Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin.
Journal: 2017/April - 3 Biotech
ISSN: 2190-572X
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.
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3 Biotech. Jan/31/2014; 4(1): 1-12
Published online Feb/18/2013

Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin

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.

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. noBioactive compoundsReferences
1CordycepinCunningham et al. (1950)
2Cordycepic acidChatterjee et al. (1957)
3N-acetylgalactosamineKawaguchi et al. (1986)
4AdenosineGuo et al. (1998)
5Ergosterol and ergosteryl estersYuan et al. (2007)
6BioxanthracenesIsaka et al. (2001)
7HypoxanthineHuang et al. (2003)
8Acid deoxyribonucleaseYe et al. (2004)
9Polysaccharide and exopolysaccharideYu et al. (2007, 2009), Xiao et al. (2010), Yan et al. (2010)
10ChitinaseLee and Min (2003)
11Macrolides (C10H14O4)Rukachaisirikul et al. (2004)
12Cicadapeptins and myriocinKrasnoff et al. (2005)
13Superoxide dismutaseWanga et al. (2005)
14ProteaseHattori et al. (2005)
15NaphthaquinoneUnagul et al. (2005)
16CordyheptapeptideRukachaisirikul et al. (2006)
17Dipicolinic acidWatanabe et al. (2006)
18Fibrynolytical enzymeKim et al. (2006)
19LectinJung et al. (2007)
20CordyminWonga 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 effectActive content of CordycepsAnimal/tissue studiedActive doseExperimental time periodReferences
Anti-angiogenicCordyceps militaris Extract (CME)HUVECs100–200 mg/LAfter 3–6 hYoo et al. (2004)
Anti-tumor/anti-proliferatoryCordyceps militaris protein (CMP)MCF-7 (breast cancer), 5637 (bladder cancer) and A-549 (lung cancer)15 μM72 hPark et al. (2009a, b, c)
Aqueous extract of C. militarisNude mice with NCI-H460 cellAt 150 and 300 mg/kg/day4 weeksPark et al. (2009a, b, c)
BuOH extracts of C. militaris grown on germinated soybean (GSC)HT-29 human colon cancer100 μg/ml48 hMollah et al. 2012
CordycepinMice150 mg/kg body weight7 daysJagger et al. (1961)
5637 and T-24 (bladder cancer) KB and HSC3 (oral squamous cell carcinoma)200 μm24 hLee et al. (2011a, b)
50 and 30 μM, respectively48 h
Anti metastasisWE of C. sinensisLLC and B16 cells100 mg/kg in LLC, 100 or 200 mg/kg in B1620 and 26 daysNakamura et al. (1999)
Cordycepin5637 and T-24 cells100 and 200 μM48 hLee et al. 2010
Induce apoptosisetOAc extract of C. sinensisHL-60 cellsED50 ≤25 μg/ml2 daysZhang et al. (2004)
Aqueous extract of C. militarisMDA-MB-2310.8 mg/ml24 hJin et al. (2008)
Paecilomyces hepiali (derivative of C. sinensis) extractA5492–4 mg/ml48–72 hThakur et al. (2011)
Water extract of C. militarisA5492 μg/ml48 hPark et al. (2009a, b, c)
CordycepinMA-10100 μM to 5 mM24 hJen et al. (2008)
SW480 & SW6202 and 0.72 mmol/L, respectively72 hHe et al. (2010)
MDA-MB-231100 μM24 hChoi et al. (2011)
U937 and THP-130 μg/ml24 hJeong et al. (2011)
SK-NBE(2)-C and SK-Mel-2 (HTB-68)120 and 80 μM, respectively24 hBaik et al. (2012)
Anti fatiguePolysaccharideMice200 mg/kgFor 21 daysLi and Li (2009)
Anti malariaCordycepinErythrocytic stages of P. knowlesi (in vitro) and P. berghei (in vivo)In vitro 106 M and in vivo 50 mg/kgIn vitro 4 hTrigg et al. (1971)
Anti fungalCordycepinMurine Model1.5 mg/kg/day30 daysSugar and Mccaffrey (1998)
HypolipidemicExo polysaccharideRats50–100 mg/kg2 weeksYang et al. (2000)
Increase hepatic energy metabolism and blood flowCordyceps sinensis ExtractMice200 mg/kg/daily4 weeksManabe et al. (2000)
ImmunomodulatoryPolysaccharide from C. sinensisHuman peripheral blood0.025–0.1 mgKuo et al. (2007)
