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3 Biotech

, Volume 4, Issue 1, pp 1–12 | Cite as

Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin

  • Hardeep S. Tuli
  • Sardul S. Sandhu
  • A. K. SharmaEmail author
Open Access
Review Article

Abstract

An entomopathogenic fungus, Cordyceps sp. has been known to have numerous pharmacological and therapeutic implications, especially, in terms of human health making it a suitable candidate for ethno-pharmacological use. Main constituent of the extract derived from this fungus comprises a novel bio-metabolite called as Cordycepin (3′deoxyadenosine) which has a very potent anti-cancer, anti-oxidant and anti-inflammatory activities. The current review discusses about the broad spectrum potential of Cordycepin including biological and pharmacological actions in immunological, hepatic, renal, cardiovascular systems as well as an anti-cancer agent. The article also reviews the current efforts to delineate the mechanism of action of Cordycepin in various bio-molecular processes. The study will certainly draw the attention of scientific community to improve the bioactivity and production of Cordycepin for its commercial use in pharmacological and medical fields.

Keywords

Cordyceps militaris Infection Cordycepin Mechanism Pharmacological effect 

Introduction

Medicinal mushrooms have been known for thousands of years to produce biometabolites which are used or studied as possible treatment for diseases. Over two-third of cancer-related deaths could be prevented or reduced by modifying our diet with mushrooms, as they contain anti-oxidants (Borchers et al. 2004; Zaidman et al. 2005). Cordyceps have a history of medicinal use spanning millennia in parts of Asia (Gu et al. 2007). The name Cordyceps has been derived from two Latin words, i.e., cord and ceps meaning club and head, respectively. Cordyceps militaris belongs to the phylum Ascomycota classified in the order hypocreales, as spores are produced internally inside a sac, called ascus (Wang et al. 2008). It is an entomopathogenic fungus having an annual appearance which often grows parasitically on lepidopteron larvae and pupae of insects and spiders. It normally inhabits on the surface of insects pupae in winters and leading to the formation of fruiting body in summers justifying its name as “winter-worm summer-grass”.

Cordyceps has been found mainly in North America, Europe and Asia (Mains 1958; Winkler 2010; Panda and Swain 2011). In India, it is prominently found in subalpine regions of grassy lands of Himalayas commonly known as “Keera Ghas”. Recently it has been reported from Sutol and Kanol villages of Chamoli district of Uttarakhand (Singh et al. 2010). The ethnopharmacological use of Cordyceps sinensis has been reported from western Nepal for the cure of different diseases like diarrhea, headache, cough, rheumatism, liver disease, etc. This herb is also referred as “Himalayan Viagra” or “Himalayan Gold” due to its broad clinical and commercial value (Devkota 2006). Cordyceps requires specific set of conditions for its growth and has small size; therefore, the large-scale collection of this mushroom is a daunting task. However, people within the age group 15–65 years including men, women, young boys and girls are the main collectors of this fungus and price for 1 kg of wild-collected mushroom in the market of Nepal varies from 30,000 to 60,000 Nepali Rupees while in India it costs about Rupees 100,000 (Sharma 2004). Past 5 years have seen tremendous exploitation of Cordyceps which has significantly reduced its wild occurrence (Negi et al. 2006; Winkler 2008). Efforts have been made to artificially cultivate this mushroom by surface and submerged fermentation techniques.

There have been a variety of pharmacologically active compounds (e.g., Cordycepin) reported from Cordyceps sp. Cordycepin (Fig. 1) has received much attention due to its broad-spectrum biological activity. It is known to interfere with various biochemical and molecular processes including purine biosynthesis (Fig. 2) (Overgaard 1964; Rottman and Guarino 1964), DNA/RNA synthesis (Fig. 3) (Holbein et al. 2009) and mTOR (mammalian target of rapamycin) signaling transduction (Fig. 4) (Wong et al. 2010). Cordyceps has been included as one of the growing numbers of fungal traditional Chinese medicine (FTCM) used as cures for modern diseases with many products available commercially. Due to recent advancements in pharmaceutical biotechniques, it is possible to isolate bioactive compounds from Cordyceps and make it available in powder as well as in capsular form (e.g., Didanosine). Cordyceps and its product have remarkable clinical health effects including action on hepatic, renal, cardiovascular, respiratory, nervous, sexual, immunological systems, besides having anti-cancer, anti-oxidant, anti-inflammatory and anti-microbial activities (Zhou et al. 2008; Wang et al. 2011; Lee et al. 2011a, b; Zhang et al. 2012; Patel and Goyal 2012; Yue et al. 2012).
Fig. 1

The figure elucidates the difference in the chemical structures of bioactive compounds, Cordycepin and adenosine, produced by Cordyceps militaris

Fig. 2

The inhibitory effect of Cordycepin in mono- and tri- phosphate states on the enzymes, phosphoribosyl pyrophosphate synthase and phosphoribosyl pyrophosphate amidotransferase, involved in purine biosynthesis pathway

Fig. 3

The addition of Cordycepin as a Co-TP (Cordycepin tri-phosphate) leads to transcriptional termination

Fig. 4

Cordycepin presumably activates the AMPK by some unknown mechanism which further negatively regulates the translation of mTOR signaling transduction pathway by the formation of a translational repressor, 4-E-binding protein-1 (4EBP1)

Keeping in view of the above facts, the current review updates us with the recent research pertaining to Cordyceps and the bioactive compounds isolated from it; especially for its ethno-pharmacological use. The study brings together a variety of mechanisms of Cordycepin at one platform and more importantly the broad spectrum pharmacological, clinical or biological activities associated with Cordyceps.

Infection to the host

Cordyceps usually infects insects at different stages of their development ranging from insect larvae to adult. Insect’s epidermis is covered with a thick layer of cuticle (procuticle and epicuticle) which is also known as integument. Insect’s integument comprises chitin, proteins and lipids. Beside this, it also contains variety of enzymes and phenolic compounds (Leger et al. 1991). Epidermis is formed by a single layer of epithelial cells followed by a thick layer of procuticle. Procuticle is differentiated into an inner soft part known as an endocuticle while the outer hard part is called exocuticle. Epicuticle and wax are known to constitute the outermost covering of the cuticle. This not only serves as a protective barrier against pathogenic organisms but also prevents water loss and acting as an interface between insect and its environment. Out of all these components, chitin which is a kind of heteropolysaccharide made with the polymerization of N-acetyl glucosamine through 1–4 β-linkage constitutes an important structural component of insect’s integument. Pathogen has to invade this tough integument covering to gain entry into the host.

Infection begins with the dispersion of fungus conidia on insect’s surface. Once conidia get settled, they start germinating within a few hours under suitable conditions. To get protection from the environmental ultraviolet radiations, protective enzymes like Cu–Zn superoxide dismutase (SOD) and peroxidases are secreted by the fungal conidia. These enzymes provide protection to the conidia from reactive oxygen species (ROS) generated due to UV rays and heat in the environment (Wanga et al. 2005). Besides this, conidia secrete certain hydrolytic enzymes like proteases, chitinases and lipases which lead to the dissolution of the integument and play a very important role in infection to the host. These enzymes not only provide a penetration path to the conidia but also provide nutrition to the germinating conidia (Ali et al. 2010).

Further a short germ tube protruding out of the conidia starts thickening at the distal end which is known as appressorium. This appressorium maintains a kind of mechanical pressure on the germinating germ tube further improving the penetration effect of germ tube so as to reach into the insect’s haemolymph (Hajek and Leger 1994). As the germ tube penetrates the epicuticle layer of insect’s integument, it starts forming a plate-like structure called penetration plate. The penetration plate further produces secondary hyphae, which cross the epidermal layer and reach into the haemocoel of insect’s body. From these hyphae, protoplast bodies bud off and start circulating into the insect’s haemocoel. Fungus now starts growing into a filamentous mode invading internal organs and tissues of the host. During growth inside the host, fungus produces various kinds of toxic secondary metabolites, which are insecticidal. These secondary metabolites take the insect to its final life stage and ultimately insect dies out. Fungal mycelium emerges out through the cuticle and lead to the formation of fruiting body under suitable environmental conditions (Webster 1980). Morphological features of fruiting body include stipitate, yellowish-orange to orange to reddish-orange fruiting stroma which is cylindrical to slightly clavate in shape. Stipes of 1.5- to 3-mm thickness with fertile clava terminal (2.0- to 6.0-mm wide) are also commonly seen in the fruiting body with overall stroma of about 1.5- to 7.0-cm tall which can vary in length depending on the size of the host.

