The genus Cordyceps: a chemical and pharmacological review

Authors


Correspondence

Meng Ye, College of Forestry, Sichuan Agricultural University, 46 Xinkang Road, Yucheng District, Ya'an 625014, Sichuan, China.

E-mail: yemeng5581@yahoo.com.cn

Abstract

Objectives

Natural remedies are becoming increasingly popular and important in the public and scientific communities. Historically, natural remedies have been shown to present interesting biological and pharmacological activity and are used as chemotherapeutic agents. For centuries Cordyceps, which is a genus of more than 400 species in the family Clavicipitaceae, has been used in traditional Chinese medicine. This study highlights the chemistry and pharmacology of Cordyceps, especially Cordyceps sinensis (Berk.) Sacc. and C. militaris (Fr.) L. Information was obtained from Google Scholar and the journal databases PubMed and Scopus.

Key findings

 Many bioactive components of Cordyceps have been extracted, such as cordycepin, cordycepic acid, ergosterol, polysaccharides, nucleosides and peptides. Studies show that Cordyceps and its active principles possess a wide range of pharmacological actions, such as anti-inflammatory, antioxidant, antitumour, antihyperglycaemic, antiapoptosis, immunomodulatory, nephroprotective, and hepatoprotective.

Summary

More research is required to discover the full extent of the activity of Cordyceps.

Introduction

Cordyceps, the name given to the fungi on insects, has been known and used as a medication in China for over 300 years, and was initially recorded in Ben-Cao-Bei-Yao by Wang Ang in 1694. In China, this fungus is usually called ‘Dong Chong Xia Cao’, which means ‘Worm in winter and grass in summer’, and the name generally refers to Cordyceps sinensis (Berk.) Sacc. This insect parasitizing fungus lives primarily on the head of the larva of one particular species of moth, Hepialus armoricanus Oberthur (Lepidoptera), but is occasionally found growing on other moth species. Cordyceps was first introduced to Western society during the 17th century. In 1878 Saccardo, an Italian scholar, named Cordyceps derived from China officially as Cordyceps sinensis (Berk.) Sacc., and this nomenclature has been adopted up to the present day.

Cordyceps is an abundant resource of useful natural products with various biological activity, and it has been used extensively as a tonic and health supplement for subhealth patients, especially seniors, in China and other Asian countries. Recently, it has become increasingly popular and important in the public and scientific communities. Many bioactive constituents have been reported, such as polysaccharides, cordycepin, mannitol, aminophenol and ergosterol. Recent studies have demonstrated that the chemical constituents extracted from Cordyceps have various pharmacological actions, such as nephroprotective, hepatoprotective, inflammatory effects, antioxidant and antiapoptotic properties. Due to the scarcity of this resource and immaturity of artificial cultivation, it has not been possible to fully meet the needs of medical use.

With the increasing interest in Cordyceps both for mycology and medicine, research is necessary to get an overview about the potential of these mushrooms. Therefore, this paper has reviewed the biology, biological activity and chemistry of the genus Cordyceps for its better utilization in the development of new drugs and therapeutics for various diseases in the future.

Biology and distribution

Cordyceps, comprising more than 400 species, was historically classified in the Clavicipitaceae, based on cylindrical asci, thickened ascus apices and filiform ascospores, which often disarticulate into part-spores. Cordyceps is characterized and distinguished from other genera of the family by its production of superficial to completely immersed perithecia on stipitate and often clavate to capitate stromata, and its ecology as a pathogen of arthropods and the fungal genus Elaphomyces.[1-3] However, the taxonomy of the genus Cordyceps is controversial. To refine the classification of Cordyceps and Clavicipitaceae, Sung et al.[4] estimated the phylogenetic relationship of 162 taxa based on analysis consisting of five to seven loci. The results strongly support the existence of three clavicipitaceous clades and reject the monophyly of both Cordyceps and Clavicipitaceae. The taxonomy of Cordyceps and Clavicipitaceae were revised to be consistent with the multi-gene phylogeny. The family Cordycipitaceae is validated based on the type of Cordyceps, C. militaris, and includes most Cordyceps species that possess brightly coloured, fleshy stromata. The new family Ophiocordycipitaceae is proposed based on Ophiocordyceps Petch, which was emended. The majority of species in this family produce darkly pigmented, tough to pliant stromata that often possess aperithecial apices. The new genus Elaphocordyceps is proposed for a subclade of the Ophiocordycipitaceae, which includes all species of Cordyceps that parasitize the fungal genus Elaphomyces and some closely related that parasitize arthropods. Two new species have been described, and lists of accepted names for species in Cordyceps, Elaphocordyceps, Metacordyceps and Ophiocordyceps provided.

Normally, Paecilomyces is considered traditionally to host the anamorphs, but this has been disputed. Cordyceps are insect parasitizing fungi, often exhibiting a high degree of host specificity. However, the Cordyceps species associated with lepidopteran hosts do not represent a monophyletic group. The host range of Cordyceps is broad, ranging from ten orders of arthropods to the truffle-like genus Elaphomyces, although most species are restricted to single host species or a set of closely related host species.[1, 2, 5] As to C. sinensis, when a larva is infected, the fungus grows through the insect by hyphae. The accumulation of the biomass, and/or the toxins that may be involved, eventually kills the host. The fungus ruptures the host insect body following overwintering and forms the sexual perithecial stroma that are connected to the dead larva below ground, which grow upward to emerge above the soil surface. The combination of insect and fungus are used traditionally for medicinal purposes.

The distribution of Cordyceps is cosmopolitan, including all terrestrial regions except Antarctica, with the height of known species diversity occurring in subtropical and tropical regions, especially east and south-east Asia. C. sinensis grows in a very restricted habitat, and is usually found in the soil of a prairie at an altitude from 3500 to 5000 m, mainly in provinces like Sichuan, Qinghai, Yunnan, Gansu and Tibet Autonomous Region in China. In Nepal, Bhutan and India, C. sinensis was recorded as well.[6] In China, over 60 species have been found, among which C. sinensis and C. militaris are the most valued species circulated in the crude drug markets for use in traditional Chinese medicine.

Chemical constituents

A variety of compounds have been extracted and purified from Cordyceps, including cordycepin and its derivatives, cordycepic acid, ergosterol, polysaccharides, nucleosides, and other compounds (Table 1[7,9–60]).

