Health Articles
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
Fig. 1. (a) Cordyceps militaris on dead insect; (b) Cordyceps polycephala on dead insect host; (c) Cordyceps spp. on Campanotus; (d) Cordyceps spp. on anunidentified moth; (e) Cordyceps spp. on a micropezid fly; (f) Cordyceps spp. on another micropezid fly.
to have been over-harvested. Furthermore, the price of nat-
In vitro culture of the fungus has been employed
ural products of CS is over US$ 12,000 kg1 (2006 prices)
increasingly and state, ‘‘It is generally
for only ‘‘average quality" (how this is determined is not
accepted that its cultivated CS fungi possess the same func-
clear) in the market and increasing ). So
tions as CS natural ‘‘herbs" (sic)". Some other issues that
one can understand the pressures on supply. The socioeco-
require addressing are that natural C. militaris is not read-
nomic implications of the FTCM are highly significant to
ily available and is costly. Thus, a growing number of so-
the regions where it is harvested. The fungus has officially
called Cordyceps products that derive from mycelial cul-
been classified as an endangered species by CITES Man-
tures of the asexual forms of these fungi have become
agement Authority of China and China Customers and this
commercially available Mycelia culti-
scarcity is of considerable concern to all. Consequently,
vation has resulted in establishing a number of cultures
living strains have been isolated from natural CS and cul-
derived from the holomorphic CS. These are referred to
tivated in large quantity by bioreactor technology which
by the anamorphic names Paecilomyces hepiali and Cepha-
is a promising method to meet the needs of human con-
losporium sinensis, although the anamorph of CS appears
sumption and to reduce the pressure on natural resources
to be Hirsutella sinensis (and see later). However, the situ-
of the species ().
ation is confused with some taxonomist using outdated
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
names. To paraphrase : while these
to show the similar effects of the cultured mycelia to the
strains undoubtedly support ecologically sustainable use of
natural products. However, the cultured material used
CS, the actual similarities between the wild fungus and the
was derived from a wide range of strains, and not from a
cultures are not clear.
valid CS. Some of these were products from the Chinese
The consumption of complimentary medicine has
Medicine Factory of Jiangxi and Hebei Boding Pharma-
increased dramatically, with over 42% of people in the Uni-
ceutical Factory. In addition, the FTCM are boiled in
ted States of America reported as ‘‘users". Sales were US$
water or soaked in alcohol to drink for medications/health
3.3 billion in 1999 (An important factor
foods. Obviously, the various solvents and temperatures
was the passage of the Dietary Supplement Health and
may have resulted in different compounds
Education Act in 1994 in the USA which opened the
). Nevertheless, state that the
market for TCM ). One can
ongoing exploration of CS has shown that the species
appreciate how journals advocating these have increased
can produce ‘‘many" bioactive compounds, and the medic-
concomitantly. Why have they not been developed by big
inal benefits of CS have been demonstrated extensively.
pharmaceutical companies and made available to the pub-
In addition, there is (unbelievably for scientific journals)
lic in pure compound form? No doubt there could be many
the use of words such as ‘‘Yin" and ‘‘Yang" as a basis for
reasons why this has not happened (e.g. not enough profit,
undertaking scientific research on material activities.
‘‘sticky" intellectual property rights issues (see
discusses kidney ‘‘yang" and one needs to ask
difficulty in mass production or synthesis, etc.) –
what this is from a scientific perspective. Why include this
apart from the possibility that they simply may not be
word when it has no scientific currency? The fungus is also
effective. Buenz et al. mention that ‘‘one of the most inter-
referred to as a herb and indeed the title of the piece asks,
esting supplements is the not yet well-characterized C. sin-
‘‘C. sinensis animal, vegetable or both?", whereas it is
ensis (Berk.) Sacc.".
CS has attracted much research interest for anti-oxidant
Various bioactive constituents from Cordyceps species
activity and there is considerable evidence of this from the
have been reported. These include cordycepin and other
fungus as a treatment of a wide range of diseases. However,
anti-bacterial and anti-tumour adenosine derivatives, ophi-
unauthenticated material has been used in some cases. For
cordin, an anti-fungal agent, and L-tryptophan. Recent
example, a polysaccharide was isolated which can protect
reports have indicated that CS contains polysaccharides
PC12 cells against hydrogen peroxide-induced neuronal
exhibiting anti-oxidant activity and nucleosides that inhibit
cell toxicity, but the Cordyceps mycelia used was from
platelet aggregation (The bioactive com-
the Wan Fong Pharmaceutical Factory (Zhejiang, China)
pounds involved in the activities claimed include polysac-
and derived from Ce. sinensis Chen sp. nov. This is a
nomenclaturally illegitimate fungal name, which raised
metabolites which are produced by this fungus and related
doubts as to its relationship to CS. In fact, it was later
species. The beneficial effects on (a) renal and hepatic func-
proved to be a different species ()
tion and (b) immunomodulation-related anti-tumour activ-
and this is a specific example of a general problem in the
ities are most promising and deserve great attention. An
field. An example of another problem is CordyMax Cs-4,
increasing number of studies have used cultured mycelia
a commercial mycelial fermentation product that lowered
in investigations. More mechanism-based, disease-oriented
fasting plasma levels of glucose and insulin, improved oral
pharmacological studies are required to ensure clinical effi-
glucose tolerance and increased the glucose–insulin index,
cacy for particular diseases. However,
which measures insulin sensitivity, in rats
state revealingly that studies have demonstrated repeatedly
However, the following statement is given on the
that many natural products marketed as nutraceuticals or
web site of the product, ‘‘These (health-related) statements
health food do not deliver the health benefit as claimed
have not been evaluated by the Food and Drug Adminis-
and are inconsistent from batch to batch.
tration. This product is not intended to diagnose, treat,
In the popular mind, CS first gained worldwide atten-
cure or prevent any disease".
tion when it was revealed that several Chinese runners
Extracts from artificially cultivated fruit-bodies of CS
who broke world records in 1993 had included this fungus
from the Xinhui Xinhan Artificial Cordyceps Factory
in their diet as part of their training program. Although sci-
(Guangdong, China) could scavenge ROS by inhibiting
entist need to desist from quoting such reports as they are
malondialdehyde formation by the peroxynitrite generator
unsubstantiated and far-fetched. Purported and unsubstan-
SIN-1. These results have been since referred to uncritically
tiated effects of the fungus include use as an aphrodisiac,
(e.g. However, the
analgesic, immune modulator, and free radical scavenger.
fungal material may have been unauthentic, because
A review of the literature uncovers the predictable collec-
reports exist that cultivation of fruit-bodies of this fungus
tion of general papers concerning medical mushrooms
was not repeatable and that the manufacturer is actually
some with a distinctly ‘‘alternative" flavour. I have no con-
selling C. militaris. Furthermore, compared
cerns about being alternative but are they scientific? These
the anti-oxidant activities of natural CS and cultured
overviews often are written in breathless, overblown and
Cordyceps mycelia from different sources and were able
unscientific terms; others are well balanced.
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
talks about ‘‘novel mushroom-based healthcare
effects. Cordycepin contributes to the anti-tumour, insecti-
products and therapeutics licensed for medical use can con-
cidal and anti-bacterial activity. Ergosterol (a universal
tribute to the good health status and feeling of the poverty-
fungal compound) exhibits anti-tumour and immunomod-
stricken strata of urban societies and populations. Indeed,
ulatory activity. Finally, a DNase has been characterized.
mushroom cultural practices and medicines are being
These are not particularly novel compounds and one won-
widely accepted as the integral skeins in the fabric of the
ders why there are so many reports of the effects of crude
human society of tomorrow".
extracts rather than much more work on the effects of
A valid response to this situation of a wide range in the
novel pure compounds.
quality of papers would be to only review those papers that
Cordycepin ), 3-deoxyadenosine, is a derivative of
have a high impact factor (or any impact factor). Tempo-
the nucleoside adenosine differing from the latter by the
rarily putting the debate about the value of impact factors
absence of oxygen in the 30 position of its ribose entity.
to one side, the reader may find it beneficial to concentrate
As such is may be quite common. Initially, it was extracted
only on those journals reviewed herein that do indeed have
from Cordyceps; however, it is now produced synthetically.
such ratings. Of course, the disadvantage is that valuable
Some enzymes do not discriminate between adenosine and
information may be missed. It may be worth mentioning
so it can participate in certain reactions. For example, it
that, Asian nations on the world stage have realised that
can be incorporated into RNA molecules causing prema-
biomedicine offers a unique chance to develop new indus-
ture termination of its synthesis. It is classified as an anti-
tries and markets. Universities in Singapore, Korea, Hong
cancer compound.
Kong and China are appearing concomitantly in world
Cordycepin inhibited the growth of Clostridium parapu-
tables for the best and citations data suggest they are pro-
trificum and Clostridium perfringens, but had no effect on
ducing well-regarded papers (
Bifidobacterium spp. and Lactobacillus spp. (
The following review concentrates on the biological
In addition, larvicidal activity against Plutella xylo-
activity of various preparations of Cordyceps spp. (the
stella after 2–4 days of treatment was observed (
name as used in the essentially non-taxonomic papers)
It is interesting that cordycepin, a compound origi-
because of the quantity of data and importance of medici-
nally isolated from C. militaris as much as 60 years ago
nal claims, at the expense of taxonomic and quality control
(), is known to exert cytotoxic
effects through nucleic acid methylation (),with possible implications for the PCR of these fungi (seeIf it is a truly useful compound it
is surprising that it is not a well-known pharmaceuticalby now.
The various pure compounds, extracts, whole fungus
The presence of cordycepin in CS has been difficult to
and other preparations as they relate to pharmacological
confirm, although it has been confirmed by NMR
activities are discussed next, as these divisions are consid-
However, other groups have not been able
ered to be most relevant to a biochemical/phytochemical
to detect this compound It is clearly
perspectives of the topic.
important to confirm the presence of the compound inCS in terms of determining the active components of the
2.1. Pure compounds
fungus and ultimately for chemotaxonomic purposes.
state that cordycepin is isolated from
Data from pure compounds are the most revealing in
C. militaris and is (claimed to be) an ingredient in TCM
terms of determining effects of the fungus/insect. It is notedthat these reports are scarce. Some compounds fromCordyceps (as defined here) are not particularly unusual.
review the chemical constituents
and pharmacological properties. The chemical constituentsinclude (a) cordycepin (30-deoxyadenosine) and its deriva-tives, (b) ergosterol, (c) polysaccharides, (d) a glycoproteinand (e) peptides containing a-aminoisobutyric acid. Theactivities ascribed to the fungus are anti-tumour, anti-metastatic, immunomodulatory, anti-oxidant, anti-inflam-matory, insecticidal, anti-microbial, hypolipidaemic, hypo-glycaemic, anti-aging, neuroprotective and renoprotectiveeffects: So a vast a range of properties from a narrowspread of compounds.
Polysaccharides account for the anti-inflammatory, anti-
oxidant, anti-tumour, anti-metastatic, immunomodula-tory, hypoglycaemic, steroidogenic and hypolipidaemic
Fig. 2. Chemical structure of cordycepin.
