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CORDYCEPS/CordycepAcid/Cordycepin

FORMEDICALPROFESSIONALSONLY3 Biotech. 2014 Feb; 4(1): 1–12.

Published online 2013 Feb 19. doi: 10.1007/s13205-013-0121-9

PMCID: PMC3909570 PMID: 28324458

Pharmacological and therapeutic potential of Cordyceps with special reference to Cordycepin Hardeep S. Tuli, Sardul S. Sandhu, and A. K. Sharma

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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

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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).

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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).

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Fig. 2

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Fig. 3

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

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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.

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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

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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

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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

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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 Bioactivecompounds References

1 Cordycepin Cunninghametal.(1950)

2 Cordycepicacid Chatterjeeetal.(1957)

3 N-acetylgalactosamine Kawaguchietal.(1986)

4 Adenosine Guoetal.(1998)

5 Ergosterolandergosterylesters Yuanetal.(2007)

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S.no Bioactivecompounds References

6 Bioxanthracenes Isakaetal.(2001)

7 Hypoxanthine Huangetal.(2003)

8 Aciddeoxyribonuclease Yeetal.(2004)

9 Polysaccharideandexopolysaccharide Yuetal.(2007,2009),Xiaoetal.(2010),Yanetal.(2010)

10 Chitinase LeeandMin(2003)

11 Macrolides(C10H14O4) Rukachaisirikuletal.(2004)

12 Cicadapeptinsandmyriocin Krasnoffetal.(2005)

13 Superoxidedismutase Wangaetal.(2005)

14 Protease Hattorietal.(2005)

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S.no Bioactivecompounds References

15 Naphthaquinone Unaguletal.(2005)

16 Cordyheptapeptide Rukachaisirikuletal.(2006)

17 Dipicolinicacid Watanabeetal.(2006)

18 Fibrynolyticalenzyme Kimetal.(2006)

19 Lectin Jungetal.(2007)

20 Cordymin Wongaetal.(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

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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).

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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

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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.

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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.

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

Anti-angiogenic Cordyceps

militarisExtract(CME)

HUVECs 100–200mg/L After3–6h Yooetal.(2004)

Anti-tumor/anti-

proliferatory

Cordyceps

militarisprotein(CMP)

MCF-7(breast

cancer),5637

(bladdercancer)

andA-549(lung

cancer)

15μM 72h Parketal.

(2009a,b,c)

AqueousextractofC.

militaris

Nudemicewith

NCI-H460cell

At150and

300mg/kg/day

4weeks Parketal.

(2009a,b,c)

BuOHextractsofC.

militarisgrownon

germinatedsoybean

(GSC)

HT-29human

coloncancer

100μg/ml 48h Mollahet

al.2012

Cordycepin Mice 150mg/kgbody

weight

7days Jaggeretal.

(1961)

5637andT-24 200μm 24h Leeetal.

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

(bladdercancer)

KBandHSC3(oral

squamouscell

carcinoma)

50and30μM,

respectively

48h

(2011a,b)

Antimetastasis WEofC.sinensis LLCandB16cells 100mg/kginLLC,

100or200mg/kgin

B16

20and26days Nakamuraetal.

(1999)

Cordycepin 5637andT-24

cells

100and200μM 48h Leeetal.2010

Induceapoptosis etOAcextractofC.

sinensis

HL-60cells ED50≤25μg/ml 2days Zhangetal.

(2004)

AqueousextractofC.

militaris

MDA-MB-231 0.8mg/ml 24h Jinetal.(2008)

Paecilomyces

hepiali(derivativeofC.

sinensis)extract

A549 2–4mg/ml 48–72h Thakuretal.

(2011)

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

WaterextractofC.

militaris

A549 2μg/ml 48h Parketal.

(2009a,b,c)

Cordycepin MA-10 100μMto5mM 24h Jenetal.(2008)

SW480&SW620 2and0.72mmol/L,

respectively

72h Heetal.(2010)

MDA-MB-231 100μM 24h Choietal.(2011)

U937andTHP-1 30μg/ml 24h Jeongetal.