Purified Cordycepin from C. militarisMouse splenocytes5 μg/ml72 hHo et al. (2012)
Anti inflammatoryC. militaris water extractMurine macrophage1,250 μg/ml24 hJo et al. (2010)
Constituents isolated from C. militarisLPS/IFN-γ stimulated Macrophage cellsRanging from 6.3 to 20 μg/ml24 hRao et al. (2010)
Anti Diabetic/HypoglycemicC. militaris extract reduce oxidative stress, induced by high glucose concentrationHUVECs25 μg/ml12–36 hChu et al. (2011)
Fractions of C. militaris as CMESS and CordycepinMice50 and 0.2 mg/kg, respectively7 daysYun et al. (2003)
Crude extract and polysaccharide rich fractionRat10 mg/kg of polysaccharide and 100 mg/kg body weight of crude extract4 daysZhang et al. (2006)
SpermatogenicCM mycelium powderSub fertile boars10 g/boar2 monthsLin and Tsai (2007)
SteroidogenesisCSNormal mouse leydig cells3 mg/ml2–3 hHuang et al. (2001)
CordycepinMA-10 mouse leydig tumor cells100 μM24 hPan et al. (2011)
Anti-agingCSEMice2.0, 4.0 g/kg6 weeksJi et al. (2009)
CordycepinHuman dermal fibroblasts50–100 μM24 hLee et al. 2009a, 2009b
Anti-fibroticEPC from C. militarisRats30 mg/kg/day4 weeksNan et al. (2001)
Cardiovascular effectsCs-41–15 minZhu et al. (1998b)
Relax aortaIsolated aorta50 μg/ml
Lower blood pressureDogs60 mg/kg
Increase coronary blood flowDogs0.425 g/kg
Lower heart rateDogs0.425 g/kg
Against arrhythmiaDogs0.25–0.5 g/kg
Against myocardial ischemiaRabbits150 mg/kg
Against platelet aggregationPlatelet2–4 mg/ml
Against thrombosisRabbits30 μg/kg/min
Renal protectionCordyceps PowderLN Patients2–4 g/day cordyceps powder, and artemisinin 0.6 g/day3 years and observed consecutively for 5 yearsLu (2002)
ErythropoiesisCordyceps sinensis crystal (CS-Cr)LACA Mouse, in vivo and vitro>150 mg/kg (vivo) 150–200 μg/ml (vitro)5 consecutive daily treatmentLi 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

  • 2. BaikJSKwonHYKimKSJeongYKChoYSLeeYCCordycepin induces apoptosis in human neuroblastoma SK-N-BE(2)-C and melanoma SK-MEL-2 cellsIndian J Biochem Biophys2012498691[PubMed][Google Scholar]
  • 3. BorchersATKeenCLGershwinMEMushroom, tumor, and immunity: an updateExp Biol Med2004229393406[Google Scholar]
  • 4. ChatterjeeRSrinivasanKSMaitiPCCordyceps sinensis (Berkeley) saccardo: structure of cordycepic acidJ Am Pharm Assoc195746114122[Google Scholar]
  • 5. ChenDGEffects of JinShuiBao capsule on the quality of life of patients with heart failureJ Admin Tradit Chin Med199554043[Google Scholar]
  • 6. ChenLSStellrechtCMGandhiVRNA-directed agent, cordycepin, induces cell death in multiple myeloma cellsBrit J Haematol2008140391682[Google Scholar]
  • 7. ChoiSLimMHKimKMJeonBHSongWOKimTWCordycepin-induced apoptosis and autophagy in breast cancer cells are independent of estrogen receptorToxicol Appl Pharmacol2011257165173[PubMed][Google Scholar]
  • 8. ChuHLChienJCDuhPDProtective effect of Cordyceps militaris against high glucose-induced oxidative stress in human umbilical vein endothelial cellsFood Chem2011129871876[PubMed][Google Scholar]
  • 9. CunninghamKGMansonWSpringFSHutchinsonSACordycepin, a metabolic product isolated from cultures of Cordyceps militaris (L.) LinkNature1950166949954[PubMed][Google Scholar]
  • 10. DaiGBaoTXuCCooperRZhuJXCordyMax™ Cs-4 improves steady-state bioenergy status in mouse liverJ Altern Complem Med20017231240[Google Scholar]
  • 11. DasSKMasudaMHatashitaMSakuraiASakakibaraMA new approach for improving cordycepin productivity in surface liquid culture of Cordyceps militaris using high-energy ion beam irradiationLett Appl Microbiol200847534538[PubMed][Google Scholar]