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
which is prescribed for various diseases, such as cancer and
related strain provided cordyheptapeptide A, cordyhepta-
chronic inflammation (again note how vague this verbatim
peptide B, and known ES-242s. The structures of the novel
statement is). In this study, the novel effect of cordycepin
bioxanthracenes were 60-O-desmethyl analogues of the
compounds described. Furthermore, cordyheptapeptide B
reported. The data suggests that the inhibitory effect of
has an N-methyl-L-phenylalanine residue in place of the
cordycepin might be associated with the down-regulation
N-methyl-L-tyrosine. The isolation, structure elucidation,
of [Ca2+]i and the elevation of cAMP/cGMP production.
and anti-malarial activity of ES-242s and their analogues
This result has obvious significance for prevention of
from the insect pathogenic fungus Cordyceps pseudomilita-
thrombus formation. Finally, cordycepin inhibited the
ris (from a Lepidoptera larva) were reported previously.
growth of B16 melanoma cells inoculated subcutaneously
Cycloheptapeptide, cordyheptapeptide A, and some known
into right murine footpads ).
ES-242s were isolated from a Cordyceps strain from an
Cordyheptapeptide A ), a novel cycloheptapep-
elaterid larva.
tide, was isolated from a strain of Cordyceps together with
In a continuing search for bioactive compounds from
four known bioxanthracenes. There were only two previ-
insect pathogenic fungi it was noticed that culture extracts
ous reports on the isolation of cyclic peptides from this
of six Cordyceps strains, collected in the same location
genus and these were from C. militaris and CS. The metab-
(from Coleoptera larvae, at Doi Innthanon National Park,
olite exhibited anti-malarial activity against Plasmodium
Chiang Mai Province, Thailand), showed similar 1H NMR
falciparum and cytotoxicity to Vero cell lines. Also, the
spectra. This suggested the presence of bioxanthracenes
anti-malarial and cytotoxic activities of the bioxanthrac-
(ES-242s) and cordyheptapeptide A as major constituents.
enes were reported ().
Two of these strains were subjected to mass fermentation
In an extensive and impressive report, compounds desig-
(15 L) and chemical investigation. As a result, five new
nated as ES-242s, were isolated from a Verticillium strain
ES-242 analogues and nine known compounds and cordy-
and identified as bioxanthracenes ().
heptapeptide A were isolated from an undefined strain.
These compounds were known to exhibit potent activity
Cordyheptapeptide B, was isolated, together with other
as N-methyl-D-aspartate (NMDA) receptor antagonists.
known compounds. Some of these were tested for activity
In addition, five novel ES-242 analogues were isolated with
against P. falciparum and cytotoxicity to KB cells (oral
nine known compounds from a Cordyceps strain. A closely
human epidermoid carcinoma), BC cells (human breastcancer), NCI-H187 cells (human small cell lung cancer),and noncancerous Vero cells (African green monkey kid-ney fibroblasts). Cordyheptapeptide A exhibited anti-malarial activity, while cordyheptapeptide B was inactiveand both cyclic peptides showed moderate cytotoxicity.
Furthermore, cordyformamide is a plausible biogeneticprecursor of xanthocillin Y, and was isolated from a cul-ture broth of Cordyceps brunnearubra BCC 1395. Cordy-formamide was found to exhibit activity against P.
falciparum, whereas it showed weak or no cytotoxicity).
Production of the nonribosomal peptides cicapeptins I
and II () were reported by which was the first report from fungi of consecutive Hypor Pro residues in a nonribosomal linear peptide. The com-pounds exhibited anti-bacterial and anti-fungal activity.
A novel immunosuppressant was isolated from the cul-
ture broth of Isaria sinclairii, the anamorph of C. sinclairii,and characterized as (2S,3S,4R)-(E)-2-amino-3,4-dihy-droxy-2-hydroxymethyl-14-oxoeicos-6-enoic acid, whichwas identical to anti-fungal substances, myriocin and ther-mozymocidin The suppressive activitywas found to be equal to, or higher than cyclosporin Awhich is used clinically. The activities of the 10 derivativeswere also examined, indicating the following relationshipsbetween structure and activity – the: (a) lactone formationbetween the carboxy group at C-1 and the hydroxy groupat C-4, and the reduction of the carbonyl group at C-14
Fig. 3. ORTEP view of cordyheptapeptide A
to the hydroxy group do not affect the suppressive activity;
(b) hydrogenation of the double bond at C-6 resulted in
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
Fig. 4. (1 and 2) Cicapeptins I and II; (3) myriocin from Cordyceps heteropoda
decreased activity; and (c) acetylation of the amino group
tosis of mesangial cells in vitro and in vivo. The conclu-
and the thioketalization on the carbonyl group at C-14
sions were that H1-A may be effective in the management
‘‘drastically" reduced the suppressive activity. Also, the
of autoimmune disorders, and the modulation of the sig-
compound suppressed the production of anti-bodies to
nal-transduction proteins may represent a target for future
sheep red blood cells and induction of cytotoxic lympho-
pharmacologic interventions. More correctly, they proba-
cyte T cells more strongly than cyclosporin A. Obviously,
bly do represent a target, and such vague statements should
this is an important lead compound and hence one of the
be avoided. In an older report, HI-A alleviated immuno-
more satisfactory papers.
globulin A nephropathy (Berger's disease) with histological
isolated a pure compound (H1-A)
and clinical improvement ). HI-A inhibited
from CS and investigated whether autoimmune disease
the proliferation of human mesangial cells and promoted
progression in mice was affected by administration of the
apoptosis by suppressing tyrosine phosphorylation of
metabolite. The authors are vague as to what the com-
Bcl-2 and Bcl-XL () and reduced anti-
pound is and state that, ‘‘it is a kind of ergosterol and looks
ds-DNA production and lymphadenopathy, delayed pro-
like testosterone". The authors also provide a chemical
gression of proteinuria, improved kidney function and
structure which confirms that it is a common sterol and a
inhibited mesangial proliferation ().
systematic name could have been provided. Their results
Moving on to more interesting compounds, cordypyri-
demonstrated that mice treated daily exhibited a progres-
dones A and B were detected from the uncommon species,
sive reduction in anti-ds-DNA production. In clinical pre-
C. nipponica. These are atropisomers, and demonstrated
potent anti-malarial activity in vitro ).
lymphadenopathy, a delayed progression of proteinuria,
state that, ‘‘in an effort to evaluate the
and an improvement in kidney function. Histological anal-
pharmacological effects, including the anti-aging effect" of
ysis of kidney tissue indicated that H1-A inhibited mesan-
the fruiting bodies of the cultivated Paecilomyces japonica
gial proliferation that was evident in lupus nephritis.
fungus, ‘‘a new type" of Cordyceps sp. was investigated.
However, there was no change in immune complex deposi-
Two pure compounds were isolated as active principles
tion. H1-A ‘‘may be" useful for treating systemic lupus ery-
from low molecular-weight fractions, and a protein-bound
thematosus in human patients. However, more work is
polysaccharide that showed a marked increase in the liver
required. H1-A was claimed to be effective in the treatment
enzyme activities, and a significant inhibition of lipid per-
of autoimmune disorders (Results dem-
oxidation was found. reported that
onstrated inhibition of cell proliferation and promotion of
ophiocordin, an anti-fungal antibiotic from Cordyceps
apoptosis of activated human mesangial cells in vitro: the
ophioglossoides ) and balanol from Ver-
activities were not a result of cytotoxicity. In addition,
ticillium balanoides are structurally identical. This may
H1-A inhibited tyrosine phosphorylation of human mesan-
gial proteins. These findings suggest that H1-A modulated
between the two taxa. The structure of ophiocordin was
some (unspecific) subcellular signal-transduction pathways
falsely assigned and balanol was the compound of interest.
and changed the balance between proliferation and apop-
Balanol was under development as an anti-cancer agent as
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
it established to be a selective inhibitor of protein kinase C
). Ergosterol peroxide isolated
It is more common for pure compounds to be tested in
from C. cicadae inhibited phytohaemagglutinin-induced T
the fields of anti-bacterial, anti-fungal, anti-malarial and
cell proliferation, and arrested the progression of activated
insecticidal activity which is to be recommended more gen-
T cells from G1 to S phase of the cell cycle. Early gene tran-
erally. Ophiocordin is an anti-fungal antibiotic isolated
scripts, in particular those of cyclin E, interferon, and inter-
from submerged cultures of C. ophioglossoides. However,
it is devoid of anti-bacterial activity ().
glycosylated form of ergosterol peroxide from CS was
Bioxanthracenes (see also previously) were isolated from
more potent than the aglycone in inhibiting proliferation
C. pseudomilitaris
of tumour cells However, ergosterol per-
and appear to be anti-malarial. Ten-membered mac-
oxide is widespread in fungi and Cordyceps does not offer
rolides, cepharosporolides C, E and F, cordycepin, pyri-
any particular advantage in its preparation.
It is worth noting that eight different Cordyceps species
hydroxybutyl) furan were reported from C. militaris by
(CS. C. militaris, C. cicadae, C. ophioglossoides, C. hetero-
However, only cordycepin
poda, C. pseudomilitaris, C. nipponica, C. sinclairii) are
was anti-malarial. reported cicada-
listed in the above paragraph indicating the extent of the
peptins I and II (nonribosomal peptides containing amino-
possible diversity involved in the biology and activity
isobutyric acid), which were anti-bacterial and antifungal,
Although whether they are distinct species
and myriocin (anti-fungal) from C. heteropoda isolated
is open to question.
from an Australian cicada. Finally, a glycoprotein contain-ing N-acetylgalactosamine was isolated from C. ophio-
2.2. Polysaccharides and fractions
glossoides but activity data are not available (
Water-soluble crude polysaccharides were obtained
An inhibitor of the prophenoloxidase activation was iso-
from the fruiting bodies of cultured C. militaris by hot-
lated from a culture filtrate of C. militaris and identified as
water extraction followed by ethanol precipitation. The
dipicolinic acid (DPA). The production of DPA in a range
polysaccharides were successively purified by chromatogra-
of Clavicipitaceae fungi was examined. Entomogenous
phy giving three polysaccharide fractions. In the in vitro
fungi that produce DPA were integrated into one group
anti-oxidant assay, P70-1 was found to possess hydroxyl
by a phylogenetic analysis based on 18S rDNA. Interest-
radical scavenging activity. The polysaccharide is a hetero-
ingly, it was suggested that the group acquired an ability
polysaccharide and is occasionally branched. The funda-
to produce DPA during its evolution from plant patho-
mental information obtained from this work is beneficial
genic fungi to entomogenous fungi ).
to the interpretation in the relationship of polysaccharide
In a useful comparison of crude extracts and pure com-
structure and its biological functions. This provides the
pound, the anti-diabetic effect of various fractions of C.