(2011)

SK-NBE(2)-Cand

SK-Mel-2(HTB-68)

120and80μM,

respectively

24h Baiketal.(2012)

Antifatigue Polysaccharide Mice 200mg/kg For21days LiandLi(2009)

Antimalaria Cordycepin Erythrocyticstages

ofP.knowlesi(in

Invitro106Mand Invitro4h Triggetal.

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

vitro)andP.

berghei(invivo)

invivo50mg/kg (1971)

Antifungal Cordycepin MurineModel 1.5mg/kg/day 30days Sugarand

Mccaffrey(1998)

Hypolipidemic Exopolysaccharide Rats 50–100mg/kg 2weeks Yangetal.(2000)

Increasehepaticenergy

metabolismandblood

flow

Cordyceps

sinensisExtract

Mice 200mg/kg/daily 4weeks Manabeetal.

(2000)

Immunomodulatory PolysaccharidefromC.

sinensis

Humanperipheral

blood

0.025–0.1mg – Kuoetal.(2007)

PurifiedCordycepin

fromC.militaris

Mouse

splenocytes

5μg/ml 72h Hoetal.(2012)

Antiinflammatory C.militariswater

extract

Murine

macrophage

1,250μg/ml 24h Joetal.(2010)

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

Constituentsisolated

fromC.militaris

LPS/IFN-γ

stimulated

Macrophagecells

Rangingfrom6.3to

20μg/ml

24h Raoetal.(2010)

Anti

Diabetic/Hypoglycemic

C.militarisextract

reduceoxidative

stress,inducedbyhigh

glucoseconcentration

HUVECs 25μg/ml 12–36h Chuetal.(2011)

FractionsofC.

militarisasCMESSand

Cordycepin

Mice 50and0.2mg/kg,

respectively

7days Yunetal.(2003)

Crudeextractand

polysacchariderich

fraction

Rat 10mg/kgof

polysaccharideand

100mg/kgbody

weightofcrude

extract

4days Zhangetal.

(2006)

Spermatogenic CMmyceliumpowder Subfertileboars 10g/boar 2months LinandTsai

(2007)

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

Steroidogenesis CS Normalmouse

leydigcells

3mg/ml 2–3h Huangetal.

(2001)

Cordycepin MA-10mouse

leydigtumorcells

100μM 24h Panetal.(2011)

Anti-aging CSE Mice 2.0,4.0g/kg 6weeks Jietal.(2009)

Cordycepin Humandermal

fibroblasts

50–100μM 24h Leeet

al.2009a,2009b

Anti-fibrotic EPCfromC.militaris Rats 30mg/kg/day 4weeks Nanetal.(2001)

Cardiovasculareffects Cs-4 1–15min Zhuetal.

(1998b)

Relaxaorta Isolatedaorta 50μg/ml

Lowerbloodpressure Dogs 60mg/kg

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

Increasecoronaryblood

flow

Dogs 0.425g/kg

Lowerheartrate Dogs 0.425g/kg

Againstarrhythmia Dogs 0.25–0.5g/kg

Againstmyocardial

ischemia

Rabbits 150mg/kg

Againstplatelet

aggregation

Platelet 2–4mg/ml

Againstthrombosis Rabbits 30μg/kg/min

Renalprotection CordycepsPowder LNPatients 2–4g/daycordyceps

powder,and

artemisinin

0.6g/day

3yearsand

observed

consecutively

for5years

Lu(2002)

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Pharmacologicaleffect Activecontent

ofCordyceps

Animal/tissue

studied

Activedose Experimental

timeperiod

References

Erythropoiesis Cordyceps

sinensiscrystal(CS-Cr)

LACAMouse,in

vivoandvitro

>150mg/kg(vivo)

150–200μg/ml

(vitro)

5consecutive

dailytreatment

Lietal.(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 Cordycepsare 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).

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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

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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).

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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 dorbital (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.

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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.

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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.

