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Journal of Pharmacy
Review
And Pharmacology

The genus Cordyceps: a chemical and pharmacological

review
Kai Yuea, Meng Yea, Zuji Zhoua, Wen Sunb and Xiao Linb
a
College of Forestry, Sichuan Agricultural University, Ya’an, and bCollege of Landscape Architecture, Sichuan Agricultural University,
Chengdu, China

Keywords
ascomycetes; Cordyceps sinensis; Cordyceps
militaris; mushroom
Correspondence
Meng Ye, College of Forestry, Sichuan
Agricultural University, 46 Xinkang Road,
Yucheng District, Ya’an 625014, Sichuan,
China.
E-mail: yemeng5581@yahoo.com.cn
Received May 17, 2012
Accepted September 14, 2012
doi: 10.1111/j.2042-7158.2012.01601.x
Abstract
Objectives Natural remedies are becoming increasingly popular and important in
the public and scientific communities. Historically, natural remedies have been
shown to present interesting biological and pharmacological activity and are used
as chemotherapeutic agents. For centuries Cordyceps, which is a genus of more
than 400 species in the family Clavicipitaceae, has been used in traditional Chinese
medicine. This study highlights the chemistry and pharmacology of Cordyceps,
especially Cordyceps sinensis (Berk.) Sacc. and C. militaris (Fr.) L. Information was
obtained from Google Scholar and the journal databases PubMed and Scopus.
Key findings Many bioactive components of Cordyceps have been extracted, such
as cordycepin, cordycepic acid, ergosterol, polysaccharides, nucleosides and pep-
tides. Studies show that Cordyceps and its active principles possess a wide range of
pharmacological actions, such as anti-inflammatory, antioxidant, antitumour,
antihyperglycaemic, antiapoptosis, immunomodulatory, nephroprotective, and
hepatoprotective.
Summary More research is required to discover the full extent of the activity of
Cordyceps.

Introduction
Cordyceps, the name given to the fungi on insects, has been
known and used as a medication in China for over 300
years, and was initially recorded in Ben-Cao-Bei-Yao by
Wang Ang in 1694. In China, this fungus is usually called
‘Dong Chong Xia Cao’, which means ‘Worm in winter and
grass in summer’, and the name generally refers to Cordyc-
eps sinensis (Berk.) Sacc. This insect parasitizing fungus lives
primarily on the head of the larva of one particular species
of moth, Hepialus armoricanus Oberthur (Lepidoptera), but
is occasionally found growing on other moth species.
Cordyceps was first introduced to Western society during the
17th century. In 1878 Saccardo, an Italian scholar, named
Cordyceps derived from China officially as Cordyceps sinensis
(Berk.) Sacc., and this nomenclature has been adopted up
to the present day.
Cordyceps is an abundant resource of useful natural
products with various biological activity, and it has been
used extensively as a tonic and health supplement for
subhealth patients, especially seniors, in China and other
Asian countries. Recently, it has become increasingly
popular and important in the public and scientific com-
munities. Many bioactive constituents have been reported,
such as polysaccharides, cordycepin, mannitol, aminophe-
nol and ergosterol. Recent studies have demonstrated
that the chemical constituents extracted from Cordyceps
have various pharmacological actions, such as nephropro-
tective, hepatoprotective, inflammatory effects, antioxidant
and antiapoptotic properties. Due to the scarcity of
this resource and immaturity of artificial cultivation, it
has not been possible to fully meet the needs of medical
use.
With the increasing interest in Cordyceps both for mycol-
ogy and medicine, research is necessary to get an overview
about the potential of these mushrooms. Therefore, this
paper has reviewed the biology, biological activity and
chemistry of the genus Cordyceps for its better utilization in
the development of new drugs and therapeutics for various
diseases in the future.

© 2012 The Authors. JPP © 2012

474 Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
Kai Yue et al.
Biology and distribution
Cordyceps, comprising more than 400 species, was histori-
cally classified in the Clavicipitaceae, based on cylindrical
asci, thickened ascus apices and filiform ascospores, which
often disarticulate into part-spores. Cordyceps is character-
ized and distinguished from other genera of the family by
its production of superficial to completely immersed
perithecia on stipitate and often clavate to capitate stro-
mata, and its ecology as a pathogen of arthropods and the
fungal genus Elaphomyces.[1–3] However, the taxonomy of
the genus Cordyceps is controversial. To refine the classifica-
tion of Cordyceps and Clavicipitaceae, Sung et al.[4] esti-
mated the phylogenetic relationship of 162 taxa based on
analysis consisting of five to seven loci. The results strongly
support the existence of three clavicipitaceous clades and
reject the monophyly of both Cordyceps and Clavicipitaceae.
The taxonomy of Cordyceps and Clavicipitaceae were
revised to be consistent with the multi-gene phylogeny. The
family Cordycipitaceae is validated based on the type of
Cordyceps, C. militaris, and includes most Cordyceps species
that possess brightly coloured, fleshy stromata. The new
family Ophiocordycipitaceae is proposed based on Ophio-
cordyceps Petch, which was emended. The majority of
species in this family produce darkly pigmented, tough to
pliant stromata that often possess aperithecial apices. The
new genus Elaphocordyceps is proposed for a subclade of the
Ophiocordycipitaceae, which includes all species of Cordyc-
eps that parasitize the fungal genus Elaphomyces and some
closely related that parasitize arthropods. Two new species
have been described, and lists of accepted names for species
in Cordyceps, Elaphocordyceps, Metacordyceps and Ophio-
cordyceps provided.
Normally, Paecilomyces is considered traditionally to host
the anamorphs, but this has been disputed. Cordyceps are
insect parasitizing fungi, often exhibiting a high degree of
host specificity. However, the Cordyceps species associated
with lepidopteran hosts do not represent a monophyletic
group. The host range of Cordyceps is broad, ranging from
ten orders of arthropods to the truffle-like genus Elaphomy-
ces, although most species are restricted to single host
species or a set of closely related host species.[1,2,5] As to
C. sinensis, when a larva is infected, the fungus grows
through the insect by hyphae. The accumulation of the
biomass, and/or the toxins that may be involved, eventually
kills the host. The fungus ruptures the host insect body fol-
lowing overwintering and forms the sexual perithecial
stroma that are connected to the dead larva below ground,
which grow upward to emerge above the soil surface. The
combination of insect and fungus are used traditionally for
medicinal purposes.
The distribution of Cordyceps is cosmopolitan, including
all terrestrial regions except Antarctica, with the height of
© 2012 The Authors. JPP © 2012
Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
A review of Cordyceps
known species diversity occurring in subtropical and tropi-
cal regions, especially east and south-east Asia. C. sinensis
grows in a very restricted habitat, and is usually found in
the soil of a prairie at an altitude from 3500 to 5000 m,
mainly in provinces like Sichuan, Qinghai, Yunnan, Gansu
and Tibet Autonomous Region in China. In Nepal, Bhutan
and India, C. sinensis was recorded as well.[6] In China, over
60 species have been found, among which C. sinensis and
C. militaris are the most valued species circulated in the
crude drug markets for use in traditional Chinese medicine.
Chemical constituents
A variety of compounds have been extracted and purified
from Cordyceps, including cordycepin and its derivatives,
cordycepic acid, ergosterol, polysaccharides, nucleosides,
and other compounds (Table 1[7,9–60]).
Cordycepin and cordycepic acid
Although the pharmacologically active components of
Cordyceps are still unresolved, at least two chemical con-
stituents, cordycepin and cordycepic acid (Figure 1), have
been identified and proposed as important active constitu-
ents.[61] It is now generally believed that cordycepin, which
was originally extracted from C. militaris and its structural
formula confirmed as 3′-deoxyadenosine, is the main bioac-
tive component of Cordyceps.[7,47]
Cordycepic acid, an isomer of quinic acid, is
one of the main active medicinal components. The
structure was first imprecisely concluded to be 1,3,4,5-
tetrahydroxycyclohexane-1-carboxylic acid in 1957.[48] Sub-
sequently, the structure of the crystalline substance was
identified as d-mannitol.[62] The content of cordycepic acid
in C. sinensis is generally 7–29%, differing in the various
growing stages of fruiting bodies.[63] It is now used in injec-
tions as raw material and as a supplement in other
medicines.
Nucleotides/nucleotide derivatives
Nucleotides and nucleotide derivatives, including cordyc-
epin, are effective components in Cordyceps. Investigations
suggested that guanosine has the highest content of all in
natural and artificial Cordyceps.[64]
Polysaccharides
Cordyceps contains a large amount of polysaccharides,
which varies in the range within 3–8% of the total weight
and usually comes from the fruiting bodies, the mycelium
of solid fermentation submerged cultures and the
broth.[65,66] As one of the main bioactive components,
475
 Table 1 The reported compounds isolated from the genus Cordyceps

