See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/24020872

Cordyceps fungi: Natural products, pharmacological functions and

developmental products

Article  in  Journal of Pharmacy and Pharmacology · April 2009

DOI: 10.1211/jpp/61.03.0002 · Source: PubMed

CITATIONS READS

221 4,287

5 authors, including:

Xuanwei Zhou Kexuan Tang

Shanghai Jiao Tong University Shanghai Jiao Tong University
64 PUBLICATIONS   1,572 CITATIONS    434 PUBLICATIONS   8,245 CITATIONS   

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Artemisinin biosynthesis View project

metabolic engineer View project

All content following this page was uploaded by Xuanwei Zhou on 21 May 2014.

The user has requested enhancement of the downloaded file.

 Review Article

JPP 2009, 61: 279–291

ß 2009 The Authors
Received May 14, 2008
Cordyceps fungi: natural products, pharmacological functions
Accepted August 28, 2008
DOI 10.1211/jpp/61.03.0002
and developmental products
ISSN 0022-3573

Xuanwei Zhoua, Zhenghua Gonga, Ying Sua, Juan Linb and

Kexuan Tanga,b
a
Plant Biotechnology Research Center, School of Agriculture and Biology, Shanghai Jiaotong University,
Shanghai and bState Key Laboratory of Genetic Engineering, School of Life Sciences,
Fudan-SJTU-Nottingham Plant Biotechnology R&D Center, Fudan University, Shanghai, P.R. China

Abstract
Objectives Parasitic Cordyceps fungi, such as Cordyceps sinensis, is a parasitic complex
of fungus and caterpillar, which has been used for medicinal purposes for centuries
particularly in China, Japan and other Asian countries. This article gives a general idea
of the latest developments in C. sinensis research, with regard to the active chemical
components, the pharmacological effects and the research and development of products in
recent years.
Key findings The common names for preparations include DongChongXiaCao in Chinese,
winter worm summer grass in English. It has many bioactive components, such as
30-deoxyadenosine, cordycepic acid and Cordyceps polysaccharides. It is commonly used to
replenish the kidney and soothe the lung, and for the treatment of fatigue. It also can be used
to treat conditions such as night sweating, hyposexuality, hyperglycaemia, hyperlipidaemia,
asthenia after severe illness, respiratory disease, renal dysfunction, renal failure, arrhythmias
and other heart disease and liver disease. Because of its rarity and outstanding curative effects,
several mycelia strains have been isolated from natural Cordyceps and manufactured by
fermentation technology, and are commonly sold as health food products. In addition, some
substitutes such as C. militaris and adulterants also have been used; therefore, quality control
of C. sinensis and its products is very important to ensure their safety and efficacy.
Summary Recent research advances in the study of Cordyceps, including Cordyceps
mushrooms, chemical components, pharmacological functions and developmental pro-
ducts, has been reviewed and discussed. Developing trends in the field have also been
appraised.
Keywords chemical components; Cordyceps; development products; pharmacological
functions

Introduction
Cordyceps sinensis (Bark) Sacc. Link (Claviceptaceae) (Ascomycetes) is an insect
parasitizing fungus. The name Cordyceps comes from the Latin words cord and ceps,
meaning ‘club’ and ‘head’, respectively. ‘DongChongXiaCao’ (DCXC), Chinese
caterpillar fungus, is the Chinese name given to the complex of larvae and fungi, which
is found at high altitudes on the Qinghai-Tibetan plateau. This fungus lives primarily on the
head of the larva of one particular species of moth, Hepialus armoricanus, but is also
occasionally found growing on other moth species.[1] It is generally called ‘DCXC’ in
Chinese and ‘Tockukaso’ in Japanese, meaning ‘winter-insect and summer-plant’ because
of the growing process: the fungus first parasitizes the larva of some species Hepiaidae,
Correspondence: Professor forming a parasitic complex that comprises the remains of the caterpillar and the stroma of
Xuanwei Zhou, Plant
the fungus. Because the larvae are infected by fungi in the summer and autumn seasons,
Biotechnology Research Center,
School of Agriculture and and consumed by mycelia and turned into ‘stiff worms’ in winter, they are called ‘winter
Biology, Fudan-SJTU- worms’ (DongChong). In the spring and summer season of the following year, the stroma
Nottingham Plant Biotechnology emerges from the ground, growing from the head of the larva, and is known as ‘summer
R&D Center, Shanghai Jiaotong grass’ (XiaCao).[2,3] C. sinensis is an invigorant in Chinese tradition and was honoured as
University, Shanghai 200240;
P.R. China. E-mail:
one of the three greatest invigorants together with Panax and Pilose antlers. It has a history
xanweizhou@sjtu.edu.cn of hundreds of years in medicine. Its name was first seen from ‘Bei Cao Cong Xin’ written
or xuanweizhou@163.com by Yiluo Wu in the Qing dynasty, 1757 AD and ‘Ben Cao Gang Mu Shi Yi’ written by

279
280 Journal of Pharmacy and Pharmacology 2009; 61: 279–291

Xueming Zhao in 1765 AD. The French mycology scientist be found in China (Zhang, 2003).[9] More than 400 Cordyceps
proved that C. sinensis is a type of Ascomycetes which species have been described worldwide and approximately
parasitizes insect larvae, grows and gradually changes into 90 Cordyceps species are distributed in China;[10] C. militaris
a fruit body.[4] It is the combination of fungus and larva. can be used to replace C. sinensis. A number of macroscopically
However, it is more difficult for authors in the scientific similar species have been described, which are either considered
literature to define a formal name. The preparation has been as being homogeneous with C. militaris, or are simply unnoticed
considered to have healing properties for the body and mind; among large collections from a variety of hosts and life-cycle
DCXC is still revered by some people. The preparation stages.[11–13] Much research into the chemical composition,
does indeed contain certain bioactive ingredients (such as pharmacological efficiency and clinical application of
30-deoxyadenosine, cordycepic acid, cordycepic polysacchar- C. sinensis and its substitutes, such as Hirsutella spp.,
ides) that might be beneficial for the prevention and Paecilomyces spp. and C. militaris, is underway.[4] However,
treatment of a variety of ailments, such as respiratory in therapeutic practice and literature citations, the term
disease, renal dysfunction, hyposexuality and cancers. Many Cordyceps always refers to the species C. sinensis.
of the related biomedical investigations have been conducted In the early 1980s, many scientific institutes began to study
predominantly in China, Japan, Korea and the US, and are the cultivation of C. sinensis. Previous work, over the course of
extensive. a decade, was mainly focused on the anamorphic fungi related
Modern experimental methods in biochemistry have to C. sinensis. Shen Nanying made a success of culturing
proved that C. sinensis consists of active constituents such fruit bodies in 1985. The Sichuan TCM Institute also achieved
as mannitol, nucleosides, ergosterol, aminophenol and trace the artificial cultivation of C. sinensis, although commercial
elements.[5] It has a broad medical effect, and its function of production has not been carried out because of the high cost
immunity regulation plays an important role in antitumour and low stability.[14] Up to now, in fact, the artificial cultivation
effects, organ transplantation and the prevention of kidney, of this valuable fungus has not been successfully achieved;
liver and heart disease.[6,7] The Chinese Pharmacopoeia only a product made using a C. sinensis anamorph has been
(2005) records that the main functions of C. sinensis are made by fermentation methods.[15] Subsequently, production of
replenishing the kidney, soothing the lung, staunching C. sinensis, mostly added to traditional Chinese medicine
bleeding and dispersing phlegm. It can also be used to (TCM) patent prescriptions, has developed rapidly, particularly
treat continuous cough caused by fatigue, asthma, haemo- in China. Nevertheless, only C. militaris, producing
ptysis, impotence, spermatorrhoea and aches in abdomen and 30-deoxyadenosine, has similar pharmacological activity to
knee.[8] Previous studies mostly focused on aspects such as C. sinensis, whose biological characteristics were studied early
the resources of C. sinensis, its active chemical components in the 1950s.[16] Compared with C. sinensis, the artificial
and its pharmacological effects. Recently people have paid cultivation of C. militaris was easier and successfully achieved
more attention to protecting the resource and seeking in the early 1980s.[17] At that time the multi-product batch
substitutes, and they hope to sustainably utilize this precious manufacture had been achieved; now the mycelia may grow in
medical epiphyte. This article gives a general overview of rice (or kernel) medium and produce fruiting bodies. The
the latest developments in C. sinensis research, with regard process of producing C. militaris fruiting bodies is the same as
to the active chemical components, the pharmacological for other cultivated edible mushrooms and can be divided into
effects and the research and development of products in two major stages. The first involves the preparation of the
recent years. fruiting culture, stock culture, mother spawn and planting
spawn, while the second entails the preparation of growth
Related Species and Artificial Cultivation substrates for mushroom cultivation.[18,19] Currently, the
method most widely adopted for commercial production is
C. sinensis is a complex of larva and parasitic fungus. Many the cooked rice in bottle procedure (for cultivation details, see
species in this genus are valuable medicinal fungi with broad Zhang[19], Ren et al.,[20] Wen et al.[21]).
development potential. The parasitic complex of the fungus
and caterpillar, well known as ‘DCXC’, is only found in the
prairie soil at an elevation of 3500–5000 m. It is mostly Natural Products
distributed in Tibet, Qinghai, Sichuan, Yunnan and Gansu
province in China. The fungus and caterpillar complex is According to chemical analysis, C. sinensis contains crude fats,
limited to C. sinensis and Hepialus armoticamus Oberthur, proteins, fibre, carbohydrate, cordycepin, cordycepic acid,
while complexes consisting of other species of fungi and polysaccharide and a series of vitamins, etc. The therapeutic
insects are called ‘ChongCao’, not ‘DCXC’.[9] applications of Cordyceps centered primarily on the key
Cordyceps encompasses several Cordyceps species, which are effects of increased oxygen utilization and ATP production,
widely used for medicinal purpose (e.g., C. liangshanensis and as well the stabilization of blood sugar metabolism.
Zhang, Liu et Hu, C. taishanensis Liu et Cao, C. shanxiensis Liu, Cordycepin, cordycepic acid and the polysaccharides, vitamins
Rong et Jin, C. gansuensis Zhang, Wang et Yan, C. grasspara and trace elements may be, at least partially, the cause of these
Zang, Yang et Li, C. kangdingensis Zang et kingjo, well-known effects.
C. guizhouensis Liu, Liang et Liu, and so on). In addition to
C. militaris, C. nutans Pat. and C. tricentri Yasuda, some species Cordycepin and Cordycepic Acid
such as C. gunnii (Berk.) Berk. and C. Roberts (Hook.) Gray, Although the pharmacologically active components of
which are usually distributed on the Australian mainland, may C. sinensis are still unresolved, at least two chemical
Cordyceps fungi Xuanwei Zhou et al. 281

