Natural C. sinensis Hepatoprotective N/A [50]
4 Water extract C. sinensis mycelium Induce steroidogenesis Activated PKC [51]
5 Polysaccharide C. sinensis fruiting bodies Anti-tumor (U937) N/A [52]
6 Water extract C. sinensis mycelium Improve fertilization Increased P450 side chain cleavage enzyme, [53]
3β- hydroxysteroid dehydrogenase and
aromatase.
7 Supercritical carbon C. sinensis mycelium Free radical scavenging and apoptotic (Hep N/A [54]
dioxide extract 3B, Hep G2, HT-29 and HCT-116)
8 Supplementation C. sinensis mycelium Improve ergogenic value N/A [55]
9 95% alcohol extract C. sinensis mycelium Antidiabetic N/A [56]
10. Water extract C. sinensis mycelium Antibacterial Increased IFN-γ, IL-12, p35, p40 and TNF- [57]
α, but did not increase IL-1β, IL-6 or IL-8
11. Water extract C. sinensis mycelium Antibacterial Increased IL-12, TNF-γand macrophage [58]
phagocytic activity
12 Methanol extract C. sinensis mycelium Radiation protective N/A [59]
13 Methanol extract C. sinensis fruiting bodies Immunomodulatory Suppressed IL-β, IL-6, TNF-α and IL-8 [60]
14 Water extract C. sinensis mycelium Antiinflammatory Directed dendritic cells driven Th1 response [61]
toward a Th2 response.
15 Water extract C. sinensis mycelium Antiinflammatory N/A [62]
16 Methanol extract C. sinensis fruiting bodies Antiinflammatory and antiproliferative Inhibited NO, TNF-α and IL-12 [63]
17 Water extract C. sinensis powder Immunosuppressant with C. sinensis N/A [64]
19
 18 Freeze-dried powder C. sinensis fruiting bodies Antidiabetic N/A [65]
19 Water extract C. sinensis mycelium Health supplement N/A [66]
20 Fraction of extract (F3) C. sinensis mycelium Increase steroid production N/A [67]
21 Fraction of extract C. sinensis mycelium Stimulate in vivo testosterone production N/A [68]
22 Protein of C. sinensis C. sinensis mycelium Stimulate the cAMP-PKA signal transduction Activated cAMP-orotein kinase A signal [69]
(regulate testosterone production) pathway, but did not activate protein kinase
C
23 Fraction of extract C. sinensis mycelium Stimulate in vivo and in vitro testosterone N/A [70]
secretion.
24 C. sinensis C. sinensis mycelium Affect transcription and translation N/A [71]
25 C. sinensis C. sinensis mycelium Activate PKA and PKC signal to stimulate Activated PKA and PKC signal transduction [72]
steroidogenesis pathway

26 C. sinensis C. sinensis mycelium Affect testosterone production N/A [73]

27 C. sinensis extract C. sinensis mycelium Does not induce StAR protein and/or other N/A [74]
protein expressions to stimulate
steroidogenesis
28 Water extract C. sinensis mycelium Does not induce in vivo corticosterone N/A [75]
production
N/A: Not be mentioned in this article.

20
Table 2
Compare different characteristic of C. militaris and C. sinensis.
Properties Cordyceps militaris Cordyceps sinensis
Type

Stroma Plural Singular

Host Lepidopteran pupa Hepialus larva
Anamorphic Paecilomyces militaris Hirsutella sinensis
Distribute location Northeast of China Southwest of China
Artificial cultured Fruiting body & mycelium Mainly mycelium
Mycelium Color White or yellow White
Fruiting body spores color Yellow or orange Dark brown
Major compound Cordycepin Adenosine

21
Table 3
Biological activities of C. militaris extracts.
No. Extract or compound Material Source Biological activity Mechanism pathway Reference
1 Water extract C. militaris Antidiabetic Reduced the caspase-3 [76]
2 Water extract C. militaris fruiting body Antidiabetic Increased the IRS-1 and GLUT- [77]
4
3 C. militaris C. militaris fruiting body and mycelium Antidiabetic Increased IRS-1, pIRS-1, AKT, [78]
pAKT and GLUT-4
4 Methanol extract C. militaris fruiting body Antiinflammatory and anti-tumor Inhibited NO, TNF-α and IL- [79]
12
5 Water extract C. militaris mycelium Apoptotic (HL-60) N/A [80]
6 Fermentation broth C. militaris mycelium Anti-tumor N/A [81]
7 Fermentation broth C. militaris mycelium Apoptotic (GBM8401) Involved to PI3K/Akt and [82]
MEK1
8 Water extract C. militaris fruiting body Anti-asthma N/A [83]
9 Water extract C. militaris mycelium Anti-oxidative N/A [84]
10. Water extract C. militaris mycelium Hepatoprotective N/A [50]
11. C. militaris supplement C. militaris mycelium Improve hormones and sperm Increased serum testosterone [85]
motility and estradiol-17
12 C. militaris supplement C. militaris mycelium Improve sperm production N/A [86]
13 Fermentation production C. militaris mycelium Improve growth and mineralization N/A [87]
N/A: Not be mentioned in this article.

22
Table 4
Biological activities of C. sobolifera and C. cicadae (Chan-hua) extracts.
No. Extract or compound Material Source Biological activity Mechanism pathway Reference
1 Lipopolysaccharide C. sobolifera mycelium Improvement of renal function N/A [88]
2 Glycoprotein C. sobolifera mycelium Improvement of renal tubule function Increased the TRMP6 and [89]
TRMP7 channels
3 Polysaccharide C. sobolifera mycelium Improvement of renal function N/A [90]
4 Ergosterol peroxide C. cicadae fruiting body Antiinflammatory Suppressed T cell, cyclin E, IL-2, [91]
IL-4, IL-10, IFN-γ, c-Fos, c-Jun
5 N6-(2-Hydroxyethyl)-adensione (HEA) C. cicadae fruiting body Antiinflammatory Suppressed TLR4-mediated NF- [92]
κB signaling pathways
6 Methanol extract C. cicadae fruiting body Immunomodulatory Suppressed IL-2; IFN-γ [93]
N/A: Not be mentioned in this article.

23