476
No. Compounds Characteristic signals or IUPAC Name Sources References

Nucleotide/nucleotides derivatives
1 Cordycepin (3′-deoxyadenosine) (2R,3R,5S)-2-(6-Aminopurin-9-yl)-5-(hydroxymethyl)oxolan-3-ol Cultured C. militaris Cunningham et al.[7]
Cultured C. sinensis Chen and Chu[8]
2 2′-Deoxyadenosine (2R,3S,5R)-5-(6-Aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-ol Cordyceps spp. Gong et al.[9]
3 Adenosine (C10H13N5O4)
A review of Cordyceps

4 Guanosine (C10H13N5O5)
5 Uracil (C4H4N2O2)
6 Uridine (C9H12N2O6)
7 Uridine-5′-monophosphate Cordyceps spp. Yang et al.[10]
8 Adenosine-5′-monophosphate
9 Guanosine-5′-monophosphate
10 Thymidine
11 Cytidine
12 Inosine (C10H12N4O5) Mycelia of C. militaris Liu et al.[11]
13 Adenine (C5H5N5)
14 Hydroxyethyladenosine (2R,3R,4S,5R)-2-[6-(2-hydroxyethylamino)purin-9-yl]-5-
(hydroxymethyl)oxolane-3,4-diol
15 2′3′-Dideoxyadenosine [(2S,5R)-5-(6-Aminopurin-9-yl)oxolan-2-yl]methanol
16 3′-Amino-3′-deoxyadenosine (2R,3R,4S,5S)-4-Amino-2-(6-aminopurin-9-yl)-5- Mycelia of C. militaris Guarino and Kredich[12]
(hydroxymethyl)tetrahydrofuran-3-ol
17 Homocitrullyl aminoadenosine A nucleoside isolated from C. militaris Mycelia of C. militaris Kredich and Guarino[13]
Polysaccharides
18 P70-1 P70-1 has a backbone of 1,6-linked a-D-mannopyranosyl residues Fruiting bodies of cultured C. militaris Yu et al.[14]
with branching 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
19 P70-2
20 P50-1
21 SCP- I SCP-I possesses a backbone of 1,4-linked a-D-glucosyl residues and Fruit mycelium of C. sinensis Wu et al.[15]
carries a single (1,6)-linked a-D-glucosyl residue as side chain
22 PC I Mycelia of C. sinensis Yuan et al.[16]
23 PCA I PCAI 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
24 PCA II PCAII possesses six pyranosyl or furanosyl monosaccharide
consisting of three mannosyl residues, two galactosyl residues and
one glucosyl residue, which is a nonlinear linked heterogeneous
oligosaccharide
25 PCB I PCBI 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
26 PCB II PCB II possesses two mannosyl residues, one galactosyl residue and
one glucosyl residue connected by a (1,3) linkage
27 PCC I
28 PCC II
29 CPS-1 Composed of mannose bonded by (1,2) linkage, xylose bonded by Cultured C. militaris Yu et al.[17]
(1,4) linkage and rhamnose boned with galactose by (1,2) or (1,3)
linkage
30 CPS-2 CPS-2 was found to be mostly of a-(1→4)-d-glucose and Cultured C. militaris Wang et al.[18]
a-(1→3)-D-mannose, branched with a-(1→4,6)-d-glucose every
twelve residues on average
31 CPS-3 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
32 Cultured mycelia of C. kyushuensis Wang et al.[19]
Kai Yue et al.

© 2012 The Authors. JPP © 2012

Composed of pyranosyl residues connected by a-glycoside linkage

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Ck1-A
 33 Ck3-A Connected by a-glycoside linkage Mycelia of C. kyushuensis Wang and Zhang[20]
34 CMB CMB possesses 1,6-linked mannosyl residues, 1,4-linked galactosyl Mycelia of C. militaris Wang et al.[21]
Kai Yue et al.

residues, and 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
a-glycoside linkage
35 CS-F10 CS-F10 has a-D-glucopyranosyl residues on the terminal of the Mycelia of C. sinensis Kiho et al.[22]

© 2012 The Authors. JPP © 2012

side-chains and 1,5-linked b-D-galactofuranosyl residues
36 CS-F3 Mycelia of C. sinensis Kiho et al.[23]
37 CM- I CM-I possesses a backbone of 1,2-linked b-mannosyl residues with Cultured liquid of C. militaris Gai and Zhang[24]
branches of 1,6-linked b-galactofuranosyl residues at the C-4 and
C-6 of galactosyl residues in the main chain
38 CI-P CI-P composed of a backbone of 1,6-linked a-D-mannopyranosyl Insect-body portion of the fungal Kiho et al.[25]
residues substituted at O-2 with single a- or b-D-galactofuranosyl preparation C. cicadae
groups, short chains of 1,2-linked b-D-galactofuranosyl residues,
or chains of 1,2-linked a-D-mannopyranosyl residues
39 CI-A CI-A possesses nearly same structure as CI-P but fewer and shorter
D-galactofuranosyl side-chains and longer 1,2-linked
a-D-mannopyranosyl side chains than CI-P
40 CT-4N Composed of a backbone of 1,6-and 1,2-linked C. sinensis Kiho et al.[26]
a-D-mannopyranosyl residues with 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
41 CO-1 CO-1 composed of a backbone of 1,3-linked b-D-glucopyranosyl The product formed on incubation of Yamada et al.[27]
residues with a b-D-glucopyranosyl group attached to O-6 of the culture filtrate of
every second D-glucopyranosyl residue of the main chain C. ophioglossoides

Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
42 C-3 C-3 composed of 1,2-linked and 1,6-linked a-D-mannopyranosyl Ascocarps of C. cicadae Ukai et al.[28]
residues 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
43 CS- I CS composed of a backbone of 1,2-linked D-mannofuranosyl Ascocarps of C. sinensis Miyazaki et al.[29]
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
D-galactofuranosyl residues and D-mannopyranosyl residues
44 CS- II
45 Exopolysaccharide fraction Cultured anamorph strains of Zhang et al.[30]
(EPSF) C. sinensis
Cultured C. militaris Kim et al.[31]
Cultured C. taii Xiao et al.[32]
46 Co-N A galactosaminoglycan from Cordyceps ophioglossoides C. ophioglossoides Ikeda et al.[33]
47 CPSN Fr I The liquid culture broth of C. militaris Lee et al.[34]
48 CPSN Fr II CPSN Fr II has a backbone of (1→2)-linked
d-mannopyranosyl
and (1→6)-linked d-mannopyranosyl residues, which
occasionally branches at O-6. The branches were mainly
composed of (1→ 4)-linked d-galactopyranosyl residues,
and terminated with d-galactopyranosyl residues, with a
degree of branching (DB) of 0.2

477
A review of Cordyceps
 Table 1 (Continued)

478
No. Compounds Characteristic signals or IUPAC Name Sources References

49 CPSN Fr III
50 CBP-1 CBP-1 has a backbone of (1→4)-a-d-mannose residues which Cultured C. militaris Yu et al.[35]
occasionally branches at O-3. The branches were mainly
composed of (1→4)-a-d-glucose residues and
A review of Cordyceps

(1→6)-b-d-galactose residues, and terminated with b-d-galactose

residues
51 CPS D-Glucan containing a-(1→4)-linked backbone Cultured mycelia of C. gunnii Zhu et al.[36]
52 EPS-1A Its backbone was composed of (1→6)-a-d-glucose residues (77%) Fermentation broth of a Tolypocladium sp. fungus isolated from Yan et al.[37]
and (1→6)-a-d-mannose residues (23%). Branching occurred at wild C. sinensis
O-3 position of (1→6)-a-d-mannose residues of the backbone
with (1→6)-a-d-mannose residues and (1→6)-a-d-glucose
residues, and terminated with b-d-galactose residues
53 WIPS WIPS and AIPS were characterized as a-d-glucans with a backbone Mycelia of C. sinensis Yan et al.[38]
of (1→4)-linked a-d-Glcp (>60%) and very similar molecular
weights WIPS had a short branch of (1→6)-linked a-d-Glcp
(-14%), but AIPS was a linear glucan, distinctive from the
branched structures of most glucans from medicinal fungi
54 AIPS
55 Cordysinocan The exo-polysaccharide contains glucose, mannose, galactose in a Cultured C. sinensis Cheung et al.[39]
ratio of 2.4 : 2 : 1
56 AEPS-1 AEPS-1 had a linear backbone of (1→3)-linked a-d-Glcp residues Mycelial culture of C. sinensis Wang et al.[40]
with two branches, a-d-Glcp and a-d-GlcUp, attached to the
main chain by (1→6) glycosidic bonds at every seventh a-d-Glcp
unit
57 PS-A The molecular weight of PS-A was estimated as 4.6 ¥ 105 Da. C. sinensis Kim[41]
Compositional analysis revealed the presence of D-glucose,
D-galactose, and D-mannose at a molar ratio of 2 : 1 : 1
Sterols and fatty acids
58 Ergosterol (3S,9S,10R,13R,14R,17R)-17-[(E,2R,5R)-5,6-Dimethylhept-3- Mycelia of C. sinensis Bok et al.[42]
en-2-yl]-10,13-dimethyl-2,3, 4,9,11,12,14,
15,16,17-Decahydro-1H-cyclopenta[a] phenanthren Cordyceps spp. Li et al.[43]
-3-ol Insect-body portion of C. cicadae Kuo et al.[44]
59 d-3-Ergosterol C. sinensis Zhu et al.[45]
60 Ergosterol peroxide (3.beta.,5.alpha.,8.alpha.,22E)-5,8-Epidioxyergosta-6,22-dien-3-ol
61 Daucosterol (2R,3R,4S,5S,6R)-2-[[(3S,8S,9S,10R,13R,14S,17R)-17-[(2R,
5R)-5-Ethyl-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,
12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-
yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol
62 Campesterol (3S,8S,9S,10R,13R,14S,17R)-17-[(2R,5S)-5,6-Dimethylheptan-2- Cordyceps spp. Yang et al.[46]
yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-
1H-cyclopenta[a]phenanthren-3-ol
63 b-Sitosterol
64 Cholesterol
65 Lauric acid
66 Myristic acid
67 Palmitoleic acid
68 Pentadecanoic acid
69 Palmitic acid
70 Linoleic acid
71 Oleic acid
72 Stearic acid
73 Docosanoic acid
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 Kai Yue et al.

Other compounds
75 Cordycepic acid C. militaris Kaczka et al.[47]
C. sinensis Chatterjee
et al.[48]
76 Cicadapeptins I The compound is acylated at the N-terminus by n-decanoic acid Fermentation extracts of C. heteropoda Krasnoff
and amidated at the C-terminus by et al.[49]

© 2012 The Authors. JPP © 2012

1,2-diamino-4-methylpentane. The amino acid sequence is
N-terminus-Hyp-Hyp-Val-Aib-Gln-
Aib-Leu-C-terminus.
77 Cicadapeptins II Ile substitutes for Leu of cicadapeptin I
78 Myriocin
79 (2S,3S,4R)-(E)-2-amino-3,4-dihydroxy-2- C. sinclairii Fujita et al.[50]
Hydroxymethyl-14-oxoeicos-6-enoic
acid
80 H1-A A pure compound extracted from C. sinensis C. sinensis Chen et al.[51]
81 Cordypyridones All the four compounds were colourless crystals, and their molecular C. nipponica Isaka et al.[52]
A-D formula were determined as C16H23NO3, C16H24NO3, C17H26NO3,
C17H26NO4, respectively.
82 Ophiocordin (4Z)-4-[(2-carboxy-6-hydroxyphenyl)-hydroxymethylidene]-3- Submerged cultures of C. ophioglossoides Kneifel et al.[53]
hydroxy-1-[(3R,4R)-3-[(4-hydroxybenzoyl)amino]-2,3,4,5-
tetrahydro-1H-azepin-4-yl]-5-oxocyclohex-2-ene-1-carboxylic
acid
Boros et al.[54]
83 Bioxanthracenes1-11 Compounds 1–6 and 11 were identical with those of ES-242 s. Compounds C. pseudomilitaris Isaka et al.[55]
7,8,11 were atropisomer of ES-242-4, ES-242-5, ES-242-8, respectively.

Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
Both compounds 9 and 10 were pale yellow powder, and their
physic-chemical properties were described.
Jaturapat
et al.[56]
84 Dipicolinic acid Pyridine-2,6-dicarboxylic acid C. militaris Rukachaisirikul
et al.[57]
Culture filtrate of C. militaris Watanabe
et al.[58]
85 2-Carboxymethyl-4-(30-hydroxybutyl)
furan
86 10-membered Compound 1 was isolated as a white solid and molecular formula was
macrolides (1–3) determined as C10H16O4. Compounds 2 and 3 were colourless gum, their
molecular formula were C10H14O4, C10H14O4, respectively.
87 Cepharosporolides
C, E, F
88 Glycoprotein C. ophioglossoides culture Kawaguchi
containing et al.[59]
N-acetylgalactosamine
89 A lectin The lectin was designated CML. Fruiting body of C. militaris Jung et al.[60]

479
A review of Cordyceps
A review of Cordyceps
NH2 O many authors (Table 2[70–95]). Ng and Wang[96] reviewed the
N HO
N Cordyceps species. The bioactivities ascribed to the fungi are
HO N N
O tory, anti-inflammatory, insecticidal, antimicrobial, hypoli-
HO
OH OH
Cordycepin Cordycepic acid
Figure 1 Chemical structure of cordycepin and cordycepic acid from
Cordyceps.
Cordyceps polysaccharide represents a class of structurally
diverse biological macromolecules with wide-ranging
physiochemical properties.
Sterols and fatty acids
Ergosterol is a sterol unique to fungi and is an important
precursor of vitamin D2, which has great medicinal value.
Ergosterol is present in two forms, as free ergosterol or
esterified ergosterol, which have different physiological
functions.[67] It was reported that the content of ergosterol
in the mycelia of Cordyceps was 1.44 mg/g, much lower than
that in the fruiting bodies of Cordyceps, which was
10.68 mg/g.[68] However, it is worth noting that ergosterol
peroxide is widespread in fungi and Cordyceps does not
offer any particular advantage in its preparation. A number
of other sterol-type compounds have been found in Cordyc-
eps: d-3-ergosterol, 3-sitosterol, daucosterol and campeas-
terol, to name a few.
Fatty acids can be classified as saturated or unsaturated
fatty acids. The unsaturated fatty acid content reached
57.84% in Cordyceps, including C16:1, C17:1, C18:1 and C18:2,
while the saturated fatty acid content was 42.16%, including
C14, C15, C16, C17, C18, C20 and C22.[69] Unsaturated fatty acid is
an effective physiologically active component, which has the
unique function of decreasing blood lipids and protecting
against cardiovascular disease.
Other compounds
Many other bioactive components have been extracted from
Cordyceps, such as crude protein, amino acids, and metal
elements, and they manifest a wide range of pharmacologi-
cal functions.[69]
Biological activity
The pharmacological actions of Cordycpes have attracted
extensive attention. A number of valuable biological activi-
ties regarding Cordyceps have been observed and studied by
480
Kai Yue et al.
chemical constituents and pharmacological actions of
OH
antitumour, antimetastatic, antioxidant, immunomodula-
pidaemic, hypoglycaemic, anti-ageing, neuroprotective,
OH
renoprotective effects, and so forth.
Immunomodulating effects
The possibility that extracts and isolated components from
mushrooms stimulate or suppress specific components of
the immune system has been studied in recent years.
Cordycepin could be an important immunoregulatory
active compound that affects the actions of immune cells
and cytokine network.[97] The effect of an exopolysaccharide
fraction (EPSF) from anamorphic strains of C. sinensis on
the immunocyte activity of tumour-bearing mice was inves-
tigated. The results indicated that EPSF not only signifi-
cantly inhibited H22 tumour growth, but elevated the
activity of the immunocytes. It enhanced the phagocytosis
capacity of peritoneal macrophages and proliferation ability
of spleen lymphocytes. EPSF boosted tumour necrosis
factor-a (TNF-a) expression of the macrophages, the cyto-
toxicity of spleen lymphocytes, and TNF-a as well as
interferon-g (IFN-g) mRNA expression of splenic lym-
phocytes.[30] The effects of C. sinensis against Group A strep-
tococcal infection in mice were studied.[70] The results
showed that mycelium extract protected by decreasing bac-
terial growth and dissemination, thereby increasing mouse
survival rate. IL-12 and IFN-g expression and macrophage
phagocytic activity also increased after C. sinensis treat-
ment. In another study, C. sinensis mycelium extract was
reported to increase phagocytosis in human monocytic
cells and abrogate inhibition of phagocytosis caused by
streptococcal pyrogenic exotoxin B by causing cytokine
production.[98]
Ethanol extracts from the fruiting bodies of Paecilomyces
japonica and C. sinensis were demonstrated to exhibit
phagocytosis enhancing activity and immunostimulating
activity measured by carbon clearance, weight-loaded
forced swimming performances, and immobilizing stress in
mice [99,100]. The ethanol extract stimulated phagocytosis and
macrophage acid phosphatase activity. Xu et al.[72] studied
the effects of the ethanol extract of C. sinensis on murine
and human in-vitro natural killer cell (NK) activity and on
murine in-vivo NK activity, and on colony formation of
B16 melanoma in mouse lungs. The results indicated that
C. sinensis may be used as an immunopotentiating agent in
cancer treatment and for patients with immunodeficiency.
Ethanol extracts of cultured mycelia and fruiting bodies of
C. militaris were reported to inhibit nitric oxide production
and inducible nitric oxide synthase (iNOS) gene expression
© 2012 The Authors. JPP © 2012
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 Table 2 Some of the biological activity of Cordyceps sinensis and C. militaris
C. sinensis
Biological activity Assay In-vivo
Immunomodulatory Murine and Natural killer cell (NK) activity of
human mouse was augmented by
intraperitoneal injection.
© 2012 The Authors. JPP © 2012
Mouse Three consecutive days of
feeding mice with C. sinensis
before Group A streptococcal
infection increased the
survival rate and reduced
local skin-tissue injury
compared with mice fed
phosphate buffered saline.
Anti-inflammatory Mouse Cordyceps, 5 g/kg (i.g.),
significantly inhibited
bronchial challenge of
ovalbumin-induced change of
RL and Cdyn (P < 0.05) and
inhibited antigen-induced
increase of eosinophils in the
BALF of rats (P < 0.05).
Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
Mouse C.sinensis mycelium significantly
inhibited IR-induced
upregulation of NF-kB
activation and the brain
production of IL-1b, TNF-a,
iNOS, ICAM-1, and COX-2.
Antitumour/anticancer Mouse
Pro-sexual Mouse Different concentrations of
C. sinensis and C. sinensis
fractions (0.02 and 0.2 mg/g
body weight) were fed to
immature or mature mice.
C. sinensis significantly
induced plasma testosterone
levels both in immature and
mature mice in three and/or
seven days treatment
(P < 0.05).
481
In-vitro
NK activity of mouse was
augmented by intraperitoneal
injection. NK activity of
human peripheral blood
mononuclear cells was
elevated by pre-incubation of
these cells with C. sinensis.
The levels of IL-1, IFN, and TNF,
produced by cultured rat
Kupffer cells were increased
in the presence of C. sinensis
or the drug serum from rats
fed on C. sinensis.
C. militaris
Kai Yue et al.
References Assay In-vivo In-vitro References
Xu et al.[70] Mouse Extractable fruiting body glucan Sone et al.[71]
and the extracellular glucan
of the mycelium showed
relatively high
growth-inhibition activity
against sarcoma 180 solid
tumour in mice.
Kuo et al.[72]
Lin et al.[73] Mouse CPS-1 50–200 mg/kg Yu et al.[17]
significantly suppressed
(P < 0.01) the mouse ear
oedema induced by croton oil
in a dose-dependent manner.
At doses of 50 and
100 mg/kg, CPS-1 exerted a
significant (P < 0.01)
inhibitory effect on the
increased vascular
permeability induced by
acetic acid in mice.
Liu et al.[74] Human Potent growth inhibition on NO, Rao et al.[75]
TNF-a and IL-12 production
with an IC50 value of 7.5,
6.3, and 7.6 mg/ml was
displayed, respectively. An
inhibitory trend on these
inflammatory mediators was
observed for compounds with
an IC50 value ranging from
10.8 to 17.2 mg/ml.
Liu et al.[76] Mouse and human A dose of 100 or 200 mg/kg Lin and Chiang[77]
body weight per day inhibited
the tumour volume by
43.81% and 48.89%,
respectively. Tumour weight
was reduced also by 31.21%
and 39.48%, respectively.
Huang et al.[78]
A review of Cordyceps
482
Table 2 (Continued)
C. sinensis C. militaris