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Pharmacogn Rev. 2016 Jan-Jun; 10(19): 1–5.

doi: 10.4103/0973-7847.176566

PMCID: PMC4791983 PMID: 27041868

Review of Naturopathy of Medical Mushroom, Ophiocordyceps Sinensis, in Sexual Dysfunction Kanitta Jiraungkoorskul and Wannee Jiraungkoorskul

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Abstract Sexual dysfunctions including desire, arousal, orgasm, and pain disorders are increasing worldwide due to etiological factors and aging. Several types of treatment are claimed in modern medicine, but they have serious side effects and higher costs. In fact, alternative approaches, such as the intake of plants, fungi, and insects, or their extracts, have also been practiced to enhance sexuality and ameliorate illness with notable successes. However, the scientific evidence related to the mechanisms and efficacy of these alternative medicines is both scarce and all too often unconvincing. Ophiocordyceps sinensis is an Ascomycetes fungus parasitic to Lepidoptera larvae, and has long been used as medicine to treat many illnesses and promote longevity in Chinese society. Previous investigations have shown that O. sinensis has many pharmacological activities. This review has focused on illustrating that O. sinensis can enhance libido and sexual performance, and can restore impaired reproductive functions, such as impotency or infertility, in both sexes.

Keywords: Aphrodisiac, fungi, mushroom, Ophiocordyceps sinensis, sexual dysfunction

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APHRODISIAC PLANTS The third International Consultation on Sexual Medicine held in Paris in July 2009 defined the disorders of sexual function as a problem or situation that occurs during any phase of the sexual response cycle that makes the individual or couple unhappy in the sexual activity.[1,2,3] The sexual response cycle consists of four stages: Excitement, plateau, orgasm, and resolution.[4,5] From this cycle, sexual dysfunction can be classified into four patterns: (i) Desire disorders, or the lack of sexual desire or moody in sex or lack of libido; (ii) Arousal disorders, or nonstimulation during sexual activity due to vaginal dryness or impotence; (iii) Orgasm disorders, or the delay or absence of the feeling of pleasure or climax; (iv) Pain disorders, or feeling hurt during intercourse, dyspareunia, vaginismus.[6,7] Among many therapeutic approaches is the use of sildanefil citrate (Viagra), which has been reported to successfully modify the hemodynamics in the penis,[8,9] but with limited efficacy, unpleasant side effects, and contraindications in certain disease conditions.[10,11] Many plants have been reported to possess aphrodisiac potential, being employed as remedies for sexual dysfunction and also reviewed by researchers from many countries such as Africa,[12] Canada,[13] India,[14,15,16,17] Nigeria,[18] Thailand,[19] Turkey,[20] and USA.[21] The aphrodisiac plants can be classified into three groups depend on the phytochemical substances: (i) Substances that enhance libido, i.e., sexual desire, arousal; (ii) substances that enhance sexual potency, i.e., effectiveness of erection; and (iii) substances that enhance sexual pleasure.[14]

Ophiocordyceps sinensis, one of the medicinal mushrooms, has long been in ethnomycological medicinal use in Bhutan,[22] China,[23] India,[24] Nepal,[25,26] and Tibet.[27] Its synonym with Sphaeria sinensis and Cordyceps sinensis. It is used worldwide as traditional medicinal mushrooms and fungi to relieve symptoms of various diseases.[28] It is commonly known as caterpillar fungus or Cordyceps mushroom. Its taxonomy is as follows: Fungi (Kingdom), Dikarya (Subkingdom), Ascomycota (Phylum), Pezizomycotina (Subphylum), Sordariomycetes (Class), Hypocreomycetidae (Subclass), Hypocreales (Order), Ophiocordycipitaceae (Family), Ophiocordyceps (Genus).[29] There are around 140 widespread species belonging to the genus Ophiocordyceps, first described scientifically by British mycologist Tom Petch (1870–1948).[30]