‘‘experimental evidence and scientific explanation for the
militaris, CCCA (crude cordycepin containing adenosine),
folkloric uses of C. militaris as a substitute for CS" (
CMESS (ethanol soluble supernatant), and cordycepin
were evaluated in diabetic mice (CMESS
The effect of an exopolysaccharide fraction (EPSF) from
showed a potent inhibitory activity of 34.7% in starch-
anamorphic strains of CS on the immunocyte activity of
loaded mice: CMESS reduced blood glucose level by
tumour-bearing mice was investigated. EPSF significantly
35.5%. However, CCCA, and cordycepin showed no differ-
inhibited the H22 tumour growth, and elevated the activity
ence. After 7 days administrations of these drugs, CMESS,
of immunocytes. It enhanced the phagocytosis capacity of
and cordycepin dramatically reduced blood glucose level.
peritoneal macrophages and proliferation ability of spleen
CCCA with a high concentration of cordycepin did not
lymphocytes. EPSF promoted (a) TNF-a expression of
reduce blood glucose level. Proliferation of T-lymphocyte
macrophages, (b) the cytotoxicity of spleen lymphocytes,
was significantly decreased; while NO production was
and (c) TNF-a and IFN-c mRNA expression of splenic
increased more than two-fold in the cordycepin-adminis-
lymphocytes ).
tered group. The proliferation of macrophages and NO
CS possesses anti-tumour, anti-oxidation and stimula-
production were significantly decreased in the CMESS
tion of the immune system activities
administered group. CMESS and cordycepin may be (a)
However, the identity of active component(s) has not been
useful tools in the control of blood glucose level in diabetes
determined Towards this end, a polysac-
and (b) promising new drugs as an anti-hyperglycemic
charide was isolated from cultured Cordyceps mycelia
agent without the defects of lowered immune responses
which had strong anti-oxidation activity, and which con-
and other side effects, the authors suggest.
tained glucose, mannose and galactose. The pre-treatment
of the isolated polysaccharide on cultured rat pheochromo-
homocitrullyl aminoadenosine, adenine, cordycepic acid
cytoma cells demonstrated strong protective effect against
and D-mannitol have been reported from Cordyceps spp.
hydrogen peroxide (H2O2)-induced insult. Treatment prior
to H2O2 exposure significantly elevated the survival of
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
PC12 cells in culture. This was the first report that identi-
conidiophores). However, it is unwise to speculate what
fied a polysaccharide from Cordyceps, which protected
the material actually is as descriptions are vague. A pro-
against the free radical-induced neuronal cell toxicity. A
tein-bound polysaccharide that inhibited lipid peroxidation
water-soluble polysaccharide fraction, a poorly water-solu-
and increased the activity of anti-oxidant was described
ble polysaccharide, and a protein fraction stimulated
from the fungus. Finally, phaeochromocytoma cells were
steroidogenesis (). Interestingly, galac-
protected against H2O2-induced injury by a 210-kDa poly-
tomannans isolated from the insect portion of C. cicadae
saccharide from CS mycelium ).
demonstrate potent hypoglycaemic activity in mice (
reported that a water-insoluble
extracellular glucan isolated from the culture filtrate of C.
In an investigation into a polysaccharide from CS myce-
ophioglossoides suppressed potently the growth of sarcoma
lium hypocholesterolaemic and hypotriglyceridaemic activ-
180 solid-type tumours. Remarkably, a protein-bound
ity in mice was exhibited ).
polysaccharide fraction from C. ophioglossoides extended
studied a polysaccharide fraction from CS as to its
the life of mice bearing Ehrlich carcinoma or a syngeneic
effect on the proliferation and differentiation of human leu-
kaemia cells using an in vitro culture system. The condi-
isolated a galactosaminoglycan that inhibited
tioned medium had an activity that significantly inhibited
the proliferation of sarcoma 180 cells and the growth of
proliferation. Differentiated cells also possessed phagocyto-
a syngeneic solid tumour in vivo: it exhibited cytotoxicity
sis functions and supported superoxide production. Anti-
against cancer cells in vitro.
body neutralization studies further revealed that the
observed that medium from blood
tumouricidal and differentiating effects of the compounds
mononuclear cells stimulated with the polysaccharide frac-
were mainly derived from the elevated cytokine concentra-
tion from CS inhibited the proliferation of human leukae-
tions. Finally, galactosaminoglycan from C. ophioglosso-
mic cells, and induced approximately 50% to differentiate
ides reacted with sera from patients with certain collagen
into mature monocytes/macrophages expressing non-spe-
diseases and its use as an index of serological activity is
cific esterase activity and certain surface antigens. The
thus of diagnostic value (
anti-proliferation and differentiating effects were demon-
An aqueous extracted polysaccharide from cultured C.
strated to be caused by an elevated production of cyto-
militaris demonstrated general anti-inflammatory activity
kines, i.e. a tumour necrosis factor and an interferon.
as did ethanolic extracts of cultured fruit-
The exopolysaccharide fraction of CS inhibited metastasis
ing bodies and mycelia of C. militaris applied topically in
of melanoma cells and down-regulated concomitantly the
the croton oil-induced ear oedema test in mice. The fact
levels of Bcl-2 protein into the lungs and the liver (
that in vitro fruiting bodies were employed rather than
in vivo is interesting as most papers report using fruiting
The exopolysaccharide fraction of cultivated Cordyceps
bodies in vivo and/or in vitro biomass. However, the paper
stimulated peritoneal macrophages to take up neutral red
is flawed as the details of the cultivation of the fruiting
and splenic lymphocytes to proliferate
bodies were not provided.
Crude and neutral polysaccharides of CS exerted
Antioxidant activity in the xanthine oxidase, haemolysis
hypoglycaemic activity in normal mice. However, the poly-
and lipid peroxidation assay systems was demonstrated by
saccharide did not affect the circulating insulin level in nor-
from water extracts, and a polysaccharide
mal mice The compound lowered the
fraction, of cultured CS mycelia. Interestingly, the fruiting
plasma glucose level in diabetic mice ().
body and the caterpillar parts of CS are claimed to be sim-
Another unspecific polysaccharide from a hot-water
ilar in chemical composition and hence anti-oxidant activ-
extract of mycelia also lowered the plasma glucose level
ity, because the fungus had presumable replaced the insect
in normal, adrenaline-induced hyperglycaemic and diabetic
constituents with fungal It would be inter-
esting to determine (a) how this occurs in terms of insect
Some Cordyceps-like strains have been isolated from the
substrate utilisation and optimisation of yields of bioactive
fruiting bodies of wild CS that have been reported to show
fungal components, (b) when the preparation is at the cor-
the same properties as the natural product. However, care
rect stage for use as a medicinal treatment, and (c) if these
in interpretation is required as these could conceivably be
data could be extrapolated to in vitro culture.
contaminants (see later). An exopolysaccharide fraction
An ambiguous statement is made by
was prepared from cultivated CS ().
‘‘Cordyceps is negative for its many biological activities
The results showed that it enhanced significantly the Neu-
and a tonic for restoring vital functions in traditional Chi-
tral Red uptake capacity of peritoneal macrophages and
nese medicine". It proceeds to state that P. japonica is a
spleen lymphocyte proliferation in melanoma-bearing
new type of Cordyceps species, which is incomprehensible.
mice. The metastasis of B16 melanoma cells to lungs and
It also mentions that P. japonica is (or produces) mush-
livers was significantly inhibited. Moreover, the levels of
rooms. Paecilomyces is considered to be an anamorph of
Bcl-2 in the lungs and livers were decreased. The results
Cordyceps and so this appears to be incorrect and, what
suggest that the polysaccharide has an immunomodulatory
appear to be mushrooms, may be synnemata (compacted
function and anti-tumour activity.
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
However, state that although certain
needs to be deemphasised in favour of that of pure
polysaccharides from CS are bioactive, the anti-tumour
effect has not been confirmed. The authors investigatedthe effects of the exopolysaccharide fraction of cultivated
2.4.1. Water extract
CS fungus on c-Myc, c-Fos, and vascular endothelial
Reports on the metal chelating and reducing power
growth factor (VEGF) expression of tumour-bearing mice.
from CS are not available in the scientific literature. There-
The expression in the lungs and livers of treated mice were
fore, there is a demand to obtain an overall measure of the
found to be significantly lower than those of untreated
anti-oxidant activity of extracts using reliable fungal mate-
mice. The authors suggest that the fraction had inhibited
rial because of increasing interest in the relationship
tumour growth in the lungs and livers of mice, and that
between anti-oxidants and diseases. The anti-oxidant activ-
it is an adjuvant in cancer therapy.
ities from natural and cultured mycelia of CS were investi-
In addition, isolated four polysaccha-
gated in vitro. Optimal effects were demonstrated on the
rides from C. militaris, CPS-1 was shown to possess a sig-
inhibition of linoleic peroxidation. The results suggested
nificant anti-inflammatory activity and suppressed the
that the cultured and natural mycelia have direct and
humoral immunity in mice but had no significant effects
potent activities and that the cultured mycelia could be
on cellular immunity and non-specific immunity. In a pre-
used for the anti-oxidant activity which would tend to
vious study using anti-oxidant activity-guided fraction-
reduce the pressures on the natural fungus, which is, after
ation CSP-1 from cultured Cordyceps, mycelium was
all, an endangered species ().
isolated. The hypoglycemic effect of CSP-1 on mice and
The anti-oxidant efficiency of C. militantis extract (CME)
rats was demonstrated. CSP-1 increased circulating insulin
and CS extract (CSE) in protecting lipid, protein, and low-
level in diabetic animals, which suggests that the com-
density lipoprotein (LDL) against oxidative damage was
pound(s) may stimulate pancreatic release of insulin and/
reported (). However, this study provoked
or reduce insulin metabolism. undertook
a strong response from which was subse-
further work on the biological activity of the isolate: the
quently rebutted by one of the original authors (
polysaccharide from fungus and its anti-oxidant activity
This is something of an unexpected bonus to a reviewer of
on H22-tumour bearing mice was investigated. The H22
the literature such as myself as another opinion is obtained.
tumour growth was inhibited and SOD activity of liver,
The questions are, what biological material is being worked
brain and serum and GSH-Px activity of liver and brain
with, and can other scientists obtain it to repeat the exper-
in tumour-bearing mice were enhanced. In general, benefi-
iment? The current author has encountered this before
cial effects were observed in the liver and brain of tumour-
where commercial interests are involved. The
bearing mice.
Hamburger response can be applied in a general sense to
Finally, four exopolysaccharides with different molecu-
some of the other work cited in the present review. CME
lar masses ranging from 50 to 2260 kDa were reported
and CSE showed weakly inhibitory effect on liposome oxi-
from C. militaris by as part of yield
dation. The inhibitory effect of CME on protein oxidation
optimisation studies. An extracellular polysaccharide
was inferior to that of CSE. CME and CSE showed inhibi-
extracted from the mycelia of CS with hot-water indicated
tion of LDL oxidation. The contents of the bioactive ingre-
that this D-glucan consisted of a backbone composed of
dients cordycepin and adenosine in CME were higher than
(1 ? 3)-b-D-glucosyl
those of CSE; however, cordycepin and adenosine showed
(1 ? 4)-b-linked D-glucosyl residue: sugar residues were
no significant anti-oxidant activity. In addition, a polysac-
linked with b-glycosidic bonds ().
charide present in CME and CSE displayed anti-oxidantactivity. The authors concluded that the protective effects
of CME and CSE against oxidative damage of biomoleculesare a result of their free radical scavenging abilities. How-
A lectin from C. militaris exhibited hemagglutination
ever, the experimental data and some of the conclusions
activity in mouse and rat erythrocytes, but not in human
need a critical comment (The author
ABO erythrocytes (However, the N-ter-
criticised the report on the bases of poor taxonomy, bio-
minal amino acid sequence differed greatly from those of
chemistry and extrapolation of data to imply possible cures
other lectins. It exhibited mitogenic activity against mouse
of diseases. In particular, the authors' claims of a potential
treatment for human disease on the basis of in vitro data arecalled into question. The rebuttal by Duh simply confirms
that appropriate information about the strains was not pro-vided; the comments on the inadequate analytical proce-
The following section concerns solvent extraction of the
dures are largely accepted. And there is no doubt that the
fungi. In effect, this is often how the preparations will be
conclusions could have been rewritten to indicate that the
consumed as a TCM. The significance of tests on extracts
results were preliminary. Hamburger (personal communi-
is much reduced compared to those of pure compounds.
cation, 2007) stated that the rebuttal was evasive, an assess-
There is a great deal of data. In general, this type of work
ment with which I agree.