Biological activity Assay In-vivo In-vitro References Assay In-vivo In-vitro References
A review of Cordyceps

Nephroprotective Mouse Both acute and chronic Zhao and Li[79]

experiments showed that
C. sinensis could protect the
kidney from ciclosporine
nephrotoxicity and ameliorate
glomerular and interstitial
injury.
Human When LDL concentrations were 5, Wu et al.[80] Human When C. militaris 100, 200, 300 Wu et al.[80]
10 or 50 mg/ml, [3H]thymidine or 400 mg/ml plus LDL 10 mg/ml,
incorporation was [3H]thymidine incorporation
919·5 ⫾ 216 kBq, 1106 ⫾ 132 was respectively 192 ⫾ 75 kBq,
kBq, and 1200 ⫾ 210 kBq, 168 ⫾ 66 kBq, 145 ⫾ 53 kBq
respectively. When C. sinensis and 72 ⫾ 16 kBq, P < 0·01
100, 200, 300, or 400 mg/ml compared with controls.
plus LDL 10 mg/ml were added,
[3H]thymidine incorporation was
99 ⫾ 19 kBq and 53 ⫾ 8 kBq,
respectively, P < 0·01 compared
with controls.
Hepatoprotective Human After three months of Gong et al.[81] Mouse The content of liver glycogen Jung et al.[82]
treatment, CD4 and CD4/CD8 tended to be lower after
ratio increased significantly treatment with C. militaris.
(P < 0.05), while HA and PCIII
decreased significantly
(P < 0.05) compared with the
control.
Mouse As compared with the model Liu and Shen[83]
control group,serum ALT, AST,
HA, and LN content levels
were markedly dropped in CS
group (86.0 ⫾ 34.4 U/L vs
224.3 ⫾ 178.9 U/L,
146.7 ⫾ 60.2 U/L vs
272.6 ⫾ 130.1 U/L,
202.0 ⫾ 79.3 mg/L vs
316.5 ⫾ 94.1 mg/L and
50.4 ⫾ 3.0 mg/L vs
59.7 ⫾ 9.8 mg/L, respectively,
P < 0.05). Tissue expression of
TGFb1 and its mRNA,
collagen I mRNA were also
markedly decreased
(0.2 ⫾ 0.14 vs 1.73 ⫾ 1.40,
1.68 ⫾ 0.47 vs 3.17 ⫾ 1.17,
1.10 ⫾ 0.84 vs 2.64 ⫾ 1.40,
respectively, P < 0.05). A
dramatic drop could be seen
in PDGF expression
(0.87 ⫾ 0.43 vs 1.91 ⫾ 0.74,
P < 0.01).
Kai Yue et al.

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Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493

Antihyperglycaemic Mouse The amount of water and food
consumption (day 15–29), the
two-hour-postprandial blood
glucose concentration (day 21
and day 28), and the serum
© 2012 The Authors. JPP © 2012
concentration of fructosamine
(day 29) were significantly
lower in the experiment
groups than in the control
group (one-way analysis of
variance, P < 0.05).
Anti-ageing/antioxidant Mouse Exopolysaccharide produced in a
mycelial liquid culture of the
C. sinensis showed moderate
antioxidant activity with a
Trolox equivalent antioxidant
capacity of 35–40 mmol
Trolox/g and a ferric reducing
ability of plasma of
50–52 mmol Fe(II)/g.
Neuroprotective
Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
Antifungal
Antiviral
Antibacterial
483
Kai Yue et al.
Lo et al.[84]
Leung et al.[85] P70-1 was found to possess Yu et al.[14]
hydroxyl radical-scavenging
activity with an IC50 value of
0.548 mg/ml.
Mouse Pretreatment with C. militaris Lee et al.[86]
(5–20 mg/ml) for one hour was
sufficient to stimulate primary
neurite sprouting and extension
of Neuro2A cells after 24-h
cultivation in a dose-dependent
manner.
Fungus The antifungal activity of the Wong
peptide was stable up to 100°C et al.[87]
and in the pH range 6–13, and
was unaffected by 10 mM Zn2+
and 10 mM Mg2+. Cordymin
inhibited HIV-1 reverse
transcriptase with an IC50 of 55
mM. Cordymin displayed
antiproliferative activity toward
breast cancer cells (MCF-7) but
there was no effect on colon
cancer cells (HT-29).
Herpes All of them demonstrated activity, de
and three showed appreciable Julián-Ortiz
antiHSV-1 activity, with IC50 et al.[88]
values of 0.9 mM.
Bacteria Cordycepin revealed potent Ahn et al.[89]
growth-inhibiting activity
toward Clostridium
paraputrificum and Clostridium
perfringens at 10 mg/disk.
A review of Cordyceps
484
A review of Cordyceps

Table 2 (Continued)
C. sinensis C. militaris

Biological activity Assay In-vivo In-vitro References Assay In-vivo In-vitro References

Insecticidal Insect In a leaf-dipping test, Kim et al.[90]

cordycepin at 500 mg/l
caused no mortality at 1 DAT
(day after treatment) but 78
and 100% mortality at 2 and
4 DAT, respectively, whereas
34 and 88% mortality at 3
and 5 DAT, respectively was
observed at 300 mg/l.
Antifibrotic Mouse Pretreatment of mice with Zhang et al.[91] Mouse Extracellular biopolymers Nan et al.[92]
C. sinensis led to a significant (30 mg/kg per day for four
attenuation of ureteric weeks, p.o.) had an
obstruction mediated renal antifibrotic effect on fibrotic
fibrosis. rats induced by BDL/S.
Hypoglycaemic Mouse A daily 0.5 g dose of C. militaris Choi et al.[93]
water extract to rats
ameliorated insulin resistance
by enhancing glucose
utilization in skeletal muscles.
Anti-HIV Human Treatment of HIV-1 infected H9 Mueller et al.[94]
cells with 1 mM of the
cordycepin core timer and its
5′-monophosphate derivative
resulted in an almost 100%
inhibition of virus production.
Anti-invasive C. sinensis exerted an Kubo et al.[95]
anti-invasive activity, by
increasing TIMP-1 secretion
from melanoma cells, and
cordycepin potentially
functioned as the effective
component.