Cordyceps diversity and cultivation

There are more than 1,200 entomopathogenic fungi reported (Humber 2000) in the literature out of which the Cordyceps constitutes one of the largest genus containing approximately 500 species and varieties (Hodge et al. 1998; Hywel 2002; Muslim and Rahman 2010). Many different species of Cordyceps are being cultivated for their medicinal and pharmaceutical properties including O. sinensis, C. militaris, C. ophioglossoides, C. sobolifera, C. liangshanesis, and C. cicadicola. Similarly many other species of Cordyceps have been documented like C. tuberculata, C. subsessilis, C. minuta, C. myrmecophila, C. Canadensis, C. agriota, C. gracilis, C. ishikariensis, C. konnoana, C. nigrella, C. nutans, C. pruinosa, C. scarabaeicola, C. sphecocephala, C. tricentri, etc., although the molecular evidence for their proper phylogenetic placement is still lacking (Shrestha and Sung 2005; Wang et al. 2008; Zhou et al. 2009).

Nearly 80–85 % of all medicinal mushroom products are extracted from their fruiting bodies while only 15 % are derived from mycelium culture (Lindequist et al. 2005). Fruiting body of Cordyceps is a very small blade-like structure, making its collection difficult and expensive. Since there is a huge requirement of medicinal mushroom bio-metabolites, it is necessary to cultivate mycelium biomass artificially for which variety of methods for its cultivation have been proposed by many research groups (Masuda et al. 2006; Das et al. 2008, 2010a). Cordyceps mycelium can grow on different nutrients containing media, but for commercial fermentation and cultivation, insect larvae (silkworm residue) and various cereal grains have been used in the past. It has been seen consistently that from both insect larvae and cereal grains, fruiting body of fungus can be obtained with almost comparable medicinal properties (Holliday et al. 2004).

There are basically two fermentation techniques by which the cultivation of mycelium biomass of Cordyceps can be achieved including surface and submerged fermentation. In surface fermentation, the cultivation of microbial biomass occurs on the surface of liquid or solid substrate. This technique, however, is very cumbersome, expensive, labor intensive and rarely used at the industrial scale. While in submerged fermentation, micro-organisms are cultivated in liquid medium aerobically with proper agitation to get homogenous growth of cells and media components. However, there is a loss of extra-cellular compounds (after harvesting mycelium) from the broth which makes it necessary to improve the culture medium composition and downstream processing technology to get large-scale production of the secondary bio-metabolites (Ni et al. 2009). It has been observed that the highest productivity can be achieved by repeated batch culture technique in which waste medium is removed at the end of the process and further refreshing the medium gives higher productivity of cells and bio metabolites.

Nutritional value of Cordyceps

In Cordyceps, there occurs a wide range of nutritionally important components including various types of essential amino acids, vitamins like B1, B2, B12 and K, different kinds of carbohydrates such as monosaccharide, oligosaccharides and various medicinally important polysaccharides, proteins, sterols, nucleosides, and other trace elements (Hyun 2008; Yang et al. 2009, 2010; Li et al. 2011). In the fruiting body and in the corpus of C. militaris, the reported total free amino acid content is 69.32 and 14.03 mg/g, respectively. The fruiting body harbors many abundant amino acids such as lysine, glutamic acid, proline and threonine as well. The fruiting body is also rich in unsaturated fatty acids (e.g., linoleic acid), which comprises of about 70 % of the total fatty acids. There are differences in adenosine (0.18 and 0.06 %) and Cordycepin (0.97 and 0.36 %) contents between the fruiting body and the corpus, respectively (Hyun 2008).

Bio-metabolites isolated from Cordyceps

Cordyceps, especially its extract has been known to contain many biologically active compounds like Cordycepin, cordycepic acid, adenosine, exo-polysaccharides, vitamins, enzymes etc. (Table 1). Out of these, Cordycepin, i.e., 3′-deoxyadenosine (Fig. 1) isolated from ascomycetes fungus C. militaris, is the main active constituent which is most widely studied for its medicinal value having a broad spectrum biological activity (Cunningham et al. 1950).
Table 1

Bioactive compounds isolated from Cordyceps sp.

S. no

Bioactive compounds

References

1

Cordycepin

Cunningham et al. (1950)

2

Cordycepic acid

Chatterjee et al. (1957)

3

N-acetylgalactosamine

Kawaguchi et al. (1986)

4

Adenosine

Guo et al. (1998)

5

Ergosterol and ergosteryl esters

Yuan et al. (2007)

6

Bioxanthracenes

Isaka et al. (2001)

7

Hypoxanthine

Huang et al. (2003)

8

Acid deoxyribonuclease

Ye et al. (2004)

9

Polysaccharide and exopolysaccharide

Yu et al. (2007, 2009), Xiao et al. (2010), Yan et al. (2010)

10

Chitinase

Lee and Min (2003)

11

Macrolides (C10H14O4)

Rukachaisirikul et al. (2004)

12

Cicadapeptins and myriocin

Krasnoff et al. (2005)

13

Superoxide dismutase

Wanga et al. (2005)

14

Protease

Hattori et al. (2005)

15

Naphthaquinone

Unagul et al. (2005)

16

Cordyheptapeptide

Rukachaisirikul et al. (2006)

17

Dipicolinic acid

Watanabe et al. (2006)

18

Fibrynolytical enzyme

Kim et al. (2006)

19

Lectin

Jung et al. (2007)

20

Cordymin

Wonga et al. (2011)

Cordycepin: mechanism of action

The structure of Cordycepin is very much similar with cellular nucleoside, adenosine (Fig. 1) and acts like a nucleoside analogue.

Inhibition of purine biosynthesis pathway

Once inside the cell, Cordycepin gets converted into 5′ mono-, di- and tri-phosphates that inhibit the activity of enzymes like ribose-phosphate pyrophosphokinase and 5-phosphoribosyl-1-pyrophosphate amidotransferase which are used in de novo biosynthesis of purines (Fig. 2) (Klenow 1963; Overgaard 1964; Rottman and Guarino 1964).

Cordycepin provokes RNA chain termination

Cordycepin lacks 3′ hydroxyl group in its structure (Fig. 1), which is the only difference from adenosine. Adenosine is a nitrogenous base and acts as cellular nucleoside, which is needed for the various molecular processes in cells like synthesis of DNA and/or RNA. During the process of transcription (RNA synthesis), some enzymes are not able to distinguish between an adenosine and Cordycepin which leads to incorporation of 3′-deoxyadenosine or Cordycepin, in place of normal nucleoside preventing further incorporation of nitrogenous bases (A, U, G, and C), leading to premature termination of transcription (Fig. 3) (Chen et al. 2008; Holbein et al. 2009).