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NOMENCLATURE The name Cordyceps comes from Latin words Cordl- “club,” ceps- “head,” and sinensis “Chinese.”[31] Cordyceps sinensis was discovered about 2000 years ago as an exotic medicinal mushroom described in traditional Chinese and Tibetan medicine. The British mycologist Miles Joseph Berkeley (1803–1889) first described it in 1843 as Sphaeria sinesis Berk. Later in 1878, Italian mycologist Pier Andrea Saccardo (1845–1920) renamed it as Cordyceps sinensis (Berk.) Sacc.[32] Based on molecular phylogenetic study, “Cordyceps” was separated into four genera: Cordyceps, Ophiocordyceps, Metacordyceps, and Elaphocordyceps, and it was also shown that C. sinesis is part of a clade based on the concept of Ophiocordyceps Petch; the correct name for it now is Ophiocordyceps sinensis (Berk.) G.H. Sung, J.M. Sung, Hywel-Jones and Spatafora.[33] The vernacular name of O. sinensis is dōng chóng xià cǎo meaning “winter-worm, summer-plant, or summer-grass, winter-insect” in Chinese. Other names are bub (Bhutanese), ruspendooder (Dutch), kiinanloisikka (Finnish), ghaas fafoond (Hindi), to chu kaso (Japanese), dong chug ha cho (Korean), jeevan buti, keeda ghass, chyou kira, sanjeevani bhooti, keera jhar (Nepali), dbyar rtswa dgun bu or yartsa gunbu (Tibetan), and chong cao (Thai).[34]

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MORPHOLOGICAL CHARACTERISTICS O. sinensis is the composite of a genus of fungus that grows on the larva of insects. To date, more than 350 related species have been found worldwide based on fungus and insect hosts. The most widespread insect is in order Lepidoptera, especially Thitarodes, formerly classified as Hepialus.[35] In the winter season, the infected larva will be changed into a sclerotium and covered by the intact exoskeleton to withstand the cold temperature, which is regarded as “winter worm.” In the summer season, a clavate stroma of the fungus grows from the sclerotium and emerged from the ground appearing as an herb, which is regarded as “summer grass.” Hepialus armoricanus Oberthur is the host insect species of O sinensis. It consists of two parts, the fruiting body (fungus) and the worm (caterpillar). The caterpillar is invaded by O. sinensis mycelia and thus the two parts show similar constituents and pharmacological functions.[36]

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PHYTOCHEMICAL SUBSTANCES The major phytochemical constituents of O. sinensis are (i) Proteins: Cadaverine, carboline, cordymin, flazin, methylpyrimidine, perlolyrine, putrescine, spermidine, spermine, tryptophan;[37,38] (ii) Nitrogenous compounds: Adenine, adenosine, cordyceamides, cordycedipeptide, cordycepin, cordymin, cordysinin, dideoxyadenosine, guanine, guanosine, hypoxanthine, inosine, thymidine, thymine, uracil, uridine;[39,40,41,42,43,44] (iii) Sterols: Campesterol, cholesterol, daucosterol, ergosterol, sitisterol, stigmasterol;[45,46] (iv) Fatty acids: Docosanoic acid, lauric acid, lignoceric acid, linoleic acid, myristic acid, oleic acid, palmitic acid, palmitoleic acid, pentadecanoic acid, stearic acid, succinic acid;[47,48] (v) Phenolic acids: Acetovanillone, hydroxybenzoic acid, protocatechuic acid, salicylic acid, syringic acid, vanillic acid49; (vi) Isoflavones: Daidzein, genistein, glycitein, orobol;[49] (vii) Polysaccharides and sugar derivatives: Cordysinocan, glucan, heteroglycan, mannitol, mannoglucan;[50,51,52,53,54] (viii) Vitamins, inorganic and volatile compounds.[55]

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TRADITIONAL USES O. sinensis is traditionally used[56,57] as antidiabetic,[58,59,60,61,62] antiinflammatory,[49,54,63] antimicrobial,[64,65] antioxidant,[66,67,68] and antitumor agent;[44,69,70,71] against hypocholesterolemia;[72,73] and for immunomodulatory properties.[74,75] It is also used for treatment in several diseases such as cardiovascular,[76,77,78,79] gastrointestinal,[80] hepatic,[81,82,83] neuromuscular,[84,85] renal,[59,85,86] and respiratory diseases.[87] Meena et al.[88] reported that laboratory-cultured mycelia powders of O. sinensis are safe and nontoxic up to 2 g/kg body weight dose. Oral administration of laboratory-cultured mycelia powders of O. sinensis did not show any sign of toxicity, as no significant change was observed in organ weight and serological parameters in rats. However, there was a significant increase in food intake, body weight gain, and hematological parameters such as white and red blood cells, hemoglobin, and lymphocytes in treated groups. Histopathology of vital organs also supported the nontoxic effect of O. sinensis.

