review article the chemical constituents and...

Review ArticleThe Chemical Constituents and Pharmacological Actions ofCordyceps sinensis

Yi Liu1 Jihui Wang2 Wei Wang1 Hanyue Zhang3 Xuelan Zhang1 and Chunchao Han1

1School of Pharmacy Shandong University of Traditional Chinese Medicine Jinan 250355 China2Teaching Experiment Center Shandong University of Traditional Chinese Medicine Jinan 250355 China3College of Acumox and Tuina Shandong University of Traditional Chinese Medicine Jinan 250355 China

Correspondence should be addressed to Chunchao Han chunchaoh126com

Received 20 August 2014 Accepted 30 September 2014

Academic Editor Jianyou Guo

Copyright copy 2015 Yi Liu et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Cordyceps sinensis also called DongChongXiaCao (winter worm summer grass) in Chinese is becoming increasingly popularand important in the public and scientific communities This study summarizes the chemical constituents and their corre-sponding pharmacological actions of Cordyceps sinensis Many bioactive components of Cordyceps sinensis have been extractedincluding nucleoside polysaccharide sterol protein amino acid and polypeptide In addition these constituentsrsquo correspondingpharmacological actions were also shown in the study such as anti-inflammatory antioxidant antitumour antiapoptosis andimmunomodulatory actions Therefore can use different effects of C sinensis against different diseases and provide reference forthe study of Cordyceps sinensis in the future

1 Introduction

The genus Cordyceps is an important kind of medicinal fungibelonging to the Ascomycota Pyrenomycetes Hypocrealesand Clavicipitaceae [1ndash5] Cordyceps are specific macrofungibecause of their characteristic parasitic habit on larvae andpupae of insects As a pleomorphic fungus distributed world-wide Cordyceps is particularly abundant in tropical forestsandhumid temperate [3ndash5]Within the genusCordyceps over400 species have been described so far [4 5] of which Cordy-ceps sinensis also called as ldquowinter worm summer grassrdquois recognized as the most famous tonic herb in traditionalChinese medicine (TCM) for centuries

Cordyceps sinensis is an abundant resource in nature withvarious biological activity and has been used extensively as atonic and health supplement for subhealth patients especiallyseniors in China and other Asian countries Till now numer-ous bioactive constituents have been extracted such as cordy-cepin polysaccharides ergosterol mannitol and adenosine[6 7] Meanwhile various pharmacological actions of thesechemical constituents have been reported including antitu-mour effect hepatoprotective and inflammatory effects andantioxidant nephroprotective and antiapoptotic properties

[8ndash14] To sum up the effect of C sinensis may be caused bya single active ingredient or by the combined action of manyactive agents that existed in the extract

Research is necessary to get an overview about the genusCordyceps sinensis because of the increasing interest both formedicine and mycology [15 16] Therefore our study hasreviewed the chemical constituents and their correspondingpharmacological actions of the Cordyceps sinensis for its sig-nificant role in the development of new drugs and therapeu-tics for various diseases Moreover realizing the pharmaco-logical action of the monomer composition could strengthenthe drug efficacy through extracting a single ingredient inCordyceps sinensis Therefore it is necessary to review thedevelopment on the research of C sinensis

2 Chemical Constituents and TheirCorresponding PharmacologicalActions of Cordyceps sinensis

21 Nucleosides Nucleosides a major active component ofC sinensis are used as a valuable chemical marker forquality control of Cordyceps [1] Besides nucleosides play

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2015 Article ID 575063 12 pageshttpdxdoiorg1011552015575063

2 Evidence-Based Complementary and Alternative Medicine

N

N

N

N

O

OH

HO

NH2

Figure 1 Chemical structure of cordycepin

an important role in the drug development of cancer andinfectious diseases andnucleosides and their derivatives havebeen widely used in anticancer and antiviral therapies Since31015840-deoxyadenosine namely cordycepin was isolated fromcultured Cordyceps militaris nucleosides in Cordyceps havebecome a focus [1] In succession more than ten nucleosidesand their related compounds including adenine adeno-sine inosine cytidine cytosine guanine uridine thymidineuracil hypoxanthine and guanosine have been isolatedfrom Cordyceps sinensis Almost all of the nucleotides andnucleosides in C sinensis can be transformed reciprocally[17] Furthermore many scholars began to study its phar-macological effects and had a lot of achievements [18 19]An UPLC method for fast simultaneous determination ofseveral nucleosides was developed this year and was alsoapplied for the determination of the analytes in culturedCordyceps sinensis [19 20] Then a series of researches aboutnucleosides was carried out quickly For example nucleosidescan adjust and control the human body physiological activ-ities through purinergic andor pyrimidine receptors [17]Therefore determination of nucleosides and their relatedcompounds is extremely important for the pharmacologicalstudy and quality control of C sinensis and its products

211 Cordycepin Early in 1950 cordycepin was first isolatedfrom C militaris and its structural formula was confirmed as31015840-deoxyadenosine but it is only found in natural C sinensiswith very low content and cannot be detected in the culturedones [17] Cordycepin is the most considerable adenosineanalogue from some Cordyceps [21] which is a derivative ofthe nucleoside adenosine differing from the latter by theabsence of oxygen in the 31015840 position of its ribose entity (Fig-ure 1) Cordycepin was separated with a mixture of acetoni-trile and water (5 95 vv) at a flow rate of 10mLmin whichis the commonly used method to extract the composition[22]