  • 12. DasSKMasudaMHatashitaMSakuraiASakakibaraMEffect of inoculation on production of anti-cancer drug-cordycepin in surface liquid culture using Cordyceps militaris mutant: a minor factor may greatly affect the resultIndian J Biotechnol20109427430[Google Scholar]
  • 13. DasSKMasudaMSakuraiASakakibaraMMedicinal uses of the mushroom Cordyceps militaris: current state and prospectsFitoterapia201081961968[PubMed][Google Scholar]
  • 14. DevkotaSYarsagumba [Cordyceps sinensis (Berk.) Sacc.]; traditional utilization in Dolpa district, western NepalOur Nat200644855[Google Scholar]
  • 15. GongZSuYHuangLLinJTangKZhouXCloning and analysis of glyceraldehyde-3-phosphate dehydrogenase gene from Cordyceps militarisAfr J Agr Res20094402408[Google Scholar]
  • 16. GuYXWangZSLiSXEffect of multiple factors on accumulation of nucleosides and bases in Cordyceps militarisFood Chem200710213041309[Google Scholar]
  • 17. GuoCZhuJZhangCZhangLDetermination of adenosine and 3′-deoxyadenosine in Cordyceps militaris (L.) Link by HPLCChin J Chinese Materia Medica199823236243[Google Scholar]
  • 18. HajekAELegerRJSInteractions between fungal pathogens and insects hostsAnnu Rev Entomol199439293322[Google Scholar]
  • 19. HattoriMIsomuraSYokoyamaEUjitaMHaraAExtracellular trypsin-like protease produced by Cordyceps militarisJ Biosci Bioeng2005100631636[PubMed][Google Scholar]
  • 20. HeWZhangMFYeJJiangTTFangXSongYCordycepin induces apoptosis by enhancing JNK and p38 kinase activity and increasing the protein expression of Bcl-2 pro-apoptotic moleculesJ Zhejiang Univ Sci B201011654660[PubMed][Google Scholar]
  • 21. HoJMSeoMJParkJUKangBWKimKSLeeJYKimGYKimJIChoiYHKimKHJeongYKEffect of cordycepin purified from Cordyceps militaris on Th1 and Th2 cytokines in mouse splenocytesJ Microbiol Biotechnol20122211611164[PubMed][Google Scholar]
  • 22. HodgeKTHumberRAWozniakCACordycepsvariabilis and the genus SyngliocladiumMycologia199890743753[Google Scholar]
  • 23. HolbeinSWengiADecourtyLFreimoserFMJacquierADichtlrnaIBCordycepin interferes with 3′ end formation in yeast independently of its potential to terminate RNA chain elongationRNA200915837849[PubMed][Google Scholar]
  • 24. HollidayJCleaverMMedicinal value of the caterpillar fungi species of the genus Cordyceps (Fr.) Link (Ascomycetes): a reviewInt J Med Mushrooms200810219234[Google Scholar]
  • 25. HollidayJCleaverPPowersMLPatelDAnalysis of quality and techniques for hybridization of medicinal fungus Cordyceps sinensisInt J Med Mushrooms20046147160[Google Scholar]
  • 26. HuangYLuJZhuBWenQJiaFZengSChenTLiYChengGYiZToxicity study of fermentation Cordyceps mycelia B414Chin Tradit Pat Med1987102425[Google Scholar]
  • 27. HuangBMHsuaCCTsaiSJSheuCCLeuSFEffects of Cordyceps sinensis on steroidogenesis in normal mouse Leydig cellsLife Sci20016925932602[PubMed][Google Scholar]
  • 28. HuangLFLiangYZGuoFQZhouZFChengBMSimultaneous separation and determination of active components in Cordyceps sinensis and Cordyceps militaris by LC/ESI-MSJ Pharm Biomed Anal20033311551162[PubMed][Google Scholar]
  • 29. HuangYLLeuSFLiuBCSheuCCHuangBMIn vivo stimulatory effect of Cordyceps sinensis mycelium and its fractions on reproductive functions in male mouseLife Sci20047510511062[PubMed][Google Scholar]
  • 30. HumberRAPriestFGoodfellowMFungal pathogens and parasites of insectsApplied microbial systematics2000DordrechtKluwer Academic Publishers203230[Google Scholar]
  • 31. HyunHChemical ingredient of Cordyceps militarisMycobiology200836233235[PubMed][Google Scholar]
  • 32. HywelNLJMultiples of eight in Cordyceps ascosporesMycol Res200210623[Google Scholar]