Table 1. The reported compounds isolated from the genus Cordyceps
No.CompoundsCharacteristic signals or IUPAC NameSourcesReferences
Nucleotide/nucleotides derivatives   
 1Cordycepin (3′-deoxyadenosine)(2R,3R,5S)-2-(6-Aminopurin-9-yl)-5-(hydroxymethyl)oxolan-3-olCultured C. militaris Cultured C. sinensisCunningham et al.[7] Chen and Chu[7]
 22′-Deoxyadenosine(2R,3S,5R)-5-(6-Aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-olCordyceps spp.Gong et al.[9]
 3Adenosine (C10H13N5O4)   
 4Guanosine (C10H13N5O5)   
 5Uracil (C4H4N2O2)   
 6Uridine (C9H12N2O6)   
 7Uridine-5′-monophosphate Cordyceps spp.Yang et al.[10]
 8Adenosine-5′-monophosphate   
 9Guanosine-5′-monophosphate   
10Thymidine   
11Cytidine   
12Inosine (C10H12N4O5) Mycelia of C. militarisLiu et al.[11]
13Adenine (C5H5N5)   
14Hydroxyethyladenosine

(2R,3R,4S,5R)-2-[6-(2-hydroxyethylamino)purin-9-yl]-5-

(hydroxymethyl)oxolane-3,4-diol

  
152′3′-Dideoxyadenosine[(2S,5R)-5-(6-Aminopurin-9-yl)oxolan-2-yl]methanol  
163′-Amino-3′-deoxyadenosine

(2R,3R,4S,5S)-4-Amino-2-(6-aminopurin-9-yl)-5-

(hydroxymethyl)tetrahydrofuran-3-ol

Mycelia of C. militarisGuarino and Kredich[12]
17Homocitrullyl aminoadenosineA nucleoside isolated from C. militarisMycelia of C. militarisKredich and Guarino[13]
Polysaccharides   
18P70-1P70-1 has a backbone of 1,6-linked α-d-mannopyranosyl residues with branching points at O-3 composed of 1,4-linked α-d-glucopyranosyl and 1,6-linked β-d-galactopyranosyl residues, and terminated with β-d-galactopyranosyl residues and α-d-glucopyranosyl residuesFruiting bodies of cultured C. militarisYu et al.[14]
19P70-2   
20P50-1   
21SCP- ISCP-I possesses a backbone of 1,4-linked α-d-glucosyl residues and carries a single (1,6)-linked α-d-glucosyl residue as side chainFruit mycelium of C. sinensisWu et al.[15]
22PC I Mycelia of C. sinensisYuan et al.[16]
23PCA IPCAI possesses a backbone of 1,4-linked mannopyranosyl residues with branches of O-2, O-3, O-6, etc of mono- or oligosaccharide composed of galactofuranosyl residues  
24PCA IIPCAII possesses six pyranosyl or furanosyl monosaccharide consisting of three mannosyl residues, two galactosyl residues and one glucosyl residue, which is a nonlinear linked heterogeneous oligosaccharide  
25PCB IPCBI possesses a backbone of 1,4-linked mannopyranosyl residues with side chains mainly composed of galactofuranosyl residues and also a few mannopyranosyl and galactopyranosyl residues  
26PCB IIPCB II possesses two mannosyl residues, one galactosyl residue and one glucosyl residue connected by a (1,3) linkage  
27PCC I   
28PCC II   
29CPS-1Composed of mannose bonded by (1,2) linkage, xylose bonded by (1,4) linkage and rhamnose boned with galactose by (1,2) or (1,3) linkageCultured C. militarisYu et al.[17]
30CPS-2CPS-2 was found to be mostly of α-(1→4)-d-glucose and α-(1→3)-d-mannose, branched with α-(1→4,6)-d-glucose every twelve residues on averageCultured C. militarisWang et al.[18]
31CPS-3Composed of 1,4-linked and 1,6-linked d-glucose with mainly an α-glycoside linkage in a molar ratio of 0.11 : 0.86 with side chains substituting at the C-6 of every eight glucose residues  
32Ck1-AComposed of pyranosyl residues connected by α-glycoside linkageCultured mycelia of C. kyushuensisWang et al.[19]
33Ck3-AConnected by α-glycoside linkageMycelia of C. kyushuensisWang and Zhang[20]
34CMBCMB possesses 1,6-linked mannosyl residues, 1,4-linked galactosyl residues, and even 1,6-linked or 1,4-linked glucosyl residues with branches of 1,4-linked and a few 1,6-linked glucosyl residues substituting at the C-3 of 1,4-linked glucosyl residues with terminal galactosyl or glucosyl residues, mainly connected by α-glycoside linkageMycelia of C. militarisWang et al.[21]
35CS-F10CS-F10 has α-d-glucopyranosyl residues on the terminal of the side-chains and 1,5-linked β-d-galactofuranosyl residuesMycelia of C. sinensisKiho et al.[22]
36CS-F3 Mycelia of C. sinensisKiho et al.[23]
37CM- ICM-I possesses a backbone of 1,2-linked b-mannosyl residues with branches of 1,6-linked β-galactofuranosyl residues at the C-4 and C-6 of galactosyl residues in the main chainCultured liquid of C. militarisGai and Zhang[24]
38CI-PCI-P composed of a backbone of 1,6-linked α-d-mannopyranosyl residues substituted at O-2 with single α- or β-d-galactofuranosyl groups, short chains of 1,2-linked β-d-galactofuranosyl residues, or chains of 1,2-linked α-d-mannopyranosyl residuesInsect-body portion of the fungal preparation C. cicadaeKiho et al.[25]
39CI-ACI-A possesses nearly same structure as CI-P but fewer and shorter d-galactofuranosyl side-chains and longer 1,2-linked α-d-mannopyranosyl side chains than CI-P  
40CT-4NComposed of a backbone of 1,6-and 1,2-linked α-d-mannopyranosyl residues with short chains of a large proportion of 1,5-linked β-d-galactofuranosyl residues and a small proportion of 1,6-linked α-d-galactopyranosyl residues at O-2, O-4 and O-6, with the nonreducing terminal groups of a large proportion of α-d-mannopyranosyl groupsC. sinensisKiho et al.[26]
41CO-1CO-1 composed of a backbone of 1,3-linked β-d-glucopyranosyl residues with a β-d-glucopyranosyl group attached to O-6 of every second d-glucopyranosyl residue of the main chainThe product formed on incubation of the culture filtrate of C. ophioglossoidesYamada et al.[27]
42C-3C-3 composed of 1,2-linked and 1,6-linked α-d-mannopyranosyl residues substituted at O-6 and O-2 with terminal β-d-galactofuranosyl and α-d-mannopyranosyl groups, and with short chains of 1,2-linked β-d-galactofuranosyl residuesAscocarps of C. cicadaeUkai et al.[28]
43CS- ICS composed of a backbone of 1,2-linked d-mannofuranosyl residues with side chains of 1,3-linked 1,5-linked and 1,6-linked d-galactofuranosyl residues and 1,4-linked d-galactopyranosyl residues and with nonreducing terminal groups of d-galactofuranosyl residues and d-mannopyranosyl residuesAscocarps of C. sinensisMiyazaki et al.[29]
44CS- II   
45Exopolysaccharide fraction (EPSF) Cultured anamorph strains of C. sinensisZhang et al.[30]
   Cultured C. militarisKim et al.[31]
   Cultured C. taiiXiao et al.[32]
46Co-NA galactosaminoglycan from Cordyceps ophioglossoidesC. ophioglossoidesIkeda et al.[33]
47CPSN Fr I The liquid culture broth of C. militarisLee et al.[34]
48CPSN Fr II