HO COOH
NH2

N
O

N
N HO OH

HO CH2OH OH

Cordycepin Cordycepic acid

Figure 1 Chemical structure of compounds in Cordyceps sinensis.

constituents, cordycepin and cordycepic acid, have been density is 1.489 (20∞C) and its boiling point is 290–295∞C
identified and proposed as important active constituents.[1,22] (467 kPa). Mannitol, as a functional polyol with notable
It is now believed that cordycepic acid is, in fact, D-mannitol, properties, has been widely used in the medicine and food
and that cordycepin is 30-deoxyadenosine (30-dA), a purine industries. The content of mannitol varies with the original
alkaloid, a derivative of the nucleoside adenosine, differing habitat. In general, there is about 29–85 mg/g in Cordyceps
from the latter by the absence of oxygen in the 30 position of fruiting bodies; the mannitol content in the mycelia of
its ribose part (Figure 1). Early in 1950 cordycepin was first Cordyceps is higher than in fruiting bodies.[33]
isolated from C. militaris and its structural formula was
confirmed as 30-deoxyadenosine.[23,24] Subsequently, by Polysaccharides
means of nuclear magnetic resonance (NMR) and infrared Cordyceps contains a large amount of polysaccharides,
(IR) spectroscopy, cordycepin as a bioactive component was which can be in the range of 3–8% of the total weight,[34,35]
extracted from the fruiting bodies and cultured mycelium of and usually comes from the fruiting bodies, the mycelium
C. sinensis and the configuration elucidated. The molecular of solid fermentation submerged cultures and the broth.
weight of cordycepin, C10H13N5O3, is 251. Its melting point is Cordyceps polysaccharide (CP), one of the main bioactive
230–231∞C, and maximum absorption is at 259 nm. It can be components, represents a class of structurally diverse
dissolved in saline, warm alcohol or methanol, but not in biological macromolecules with wide-ranging physiochem-
benzene, ether or chloroform, so many researchers in ical properties. The anti-tumour and immunomodulating
laboratories used sterilized saline and phosphate-buffered activity of the medicinal mushrooms has already been
saline (PBS) as solvent.[25] In general, the content of 30-dA in brought to scientific and commercial attention.[36,37] Since
the mycelia fermentation preparations (40.8 mg/g)[26] is more 1977, much of scientific investigation in Japan and China has
than that in the fruiting bodies of C. sinensis (< 5.4 mg/g).[27,28] been performed to discover possible functional polysacchar-
Cordycepic acid, an isomer of quinic acid, is one of the ides; many CPs and their components have been isolated and
main active medicinal components. The chemical constituents characterized from wild and cultivated Cordyceps species
of C. sinensis were first studied in 1957, when a crystalline (Table 1).
substance was isolated and the structure was imprecisely CP is a multi-branched galactomannan. Based on activity-
concluded to be 1,3,4,5-tetrahydroxycyclohexane-1-carboxylic guided fractionation, a water-soluble protein-containing
acid.[29] Subsequently, the structure of the crystalline substance galactomannan was isolated from the sodium carbonate
named ‘cordycepic acid’ was identified by Sprecher and extract of Cordyceps, and its molecular weight was estimated
Sprinson[30] as D-mannitol. Mannitol is a major bio-product by gel filtration to be 23 kDa. The isolated compound is
with important biological activity, and exists in the wild in the composed of D-mannose and D-galactose in a molar ratio of
roots, stems and leaves of plants, while more is found in edible 3 : 5, and contains a small proportion of protein. It is a highly
fungus, carrot and lichens. In general, the content of cordycepic branched structure and composed of (1!6)- and (1!2)-linked
acid in DCXC is 7–29%, differing in the various growing stages a-D-mannopyranosyl residues in the main chain.[56] Cai et al.[60]
of the fruiting bodies.[31] It is used not only in injections as developed a method to study the topography of CP by using an
raw material, but also as a supplement in other medicines.[32] atomic force microscope (AFM). The result showed that CP has
Chemically, mannitol is an alcohol and a sugar, or a polyol; it a multi-branched structure and a variety of different linkages
is similar to xylitol and sorbitol. However, mannitol has a between adjacent monosaccharides, which make up the small
tendency to lose hydrogen ions in aqueous solution, which rings and helical structures. However, a neutral mannoglucan
causes the solution to become acidic. For this reason, it is not with a molar mass of approximately 7700 g/mol was obtained
uncommon to add a substance to adjust its pH, such as sodium recently from CP, which consisted of Man and Glc units
bicarbonate. The chemical formula of mannitol is C6H14O6, its in the molar ratio of 1 : 9. Analysis showed that it had an
molecular weight is 182, its melting point is 166∞, its relative alpha-D-glucan backbone with (1!4)- and (1!3) linkages, and
Table 1 Cordyceps polysaccharides and their physical and chemical characteristics
282

No. Name Molecular Glycosyl residue composition Glycosyl linkage and branches (characteristic signals) Source
weight (molar ratio)

1 P70-1 4.2 ¥ 104 Man:Gal:Glc = 3.12:1.45:1.00 P70-1 has a backbone of 1,6-linked a-D-mannopyranosyl residues with branching Fruiting bodies of cultured C. militaris[38]
points at O-3 composed of 1,4-linked a-D-glucopyranosyl and 1,6-linked
b-D-galactopyranosyl residues, and terminated with b-D-galactopyranosyl
residues and a-D-glucopyranosyl residues
2 P70-2 2.6 ¥ 104 Man:Gal:Glc = 1.75:1.31:1.00
3 P50-1 5 ¥ 104 Man:Gal:Glc = 2.80:2.62:1.00
4 SCP-I 1.84 ¥ 105 Glu SCP-I possesses a backbone of 1,4-linked a-D-glucosyl residues and carries Fruit mycelium of C. sinensis[39]
a single (1,6)-linked a-D-glucosyl residue as side chain
a
5 PC I 3.5 ¥ 105 Man:Gal:Glu = 1:0.65:0.30 Mycelia of C. sinensis[40]
a
6 PCA I 5.56 ¥ 105 Man:Gal = 1:1 PCA I possesses a backbone of 1,4-linked mannopyranosyl residues with branches
of O-2, O-3, O-6, etc of mono- or oligosaccharide composed of galactofuranosyl
residues
a
7 PCA II 1.67 ¥ 103 Man:Gal:Glu = 1:0.71:0.42 PCA II possesses 6 pyranosyl or furanosyl monosaccharide consisting
of 3 mannosyl residues, 2 galactosyl residues and 1 glucosyl residue,
which is a non-linear linked heterogeneous oligosaccharide
a
Journal of Pharmacy and Pharmacology

8 PCB I 6 ¥ 104 Man:Gal = 1:0.73 PCB I possesses a backbone of 1,4-linked mannopyranosyl residues with side
chains mainly composed of galactofuranosyl residues and also a few
mannopyranosyl and galactopyranosyl residues
a
9 PCB II 6 ¥ 104 Man:Gal:Glu = 1:0.51:0.50 PCB II possesses 2 mannosyl residues, 1 galactosyl residue and 1 glucosyl residue
connected by a (1,3) linkage
a
10 PCC I 5.7 ¥ 104
11 PCC II
a
12 2.01 ¥ 104 Ara:Man:Gal:Glc = Composed of a (1,3)-b-D-glucan backbone substituted at O-6 with side chains of Fermentation broth of C. dipterigena[41]
1.86:29.08:25.86:43.05 (1,6)-b-D-glucopyranosyl units, (1,3)-galactan and (1,2)- mannan
2009; 61: 279–291