Cordycepin is a category of compounds that exhibitssignificant therapeutic potential and has many intracellulartargets including nucleic acid apoptosis and cell cycle Tuliet al researched the variety of molecular mechanisms thatmediate the pharmacological effects of cordycepin Besidesthey deem that cordycepin can participate in various molec-ular processes in cells because of its similarity with adenosine

[7] Wang et al investigated the effects of cordycepin inprevention of focal cerebral ischemicreperfusion (IR) injuryand suggested that cordycepin has a neuroprotective effect inthe ischemic brain which is due to the inhibition of inflam-mation and increase of antioxidants activity related to lesionpathogenesis [23 24] So cordycepin could be an attractivetherapeutic candidatewith oral activity against IR-associatedheart diseases such as myocardial infarction [25] Besidescordycepin showed the obvious analgesic effect throughacetic acid-induced abdominal constrictions hot-plate testand neurolysin inhibition assay in mice [26] Qian et alconsidered that cordycepin is a potent anti-inflammatory andanalgesic medicine There are several studies demonstratingthat C sinensis stimulates steroidogenesis in primary mouseLeydig cell and activates apoptosis in MA-10 mouse Leydigtumor cells in dose- and time-dependent manners [27 28]The steroidogenic and apoptotic mechanism of cordycepin isalso clearmdashcordycepin stimulated intracellular PLCPKCandMAPK signal transduction pathways to induce steroidogene-sis and cell death inMA-10 mouse Leydig tumor cells [29] Inaddition cordycepin stimulated the release of some cytokinesof resting PBMCs and influenced proliferation of PBMCsand transcription factors in THP-1 cell line Accordinglycordycepin can intensively regulate the functions of humanimmune cells in vitro [30] Besides cordycepin is a broadspectrum biocidal compound possessing not only antitumoractivity but also antibacteria antivirus and insecticidal activ-ities [2] To sum up cordycepin was confirmed as a markerfor C militaris within the content profiles of nucleosides inCordyceps product [1]

212Adenosine Adenosine (Figure 2) which plays an impor-tant role in biochemical process in the organism is a majornucleoside in Cordyceps spp [31] The content of adenosineis much higher in cultured Cordyceps sinensis than in thenatural one Among them cultured C sinensis has a largenumber of adenosines which are much higher than those incultured C militaris [20 31] Nucleotide named AMP can bedegraded to adenosine and the source of inosine in natural Csinensismay be the oxidative deamination of adenosine [17]Many other adenosine analogues such as 21015840-deoxyadenosine2101584031015840-dideoxyadenosine cordycepin triphosphate and 31015840-amino-31015840-deoxyadenosine have also been found inCordycepssinensis [1] Yang and Li introduced three methods to extractadenosine organic solvent pressurized liquid extractionboiling water extraction and ambient temperature waterextraction They found that the extraction ratio of adenosineis much affected by extracting time and natural Cordycepssinensis may contain some enzymes which can decomposeadenosine [32ndash34]

Also adenosine is an energy transfer and signal trans-ductant in cells and can still exert a wide spectrum of cyto-protection or prevent tissue damage such as treating chronicheart failure anti-inflammatory properties and anticonvul-sant activity [35ndash38] In addition adenosine is reported tosuppress cell growth via diverse extrinsic and intrinsic sig-naling pathways In both pathways adenosine activates cas-pases in a mitochondria-dependent andor -independentmanner [39ndash41] For example Ma et al first observed that

Evidence-Based Complementary and Alternative Medicine 3

N

N

N

N

O

OH OH

HO

NH2

Figure 2 Chemical structure of adenosine

adenosine increases ROS production in tumor cells andidentified the positive feedback loop for ROS-mediatedmitochondrial membrane dysfunction which amplifies thedeath signals in the cells [42] However Iannone et al sup-port the hypothesis that inhibition of adenosine productionin tumors or inhibition of A2aR is a promising strategyto increase the effectiveness of melanoma immunotherapybecause they have done a lot of experiments proving thatadenosine can limit the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model [43] In factadenosine mediates its effects through activation of a familyof four G-protein coupled receptors namely A

1 A2A A2B

and A3[44] This nucleoside plays an important role in

immunity and inflammation and the adenosine A2A plays

an important role in depression locomotion and anxiety[45] In particular in skin cells this endogenous nucleosideacting at one or more of its receptors could participate indermal tissue protection and repair To sum up adenosineand its analogues have received somuch attention due to theirvarious pharmacological effects

213 Nucleobases To date six nucleobases (Figure 3)including cytosine uracil thymine adenine guanine andhypoxanthine were determined in natural and culturedCordyceps sinensisThe overall content of nucleosides ismuchhigher in cultured Cordyceps sinensis than in natural ones bycomparison [32] A method based on optimum acid hydrol-ysis followed by high-performance liquid chromatography(HPLC)with diode array detectionwas developed for quanti-tative determination of these bioavailable nucleosides by Fanet al which is now the most recognized appraisal method[46] As a result the total purine and pyrimidine bases maybe the reasonable marker for evaluation of the nutritionof the materials containing nucleosides [47] However thepharmacological effects on nucleobases alone have not beenreported currently