CPSN Fr II has a backbone of (1→2)-linked d-mannopyranosyl

and (1→6)-linked d-mannopyranosyl residues, which occasionally branches at O-6. The branches were mainly composed of (1→ 4)-linked d-galactopyranosyl residues, and terminated with d-galactopyranosyl residues, with a degree of branching (DB) of 0.2

  
49CPSN Fr III   
50CBP-1CBP-1 has a backbone of (1→4)-α-d-mannose residues which occasionally branches at O-3. The branches were mainly composed of (1→4)-α-d-glucose residues and (1→6)-β-d-galactose residues, and terminated with β-d-galactose residuesCultured C. militarisYu et al.[35]
51CPSD-Glucan containing α-(1→4)-linked backboneCultured mycelia of C. gunniiZhu et al.[36]
52EPS-1AIts backbone was composed of (1→6)-α-d-glucose residues (77%) and (1→6)-α-d-mannose residues (23%). Branching occurred at O-3 position of (1→6)-α-d-mannose residues of the backbone with (1→6)-α-d-mannose residues and (1→6)-α-d-glucose residues, and terminated with β-d-galactose residuesFermentation broth of a Tolypocladium sp. fungus isolated from wild C. sinensisYan et al.[37]
53WIPSWIPS and AIPS were characterized as α-d-glucans with a backbone of (1→4)-linked α-d-Glcp (>60%) and very similar molecular weights WIPS had a short branch of (1→6)-linked α-d-Glcp (−14%), but AIPS was a linear glucan, distinctive from the branched structures of most glucans from medicinal fungiMycelia of C. sinensisYan et al.[38]
54AIPS   
55CordysinocanThe exo-polysaccharide contains glucose, mannose, galactose in a ratio of 2.4 : 2 : 1Cultured C. sinensisCheung et al.[39]
56AEPS-1AEPS-1 had a linear backbone of (1→3)-linked α-d-Glcp residues with two branches, α-d-Glcp and α-d-GlcUp, attached to the main chain by (1→6) glycosidic bonds at every seventh α-d-Glcp unitMycelial culture of C. sinensisWang et al.[40]
57PS-AThe molecular weight of PS-A was estimated as 4.6 × 105 Da. Compositional analysis revealed the presence of d-glucose, d-galactose, and d-mannose at a molar ratio of 2 : 1 : 1C. sinensisKim[41]
Sterols and fatty acids   
58Ergosterol(3S,9S,10R,13R,14R,17R)-17-[(E,2R,5R)-5,6-Dimethylhept-3- en-2-yl]-10,13-dimethyl-2,3, 4,9,11,12,14,Mycelia of C. sinensisBok et al.[42]
  15,16,17-Decahydro-1H-cyclopenta[a] phenanthrenCordyceps spp.Li et al.[43]
  -3-olInsect-body portion of C. cicadaeKuo et al.[44]
59δ-3-Ergosterol C. sinensisZhu et al.[45]
60Ergosterol peroxide(3.beta.,5.alpha.,8.alpha.,22E)-5,8-Epidioxyergosta-6,22-dien-3-ol  
61Daucosterol

(2R,3R,4S,5S,6R)-2-[[(3S,8S,9S,10R,13R,14S,17R)-17-[(2R,

5R)-5-Ethyl-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,

12,14,15,16,17-dodecahydro-1H-cyclopenta[α]phenanthren-3-

yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol

  
62Campesterol

(3S,8S,9S,10R,13R,14S,17R)-17-[(2R,5S)-5,6-Dimethylheptan-2-

yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-

1H-cyclopenta[a]phenanthren-3-ol

Cordyceps spp.Yang et al.[46]
63β-Sitosterol   
64Cholesterol   
65Lauric acid   
66Myristic acid   
67Palmitoleic acid   
68Pentadecanoic acid   
69Palmitic acid   
70Linoleic acid   
71Oleic acid   
72Stearic acid   
73Docosanoic acid   
74Lignoceric acid(2R,3R,4R,5R)-Hexane-1,2,3,4,5,6-hexol  
Other compounds   
75Cordycepic acid C. militarisKaczka et al.[47]
   C. sinensisChatterjee et al.[48]
76Cicadapeptins I

The compound is acylated at the N-terminus by n-decanoic acid and amidated at the C-terminus by 1,2-diamino-4-methylpentane. The amino acid sequence is N-terminus-Hyp-Hyp-Val-Aib-Gln-

Aib-Leu-C-terminus.

Fermentation extracts of C. heteropodaKrasnoff et al.[49]
77Cicadapeptins IIIle substitutes for Leu of cicadapeptin I  
78Myriocin   
79(2S,3S,4R)-(E)-2-amino-3,4-dihydroxy-2- C. sinclairiiFujita et al.[50]
 Hydroxymethyl-14-oxoeicos-6-enoic acid   
80H1-AA pure compound extracted from C. sinensisC. sinensisChen et al.[51]
81Cordypyridones A-DAll the four compounds were colourless crystals, and their molecular formula were determined as C16H23NO3, C16H24NO3, C17H26NO3, C17H26NO4, respectively.C. nipponicaIsaka et al.[52]
82Ophiocordin

(4Z)-4-[(2-carboxy-6-hydroxyphenyl)-hydroxymethylidene]-3-

hydroxy-1-[(3R,4R)-3-[(4-hydroxybenzoyl)amino]-2,3,4,5-

tetrahydro-1H-azepin-4-yl]-5-oxocyclohex-2-ene-1-carboxylic acid

Submerged cultures of C. ophioglossoidesKneifel et al.[53]
    Boros et al.[54]
83Bioxanthracenes1-11Compounds 1–6 and 11 were identical with those of ES-242 s. Compounds 7,8,11 were atropisomer of ES-242-4, ES-242-5, ES-242-8, respectively. Both compounds 9 and 10 were pale yellow powder, and their physic-chemical properties were described.C. pseudomilitarisIsaka et al.[55]
    Jaturapat et al.[56]
84Dipicolinic acidPyridine-2,6-dicarboxylic acidC. militarisRukachaisirikul et al.[57]
   Culture filtrate of C. militarisWatanabe et al.[58]
852-Carboxymethyl-4-(30-hydroxybutyl) furan   
8610-membered macrolides (1–3)Compound 1 was isolated as a white solid and molecular formula was determined as C10H16O4. Compounds 2 and 3 were colourless gum, their molecular formula were C10H14O4, C10H14O4, respectively.  
87Cepharosporolides C, E, F   
88Glycoprotein containing N-acetylgalactosamine C. ophioglossoides cultureKawaguchi et al.[59]
89A lectinThe lectin was designated CML.Fruiting body of C. militarisJung et al.[60]

Cordycepin and cordycepic acid

Although the pharmacologically active components of Cordyceps are still unresolved, at least two chemical constituents, cordycepin and cordycepic acid (Figure 1), have been identified and proposed as important active constituents.[61] It is now generally believed that cordycepin, which was originally extracted from C. militaris and its structural formula confirmed as 3′-deoxyadenosine, is the main bioactive component of Cordyceps.[7, 47]

Figure 1.