CPS-1, is the compound 29; RL, lung resistance; Cdyn, dynamic lung compliance; BALF, bronchoalveolar lavage fluid; IR, ischemia–reperfusion; NF-kB, nuclear factor kappaB; iNOS, inducible nitric oxide synthase; IL-1b, interleukin-1b; TNF-a, tumor
necrosis factor-a; ICAM-1, adhesion molecule; COX-2, cyclooxygenase-2; NO, nitric oxide; IL-12, interleukin-12; IC50, half maximal (50%) inhibitory concentration of a substance; IL-1, interleukin-1; IFN, interferon; TNF, tumour necrosis factor; LDL,
low density lipoprotein; CD4, CD8, T lymphocyte subsets; HC, hyaluronic acid, PCIII, precollagen type III; ALT, alanine aminotransferase; AST, glutamic-oxalacetic transaminease; HA, Hemagglutinin; LN, laminin; CS, C. sinensis; TGFb1, transforming
growth factor b1; PDGF, platelet-derived growth factor; HIV-1, human immunodeficiency virus-1; HSV-1, Herpes simplex virus-1; BDL/S, a bile duct ligation and scission; TIMP-1, tissue inhibitor of metalloproteinase.
Kai Yue et al.

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Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
Kai Yue et al.
upon stimulation by lipopolysaccharide in RAW 264.7, a
murine macrophage cell line.[101]
The adjunctive effects of C. sinensis in clinical renal
transplantation were explored.[102] Patients (n = 202) were
divided randomly by lottery into a treatment group (n = 93)
or a control group (n = 109). Patients in the treatment
group were treated with C. sinensis 1.0 g three-times a day
in addition to the immunosuppressive regimen given to the
control group. Patient and graft survivals were compared, as
was incidence, time and severity of acute rejection episodes,
chronic allograft nephropathy (CAN), hepatotoxicity and
nephrotoxicity, biochemistry parameters including indica-
tors of liver and kidney functions, fats, proteinuria, dosages,
and whole blood concentrations of ciclosporin. The results
suggested that the use of C. sinensis may allow decreased
doses and concentrations of ciclosporin, causing fewer side
effects without an increased risk of acute rejection. In addi-
tion, C. sinensis with a reduced dose of ciclosporin may
decrease proteinuria and retard CAN progression.
Antioxidant activity
Antioxidant activity in the xanthine oxidase, haemolysis
and lipid peroxidation assay systems was demonstrated
from a polysaccharide fraction of cultured C. sinensis myc-
elia.[65] Pheochromocytoma PC12 cells were protected
against H2O2-induced injury by a 210-kDa polysaccharide
from C. sinensis mycelia.[103] Treatment of the cells with the
polysaccharide at 100 mg/ml before H2O2 exposure signifi-
cantly elevated the survival of PC12 cells in culture by over
60%. In parallel, the H2O2-induced production of malondi-
aldehyde in cultured cells was markedly reduced by the
polysaccharide treatment, and the pretreatment of the
polysaccharide significantly attenuated the changes of glu-
tathione peroxidase and superoxide dismutase activity in
H2O2-treated cells in a dose-dependent manner. The bioac-
tivity of the polysaccharide from C. sinensis fungus and its
antioxidant activity on H22-tumour bearing mice was
undertaken.[104] The H22 tumour growth was inhibited and
superoxide dismutase activity of liver, brain and serum,
and glutathione peroxidase activity of liver and brain in
tumour-bearing mice were enhanced. The water and
ethanol extracts of the cultured fruiting bodies of C. sinensis
were found to possess a potent antioxidant activity.[105] Also,
anti-lipid peroxidation activity was detected and accumula-
tion of cholesteryl ester in macrophages was inhibited via
suppression of low-density lipoprotein (LDL) oxidation.
Antitumour activity
A variety of bioactive compounds isolated from Cordyceps
were reported to display antitumour activity. Cordycepin
displayed an antitumour effect by stimulating adenosine
A(3) receptors, followed by activation of a glycogen syn-
© 2012 The Authors. JPP © 2012
Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
A review of Cordyceps
thase kinase-3b in the Wnt signalling pathway, and
inhibited the growth of B16 melanoma cells inoculated
subcutaneously into right murine footpads.[106,107]
Ergosterol peroxide isolated from C. ciacadae inhibited
phytohaemagglutinin-induced T-cell proliferation, and
arrested the progression of activated T cells from G1 to S
phase of the cell cycle. Early gene transcripts, in particular
those of cyclin E, interferon, and interleukins were sup-
pressed.[44] The esterified form of ergosterol peroxide from
C. sinensis was more potent than the aglycon in inhibiting
proliferation of tumour cells.[42] A polysaccharide fraction
from C. sinensis was studied as to its effect on the prolifera-
tion and differentiation of human leukaemia cells using an
in-vitro culture system.[108] The conditioned medium had
an activity that significantly inhibited proliferation of U937
cells, and differentiated U937 cells also had functions of
phagocytosis and superoxide production. Antibody neu-
tralization studies further revealed that the tumoricidal and
differentiating effects of the compounds were mainly
derived from the elevated cytokine concentrations. An
exopolysaccharide fraction of C. sinensis inhibited metasta-
sis of melanoma cells and downregulated concomitantly the
levels of Bcl-2 protein into the lungs and the liver.[109] A
water-insoluble extracellular glucan isolated from the
culture filtrate of C. ophioglossoides was reported to sup-
press potently the growth of sarcoma 180 solid-type
tumours.[27] Also, a galactosaminoglycan was isolated from
C. ophioglossoides [110,111]. It inhibited the proliferation of
sarcoma 180 cells and the growth of a syngeneic solid
tumour in vivo and exhibited cytotoxicity against cancer
cells in vitro.
In a series of studies, water extracts of C. sinensis were
reported to: increase the survival time of mice inoculated
with carcinoma cells or syngeneic fibrosarcoma cells; inhibit
spontaneously liver metastasis of carcinoma cells and
melanoma in syngeneic mice, and the results suggested that
the activity was not attributable to cordycepin; prolong the
survival period of mice inoculated with B16 melanoma cells
when co-administered with methotrexate; and cause apop-
tosis of melanoma cells.[112–115] A water soluble fraction of
C. militaris showed cytotoxic activity on three human
cancer cell lines: stomach adenocarcinoma (SNU-1); color-
ectal adenocarcinoma (SUN-C4); and hepatocellular carci-
noma (SNH-354).[116] Cytotoxic activity guided isolation
and identification of active fractions afforded cordycepin as
an active component. Two fractions of methanol extracts,
rather than cordycepin or polysaccharides, from fruiting
bodies of C. sinensis were reported to inhibit the growth of
K562, Vero, Wish, Calu-1 and Raji tumour cell lines.[117]
Also, these two fractions significantly inhibited the blast-
ogenesis response, natural killer cell activity, interleukin-2
production and TNF production in phytohaemagglutinin-
stimulated human mononuclear cells.[118]
485
A review of Cordyceps
The effects of C. militaris extract on angiogenesis and
tumour growth were evaluated.[119] The growth of human
umbilical vein endothelial cells (HUVEC), HT1080 and
B16-F10 cells were inhibited. The extract downregulated, in
a dose- and time-dependent manner, bFGF gene expression
in HUVEC cells and MMP-9 gene expression in HT 1080
cells. The growth of melanoma cells in mice was suppressed
and anti-angiogenic activity was manifested. The biochemi-
cal mechanisms of antiproliferative effects by aqueous
extract of C. militaris in human leukaemia U937 cells were
investigated.[120] It was found that they could inhibit cell
growth of U937 cells in a dose-dependent manner, which
was associated with morphological change and apoptotic
cell death such as formation of apoptotic bodies and DNA
fragmentation. Moreover, the treatment caused a dose-