214Nucleotides Three nucleotides namely uridine-51015840-mono-phosphate (UMP) adenosine-51015840-monophosphate (AMP) andguanosine-51015840-monophosphate (GMP) were separated by ion-pairing reversed-phase liquid chromatography-mass spec-trometry (IP-RP-LC-MS) developed by Yang et al [17] Inthe pharmacological aspect nucleotides were reported to

Cytosine

NH

N

O

NH2

Uracil

NH

O

O

NH

Thymine

NH

O

O

NH

Adenine

NH

NN

N

NH2

Guanine

NN H

NHN

O

H2N

Hypoxanthine

NN H

NHN

O

Figure 3 Chemical structure of six nucleosides

enhance the immune response influence metabolism of fattyacids help the absorption of iron gut and improve thegastrointestinal injury after repair [17 48] The nucleotidessuch as AMP GMP and UMP can be degraded to adenosineguanosine and uridine respectively Actually nucleotidescould be considered as an amphoteric molecule with baseand phosphoric acid Guanosine has the highest content of allin natural and artificial Cordyceps sinensis showed by manyinvestigations [48] Nucleotides can inhibit urethral inflam-mation promote blood circulation and improve brain func-tion and their most important effect is enhancing humanimmunity which has been reported in previous studies [49]

22 Polysaccharides Cordyceps sinensis contains a greatdeal of polysaccharides which can be in the range of 3ndash8 of the total weight [50 51] Cordyceps polysaccharidesmainly include extracellular polysaccharide and intracellularpolysaccharide A large amount of experimental evidencehas shown that fungal polysaccharides have a wide range ofbioactivities including antitumor [52] anti-influenza virus[53] immunopotentiation [54] hypoglycemic [55] hypo-cholesterolemic [56] and antioxidant effects [51] Otherstudies have suggested that the pharmacological activityof the polysaccharide was correlated with its character-istics For example it is polysaccharidesrsquo high molecularweight that determines the antitumor activity [57] In otherwords Sasaki et al confirmed that the fungi polysaccha-ridersquos antitumor activity is related to the molecular weightand the fungi polysaccharide has antitumor activity if itsmolecular weight is greater than 16000 But beyond thatten monosaccharides namely rhamnose ribose arabinosexylose mannose glucose galactose mannitol fructose andsorbose in 13 samples of natural and cultured C sinensiswere qualitatively and quantitatively analyzed [58] HoweverCordyceps polysaccharides were usually composed of thesemonosaccharides and they play a prominent role in theorganism Polysaccharides are the main contributor towardsthe pharmacological properties of C sinensis Nevertheless


its application has been limited so far because of its limitedsupply It is an endangered species due to the excessive harvestof the natural fungus [59 60]Meanwhile culturedC sinensishas shown as many pharmacological properties as natural Csinensis [50]

221 EPSF Exopolysaccharide fraction (EPSF) a het-eropolysaccharide was extracted from the cultured super-natant of C sinensis The cultured supernatant was collectedand then treated with three times volume of 95 ethanolfor precipitation As a result the sediment contains a largenumber of EPSF [60] EPSF has a large number of pharma-cological effects two of the most important are immuno-modulatory and antitumour effects [61] Previous reportshave shown that EPSF could scavenge free radical inducedifferentiation of cancer cells and enhance antitumor abilityvia activating different immune responses in the host [61]Thus it can be seen that elevating immunity ismuch helpful intumor therapy In order to explore the effects of exopolysac-charide fraction (EPSF) ICR mice were treated with EPSFfor 7 days at different doses after H

22tumor cellsrsquo injection

The data of these studies show that EPSF could elevate theimmunocytesrsquo activities in H

22tumor-bearing mice which

might be closely related to elevating peritoneal macrophagesrsquoand splenic lymphocytesrsquo activity [60] Studies have shownthat mature DCs (dendritic cells) are important modulatorsof immune response and their ability to initiate cytotoxicT lymphocyte is very valuable in cancer immunotherapyand maturation of DCs is a critical factor for the initiationof immune response [62] Song et al found that EPSF canpromote DCrsquos maturation and activation which is probablyrelated to the inhibition of STAT3 phosphorylation [63]Thisis another mechanism of EPSFrsquos antitumor effect Yang et alhave investigated the effects of the EPSF on c-Myc c-Fosand vascular endothelial growth factor (VEGF) expressionof tumor-bearing mice using Simple PCI image analysissoftware The c-Myc c-Fos and VEGF levels in the lungsand livers of EPSF-treatedmice were found to be significantlylower than those of untreatedmice which suggests that EPSFhad inhibited tumor growth in the lungs and livers of miceAs a result it might be a potential adjuvant in cancer therapy[64] As mentioned above the EPSF can inhibit a varietyof cancer cells moreover it may enhance the antitumourability of animals or humans by activating different immuneresponses in the host EPS-1 which is an exopolysaccharideproduced by the medicinal fungus Cordyceps sinensis hasbeen specifically named and widely concerned A recentstudy has shown that the sulfated EPS-1 derivatives haveremarkable antioxidant activities So sulfation was an effec-tive and favorable strategy for improving the physicochemicalproperties and bioactivities of fungal polysaccharides [65]which is a good idea for the study of polysaccharides