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SEXUAL PERFORMANCE ENHANCEMENT AND/OR IMPROVEMENT Medicinal plants have attracted great interest from researchers around the world because of their positive bioactive effects.[89] However, there are still not many data available about the positive action on sexual dysfunction of this medicinal mushroom, O. sinensis. During the review, searches were done on scientific databases such as ScienceDirect, SpringerLink, PubMed, Google Scholar. Moreover, internet searches were performed on the search engine. Different combinations of keywords as well as synonyms for keywords were used during the searches. This review has illustrated the properties of O. sinensis in sexual performance as follows.

In vitro and in vivo animal study

Several reports have previously demonstrated that C. sinensis could stimulate steroid production or steroidogenesis in both primary normal mouse Leydig cells and tumor cells[90,91,92,93,94,95] and also in human granulosa lutein cells.[96] Huang et al.[97] reported that C. sinensis (0.02 mg and 0. 2 mg) were fed per gram of body weight to immature or mature mice for 7 days, significantly can induced the plasma testosterone levels but did not have that effect on the weights of reproductive organs. Ji et al.[98] reported that the hot water extract of C. sinensis has a mild beneficial effect on sexual function in castrated rats.

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CLINICAL STUDY Guo[99] reported that when C. sinensis supplement was administered to 22 males for 8 weeks, it showed 33% increase in sperm count and 29% decrease in the sperm malformations, and 79% increase in the sperm survival rate. Huang et al.[100] reported that C. sinensis dietary supplement can cause the prevention and improvement of adrenal glands and thymus hormones, and the infertile sperm count improved by 300%. Wan et al.[101] reported that when C. sinensis supplement to 189 both men and women, libido decreased and there was improvement of symptoms and desire by 66%. Dong and Yao[102] reported that C. sinensis supplement caused improvement of libido and desire at 86% in women.

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MECHANISM

Steroidogenesis stimulation

The carbohydrate moiety of the glycoprotein luteinizing hormone/chorionic gonadotropin plays an important role in recognizing luteinizing hormone receptor to activate a signal pathway for steroidogenesis.[103] Therefore, the polysaccharides and/or glycoproteins in C. sinensis may be similar to luteinizing hormone in structure and have the ability to recognize luteinizing hormone receptors on Leydig cells to stimulate testosterone production.[97]

Luteinizing hormone binds to its receptors to activate G-proteins and, in turn, adenylate cyclase, which can increase cyclic AMP formation. cAMP will then stimulate protein kinase A (PKA), which will phosphorylate proteins. The phosphorylated proteins will further phosphorylate other proteins or induce new protein synthesis, i.e. steroidogenic acute regulatory protein.[104] The function of steroidogenic acute regulatory protein is to transfer free cholesterol from the cytoplasm into the inner membrane of mitochondria, where cytochrome P450 side-chain cleavage enzyme converts cholesterol to pregnenolone.[105,106] Pregnenolone will then be transported to smooth endoplasmic reticulum for testosterone synthesis, which is an essential steroid hormone for reproduction in males.[107] It has also been shown that activation of the protein kinase C (PKC) signal pathway can strongly modulate Leydig cell steroidogenesis.[108] Chen et al.[109] explained that C. sinensis activated both PKA and PKC signal transduction pathways to stimulate cell steroidogenesis.