13 CG-1 Glu Composed of 1,6-linked a-glucopyranosyl residues Cultured mycelia of C. gunni[42]

14 CPS-1 2.3 ¥ 105 Rha:Xyl:Man:Glc:Gla = Composed of mannose bonded by (1,2) linkage, xylose bonded by (1,4) linkage and Cultured C. militaris[43]
1:6.43:25.6:16.0:13.8 rhamnose boned with galactose by (1,2) or (1,3) linkage
a
15 CPS-2 1.3 ¥ 104 Rha:Glc:Gal = 1:4.46:2.43 Cultured C. militaris[44]
16 CPS-3 5 ¥ 103 Glu Composed of 1,4-linked and 1,6-linked D-glucose with mainly an a-glycoside
linkage in a molar ratio of 0.11:0.86 with side chains substituting at the C-6 of
every eight glucose residues
17 CPS-1 2.3 ¥ 104 Rha:Xyl:Man:Glc:Gal = CPS-1 composed of five kinds of monosaccharide connected by b configuration Cultured C. militaris[45]
1:6.43:25.6:16.0:13.8
a
18 CPS-2 1.29 ¥ 104 Rha:Glc:Gal = 1:4.46:2.43 CPS-2 composed of three kinds of monosaccharide connected by a configuration
19 CPS-3 5 ¥ 103 Glu CPS-3 composed only of glucose connected by a configuration
20 Ck1-A 9.27 ¥ 105 A small quantity of uronic Composed of pyranosyl residues connected by a-glycoside linkage Cultured mycelia of C. kyushuensis[46]
acid (GlcA)
21 Ck3-A 9.25 ¥ 104 May contain a mannose and Connected by a-glycoside linkage Mycelia of C. kyushuensis[47]
a little glycuronic acid
22 CMPS 3 ¥ 104 Rha:Xyl:Man:Glc:Gal = CMPS composed of a backbone of 1,2-linked mannosyl residues, 1,4- or 1,6-linked Fruiting bodies of C. militaris[48]
1.00:0.50:51.99:2.38:36.50 galactosyl residues, and 1,2-linked galactosyl uronic acid with branches of
1,3-linked glucosyl uronic acid at the C-2 or C-3 of 1,4-linked galactosyl residues
in the main chain, mainly bonded by b configuration
23 CS-F10 1.5 ¥ 104 Glu CS-F10 has a-D-glucopyranosyl residues on the terminal of the side-chains and Mycelia of C. sinensis[49]
1,5-linked b-D-galactofuranosyl residues
24 CMB 6 ¥ 104 Gal:Man:Glc = 1.15:1.00:4.79 CMB possesses 1,6-linked mannosyl residues, 1,4-linked galactosyl residues, and Mycelia of C. militaris[50]
even 1,6-linked or 1,4-linked glucosyl residues with branches of 1,4-linked and
a few 1,6-linked glucosyl residues substituting at the C-3 of 1,4-linked glucosyl
residues with terminal galactosyl or glucosyl residues, mainly connected by
Cordyceps fungi

a-glycoside linkage
25 CS-F3 4.5 ¥ 104 Gal: Glc: Man = 62:28:10 Mycelia of C. sinensis[51]
26 CM-I 2.7 ¥ 104 Gal:Man = 6:5 CM-I possesses a backbone of 1,2-linked b-mannosyl residues with branches of Culture liquid of C. militaris[52]
1,6-linked b-galactofuranosyl residues at the C-4 and C-6 of galactosyl residues
in the main chian
27 CS- 4.3 ¥ 104 Man:Gal:Glc = 10.3:3.6:1 Consists of a backbone of 1,6-linked mannopyranosyl residues with branches of Fermentation medium of C. sinensis[53]
81002 1,3-linked galactofuranosyl residues, 1,4-linked glucofuranosyl residues and
1,4-linked or 1,2-linked mannopyranosyl at the C-3 and C-2 of mannosyl residues
of the main chain in a molar ratio of 6:4
28 CI-P 2.5 ¥ 104 Man:Gal = 1:0.85 with CI-P composed of a backbone of 1,6-linked a-D-mannopyranosyl residues Insect-body portion of the fungal preparation
traces of D-glucose substituted at O-2 with single a- or b-D-galactofuranosyl groups, short chains of C. cicadae[54]
1,2-linked b-D-galactofuranosyl residues, or chains of 1,2-linked
a-D-mannopyranosyl residues
29 CI-A 2.5 ¥ 104 Man:Gal = 1:0.57 with CI-A possesses nearly same structure as CI-P but fewer and shorter
traces of D-glucose D-galactofuranosyl side-chains and longer 1,2-linked a-D-mannopyranosyl side
chains than CI-P
30 Ch-1 4.3 ¥ 104 Mannose and gaIactose Both polysaccharides possess backbones of 1,4-linked b-galactosyl and Fruit body of C. hawkesii[55]
b-mannosyl residues with 1,3-linked and 1,2-linked side chains substituted at O-6
31 Ch-2 4 ¥ 103
32 CT-4N 2.3 ¥ 104 Man:Gal = 3:5 Composed of a backbone of 1,6-and 1,2-linked a-D-mannopyranosyl residues with C. sinensis[56]
short chains of a large proportion of 1,5-linked b-D-galactofuranosyl residues
and a small proportion of 1,6-linked a-D-galactopyranosyl residues at O-2, O-4
and O-6, with the nonreducing terminal groups of a large proportion of
a-D-mannopyranosyl groups
33 CO-1 6.32 ¥ 105 Glu CO-1 composed of a backbone of 1,3-linked b-D-glucopyranosyl residues with The product formed on incubation of the
a b-D-glucopyranosyl group attached to O-6 of every second D-glucopyranosyl culture filtrate of C. ophioglossoides[57]
residue of the main chain
34 C-3 2.7 ¥ 104 Man:Gal = 4:3 C-3 composed of 1,2-linked and 1,6-linked a-D-mannopyranosyl residues Ascocarps of C. cicadae[58]
substituted at O-6 and O-2 with terminal b-D-galactofuranosyl and
a-D-mannopyranosyl groups, and with short chains of 1,2-linked
b-D-galactofuranosyl residues
35 CS-I Gal:Man = 1:1 CS composed of a backbone of 1,2-linked D-mannofuranosyl residues with side
chains of 1,3-linked 1,5-linked and 1,6-linked D-galactofuranosyl residues and
1,4-linked D-galactopyranosyl residues and with nonreducing terminal groups of
[59]
D-galactofuranosyl residues and D-mannopyranosyl residues
36 CS-II
a
The component is a proteoglycan or a glycoprotein.
Xuanwei Zhou et al.
283
284 Journal of Pharmacy and Pharmacology 2009; 61: 279–291