222 APS An acid polysaccharide (APS) was isolated fromcultivated C sinensis mycelia by ion-exchange and sizingchromatography APS is composed of mannose glucose andgalactose in an approximate molar ratio of 33 23 1 [66] Inthe present study pretreatment of PC

12cells with APS could

reduce H2O2-induced cell death which was investigated by

measuring cell viability lactate dehydrogenase (LDH) releaseantioxidant enzyme activity malondialdehyde (MDA) levelsand intracellular accumulation of reactive oxygen species(ROS) and Ca2+ [66] In conclusion APS possesses protec-tive effects in PC

12cells against H

2O2-induced injury [67]

However the antioxidantmechanism of APS remains unclearand needs further investigation In view of the fact that acidpolysaccharide fraction (APSF) extracted from C sinensisfungus has stimulating effects on macrophages [68] Chenet al have proved that APSFmay convert M

2macrophages to

M1phenotype by activatingNF-120581Bpathway SoAPSF also has

immunomodulatory effects as many other polysaccharides[69]

223 CPS-1 A water-soluble polysaccharide named CPS-1had been isolated from C sinensis mycelium by hot waterextraction ethanol precipitation anion-exchange and gelpermeation chromatography [70] CPS-1 was a glucoman-nogalactan with the monosaccharide composition of glu-cose mannose galactose = 28 29 1 (1rarr ) and (1rarr 36)linkage of glucose composed the backbone of CPS-1 Presentstudies have demonstrated that CSP-1 had strong antioxida-tion activities which can be used to reduce the blood glucoselevel [71] and treat renal failure [70] On one hand CPS-1can scavenge hydroxyl radicals and reduce power- and Fe2+-chelating That indicated a connection between antioxidantactivity and reparation of renal failure On the other handCPS-1 stimulates pancreatic release of insulin andor reducesinsulin metabolism so the polysaccharide can treat diabetesEspecially the reducing power of CPS-1 was very potent andnearly as effective as ascorbic acid [71]

224 CPS-2 CPS-2 aCordyceps sinensis polysaccharide wasfound to be mostly of 120572-(1rarr 4)-D-glucose and 120572-(1rarr 3)-D-mannose branched with 120572-(1rarr 46)-D-glucose every twelveresidues on average (Figure 4) A monosaccharide analy-sis conducted by the PMP precolumn derivation methodshowed that CPS-2 was composed of mannose glucose andgalactosewith the ratio of 4 11 1 [72] CPS-2 which appearedas white powder has been demonstrated to have significanttherapeutic activity against chronic renal failure Recently theunderlying molecular mechanism has been explored by sci-entistsWang et al found that CPS-2 could reduce PDGF-BB-induced cell proliferation through the PDGFERK and TGF-b1Smad pathways [73] As a result CPS-2 inhibits PDGF-BB-induced human mesangial cells (HMCs) proliferation ina dose-dependent manner

225 Other Polysaccharides A neutral mannoglucan witha molecular weight of 77 times 103Da was obtained from the005M acetate buffer extract of C sinensis mycelium It is abranched polysaccharide with a backbone composed mainlyof (1rarr 4)- and (1rarr 3)-linkedD-glucosyl residues Moreovermannoglucan showedweak cytotoxicity activity against SPC-I cancer line and no obvious cytotoxicity activities againstBCAP37 and SW480 cancer line [74] Similarly a water-soluble polysaccharide fraction CME-1 with a molecularmass of 276 kDa was prepared from Cordyceps sinensis


O

O

O

O

OO

O

O

O

O

O

O

OH

OH

OH

OH

OH OH

OH

OH

OHOH

HO

HOHO

HO

HOHO

HO

HO

39

Figure 4 Predicted structure of CPS-2 isolated from the fruiting bodies of cultured Cordyceps sinensis

mycelia and identified by NMR and GC-MS [75] Wanget al finally found that CME-1 can protect RAW2647cells against oxidative stress through inhibition of SMaseactivity and reduction of C

16- and C

18-ceramide levels [75]

In addition a new component named cordyglucans wasreleased by successive extractions with hot water and 005Msodium hydroxide solutions Cordyglucans were found toexhibit potent antitumor activity which could be correlatedto their (1rarr 3)-120573-D-glucan linkages [76] Besides two otherpolysaccharides named CS-F10 and cordysinocan wereextracted from the cultured mycelium of Cordyceps sinensisrespectivelyThe former has the hypoglycemic activity whichcan lower the plasma glucose level and decrease proteincontent of facilitative glucose transporter isoform 2 fromrat liver following ip administration [55] and the lattercan not only induce the cell proliferation but also increasethe phagocytosis activity and the enzymatic activity of acidphosphatase [77]

23 Sterols Sterols components of fungus have importantphysiological function they also have a variety of biologicalactivities at the same time So studying sterols has importanttheoretical significance and application prospects

231 Ergosterol Ergosterol (Figure 5) is a characteristic offungi sterol and an important source of vitamin D

2[78]