dependent inhibition of cyclooxygenase-2 and prostaglan-
din E2 accumulation. Taken together, these results indicated
that the antiproliferative effects of these extracts were asso-
ciated with the induction of apoptotic cell death through
regulation of several major growth regulatory gene prod-
ucts such as Bcl-2 family expression and caspase protease
activity, and the extracts may have therapeutic potential in
human leukaemia treatment.
Effects on apoptotic homeostasis
Apoptosis, or programmed cell death, is an essential event
in organism development and homeostasis. There are
numerous events that can induce a cell to undergo apopto-
sis and since the implication of apoptosis in various
disease states as an effector mechanism, the ability to
inhibit apoptosis has emerged as an important potential
therapy. There are many reports of Cordyceps extracts
inhibiting and inducing apoptosis. The effects of C. sinen-
sis on apoptotic homeostasis have been well reviewed by
Buenz et al.[121]
Hepatoprotective
Animal tests and clinical research data have showed that
Cordyceps has a protective effect in liver patients, including
those with viral hepatitis A, chronic hepatitis B, chronic
hepatitis C and hepatic fibrosis. Bioactive components of
Cordyceps for liver protection are mostly Cordyceps polysac-
charides. Although the content and efficacy of Cordyceps
polysaccharides vary with the species, they can improve the
immunological functions of organic cells, removing
harmful components and thus reducing the injury to liver
cells. Four aspects of the effects in protecting the liver were
presented as follows: protective effect on immune liver
injury; effect on patients with hepatocirrhosis after hepati-
tis; effect on patients with chronic hepatitis B; protective
effect on liver fibrosis.
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Kai Yue et al.
In one study, Cordyceps extract was used in combination
with several other medicinal mushroom extracts as an
adjunct to lamivudine, for the treatment of hepatitis B.
Lamivudine is a common antiviral drug used in the treat-
ment of hepatitis. In the study, the group receiving Cordyc-
eps along with other medicinal mushroom extracts had
much better results in a shorter period of time than the
control group, who received only lamivudine.[122]
Nephroprotective
A traditional view held of the Cordyceps species is that its
consumption strengthens the kidneys. Studies have shown
that much of the kidney-enhancing potential of Cordyceps
stems from its ability to increase 17-hydroxy-corticosteroid
and 17-ketosteroid levels in the body.[45] The effects in pro-
tecting the kidney are mainly presented as three aspects:
protecting against chronic renal function failure; a thera-
peutic effect on toxic kidney injury; reversing the effect of
glomerulonephritis in an animal model. All these have been
proved by a series of experiments.
H1-A was reported to inhibit tyrosine phosphorylation
of human mesangial proteins.[123] In an earlier report, H1-A
alleviated immunoglobulin A nephropathy (Berger’s
disease) with histological and clinical improvement.[124]
H1-A reduced anti-double-stranded DNA production and
lymphadenopathy, delayed progression of proteinuria,
improved kidney function and inhibited the proliferation
of human mesangial cells, and promoted apoptosis
by suppressing tyrosine phosphorylation of Bcl-2 and
Bcl-XL.[123,125]
Hypoglycaemic and hypocholesterolaemic
A polysaccharide (CS-F30) obtained from the culture myc-
elium of C. sinensis showed potent hypoglycaemic activity
in genetic diabetic mice after intraperitoneal administra-
tion. The plasma glucose level was quickly reduced in
normal and streptozocin-induced diabetic mice after intra-
venous administration.[126] Crude and neutral polysaccha-
rides of C. sinensis exerted hypoglycaemic activity in normal
mice, but did not affect the circulating insulin level in
normal mice.[23] A polysaccharide (CS-F10), which was
purified from a hot-water extract of the cultured mycelia of
C. sinensis and composed of galactose, glucose and
mannose in a molar ratio of 43 : 33 : 24, lowered the plasma
glucose level in normal, adrenaline-induced hyperglycaemic
and diabetic mice.[22]
The mater extracts of cultured fruiting bodies of C. sin-
ensis prevented cholesterol deposition in the aorta of
atherosclerotic mice by inhibition of LDL oxidation medi-
ated by free radicals in an investigation into hypolipidaemic
activity.[127] A hypocholesterolaemic effect of hot-water
extract from mycelia of C. sinensis was investigated.[128] The
© 2012 The Authors. JPP © 2012
Kai Yue et al.
results suggested that it lowered the total cholesterol
concentration, reduced the concentration of cholesterol
carried by LDL and very-low-density lipoprotein, and
elevated the high density lipoprotein (HDL)-cholesterol
concentration in the serum of mice fed a cholesterol-
enriched diet.
Other bioactivity
The novel effect of cordycepin inhibiting collagen-induced
platelet aggregation was reported.[129] The data suggested
that the inhibitory effect of cordycepin might be associated
with the downregulation of [Ca2+]i and the elevation of
cAMP/cGMP production. Cordyheptapetide A, a novel
cycloheptapeptide, was isolated from a strain of Cordyceps
together with four known bioxanthracenes. There were only
two previous reports on the isolation of cyclic peptides
from this genus and these were from C. sinensis and C. mili-
taris, and the antimalarial and cytotoxic activity of the biox-
anthracenes were reported.[130] Cordyformamide was found
to exhibit activity against Plasmodium falciparum (Welch)
Schaudinn (Plasmodidae), whereas it showed weak or no
cytotoxicity.[131] Ophiocordin, an antifungal antibiotic
which was isolated from submerged cultures of C. ophi-
oglossoides, is devoid of antibacterial activity.[53] Bioxanthra-
cenes appear to be antimalarial, while the bioactivity data
for glycoprotein containing N-acetylgalactosamine isolated
from C. ophioglossoides are not available.[55,56,59] Chiou
et al.[132] observed a hypotensive effect of C. sinensis in
anaesthetized rats and a vasorelaxant effect in isolated
aorta. The fungus counteracted arrhythmia in rats and
increased the dosage of ouabain required to produce
arrhythmia in guinea-pigs.
The methanol extracts of C. ophioglossoides were
reported to protect the b-induced neuronal cell death and
memory loss through free radical scavenging activity in
rats.[133] The results suggested that C. ophioglossoides myc-
elium may be valuable for the protection from Alzheimer’s
dementia. A fraction dependently suppressed bronchoal-
veolar lavage fluid (BALF) cell proliferation, reduced inter-
leukin production in lipopolysaccharide-activated BALF
cell cultures, and affected interleukin mRNAs in various
significant ways.[134] Antifibrotic effect of extracellular
biopolymer from submerged mycelia cultures of C. milita-
ris on liver fibrosis was investigated.[92] The results indi-
cated that extracellular biopolymer had an antifibrotic
effect on fibrotic rats induced by a bile duct ligation and
scission operation. An ethyl acetate extract of C. militaris
was reported to inhibit IgE-mediated allergic responses in
mast cells and passive cutaneous anaphylaxis reaction in
mice.[135] An alcoholic extract of C. sinensis inhibited
abdominal aortic thrombus formation in rabbits by pre-
venting platelet aggregation.[136] The in-vivo and in-vitro
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Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
A review of Cordyceps
effects and its extracted fractions on the secretion of testo-
sterone in mice were studied.[137] C. sinensis, protein, and
poorly water-soluble polysaccharide and protein signifi-
cantly stimulated in-vitro testosterone production in puri-
fied mouse Leydig cells. Extracts enhanced the antibody
response, restored the phagocytic activity of macrophages