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
describe the effects of CS against
of carcinoma cells and melanoma in syngeneic mice and
Group A streptococcus infection in mice. The preparation
results suggested that the activity was not attributable to
protected by decreasing bacterial growth ‘‘and dissemina-
cordycepin (); prolonged the sur-
tion", thereby increasing mouse survival rate. IL-12 and
vival period of mice inoculated with B16 melanoma cells
IFN-gamma expression and macrophage phagocytic activ-
ity also increased. claim to demonstrate
and caused apoptosis of melanoma cells
that CS increased phagocytosis in human monocytic cells
and abrogated inhibition of phagocytosis by causing cyto-
An orally administered CS was considered to be ‘‘quite"
kine production. These two reports are sound and in good
safe based on body weight gain, and liver/kidney weights of
journals. However, the fungus used was from a company
mice The authors concluded
called Simpson Biotech and very few or no details are sup-
the extract could inhibit aortic cholesterol deposition in
plied about how the material was collected, identified,
atherosclerotic mice by scavenging free radicals in vivo.
maintained, and grown. Of course, this is unsatisfactory.
These extracts ‘‘may have" beneficial effects on the process
refer somewhat unusually to CS as a
of atherogenesis and aging with few side effects (
‘‘black blade" fungus. Their results showed that CS
). This is good news but surely more evi-
improved renal function and reduced the expression of
dence is required. Towards these ends,
inflammatory and apoptotic genes in rats. The authors
also demonstrated the hydroxyl radical scavenging activity
make the very conditional statement that, CS extract may
of CS. Whereas reduced lipid peroxidation in rats was dem-
play a potential therapeutic role in renal transplantation";
onstrated by Antioxidant activity in
on the other hand it may not play an actual role. After all,
the xanthine oxidase, haemolysis and lipid peroxidation
precision in what is written in such important areas of
assay systems was reported from water extracts, and a
medicinal research is crucial. The authenticity of the fungal
polysaccharide fraction, of cultured CS mycelia (
material can be questioned: it was obtained from a com-
As mentioned previously, the fruiting body and
pany from the United States of America and there is little
the caterpillar parts of CS are claimed to be similar in
indication about the standards of collecting, purity, identi-
chemical composition and hence anti-oxidant activity
ties and maintenance of the materials. Basically, what level
). It would be interesting to determine (a) how
of accreditation applies to such organizations?
this occurs in terms of insect substrate utilisation by the
A C. militaris inhibited the growth of human umbilical
fungus with a view to optimising yields of bioactive fungal
vein endothelial cells (HUVEC) and HT 1080 cells. It
components, (b) when the preparation is at the correct
down-regulated, in dose- and time-dependent manners,
stage for use as a medicinal treatment, and (c) if these data
bFGF gene expression in HUVEC cells and MMP-9 gene
could be extrapolated to in vitro culture.
expression in HT 1080 cells. The growth of melanoma cells
also reported radical scavenging
in mice was suppressed. In addition, anti-angiogenic activ-
activity with Wang et al. reporting activity against colorec-
ity was manifested ). It is gratifying that
tal tumour cells.
adequate details of the fungal material are provided in this
The influence of CS on the immunoactivity of macro-
Chinese journal, which acts as a model for others generally.
phages was determined to probe the mechanism of its
observed a hypotensive effect of CS
alleged tonic effect. The phagocytosis of macrophages were
in anaesthetized rats and a vaso-relaxant effect in isolated
enhanced significantly and ‘‘maybe" the
aorta. The fungus counteracted arrhythmia in rats and
tonic effect of CS is accomplished by an enhancing effect on
increased the dosage of ouabain required to produce
the immune system. Some chemical fractions had insulin
arrhythmia in guinea-pigs. In addition, the heart rate in
like and insulin release promoting activity and ‘‘could be
anaesthetized rats and the contractility of isolated papillary
developed" as an anti-diabetic agent ).
muscle or atria in guinea-pigs were decreased (
Cordyceps possessed a strong anti-oxidation activity in all
assays tested by . The cultured Cordyceps
Cultured fruiting bodies of CS prevented deposition of
mycelia had equally strong anti-oxidation activity com-
cholesterol in the aorta of atherosclerotic mice by inhibit-
pared to in vivo Cordyceps. Further, the anti-oxidation
ing free radical-mediated LDL oxidation in an investiga-
activities were increased 10–30 in the partially purified
tion into hypolipidaemic activity
polysaccharide fractions. In an intriguing report,
). A hot-water extract of mycelia (a) lowered the total
mentions that identification of an effective non-toxic
cholesterol concentration, (b) reduced the concentration of
biological radioactivity protector is a ‘‘matter of some
cholesterol carried by LDL and very-low-density lipopro-
urgency". Orally administered CS protected mice from
tein, and (c) elevated the high density lipoprotein
bone marrow and intestinal injuries after total-body irradi-
(HDL)-cholesterol concentration in the serum of mice fed
ation. The levels of free radical species within cells are sug-
a cholesterol enriched diet ). Water
gested to be a likely mechanism for the purported effects.
extracts of CS: increased survival time of mice inoculated
The biochemical mechanisms of anti-proliferative effects
with carcinoma cells or syngeneic fibrosarcoma cells
of C. militaris in human leukemia cells were investigated
); inhibited spontaneously liver metastasis
in a convincing study involving cancer treatment (
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
). It was found that they inhibited cell growth in a
). It represents a bizarre rational for undertaking the
dose-dependent manner, which was associated with mor-
work and it is surprising that it was published from a scien-
phological change and apoptotic cell death such as forma-
tific perspective. The rational for the work is that CS is a
tion of apoptotic bodies and DNA fragmentation.
popular Chinese tonifying herb, and was/is revered for
Furthermore, the treatment caused a dose-dependent inhi-
being, what is referred to as, ‘Yin-nourishing' and ‘Yang-
bition of cyclooxygenase-2 (see ) and prosta-
invigorating' in Chinese medicine In
glandin E2 accumulation. Taken together, these results
order to establish the pharmacological basis for the ‘Yin-
indicated that the anti-proliferative effects were associated
nourishing' and ‘Yang-invigorating' action of Cordyceps,
with the induction of apoptotic cell death through regula-
the effects of wild and cultured Cordyceps on concanavalin
tion of several major growth regulatory gene products.
A stimulated splenocytes, an in vitro bioassay for ‘Yin-
The extracts ‘‘may have therapeutic potential" in human
nourishment', and myocardial ATP generation capacity,
leukemia treatment. In addition, corticosterone output by
an ex vivo bioassay for ‘Yang-invigoration', were investi-
cultured rat adrenocortical cells was increased without
gated in mice. The results indicated that wild and cultured
increasing the intracellular cAMP level. The steroidogenic
Cordyceps enhanced the Con A-stimulated splenocyte pro-
effect was abolished by the protein kinase C inhibitor cal-
liferation in vitro and myocardial mitochondrial ATP gen-
phostin C, indicating that its action may involve stimulation
eration ex vivo in mice, with no significant difference in
of protein kinase C (C. militaris reduced
potency of action between the two types of Cordyceps.
the fasting serum glucose level and enhances glucose utilisa-
While the immunopotentiating effect was associated with
tion in skeletal muscles in rats (). The fun-
the increase in interleukin-2 production, the stimulation
gus demonstrated cytotoxic activities on the three kinds of
of myocardial ATP generation was paralleled by an
human cancer cell lines, stomachic adenocarcinoma, colo-
enhancement in mitochondrial electron transport. When
rectal adenocarcinoma, and hepatocellular carcinoma
compared with typical ‘Yin' and ‘Yang' tonifying Chinese
(Cytotoxic activity-guided isolation and
herbs, Cordyceps was found to possess both ‘Yin-nourish-
identification of active fractions afforded the well-known,
ing' and ‘Yang-invigorating' activities, with a lower
cordycepin as an active component (see above).
potency in both modes of action. It is impossible to take
reported that CS mycelia prolonged
reports such as these seriously from a scientific standpoint
swimming endurance capacity and produced an anti-fati-
and is given considerable space here to indicate a general
gue action in mice. CS reduced the hepatic content of mal-
problem which may have motivated some of the published
reports reviewed herein. This is without attempting to
transaminases and alkaline phosphatase in rats with hepa-
detract from the philosophical aspects of the concepts of
tic fibrosis. Treatment with the extracellular biopolymers
Yin and Yang in terms of two mutually correlated oppo-
resulted in a reduction in hepatic hydroxyproline content
sites in a general sense. A comprehensive definition of the
and normalization of morphological characteristics of the
corresponding philosophy of science is inappropriate: It
liver, indicating an anti-fibrotic action ().
is enough to state that it is vitally important for science that
Finally, crystals of the fungus stimulated proliferation of
the information about the surrounding world and the
erythroid progenitor cells in mouse bone marrow
objects of study be as accurate and as reliable as possible.
To continue, CS fruiting bodies inhibited various
tumour cell lines (): two fractions were par-
ticularly potent. Growth inhibitors other than cordycepin
In a very interesting report, the insect-body part (of the
and polysaccharides may have been involved; two fractions
TCM) inhibited proliferation of enhanced human mononu-
significantly inhibited (a) the blastogenesis response, (b)
clear cells (HMNC). Any differences between the fungus
NK cell activity and (c) IL-2 production
and insect components are well worth further investigation.