Ergosterol did not get enough attention in the study of Csinensis although it is a characteristic of fungi sterol [79] YH Li and X L Li determined the content of ergosterol inCordyceps sinensis with HPLC method and obtained a highyield They also presented that ergosterol existed in free andcombined states [80] It is important that ergosterol is a foodfeed and pharmaceutical raw material In addition it is animportant raw material in the production of steroid hor-mone drugs [81] Zheng et al have proved the cytotoxicityand antimicrobial activity of ergosterol it possesses weak

H H

H

HO

Figure 5 The structure of ergosterol

cytotoxicity against HL-60 and BEL-7402 cell lines and mod-erate antimicrobial activity against the bacteria E aerogenesand P aeruginosa and the fungus C albicans [82] At presentthe ergosterol biosynthesis pathway research has made greatprogress which will provide theoretical guidance to get highyield strains by genetic engineering [83]

232 H1-A H1-A (Figure 6) a pure compound used in tradi-tional Chinese medicine has been isolated from C sinensisTo clarify the pharmacologic properties of H1-A a series ofresearches studied its effect on mesangial cell proliferationcytotoxicity cell cycles and apoptosisThese findings suggestthat H1-A modulates some subcellular signal transductionpathways and changes the balance between proliferation andapoptosis of mesangial cells in vitro or in vivo H1-A maybe effective in the management of autoimmune disordersand the modulation of the signal transduction proteins Bcl-2and Bcl-XL may represent a target for future pharmacologicinterventions [84] As early as four years ago they havereported the effect of H1-A on inhibiting autoimmune diseasein MRL lprlpr mice Additionally the structure has been


HO

H1-A

O

Figure 6 Chemical structure of compound H1-A

analyzed with NMR by Yang et al as shown in Figure 6 Itis like an ergosterol and has been proved to be without gluco-corticosteroid receptor binding ability From another point ofview H1-A is a kind of ergosterol and its structure looks liketestosterone and dehydroepiandrosterone [85] MeanwhileH1-A can suppress the activated HMC and alleviate IgAN(Bergerrsquos disease) with clinical and histologic improvementLin et al predicted that H1-A as a therapeutic regimen mightbe used in the future [86]

233 Other Sterols Two identified compounds ergosteryl-3-O-120573-D-glucopyranoside (a) and 2223-dihydroergosteryl-3-O-120573-D-glucopyranoside (b) were isolated during the frac-tionation of the methanol extract of C sinensis [87] Besides51205728120572-epidioxy-24(R)-methylcholesta-622-dien-3120573-D-gluco-pyranoside (c) and 51205726120572-epoxy-24(R)-methylcholesta-722-dien-3120573-ol (d) are two glycoside derivatives of a sterol andthey also exist in the methanol extract of C sinensis [87 88]These are the other four important sterol compounds (Fig-ure 7) which are sterol derivatives and their structure asshown in Figure 7 Moreover Matsuda et al have confirmedthrough a large number of experiments that the latter twohave the anticancer activity but the first two do not [88]The glycosylated form of ergosterol peroxide was found tobe a greater inhibitor to the proliferation of K562 JurkatWM-1341 HL-60 and RPMI-8226 tumor cell lines [88]

24 Protein Most of the proteins in C sinensis are enzymesincluding the intracellular proteases and extracellular pro-teases

241 CSDNase A new acid deoxyribonuclease (DNase) thatacted at an acidic pH without divalent ions was extractedfrom C sinensis and designated CSDNase Although acidDNase was first studied biochemically in the 1960s [89] itsstructure has not been elucidated DNases may be broadlydivided into two classes DNase I and DNase II CSDNasebelongs to the latter The protein was purified by (NH

4)2SO4

precipitation and a series of chromatographic separations Itwas found to be single-chained with an apparent molecularmass of 34 kDa and act on both dsDNA and ssDNA asa deoxyribonuclease but act preferentially on dsDNA Theactivity of CSDNase was primarily expressed during fungal

mycelium growth and it was an endocellular enzyme [90]Furthermore CSDNase was an endonuclease which wasfound to hydrolyze DNA and to generate 3-phosphate and5-OH termini These results indicated that the nucleolyticproperties of CSDNase were essentially the same as those ofother well characterized acid DNases

242 CSP A novel serine protease with fibrinolytic activitynamed CSP was purified from the culture supernatant ofthe fungus Cordyceps sinensis CSP is a single polypeptidechain with an apparent molecular weight of 31 kD It is anovel extracellular protease with a free cysteine residue nearthe active site It also can hydrolyse bovine serum albumin(BSA) and human serum albumin (HSA) to a lesser extentLi et al have found that CSP was a plasmin-link proteasebut not a plasminogen activator and it preferentially cleavedthe A120572 chain of fibrinogen and the 120572-chain of fibrin Inconclusion the presence of CSP possibly linked C sinensisto its pharmacological use for cardiovascular disease whichwill provide a new insight into the protein engineering of newthrombolytic agents [91]

25 Amino Acid and Polypeptide C sinensis contains manyamino acids and polypeptides which played an importantrole in clinical trials For example some polypeptide macro-molecule in C sinensis could significantly reduce the meanarterial pressure of rats and induce a direct endothelium-dependent vasorelaxant effect by stimulating the productionof nitric oxide and endothelium-derived hyperpolarizingfactor [92] Thus it could be used for the treatment ofhypertension As a result it is necessary to explore thepharmacological effects of amino acid and polypeptide in Csinensis