in tumour-bearing mice, and lengthened the survival
period of the mice.[138]
A mushroom lectin designated as CML has been purified
from C. militaris.[60] The lectin exhibited haemagglutination
activity in mouse and rat erythrocytes, but not in human
ABO erythrocytes. However, the N-terminal amino
acid sequence of CML differs greatly from those of other
lectins. CML exhibited mitogenic activity against mouse
splenocytes.
Bioactivity of the insect
Do extracts from the healthy insect show interesting activi-
ties, and at what stage does the activity occur in the
infected insect? This is an area of investigation which is
hardly reported. The accumulation of bioactive plant
metabolites by insects is well documented and insects are
used as medicines.[139,140] There are several reports about
the differences between the fungus and the insect parts.
Galactomannans isolated from the insect portion of C.
cicadae demonstrate potent hypoglycaemic activity in
mice.[141] The methanol extracts of C. cicadae insect-body
portion suppressed human mononuclear cell (HMNC)
proliferation, while aqueous methanol extracts of the asco-
carps portion enhanced HMNC proliferation activated
with phytohaemagglutinin.[142] The water extracts from the
fruiting body and insect of natural Cordyceps were ana-
lysed for their content of nucleosides and polysaccharides,
and the results showed that the insect had a chemical
composition similar to the fruiting body.[66] Furthermore,
both the fruiting body and worm of Cordyceps showed
similar potency in their antioxidation activity in the xan-
thine oxidase assay, the induction of haemolysis assay and
the lipid-peroxidation assay. Another paper reported that
the fruiting body and the host caterpillar had similar
ergosterol compositions, but the level of ergosteryl esters
in the host caterpillar was much higher than that in the
fruiting body.[67]
Current state and prospects
Current state
Nowadays, natural remedies are becoming increasingly
popular worldwide, and this leads to elaborate research in
more and more universities and research institutions. The
use of natural remedies is steadily growing in the United
States and this raises concerns about safety, efficacy, and
487
A review of Cordyceps
how they affect safe patient care.[143] According to the
world Health Organisation, it is estimated that about
three-quarters of the world’s population currently use
natural remedies and other forms of traditional medicines
to treat disease.[144] Cordyceps and its related products are
available in western countries as over-the-counter medi-
cine or tonics for their anti-ageing, ‘pro-sexual’, anticancer
and immune boosting effects, but poor supporting
scientific evidence is available.[145] It is a widely held
belief that herbal preparations are ‘natural’ and are there-
fore somehow safer and more efficacious with fewer side
effects[146,147]. Therefore, with the increasing recognition
and acceptance of natural remedies, and with the concep-
tion that natural medicines are much better than remedies
that are pharmaceutically derived, further scientific
research on pharmacological functions and chemical con-
stituents of natural remedies, especially C. sinensis, are
desirable.
Due to environmental and ecological factors, the annual
harvest of natural C. sinensis has been steadily declining,
while at the same time its worldwide demand has been
increasing. This situation has driven Cordyceps spp. prices
into an ever-increasing spiral, propelling researchers to
determine ways of cultivating it to make it a more afford-
able material for commercial trade.[148] In the present state,
the artificial cultivation of C. sinensis is not likely to reach
commercial levels, and many scientific and technical prob-
lems remain to be solved, such as the mechanism and
approach of parasitizing, and the screening of highly viru-
lent strains. Experimental evidence and scientific explana-
tion have been provided for the use of C. militaris as a
substitute for C. sinensis, and this may provide a solution to
the demand for C. sinensis. [14]
Since the discovery Cordyceps as an ancient natural
remedy and tonic, it has undergone much research,
however, many of its medicinal claims are still unsubstanti-
ated. According to Li et al.[103], C. sinensis possesses antitu-
mour and antioxidation activity, and stimulates the
immune system, but the identity of the active component,
or components, has not been determined. Yang et al.[149]
stated that although certain polysaccharides from C. sinensis
are bioactive, the antitumour effect has not been confirmed.
Many papers have reported on the effects of the crude
extracts, rather than on the effects of the novel pure com-
pounds, which are the most revealing in terms of determin-
ing the effects of the fungus. Also, the problem of over
extrapolation of in-vitro data to imply therapeutic value
should be brought to the forefront.
At the end of the day, our challenge in the modern age is
to scientifically unravel the claims and problems of this
natural medicine, for example, bioactive compounds,
research on biological screening, artificial cultivation of the
fungus, a better understanding of the status in natural
488 Royal Pharmaceutical Society 2013 Journal of Pharmacy and Pharmacology, 65, pp. 474–493
Kai Yue et al.
habitats, the differences between the fungus and the insect
components.
Prospects
Nowadays, with the theory of ‘back to the pavilion’, people
are more willing to take natural medicines rather than the
synthetic drugs. Natural medicines, such as medicinal
mushroom, can conquer life-claiming diseases leaving little
side effects on human health. Although the artificial cultiva-
tion of C. sinensis has not been completely achieved, the
highest cordycepin production was obtained in surface
liquid culture using C. militaris mutant.[150] With the
advance of science and technology, through innovation, the
pharmaceutical industry is able to maintain a high output
rate on low-cost materials with reasonable safety. Therefore,
biometabolites extracted from medicinal mushroom like
Cordyceps will be the key future driving force in the realm of
green pharmacology and pharmacognosy.
Conclusions
In China, Cordyceps has been used as a traditional medicine
throughout history. It seems logical that there should be
some truth behind the myths of its effectiveness for certain
ailments. During recent decades, as new uses have been
found for Cordyceps and as the development of Cordyceps
preparations has continued, some correlative products have
rapidly appeared one after another, and the development of
curative and health-care products from Cordyceps have
become more and more favourable among people in China.
As investigation into this fungus continues, more bioactive
components with potential therapeutic value will be iso-
lated. However, new methods and technologies must be
adopted to extract and analyse the components, requiring
evaluation along modern scientific lines, such as biological
screening, accurate phytochemical analysis, pharmacologi-
cal investigation, gene sequencing and clinical trials. At the
same time, due to the enormous cost of research and the
scarcity of C. sinensis, to find and investigate substitutes
having the same efficacy as C. sinensis, such as C. militaris
and its related species, will be of great importance. Overall,
so far, we know only a little of the wonders of this creature
and it still has many secrets for us to discover. More
research is needed on the herbal medicine and its related
species.
Declarations
Conflict of interest
The Author(s) declare(s) that they have no conflicts of
interest to disclose.
© 2012 The Authors. JPP © 2012
Kai Yue et al.
Funding
This review received no specific grant from any
funding agency in the public, commercial, or not-for-profit
sectors.
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