Cordycepin interferes in mTOR signal transduction

Cordycepin has been reported to shorten the poly A tail of m-RNA which further affects its stability inside the cytoplasm. It was observed that inhibition of polyadenylation with Cordycepin of some m-RNAs made them more sensitive than the other mRNAs. At higher doses, Cordycepin inhibits cell attachment and reduces focal adhesion. Further increase in the dosage of Cordycepin may shutdown mTOR (mammalian target of rapamycin) signaling pathway (Fig. 4) (Wong et al. 2010). The name mTOR has been derived from the drug rapamycin, because this drug inhibits mTOR activity. The mTOR inhibitors such as rapamycin and CCI-779 have been tested as anti-cancer drugs, because they inhibit or block mTOR signaling pathway. mTOR is a 298 kDa serine/threonine protein kinase from the family PIKK (Phosphatidylinositol 3-kinase-related kinase). The mTOR plays a very important role to regulate proteins synthesis. However, mTOR itself is regulated by various kinds of cellular signals like growth factors, hormones, nutritional environment, and cellular energy level of cells. As growth factors bind with cell receptor, Phosphatidyl inositol 3 kinase (PI3K) gets activated, converts phosphatidyl inositol bisphosphate (PIP2) to phosphatidyl inositol trisphosphate (PIP3). PIP3 further activates PDK1 (phosphoinositide dependent protein kinase 1). The activated PDK1 then phosphorylates AKT 1 kinase and makes it partially activated which is further made fully activated by mTORC2 complex. The activated AKT 1 kinase now activates mTORC1 complex that leads to the phosphorylation of 4EBP1 (translational repressor) and makes it inactive, switching on the protein synthesis (Wong et al. 2010). The study confirmed that under low nutritional stress, Cordycepin activates AMPK which blocks the activity of mTORC1 and mTORC2 complex by some unknown mechanism. The inactivated mTORC2 complex cannot activate AKT 1 kinase fully, which in turn blocks mTOR signal transduction inhibiting translation and further cell proliferation and growth (Fig. 4).

Molecular studies of genes isolated from Cordyceps sp.

It is necessary to understand the genetic makeup and molecular biology of Cordyceps not only to enhance the production of Cordycepin and exopolysaccharides but also to figure out the biochemical synthetic pathway of the above bio-metabolites. Cordycepin and exopolysaccharides are some of the major pharmacologically active constituents of Cordyceps. There exists a variety of valuable genes encoding enzymes isolated and subsequently cloned from this medicinally important insect fungus. Isolation and cloning of FKS1 gene has been carried out successfully from Cordyceps which encodes for an integral membrane protein acting as a catalytic subunit for enzyme β-1,3 glucan synthase and responsible for the biosynthesis of a potent immunological activator, i.e., β-glucan (Ujita et al. 2006). Another group isolated Cu, Zn SOD 1 gene (SOD 1) from Cordyceps militaris which not only acts as an anti-oxidant and anti-inflammatory agent but also neutralizes free radicals which could be a potential anti-aging drug (Park et al. 2005). From Cordyceps sinensis, two cuticle degrading serine protease genes, i.e., csp 1 and csp 2 have been cloned and expressed in yeast Pichia pastoris. The genes, csp1 and csp 2 were further characterized using synthetic substrate N-suc-AAPF-p-NA to understand the pathobiology and infection to the host (Zhang et al. 2008). Similar studies were carried out to clone and analyse glyceraldehyde-3-phosphate-dehydrogenase (GPD) gene from Cordyceps militaris. GPD is an important enzyme used in the glycolytic pathway, which catalyses the phosphorylation of glyceraldehyde-3-phosphate to form 1, 3-diphosphoglycerate, an important reaction to maintain life activities in a cell for the generation of ATP (Gong et al. 2009). Further studies could be directed toward improving Cordyceps sp. by developing an effective transformation system.

Pharmaceutical and therapeutic potential of Cordyceps sp.

Cordyceps species is also known as traditional Chinese medicine (TCM) as it has wide applications in pharmaceutical (Table 2) and health sector (Ng and Wang 2005; Russell and Paterson 2008). This medicinal mushroom was in the limelight during the Chinese National Games in 1993, when a group of women athletes broke nine world records, committed that they had been taking Cordyceps regularly. It has been seen previously reported that Cordyceps also enhances physical stamina making it very useful for the elderly people and athletes. Recent literature further confirms that Cordyceps enhances cellular energy in the form of ATP (adenosine tri-phosphate). Upon hydrolysis of phosphates from ATP, lots of energy is released which is further used by the cell (Dai et al. 2001; Siu et al. 2004). The studies by many researchers in the past on Cordyceps have demonstrated that it has anti-bacterial, anti-fungal, larvicidal, anti-inflammatory, anti-diabetic, anti-oxidant, anti-tumor, pro-sexual, apoptotic, immunomodulatory, anti-HIV and many more activities (Table 2).
Table 2

Summary of various pharmacological and therapeutic effects of Cordyceps sp.

Pharmacological effect

Active content of Cordyceps

Animal/tissue studied

Active dose

Experimental time period

References

Anti-angiogenic

Cordyceps militaris Extract (CME)

HUVECs

100–200 mg/L

After 3–6 h

Yoo et al. (2004)

Anti-tumor/anti-proliferatory

Cordyceps militaris protein (CMP)

MCF-7 (breast cancer), 5637 (bladder cancer) and A-549 (lung cancer)

15 μM

72 h

Park et al. (2009a, b, c)

Aqueous extract of C. militaris

Nude mice with NCI-H460 cell

At 150 and 300 mg/kg/day

4 weeks

Park et al. (2009a, b, c)

BuOH extracts of C. militaris grown on germinated soybean (GSC)

HT-29 human colon cancer

100 μg/ml

48 h

Mollah et al. 2012

Cordycepin

Mice

150 mg/kg body weight

7 days

Jagger et al. (1961)

5637 and T-24 (bladder cancer) KB and HSC3 (oral squamous cell carcinoma)

200 μm

24 h

Lee et al. (2011a, b)

50 and 30 μM, respectively

48 h

Anti metastasis

WE of C. sinensis

LLC and B16 cells

100 mg/kg in LLC, 100 or 200 mg/kg in B16

20 and 26 days

Nakamura et al. (1999)

Cordycepin

5637 and T-24 cells

100 and 200 μM

48 h

Lee et al. 2010

Induce apoptosis

etOAc extract of C. sinensis

HL-60 cells

ED50 ≤25 μg/ml

2 days

Zhang et al. (2004)

Aqueous extract of C. militaris

MDA-MB-231

0.8 mg/ml

24 h

Jin et al. (2008)

Paecilomyces hepiali (derivative of C. sinensis) extract

A549

2–4 mg/ml

48–72 h

Thakur et al. (2011)

Water extract of C. militaris

A549

2 μg/ml

48 h

Park et al. (2009a, b, c)

Cordycepin

MA-10

100 μM to 5 mM

24 h

Jen et al. (2008)

SW480 & SW620

2 and 0.72 mmol/L, respectively

72 h

He et al. (2010)

MDA-MB-231

100 μM

24 h

Choi et al. (2011)

U937 and THP-1

30 μg/ml

24 h

Jeong et al. (2011)

SK-NBE(2)-C and SK-Mel-2 (HTB-68)

120 and 80 μM, respectively

24 h

Baik et al. (2012)

Anti fatigue

Polysaccharide

Mice

200 mg/kg

For 21 days

Li and Li (2009)

Anti malaria

Cordycepin

Erythrocytic stages of P. knowlesi (in vitro) and P. berghei (in vivo)

In vitro 106 M and in vivo 50 mg/kg

In vitro 4 h

Trigg et al. (1971)

Anti fungal

Cordycepin

Murine Model

1.5 mg/kg/day

30 days

Sugar and Mccaffrey (1998)

Hypolipidemic

Exo polysaccharide

Rats

50–100 mg/kg

2 weeks

Yang et al. (2000)

Increase hepatic energy metabolism and blood flow

Cordyceps sinensis Extract

Mice

200 mg/kg/daily

4 weeks

Manabe et al. (2000)

Immunomodulatory

Polysaccharide from C. sinensis

Human peripheral blood

0.025–0.1 mg

Kuo et al. (2007)

Purified Cordycepin from C. militaris

Mouse splenocytes

5 μg/ml

72 h

Ho et al. (2012)

Anti inflammatory

C. militaris water extract

Murine macrophage

1,250 μg/ml

24 h

Jo et al. (2010)