251 Cordymin Cordymin is a peptide from the medicinalmushroom Cordyceps sinensis with the putative beneficialeffect on diabetic osteopenia in diabetic ratsThe relationshipbetween diabetes and osteoporosis is widely studied [93 94]However the mechanism of cordymin for the treatment ofdiabetic osteopenia is complicated To sum up the significanteffect of cordymin on diabetic osteopenia might be directlythrough weakening ALP and TRAP activity and mediatelythrough recovery of 120573 cells and lowering the concentration ofserum glucose which subsequently triggered a lower extentof oxidative stress in diabetic rats [95] All those findingsindicated a major breakthrough for the treatment of diabeticosteopenia using monomer compositionmdashcordymin

252 Cordycedipeptide A A new cyclodipeptide named cor-dycedipeptide A was isolated from the culture liquid of Cor-dyceps sinensis (Figure 8) Its structure was elucidated as3-acetamino-6-isobutyl-25-dioxopiperazine Jia et al havereported the cytotoxic activities of the constituent to L-929A375 andHela and its better effect on several tumor cell lines[96] another pharmacological action of cordycedipeptide Aremains to be further researched however

253 Cordyceamides A and B Two new aurantiamidesnamed as cordyceamides A and B were isolated from


Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)

Figure 7 Four important sterol compounds

H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2

Figure 8 The structure of cordycedipeptide A

the culture liquid of Cordyceps sinensis (Figure 9) Theirstructures were elucidated as N-benzoyl-L-tyrosinyl-L-phe-nylalaninol acetate and N-benzoyl-L-tyrosinyl-L-p-hydro-xyphenylalaninol acetate by NMR techniques Previous stud-ies suggested that both Cordyceamides A and B had cytotoxiceffects on L929 A375 and Hela cell lines A showed bettereffect than B on L929 cell and A375 cell but on Hela cell Bshowed better effect [97]

254 Tryptophan There are 18 kinds of amino acids in Csinensis and they mainly played a sedative hypnotic effectTryptophan is the most effective ingredient among themTryptophan is the precursor of serotonin material which hasclose relationship with animalsrsquo insomnia [98] Otherwiseglutamic acid has the effect of immune inhibition Due tothe performance of the combined effect being more complexmore research needs to be explored

R2

R1

OO

O

O

HN

NH

(a) R1=OH R2=H (b) R1=OH R2=OH

Figure 9 The structure of (a) and (b) (a) Cordyceamides A (b)Cordyceamides B


Table 1 Chemical constituents and their corresponding pharmacological actions of C sinensis

Chemical constituents of C sinensis Pharmacological effects References

Cordycepin

Anti-inflammatory effect

[17 21ndash30]

Analgesic effectStimulates steroidogenesis

Enhances immunityAntitumor activity

Antibacteria antivirus and insecticidal activities

AdenosineAnticonvulsant activity

[20 31ndash46]Inhibits cancer cell growthAnti-inflammatory effect

EPSFImmunomodulatory effect

[60ndash65]Antitumour effectAntioxidant effect

APS Antioxidant effect [66ndash69]Immunomodulatory effects

CPS-1 Antioxidant effect [70 71]CPS-2 Inhibits cell proliferation [72 73]Mannoglucan Cytotoxicity activity [74]CME-1 Antioxidant effect [75]Cordyglucans Antitumour effect [76]CS-F10 Hypoglycemic activity [55 77]Cordysinocan Induces cell proliferation [77]

Ergosterol Cytotoxicity [78ndash83]Antimicrobial activity

H1-A Immunoregulation [84ndash86]

CSDNase Hydrolyzes DNA [89 90]Nucleolytic properties

CSP Fibrinolytic activity [91]Cordymin Antidiabetic [93ndash95]Tryptophan Sedative hypnotic effect [98]

Cordycepic acidTreating liver fibrosis diuretic

[99ndash103]Improving the plasma osmotic pressureAnti-free radical

Monosaccharide saponins Antitumor activity [104]

26 Others C sinensis contains a lot of D-mannitol alsoknown as cordycepic acid and the content in insect body ishigher than that in stroma Its structure has been determinedas 1345-tetrahydroxy-cyclohexanoic acid isomeric withquinic acid It differs mainly from the natural quinic acidin being dextrorotatory and not forming the lactone [99]Cordycepic acid played a significant role in treating liverfibrosis of hepatic stellate cells Liver fibrosis is a variety offactors involved in complex process [100] Cordycepic acidameliorates the LPs-induced inflammatory phenotype andTGF1205731-induced fibrogenic response of cultured HSCs whichare the drugrsquos therapeutic mechanisms to inhibit and resolveliver fibrosis [101] Additionally cordycepic acid in C sinen-sis has effects on diuretic improving the plasma osmoticpressure and anti-free radical according to pharmacologicalresearch and clinical reports [102 103] So it is regarded asone of the active ingredients in C sinensis

