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
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Doi:10.1016/j.phytochem.2008.01.027Available online at www.sciencedirect.com Phytochemistry 69 (2008) 1469–1495 Cordyceps – A traditional Chinese medicine and another fungal therapeutic biofactory? R. Russell M. Paterson * Institute for Biotechnology and Bioengineering (IBB), Centre of Biological Engineering, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal Received 17 December 2007; received in revised form 17 January 2008 Available online 17 March 2008 Traditional Chinese medicines (TCM) are growing in popularity. However, are they eﬀective? Cordyceps is not studied as systemat- ically for bioactivity as another TCM, Ganoderma. Cordyceps is fascinating per se, especially because of the pathogenic lifestyle on Lepi-dopteron insects. The combination of the fungus and dead insect has been used as a TCM for centuries. However, the natural fungus hasbeen harvested to the extent that it is an endangered species. The eﬀectiveness has been attributed to the Chinese philosophical concept ofYin and Yang and can this be compatible with scientiﬁc philosophy? A vast literature exists, some of which is scientiﬁc, although othersare popular myth, and even hype. Cordyceps sinensis is the most explored species followed by Cordyceps militaris. However, taxonomicconcepts were confused until a recent revision, with undeﬁned material being used that cannot be veriﬁed. Holomorphism is relevant andcontamination might account for some of the activity. The role of the insect has been ignored. Some of the analytical methodologies arepoor. Data on the ‘‘old" compound cordycepin are still being published: ergosterol and related compounds are reported despite beinguniversal to fungi. There is too much work on crude extracts rather than pure compounds with water and methanol solvents being over-represented in this respect (although methanol is an eﬀective solvent). Excessive speculation exists as to the curative properties. However,there are some excellent pharmacological data and relating to apoptosis. For example, some preparations are active against cancers ordiabetes which should be fully investigated. Polysaccharides and secondary metabolites are of particular interest. The use of genuine ana-morphic forms in bioreactors is encouraged.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Fungus; Cordyceps sinensis; Cordyceps militaris; Lepidopteron; Traditional Chinese medicine; Cancer; Diabetes; Apoptosis * Tel.: +351 253 604 400; fax: +351 253 678 986.
0031-9422/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.phytochem.2008.01.027 R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495 The title relates to another in this journal concerning the fungal traditional Chinese medicine (FTCM), Ganoderma Too much about Cordyceps is unsubstantiated. This lit- (In that case, the fungus was indeed a bio- erature is written to sell so-called medicines to potentially factory in the sense that numerous compounds have been vulnerable people with serious diseases. On the other hand, reported from the fungus. What is the situation with there is convincing scientiﬁc information that indicates sig- another FTCM, Cordyceps? The immediate answer is that niﬁcant pharmacological properties which are worth the state of the art is considerably less developed (see assessing (see The present large review undertakes for a list of secondary metabolites). There is a general this task and deals with papers that use the name Cordy- impression that this fungus is being used in a modern con- ceps sometimes in its most general sense, especially when text, before the beneﬁts, and even what is being used, have the revision of is considered. There fol- been determined scientiﬁcally. Cordyceps is one of a grow- lows an extended introduction to the topic.
ing number of FTCM being considered as cures for mod- Table 1Medically related purported eﬀects of various Cordyceps taxa (or preparations) as described by various authors Purported eﬀect Negative for its many biological activities (sic); tonic to restore vital functions Reputed for broad biological activities; tonic to replenish vital function Prevents disease and onset of senility Replenishment of body health ()Maintain balance of Yin and Yang (sic) ) Immunomodulatory; increases survival of lupus mice ()Eternal youth (Treats a wide range of disorders; used for centuries; cultivated has same properties as natural ()Precious tonic and medicine since ancient times Treatment for wide range of diseases; anti-oxidant/anti-apoptotic properties )Wide range of diseases Treats asthma, and bronchial and lung inﬂammation )Replenishment of body health (One of most valued herbs in TCM )Treats general debility after sickness and for old persons CTM for nephritis ()Prized traditional medical materials Immunomodulator ()Highly valued for properties )Well known for eﬀect on immune system (Beneﬁts to the kidneys ( Tonic Wide range of diseases Prized traditional medical materials Cancer (in oriental medicine) )Popular nutraceutical and TCM ) Prized traditional medical material () C. ophioglossoides Prized traditional medical material () R. Russell M. Paterson / Phytochemistry 69 (2008) 1469–1495 C. sinensis (Berk.) Sacc., is one of the most famous tra- Example of the range of species and some of the low molecular-weight ditional Chinese