the side chains of alpha-D-(1!6)-mannopyranose (Manp) were Crude protein and amino acids
attached to the backbone via the O-6 of alpha-(1!3)- Previous papers have reported that the content of crude protein
glucopyranosyl (Glcp) residues.[61] The study showed that the was in the range 29.1–33%.[27,33,66] The protein was composed
pharmacological activity of the polysaccharide was correlated of 18 amino acids, including aspartic acid, threonine, serine,
with its characteristics such as molecular weight. It has glutamate, proline, glycine, valine, methionine, isoleucine,
been reported that polyglucans with higher molecular weight leucine, tyrosine, phenylalanine, lysine, histidine, cystine,
(10–1000 kDa) tend to have greater water solubility and cysteine and tryptophan. The content of amino acids after
therefore have a more effective antitumour activity. The hydrolysis is mostly reported as 20–25%, the lowest being
anticancer effects of fungal polysaccharides arise from the 5.53%, the highest being 39.22%. The highest contents are
enhancement of the body’s immune system rather than direct glutamate, arginine and aspartic acid, and the major pharmaco-
cytocidal effects.[62] logical components are arginine, glutamate, tryptophan and
The physicochemical properties of an aqueous solution of tyrosine.[67] The content of amino acids in the commercial
crude CP have been analysed, and the result showed some preparation of Cordyceps is significantly higher than in the
good properties, such as thickening and thixotropic properties, mycelia of C. sinensis, which is similar to the content in the fruit
salt and heat resistance and stability over a wide pH range. body of C. sinensis. The content of amino acids in C. sinensis
The dynamic viscosity of CP varies little over the pH range and related products are shown as in Table 2.
of 4–14. There was a positive relationship between CP oral
dosage and its therapeutic effects (the lowest effective dosage Fatty acids and metal elements
of CP is 180 mg per day).[40] In addition it is colourless and Fatty acids are composed of carbon, hydrogen and oxygen
odourless and has good solubility and stability in water.[63] and are the major component of lipids, phospholipids and
glycolipids; they can be classified as saturated or unsaturated
Other Bioactive Components fatty acids. In Cordyceps, the unsaturated fatty acid content
Nucleotides reaches 57.84%, including Cl6:1, Cl7:1, Cl8:l and Cl8:2. The
Nucleotides (including adenosine, uridine and guanosine) are linoleic acid content is the highest at 38.44%, followed by the
effective components in Cordyceps mushrooms. Investiga- oleic acid, which is 17.94%. The saturated fatty acid content
tions show that guanosine has the highest content of all in is 42.16%, including Cl4, Cl5, Cl6, Cl7, Cl8, C20 and C22. The
natural and artificial Cordyceps.[64] The content of nucleo- palmitic acid and the octadeca acid contents are the highest,
tides in artificial Cordyceps is obviously higher than and are 21.86% and 15.78%, respectively. Unsaturated fatty
in natural Cordyceps. This may be related to the rapid acid is an effective physiologically active component, which
metabolism of artificial cultures. A remarkable variation in has the unique function of decreasing blood lipids and
the adenosine content is found in artificial Cordyceps, with protecting against cardiovascular disease. The content of
the highest concentration being over six times that of the unsaturated fatty acid is higher than that of saturated fatty
lowest. The content of adenosine in freshly acquired natural acid in commercial preparations of Cordyceps, and the linoleic
Cordyceps is too low to quantity, but the content of the acid and oleic acid contents are significantly higher than others.
nucleotide in a preparation stored for a long time is higher.
This shows that nucleotides in natural Cordyceps derive from Table 2 Amino acid levels in Cordyceps sinensis mycelia fermentation
degradation of the nucleoside during the storage process. preparations and two samples of fruit body
Subsequent research found that dampness and warmth can
Amino acid Mycelium Mycelia Fruit body A Fruit body B
significantly increase the nucleotide content in Cordyceps.
composition powders
At a temperature of 40∞C and relative humidity of 75%,
Cordyceps were stored for 10 days, when the content of Asp 2.47 1.05 1.67 1.84
nucleotides increased 1–10 fold, while in artificial Cordyceps Thr 0.95 0.65 1.47 0.83
adenosine, uridine and guanosine showed no obvious change Ser 0.82 0.49 1.51 0.78
in content. This suggests that the nucleotides in natural and Glu 3.55 1.12 3.44 2.66
artificial Cordyceps are to some extent different.[5] Pro 0.90 0.72 0.96 0.95
Gly 1.19 0.58 1.25 0.73
Ergosterol Ala 1.21 0.75 1.40 0.95
Cys 0.25 0.43
Ergosterol is a sterol unique to fungi and is an important
Val 1.42 0.63 1.13 0.80
precursor of vitamin D2, which has important medicinal Met 0.47 0.18 0.25 0.18
value. The content of free ergosterol from natural and Ile 1.14 0.44 0.62 0.53
artificial Cordyceps has been compared. The result showed Leu 1.84 0.69 1.20 0.95
that the content of free ergosterol in different natural Tyr 0.89 0.31 0.88 0.67
Cordyceps varies significantly, but is evidently higher than Phe 1.84 0.51 0.71 0.61
than in the mycelia of Cordyceps. The content of ergosterol Lys 1.27 0.81 1.66 1.15
in the artificial fruit body of C. militaris is very high, only His 0.58 0.28 1.71 1.13
lower than that of natural Cordyceps in Tibet, and higher Arg 1.47 0.04 2.88 1.6
than that in Qinghai and Sichuan. Li et al.[65] reported that Total content 21.59 9.23 23.15 16.40
the content of ergosterol in the mycelia of Cordyceps was The amino acid level in the C. sinensis fermentation preparations were
1.44 mg/g, much lower than that in the fruit bodies of more than those in the C. sinensis fruit body.
Cordyceps (10.68 mg/g).
Cordyceps fungi Xuanwei Zhou et al. 285

Investigations show that Cordyceps contains many metal and adenosine. The antitumour action of CP has been proved
elements, and the content significantly depends on different extensively,[40,59,78,79] and that of sterols and adenosine is
species and metal elements (Table 3).[26,68,69] Many metal a hot research topic in Cordyceps.[80,81] New antitumour
elements, Zn, Mg, Mn and so on, are of great significance to compounds have been continually isolated, and the effects of
the development and maintenance of function of the gonads. Cordyceps extract on tumour growth have been evaluated.[82,83]
Zn is effective in the kidney at preventing cadmium from For instance, Zhang et al.[84] compared the antitumour effects
damaging the nephrons.[70] High contents of Zn, Mg, Mn and chemical components of the extracts of cultivated
play an important role in warming and tonifying the kidney C. sinensis with natural C. sinensis. The Cordyceps was
yang effectively, aiding kidney recovery and improving the extracted with petroleum ether (PE), ethyl acetate (EtOAc),
essence of life.[71] ethanol (EtOH) or water. The cytotoxicity of all the
extracts was observed with MTT assay on a breast cancer
cell line (MCF-7), a mouse melanoma cell line (B16), a human
Pharmacological Function premyelocytic leukaemia cell line (HL-60) and a human
Fungi are an important source of material in TCM. Medicinal hepatocellular carcinoma cell line (Hep G2). The chemical
mushrooms have an established history of use in traditional constituents in the extracts were analysed by HPLC. The results
oriental therapies. Extracts from about 200 species of fungi showed that all of the extracts from the Cordyceps mushroom
have been shown to stimulate immunoreactivity and inhibit had much stronger cytotoxicity on the B16 cell line and the
the growth of different kinds of tumours.[72–75] According to EtOAc extract had the most potent activity; the chemical
the theory of TCM, the main effects of Cordyceps are components of all the extracts were analysed and ergosterol and
enriching the lung yin and yang, which includes treating adenosine were found to be potential compounds.[84] We still
chronic lower back pain, sensitivity to cold, over abundance do not know the mechanism by which Cordyceps inhibits
of mucus and tears, chronic cough and wheezing, blood in the growth of various cancer cells; inhibition might occur by
phlegm from consumption due to kidney yang (shenyangxu), one of several means, summarized as follows: (1) enhancing
etc. Based on Western medicine, Cordyceps has an immunological function and non-specific immunity;[85]
antibacterial function, and reduces asthma, lowers blood (2) selectively inhibiting RNA synthesis, thereby affecting the
pressure and strengthens the heart beat. In the public domain, protein synthesis;[86] (3) restricting the sprouting of blood
people often add it into hen or duck soup to strengthen vessels;[87] (4) inducing tumour cell apoptosis;[88] (5) regulation
the body and ‘renew’ sick people.[3,76] Although there are of signal pathways;[89] (6) antioxidation and anti-free radical
300 species of Cordyceps, the research into its pharmacolo- activity;[90] (7) anti-mutation effect; (8) interfering with the
gical effect has focused only on two species, C. sinensis and replication of tumour-inducing viruses; (9) inducing nucleic
C. militaris. acid methylation.[91]

Antitumour effects Immunomodulating effects

Tumour diseases are one of the main causes of death in the The possibility that extracts and isolated components from
world. Antitumour activity is the most significant therapeutic mushrooms stimulate or suppress specific components of the
interest associated with these mushrooms. The ability to immune system has been studied in recent years. Immunomo-
inhibit the growth of different tumours was detected in many dulators can be effective agents for treating or preventing dis-
genera of Cordyceps species. Cordyceps species and their eases and illnesses that stem from certain immunodeficiencies
extracts have been recognized as a traditional remedy, used and other depressed states of immunity.[92] There is an extensive
in TCM for the prevention and treatment of cancer and body of research focused on the immuno-enhancing and
several other diseases.[77] immunosuppressive properties of various Cordyceps spe-
The bioactive components in Cordyceps that have cies.[93,94] As previously stated, several major substances with
antitumour activity are mainly the polysaccharides, sterols immunomodulatory activity have been isolated from Cordyceps.

Table 3 Amount of metal elements in mycelial fermentation preparations and fruit body of Cordyceps sinensis

Metal element Mycelium powder (mg/kg) Fruit body (mg/kg) Metal element Mycelium powder (mg/kg) Fruit body (mg/kg)

K 11500a 3975 Fe 205 3136

P 3600 3671 Cu 8.86a 2.8
Na 310 547 Zn 152a 13.9
Mg 2700a 1813 Mn 45.6a 39.2
Ca 800 1656 Si 54.3a n.t.
Al 169 7664 Co 0.21 1.097
B 15.4a 7.79a Ni 2.05 3.76
Mo 0.3a n.d. Se 0.52a 0.34
Cd 0.22a 0.051 V 1.10 11.82
Pb 0.2 0.36 Cr 0.97 4.42
a
Metal levels in Cordyceps sinensis mycelium preparation were more than those in fruit body; n.d., not detected; n.t., not tested.
286 Journal of Pharmacy and Pharmacology 2009; 61: 279–291