A new monosaccharide saponin whose structure is 3-O-glucopyranoside was isolated and identified from themyceliaof C sinensis It displayed very good antitumor activity butthe content of the mycelia was very low [104]

Moreover there are many other ingredients in the fungiC sinensis for example alkane polyamine vitamin andmicroelement Each of these has its own pharmacologicaleffects More constituents need to be separated and studiedin the future research work however

3 Conclusion

C sinensis a macro fungus of biomedical importance con-tains a number of bioactive components (Table 1) Many ofthem are biological response modifiers which activate ourimmune systems for a multitude of defensive functions Theimmunomodulating effects are associatedwith its antitumour


activity which is the most proverbial effect of C sinensisMany ingredients in C sinensis have the antitumour activ-ity as shown above such as cordycepin adenosine EPSFcordyglucans and monosaccharide saponins As investiga-tion into this fungus continues more bioactive constituentswith potential therapeutic value will be isolated Howevernew methods and technologies need to be adopted to extractand analyse the components requiring evaluation along themodern scientific line Overall so far we know only a little ofthe wonders of this creature and it still hasmany secrets for usto discover More research is needed on the herbal medicineand its related species

Conflict of Interests

The authors declare that there is no conflict of interests

Acknowledgments

This work was supported by the Foundation of Jinan Scienceand Technology Development Program (201303055) Projectof Shandong Province Higher Educational Science and Tech-nology Program (J14LK61) and National Natural ScienceFoundation of China (81373780) and (81373968)

References

[1] J H Xiao Y Qi and Q Xiong ldquoNucleosides a valuable chem-ical marker for quality control in traditional Chinese medicineCordycepsrdquoRecent Patents onBiotechnology vol 7 no 2 pp 153ndash166 2013

[2] T B Ng and H X Wang ldquoPharmacological actions of Cordy-ceps a prized folk medicinerdquo The Journal of Pharmacy andPharmacology vol 57 no 12 pp 1509ndash1519 2005

[3] B Shrestha and J-M Sung ldquoNotes on Cordyceps species col-lected from the central region of Nepalrdquo Mycobiology vol 33no 4 pp 235ndash239 2005

[4] K LWong E C So C C Chen R S CWu and B-M HuangldquoRegulation of steroidogenesis by Cordyceps sinensis myceliumextracted fractions with (hCG) treatment in mouse Leydigcellsrdquo Archives of Andrology vol 53 no 2 pp 75ndash77 2007

[5] HM Yu B-SWang S CHuang and P-DDuh ldquoComparisonof protective effects between cultured Cordyceps militaris andnatural Cordyceps sinensis against oxidative damagerdquo Journal ofAgricultural and Food Chemistry vol 54 no 8 pp 3132ndash31382006

[6] K Yue M Ye Z Zhou W Sun and X Lin ldquoThe genus Cordy-ceps a chemical and pharmacological reviewrdquo Journal of Phar-macy and Pharmacology vol 65 no 4 pp 474ndash493 2013

[7] H S Tuli A K Sharma S S Sandhu and D Kashyap ldquoCor-dycepin a bioactive metabolite with therapeutic potentialrdquo LifeSciences vol 93 no 23 pp 863ndash869 2013

[8] F Zhong X Liu Q Zhou et al ldquo1HNMR spectroscopy analysisof metabolites in the kidneys provides new insight into patho-physiological mechanisms applications for treatment withCor-dyceps sinensisrdquoNephrology Dialysis Transplantation vol 27 no2 pp 556ndash565 2012

[9] C-F Kuo C-C Chen C-F Lin et al ldquoAbrogation of strepto-coccal pyrogenic exotoxin B-mediated suppression of phago-cytosis in U937 cells by Cordyceps sinensis mycelium viaproduction of cytokinesrdquo Food andChemical Toxicology vol 45no 2 pp 278ndash285 2007

[10] Y-C Chen Y-L Huang and B-M Huang ldquoCordyceps sinensismycelium activates PKA and PKC signal pathways to stimulatesteroidogenesis in MA-10 mouse Leydig tumor cellsrdquo TheInternational Journal of Biochemistry and Cell Biology vol 37no 1 pp 214ndash223 2005

[11] N Yamaguchi J Yoshida L J Ren et al ldquoAugmentation ofvarious immune reactivities of tumor-bearing hosts with anextract of Cordyceps sinensisrdquo Biotherapy vol 2 no 3 pp 199ndash205 1990

[12] H-C Lo T-H Hsu S-T Tu and K-C Lin ldquoAnti-hyper-glycemic activity of natural and fermentedCordyceps sinensis inrats with diabetes induced by nicotinamide and streptozotocinrdquoThe American Journal of Chinese Medicine vol 34 no 5 pp819ndash832 2006

[13] K Nakamura K Konoha Y Yamaguchi S Kagota K Shi-nozuka and M Kunitomo ldquoCombined effects of Cordycepssinensis and methotrexate on hematogenic lung metastasis inmicerdquo Receptors and Channels vol 9 no 5 pp 329ndash334 2003

[14] J L Jordan G M Hirsch and T D G Lee ldquoC sinensis ablatesallograft vasculopathy when used as an adjuvant therapy withcyclosporinArdquoTransplant Immunology vol 19 no 3-4 pp 159ndash166 2008