  • 33. IsakaMKongsaereePThebtaranonthYBioxanthracenes from the insect pathogenic fungus Cordyceps pseudomilitaris BCC 1620. II. Structure elucidationJ Antibiot (Tokyo)2001543643[PubMed][Google Scholar]
  • 34. JaggerDVKredichNMGuarinoAJInhibition of Ehrlich mouse ascites tumor growth by cordycepinCancer Res196121216220[PubMed][Google Scholar]
  • 35. JenCYLinCYHuangBMLeuSFCordycepin induced MA-10 mouse leydig tumor cell apoptosis through Caspase-9 PathwayEvid Based Complement Alternat Med20082011111[Google Scholar]
  • 36. JeongJWJinCYParkCHongSHKimGYJeongYKLeeJDYooYHChoiYHInduction of apoptosis by cordycepin via reactive oxygen species generation in human leukemia cellsToxicol In Vitro201125817824[PubMed][Google Scholar]
  • 37. JiDBYeJLiCLWangYHZhaoJCaiSQAnti-aging effect of Cordyceps sinensis extractPhytother Res200923116122[PubMed][Google Scholar]
  • 38. JinYun CKimGYChoiYHInduction of apoptosis by aqueous extract of Cordyceps militaris through activation of caspases and inactivation of Akt in human breast cancer MDA-MB-231 cellsJ Microbiol Biotechnol20081819972003[PubMed][Google Scholar]
  • 39. JoWSChoiYJKimHJLeeJYNamBHLeeJDLeeSWSeoSYJeongMHThe anti-inflammatory effects of water extract from Cordyceps militaris in murine macrophageMycobiology2010384651[PubMed][Google Scholar]
  • 40. JungECKimKDBaiCHKimJCKimDKKimHHA mushroom lectin from ascomycete Cordyceps militarisBBA-Gen Subj20071770833841[Google Scholar]
  • 41. KawaguchiNOhmoriTTakeshitaYKawanishiGKatayamaSYamadaHOccurrence of Gal beta (1–3) GalNAc-Ser/Thr in the linkage region of polygalactosamine containing fungal glycoprotein from Cordyceps ophioglossoidesBiochem Biophys Res Commun1986140350356[PubMed][Google Scholar]
  • 42. KimJSSapkotaKParkSEChoiBSKimSNguyenTHKimCSChoiHSKimMKChunHSParkYKimSJA fibrinolytic enzyme from the medicinal mushroom Cordyceps militarisJ Microbiol200644622631[PubMed][Google Scholar]
  • 43. KlenowHFormation of the mono-, di- and triphosphate of cordycepin in Ehrlich ascites-tumor cells in vitroBiochim Biophys Acta196376347353[PubMed][Google Scholar]
  • 44. KrasnoffSBReateguiRFWagenaarMMGloerJBGibsonDMCicadapeptins I and II: new Aib-containing peptides from the entomopathogenic fungus Cordyceps heteropodaJ Nat Prod2005685055[PubMed][Google Scholar]
  • 45. KuoMCChangCYChengTLWuMJImmunomodulatory effect of exo-polysaccharides from submerged cultured Cordyceps sinensis: enhancement of cytokine synthesis, CD11b expression, and phagocytosisAppl Microbiol Biotechnol200775769775[PubMed][Google Scholar]
  • 46. LeeKHMinTJPurification and characterization of a chitinase in culture media of Cordyceps militaris (L.) LinkKorean J Med Mycol200331168174[Google Scholar]
  • 47. LeeSJKimSKChoiWSKimWJMoonSKCordycepin causes p21WAF1-mediated G2/M cell-cycle arrest by regulating c-Jun N-terminal kinase activation in human bladder cancer cellsArch Biochem Biophys2009490103109[PubMed][Google Scholar]
  • 48. LeeYRNohEMJeongEYYunSKJeongYJKimJYKwonKBKimBSLeeSHPParkCSKimJSCordycepin inhibits UVB-induced matrix metalloproteinase expression by suppressing the NF-κB pathway in human dermal fibroblastsExp Mol Med200941548554[PubMed][Google Scholar]
  • 49. LeeEJKimWJMoonSWCordycepin suppresses TNF-alpha-induced invasion, migration and matrix metalloproteinase-9 expression in human bladder cancer cellsPhytother Res20102417551761[PubMed][Google Scholar]
  • 50. LeeBParkJParkJShinHJKwonSYeomMSurBKimSKimMLeeHYoonSHHahmDHCordyceps militaris improves neurite outgrowth in neuro2A cells and reverses memory impairment in ratsFood Sci Biotechnol20112015991608[Google Scholar]