The major immunomodulating effects of the active substances so on.[100] In recent years, significant progress has been
derived from these mushrooms include mitogenicity and made in the prevention of liver disease. For instance, to find an
activation of immune cells, such as the lymph proliferative effective drug to cure patients with chronic hepatitis B, Gong
response, natural killer (NK) cell activity and phytohaemagglu- et al.[101] have treated 25 patients with C. sinensis.
tinin (PHA)-stimulated interleukin-2 (IL-2) and tumour T lymphocyte subsets (CD4, CD2), hyaluronic acid (HC)
necrosis factor-a (TNF-a) production on human mononuclear and precollagen type III (PC III), were observed before and
cells (HMNC),[6] resulting in the production of cytokines. The after treatment. After 3 months of treatment, CD4 and CD4/
therapeutic effects of the mushrooms, such as suppression of CD2 ratio increased significantly (P < 0.05), while HA and
autoimmune diseases and allergy, have been associated in many PC III decreased significantly (P < 0.05) compared with the
cases with their immunomodulating effects.[95–97] control. These results suggested that beneficial effects might
While it is known that Cordyceps extracts have be obtained by using C. sinensis to adjust the T lymphocyte
immunomodulatory activity, the standard approach has subset levels and to treat hepatic fibrosis in patient with
been to isolate, characterize and administer the pure active chronic hepatitis B.[101]
constituents. However, different components in a Cordyceps Bioactive components of cordyceps for liver protection are
species extract may have synergistic activity. There are mostly CPs. The CPs can improve the immunological functions
several reports of mushrooms containing more than one of organic cells, removing harmful components and thus
polysaccharide with immunomodulatory activity. For exam- reducing the injury to liver cells. However the content and
ple, Yu et al.[98] used components I, II, III and IV of efficacy of CPs vary with the species.[102,103] The effects of
polysaccharide groups and a negative control group. Admin- CPs in protecting the liver were presented as follows:[104]
istration of C. sinensis polysaccharides to NIH mice lasted (1) protective effect on immune liver injury; (2) effect on
for five days at a dose of 35 mg/kg by intraperitoneal and patients with chronic hepatitis B; (3) effect on patients with
subcutaneous injection. They investigated the pharmaco- hepatocirrhosis after hepatitis;[105] (4) protective effect on liver
dynamics of immune activity of different components, fibrosis.[101]
measured the weight of thymus and spleen of mice injected The key to treating liver disease is to inhibit and clear the
intraperitoneally, and then calculated the viscera index for virus from the liver of patients, regulate the immunological
those injected subcutaneously. The results indicated that function of the organism, and reverse the developing process
different components of C. sinensis polysaccharides could of liver fibrosis, etc. C. sinensis and its related products
enhance the immune response, spleen index, thymus index obviously act to hasten macrophage phagocytosis, and
and the phagocytic function of monocyte-macrophages.[98] enhance the immune function of organisms and possess a
The response to different polysaccharides is likely to be strong capacity to clear the virus.[106]
mediated by different cell surface receptors, which may be
present only on specific subsets of cells and may trigger Protection of kidney
distinct downstream responses. A combination of such Nephrosis is a kidney disease, always considered to be
responses involving different cell subsets could conceivably serious, which is harmful to the health of the urinary system.
provide greater tumour inhibition than that which could be It can recur easily and acutely, while it is difficult to cure.
induced by a single polysaccharide.[78] On the other hand, The modern method of treatment still lacks a satisfactory
latest reports show that Cordyceps has an anti-rejection effect curative effect. The medical treatment for the disease mainly
in the experimental research of organ transplantation. For uses glucocorticoids and an immunodepressant. The Chinese
example, Guan and Yu[99] studied the prevention of rejection native medicinal treatment for nephrosis has a rapid effect,
of transplanted kidney by artificial cultured Cordyceps in and the side effects are also very small, so it is given
rats; the results showed that Cordyceps powder can markedly prominence.[107]
prolong rat renal allograft survival. In DCXC, there are about 19 amino acids, alcoholic
components, nucleotides, trace elements and vitamins as
previously stated. The effects in protecting the kidney are
Protective effects on human organs mainly presented as three aspects: (1) a therapeutic effect on
Protection of liver toxic kidney injury; (2) protecting against chronic renal
Liver disease is one of the major diseases that is seriously function failure; (3) reversing the effect of glomerulone-
harmful to human health and affects quality of life. The phritis in an animal model.[7] These have been proved by a
incidence of primary liver cancer is continuously rising in the series of experiments.
world, and about 50 000 people die of this disease every year,
of which about 40% are in China, which may be related to Protection of heart and antihypertensive effects
hepatitis virus infection. Thus effort has concentrated on C. sinensis extracts were tested on myocardial ischaemia/
preventing liver disease using TCM, and Cordyceps is one of reperfusion injury in rat isolated hearts. Xu et al.[108] reported
the various materials of TCM. that the alcoholic extracts had a protective effect on
Animal tests and clinical research data show that myocardial injury induced by adriamycin in rats. The
Cordyceps has a protective effect in liver patients, including mechanism was suggested to be that mannitol, amino acids
those with viral hepatitis A, chronic hepatitis B, chronic and polysaccharides in the extracts played an important
hepatitis C, hepatic fibrosis, etc. It enhances organic cell role; all the substances had the effect of nourishing the
immunological function, reverts HBeAg-positive to HBeAg- myocardium and enhancing its anti-injury capacity.[108] With
negative, improves liver function, inhibits hepatic fibrosis, and the same experimental methods, Gu et al.[109] reported that
Cordyceps fungi Xuanwei Zhou et al. 287

Lungfit (C. sinensis compounds) could be beneficial for Dietetic Chinese drugs
myocardial ischaemia/reperfusion injury as well. However, Dietetic Chinese drugs are also known as ‘edible Chinese
both alcohol and water extracts had obviously protective drugs’, ‘dietetic material medicine’ or ‘medicinal food’,
effects on the rat isolated heart. although the word ‘drug’ could be misinterpreted in the
On the other hand, C. sinensis has an inhibitory effect West. The basic theories of the Chinese medicated diet
on arrhythmias induced by aconitine, barium chloride and (CMD) arose from the main theories of herbal medicine in
adrenaline, and can increase nutritional myocardial blood TCM.[117] Accordingly, the homologous culture of medicine
flow, thereby improving myocardial ischaemia.[110] Some and food are an important part of TCM theory; there is a
other papers reported similar findings, but isolates came saying: ‘food is your medicine, and medicine is your food’.
from different extraction methods.[111] Considering antihy- Much Chinese herbal medicine not only involves the
pertensive effects, Wu et al.[112,113] observed the effect of treatment of disease, but also includes very good food,
C. sinensis on blood pressure in renal hypertensive rats. The such as daily vegetables and fruits, which have the dual role
results showed that the renal hypertension could be prevented of being food and drug at the same time. C. militaris, as
significantly by treatment with C. sinensis since the cardiac healthy green food, could be used in stir-fries or be added
hypertrophy and vascular remodelling were reversed. There- to stewed chicken or duck, cooking soup, hot pot and tea.
fore, they came to the conclusion that C. sinensis has a Especially, cooking soup with Cordyceps is very popular.
curative role in renal hypertension.[112,113] Now the Guangdong Academy of Agricultural Sciences
In short, C. sinensis has many effects on the cardiovas- Institute of Sericulture and Insects has developed a series of
cular system, such as having a negative frequency, reducing tea herbs. What’s more, the Chengdu JinCao Company has
myocardial oxygen consumption, improving myocardial prepared food with C. militaris which is aimed for mass
ischaemia, anti-platelet aggregation and anti-arrhythmic consumption, such as Cordyceps-Saussurea, Cordyceps-Aloe
effects, etc. On the haematopoietic system, C. sinensis has and Cordyceps-Dictyophora soup.[118]
a protective effect on mice platelet reduction and platelet
ultrastructural damage. Health food
Protection of other organs Health food, also called ‘functional food’, is used widely and
C. sinensis also has obvious effects on other organ designed as foods or food components that help to modulate
systems.[114–116] For example, on the central nervous system, the human body and cure or prevent diseases. Many other
C. sinensis has sedative, anticonvulsant and cooling effects. terms, such as ‘medical foods’, ‘nutraceuticals’, ‘nutritional
On the respiratory system, C. sinensis has a significant foods’ and ‘designed foods’, as well as their definitions, have
relaxant role in the bronchi, markedly increases adrenaline also emerged. Health foods need to be approved by the
secretion from the adrenal glands and also has a role in SFDA (State Food and Drug Administration) in China
tracheal contraction caused by histamine; it also has an and before marketing. Therefore, developing health food is
antitussive, expectorant and anti-asthmatic action and another important way to develop Cordyceps products
prevents pulmonary emphysema. On the endocrine system, directed to different people and different physiological states
C. sinensis has effects as a male hormone; CP can increase with different demands of nutrition and health. There has
plasma corticosterone levels, etc. been some C. militaris health food on the market, such as
oral liquid Cordyceps tonic, tonic Cordyceps wine for kidney
reinforcing,[119] Cordyceps health beer, Cordyceps capsules
Developmental Products (such as AiMei soft capsule, using the tradename ‘Xinkeqi’,
In recent years, functional foods, also known as nutraceu- which has the unique function of immunomodulation
ticals, medical foods or nutritional foods, are driving food and delaying senility, produced by Jilin Xinkeqi Health
markets around the world and are expected to be one of the Food Co., Ltd), and so on.[120] These have been used mainly
emerging trends for the food industry in the new millennium. by the following groups: young people, the elderly, pregnant
Cordyceps are important raw sources. As the prices of women, people with nutritional imbalance and so on.
Cordyceps are rising fast, many people harvest them. Focused design like this not only influences physiological
Meanwhile animal husbandry is developing rapidly, which regulation, but also regulates the nutrition and senses.
destroys the ecological equilibrium, reducing the wild It is worth noting that, in recent years, as increasing
Cordyceps resources. To increase the yields of Cordyceps attention is given to the function of C. militaris, foreign
and meet medicinal demand, researchers have tried to obtain manufacturers have shown an interest, and export volumes
the purified mycelium of Cordyceps from the artificial are increasing. Presently Japan, Korea, Malaysia and other
fermentation of the stroma of Cordyceps since the 1970s. countries are increasing their research and development of
Due to their similarity in biological activity and chemical Cordyceps functional food.[10]
composition, there will be a trend towards replacing natural
Cordyceps resources. So far many fungi have been studied Developing the ‘drugs’
further, including Cephalosporium sinensis, Paecilomyces The most bioactive components extracted from Cordyceps,
hepiali, P. sinensis, Scydalium spp. and C. militaris, and such as cordycepin, cordycepic acid and CP, which have
many different improved productions have appeared on the anti-aging and sleep regulating effects, have been authorized
market.[13] At present, the development of Cordyceps and its as new medicinal resources by the SFDA of China.
substitutes is mainly focused on the following three areas. Therefore, using Cordyceps (including its extracts) and
288 Journal of Pharmacy and Pharmacology 2009; 61: 279–291