Constituents isolated from C. militaris

LPS/IFN-γ stimulated Macrophage cells

Ranging from 6.3 to 20 μg/ml

24 h

Rao et al. (2010)

Anti Diabetic/Hypoglycemic

C. militaris extract reduce oxidative stress, induced by high glucose concentration

HUVECs

25 μg/ml

12–36 h

Chu et al. (2011)

Fractions of C. militaris as CMESS and Cordycepin

Mice

50 and 0.2 mg/kg, respectively

7 days

Yun et al. (2003)

Crude extract and polysaccharide rich fraction

Rat

10 mg/kg of polysaccharide and 100 mg/kg body weight of crude extract

4 days

Zhang et al. (2006)

Spermatogenic

CM mycelium powder

Sub fertile boars

10 g/boar

2 months

Lin and Tsai (2007)

Steroidogenesis

CS

Normal mouse leydig cells

3 mg/ml

2–3 h

Huang et al. (2001)

Cordycepin

MA-10 mouse leydig tumor cells

100 μM

24 h

Pan et al. (2011)

Anti-aging

CSE

Mice

2.0, 4.0 g/kg

6 weeks

Ji et al. (2009)

Cordycepin

Human dermal fibroblasts

50–100 μM

24 h

Lee et al. 2009a, 2009b

Anti-fibrotic

EPC from C. militaris

Rats

30 mg/kg/day

4 weeks

Nan et al. (2001)

Cardiovascular effects

Cs-4

  

1–15 min

Zhu et al. (1998b)

Relax aorta

 

Isolated aorta

50 μg/ml

  

Lower blood pressure

 

Dogs

60 mg/kg

Increase coronary blood flow

 

Dogs

0.425 g/kg

Lower heart rate

 

Dogs

0.425 g/kg

Against arrhythmia

 

Dogs

0.25–0.5 g/kg

Against myocardial ischemia

 

Rabbits

150 mg/kg

 

Against platelet aggregation

 

Platelet

2–4 mg/ml

Against thrombosis

 

Rabbits

30 μg/kg/min

Renal protection

Cordyceps Powder

LN Patients

2–4 g/day cordyceps powder, and artemisinin 0.6 g/day

3 years and observed consecutively for 5 years

Lu (2002)

Erythropoiesis

Cordyceps sinensis crystal (CS-Cr)

LACA Mouse, in vivo and vitro

>150 mg/kg (vivo) 150–200 μg/ml (vitro)

5 consecutive daily treatment

Li et al. (1993)

Cordyceps has a long history of use as a lung and kidney tonic, and for the treatment of chronic bronchitis, asthma, tuberculosis and other diseases of the respiratory system. The cardiovascular effects of Cordyceps are being noticed more frequently by researchers as it works through variety of possible ways either by lowering high blood pressure via direct dilatory effects or mediated through M-cholinergic receptors resulting in improvement in the coronary and cerebral blood circulation (Zhu et al. 1998b). Thus, Cordyceps has implications at the therapeutic level as well by rectifying the abnormalities in rhythmic contractions (also known as cardiac arrhythmia). Cordyceps extract has also been found as a promising source to increase cardiac output up to 60 % in augmentation with conventional treatment of chronic heart failure (Chen 1995). The product from wild type and cultured Cordyceps has also been shown to significantly decrease blood viscosity and fibrinogen levels preventing myocardial infarction (Zhu et al. 1998b). Another study showed that the fermentation products of Cs-4 reduce myocardial oxygen consumption in animals under experimental lab conditions revealing dramatic anti-anoxic effects (Zhu et al. 1998a). These studies provide strong evidence that Cs-4 and its fermentative solution prevent platelet aggregation stimulated by collagen or adenosine di-phosphate (ADP). An intravenous injection of concentrated Cordyceps extract (90 μg/kg per min, i.v.) resulted in 51–71 % reduction in 51Cr-labeled platelet aggregation in the endothelial abdominal aorta in rabbit (Zhu et al. 1998b).

Toxicological and dosage related studies of Cordyceps

Cordyceps is one of the best medicinal fungi known for numerous positive aspects in terms of pharmacological effects and considered to be safe. Some reports are published on its adverse gastrointestinal behaviors like dry mouth, nausea and diarrhea (Zhou et al. 1998). In some patients, allergic response has been seen during treatment with a strain of Cordyceps, i.e., CS-4 (Xu 1994). Patients, who suffer from autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, are generally suggested to avoid its use. Reports are still lacking on pregnant and lactating women but some animal studies in mice have revealed that Cordyceps have effects on plasma testosterone levels (Huang et al. 2004; Wong et al. 2007). There has been couple of reports on lead poisoning in patients taking Cordyceps herbal medicine for treatment. The lead content in the Cordyceps powder in these cases was significantly high (20,000 ppm) (Wu et al. 1996). However, the blood lead levels returned to normal upon termination of the product consumption.

Besides few negatively published data, Cordyceps is relatively considered to be a non-toxic medicinal mushroom. Cordyceps dose in patients suffering from long-term renal failure was demonstrated up to 3–6 g/day (Zhu et al. 1998b). In clinical studies involving lung cancer, chemotherapy was carried out with the combination of Cordyceps (Holliday and Cleaver 2008). In another clinical trial, results of Cordyceps (3.15 g for 5 weeks) were compared with placebo to evaluate its effects on physical performance (Parcell et al. 2004). In general, researchers demonstrated that 3–4.5 g of Cordyceps/day is sufficient except in patients suffering from severe liver disease (Mizuno 1999). However, no human toxicity report was found and even animal models were failed to determine median lethal dose. Cordyceps dosage up to 80 g/kg body weight/day for 7 days was injected intraperitonealy in mice and even then it did not cause any fatality (Li et al. 2006). In another study, rabbits fed through mouth for 3 months at a dose of 10 g/kg/day did not show any deviancy in blood reports, or in kidney, liver functioning (Huang et al. 1987). Even water extract of Cordyceps sinensis was found to be non-toxic on macrophage cells line RAW264.7 proliferation (Mizuha et al. 2007). It is suggested that caution should be taken while taking Cordyceps by patients who are undergoing anti-viral or diabetic drug treatments as Cordyceps contains hypoglycemic and anti-viral agents, which can further affect the dosage of these drugs (Holliday and Cleaver 2008).

Future perspective

Cordyceps is a natural medicinal mushroom which is well liked by people nowadays as they believe more in natural therapy than chemotherapy because of lesser side effects. Growth characteristics of Cordyceps militaris have to be studied in-depth to cultivate this mushroom for its mass-scale production so that one could collect enough bio-metabolites from its mycelium extract. There is a strong urge to use interdisciplinary biotechnological and chemical tools to isolate and enhance the bioactivity of the metabolites from this entomopathogenic fungus. The structure of Cordycepin suggests that it has five N and three O atoms which one can imagine could form transition metal complexes in the form of di-, tri- and tetra-dentate ligands as metals can accommodate donor atom’s lone pair of electrons into their empty d orbital (Fig. 5). Complexity of the resulting compound and its molecular mass can be predicted with the help of spectroscopic tools like IR and mass spectroscopy, respectively, which can further improve the bioactivity of the compounds.
Fig. 5

Proposed metal complexes of Cordycepin which could be formed with various transition metals ion

The remaining pharmacologically active compounds apart from Cordycepin also need to be identified and elucidate their structure–function relationship.

Conclusions

The usage of natural/herbal medicines over the synthetic ones has seen an upward trend in the recent past. Cordyceps being an ancient medicinal mushroom used as a crude drug for the welfare of mankind in old civilization is now a matter of great concern because of its unexplored potentials obtained by various culture techniques and being an excellent source of bioactive metabolites with more than 21 clinically approved benefits on human health including anti-diabetic, anti-tumor, anti-oxidative, immunomodulatory, sexual potentiator and anti-ageing effects (Das et al. 2010b). Cordycepin alone has been widely explored for its anti-cancer/anti-oxidant activities, thus, holding a strong pharmacological and therapeutic potential to cure many dreadful diseases in future. Further investigations need to be focused on to study the mechanistic insight into the mysterious potential of this medicinal mushroom on human health and promoting its cultivation strategies for commercialization and ethno-pharmacological use of this wonderful herb.