  • 51. LeeJHHongSMYunJYMyoungHKimMJAnti-cancer effects of cordycepin on oral squamous cell carcinoma proliferation and apoptosis in vitroJ Cancer Ther20112224234[Google Scholar]
  • 52. LegerRJSBidochkaMJStaplesRCPreparation events during infection of host cuticle by Metarhizium anisopliaeJ Invertebr Pathol199158168179[Google Scholar]
  • 53. LiTLiWImpact of polysaccharides from Cordyceps on antifatigue in miceSci Res Essays20094705709[Google Scholar]
  • 54. LiYChenGZJiangDZEffect of Cordyceps sinensis on erythropoiesis in mouse bone marrowChinese Med J1993106313316[Google Scholar]
  • 55. LiSPYangFQTsimKWQuality control of Cordyceps sinensis, a valued traditional Chinese medicineJ Pharm Biomed Anal20064115711584[PubMed][Google Scholar]
  • 56. LiSLiPJiHRP-HPLC determination of ergosterol in natural and cultured CordycepsChin J Mod Appl Pharm201118297299[Google Scholar]
  • 57. LinWHTsaiMTImprovement of sperm production in subfertile Boars by Cordyceps militaris supplementAm J Chinese Med200735631641[Google Scholar]
  • 58. LindequistUNiedermeyerTHJJulichWDThe pharmacological potential of mushroomsEvid Based Complement Alternat Med20052285299[PubMed][Google Scholar]
  • 59. LuLStudy on effect of Cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritisChin J Integr Med200222169171[Google Scholar]
  • 60. MainsEBNorth American entomogenous species of CordycepsMycologia195850169222[Google Scholar]
  • 61. ManabeNAzumaYSugimotoMUchioKMiyamotoMTaketomoNTsuchitaHMiyamotoHEffects of the mycelial extract of cultured Cordyceps sinensis on in vivo hepatic energy metabolism and blood flow in dietary hypoferric anaemic miceBr J Nutr200083197204[PubMed][Google Scholar]
  • 62. MasudaMUrabeESakuraiASakakibaraMProduction of cordycepin by surface culture using the medicinal mushroom Cordyceps militarisEnzyme Microb Tech200639641646[Google Scholar]
  • 63. MizuhaYYamamotoHSatoTTsujiMMasudaMUchidaMSakaiKTaketaniYYasutomoKSasakiHTakedaEWater extract of Cordycepssinensis (WECS) inhibits the RANKL-induced osteoclast differentiationBiol Factors200730105116[Google Scholar]
  • 64. MizunoTMedicinal effects and utilization of Cordyceps (Fr.) Link (Ascomycetes) and Isaria Fr. (Mitosporic fungi) Chinese caterpillar fungi, “Tochukaso” (review)Int J Med Mushrooms19991251262[Google Scholar]
  • 65. MollahMLPParkDKParkHJCordyceps militaris grown on germinated soybean induces G2/M cell cycle arrest through downregulation of Cyclin B1 and Cdc25c in human colon cancer HT-29 cellsEvid Based Complement Alternat Med2012201217[Google Scholar]
  • 66. MuslimNRahmanHA possible new record of Cordyceps species from Ginseng Camp, Maliau Basin, Sabah, MalaysiaJTBC201063941[Google Scholar]
  • 67. NakamuraKYamaguchiYKagotaSKwonYMShinozukaKKunitomoMInhibitory effect of Cordyceps sinensis on spontaneous liver metastasis of lewis lung carcinoma and B16 melanoma cells in syngeneic miceJpn J Pharmacol199979335341[PubMed][Google Scholar]
  • 68. NanJXParkEJYangBKSongCHKoGSohnDHAnti-fibrotic effect of extracellular biopolymer from submerged mycelial cultures of Cordyceps militaris on liver fibrosis induced by bile duct ligation and scission in ratsArch Pharm Res200124327332[PubMed][Google Scholar]
  • 69. NegiCSKorangaPRGhingaHSGumbaYar tsa (Cordyceps sinensis): A call for its sustainable exploitationInt J Sust Dev World20061318[Google Scholar]
  • 70. NgTBWangHXPharmacological actions of Cordyceps, a prized folk medicineJ Pharm Pharmacol20055715091519[PubMed][Google Scholar]
  • 71. NiHZhouXHLiHHHuangWFColumn chromatographic extraction and preparation of cordycepin from Cordyceps militaris waster mediumJ Chromatogr B200987721352141[Google Scholar]