Chemical structure of cordycepin and cordycepic acid from Cordyceps.

Cordycepic acid, an isomer of quinic acid, is one of the main active medicinal components. The structure was first imprecisely concluded to be 1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid in 1957.[48] Subsequently, the structure of the crystalline substance was identified as d-mannitol.[62] The content of cordycepic acid in C. sinensis is generally 7–29%, differing in the various growing stages of fruiting bodies.[63] It is now used in injections as raw material and as a supplement in other medicines.

Nucleotides/nucleotide derivatives

Nucleotides and nucleotide derivatives, including cordycepin, are effective components in Cordyceps. Investigations suggested that guanosine has the highest content of all in natural and artificial Cordyceps.[64]

Polysaccharides

Cordyceps contains a large amount of polysaccharides, which varies in the range within 3–8% of the total weight and usually comes from the fruiting bodies, the mycelium of solid fermentation submerged cultures and the broth.[65, 66] As one of the main bioactive components, Cordyceps polysaccharide represents a class of structurally diverse biological macromolecules with wide-ranging physiochemical properties.

Sterols and fatty acids

Ergosterol is a sterol unique to fungi and is an important precursor of vitamin D2, which has great medicinal value. Ergosterol is present in two forms, as free ergosterol or esterified ergosterol, which have different physiological functions.[67] It was reported that the content of ergosterol in the mycelia of Cordyceps was 1.44 mg/g, much lower than that in the fruiting bodies of Cordyceps, which was 10.68 mg/g.[68] However, it is worth noting that ergosterol peroxide is widespread in fungi and Cordyceps does not offer any particular advantage in its preparation. A number of other sterol-type compounds have been found in Cordyceps: δ-3-ergosterol, 3-sitosterol, daucosterol and campeasterol, to name a few.

Fatty acids can be classified as saturated or unsaturated fatty acids. The unsaturated fatty acid content reached 57.84% in Cordyceps, including C16:1, C17:1, C18:1 and C18:2, while the saturated fatty acid content was 42.16%, including C14, C15, C16, C17, C18, C20 and C22.[69] Unsaturated fatty acid is an effective physiologically active component, which has the unique function of decreasing blood lipids and protecting against cardiovascular disease.

Other compounds

Many other bioactive components have been extracted from Cordyceps, such as crude protein, amino acids, and metal elements, and they manifest a wide range of pharmacological functions.[69]

Biological activity

The pharmacological actions of Cordycpes have attracted extensive attention. A number of valuable biological activities regarding Cordyceps have been observed and studied by many authors (Table 2[70–95]). Ng and Wang[96] reviewed the chemical constituents and pharmacological actions of Cordyceps species. The bioactivities ascribed to the fungi are antitumour, antimetastatic, antioxidant, immunomodulatory, anti-inflammatory, insecticidal, antimicrobial, hypolipidaemic, hypoglycaemic, anti-ageing, neuroprotective, renoprotective effects, and so forth.