adding other TCM materials or other nutrient resources, we Shanghai, Shanxi, Jiangxi and Qinghai provinces, after the
can develop many products through modern technology. national science committee put research into C. sinensis in the
These products have many functions that are mainly focused Spark Plan Project. Subsequently, the research and development
on the following aspects: enhancing physique, anti-aging, of Cordyceps has been listed as a key project to be pursued in the
protecting the heart, improving sleep, increasing appetite, science and technology area for three continuous five-year plans
increasing immunity, etc. For example, ‘C. militaris mycelia (1986–2000), from the seventh five-year plan (1986–1990)
powder and the capsule of C. militaris mycelia powder’ had to the ninth five-year plan (1996–2000). For example, ‘wild
been authorized as a Chinese national drug in April 2003; cultivation, research and development of C. sinensis in the Naqu
Jilin Northeast Tiger Pharmaceutical Co., Ltd reported to the District of Tibet’, China Key Science Program in the national
State Ministry of Health to declare classes of new drugs, ninth five-year plan, strongly supports the cultivation of
which have been approved and called Xinkeqi Capsules. C. sinensis by simulating its naturally growing environment,
Meanwhile, ‘C. sinensis polysaccharide liposomal oral and exploiting its production in the north Tibet altiplano.[4] ‘The
liquid’ (Guangzhou Xingqun Pharmaceutical Co., Ltd),[121] R&D of cordycepin polysaccharide’ (No. 96-C03-01-03), which
and ‘Bailing Capsules’ (Hangzhou Eastchina Pharmaceutical was listed in the key project of the ninth five-year plan, is not
Co., Ltd),[122] have also been approved for entry into the only a breakthrough in the theoretical research of Cordyceps, but
market. So far, there are approximately twenty types of it also has an active significance for the development of
TCM preparation related to Cordyceps, many of which are Cordyceps products.[127] During recent decades, as the findings
polysaccharide products.[123] of new uses for Cordyceps and development of Cordyceps
preparations continues, some correlative products have rapidly
Concluding Remarks appeared one after another, such as Cordyceps capsule,
Cordyceps oral liquid, Cordyceps drink and so on. The
Cordyceps, one of the well-known TCMs, consists of the dried development of the curative and health-care products from
fungus C. sinensis growing on caterpillar larvae. These larvae Cordyceps is more and more favourable among people in China.
include about 20 species of five genera, Hepialus, Hepialiscas, Meanwhile, we are facing an arduous task. C. sinensis, with its
Napialus, Forkalus and Bipectilus, which are classified as long history and remarkable efficacy, cannot continue to serve
Hepialidae. Among them, Hepialus armoricanus, H. obilfur- for the health of human beings, so we must be clearly aware of
cus, H. baimaensis and H. renzhiensis are predominant hosts of this and make efforts to discover a substitute for C. sinensis. It is
C. sinensis.[124] The parasitic complex of the fungus and the delightful that the eleventh five-year-plan annual emphasis item
caterpillar is found in the soil of the prairie at an elevation of of 2007 in the medicine technology field of 863 Program
3500–5000 m.[122] It is commonly used in China to replenish (Hi-tech research and development program of China) also
the kidney and soothe the lung, for the treatment of fatigue, strongly supports the research on C. militaris as a substitute for
night sweating, hyposexuality, hyperglycaemia, hyperlipidae- C. sinensis. It is credible that a substitute having the same
mia, asthenia after severe illness, respiratory disease, renal efficacy as C. sinensis will appear in the near future and well
dysfunction and renal failure, arrhythmias and other serve the human being’s health project.
heart disease and liver disease. The natural Cordyceps (wild
C. sinensis) is rare and expensive in the local market; Acknowledgment
researchers in China have extensively observed its life cycle The authors wish to thank Director Xin Wang and Guojun
with the aim of developing techniques for isolating fermentable Wang (Heilongjiang Xinyisheng Pharmaceutical Co., Ltd,
strains of C. sinensis. Several mycelial strains have been China) for their help collecting product information.
isolated from natural Cordyceps and manufactured in large
quantity by fermentation technology. At present, cultured Conflict of interest
Cordyceps mycelia are commonly sold as health-food products The Author(s) declare(s) that they have no conflicts of
in South East Asia.[125] interest to disclose.
According to incomplete statistics, at present there are
about 100 scientific research institutes working on the Funding
research and development of medicinal fungi. More than
200 factories are engaged in producing fungus preparations. This research is financially supported by the Shanghai
In China, there are more than 30 kinds of medicinal fungus Science and Technology Committee, and Heilongjiang
that are used for obtaining their active component or Xinyisheng Pharmaceutical Co., Ltd, China.
mycelium and fermentation production by solid-state fer-
menting or deep-seated fermenting. This provides abundant References
materials for manufacturing medicine. By now, there are
20–30 types medicament products and approximately 1. Zhu JS et al. The scientific rediscovery of an ancient Chinese
100 types of health-care products.[126] herbal medicine: Cordyceps sinensis: part I. J Altern Comple-
ment Med 1998; 4: 289–303.
In order to develop, utilize and protect this rare medicinal
2. Pegler DN et al. The Chinese ‘caterpillar fungus’. Mycologist
resource, the Chinese government has bestowed it special 1994; 8: 3–5.
support and sponsored much research by the national research 3. Mizuno T. Medicinal effects and utilization of Cordyceps (Fr.)
foundations over recent years. For instance, during the seventh Link (Ascomycetes) and Isaria Fr. (Mitosporic Fungi) Chinese
five-year plan (1986–1990), many research institutes were caterpillar fungi, ‘Tochukaso’ (review). Int J Med Mushrooms
engaged in the research and development of Cordyceps in 1999; 1: 251–261.
Cordyceps fungi Xuanwei Zhou et al. 289