). Neither fraction was cytotoxic, and immunosup-
The production of interleukin-2 and interferon was stimu-
pressive ingredients were found to be intracellular. Fruiting
lated by the aqueous methanolic extracts and inhibited by
bodies inhibited human mesangial cells (HMC) activation
the methanolic extracts ). Treatment of
by IL-1 plus IL-6 () and liver toxicity or
patients with condyloma acuminata brought about an
mutagenicity were not observed. The fraction was purified
increase in interleukin-2 and a decrease in interleukin-10,
to obtain purified compound H1-A (see above). The
indicating a recovery in the balance of Th1/Th2 cytokines.
authors claim a novel treatment for human Berger's disease
Recurrence was also diminished ). Inter-
‘‘in the future". A fraction (a) dose dependently suppressed
estingly, the ergosterol esters concentrations were much
bronchoalveolar lavage fluids (BALF) cells proliferation,
higher in the (dead) caterpillar than the fruiting bodies
(b) reduced interleukin production in LPS activated BALF
(although ergosterol was similar.
cell cultures and (c) affected interleukin mRNAs in various
Although why these compounds are of particular interest
significant manners The purported ther-
is ‘‘mystifying" as they are universal in fungi.
apeutic activity may be related to modulation of cells func-
In a surprising paper, the following may be an example
tions in bronchial airways. Furthermore, the molecular
of the mystical nature of some of the reports (see
mechanism of Cordyceps pruinosa pharmacological and
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
biochemical actions of macrophages in inflammation has
exhibited potent intestinal immune system-modulating
not been clearly elucidated The authors
activity, while the methanol-soluble fraction manifested
suggest that an extract suppresses inflammation through
intermediate activity ).
expression, and hence may be beneficial for treatment of
endotoxin shock or sepsis.
detected inhibition in melanoma colony
wrote that they attempted to develop
formation in murine lungs by CS. The fruiting bodies of
‘‘a new type Cordyceps". To obtain this, they investigated
‘‘P. japonica" reduced tumour weight and volume and
the effects of the fruiting bodies of the cultivated fungus
lengthened the life span of mice inoculated with sarcoma
of P. japonica grown on silkworm larvae on hyperglycemia
180 cells (but what this fungus represents
in rats and mice and on immunological functions in mice.
in unclear. Water and ethanol extracts of CS possessed a
As mentioned previously, it is not at all clear whether Pae-
potent anti-oxidant activity ().
cilomyces (even) contains anamorphs of Cordyceps. There-
Anti-lipid peroxidation activities also were detected and
accumulation of cholesteryl ester in macrophages was
Immunostimulating activity and a significant anti-fatigue
inhibited via suppression of LDL oxidation. Hot-water
effect in mice were observed. reported
extracts were particularly effective. ‘‘P. japonica" exhibited
unidentified substances which inhibited tumour cells, but
immunostimulating activity. Its ethanolic extract stimu-
which were not cordycepin or polysaccharides, in the meth-
lated phagocyteosis and macrophage acid phosphatase
anolic extract of CS – this report requires further
C. militaris demonstrated general anti-inflammatory
C. cicadae ascocarps enhanced HMNC proliferation
activity ) in mice. The fact that cultured
). In contrast, the insect-body portion
fruiting bodies were employed is interesting rather than
suppressed HMNC proliferation. This is a most interesting
extraction from those from the wild and most papers seen
result in the current author's opinion because of the differ-
for this review either use fruiting bodies from the wild and/
ent effects of the two components. The action mechanisms
or in vitro biomass. However, it is disappointing that
of the fractions may involve the regulation of interleukin
details of the cultivation of the fruiting bodies are not pro-
and interferon production in HMNC. Overall, the results
vided as this is required. Nitric oxide production and iNOS
demonstrated that C. cicadae contained growth modula-
gene expression in LPS-stimulated RAW 264.7 cells are
tors for HMNC. Unfortunately, the compounds responsi-
suppressed by ethanolic preparations
A unique insight into how the cultured fruiting
demonstrated that a hot-water extract modulated interleu-
bodies were produced in this report and should be referred
kin-6 production by activation of macrophages and aug-
to: this detail is required in future reports. CS (as supplied
mented the secretion of haematopoietic growth factors.
by the ‘‘Xinhui Xinhan Artificial Cordyceps Factory" (sic))
Whereas aqueous methanolic extracts of the ascocarp stim-
inhibited MDA generation via hydroxyl radicals induced
ulated proliferation of phytohaemagglutinin-induced pro-
by the peroxynitrite generator SIN-1 and macrophage
liferation of HMNC. Of course, such differences indicate
accumulation of esterified cholesterol (
that different compounds are involved or the same com-
). The authors concluded that the cultured CS has
pounds are at different concentrations.
anti-oxidant and anti-lipid peroxidation properties and
C. ophioglossoides mycelia prevented cell death in neuro-
inhibits accumulation of cholesteryl ester in macrophages
nal cells and memory deficits in rats (). Two
via suppression of LDL oxidation. The authors conclude
fractions from fruiting bodies inhibited (a) the blastogene-
correctly that this cultured Chinese medicine appears to
sis response, (b) natural killer cell activity, (c) interleukin-2
merit further investigation as an anti-atherosclerotic.
production and (d) tumour necrosis factor production inphytohaemagglutinin-stimulated human mononuclear cells
2.4.4. Ethyl acetate
). The levels of interferon, interleukin-1
In the unusual use of this solvent to create an extract
and tumour necrosis factor produced by cultured rat Kupf-
from CS mycelia, apoptosis in human pre-myelocytic leu-
fer cells were increased by the fungus (
kaemia HL60 cells was induced. In addition, cell prolifera-
Proliferation of cells in BALF was inhibited which also
tion was inhibited (). Obviously, ethyl
reduced tumour necrosis factor ).
acetate may extract different compounds from the fungus
In an effort to evaluate the pharmacological effects,
compared to the more common water or methanol extracts
including the anti-aging, of the fruiting bodies of the culti-
and the constituents need to be determined.
vated P. japonica fungus, a new type of Cordyceps sp. wasinvestigated (This statement by the
authors is incomprehensible (see above). Types of fungi
An alcoholic extract of CS inhibited abdominal aortic
are the typical specimens often held in culture collections.
thrombus formation in rabbits by preventing platelet aggre-
It is not proposed to discuss the described effects herein.
gation ). CS was extracted in PBS and dialyzed
Hot-water extracts of Cordyceps scarabaecola stromata
(the resulting macromolecule fraction
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
was assayed in anesthetized rats for hypotensive effects and
tions may have to be prepared in water or ethanol in
in isolated aorta for vasorelaxant effects. A constituent(s) in
CS relaxed vascular beds directly. The in vivo and in vitroeffects and its extracted fractions on the secretion of testos-
2.5. Whole fungus
terone in mice were studied (). CS, water-soluble protein, and poorly water-soluble polysaccharide
CS down-regulated inflammation-related genes in the
and protein significantly stimulated in vitro testosterone
rat kidney following ischaemia/reperfusion
production in purified mouse Leydig cells. The authors con-
). A similar treatment improved lung function in gui-
cluded that it is ‘‘possible" that CS ‘‘might" contribute to an
nea-pigs and airway inflammation in rats, suggesting a pos-
alternative medicine for the treatment of some reproductive
sible asthma treatment ). C. pruinosa
problems caused by insufficient testosterone levels in human
inhibited (a) gene expression of an interleukin tumour
males, which is a large leap in conclusions. Increase antigen
necrosis factor, (b) inducible nitric oxide synthase (iNOS)
expression was found in hepatoma cells and ‘‘will" provide
and cyclooxygenase-2, and (c) nuclear transcription factor
more effective host immune surveillance against tumour
NF-jB activation in a lipopolysaccharide (LPS)-stimulated
cells ) from a Cordyceps extract. In an interest-
mouse macrophage cell line: This indicated a role in the
ing study, the beneficial effects of the ‘‘traditional Chinese
treatment of endotoxin shock or sepsis (
medicine CS", on mice with hypoferric anaemia were eval-
Anti-ds-DNA production was inhibited and improved
uated by NMR spectroscopy (). The
survival in mice indicated that CS may be beneficial to
extract increased hepatic energy metabolism in anaemic
patients with systemic lupus erythematosus, an autoim-
mice and was concluded to be due to increased hepatic
mune disease with involvement of multiple organ systems
blood flow. concluded that ‘‘their"
The fungus inhibited lymphadenectasis,
extract ‘‘is" effective in resisting the oxidative damage on
reduced proteinuria and plasma anti-ds-DNA antibody
liver mitochondria of diabetic mice.
and improved renal function in MRL 1pr/1pr mice (
attempted to identify the signaling
An oral dose of 2–4 g daily for 3 years pre-
pathways for the induction of HL-60 cell apoptosis by CS
vented the recurrence of lupus nephritis and protected
mycelium extract (CSME). CSME induced nuclear frag-
renal function in lupus nephritis patients ).
mentation and DNA degradation, two hallmark events of
Carcinogenesis in the murine forestomach was sup-
apoptosis, in the HL-60 cells within 12-24 h of treatment.
pressed by Cordyceps ). Results from
Concomitantly, several major events in the mitochondrial
indicated that the levels of IL-1 and INF, produced
signal pathway occurred, including (a) the loss of MTP,
by cultured rat kupffer cells were increased from rats fed on
(b) cytochrome c release into the cytoplasm, (c) the
CS. Studies have demonstrated that polysaccharides
decrease in Bcl-2 protein level, (d) the translocation of
extracted from these natural products have anti-hypergly-
Bax protein from cytoplasm into mitochondria, and (e)
cemic effects (). These authors investigated
the activation of caspase-2, -3, and -9. However, caspase-
the effects of intragastrically administered Cordyceps sp.
8, the initiator caspase in the death receptor pathway,
for alleviating fasting hyperglycemia in diabetic rats. Ani-
was not activated. These results suggest that CSME
mals had significantly increased serum levels of triglyceride,
induces apoptosis in HL-60 cell through the mitochondrial
cholesterol and blood urea nitrogen, and significantly
pathway rather than the death receptor pathway.
decreased body weight, serum albumin levels and weights
Treatment of D-galactose-induced-aged-mice with an
of the thymus, lungs and gastrocnemius muscle compared
unspecific CS extract resulted in (a) an improved learning
to animals in the control group. In addition, blood glucose
ability and memory, (b) an increase in superoxide dismu-
was significantly increased compared to the control group;
tase activity in erythrocytes, liver and brain, (c) an increase
these results suggest that enterally administered Cordyceps
in catalase and glutathione peroxidase activity in blood, (d)
sp. has potential anti-hyperglycemic ability. These findings
reductions in malondialdehyde levels in brain and liver and
reveal that the fungus ‘‘may be used as a nutraceutical to
(e) a reduction in monoamine oxidase activity in the brain
alleviate hyperglycemia in diabetes".
(). Extracts enhanced the antibody
Oral administration of Cordyceps alleviates fasting
response, restored the phagocytic activity of macrophages
hyperglycemia ). Recent evidence has
in tumour-bearing mice, and lengthened the survival period
shown that an extract has immunoregulatory activity.
of the mice ). An extract down-reg-
The objective was to investigate whether Cordyceps has
ulated apoptotic genes in the rat kidney following ischae-
biological activity in regulating the lymphocyte subsets in
mia/reperfusion ().
diabetes. After 2 weeks, body weight, thymus weight, thy-
found that a mycelial extract increased hepatic
mocyte number, and the percentages of total T and T
energy metabolism, as demonstrated by liver ATP:Pi value,
helper cells in the thymus were significantly lower in the
in diet-induced hypoferric anaemic mice by increasing
treatment groups than in the controls. Results demonstrate
hepatic blood flow.
that STZ-induced diabetic rats had significantly decreased
The following section considers the use of the fungus as
numbers and subsets of T cells in the thymus. However,
whole mycelium and/or fruit-bodies, although the prepara-
oral administration of Cordyceps did not improve these
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
changes. The results suggested that oral administration had
the components of Fuzheng Huayu recipe, which is used to
no significant effect on lymphocyte subsets in STZ-induced
control the development of post-hepatic cirrhosis or to pre-
diabetic rats.
vent complications from the disease
demonstrated in a convincing study,
The macrophage-stimulating activity of natural fungus
that CS mycelium regulates mouse cell testosterone pro-
and cultured mycelia has been described by
duction and may suppress stimulated testosterone produc-
. demonstrated immunosup-
tion via P450 scc enzyme activity.
pressant effects in the heterotropic heart allograft model
demonstrated that the fungus and fractions from it were
in rats and determined that prolonged survival periods
capable of stimulating testosterone production. The steroi-
were possible. Also, found prolonged
dogenic activity was observed in vivo in male mice after 7
mouse skin allograft survival time. The number of T helper
days of treatment
cells was increased, as were Lyt-1/Lyt-2 (T helper cells to T
found that protein kinase A and protein kinase C
suppressor cells) in peripheral blood and spleen
pathways are acted upon to stimulate steroidogenesis in
). A mitogenic action was demonstrated on sple-
MA-10 mouse Leydig tumour cells. Inhibitors of protein
nic lymphocytes and interleukin-2 from spleen cells of rats
kinase A, protein kinase C and phospholipase C and cal-
with chronic renal failure was augmented ). In
modulin antagonists (see reduce Leydig
addition, natural killer cell activity was enhanced
cell steroidogenesis induced by the fungus.