Hypothalamus–pituitary–gonad axis

Aphrodisiac activity of C. sinensis has been reported because of the testosterone-like metabolites and libido-promoting activity. Moreover, Wang et al.[110] reported that C. sinensis contains a factor that enhances corticosteroid hormone. In the study, the water-crude extract of C. sinensis was investigated for its pharmacological function on primary rat adrenal cell cultures. However, the authors are not sure about the mechanism of C. sinensis-induced steriodogenesis, whether its mechanism acts on the adrenal glands or via the hypothalamus–pituitary axis.

Phytochemical substance

It is possible that the C. sinensis supplement might affect spermatogenesis through the effect of cordycepin (3’deoxyadenosine), because the increased serum cordycepin concentration paralleled the enhancement of sperm production and increased

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testosterone levels.[111] Leu et al.[112] and Tuli et al.[113] reported that cordycepin was as an adenosine analog that increased the plasma testosterone concentration and associated with adenosine receptors to activate the cAMP-PKA-StAR signal pathway and steroidogenesis in mouse Leydig cells.

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CONCLUSION In conclusion, sexual dysfunction is one of the important health problems affecting men and women. Of the available treatments, several are pharmacologically proven and tested medications. However, there are significant users of unproven medical plants and mushrooms for sexual health. Ophiocordyceps species have been traditionally used as for the enhancement of sexual function, but direct evidence is lacking. This review paper descriptively highlights the naturopathy of the medicinal mushroom, O. sinensis, in sexual dysfunction. This review shows that O. sinensis supplementation increased the total sperm number, the percentage of motile sperm cells, and serum testosterone.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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ABOUT AUTHORS

Kanitta Jiraungkoorskul

Kanitta Jiraungkoorskul, received her B.PH. in Environmental Science and Technology, and M.Sc. in Industrial Hygiene and Safety with thesis in title “Factors affecting urinary cadmium level and health risk assessment among farmer in Phrathatphadaeng Subdistrict, Mae Sod District, Tak Province.

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Wannee Jiraungkoorskul

Wannee Jiraungkoorskul, is currently working as Assistant Professor in Department of Pathobiology, Faculty of Science, Mahidol University, Thailand. She received her B.Sc. in Medical Technology, M.Sc. in Physiology, and Ph.D. in Biology. Dr. Wannee Jiraungkoorskul's current research interests are aquatic toxicopathology and efficiency of medicinal herbs.

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Acknowledgments This review article was funded in part by the Thailand Research Fund and the Commission on Higher Education: Research Grant for Mid-Career University Faculty. Thanks should be addressed to the members of the Fish Research Unit, Department of Pathobiology, Faculty of Science, Mahidol University for their support. The authors also give many thanks to the anonymous referees and the editor for their perceptive comments on and positive criticism of this review article.

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New insights into mushroom-derived drug promising for cancer treatment

04 Jan 2010 14:07:00.000

PA01/10

A promising cancer drug, first discovered in a mushroom commonly used in Chinese medicine, could be made more effective thanks to researchers who have discovered how the drug works. The research, carried out by The University of Nottingham, was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).

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In research to be published in the Journal of Biological Chemistry, Dr Cornelia de Moor and her team, in the School of Pharmacy, investigated a drug called cordycepin, which was originally extracted from a rare kind of wild mushroom called cordyceps — a strange parasitic mushroom that grows on caterpillars (see image and notes on use of image) — and is now prepared from a cultivated form.

Dr de Moor said: “Our discovery will open up the possibility of investigating the range of different cancers that could be treated with cordycepin. We have also developed a very effective method that can be used to test new, more efficient or more stable versions of the drug in the Petri dish. This is a great advantage as it will allow us to rule out any non-runners before anyone considers testing them in animals.”

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Story credits

More information is available from Dr Cornelia de Moor , cornelia.demoor@nottingham.ac.uk; or Nancy Mendoza , +44 (0)1793 413355 , nancy.mendoza@bbsrc.ac.uk ; or Lindsay Brooke , Media Relations Manager, The University of Nottingham on +44 (0)115 951 5751 ,

lindsay.brooke@nottingham.ac.uk

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Cordycepin Inhibits Protein Synthesis and Cell Adhesion through Effects on Signal Transduction*

‡,4 +Author Affiliations

From the ‡School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD and

the §Department of Chemistry and Biochemistry, School of Life Sciences, University of Sussex, Sussex BN1 9QG, United Kingdom

+Author Notes

�3 Present address: Division of Respiratory Medicine, School of Medical and Surgical Sciences, University of Nottingham, Nottingham NG5 1PB, UK.