  • 72. OvergaardKHThe inhibition of 5-phosphoribosyl-1- pyrophosphate formation by Cordycepin triphosphate in extracts of Ehrlich ascites tumor cellsBiochim Biophys Acta196480504507[PubMed][Google Scholar]
  • 73. PanBSLinCYHuangBMThe effect of cordycepin on steroidogenesis and apoptosis in MA-10 mouse leydig tumor cellsEvid Based Complement Alternat Med20112011114[Google Scholar]
  • 74. PandaAKSwainKCTraditional uses and medicinal potential of Cordyceps sinensis of SikkimJ Ayurveda Integr Med20112913[PubMed][Google Scholar]
  • 75. ParcellACSmithJMSchulthiesSSMyrerJWFellinghamGCordyceps Sinensis (CordyMax Cs-4) supplementation does not improve endurance exercise performanceInt J Sport Nutr Exerc Metabol200414236242[Google Scholar]
  • 76. ParkNSLeeKSSohnHDKimDHMolecular cloning, expression, and characterization of the Cu, Zn superoxide dismutase (SOD1) gene from the entomopathogenic fungus Cordyceps militarisMycologia200597130138[PubMed][Google Scholar]
  • 77. ParkBTNaKHJungECParkJWKimHHAnti-fungal and -cancer activities of a protein from the mushroom Cordyceps militarisKorean J Physiol Pharmacol2009134954[PubMed][Google Scholar]
  • 78. ParkSEKimJLeeYWYooHSChoCKAntitumor activity of water extracts from Cordyceps militaris in NCI-H460 cell xenografted nude miceJ Acupunct Meridian Stud20092294300[PubMed][Google Scholar]
  • 79. ParkSEYooHSJinCYHongSHLeeYWKimBWLeeSHKimWJChoCKChoiYHInduction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militarisFood Chem Toxicol20094716671675[PubMed][Google Scholar]
  • 80. PatelSGoyalARecent developments in mushrooms as anti-cancer therapeutics: a review3 Biotech20122115[Google Scholar]
  • 81. RaoYKFangSHWuWSTzengYMConstituents isolated from Cordyceps militaris suppress enhanced inflammatory mediator’s production and human cancer cell proliferationJ Ethnopharmacol2010131363367[PubMed][Google Scholar]
  • 82. RottmanFGuarinoAJThe inhibition of phosphoribosyl-pyrophosphate amidotransferase activity by cordycepin mono phosphateBiochim Biophys Acta196489465472[PubMed][Google Scholar]
  • 83. RukachaisirikulVPramjitSPakawatchaiCIsakaMSupothinaS10- membered macrolides from the insect pathogenic fungus Cordyceps militaris BCC 2816J Nat Prod20046719531958[PubMed][Google Scholar]
  • 84. RukachaisirikulVChantarukSTansakulCSaithongSChaicharernwimonkoonLPakawatchaiCIsakaMIntereyaKA cyclopeptide from the insect pathogenic fungus Cordyceps sp. BCC 1788J Nat Prod200669305307[PubMed][Google Scholar]
  • 85. RussellRPatersonMCordyceps—a traditional Chinese medicine and another fungal therapeutic biofactory?Phytochem20086914691495[Google Scholar]
  • 86. SharmaSTrade of Cordyceps sinensis from high altitudes of the Indian Himalaya: conservation and biotechnological prioritiesCurr Sci20048616141619[Google Scholar]
  • 87. ShresthaBSungJMNotes on Cordyceps species collected from the central region of NepalMycobiology200533235239[PubMed][Google Scholar]
  • 88. SinghNPathakRSinghAKRautelaDDubeyACollection of Cordyceps sinensis (Berk.) Sacc. in the interior villages of Chamoli district in Garhwal Himalaya (Uttarakhand) and its social impactsJ Am Sci2010659[Google Scholar]
  • 89. SiuKMMakHFDChiuPYPoonKTMDuYKoKMPharmacological basis of ‘Yin-nourishing’ and ‘Yang-invigorating’ actions of Cordyceps, a Chinese tonifying herbLife Sci200476385395[PubMed][Google Scholar]
  • 90. SugarAMMccaffreyRPAntifungal activity of 3′-deoxyadenosine (cordycepin)Antimicrob Agents Chemother19984214241427[PubMed][Google Scholar]