Table 2. Some of the biological activity of Cordyceps sinensis and C. militaris
Biological activityC. sinensisC. militaris
AssayIn-vivoIn-vitroReferencesAssayIn-vivoIn-vitroReferences
  1. CPS-1, is the compound 29; RL, lung resistance; Cdyn, dynamic lung compliance; BALF, bronchoalveolar lavage fluid; IR, ischemia–reperfusion; NF-kB, nuclear factor kappaB; iNOS, inducible nitric oxide synthase; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; ICAM-1, adhesion molecule; COX-2, cyclooxygenase-2; NO, nitric oxide; IL-12, interleukin-12; IC50, half maximal (50%) inhibitory concentration of a substance; IL-1, interleukin-1; IFN, interferon; TNF, tumour necrosis factor; LDL, low density lipoprotein; CD4, CD8, T lymphocyte subsets; HC, hyaluronic acid, PCIII, precollagen type III; ALT, alanine aminotransferase; AST, glutamic-oxalacetic transaminease; HA, Hemagglutinin; LN, laminin; CS, C. sinensis; TGFβ1, transforming growth factor β1; PDGF, platelet-derived growth factor; HIV-1, human immunodeficiency virus-1; HSV-1, Herpes simplex virus-1; BDL/S, a bile duct ligation and scission; TIMP-1, tissue inhibitor of metalloproteinase.
ImmunomodulatoryMurine and humanNatural killer cell (NK) activity of mouse was augmented by intraperitoneal injection.NK activity of mouse was augmented by intraperitoneal injection. NK activity of human peripheral blood mononuclear cells was elevated by pre-incubation of these cells with C. sinensis.Xu et al.[70]MouseExtractable fruiting body glucan and the extracellular glucan of the mycelium showed relatively high growth-inhibition activity against sarcoma 180 solid tumour in mice. Sone et al.[71]
 MouseThree consecutive days of feeding mice with C. sinensis before Group A streptococcal infection increased the survival rate and reduced local skin-tissue injury compared with mice fed phosphate buffered saline. Kuo et al.[72]    
Anti-inflammatoryMouseCordyceps, 5 g/kg (i.g.), significantly inhibited bronchial challenge of ovalbumin-induced change of RL and Cdyn (P < 0.05) and inhibited antigen-induced increase of eosinophils in the BALF of rats (P < 0.05). Lin et al.[73]MouseCPS-1 50–200 mg/kg significantly suppressed (P < 0.01) the mouse ear oedema induced by croton oil in a dose-dependent manner. At doses of 50 and 100 mg/kg, CPS-1 exerted a significant (P < 0.01) inhibitory effect on the increased vascular permeability induced by acetic acid in mice. Yu et al.[17]
 MouseC.sinensis mycelium significantly inhibited IR-induced upregulation of NF-κB activation and the brain production of IL-1β, TNF-α, iNOS, ICAM-1, and COX-2. Liu et al.[74]Human Potent growth inhibition on NO, TNF-α and IL-12 production with an IC50 value of 7.5, 6.3, and 7.6 μg/ml was displayed, respectively. An inhibitory trend on these inflammatory mediators was observed for compounds with an IC50 value ranging from 10.8 to 17.2 μg/ml.Rao et al.[75]
Antitumour/anticancerMouse The levels of IL-1, IFN, and TNF, produced by cultured rat Kupffer cells were increased in the presence of C. sinensis or the drug serum from rats fed on C. sinensis.Liu et al.[76]Mouse and human A dose of 100 or 200 mg/kg body weight per day inhibited the tumour volume by 43.81% and 48.89%, respectively. Tumour weight was reduced also by 31.21% and 39.48%, respectively.Lin and Chiang[77]
Pro-sexualMouseDifferent concentrations of C. sinensis and C. sinensis fractions (0.02 and 0.2 mg/g body weight) were fed to immature or mature mice. C. sinensis significantly induced plasma testosterone levels both in immature and mature mice in three and/or seven days treatment (P < 0.05). Huang et al.[78]    
NephroprotectiveMouseBoth acute and chronic experiments showed that C. sinensis could protect the kidney from ciclosporine nephrotoxicity and ameliorate glomerular and interstitial injury. Zhao and Li[79]    
 Human When LDL concentrations were 5, 10 or 50 μg/ml, [3H]thymidine incorporation was 919·5 ± 216 kBq, 1106 ± 132 kBq, and 1200 ± 210 kBq, respectively. When C. sinensis 100, 200, 300, or 400 μg/ml plus LDL 10 μg/ml were added, [3H]thymidine incorporation was 99 ± 19 kBq and 53 ± 8 kBq, respectively, P < 0·01 compared with controls.Wu et al.[80]Human When C. militaris 100, 200, 300 or 400 μg/ml plus LDL 10 μg/ml, [3H]thymidine incorporation was respectively 192 ± 75 kBq, 168 ± 66 kBq, 145 ± 53 kBq and 72 ± 16 kBq, P < 0·01 compared with controls.Wu et al.[80]
HepatoprotectiveHumanAfter three months of treatment, CD4 and CD4/CD8 ratio increased significantly (P < 0.05), while HA and PCIII decreased significantly (P < 0.05) compared with the control. Gong et al.[81]MouseThe content of liver glycogen tended to be lower after treatment with C. militaris. Jung et al.[82]
 MouseAs compared with the model control group,serum ALT, AST, HA, and LN content levels were markedly dropped in CS group (86.0 ± 34.4 U/L vs 224.3 ± 178.9 U/L, 146.7 ± 60.2 U/L vs 272.6 ± 130.1 U/L, 202.0 ± 79.3 mg/L vs 316.5 ± 94.1 mg/L and 50.4 ± 3.0 mg/L vs 59.7 ± 9.8 mg/L, respectively, P < 0.05). Tissue expression of TGFβ1 and its mRNA, collagen I mRNA were also markedly decreased (0.2 ± 0.14 vs 1.73 ± 1.40, 1.68 ± 0.47 vs 3.17 ± 1.17, 1.10 ± 0.84 vs 2.64 ± 1.40, respectively, P < 0.05). A dramatic drop could be seen in PDGF expression (0.87 ± 0.43 vs 1.91 ± 0.74, P < 0.01). Liu and Shen[83]    
AntihyperglycaemicMouseThe amount of water and food consumption (day 15–29), the two-hour-postprandial blood glucose concentration (day 21 and day 28), and the serum concentration of fructosamine (day 29) were significantly lower in the experiment groups than in the control group (one-way analysis of variance, P < 0.05). Lo et al.[84]    
Anti-ageing/antioxidantMouseExopolysaccharide produced in a mycelial liquid culture of the C. sinensis showed moderate antioxidant activity with a Trolox equivalent antioxidant capacity of 35–40 μmol Trolox/g and a ferric reducing ability of plasma of 50–52 μmol Fe(II)/g. Leung et al.[85]  P70-1 was found to possess hydroxyl radical-scavenging activity with an IC50 value of 0.548 mg/ml.Yu et al.[14]
Neuroprotective    Mouse Pretreatment with C. militaris (5–20 μg/ml) for one hour was sufficient to stimulate primary neurite sprouting and extension of Neuro2A cells after 24-h cultivation in a dose-dependent manner.Lee et al.[86]
Antifungal    Fungus The antifungal activity of the peptide was stable up to 100°C and in the pH range 6–13, and was unaffected by 10 mm Zn2+ and 10 mm Mg2+. Cordymin inhibited HIV-1 reverse transcriptase with an IC50 of 55 μm. Cordymin displayed antiproliferative activity toward breast cancer cells (MCF-7) but there was no effect on colon cancer cells (HT-29).Wong et al.[87]
Antiviral    Herpes All of them demonstrated activity, and three showed appreciable antiHSV-1 activity, with IC50 values of 0.9 μm.de Julián-Ortiz et al.[88]
Antibacterial    Bacteria Cordycepin revealed potent growth-inhibiting activity toward Clostridium paraputrificum and Clostridium perfringens at 10 μg/disk.Ahn et al.[89]
Insecticidal    Insect In a leaf-dipping test, cordycepin at 500 mg/l caused no mortality at 1 DAT (day after treatment) but 78 and 100% mortality at 2 and 4 DAT, respectively, whereas 34 and 88% mortality at 3 and 5 DAT, respectively was observed at 300 mg/l.Kim et al.[90]
AntifibroticMousePretreatment of mice with C. sinensis led to a significant attenuation of ureteric obstruction mediated renal fibrosis. Zhang et al.[91]MouseExtracellular biopolymers (30 mg/kg per day for four weeks, p.o.) had an antifibrotic effect on fibrotic rats induced by BDL/S. Nan et al.[92]
Hypoglycaemic    MouseA daily 0.5 g dose of C. militaris water extract to rats ameliorated insulin resistance by enhancing glucose utilization in skeletal muscles. Choi et al.[93]
Anti-HIV    Human Treatment of HIV-1 infected H9 cells with 1 μm of the cordycepin core timer and its 5′-monophosphate derivative resulted in an almost 100% inhibition of virus production.Mueller et al.[94]
Anti-invasive      C. sinensis exerted an anti-invasive activity, by increasing TIMP-1 secretion from melanoma cells, and cordycepin potentially functioned as the effective component.Kubo et al.[95]

Immunomodulating effects

The possibility that extracts and isolated components from mushrooms stimulate or suppress specific components of the immune system has been studied in recent years. Cordycepin could be an important immunoregulatory active compound that affects the actions of immune cells and cytokine network.[97] The effect of an exopolysaccharide fraction (EPSF) from anamorphic strains of C. sinensis on the immunocyte activity of tumour-bearing mice was investigated. The results indicated that EPSF not only significantly inhibited H22 tumour growth, but elevated the activity of the immunocytes. It enhanced the phagocytosis capacity of peritoneal macrophages and proliferation ability of spleen lymphocytes. EPSF boosted tumour necrosis factor-α (TNF-α) expression of the macrophages, the cytotoxicity of spleen lymphocytes, and TNF-α as well as interferon-γ (IFN-γ) mRNA expression of splenic lymphocytes.[30] The effects of C. sinensis against Group A streptococcal infection in mice were studied.[70] The results showed that mycelium extract protected by decreasing bacterial growth and dissemination, thereby increasing mouse survival rate. IL-12 and IFN-γ expression and macrophage phagocytic activity also increased after C. sinensis treatment. In another study, C. sinensis mycelium extract was reported to increase phagocytosis in human monocytic cells and abrogate inhibition of phagocytosis caused by streptococcal pyrogenic exotoxin B by causing cytokine production.[98]