Treatment of patients with post-hepatic cir-
C. militaris inhibited (a) the growth and metastasis of
rhosis resulted in (a) enhancement of natural killer cell
Lewis lung cancer cells, and (b) the growth of sarcoma
function, (b) increased number and improved ratio of
S180 cells implanted in mice. In addition, the survival per-
CD4þ and CD8þ cells, and (c) reduction in IgA and IgG
iod of the mice was increased ).
levels (). Treatment of chronic hepatitis
showed that P. sinensis inhibited lipid peroxidation
B resulted in increased CD4/CD8 ratios, and reductions in
but increases the amount of glutathione peroxidase and
hyaluronic acid and procollagen type III. The data indicate
superoxide dismutase in mouse liver. Again the name of
the usefulness of the fungus in adjusting the level of T lym-
the fungus raises similar questions as to those raised for
phocyte subsets and treating hepatic fibrosis
P. japonica and consequently as to what material is being
demonstrated increased peripheral
used and whether the experiments could be repeated.
natural killer cell activity from healthy subjects and leukae-
Finally, Cordyceps is included in a list of anti-aging TCM
mia patients. Improved renal function and augmented cel-
lular immune function in chronic renal failure has also been
CS stimulated mitochondrial electron transport and
observed (The fruiting body portion,
ATP production (). The effect of the fungus
but not the carcass portion, of Cordyceps reduced weight
on hepatic fibrogenesis induced in rats was studied by
loss, polydipsia and hyperglycaemia in diabetic rats (
. It was found that it delayed cirrhotic
development and improves liver function by inhibiting
Some other somewhat obscure papers are available on
expression of transforming growth factor- and platelet-
the effect of whole fungi (i.e.
derived growth factor and deposition of procollagen I
and III. presented evidence for the ben-
eficial effects of CS on chronic hepatitis B.
The fungus increased DNA synthesis in primary cul-
tured rat tubular epithelial cells (Proxi-mal tubular cells were protected from the toxic effects of
reported the vasodilating effect of cul-
gentamicin. The possible mechanisms include protection
tured mycelia of CS in an investigation of the cardiovascu-
of sodium pump activity, reduction of lipid peroxidation
lar system of dogs. Thirty three cases of chronic hepatitis B
and attenuation of lysosomal over-activity in tubular cells
patients treated with cultured CS mycelia have shown that
due to phagocytosis of gentamicin (
the drug (a) improves liver function, (b) promotes negative
Also, rat kidneys were protected from cyclo-
transfer HBsAg, (c) markedly helps to raise plasma albu-
sporin-induced nephrotoxicity and ameliorated glomerular
min, (d) helps patients resist high gamma globulin and (e)
and interstitial damage ).
adjusts body immunocompetence ). It is
reported that ‘‘old" patients were protected from
suggested that the fungus may be a medicine for chronic
amikacin sulphate toxicity as demonstrated by decreases
hepatitis B patients in adjusting protein metabolism and
in urinary nephroaminoglycosidase and microglobulin.
correcting inversion of albumin and globulin. Since inflam-
Also, inhibition by C. militaris of LDL-induced prolifera-
mation has been reported to be associated with chronic dis-
tion of cultured human glomerular mesangial cells, which
eases inhibitory dietary factors such as the fungus may be
are involved in the development of glomerulosclerosis
beneficial in alleviating disease
was observed Treatment of mice
17b-Estradiol may directly influence the quality of
with C. militaris lengthened the swimming time to exhaus-
maturing oocytes and thus the outcome of assisted repro-
tion (An unspecified Cordyceps is one of
duction treatment. CS mycelium is ‘‘believed" to enhance
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
libido and fertility in both sexes. However, the mechanism
tional herbal medicine. Importantly, and unusually, the
of its effect in women has not been determined. This is
study followed a double blind, randomized, placebo-treat-
surely a rather thin basis on which to undertake research.
ment, pre-post test design. Essentially no effect was
concluded that treatment of granu-
observed. This is an example of why scientists need to cir-
losa-lutein cells with CS results in increased 17b-estradiol
cumspect about making unsubstantiated claims about the
production due, in part, to increased StAR and aromatase
powers of these preparations even if spin does help project
expression. If these data are confirmed, CS may help in the
development of treatment regimens to improve the success
‘‘In this regard, the maintenance of a balance of Yin and
rate of in vitro fertilization, they state.
Yang – two opposing components involved in life activities
found that cultivated Cordyceps
as exemplified by the antagonistic action of the sympathetic
mycelia inhibited humoral immune hyperfunction and
and parasympathetic nervous systems-is essential in achiev-
increase the serum complement level in patients with
ing a healthy condition" Statements
post-hepatic cirrhosis, and improved liver function. Whole
such as these leaves the current reviewer bewildered. Why
body insulin sensitivity in rats was increased
these terms are used in a scientific publication does not
The fungus increased the basal plasma insulin level
appear to merit comment. Previous studies have shown
(and inhibited hepatic fibrogenesis
that long-term treatment with a ‘‘Yang-invigorating" Chi-
() in rats with CCl4-induced liver fibro-
nese herbal formula (VI-28) could increase red cell CuZn-
sis. Previous studies by demonstrated that
superoxide dismutase (SOD) activity in male human sub-
the fruiting bodies of CS attenuated diabetes-induced
jects. Yet the authors conclude, the beneficial effect of
weight loss, polydipsia, and hyperglycemia in rats. Rats
VI-28 treatment on mitochondrial functional ability and
were orally administered, fruiting bodies, fermented myce-
antioxidant capacity may have clinical implications in the
lia, spent broth, or mycelia plus spent broth of the fungus.
prevention of age-related diseases.
The results revealed that the mycelia and spent broth had
investigated a commercial
anti-hyperglycemic activities similar to those of the fruiting
preparation of a cultivated strain of CS. They state that
bodies. The authors, bold claim that the fermented prod-
the immunomodulatory activities have been renowned for
ucts could be developed as potential anti-diabetic agents
centuries. The report describes positively the immunomod-
or functional foods for persons with a high risk of diabetes
ulatory features: In vitro results demonstrated that the fun-
mellitus needs further confirmation.
gus induced the production of interleukin (IL)-1, IL-6, IL-
mention that mycelium can inhibit tumour growth and
10 and tumour necrosis factor alpha, augmented surface
induce tumour cell apoptosis. However, the antitumour
expression of CD25 on lymphocytes, and elevated macro-
mechanisms are not fully understood. So, the molecular
phage phagocytosis and monocyte production of H2O2.
mechanism was determined. The authors conclude that cell
The authors state that, ‘‘Our results possibly provide the
apoptosis is induced by activating caspase-8-dependent and
biochemical basis for future clinical trials". The current
caspase-9-independent pathways and downregulating NF-
author emphasises that such over extrapolation of data
jB protein expression.
needs to be discouraged.
Mycelia induced human granulosa-lutein cells to pro-
found that CordyMax Cs-4 (a mycelial
duce 17b-estradiol by upregulating expression of steroido-
fermentation product of CS) ‘‘improved the bioenergy sta-
genic acute regulatory protein (StAR) and aromatase
tus" in the mouse liver. These findings may explain why
(). Also, steroidogenesis in mouse Ley-
CordyMax Cs-4 is claimed to alleviate fatigue and improve
dig tumour cells was stimulated with-
physical endurance especially in aged subjects. Reports of
athletes' performance being improved may also be sup-
Testosterone production was inhibited by human chorionic
ported from these types of reports. CordyMax Cs-4 low-
gonadotropin or dibutyryl cyclic AMP. Thus, its effect on
ered fasting plasma levels of glucose and insulin,
the signal-transduction pathway for steroidogenesis may
improved oral glucose tolerance and increased the glu-
be after the production of cyclic AMP.
cose–insulin index, which measures insulin sensitivity, inrats ).
2.7. Commercial preparations
An unspecified Cordyceps is reported to be a component
of Fuzheng Huayu recipe, which is used to control the
It is revealing to read the web sites of some of the com-
development of post-hepatic cirrhosis or to prevent its
mercial products: These are often written in unscientific
complications (). As part of the eternal
terms. The best of them at least contain warnings that,
search to find an excelsior of youth, many are interested
‘‘These statements have not been evaluated by the (US)
in anti-aging activity but it is difficult to define what his
Food and Drug Administration. This product is not
means scientifically. Are the authors stating that the aging
intended to diagnose, treat, cure or prevent any disease".
process is slowed for example? Do people live longer? In
undertook a revealing experiment to
any case, this was published in the journal, Chinese Journal
determine the effect on male cyclists' performance using a
of Integrated Traditional and Western Medicine which is an
combination of CS and Rhodiola rosea ‘‘herbs" – a tradi-
admirable sentiment but difficult to do in practice. A prep-
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
aration of CS referred to as Jinshuibao capsule, increased
Furthermore, an isolated extract of CS, H1-A (this is
the depressed superoxide dismutase activity and reduced
reported as a pure compound (see above), inhibited
elevated malondialdehyde (MDA) level caused by aging
induced apoptosis, by permeabilizing the cell membrane
when tested in senile patients. In addition, they enhanced
and upregulating nitric oxide synthase (
the repair of damaged non human animal DNA
On the other hand, extracts of CS did not inhibit
). Quite extraordinarily beneficial effects on
hydrogen peroxide-induced apoptosis (
senile patients are claimed and, of course, the constituents
in a reactive oxygen species model (
of the capsule may be difficult to verify.
Alternatively, CS down-regulated apoptotic
used ‘‘Jinshuibao", to restore cellular immune func-
genes and modulated apoptosis in a rat kidney ischemia
tion and ‘‘improve the quality of life" of patients with
reperfusion model.
advanced cancer without affecting humoral immune func-
Reported anti-apoptotic effects of CS include in (a) the
tion. Obviously, quality of life is a subjective notion and
mouse (anti-cytotoxic activity, anti-oxidant activity, cell
is difficult to define.
proliferation inhibition), (b) cell culture (anti-proliferation
Remarkably, a dried powder preparation of mycelia
activity, cell proliferation inhibition, hemolysis inhibitory
called Bailing capsule (a) prevented rejection of renal
activity, lipid peroxide formation inhibition, radical scav-
transplants, (b) protected renal and hepatic function, (c)
enging effect), (c) human cells (proliferation inhibition, nat-
stimulated haematopoietic function, (d) improved hypopro-
ural killer cell inhibition, tumour necrosis factor inhibition)
teinaemia and hyperlipidaemia and (e) reduced the incidence
and (d) the rat (gene expression inhibition). Whereas the
of infections (However, such claims must
reported apoptotic effects of the fungus are in: (a) the
surely carry considerable elements of doubt.
mouse (anti-tumour activity, metastasis inhibition) and
In another case of a combined treatment with as many
(b) cell culture (proliferation stimulation, cytotoxic activ-
as six other components in addition to CS, the treatment
ity). In reality these opposite effects are not incompatible.
was more effective at preventing acute renal failure than
There are three prominent factors that may contribute to
chronic in rats. Obviously, it is difficult or impossible to
the apparent discrepancies (the first and third are fairly
assess the efficacy of the individual components
obvious). First, certain fungi contain different biologically
active compounds. Second, extracts may contain a pro-drug; a metabolism step may be required to generate thebiologically active form. Third, different constituents may
be assayed as there are multiple methods of extraction uti-lized in the literature.