  • 91. ThakurAHuiRHongyanZTianYTianjunCMingweiCPro-apoptotic effects of Paecilomyces hepiali, a Cordyceps sinensis extract on human lung adenocarcinoma A549 cells in vitroJ Can Res and Ther20117421426[Google Scholar]
  • 92. TriggPGutteridgeWEWilliamsonJThe effect of Cordycepin on malarial parasitesT Roy Soc Trop Med H197165514520[Google Scholar]
  • 93. UjitaMKatsunoYSuzukiKSugiyamaKTakedaEYokoyamaEHaraAMolecular cloning and sequence analysis of the beta-1,3-glucan synthase catalytic subunit gene from a medicinal fungus, Cordyceps militarisMycoscience20064798105[Google Scholar]
  • 94. UnagulPWongsaPKittakoopPIntamasSSrikitikulchaiPTanticharoenMProduction of red pigments by the insect pathogenic fungus Cordyceps unilateralis BCC 1869J Ind Microbiol Biot200532135140[Google Scholar]
  • 95. WangLZhangWMHuBChenYQQuLHGenetic variation of Cordyceps militaris and its allies based on phylogenetic analysis of rDNA ITS sequence dataFungal Divers200831147156[Google Scholar]
  • 96. WangZMPengXLeeKLDTangJCOCheungPCKWuJYStructural characterisation and immunomodulatory property of an acidic polysaccharide from mycelial culture of Cordyceps sinensis fungus Cs-HK1Food Chem2011125637643[Google Scholar]
  • 97. WangaZHebZLibSYuanbQPurification and partial characterization of Cu, Zn containing superoxide dismutase from entomogenous fungal species Cordyceps militarisEnzyme Microb Tech200536862869[Google Scholar]
  • 98. WatanabeNHattoriMYokoyamaEIsomuraSUjitaMHaraAEntomogenous fungi that produce 2, 6-pyridine dicarboxylic acid (dipicolinic acid)J Biosci Bioeng2006102365373[PubMed][Google Scholar]
  • 99. WebsterJIntroduction to fungi19802CambridgeCambridge University Press355
  • 100. WinklerD‘Yartsa Gunbu (Cordyceps sinensis) and the fungal commodification of the rural economy in Tibet AREcon Bot200863291305[Google Scholar]
  • 101. WinklerDCordyceps sinensis—a precious parasitic fungus infecting TibetField Mycol2010116067[Google Scholar]
  • 102. WongKLSoECChenCCWuRSHuangBMRegulation of steroidogenesis by Cordyceps sinensis mycelium extracted fractions with (hCG) treatment in mouse Leydig cellsArch Androl2007537577[PubMed][Google Scholar]
  • 103. WongYYMoonADuffinRBarthet-BarateigAMeijerHAClemensMJde MoorCHCordycepin inhibits protein synthesis and cell adhesion through effects on signal transductionJ Biol Chem201028526102621[PubMed][Google Scholar]
  • 104. WongaJHNgaTBWangbHSzecSCWZhangcKYLidQLueXCordymin, an antifungal peptide from the medicinal fungus Cordyceps militarisPhytomedicine201118387392[PubMed][Google Scholar]
  • 105. WuTNYangKCWangCMLaiJSKoKNChangPYLiouSHLead poisoning caused by contaminated Cordyceps, a Chinese herbal medicine: two case reportsSci Total Environ1996182193195[PubMed][Google Scholar]
  • 106. XiaoJHXiaoDMXiongQLiangZQZhongJJNutritional requirements for the hyperproduction of bioactive exopolysaccharides by submerged fermentation of the edible medicinal fungus Cordyceps taiiBiochem Eng J201049241249[Google Scholar]
  • 107. XuYDrug allergy occurred in a patient after orally taken JinShuiBao capsuleChin J Chinese Materia Medica199419503[Google Scholar]
  • 108. YanJKLiLWangZMWuJYStructural elucidation of an exopolysaccharide from mycelia fermentation of a Tolypocladium sp. fungus isolated from wild Cordyceps sinensisCarbohydr Polym201079125130[Google Scholar]
  • 109. YangBKHaJYJeongSCDasSYunJWLeeYSChoiJWSongCHProduction of exo-polymers by submerged mycelial culture of Cordyceps militaris and its hypolipidemic effectJ Microbio Biotechnol200010784788[Google Scholar]
  • 110. YangFQFengKZhaoJLiSPAnalysis of sterols and fatty acids in natural and cultured Cordyceps by one-step derivatization followed with gas chromatography mass spectrometryJ Pharm Biomed Anal20094911721178[PubMed][Google Scholar]