References

  1. Ali S, Ren S, Huang Z, Wu J (2010) Purification of enzymes related to host penetration and pathogenesis from entomopathogenic fungi. In: Mendez-Vilas A (ed) Current Research, Technology and Education Topics in Applied Microbiology and Microbial Biotechnology, Formatex Research Center, Spain, pp 15–22Google Scholar
  2. Baik JS, Kwon HY, Kim KS, Jeong YK, Cho YS, Lee YC (2012) Cordycepin induces apoptosis in human neuroblastoma SK-N-BE(2)-C and melanoma SK-MEL-2 cells. Indian J Biochem Biophys 49:86–91Google Scholar
  3. Borchers AT, Keen CL, Gershwin ME (2004) Mushroom, tumor, and immunity: an update. Exp Biol Med 229:393–406Google Scholar
  4. Chatterjee R, Srinivasan KS, Maiti PC (1957) Cordyceps sinensis (Berkeley) saccardo: structure of cordycepic acid. J Am Pharm Assoc 46:114–122Google Scholar
  5. Chen DG (1995) Effects of JinShuiBao capsule on the quality of life of patients with heart failure. J Admin Tradit Chin Med 5:40–43Google Scholar
  6. Chen LS, Stellrecht CM, Gandhi V (2008) RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells. Brit J Haematol 140:391–682Google Scholar
  7. Choi S, Lim MH, Kim KM, Jeon BH, Song WO, Kim TW (2011) Cordycepin-induced apoptosis and autophagy in breast cancer cells are independent of estrogen receptor. Toxicol Appl Pharmacol 257:165–173Google Scholar
  8. Chu HL, Chien JC, Duh PD (2011) Protective effect of Cordyceps militaris against high glucose-induced oxidative stress in human umbilical vein endothelial cells. Food Chem 129:871–876Google Scholar
  9. Cunningham KG, Manson W, Spring FS, Hutchinson SA (1950) Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (L.) Link. Nature 166:949–954Google Scholar
  10. Dai G, Bao T, Xu C, Cooper R, Zhu JX (2001) CordyMax™ Cs-4 improves steady-state bioenergy status in mouse liver. J Altern Complem Med 7:231–240Google Scholar
  11. Das SK, Masuda M, Hatashita M, Sakurai A, Sakakibara M (2008) A new approach for improving cordycepin productivity in surface liquid culture of Cordyceps militaris using high-energy ion beam irradiation. Lett Appl Microbiol 47:534–538Google Scholar
  12. Das SK, Masuda M, Hatashita M, Sakurai A, Sakakibara M (2010a) Effect of inoculation on production of anti-cancer drug-cordycepin in surface liquid culture using Cordyceps militaris mutant: a minor factor may greatly affect the result. Indian J Biotechnol 9:427–430Google Scholar
  13. Das SK, Masuda M, Sakurai A, Sakakibara M (2010b) Medicinal uses of the mushroom Cordyceps militaris: current state and prospects. Fitoterapia 81:961–968Google Scholar
  14. Devkota S (2006) Yarsagumba [Cordyceps sinensis (Berk.) Sacc.]; traditional utilization in Dolpa district, western Nepal. Our Nat 4:48–55Google Scholar
  15. Gong Z, Su Y, Huang L, Lin J, Tang K, Zhou X (2009) Cloning and analysis of glyceraldehyde-3-phosphate dehydrogenase gene from Cordyceps militaris. Afr J Agr Res 4:402–408Google Scholar
  16. Gu YX, Wang ZS, Li SX (2007) Effect of multiple factors on accumulation of nucleosides and bases in Cordyceps militaris. Food Chem 102:1304–1309Google Scholar
  17. Guo C, Zhu J, Zhang C, Zhang L (1998) Determination of adenosine and 3′-deoxyadenosine in Cordyceps militaris (L.) Link by HPLC. Chin J Chinese Materia Medica 23:236–243Google Scholar
  18. Hajek AE, Leger RJS (1994) Interactions between fungal pathogens and insects hosts. Annu Rev Entomol 39:293–322Google Scholar
  19. Hattori M, Isomura S, Yokoyama E, Ujita M, Hara A (2005) Extracellular trypsin-like protease produced by Cordyceps militaris. J Biosci Bioeng 100:631–636Google Scholar
  20. He W, Zhang MF, Ye J, Jiang TT, Fang X, Song Y (2010) Cordycepin induces apoptosis by enhancing JNK and p38 kinase activity and increasing the protein expression of Bcl-2 pro-apoptotic molecules. J Zhejiang Univ Sci B 11:654–660Google Scholar
  21. Ho JM, Seo MJ, Park JU, Kang BW, Kim KS, Lee JY, Kim GY, Kim JI, Choi YH, Kim KH, Jeong YK (2012) Effect of cordycepin purified from Cordyceps militaris on Th1 and Th2 cytokines in mouse splenocytes. J Microbiol Biotechnol 22:1161–1164Google Scholar
  22. Hodge KT, Humber RA, Wozniak CA (1998) Cordycepsvariabilis and the genus Syngliocladium. Mycologia 90:743–753Google Scholar
  23. Holbein S, Wengi A, Decourty L, Freimoser FM, Jacquier A, DichtlrnaI B (2009) Cordycepin interferes with 3′ end formation in yeast independently of its potential to terminate RNA chain elongation. RNA 15:837–849Google Scholar
  24. Holliday J, Cleaver M (2008) Medicinal value of the caterpillar fungi species of the genus Cordyceps (Fr.) Link (Ascomycetes): a review. Int J Med Mushrooms 10:219–234Google Scholar
  25. Holliday J, Cleaver P, Powers ML, Patel D (2004) Analysis of quality and techniques for hybridization of medicinal fungus Cordyceps sinensis. Int J Med Mushrooms 6:147–160Google Scholar
  26. Huang Y, Lu J, Zhu B, Wen Q, Jia F, Zeng S, Chen T, Li Y, Cheng G, Yi Z (1987) Toxicity study of fermentation Cordyceps mycelia B414. Chin Tradit Pat Med 10:24–25Google Scholar
  27. Huang BM, Hsua CC, Tsai SJ, Sheu CC, Leu SF (2001) Effects of Cordyceps sinensis on steroidogenesis in normal mouse Leydig cells. Life Sci 69:2593–2602Google Scholar
  28. Huang LF, Liang YZ, Guo FQ, Zhou ZF, Cheng BM (2003) Simultaneous separation and determination of active components in Cordyceps sinensis and Cordyceps militaris by LC/ESI-MS. J Pharm Biomed Anal 33:1155–1162Google Scholar
  29. Huang YL, Leu SF, Liu BC, Sheu CC, Huang BM (2004) In vivo stimulatory effect of Cordyceps sinensis mycelium and its fractions on reproductive functions in male mouse. Life Sci 75:1051–1062Google Scholar
  30. Humber RA (2000) Fungal pathogens and parasites of insects. In: Priest F, Goodfellow M (eds) Applied microbial systematics. Kluwer Academic Publishers, Dordrecht, pp 203–230Google Scholar
  31. Hyun H (2008) Chemical ingredient of Cordyceps militaris. Mycobiology 36:233–235Google Scholar
  32. Hywel NLJ (2002) Multiples of eight in Cordyceps ascospores. Mycol Res 106:2–3Google Scholar
  33. Isaka M, Kongsaeree P, Thebtaranonth Y (2001) Bioxanthracenes from the insect pathogenic fungus Cordyceps pseudomilitaris BCC 1620. II. Structure elucidation. J Antibiot (Tokyo) 54:36–43Google Scholar
  34. Jagger DV, Kredich NM, Guarino AJ (1961) Inhibition of Ehrlich mouse ascites tumor growth by cordycepin. Cancer Res 21:216–220Google Scholar