4. Gu DX et al. A review and prospect on the studies of Cordyceps 30. Sprecher M, Sprinson DB. A reinvestigation of the structure of
sinensis (Berk) Sacc. J Chin Inst Food Sci Technol 2006; ‘cordycepic acid’. J Org Chem 1963; 28: 2490–2491.
6: 137–141. 31. Jiang P. Pharmacology constituent and function of Cordyceps
5. Wei L et al. Research advanced in functional composition sinensis. J Westnorthern Med 1987; 2: 43–44.
content of Cordyceps. West Chin J Pharm Sci 2003; 18: 359–360. 32. Zhan TR, Song JM. Progress in studies of mannitol in medicinal
6. Kuo YC et al. Cordyceps sinensis as an immunomodulatory application. Chin J Marine Drugs 2003; 22: 57–61.
agent. Am J Chin Med 1996; 24: 111–125. 33. Xu JT. China Medicinal and Edible Fungi. Beijing: Beijing
7. Shi YX. Update on researches of pharmacological effects of Medical University and China Xiehe Medical University Press,
Cordyceps. Chin Pharm 2005; 14: 72–74. 1997.
8. The State Pharmacopoeia Committee of People Republic of 34. Li SP et al. Anti-oxidation activity of different types of natural
China. Pharmacopoeia of the People’s Republic of China, Part I. Cordyceps sinensis and cultured Cordyceps mycelia. Phyto-
Beijing: Chemical Industry Publishing House, 2005. medicine 2001; 8: 207–212.
9. Zhang P. Advances on Cordyceps genus fungi research. J Biol 35. Li SP et al. The fruiting body and its host of Cordyceps sinensis
2003; 20: 43–45. show close resemblance in main constituents and anti-oxidation
10. Liang ZQ. Current situation and ponderation of Cordyceps Fr. activity. Phytomedicine 2002; 9: 319–324.
research and exploitation in China. Acta Edulis Fungi 2001; 36. Wang JF et al. Research progress on polysaccharides from
8: 53–62. Cordyceps sinensis. Chin Trad Herbal Drugs 2006; 37: 6–8.
11. Liang ZQ et al. Some entomogenous fungi from Wuyishan and 37. Koh JH et al. Antifatigue and antistress effect of the hot-water
Zhangjiajie nature reserves I. Cordyceps. Mycosystema 2002; fraction from mycelia of Cordyceps sinensis. Biol Pharm Bull
21: 162–166. 2003; 26: 691–694.
12. Sung GH, Spatafora JW. Cordyceps cardinalis sp. nov., a new 38. Yu RM et al. Structural characterization and antioxidant activity
species of Cordyceps with an east Asian-eastern North of a polysaccharide from the fruiting bodies of cultured
American distribution. Mycologia 2004; 96: 658–666. Cordyceps militaris. Carbohydr Polym 2007; 70: 430–436.
13. Lei WS et al. General situation of research on Cordyceps 39. Wu YL et al. Studies on isolation and structural features of a
sinensis. J Navy Med 2006; 27: 262–269. polysaccharide from the mycelium of a Chinese edible fungus
14. Guo HC et al. Research and development for Cordyceps (Cordyceps sinensis). Carbohydr Polym 2006; 63: 251–256.
sinensis. J Microbiol 2003; 23: 50–55. 40. Yuan JG et al. Studies on the components and pharmacological
15. Jiang Y, Yao YJ. Anamorphic fungi related to Cordyceps action of polysaccharide from Cordyceps sinensis. Food Drug
sinensis. Mycosystema 2003; 22: 161–176. 2005; 7: 45–48.
16. Wu W et al. Review on studies and applications of Cordyceps 41. Methacanon P et al. Structural elucidation of bioactive fungi-
militaris. Acta Agric Shanghai 2000; 16: 99–104. derived polymers. Carbohydr Polym 2005; 60: 199–203.
17. Gu HS, Liang MY. Study on the manual cultivation of 42. Zhang YM et al. Research situation and development trends of
Cordyceps militaris. Med Inf Lett 1987; 5: 51–52. Cordyceps gunnii. Guizhou Agric Sci 2006; 34: 121–123.
18. Wang JF, Yang CQ. Research advancement of Cordyceps 43. Yu RM et al. Isolation and biological properties of poly-
militaris on product development and artificial cultivation. saccharide CPS-1 from cultured Cordyceps militaris. Fitoter-
Lishizhen Med Mat Med Res 2006; 17: 268–269. apia 2004; 75: 465–472.
19. Zhang HF. Study on conditions of culture on fruiting body of 44. Yu RM et al. Isolation, purification and identification of
Cordyceps militaris. J Jilin Med Coll 2005; 26: 192–194. polysaccharides from cultured Cordyceps militaris. Fitoterapia
20. Ren GL et al. A study on indoor cultivation technique of 2004; 75: 662–666.
Cordyceps militaris. J Henan Agric Univ 2006; 40: 66–68. 45. Wang L et al. Separation, purification and structural analysis of
21. Wen L et al. Optimization of Cordyceps militaris cultivation for polysaccharides in cultured Cordyceps militaris L. Link. Chin J
high production of cordycepin and adenosine. Jiangsu J Agric Biochem Pharm 2003; 24: 23–25.
Sci 2005; 21: 359–363. 46. Wang YB et al. Purification and properties of polysaccharide
22. Huang LF et al. Simultaneous separation and determination of Ck1-A from cultured mycelia of Cordyceps kyushuensis.
active components in Cordyceps sinensis and Cordyceps militaris Mycosystema 2003; 22: 452–456.
by LC/ESI-MS. J Pharm Biomed Anal 2003; 33: 1155–1162. 47. Wang YB, Zhang CK. Isolation, purification and properties of
23. Cunningham KG et al. Cordycepin, a metabolic product from a polysaccharide Ck3-A from Cordyceps kyushuensis cultured
cultures of cordyceps militaries (Linn.) link. Part I. Isolation and mycelium. Food Ferment Ind 2003; 29: 25–27.
characterization. J Chem Soc 1951; 43: 2299–2300. 48. Bin W et al. Studies on polysaccharide in the tissue cultures of
24. Kaczka EA et al. Identification of cordycepin, a metabolite of Cordyceps militaris. J ShenYang Pharm Univ 2000; 17: 361–364.
Cordyceps militaris, as 30-deoxyadenosine. Biochem Biophys 49. Kiho T et al. Structural features and hypoglycemic activity of
Res Commun 1964; 14: 456–457. a polysaccharide (CS-F10) from the cultured mycelium of
25. Li J, Jiang HY. Progression on study of Cordycepin. US Chin Cordyceps sinensis. Biol Pharm Bull 1999; 22: 966–970.
Health Hyg J 2005; 8: 27–30. 50. Wang BJ et al. Studies on structure and properties of water
26. Wang ZS et al. Chemical components of Cordyceps sinensis soluble polysaccharide from fruiting body of Cordyceps
mycelial fermentation preparations in solid media. Nat Prod Res militaris (L.) Link. Chem Res Chin Univ 2003; 19: 37–40.
Dev 2005; 17: 331–336. 51. Kiho T et al. Polysaccharides in fungi. XXXII. Hypoglycemic
27. Hsu TH et al. A comparison of the chemical composition and activity and chemical properties of a polysaccharide from the
bioactive ingredients of the Chinese medicinal mushroom cultural mycelium of Cordyceps sinensis. Biol Pharm Bull
DongChongXiaCao, its counterfeit and mimic, and fermented 1993; 16: 1291–1293.
mycelium of Cordyceps sinensis. Food Chem 2002; 78: 463–469. 52. Gai XJ, Zhang YS. Study of extracellular polysaccharide from
28. Lu P et al. Capillary zone electrophoresis determination of Cordyceps militaris (L.) Link I. purification and structural study
cordycepin in Cordyceps spp. extracted by using ultrasonic. of Galactomannan (CM-I). Mycosystema 1992; 11: 300–307.
Mycosystema 2002; 21: 394–399. 53. Gong M et al. Molecular structure and immunoactivity of the
29. Chatterjee R et al. Cordyceps sinesis (Berkeley) Saccardo: structure polysaccharide from Cordyceps sinensis (Berk) Sacc. Chin J
of cordycepic acid. J Am Pharm Assoc 1957; 46: 114–118. Biochem Mol Biol 1990; 6: 486–492.
290 Journal of Pharmacy and Pharmacology 2009; 61: 279–291