Ethanol extracts from the fruiting bodies of Paecilomyces japonica and C. sinensis were demonstrated to exhibit phagocytosis enhancing activity and immunostimulating activity measured by carbon clearance, weight-loaded forced swimming performances, and immobilizing stress in mice [99, 100]. The ethanol extract stimulated phagocytosis and macrophage acid phosphatase activity. Xu et al.[72] studied the effects of the ethanol extract of C. sinensis on murine and human in-vitro natural killer cell (NK) activity and on murine in-vivo NK activity, and on colony formation of B16 melanoma in mouse lungs. The results indicated that C. sinensis may be used as an immunopotentiating agent in cancer treatment and for patients with immunodeficiency. Ethanol extracts of cultured mycelia and fruiting bodies of C. militaris were reported to inhibit nitric oxide production and inducible nitric oxide synthase (iNOS) gene expression upon stimulation by lipopolysaccharide in RAW 264.7, a murine macrophage cell line.[101]

The adjunctive effects of C. sinensis in clinical renal transplantation were explored.[102] Patients (n = 202) were divided randomly by lottery into a treatment group (n = 93) or a control group (n = 109). Patients in the treatment group were treated with C. sinensis 1.0 g three-times a day in addition to the immunosuppressive regimen given to the control group. Patient and graft survivals were compared, as was incidence, time and severity of acute rejection episodes, chronic allograft nephropathy (CAN), hepatotoxicity and nephrotoxicity, biochemistry parameters including indicators of liver and kidney functions, fats, proteinuria, dosages, and whole blood concentrations of ciclosporin. The results suggested that the use of C. sinensis may allow decreased doses and concentrations of ciclosporin, causing fewer side effects without an increased risk of acute rejection. In addition, C. sinensis with a reduced dose of ciclosporin may decrease proteinuria and retard CAN progression.

Antioxidant activity

Antioxidant activity in the xanthine oxidase, haemolysis and lipid peroxidation assay systems was demonstrated from a polysaccharide fraction of cultured C. sinensis mycelia.[65] Pheochromocytoma PC12 cells were protected against H2O2-induced injury by a 210-kDa polysaccharide from C. sinensis mycelia.[103] Treatment of the cells with the polysaccharide at 100 μg/ml before H2O2 exposure significantly elevated the survival of PC12 cells in culture by over 60%. In parallel, the H2O2-induced production of malondialdehyde in cultured cells was markedly reduced by the polysaccharide treatment, and the pretreatment of the polysaccharide significantly attenuated the changes of glutathione peroxidase and superoxide dismutase activity in H2O2-treated cells in a dose-dependent manner. The bioactivity of the polysaccharide from C. sinensis fungus and its antioxidant activity on H22-tumour bearing mice was undertaken.[104] The H22 tumour growth was inhibited and superoxide dismutase activity of liver, brain and serum, and glutathione peroxidase activity of liver and brain in tumour-bearing mice were enhanced. The water and ethanol extracts of the cultured fruiting bodies of C. sinensis were found to possess a potent antioxidant activity.[105] Also, anti-lipid peroxidation activity was detected and accumulation of cholesteryl ester in macrophages was inhibited via suppression of low-density lipoprotein (LDL) oxidation.

Antitumour activity

A variety of bioactive compounds isolated from Cordyceps were reported to display antitumour activity. Cordycepin displayed an antitumour effect by stimulating adenosine A(3) receptors, followed by activation of a glycogen synthase kinase-3β in the Wnt signalling pathway, and inhibited the growth of B16 melanoma cells inoculated subcutaneously into right murine footpads.[106, 107] Ergosterol peroxide isolated from C. ciacadae inhibited phytohaemagglutinin-induced T-cell proliferation, and arrested the progression of activated T cells from G1 to S phase of the cell cycle. Early gene transcripts, in particular those of cyclin E, interferon, and interleukins were suppressed.[44] The esterified form of ergosterol peroxide from C. sinensis was more potent than the aglycon in inhibiting proliferation of tumour cells.[42] A polysaccharide fraction from C. sinensis was studied as to its effect on the proliferation and differentiation of human leukaemia cells using an in-vitro culture system.[108] The conditioned medium had an activity that significantly inhibited proliferation of U937 cells, and differentiated U937 cells also had functions of phagocytosis and superoxide production. Antibody neutralization studies further revealed that the tumoricidal and differentiating effects of the compounds were mainly derived from the elevated cytokine concentrations. An exopolysaccharide fraction of C. sinensis inhibited metastasis of melanoma cells and downregulated concomitantly the levels of Bcl-2 protein into the lungs and the liver.[109] A water-insoluble extracellular glucan isolated from the culture filtrate of C. ophioglossoides was reported to suppress potently the growth of sarcoma 180 solid-type tumours.[27] Also, a galactosaminoglycan was isolated from C. ophioglossoides [110, 111]. It inhibited the proliferation of sarcoma 180 cells and the growth of a syngeneic solid tumour in vivo and exhibited cytotoxicity against cancer cells in vitro.

In a series of studies, water extracts of C. sinensis were reported to: increase the survival time of mice inoculated with carcinoma cells or syngeneic fibrosarcoma cells; inhibit spontaneously liver metastasis of carcinoma cells and melanoma in syngeneic mice, and the results suggested that the activity was not attributable to cordycepin; prolong the survival period of mice inoculated with B16 melanoma cells when co-administered with methotrexate; and cause apoptosis of melanoma cells.[112-115] A water soluble fraction of C. militaris showed cytotoxic activity on three human cancer cell lines: stomach adenocarcinoma (SNU-1); colorectal adenocarcinoma (SUN-C4); and hepatocellular carcinoma (SNH-354).[116] Cytotoxic activity guided isolation and identification of active fractions afforded cordycepin as an active component. Two fractions of methanol extracts, rather than cordycepin or polysaccharides, from fruiting bodies of C. sinensis were reported to inhibit the growth of K562, Vero, Wish, Calu-1 and Raji tumour cell lines.[117] Also, these two fractions significantly inhibited the blastogenesis response, natural killer cell activity, interleukin-2 production and TNF production in phytohaemagglutinin-stimulated human mononuclear cells.[118]