medicines (TCM) and health foods. The secondary metabolites from Cordyceps fungus parasitises larvae of moths (Lepidoptera), especially Secondary metabolites Hepialus armoricanus (and Thitarodes), and converts each Cyclic peptides, H1-A larva into a sclerotium, from which the stroma and fruit- Cyclic peptides, cordycepin, 10-membered body grows. The complex (including the larva body) has macrolides, cepharosporolides C, E and F, been used as a health food and traditional medicine to pyridine-2,6-dicarboxylic acid and 2- ‘‘invigorate the lung and nourish the kidney" in China for hundreds of years, and at least from the 17th century C. pseudomilitaris these preparations actually represented is impossible to determine given the diﬃculties in taxonomy of even mod- ern times ; and see Ergosterol peroxide Cordypyridones A and B ). Understandably, conservation and sustainable har- C. ophioglossoides Ophiocordin, glycoprotein containing N- vest are important issues. There is need for (a) research on biological screening, (b) a better understanding of the Cicadapeptins I and II, myriocin status in natural habitats, and (c) artiﬁcial cultivation of The number of compounds is small compared to that for Ganoderma Cordyceps and products are available in ‘‘Western" countries as over-the-counter medicine/tonics which adver- ern human diseases. Many commercial products are avail- tise them as Chinese herbs with anti-aging, ‘‘pro-sexual", able in the market (e.g. Didanosine from Cordyceps milita- anti-cancer and immune boosting eﬀects, although with ris). These nutraceuticals are considered to relieve the poor supporting scientiﬁc evidence. The believe is that C.
‘‘stress for humans of living in technologically developed sinensis (CS) has various beneﬁcial eﬀects on humans, societies" by stimulating basic and secondary responses including those of a psychological nature. The FTCM, is of the immune system also called Dong Chong Xia Cao in Chinese (=winter The fungus represents a genus of perithecial ascomyce- worm summer grass) (). Primarily it is pre- tes (Phylum Ascomycota) classiﬁed in the Clavicipitaceae, scribed as a tonic for body strengthening after serious dis- a monophyletic group included in the order Hypocreales.
ease. More recently other treatments have been claimed The genus contains over 400 species and the anamorphs such as for (a) respiratory, renal, liver, nervous system of most are unknown. Paecilomyces is considered tradi- and cardiovascular diseases, and (b) tumours, aging, hypo- tionally to host the anamorphs but this has been disputed.
sexuality and hyperlipidemia should be consulted for an up-to-date ). It has been oﬃcially classi- revision (and see later). Cordyceps are parasites of insects ﬁed as a drug in the Chinese Pharmacopoeia since 1964.
or fungi, often exhibiting a high degree of host speciﬁcity Furthermore, the outbreak of the Severe Acute Respira- (). However, the Cordyceps species associated with tory Syndrome (SARS) in China in 2003 has increased Lepidopteran hosts do not represent a monophyletic use considerably. This would have been an excellent oppor- group. There is even a high degree of genetic variation tunity to have determined how eﬀective it was. However, within Cordyceps sinensis which creates diﬃculties in veri- this does not appear to have been undertaken. The market fying samples. A taxonomic review of the fungus is now demand for CS is growing sharply in many countries available (see later section) a similar review is required ). They would surely be hailed as for Ganoderma (e.g. see Larval medical breakthroughs if the eﬃcacy of any of these treat- infection via meiotic and/or mitotic spores/conidia and ments were conﬁrmed. Nevertheless, the identities of active multiplication within the insect is from yeast-like budding.
components have not been determined (in all cases) ( However, the fungus grows through the insect by hyphae.
). Research has shown that at least some of The accumulation of the biomass eventually kills the host the traditional uses ‘‘may" relate to pharmacological activ- (and/or a toxin(s) may be involved). It would be interesting ities ) (if not pharmacological activities to determine the biochemical parameters that cause these then what?). Herbs have been used throughout history to changes but this is not reported in the literature. The fun- enhance physical performance, but scientiﬁc scrutiny with gus ruptures the host body following over wintering and controlled clinical trials has only recently been used to forms the sexual perithecial stroma that are connected to study such eﬀects ). The authors mention that the dead larva below ground which grow upward to Cordyceps remain untested which is surprising given the emerge above the soil surface The complete interest in the fungus.
insect/fungus combination is used traditionally, but not The fungus is endemic to the alpine habitats of the Tibe- exclusively, for medicinal purposes. The present reviewer tan Plateau above 3000 m in south-western China, and has seen no reports of the insect per se being given as a there has been large-scale harvesting of the wild material from Nepal and India more recently. It is agreed generally
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.
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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.
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.