54. Kiho T et al. Minor, protein-containing galactomannans from 77. He JC, Zhang YH. Advances in studies on the anti-tumor
the insect-body portion of the fungal preparation Chan hua activity of Cordyceps sinensis. Chin J Trad West Med 2006;
(Cordyceps cicadae). Carbohydr Res 1988; 181: 207–215. 7: 2144–2147.
55. Chen AP, Wu DR. Studies on fungi polysaccharide I. isolation 78. Ohno N et al. Antitumor activity of a beta-1,3,3-glucan obtained
and some properties of water-soluble polysaccharide of from liquid cultured mycelium of Grifola frondosa. J Pharma-
Cordyceps hawkesii. J Anhui Univ (Nat Sci) 1987; 11: 70–75. cobiodyn 1986; 9: 861–864.
56. Kiho T et al. A minor, protein-containing galactomannan from a 79. Cheng WR et al. Progress of study on polysaccharide from
sodium carbonate extract of Cordyceps sinensis. Carbohydr Res Cordyceps sinensis. Mod Food Sci. Technol 2006; 22: 284–286,
1986; 156: 189–197. 289.
57. Yamada H et al. Structure and antitumor activity of an alkali- 80. Jagger DV et al. Inhibition of Ehrlich mouse ascites tumor
soluble polysaccharide from Cordyceps ophioglossoides. growth by cordycepin. Cancer Res 1961; 21: 216–220.
Carbohydr Res 1984; 125: 107–115. 81. Huang H et al. Inhibitory effects of Cordyceps extract on growth
58. Ukai S et al. Structure of a new galactomannan from the of colon cancer cells. J Chin Med Mater 2007; 30: 310–313.
ascocarps of Cordyceps cicadae Shing. Carbohydr Res 1982; 82. Bok JW et al. Antitumor sterols from the mycelia of Cordyceps
101: 109–116. sinensis. Phytochemistry 1999; 51: 891–898.
59. Miyazaki T et al. Studies on fungal polysaccharides XX. 83. Ohta Y et al. In vivo anti-influenza virus activity of an
galactomannan of Cordyceps sinesis. Chem Pharm Bull 1977; immunomodulatory acidic polysaccharide isolated from Cordy-
25: 3325–3328. ceps militaris grown on germinated soybeans. J Agric Food
60. Cai LT et al. Observation of the structure morphology of Chem 2007; 55: 10194–10199.
Cordyceps polysaccharide by atomic force microscope. J Chin 84. Zhang QX et al. Comparison of antitumor effect of extracts in
Electron Microsc Soc 1999; 18: 103–105. cultivated Cordyceps sinensis fungus HK-1 and natural
61. Wu Y et al. Isolation and characterization of a mannoglucan Cordyceps sinensis. Chin Tradit Herbal Drugs 2005; 36:
from edible Cordyceps sinensis mycelium. Carbohydr Res 1346–1349.
2007; 342: 870–875. 85. Sun Y et al. Experimental study on fruiting bodies of Cordyceps
62. Zhou XW et al. Ganodermataceae: natural products and their related militaris in inhibiting the growth of carcinoma in mice with
pharmacological functions. Am J Chin Med 2007; 35: 559–574. hepatocarcinoma and promoting the activity of IL-2 and NK
63. Li X, Xu L. Studies on expolysaccharide (EPS) fermentation by cells. Chin Pharm 2002; 11: 39–40.
Cordyceps militaris, and on its physical and chemical properties 86. Wu GQ et al. Study progress in research tumour with aweto.
and antioxidation. J Microbiol 1997; 17: 13–17. Guiding J TCM 2005; 11: 80–82.
64. Li SP et al. The nucleosides contents and their variation in 87. Yoo HS et al. Effects of Cordyceps militaris extract on
natural Cordyceps sinensis and cultured Cordyceps mycelia. angiogenesis and tumor growth. Acta Pharm Sin 2004; 25:
J. Chin. Pharm. Sci. 2001; 10: 175–179. 657–665.
65. Li SP et al. RP-HPLC determination of ergosterol in natural 88. Koc Y et al. Induction of apoptosis by cordycepin in ADA-
and cultured Cordyceps. Chin J Mod Appl Pharm 2001; 18: inhibited TdT-positive leukemia cells. Leukemia 1996; 10:
297–299. 1019–1024.
66. Crisan EV, Sands A. Nutrition value. In: Chang ST, Hayes WA, 89. Fuller BB et al. Alpha-melanocyte-stimulating hormone
eds. The Biology and Cultivation of Edible Mushrooms. regulation of tyrosinase in Cloudman S-91 mouse melanoma
New York: Academic Press, 1978: 137–165. cell cultures. J Biol Chem 1987; 262: 4024–4033.
67. Ji S et al. Introduction of the research status in chemical 90. Li SP et al. A polysaccharide isolated from Cordyceps sinensis, a
constituents of Cordyceps. J Fujian Coll Trad Chin Med 1999; traditional Chinese medicine, protects PC12 cells against hydro-
9: 46–47. gen peroxide-induced injury. Life Sci. 2003; 73: 2503–2513.
68. Ma BR et al. Compared of chemical composition between 91. Ji PY et al. On activity and mechanism of anti-tumor of
Cordyceps militaris and Cordyceps sinensis. Chin Edible Fungi Cordyceps militaris. J Beihua Univ (Nat Sci) 2005; 6: 324–329.
1993; 13: 34–40. 92. Chirigos MA. Immunomodulators: current and future develop-
69. Li DS et al. Contrast analysis of mainly chemical ingredient of ment and application. Thy Res 1992; 19: S7–S20.
Cordyceps menshannsis and Cordyceps sinensis. Edible Fungi 93. Koh JH et al. Activation of macrophages and the intestinal
China 2002; 21: 35–37. immune system by an orally administered decoction from
70. Chen Q. Microelement and Health. Beijing: Beijing University cultured medium of Corydyceps sinensis. Biosci Biotechnol
Press, 1989. Biochem 2002; 66: 407–411.
71. Zhu J, Wang ZG. Several metal tests in Cordyceps sinesis and 94. Ko KM, Leung HY. Enhancement of ATP generation capacity,
its mycelium. J Jining Med Coll 1993; 12: 52–54. antioxidant activity and immunomodulatory activities by
72. Lull C et al. Antiinflammatory and immunomodulating proper- Chinese Yang and Yin tonifying herbs. Chin Med 2007; 2: 1–3.
ties of fungal metabolites. Mediators Inflamm 2005; 2: 63–80. 95. Zhao KR et al. Pharmacological effects of Cordyceps sinensis.
73. Wojcikowski K et al. Herbs or natural substances as World Phytomed 2006; 21: 105–108.
complementary therapies for chronic kidney disease: ideas for 96. Shin KH et al. Anti-tumour and immunostimulating activities
future studies. J Lab Clin Med 2006; 147: 160–166. of the fruiting bodies of Paecilomyces japonica, a new type of
74. Zhang QX, Wu JY. Cordyceps sinensis mycelium extract Cordyceps spp. Phytother Res 2003; 17: 830–833.
induces human premyelocytic leukemia cell apoptosis through 97. Shin KH et al. Antioxidant and immunostimulating activities of
mitochondrion pathway. Exp Biol Med 2007; 232: 52–57. the fruiting bodies of Paecilomyces japonica, a new type of
75. Wang HX et al. A polysaccharide-peptide complex from Cordyceps sp. Ann NY Acad Sci 2001; 928: 261–273.
cultured mycelia of the mushroom Tricholoma mongolicum 98. Yu LX et al. Effects of different components of Cordyceps
with immunoenhancing and antitumor activities. Biochem Cell sinensis polysaccharide on immune function. J Zhejiang Coll
Biol 1996; 74: 95–100. Tradit Chin Med 2004; 28: 49–50.
76. Ng TB, Wang HX. Pharmacological actions of Cordyceps, 99. Guan DL, Yu HY. Experimental study of cultured Cordyceps
a prized folk medicine. J Pharm Pharmacol 2005; 57: mycelium in inhibiting the rejection of kidney transplantation in
1509–1519. rat. Chin J Urol 1991; 12: 332–334.
Cordyceps fungi Xuanwei Zhou et al. 291

100. Liu YK, Shen W. Inhibitive effect of Cordyceps sinensis on 113. Wu XX et al. Effect of Cordyceps sinensis on blood pressure in
experimental hepatic fibrosis and its possible mechanism. renal hypertensive rats. J Jinzhou Med Coll 2001; 22: 10–11.
World J Gastroenterol 2003; 9: 529–533. 114. Guo TF, Guo TY. Study on pharmacological action and
101. Gong HY et al. Effects of Cordyceps sinensis on T lymphocyte clinical application of Cordyceps sinensis. J Jindongnan
subsets and hepatofibrosis in patients with chronic hepatitis B. Teachers Coll 2000; 21: 70–73.
Bull Hunan Med Univ 2000; 25: 248–250. 115. Xu CD. Advances of researches on Cordyceps sinensis.
102. Ma DY et al. Research progress in pharmacological actions of J Fungal Res 2006; 4: 60–64.
Cordyceps sinensis and its mycelia. J Chin Med Mat 2001; 24: 116. Zhang CK, Yuan SR. Recent advance in studies on immuno
455–458. pharmacological activities of Cordyceps sinensis and its sub-
103. Fan MZ et al. Evaluation for the protective effect of Cordyceps merge-cultured mycelia. J Capital Univ Med Sci 1997; 18: 37–38.
polysaccharides on immunological liver injury in mice. Acta 117. Xu Y. Perspectives on the 21st century development of functio
Univ Med Anhui 1999; 34: 173–175. nal foods: bridging Chinese medicated diet and functional
104. Chen HX, Jia XB. Research progress on pharmacological foods. Int J Food Sci Technol 2001; 36: 229–242.
actions of cordyceps polysaccharides from Cordyceps mili- 118. Du XF et al. Research progress of Cordyceps militaris.
taris. J JiangsSu Univ (Med) 2005; 15: 74–77. Liaoning Agric Sci 2003; 4: 26–28.
105. Qiu DK et al. Cordyceps sinensis liposome oral liquid on the 119. Li N et al. Research and development of manual cultivation
immunomodulation of T cells in treatment of patients with technique and health food. J Changchun Normal Univ 2001a;
chronic hepatitis B. Chin J Digestion 1995; 15: 265–267. 20: 36–37.
106. Liu JL, Zhou YC. Effect of Cordyceps taii on macrophage 120. Wang X et al. Manufacture of north aweto beverage. Acad
phagocytosis and uviofast protection. Nat Prod Res Dev 2001; Periodical Farm Prod Process 2006; 5: 43–45.
13: 20–22. 121. Feng ZZ et al. Quality standards for the Cordyceps sinensis
107. Xie HH. Nephrosis Chinese native medicine treatment Sacc polysaccharide liposomal oral liquid. J ShengYang
research progress. World Health Digest (Medical Periodical) Pharm Univ 2005; 22: 203–206.
2007; 4: 46–48. 122. Ma CJ et al. Extract and content measuring of cordycepic
108. Xu HY et al. The protective effect of Cordyceps sinensis on polyasccharide in Bailing Capsule. J Zhejiang Coll Trad Chin
adriamycin-induced myocardial damage. Acta Chin Med Med 2004; 7: 81–82.
Pharmacol 2000; 28: 64–65. 123. Hu QX et al. Countermeasures for protecting, developing and
109. Gu ZL et al. The protective effect of lung fit on myocardial utilizing Chinese caterpillar fungus and their resources in China.
ischemia/reperfusion injury in isolated rat heart. Chin J Chin J Agric Resour Regional Planning 2005; 26: 43–47.
Hemorheol 2002; 12: 279–282. 124. Gao HC et al. Research and development for Cordyceps
110. Guo HP, Yang ZM. Study progress in pharmacologic action of sinensis. J Microbiol 2003; 23: 50–55.
Cordyceps sinensis. Chin Trad Herb Drugs 1999; 30: 125. Li SP et al. The contents and their change of nucleosides from
231–233. natural Cordyceps sinensis and cultured Cordyceps mycelia.
111. Yu Z et al. The effect of Cordyceps sinensis on the injury Acta Pharm Sin 2001; 36: 436–439.
of cultured neonatal rat myocardial cells due to anoxia- 126. Yang LH et al. Chinese medicinal fungus and research &
reoxygenation. J First Military Med Univ 1998; 18: 108–109. development of their production. Contemporary Eco-Agric
112. Wu XX et al. Effect of Cordyceps sinensis on cardiac and 2003; 1: 30–33.
vascular function in renal hypertensive rats. Chin J Integr Med 127. Yuan JG et al. R & D of Cordycepin polysaccharide. Fine
Cardio-/cerebro Vascular Dis 2005; 3: 137–138. Specialty Chem 2002; 10: 15–17.
View publication stats