The effects of C. militaris extract on angiogenesis and tumour growth were evaluated.[119] The growth of human umbilical vein endothelial cells (HUVEC), HT1080 and B16-F10 cells were inhibited. The extract downregulated, in a dose- and time-dependent manner, bFGF gene expression in HUVEC cells and MMP-9 gene expression in HT 1080 cells. The growth of melanoma cells in mice was suppressed and anti-angiogenic activity was manifested. The biochemical mechanisms of antiproliferative effects by aqueous extract of C. militaris in human leukaemia U937 cells were investigated.[120] It was found that they could inhibit cell growth of U937 cells in a dose-dependent manner, which was associated with morphological change and apoptotic cell death such as formation of apoptotic bodies and DNA fragmentation. Moreover, the treatment caused a dose-dependent inhibition of cyclooxygenase-2 and prostaglandin E2 accumulation. Taken together, these results indicated that the antiproliferative effects of these extracts were associated with the induction of apoptotic cell death through regulation of several major growth regulatory gene products such as Bcl-2 family expression and caspase protease activity, and the extracts may have therapeutic potential in human leukaemia treatment.

Effects on apoptotic homeostasis

Apoptosis, or programmed cell death, is an essential event in organism development and homeostasis. There are numerous events that can induce a cell to undergo apoptosis and since the implication of apoptosis in various disease states as an effector mechanism, the ability to inhibit apoptosis has emerged as an important potential therapy. There are many reports of Cordyceps extracts inhibiting and inducing apoptosis. The effects of C. sinensis on apoptotic homeostasis have been well reviewed by Buenz et al.[121]

Hepatoprotective

Animal tests and clinical research data have showed that Cordyceps has a protective effect in liver patients, including those with viral hepatitis A, chronic hepatitis B, chronic hepatitis C and hepatic fibrosis. Bioactive components of Cordyceps for liver protection are mostly Cordyceps polysaccharides. Although the content and efficacy of Cordyceps polysaccharides vary with the species, they can improve the immunological functions of organic cells, removing harmful components and thus reducing the injury to liver cells. Four aspects of the effects in protecting the liver were presented as follows: protective effect on immune liver injury; effect on patients with hepatocirrhosis after hepatitis; effect on patients with chronic hepatitis B; protective effect on liver fibrosis.

In one study, Cordyceps extract was used in combination with several other medicinal mushroom extracts as an adjunct to lamivudine, for the treatment of hepatitis B. Lamivudine is a common antiviral drug used in the treatment of hepatitis. In the study, the group receiving Cordyceps along with other medicinal mushroom extracts had much better results in a shorter period of time than the control group, who received only lamivudine.[122]

Nephroprotective

A traditional view held of the Cordyceps species is that its consumption strengthens the kidneys. Studies have shown that much of the kidney-enhancing potential of Cordyceps stems from its ability to increase 17-hydroxy-corticosteroid and 17-ketosteroid levels in the body.[45] The effects in protecting the kidney are mainly presented as three aspects: protecting against chronic renal function failure; a therapeutic effect on toxic kidney injury; reversing the effect of glomerulonephritis in an animal model. All these have been proved by a series of experiments.

H1-A was reported to inhibit tyrosine phosphorylation of human mesangial proteins.[123] In an earlier report, H1-A alleviated immunoglobulin A nephropathy (Berger's disease) with histological and clinical improvement.[124] H1-A reduced anti-double-stranded DNA production and lymphadenopathy, delayed progression of proteinuria, improved kidney function and inhibited the proliferation of human mesangial cells, and promoted apoptosis by suppressing tyrosine phosphorylation of Bcl-2 and Bcl-XL.[123, 125]

Hypoglycaemic and hypocholesterolaemic

A polysaccharide (CS-F30) obtained from the culture mycelium of C. sinensis showed potent hypoglycaemic activity in genetic diabetic mice after intraperitoneal administration. The plasma glucose level was quickly reduced in normal and streptozocin-induced diabetic mice after intravenous administration.[126] Crude and neutral polysaccharides of C. sinensis exerted hypoglycaemic activity in normal mice, but did not affect the circulating insulin level in normal mice.[23] A polysaccharide (CS-F10), which was purified from a hot-water extract of the cultured mycelia of C. sinensis and composed of galactose, glucose and mannose in a molar ratio of 43 : 33 : 24, lowered the plasma glucose level in normal, adrenaline-induced hyperglycaemic and diabetic mice.[22]

The mater extracts of cultured fruiting bodies of C. sinensis prevented cholesterol deposition in the aorta of atherosclerotic mice by inhibition of LDL oxidation mediated by free radicals in an investigation into hypolipidaemic activity.[127] A hypocholesterolaemic effect of hot-water extract from mycelia of C. sinensis was investigated.[128] The results suggested that it lowered the total cholesterol concentration, reduced the concentration of cholesterol carried by LDL and very-low-density lipoprotein, and elevated the high density lipoprotein (HDL)-cholesterol concentration in the serum of mice fed a cholesterol-enriched diet.

Other bioactivity

The novel effect of cordycepin inhibiting collagen-induced platelet aggregation was reported.[129] The data suggested that the inhibitory effect of cordycepin might be associated with the downregulation of [Ca2+]i and the elevation of cAMP/cGMP production. Cordyheptapetide A, a novel cycloheptapeptide, was isolated from a strain of Cordyceps together with four known bioxanthracenes. There were only two previous reports on the isolation of cyclic peptides from this genus and these were from C. sinensis and C. militaris, and the antimalarial and cytotoxic activity of the bioxanthracenes were reported.[130] Cordyformamide was found to exhibit activity against Plasmodium falciparum (Welch) Schaudinn (Plasmodidae), whereas it showed weak or no cytotoxicity.[131] Ophiocordin, an antifungal antibiotic which was isolated from submerged cultures of C. ophioglossoides, is devoid of antibacterial activity.[53] Bioxanthracenes appear to be antimalarial, while the bioactivity data for glycoprotein containing N-acetylgalactosamine isolated from C. ophioglossoides are not available.[55, 56, 59] Chiou et al.[132] observed a hypotensive effect of C. sinensis in anaesthetized rats and a vasorelaxant effect in isolated aorta. The fungus counteracted arrhythmia in rats and increased the dosage of ouabain required to produce arrhythmia in guinea-pigs.