  35. Jen CY, Lin CY, Huang BM, Leu SF (2008) Cordycepin induced MA-10 mouse leydig tumor cell apoptosis through Caspase-9 Pathway. Evid Based Complement Alternat Med 2011:1–11Google Scholar
  36. Jeong JW, Jin CY, Park C, Hong SH, Kim GY, Jeong YK, Lee JD, Yoo YH, Choi YH (2011) Induction of apoptosis by cordycepin via reactive oxygen species generation in human leukemia cells. Toxicol In Vitro 25:817–824Google Scholar
  37. Ji DB, Ye J, Li CL, Wang YH, Zhao J, Cai SQ (2009) Anti-aging effect of Cordyceps sinensis extract. Phytother Res 23:116–122Google Scholar
  38. Jin Yun C, Kim GY, Choi YH (2008) Induction of apoptosis by aqueous extract of Cordyceps militaris through activation of caspases and inactivation of Akt in human breast cancer MDA-MB-231 cells. J Microbiol Biotechnol 18:1997–2003Google Scholar
  39. Jo WS, Choi YJ, Kim HJ, Lee JY, Nam BH, Lee JD, Lee SW, Seo SY, Jeong MH (2010) The anti-inflammatory effects of water extract from Cordyceps militaris in murine macrophage. Mycobiology 38:46–51Google Scholar
  40. Jung EC, Kim KD, Bai CH, Kim JC, Kim DK, Kim HH (2007) A mushroom lectin from ascomycete Cordyceps militaris. BBA-Gen Subj 1770:833–841Google Scholar
  41. Kawaguchi N, Ohmori T, Takeshita Y, Kawanishi G, Katayama S, Yamada H (1986) Occurrence of Gal beta (1–3) GalNAc-Ser/Thr in the linkage region of polygalactosamine containing fungal glycoprotein from Cordyceps ophioglossoides. Biochem Biophys Res Commun 140:350–356Google Scholar
  42. Kim JS, Sapkota K, Park SE, Choi BS, Kim S, Nguyen TH, Kim CS, Choi HS, Kim MK, Chun HS, Park Y, Kim SJ (2006) A fibrinolytic enzyme from the medicinal mushroom Cordyceps militaris. J Microbiol 44:622–631Google Scholar
  43. Klenow H (1963) Formation of the mono-, di- and triphosphate of cordycepin in Ehrlich ascites-tumor cells in vitro. Biochim Biophys Acta 76:347–353Google Scholar
  44. Krasnoff SB, Reategui RF, Wagenaar MM, Gloer JB, Gibson DM (2005) Cicadapeptins I and II: new Aib-containing peptides from the entomopathogenic fungus Cordyceps heteropoda. J Nat Prod 68:50–55Google Scholar
  45. Kuo MC, Chang CY, Cheng TL, Wu MJ (2007) Immunomodulatory effect of exo-polysaccharides from submerged cultured Cordyceps sinensis: enhancement of cytokine synthesis, CD11b expression, and phagocytosis. Appl Microbiol Biotechnol 75:769–775Google Scholar
  46. Lee KH, Min TJ (2003) Purification and characterization of a chitinase in culture media of Cordyceps militaris (L.) Link. Korean J Med Mycol 31:168–174Google Scholar
  47. Lee SJ, Kim SK, Choi WS, Kim WJ, Moon SK (2009a) Cordycepin causes p21WAF1-mediated G2/M cell-cycle arrest by regulating c-Jun N-terminal kinase activation in human bladder cancer cells. Arch Biochem Biophys 490:103–109Google Scholar
  48. Lee YR, Noh EM, Jeong EY, Yun SK, Jeong YJ, Kim JY, Kwon KB, Kim BS, Lee SH, PPark CS, Kim JS (2009b) Cordycepin inhibits UVB-induced matrix metalloproteinase expression by suppressing the NF-κB pathway in human dermal fibroblasts. Exp Mol Med 41:548–554Google Scholar
  49. Lee EJ, Kim WJ, Moon SW (2010) Cordycepin suppresses TNF-alpha-induced invasion, migration and matrix metalloproteinase-9 expression in human bladder cancer cells. Phytother Res 24:1755–1761Google Scholar
  50. Lee B, Park J, Park J, Shin HJ, Kwon S, Yeom M, Sur B, Kim S, Kim M, Lee H, Yoon SH, Hahm DH (2011a) Cordyceps militaris improves neurite outgrowth in neuro2A cells and reverses memory impairment in rats. Food Sci Biotechnol 20:1599–1608Google Scholar
  51. Lee JH, Hong SM, Yun JY, Myoung H, Kim MJ (2011b) Anti-cancer effects of cordycepin on oral squamous cell carcinoma proliferation and apoptosis in vitro. J Cancer Ther 2:224–234Google Scholar
  52. Leger RJS, Bidochka MJ, Staples RC (1991) Preparation events during infection of host cuticle by Metarhizium anisopliae. J Invertebr Pathol 58:168–179Google Scholar
  53. Li T, Li W (2009) Impact of polysaccharides from Cordyceps on antifatigue in mice. Sci Res Essays 4:705–709Google Scholar
  54. Li Y, Chen GZ, Jiang DZ (1993) Effect of Cordyceps sinensis on erythropoiesis in mouse bone marrow. Chinese Med J 106:313–316Google Scholar
  55. Li SP, Yang FQ, Tsim KW (2006) Quality control of Cordyceps sinensis, a valued traditional Chinese medicine. J Pharm Biomed Anal 41:1571–1584Google Scholar
  56. Li S, Li P, Ji H (2011) RP-HPLC determination of ergosterol in natural and cultured Cordyceps. Chin J Mod Appl Pharm 18:297–299Google Scholar
  57. Lin WH, Tsai MT (2007) Improvement of sperm production in subfertile Boars by Cordyceps militaris supplement. Am J Chinese Med 35:631–641Google Scholar
  58. Lindequist U, Niedermeyer THJ, Julich WD (2005) The pharmacological potential of mushrooms. Evid Based Complement Alternat Med 2:285–299Google Scholar
  59. Lu L (2002) Study on effect of Cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritis. Chin J Integr Med 22:169–171Google Scholar
  60. Mains EB (1958) North American entomogenous species of Cordyceps. Mycologia 50:169–222Google Scholar
  61. Manabe N, Azuma Y, Sugimoto M, Uchio K, Miyamoto M, Taketomo N, Tsuchita H, Miyamoto H (2000) Effects of the mycelial extract of cultured Cordyceps sinensis on in vivo hepatic energy metabolism and blood flow in dietary hypoferric anaemic mice. Br J Nutr 83:197–204Google Scholar
  62. Masuda M, Urabe E, Sakurai A, Sakakibara M (2006) Production of cordycepin by surface culture using the medicinal mushroom Cordyceps militaris. Enzyme Microb Tech 39:641–646Google Scholar
  63. Mizuha Y, Yamamoto H, Sato T, Tsuji M, Masuda M, Uchida M, Sakai K, Taketani Y, Yasutomo K, Sasaki H, Takeda E (2007) Water extract of Cordycepssinensis (WECS) inhibits the RANKL-induced osteoclast differentiation. Biol Factors 30:105–116Google Scholar
  64. Mizuno T (1999) Medicinal effects and utilization of Cordyceps (Fr.) Link (Ascomycetes) and Isaria Fr. (Mitosporic fungi) Chinese caterpillar fungi, “Tochukaso” (review). Int J Med Mushrooms 1:251–262Google Scholar
  65. Mollah ML, PPark DK, Park HJ (2012) Cordyceps militaris grown on germinated soybean induces G2/M cell cycle arrest through downregulation of Cyclin B1 and Cdc25c in human colon cancer HT-29 cells. Evid Based Complement Alternat Med 2012:1–7Google Scholar
  66. Muslim N, Rahman H (2010) A possible new record of Cordyceps species from Ginseng Camp, Maliau Basin, Sabah, Malaysia. JTBC 6:39–41Google Scholar