Inhibition of apoptosis is a novel area of clinical inves-
Furthermore, decreases in Fas, Fas ligand and tumour
tigation with great promise and so merits a separate section
necrosis factor expression and decreased caspase-3 activity
in this review and will be of particular interest to pharma-
have been demonstrated ). CS inhibited
cologists. In one of the more critical papers,
TNF-a expression However, when
mention that there is a wide range of uses of CS
apoptosis was initiated via a Fas agonist antibody (CH-
in the literature, and those claiming altered apoptotic
11) (aqueous and alcohol extracts
homeostasis are of the most intriguing. However, they
of CS did not rescue cells induced by Fas receptor ligation
emphasize problems created by the (a) difficulty of identify-
(). Furthermore, cell cycle arrest and/or
ing the species of Cordyceps and (b) many conflicting
inhibition of proliferation yield cells resistant to apoptosis.
reports of pharmacological function. In response, the
Papers concerning proliferation of leukemic U937 cells
authors (a) outline what is known about the ability of CS
() and glomerular mesangial cells inhibi-
to alter apoptotic homeostasis, (b) attempt to reconcile dif-
ferences in function, and (c) identify the challenges and
explained by conferring a apoptotic resistance to cells:
how to progress CS research.
the alteration may involve p53
Many disorders (e.g. stroke, myocardial infarction and
HIV) incorporate apoptosis in their aetiology and patho-
Overall, aqueous, and organic extracts of CS have the
genesis. The ability to inhibit apoptosis has emerged as
ability to inhibit apoptosis. Cells pre-incubated with CS
an important potential therapy (e.g. cancer). There are
extracts were equally sensitive to hydrogen peroxide and
reports of CS extracts inhibiting and inducing apoptosis
Fas-mediated apoptosis. Thus, the putative antioxidant
); this is not contradictory but allows
and anti-apoptotic properties of CS were insufficient to res-
a foundation to determine the molecular mechanism of
cue cells from apoptosis in vitro (). Fur-
activity. Indeed, Cordyceps may contain compounds that
thermore, cancer chemotherapeutics have involved the
inhibit apoptosis; however, conflicting evidence has been
ability to induce apoptosis. Hence the polysaccharide frac-
obtained. The fungus can scavenge reactive oxygen species
tion (H1-A) induced apoptosis by inhibiting (a) phosphor-
by inhibiting malondialdehyde formation by SIN-1, the
ylation of Bcl-2 and Bcl-xL and (b) apoptosis induced by
peroxynitrite generator, which has been confirmed by xan-
dimethyl sulfoxide (These data require
thine oxidase, hemolysis, and lipid peroxidation assays.
to be confirmed by further work ().
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
Finally, direct cytotoxic activity may be a factor (
polydipsia and hyperglycaemia in diabetic rats (
). Aqueous methanol extracts of C. cicadae ascocarps
enhanced human mononuclear cells (HMNC) proliferationIn contrast, the methanol (100%)extracts of the C. cicadae insect-body portion suppressed
4. Compounds of fungi isolated from Cordyceps
HMNC proliferation. Interestingly, the ergosterol estersconcentrations were much higher in the (dead) caterpillar
A factor which is not often considered is whether the
than the fruiting bodies although ergos-
activities of extracts and pure compounds are from the
terol was similar. Finally, the fruiting body and the cater-
Cordyceps of interest or from other contaminating fungi.
pillar parts of CS are claimed to be similar in chemical
The issues of anamorph/teleomorph associations are rele-
composition and hence anti-oxidant activity because the
vant here. For example, epicoccins A–D were isolated from
fungus had presumable replaced the insect constituents
cultures of a Cordyceps-colonizing isolate of Epicoccum
nigrum (Gliocladinins A and B are
Little scientific evidence exists to support the numerous
of an isolate of Gliocladium sp. that colonized CS (
herbs used to improve diabetes-related metabolic disor-
). It is essential that such activity is differentiated
ders (The dual organism medicine (i.e.
from that obtained from the traditional medicine or Cordy-
fruiting body and carcass) has been proposed to have
ceps per se. In a series of papers, (a) Paecilomyces militaris
multiple medicinal activities. In one investigation, the
is shown to possess militarinones A, B, C, D and (b) farino-
effects of the fruiting body and carcass of the preparation
somes and a deoxymilitarinone substance were detected
on hyperglycemia were investigated. Diabetic rats had sig-
from Paecilomyces farinosus
nificantly lower weight gain and higher blood glucose
). The authors do not make state-
response in oral glucose tolerance test than the control
ments as to the holomophic connections to Cordyceps.
rats; and these changes were significantly reduced by
does make this link to C. militaris (tele-
administrating the fruiting body of Cordyceps. The results
omorph) from P. militaris (anamorph) apparently on the
revealed that the fruiting body (not the carcass) of Cordy-
basis of the same pigment production. However, it is has
ceps attenuated the diabetes-induced weight loss, polydip-
been suggested that Paecilomyces does not contain anamo-
sia and hyperglycemia, and these improvements suggest
phic species of Cordyceps (Hence, com-
that fruiting body has a potential to be a functional food
ment on these reports is avoided by the current author
for diabetes.
because the relationships between Paecilomyces and Cordy-
The water extracts from the fruiting body and ‘‘worm"
ceps remain ill-defined.
of natural Cordyceps were analyzed for their content ofnucleosides and polysaccharides; the results showed thatthe worm had a chemical composition similar to the fruit-
5. What about the insect?
ing body (In addition, both the fruitingbody and worm of Cordyceps showed similar potency in
Another complicating facet is that the medicine may
their anti-oxidation activities in the xanthine oxidase assay,
contain a proportion of the insect host and so what does
the induction of hemolysis assay and the lipid peroxidation
this bring to the activity? This is an area of investigation
assay. These results suggest that the function of the worm
which simply is not reported. Indeed does the healthy
is to provide a growth medium for the fruiting body, and
insect have interesting activities, and/or at what stage does
that eventually, the worm is totally invaded by mycelia.
the activity occur in the infected insect? Could the activity
Aqueous methanol extracts of C. cicadae ascocarps
be greater at these stages? The accumulation of bioactive
enhanced human mononuclear cells HMNC proliferation
plant metabolites by insects is well documented
In contrast, the methanol (100%)
) and insects are used as medicines
extracts of the C. cicadae insect-body portion suppressed
). These aspects are almost totally ignored in
HMNC proliferation. This is a most interesting result in
the case of the medicinal Cordyceps. It appears as if ento-
the current author's opinion.
mologists have simply not been involved in the field. Doesthe insect have to be dead before the system works or aremore active components produced by the fungus as it is
6. Profiling chemical constituents
in the process of killing the insect? Research into these fac-tors could be fruitful.
The following are references concerning the chemical
Hence, it is worth reporting what is known about the
constituents as determined by analytical profiles (
differences between the insect and fungus parts: Interest-
ingly, galactomannans isolated from the insect portion of
oped a method involving ‘‘biospecific" extraction and
C. cicadae demonstrate potent hypoglycaemic activity in
HPLC for potential immunological components in CS.
mice (). The fruiting body portion, but
The two active compounds were identified as guanosine
not the carcass portion, of Cordyceps reduced weight loss,
and adenosine. found that cultured CS
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
mycelia have a much higher content of nucleosides than
9. Taxonomic considerations
natural CS. described an HPLC methodfor quantitative determination of adenosine and deoxya-
This present review is not intended to be a taxonomic
denosine. determined adenosine in fer-
paper, but is essentially a review of the papers that employ
mented products of Cordyceps by reversed-phase HPLC.
the name Cordyceps more or less loosely, to describe the
Ergosterol in CS can be determined by HPLC (
fungus used in medicinally related experiments. However,
), and, of course, ergosterol is present
in a most impressive paper, state that
in all fungi.
Cordyceps comprise over 400 species in their modern phy-logenetic classification of Cordyceps and the clavicipita-ceous fungi. Cordyceps Fr. host range is broad, ranging
from 10 orders of arthropods to the truffle-like genusElaphomyces, although most species are restricted to a sin-
When there are many questions as to what are the active
gle host species or closely related host species. The main
components, a section on optimisation may seem prema-
objectives of the study was to reassess the (a) morphologi-
ture. However, investigated the opti-
cal traits used currently, (b) taxonomic utility of the ana-
morphic forms and (3) classification in relation to
exopolysaccharides (EPS) and cordycepin during sub-
phylogenetic relationships. It may be worth mentioning
merged mycelial culture of C. militaris and CS. This was
that PCRs may be subjected to inhibition, and nucleic acids
not done in the paper comments upon.
may be affected by the medium in which the fungus was
Fermentations were performed in flasks and in 5-L stirred-
grown (see ). Unfortunately,
tank bioreactors. The concentrations of mycelial biomass,
do not provide details of how the fungi were
EPS and cordycepin achieved in submerged culture of C.
grown for analysis and so it is difficult to conjecture. Obvi-
militaris were higher than those of CS. As the authors
ously, as discussed in this review, the fungus produces
claim, comparative studies between the two fungi are not
numerous bioactive compounds which may be inhibitors
available and the paper was the first report on the optimum
or mutagens and the effect of metabolite production on
medium composition for submerged culture of CS. Cordy-
the DNA preparations need to be determined or misleading
ceps nutans Pat. is another entomopathogenitic Ascomy-
results may be obtained.
cete belonging to the family Clavicipitaceae which is
However, to continue, it is worth mentioning that C.
parasitic on hemipteran insects Very
militaris maintains its name in the study while C. sinensis
few investigations have been made with this fungus. In this
is now classified as Ophiocordyceps sinensis. The taxon
research, optimum temperature and pH for mycelial
was historically classified in the Clavicipitaceae, based on
growth was determined. However, it appeared that growth
cylindrical asci, thickened ascus apices and filiform ascosp-
remained low and commercial exploitation perhaps lim-
ores, which often disarticulate into part-spores. The fungus
ited. However, it would be interesting to include this spe-
was characterized by having a pathological ecology on
cies in any future taxonomic treatments of the genus.
Elaphomyces and arthropods, with infrageneric classifica-
Optimisation of culture conditions for mycelial growth
tions emphasizing ascospore morphology, host affiliation
and production of polysaccharides and cordycepin were
and arrangement of perithecia. The production of well-
developed often stipitate stromata was typical. Sung et al.
re-classified on the basis of phylogenetic relationships
, although cordycepin is usu-
between 162 taxa by employing five to seven genetic loci.
ally produced synthetically at present.