�4 To whom correspondence should be addressed. Tel.: 44-011-5951-5041; Fax: 44-011-5846-8002; E-mail: cornelia.demoor@nottingham.ac.uk.

�2 Contributed during the final year for a project for the M.Pharm degree in 2008.

Abstract 3′-Deoxyadenosine, also known as cordycepin, is a known polyadenylation inhibitor with a large spectrum of biological activities, including anti-proliferative, pro-apoptotic and anti-inflammatory effects. In this study we confirm that cordycepin reduces the length of poly(A) tails, with some mRNAs being much more sensitive than others. The low doses of cordycepin that cause poly(A) changes also reduce the proliferation of NIH3T3 fibroblasts. At higher doses of the drug we observed inhibition of cell attachment and a reduction of focal adhesions. Furthermore, we observed a strong inhibition of total protein synthesis that correlates with an inhibition of mammalian target of rapamycin (mTOR) signaling, as observed by reductions in Akt kinase and 4E-binding protein (4EBP) phosphorylation. In 4EBP knock-out cells, the effect of cordycepin on translation is strongly reduced, confirming the role of this modification. In addition, the AMP-activated kinase (AMPK) was shown to be activated. Inhibition of AMPK prevented translation repression by cordycepin and abolished 4EBP1 dephosphorylation, indicating that the effect of cordycepin on mTOR signaling and protein synthesis is mediated by AMPK activation. We conclude that many of the reported biological effects of cordycepin are likely to be due to its effects on mTOR and AMPK signaling.

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Cordyceps sinensis promotes exercise endurance capacity of rats by activating skeletal muscle metabolic regulators.

Kumar R1, Negi PS, Singh B, Ilavazhagan G, Bhargava K, Sethy NK.

Author information Abstract ETHNOPHARMACOLOGICAL RELEVANCE:

Cordyceps sinensis is a traditional Chinese medicine used for promotion of health, longevity and athletic power. However, the molecular mechanism for anti-fatigue activity and physical fitness has not yet been reported.

AIM OF THE STUDY:

The present study was conducted to evaluate the exercise endurance promoting activities of fungal traditional Chinese medicine (FTCM) Cordyceps sinensis cultured whole mycelium (CS) and the underlying mechanisms.

MATERIALS AND METHODS:

CS was orally supplemented (200mg/kg body weight/day) to rats for 15days with or without swimming exercise along with exercise and placebo groups.

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RESULTS:

Both CS supplementation and supplementation concurrent with exercise improved exercise endurance by 1.79- (P<0.05) and 2.9-fold (P<0.01) respectively as compared to placebo rats. CS supplementation concurrent with exercise also increased the swimming endurance by 1.32-fold (P<0.05) over the exercise group. To study the molecular mechanism of the observed effect, we measured the expression levels of endurance responsive skeletal muscle metabolic regulators AMPK, PGC-1α and PPAR-δ as well as endurance promoting and antioxidant genes like MCT1, MCT4, GLUT4, VEGF, NRF-2, SOD1 and TRX in red gastrocnemius muscle. Our results indicate that CS supplementation significantly upregulates the skeletal muscle metabolic regulators, angiogenesis, better glucose and lactate uptake both in exercised and non-exercised rats. We have also observed increased expression of oxidative stress responsive transcription factor NRF-2 and its downstream targets SOD1 and TRX by CS supplementation.

CONCLUSION:

CS supplementation with or without exercise improves exercise endurance capacity by activating the skeletal muscle metabolic regulators and a coordinated antioxidant response. Consequently, CS can be used as a potent natural exercise mimetic.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PMID:21549819

DOI:10.1016/j.jep.2011.04.040

[Indexed for MEDLINE]