  67. Nakamura K, Yamaguchi Y, Kagota S, Kwon YM, Shinozuka K, Kunitomo M (1999) Inhibitory effect of Cordyceps sinensis on spontaneous liver metastasis of lewis lung carcinoma and B16 melanoma cells in syngeneic mice. Jpn J Pharmacol 79:335–341Google Scholar
  68. Nan JX, Park EJ, Yang BK, Song CH, Ko G, Sohn DH (2001) Anti-fibrotic effect of extracellular biopolymer from submerged mycelial cultures of Cordyceps militaris on liver fibrosis induced by bile duct ligation and scission in rats. Arch Pharm Res 24:327–332Google Scholar
  69. Negi CS, Koranga PR, Ghinga HS, Gumba (2006) Yar tsa (Cordyceps sinensis): A call for its sustainable exploitation. Int J Sust Dev World 13:1–8Google Scholar
  70. Ng TB, Wang HX (2005) Pharmacological actions of Cordyceps, a prized folk medicine. J Pharm Pharmacol 57:1509–1519Google Scholar
  71. Ni H, Zhou XH, Li HH, Huang WF (2009) Column chromatographic extraction and preparation of cordycepin from Cordyceps militaris waster medium. J Chromatogr B 877:2135–2141Google Scholar
  72. Overgaard KH (1964) The inhibition of 5-phosphoribosyl-1-pyrophosphate formation by Cordycepin triphosphate in extracts of Ehrlich ascites tumor cells. Biochim Biophys Acta 80:504–507Google Scholar
  73. Pan BS, Lin CY, Huang BM (2011) The effect of cordycepin on steroidogenesis and apoptosis in MA-10 mouse leydig tumor cells. Evid Based Complement Alternat Med 2011:1–14Google Scholar
  74. Panda AK, Swain KC (2011) Traditional uses and medicinal potential of Cordyceps sinensis of Sikkim. J Ayurveda Integr Med 2:9–13Google Scholar
  75. Parcell AC, Smith JM, Schulthies SS, Myrer JW, Fellingham G (2004) Cordyceps Sinensis (CordyMax Cs-4) supplementation does not improve endurance exercise performance. Int J Sport Nutr Exerc Metabol 14:236–242Google Scholar
  76. Park NS, Lee KS, Sohn HD, Kim DH (2005) Molecular cloning, expression, and characterization of the Cu, Zn superoxide dismutase (SOD1) gene from the entomopathogenic fungus Cordyceps militaris. Mycologia 97:130–138Google Scholar
  77. Park BT, Na KH, Jung EC, Park JW, Kim HH (2009a) Anti-fungal and -cancer activities of a protein from the mushroom Cordyceps militaris. Korean J Physiol Pharmacol 13:49–54Google Scholar
  78. Park SE, Kim J, Lee YW, Yoo HS, Cho CK (2009b) Antitumor activity of water extracts from Cordyceps militaris in NCI-H460 cell xenografted nude mice. J Acupunct Meridian Stud 2:294–300Google Scholar
  79. Park SE, Yoo HS, Jin CY, Hong SH, Lee YW, Kim BW, Lee SH, Kim WJ, Cho CK, Choi YH (2009c) Induction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militaris. Food Chem Toxicol 47:1667–1675Google Scholar
  80. Patel S, Goyal A (2012) Recent developments in mushrooms as anti-cancer therapeutics: a review. 3 Biotech 2:1–15Google Scholar
  81. Rao YK, Fang SH, Wu WS, Tzeng YM (2010) Constituents isolated from Cordyceps militaris suppress enhanced inflammatory mediator’s production and human cancer cell proliferation. J Ethnopharmacol 131:363–367Google Scholar
  82. Rottman F, Guarino AJ (1964) The inhibition of phosphoribosyl-pyrophosphate amidotransferase activity by cordycepin mono phosphate. Biochim Biophys Acta 89:465–472Google Scholar
  83. Rukachaisirikul V, Pramjit S, Pakawatchai C, Isaka M, Supothina S (2004) 10- membered macrolides from the insect pathogenic fungus Cordyceps militaris BCC 2816. J Nat Prod 67:1953–1958Google Scholar
  84. Rukachaisirikul V, Chantaruk S, Tansakul C, Saithong S, Chaicharernwimonkoon L, Pakawatchai C, Isaka M, Intereya K (2006) A cyclopeptide from the insect pathogenic fungus Cordyceps sp. BCC 1788. J Nat Prod 69:305–307Google Scholar
  85. Russell R, Paterson M (2008) Cordyceps—a traditional Chinese medicine and another fungal therapeutic biofactory? Phytochem 69:1469–1495Google Scholar
  86. Sharma S (2004) Trade of Cordyceps sinensis from high altitudes of the Indian Himalaya: conservation and biotechnological priorities. Curr Sci 86:1614–1619Google Scholar
  87. Shrestha B, Sung JM (2005) Notes on Cordyceps species collected from the central region of Nepal. Mycobiology 33:235–239Google Scholar
  88. Singh N, Pathak R, Singh AK, Rautela D, Dubey A (2010) Collection of Cordyceps sinensis (Berk.) Sacc. in the interior villages of Chamoli district in Garhwal Himalaya (Uttarakhand) and its social impacts. J Am Sci 6:5–9Google Scholar
  89. Siu KM, Mak HFD, Chiu PY, Poon KTM, Du Y, Ko KM (2004) Pharmacological basis of ‘Yin-nourishing’ and ‘Yang-invigorating’ actions of Cordyceps, a Chinese tonifying herb. Life Sci 76:385–395Google Scholar
  90. Sugar AM, Mccaffrey RP (1998) Antifungal activity of 3′-deoxyadenosine (cordycepin). Antimicrob Agents Chemother 42:1424–1427Google Scholar
  91. Thakur A, Hui R, Hongyan Z, Tian Y, Tianjun C, Mingwei C (2011) Pro-apoptotic effects of Paecilomyces hepiali, a Cordyceps sinensis extract on human lung adenocarcinoma A549 cells in vitro. J Can Res and Ther 7:421–426Google Scholar
  92. Trigg P, Gutteridge WE, Williamson J (1971) The effect of Cordycepin on malarial parasites. T Roy Soc Trop Med H 65:514–520Google Scholar
  93. Ujita M, Katsuno Y, Suzuki K, Sugiyama K, Takeda E, Yokoyama E, Hara A (2006) Molecular cloning and sequence analysis of the beta-1,3-glucan synthase catalytic subunit gene from a medicinal fungus, Cordyceps militaris. Mycoscience 47:98–105Google Scholar
  94. Unagul P, Wongsa P, Kittakoop P, Intamas S, Srikitikulchai P, Tanticharoen M (2005) Production of red pigments by the insect pathogenic fungus Cordyceps unilateralis BCC 1869. J Ind Microbiol Biot 32:135–140Google Scholar
  95. Wang L, Zhang WM, Hu B, Chen YQ, Qu LH (2008) Genetic variation of Cordyceps militaris and its allies based on phylogenetic analysis of rDNA ITS sequence data. Fungal Divers 31:147–156Google Scholar
  96. Wang ZM, Peng X, Lee KLD, Tang JCO, Cheung PCK, Wu JY (2011) Structural characterisation and immunomodulatory property of an acidic polysaccharide from mycelial culture of Cordyceps sinensis fungus Cs-HK1. Food Chem 125:637–643Google Scholar
  97. Wanga Z, Heb Z, Lib S, Yuanb Q (2005) Purification and partial characterization of Cu, Zn containing superoxide dismutase from entomogenous fungal species Cordyceps militaris. Enzyme Microb Tech 36:862–869Google Scholar
  98. Watanabe N, Hattori M, Yokoyama E, Isomura S, Ujita M, Hara A (2006) Entomogenous fungi that produce 2, 6-pyridine dicarboxylic acid (dipicolinic acid). J Biosci Bioeng 102:365–373Google Scholar
  99. Webster J (1980) Introduction to fungi, 2nd edn. Cambridge University Press, Cambridge, p 355Google Scholar