  • 111. YangFQLiDQFengKHuDJLiSPDetermination of nucleotides, nucleosides and their transformation products in Cordyceps by ion-pairing reversed-phase liquid chromatography-mass spectrometryJ Chromatogr A2010121755015510[PubMed][Google Scholar]
  • 112. YeMQHuZFanYHeLXiaFBZouGLPurification and characterization of an acid deoxyribonuclease from the cultured mycelia of Cordyceps sinensisJ Biochem Mol Biol200437466473[PubMed][Google Scholar]
  • 113. YooHSShinJWChoJHSonCGLeeYWParkSYChoCKEffects of Cordyceps militaris extract on angiogenesis and tumor growthActa Pharm Sinic200425657665[Google Scholar]
  • 114. YuRMYangWSongLYYanCYZhangZZhaoYStructural characterization and antioxidant activity of a polysaccharide from the fruiting bodies of cultured Cordyceps militarisCarbohydr Polym200770430436[Google Scholar]
  • 115. YuRYinYYangWMaWYangLChenXZhangZYeBSongLStructural elucidation and biological activity of a novel polysaccharide by alkaline extraction from cultured Cordyceps militarisCarbohydr Polym200975166171[Google Scholar]
  • 116. YuanJPWangJHLiuXKuangHCZhaoSHSimultaneous determination of free ergosterol and ergosteryl esters in Cordyceps sinensis by HPLCFood Chem200710517551759[Google Scholar]
  • 117. YueKYeMZhouZSunWLinXThe genus Cordyceps: a chemical and pharmacological reviewJ Pharm Pharmacol2012[Google Scholar]
  • 118. YunYHanSLeeSKoSLeeCHaNKimKAnti-diabetic effects of CCCA, CMESS, and cordycepin from Cordyceps militaris and the immune responses in streptozotocin- induced diabetic miceNat Prod Sci20039291298[Google Scholar]
  • 119. ZaidmanBZYassinMMahajnaJWasserSPMedicinal mushroom modulators of molecular targets as cancer therapeuticsAppl Microbiol Biotechnol200567453468[PubMed][Google Scholar]
  • 120. ZhangQWuJHuZZhangDInduction of HL-60 apoptosis by ethyl acetate extract of Cordyceps sinensis fungal myceliumLife Sci20047529112919[PubMed][Google Scholar]
  • 121. ZhangGHuangYBianYWongJHNgTBWangHHypoglycemic activity of the fungi Cordyceps militaris, Cordyceps sinensis, Triccholoma mongolicum, and Omphalia lapidescens in streptozotocin-induced diabetic ratsAppl Microbiol Biotechnol20067211521156[PubMed][Google Scholar]
  • 122. ZhangYLiuXWangMCloning, expression, and characterization of two novel cuticle-degrading serine proteases from the entomopathogenic fungus Cordyceps sinensisRes Microbiol2008159462471[PubMed][Google Scholar]
  • 123. ZhangXLChengLBAssafSAPhillipsGOPhillipsAOCordyceps sinensis decreases TGF-b1 dependent epithelial to mesenchymal transdifferentiation and attenuates renal fibrosisFood Hydrocolloids201228200212[Google Scholar]
  • 124. ZhouJSHalpernGJonesKThe scientifi c rediscovery of an ancient Chinese herbal medicine: cordyceps sinensisJ Altern Complem Med19984429457[Google Scholar]
  • 125. ZhouXLuoLDresselWShadierGKrumbiegelDSchmidtkePZeppFMeyerCUCordycepin is an immunoregulatory active ingredient of Cordyceps sinensisAm J Chin Med200836967980[PubMed][Google Scholar]
  • 126. ZhouXGongZSuYLinJTangKCordyceps fungi: natural products, pharmacological functions and developmental productsJ Pharm Pharmcol200961279291[Google Scholar]
  • 127. ZhuJSHalpernGMJonesKThe scientific rediscovery of an ancient Chinese herbal medicine: cordyceps sinensis: part IJ Altern Complem Med19984289303[Google Scholar]
  • 128. ZhuJSHalpernGMJonesKThe scientific rediscovery of a precious ancient Chinese herbal regimen: Cordyceps sinensis: part IIJ Altern Complem Med19984429457[Google Scholar]
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