The methanol extracts of C. ophioglossoides were reported to protect the β-induced neuronal cell death and memory loss through free radical scavenging activity in rats.[133] The results suggested that C. ophioglossoides mycelium may be valuable for the protection from Alzheimer's dementia. A fraction dependently suppressed bronchoalveolar lavage fluid (BALF) cell proliferation, reduced interleukin production in lipopolysaccharide-activated BALF cell cultures, and affected interleukin mRNAs in various significant ways.[134] Antifibrotic effect of extracellular biopolymer from submerged mycelia cultures of C. militaris on liver fibrosis was investigated.[93] The results indicated that extracellular biopolymer had an antifibrotic effect on fibrotic rats induced by a bile duct ligation and scission operation. An ethyl acetate extract of C. militaris was reported to inhibit IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice.[135] An alcoholic extract of C. sinensis inhibited abdominal aortic thrombus formation in rabbits by preventing platelet aggregation.[136] The in-vivo and in-vitro effects and its extracted fractions on the secretion of testosterone in mice were studied.[137] C. sinensis, protein, and poorly water-soluble polysaccharide and protein significantly stimulated in-vitro testosterone production in purified mouse Leydig cells. Extracts enhanced the antibody response, restored the phagocytic activity of macrophages in tumour-bearing mice, and lengthened the survival period of the mice.[138]

A mushroom lectin designated as CML has been purified from C. militaris.[60] The lectin exhibited haemagglutination activity in mouse and rat erythrocytes, but not in human ABO erythrocytes. However, the N-terminal amino acid sequence of CML differs greatly from those of other lectins. CML exhibited mitogenic activity against mouse splenocytes.

Bioactivity of the insect

Do extracts from the healthy insect show interesting activities, and at what stage does the activity occur in the infected insect? This is an area of investigation which is hardly reported. The accumulation of bioactive plant metabolites by insects is well documented and insects are used as medicines.[139, 140] There are several reports about the differences between the fungus and the insect parts. Galactomannans isolated from the insect portion of C. cicadae demonstrate potent hypoglycaemic activity in mice.[141] The methanol extracts of C. cicadae insect-body portion suppressed human mononuclear cell (HMNC) proliferation, while aqueous methanol extracts of the ascocarps portion enhanced HMNC proliferation activated with phytohaemagglutinin.[142] The water extracts from the fruiting body and insect of natural Cordyceps were analysed for their content of nucleosides and polysaccharides, and the results showed that the insect had a chemical composition similar to the fruiting body.[66] Furthermore, both the fruiting body and worm of Cordyceps showed similar potency in their antioxidation activity in the xanthine oxidase assay, the induction of haemolysis assay and the lipid-peroxidation assay. Another paper reported that the fruiting body and the host caterpillar had similar ergosterol compositions, but the level of ergosteryl esters in the host caterpillar was much higher than that in the fruiting body.[67]

Current state and prospects

Current state

Nowadays, natural remedies are becoming increasingly popular worldwide, and this leads to elaborate research in more and more universities and research institutions. The use of natural remedies is steadily growing in the United States and this raises concerns about safety, efficacy, and how they affect safe patient care.[143] According to the world Health Organisation, it is estimated that about three-quarters of the world's population currently use natural remedies and other forms of traditional medicines to treat disease.[144] Cordyceps and its related products are available in western countries as over-the-counter medicine or tonics for their anti-ageing, ‘pro-sexual’, anticancer and immune boosting effects, but poor supporting scientific evidence is available.[145] It is a widely held belief that herbal preparations are ‘natural’ and are therefore somehow safer and more efficacious with fewer side effects[146, 147]. Therefore, with the increasing recognition and acceptance of natural remedies, and with the conception that natural medicines are much better than remedies that are pharmaceutically derived, further scientific research on pharmacological functions and chemical constituents of natural remedies, especially C. sinensis, are desirable.

Due to environmental and ecological factors, the annual harvest of natural C. sinensis has been steadily declining, while at the same time its worldwide demand has been increasing. This situation has driven Cordyceps spp. prices into an ever-increasing spiral, propelling researchers to determine ways of cultivating it to make it a more affordable material for commercial trade.[148] In the present state, the artificial cultivation of C. sinensis is not likely to reach commercial levels, and many scientific and technical problems remain to be solved, such as the mechanism and approach of parasitizing, and the screening of highly virulent strains. Experimental evidence and scientific explanation have been provided for the use of C. militaris as a substitute for C. sinensis, and this may provide a solution to the demand for C. sinensis. [14]

Since the discovery Cordyceps as an ancient natural remedy and tonic, it has undergone much research, however, many of its medicinal claims are still unsubstantiated. According to Li et al.[103], C. sinensis possesses antitumour and antioxidation activity, and stimulates the immune system, but the identity of the active component, or components, has not been determined. Yang et al.[149] stated that although certain polysaccharides from C. sinensis are bioactive, the antitumour effect has not been confirmed. Many papers have reported on the effects of the crude extracts, rather than on the effects of the novel pure compounds, which are the most revealing in terms of determining the effects of the fungus. Also, the problem of over extrapolation of in-vitro data to imply therapeutic value should be brought to the forefront.

At the end of the day, our challenge in the modern age is to scientifically unravel the claims and problems of this natural medicine, for example, bioactive compounds, research on biological screening, artificial cultivation of the fungus, a better understanding of the status in natural habitats, the differences between the fungus and the insect components.

Prospects

Nowadays, with the theory of ‘back to the pavilion’, people are more willing to take natural medicines rather than the synthetic drugs. Natural medicines, such as medicinal mushroom, can conquer life-claiming diseases leaving little side effects on human health. Although the artificial cultivation of C. sinensis has not been completely achieved, the highest cordycepin production was obtained in surface liquid culture using C. militaris mutant.[150] With the advance of science and technology, through innovation, the pharmaceutical industry is able to maintain a high output rate on low-cost materials with reasonable safety. Therefore, biometabolites extracted from medicinal mushroom like Cordyceps will be the key future driving force in the realm of green pharmacology and pharmacognosy.

Conclusions

In China, Cordyceps has been used as a traditional medicine throughout history. It seems logical that there should be some truth behind the myths of its effectiveness for certain ailments. During recent decades, as new uses have been found for Cordyceps and as the development of Cordyceps preparations has continued, some correlative products have rapidly appeared one after another, and the development of curative and health-care products from Cordyceps have become more and more favourable among people in China. As investigation into this fungus continues, more bioactive components with potential therapeutic value will be isolated. However, new methods and technologies must be adopted to extract and analyse the components, requiring evaluation along modern scientific lines, such as biological screening, accurate phytochemical analysis, pharmacological investigation, gene sequencing and clinical trials. At the same time, due to the enormous cost of research and the scarcity of C. sinensis, to find and investigate substitutes having the same efficacy as C. sinensis, such as C. militaris and its related species, will be of great importance. Overall, so far, we know only a little of the wonders of this creature and it still has many secrets for us to discover. More research is needed on the herbal medicine and its related species.

Declarations

Conflict of interest

The Author(s) declare(s) that they have no conflicts of interest to disclose.

Funding

This review received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgements

We are indebted to Jiulin Zhang from Southwest University and Leilei Ma from Southwest Jiaotong University for their great help with the language.

Ancillary