  100. Winkler D (2008) ‘Yartsa Gunbu (Cordyceps sinensis) and the fungal commodification of the rural economy in Tibet AR. Econ Bot 63:291–305Google Scholar
  101. Winkler D (2010) Cordyceps sinensis—a precious parasitic fungus infecting Tibet. Field Mycol 11:60–67Google Scholar
  102. Wong KL, So EC, Chen CC, Wu RS, Huang BM (2007) Regulation of steroidogenesis by Cordyceps sinensis mycelium extracted fractions with (hCG) treatment in mouse Leydig cells. Arch Androl 53:75–77Google Scholar
  103. Wong YY, Moon A, Duffin R, Barthet-Barateig A, Meijer HA, Clemens MJ, de Moor CH (2010) Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction. J Biol Chem 285:2610–2621Google Scholar
  104. Wonga JH, Nga TB, Wangb H, Szec SCW, Zhangc KY, Lid Q, Lue X (2011) Cordymin, an antifungal peptide from the medicinal fungus Cordyceps militaris. Phytomedicine 18:387–392Google Scholar
  105. Wu TN, Yang KC, Wang CM, Lai JS, Ko KN, Chang PY, Liou SH (1996) Lead poisoning caused by contaminated Cordyceps, a Chinese herbal medicine: two case reports. Sci Total Environ 182:193–195Google Scholar
  106. Xiao JH, Xiao DM, Xiong Q, Liang ZQ, Zhong JJ (2010) Nutritional requirements for the hyperproduction of bioactive exopolysaccharides by submerged fermentation of the edible medicinal fungus Cordyceps taii. Biochem Eng J 49:241–249Google Scholar
  107. Xu Y (1994) Drug allergy occurred in a patient after orally taken JinShuiBao capsule. Chin J Chinese Materia Medica 19:503Google Scholar
  108. Yan JK, Li L, Wang ZM, Wu JY (2010) Structural elucidation of an exopolysaccharide from mycelia fermentation of a Tolypocladium sp. fungus isolated from wild Cordyceps sinensis. Carbohydr Polym 79:125–130Google Scholar
  109. Yang BK, Ha JY, Jeong SC, Das S, Yun JW, Lee YS, Choi JW, Song CH (2000) Production of exo-polymers by submerged mycelial culture of Cordyceps militaris and its hypolipidemic effect. J Microbio Biotechnol 10:784–788Google Scholar
  110. Yang FQ, Feng K, Zhao J, Li SP (2009) Analysis of sterols and fatty acids in natural and cultured Cordyceps by one-step derivatization followed with gas chromatography mass spectrometry. J Pharm Biomed Anal 49:1172–1178Google Scholar
  111. Yang FQ, Li DQ, Feng K, Hu DJ, Li SP (2010) Determination of nucleotides, nucleosides and their transformation products in Cordyceps by ion-pairing reversed-phase liquid chromatography-mass spectrometry. J Chromatogr A 1217:5501–5510Google Scholar
  112. Ye MQ, Hu Z, Fan Y, He L, Xia FB, Zou GL (2004) Purification and characterization of an acid deoxyribonuclease from the cultured mycelia of Cordyceps sinensis. J Biochem Mol Biol 37:466–473Google Scholar
  113. Yoo HS, Shin JW, Cho JH, Son CG, Lee YW, Park SY, Cho CK (2004) Effects of Cordyceps militaris extract on angiogenesis and tumor growth. Acta Pharm Sinic 25:657–665Google Scholar
  114. Yu RM, Yang W, Song LY, Yan CY, Zhang Z, Zhao Y (2007) Structural characterization and antioxidant activity of a polysaccharide from the fruiting bodies of cultured Cordyceps militaris. Carbohydr Polym 70:430–436Google Scholar
  115. Yu R, Yin Y, Yang W, Ma W, Yang L, Chen X, Zhang Z, Ye B, Song L (2009) Structural elucidation and biological activity of a novel polysaccharide by alkaline extraction from cultured Cordyceps militaris. Carbohydr Polym 75:166–171Google Scholar
  116. Yuan JP, Wang JH, Liu X, Kuang HC, Zhao SH (2007) Simultaneous determination of free ergosterol and ergosteryl esters in Cordyceps sinensis by HPLC. Food Chem 105:1755–1759Google Scholar
  117. Yue K, Ye M, Zhou Z, Sun W, Lin X (2012) The genus Cordyceps: a chemical and pharmacological review. J Pharm Pharmacol. doi: 10.1111/j.2042-7158.2012.01601.xGoogle Scholar
  118. Yun Y, Han S, Lee S, Ko S, Lee C, Ha N, Kim K (2003) Anti-diabetic effects of CCCA, CMESS, and cordycepin from Cordyceps militaris and the immune responses in streptozotocin- induced diabetic mice. Nat Prod Sci 9:291–298Google Scholar
  119. Zaidman BZ, Yassin M, Mahajna J, Wasser SP (2005) Medicinal mushroom modulators of molecular targets as cancer therapeutics. Appl Microbiol Biotechnol 67:453–468Google Scholar
  120. Zhang Q, Wu J, Hu Z, Zhang D (2004) Induction of HL-60 apoptosis by ethyl acetate extract of Cordyceps sinensis fungal mycelium. Life Sci 75:2911–2919Google Scholar
  121. Zhang G, Huang Y, Bian Y, Wong JH, Ng TB, Wang H (2006) Hypoglycemic activity of the fungi Cordyceps militaris, Cordyceps sinensis, Triccholoma mongolicum, and Omphalia lapidescens in streptozotocin-induced diabetic rats. Appl Microbiol Biotechnol 72:1152–1156Google Scholar
  122. Zhang Y, Liu X, Wang M (2008) Cloning, expression, and characterization of two novel cuticle-degrading serine proteases from the entomopathogenic fungus Cordyceps sinensis. Res Microbiol 159:462–471Google Scholar
  123. Zhang XL, Cheng LB, Assaf SA, Phillips GO, Phillips AO (2012) Cordyceps sinensis decreases TGF-b1 dependent epithelial to mesenchymal transdifferentiation and attenuates renal fibrosis. Food Hydrocolloids 28:200–212Google Scholar
  124. Zhou JS, Halpern G, Jones K (1998) The scientifi c rediscovery of an ancient Chinese herbal medicine: cordyceps sinensis. J Altern Complem Med 4:429–457Google Scholar
  125. Zhou X, Luo L, Dressel W, Shadier G, Krumbiegel D, Schmidtke P, Zepp F, Meyer CU (2008) Cordycepin is an immunoregulatory active ingredient of Cordyceps sinensis. Am J Chin Med 36:967–980Google Scholar
  126. Zhou X, Gong Z, Su Y, Lin J, Tang K (2009) Cordyceps fungi: natural products, pharmacological functions and developmental products. J Pharm Pharmcol 61:279–291Google Scholar
  127. Zhu JS, Halpern GM, Jones K (1998a) The scientific rediscovery of an ancient Chinese herbal medicine: cordyceps sinensis: part I. J Altern Complem Med 4:289–303Google Scholar
  128. Zhu JS, Halpern GM, Jones K (1998b) The scientific rediscovery of a precious ancient Chinese herbal regimen: Cordyceps sinensis: part II. J Altern Complem Med 4:429–457Google Scholar

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© The Author(s) 2013

Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Hardeep S. Tuli
    • 1
  • Sardul S. Sandhu
    • 2
  • A. K. Sharma
    • 1
    Email author
  1. 1.Department of BiotechnologyM.M.E.C., Maharishi Markandeshwar UniversityAmbalaIndia
  2. 2.Department of Biological SciencesR. D. UniversityJabalpurIndia

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