Three clavicipitaceous clades were determined whichrejected the monophyly of Cordyceps and Clavicipitaceaeand most diagnostic characters used in Cordyceps were
not supported as being phylogenetically informative. How-ever, the most consistent characters with the phylogeny
Two cases of lead poisoning were reported (
were pigmentation, morphology and morphology of stro-
). These two patients took Cordyceps herbal medicine
mata. Cordycipitaceae was validated based on C. militaris,
for treatment of underlying diseases. Loss of appetite and
the type of Cordyceps, which included most Cordyceps spe-
anemic signs of lead poisoning were manifested in one
cies that possess bright, fleshy stromata. The new family
patient with a high blood lead level, while the other patient
Ophiocordycipitaceae was proposed. The majority of spe-
was asymptomatic. The lead content in the Cordyceps pow-
cies here produce stromata that often possess aperithecial
der was found to be as high as 20,000 ppm. After cessation
apices and are darkly pigmented, tough to pliant. Elapho-
of intake in the asymptomatic patient, and cessation of
cordyceps was proposed for a subclade of the Ophiocordyci-
intake and treatment with chelating agents in the symptom-
atic patient, the blood lead levels returned to normal range.
parasitize (a) the fungal genus Elaphomyces and (b) arthro-
This report raises concerns about lead poisoning from unu-
pods. The family Clavicipitaceae included the core clade of
sual herbal medicine in general.
grass symbionts, and the entomopathogenic genus Hypoc-
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
rella and relatives. The new genus Metacordyceps is pro-
employed to extract the components and, for example,
posed for Cordyceps species that are closely related to the
chloroform/methanol is particularly efficacious for fungal
grass symbionts in the Clavicipitaceae s. s. Metacordyceps
compounds (e.g. ). There is very
includes teleomorphs linked to Metarhizium and other clo-
little on the use of non-polar solvents.
sely related anamorphs. Lists of accepted names for species
in Cordyceps, Elaphocordyceps, Metacordyceps and Ophio-
cated a method which may have utility in standardising
cordyceps are provided. Obviously, this work needs to be
bioactive fungi. In this scheme, a ‘‘common, readily identi-
consulted in future work on the fungus for medicinal prop-
fiable" morphological character is determined and then the
fungus is analyzed for particular metabolites. In this casethe steps may be:
1. Produces stroma on Lepidopteron insects.
2. Produces detectable concentrations of, for example,
Too often authors have used highly conditional state-
ments such as; the preparation ‘‘may" have ‘‘possible"activity against, for example, cancer, which are meaning-
The analysis for other compounds would be desirable
less. It is claimed that modern studies are demonstrating
and some potential marker compounds are provided in
anti-oxidant, vascular, immune, and anti-inflammatory
. However, the phylogenic approach of
effects () and the mechanisms by
will set the standards for decades to come and will
which these mushrooms work are being elucidated. How-
profoundly influence future publications in all fields relat-
ever, the journal in which the paper is published is dedi-
ing to Cordyceps.
cated to complimentary and alternative medicines. Thisimplies it is not mainstream scientific and so scientistsmay not give it as much weight in comparison to, for exam-
ple, Phytochemistry or the Journal of Natural Products.
Nevertheless, the former reports could be considered as
R.R.M. Paterson is funded by Grant SFRH/BPD/
providing leads for more scientific research.
34879/2007 from Fundacßa˜o para a Cieˆncia e a Tecnologia,
In general, problems include too many chemically
Portugal. Professor Nelson Lima, Universidade do Minho
uncharacterised crude extracts, inadequate taxonomic vig-
is gratefully appreciated for his unstinting support, as are
our, and over extrapolation of in vitro data to imply ther-
other colleagues therein. L.E. Gilbert, University of Texas,
apeutic value. This needs to be avoided as it falsely raises
Austin was generous for allowing the use of his images of
hopes for cures for serious diseases. Furthermore, there
infected insects (. Marc Stadler, University of
are no biochemical data on how the insect are converted
Bayreuth, Germany is thanked for discussions.
into fungal components, or if the insect host per se haspharmacological properties. Poor (i.e. inadequate or obso-lete) biochemical procedures and assays can also becauseproblems (see ). The biological material
being used often is not well characterised and there arefew indications of specimens being available for other
Ahn, Y.J., Park, S.J., Lee, S.G., Shin, S.C., Choi, D.H., 2000. Cordycepin:
selective growth inhibitor derived from liquid culture of Cordyceps
workers to repeat the described work for example (i.e. no
militaris against Clostridium spp. J. Agric. Food Chem. 48, 2744–2748.
voucher specimens are available), with some notable excep-
Alderson, M.R., Tough, T.W., Braddy, S., Davis-Smith, T., Roux, E.,
tions. A rather limited range of solvents have been
Schooley, K., Miller, R.E., Lynch, D.H., 1994. Regulation of
Table 3Summary of markers currently used for quality control of Cordyceps and associated activities (after
Anti-tumour activities; Ca2+ antagonist; the release of various
Nucleosides, especially adenosine, are usually used as
neurotransmitters presynaptically and anticonvulsant activity;
markers, and the profiles can be applied for authentication
stimulate axon growth in vitro and in the adult central nerve system
Anti-oxidation, immunopotentiation, anti-tumour, and hypoglycemic
Represents the most biological properties of Cordyceps, and
activity; anti-inflammatory activity and suppress the humoral
less used as marker for quality control. Thus, it should be
Cytotoxic activity, anti-viral activity, and anti-arrhythmia effect;
Ergosterol can be used as marker for quality control
suppress the activated human mesangial cells and alleviateimmunoglobulin A nephropathy (Berger's disease)
Diuretic, anti-tussive and anti-free radical activities
It sometimes is used as marker for quality control
Anti-tumour and immunopotentiation activities
A potential marker for quality control
R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495
apoptosis and T cell activation by Fas-specific mAb. Int. Immunol. 6,
Cheng, Q., 1992. Effect of Cordyceps sinensis on cellular immunity in rats
with chronic renal insufficiency. Zhonghua Yi Xue Za Zhi 72, 27–
Balon, T.W., Jasman, A.P., Zhu, J.S., 2002. A fermentation product of
Cordyceps sinensis increases whole-body insulin sensitivity in rats. J.
Cheng, Y., Schneider, B., Riese, U., Schubert, B., Li, Z., Hamburger,
Alternat. Complement. Med. 8, 315–323.
M.J., 2004. Farinosones A–C, neurotrophic alkaloidal metabolites
Bao, Z.D., Wu, Z.G., Zheng, F., 1994. Amelioration of aminoglycoside
from the entomogenous Deuteromycete Paecilomyces farinosus. J. Nat.
nephrotoxicity by Cordyceps sinensis in old patients. Zhongguo Zhong
Prod. 67, 1854–1858.
Xi Yi Jie He Za Zhi 14, 271–273.
Cheng, Y., Schneider, B., Riese, U., Schubert, B., Li, Z., Hamburger, M.,
Bok, J.W., Lermer, L., Chilton, J., Klingeman, H.G., Towers, G.H., 1999.
2006. Novel tetramic acids and pyridone alkaloids, militarinones B, C,
Antitumor sterols from the mycelia of Cordyceps sinensis. Phytochem-
and D, from the insect pathogenic fungus Paecilomyces militaris. J.
istry 51, 891–898.
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ethyl acetate extract of Cordyceps sinensis fungal mycelium. Life Sci.
Zhu, X.Y., Yu, H.Y., 1990. Immunosuppressive effect of cultured
75, 2911–2919.
Cordyceps sinensis on cellular immune response. Zhong Xi Yi Jie He
Zhang, S.L., 1985. Activation of murine peritoneal macrophages by
Za Zhi 10, 485–487.
natural Cordyceps sinensis and its cultured mycelia. Zhong Xi Yi JieHe Za Zhi 5, 45–47.
Zhang, S.L., 1987. Lewis lung cancer of mice treated with Cordyceps
R. Russell M. Paterson is working as a research
sinensis and its artificial cultured mycelia. Zhong Yao Tong Bao
scientist at the Institute for Biotechnology and
(Beijing, China: 1981) 12, 53–54.
Bioengineering (IBB), Centre of Bioengineer-
Zhang, W., Li, J., Qiu, S., Chen, J., Zheng, Y., 2007a. Effects of the
ing, University of Minho, Portugal. A second-
exopolysaccharide fraction (EPSF) from a cultivated Cordyceps
ment for the IOI Professorial Chair, Faculty of
sinensis on immunocytes of H22 tumor bearing mice. Fitoterapia.
Malaysia, has been accepted by him recently,
Zhang, W., Yang, J., Chen, J., Hou, Y., Han, X., 2005. Immunomod-
which will commence in early 2008. His B.Sc. in
ulatory and antitumour effects of an exopolysaccharide fraction from
Applied Microbiology was obtained at the
cultivated Cordyceps sinensis (Chinese caterpillar fungus) on tumour-
University of Strathclyde, Glasgow, where his
bearing mice. Biotechnol. Appl. Biochem. 42, 9–15.
nascent interest in filamentous fungi was nur-
Zhang, X., Liu, Y.K., Shen, W., Shen, D.M., 2004b. Dynamical influence
tured by Professor J.E. Smith. Crucially, he undertook his Ph.D. in the
of Cordyceps sinensis on the activity of hepatic insulinase of experi-
Microbial Chemistry Laboratory of Professor J.D. Bu'Lock, the ‘‘inven-
mental liver cirrhosis. Hepatob. Pancreat. Dis. Int. 3, 99–101.
tor" of fungal secondary metabolism. Postdoctoral studies took him to
Zhang, X., Liu, Y.K., Zheng, Q., Shen, W., Shen, D.M., 2003. Influence of
The Boyce Thompson Institute at Cornell University, New York, where he
Cordyceps sinensis on pancreatic islet beta cells in rats with experi-
worked at United States Department of Agriculture laboratories on insect
mental liver fibrogenesis. Zhonghua Gan Zang Bing Za Zhi 11, 93–94.
pathogenic fungi under the supervision of Dr Dick Soper, which is rele-
Zhang, Y., Liu, S., Che, Y., Liu, X., 2007b. Epicoccins A–D, pipolythio-
vant particularly to the present review. After his return to the University
dioxopiperazines from a Cordyceps-colonizing isolate of Epicoccum
of Strathclyde, he was employed as a fungal natural products specialist at
nigrum. J. Nat. Prod. 70, 1522–1525.
CABI Bioscience, Egham, where he was privileged to be employed in the
Zhang, Z.J., Luo, H.L., Li, J.S., 1997. Clinical and experimental studies on
era when Professor D. L. Hawksworth was the director. The secondary
elimination of oxygen free radical of jinshuibao capsule in treating
metabolism of fungi is his primary interest and vice versa.
Source: http://www.bluvela.eu/download/knowledge/Cordyceps-sd.pdf
Wildlife Rehabilitation and Release Intake Center volunteers include, from left, Patty Thurston, Deb Kirkpatrick Nancy McLachlin, Bev Myers, Ellyn Cook, Janet Helminiak, Janey Powers, Laurel Gunderson,and Laura Vanderpool. WRR Intake Center has a Successful First Season By Janey Powers and as with all first-time ventures, a lot
the times Saturday October 11 2014 the times Saturday October 11 2014 6 Body + Soul Body + Soul 7 The good back guide: what the experts do to beat the pain Almost 80 per cent of us suffer back pain "The simplest thing to do is go hands- will still function as a paperclip. People You could also try standing on one free or use a head set," Loatey says.