[15] R Ikeda M Nishimura Y Sun M Wada and K NakashimaldquoSimple HPLC-UV determination of nucleosides and its appli-cation to the authentication ofCordyceps and its alliesrdquo Biomed-ical Chromatography vol 22 no 6 pp 630ndash636 2008

[16] J Guan J Zhao K Feng D-J Hu and S-P Li ldquoCompari-son and characterization of polysaccharides from natural andcultured Cordyceps using saccharide mappingrdquo Analytical andBioanalytical Chemistry vol 399 no 10 pp 3465ndash3474 2011

[17] F Q Yang D Q Li K Feng D J Hu and S P Li ldquoDetermi-nation of nucleotides nucleosides and their transformationproducts in Cordyceps by ion-pairing reversed-phase liquidchromatography-mass spectrometryrdquo Journal of Chromatogra-phy A vol 1217 no 34 pp 5501ndash5510 2010

[18] T Furuya M Hirotani and M Matsuzawa ldquoA study on thecomposition of Cordyceps militaris extract and myceliumrdquoPhytochemistry vol 22 pp 2509ndash2512 1983

[19] C-H Dong and Y-J Yao ldquoNutritional requirements of mycelialgrowth of Cordyceps sinensis in submerged culturerdquo Journal ofApplied Microbiology vol 99 no 3 pp 483ndash492 2005

[20] F Q Yang J Guan and S P Li ldquoFast simultaneous determi-nation of 14 nucleosides and nucleobases in cultured Cordycepsusing ultra-performance liquid chromatographyrdquo Talanta vol73 no 2 pp 269ndash273 2007

[21] R R M Paterson ldquoCordycepsmdasha traditional Chinese medicineand another fungal therapeutic biofactoryrdquo Phytochemistryvol 69 no 7 pp 1469ndash1495 2008


[23] J Wang Y-M Liu W Cao K-W Yao Z-Q Liu and J-YGuo ldquoAnti-inflammation and antioxidant effect of cordymina peptide purified from the medicinal mushroom Cordycepssinensis in middle cerebral artery occlusion-induced focalcerebral ischemia in ratsrdquo Metabolic Brain Disease vol 27 no2 pp 159ndash165 2012

[24] X Z Ying L PengH Chen Y Shen K Yu and S Cheng ldquoCor-dycepin prevented IL-120573-induced expression of inflammatorymediators in human osteoarthritis chondrocytesrdquo InternationalOrthopaedics vol 38 no 7 pp 1519ndash1526 2014


[25] E-S Park D-H Kang M-K Yang et al ldquoCordycepin 31015840-deoxyadenosine prevents rat hearts from ischemiareperfusioninjury via activation of AktGSK-3120573p70S6K signaling pathwayand HO-1 expressionrdquo Cardiovascular Toxicology vol 14 no 1pp 1ndash9 2014

[26] G-M Qian G-F Pan and J-Y Guo ldquoAnti-inflammatory andantinociceptive effects of cordymin a peptide purified fromthe medicinal mushroom Cordyceps sinensisrdquo Natural ProductResearch vol 26 no 24 pp 2358ndash2362 2012

[27] B-S Pan C-Y Lin and B-M Huang ldquoThe effect of cordycepinon steroidogenesis and apoptosis in MA-10 mouse Leydigtumor cellsrdquo Evidence-Based Complementary and AlternativeMedicine vol 2011 Article ID 750468 14 pages 2011

[28] S-F Leu S L Poon H-Y Pao and B-M Huang ldquoThein vivo and in vitro stimulatory effects of cordycepin onmouse Leydig cell steroidogenesisrdquo Bioscience Biotechnologyand Biochemistry vol 75 no 4 pp 723ndash731 2011

[29] H Y Pao B S Pan S F Leu and B M Huang ldquoCordycepinstimulated steroidogenesis in MA-10 mouse Leydig tumor cellsthrough the protein kinase C pathwayrdquo Journal of Agriculturaland Food Chemistry vol 60 no 19 pp 4905ndash4913 2012

[30] X X Zhou L P Luo W K Dressel et al ldquoCordycepin is animmunoregulatory active ingredient of Cordyceps sinensisrdquoTheAmerican Journal of Chinese Medicine vol 36 no 5 pp 967ndash980 2008

[31] F Q Yang S P Li P Li and Y T Wang ldquoOptimization ofCEC for simultaneous determination of eleven nucleosidesand nucleobases in Cordyceps using central composite designrdquoElectrophoresis vol 28 no 11 pp 1681ndash1688 2007

[32] F-Q Yang L Ge J W H Yong S N Tan and S-P Li ldquoDeter-mination of nucleosides and nucleobases in different speciesof Cordyceps by capillary electrophoresis-mass spectrometryrdquoJournal of Pharmaceutical and Biomedical Analysis vol 50 no3 pp 307ndash314 2009

[33] L-F Huang Y-Z Liang F-Q Guo Z-F Zhou and B-MCheng ldquoSimultaneous separation and determination of activecomponents in Cordyceps sinensis and Cordyceps militarrisby LCESI-MSrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 33 no 5 pp 1155ndash1162 2003

[34] F Q Yang and S P Li ldquoEffects of sample preparation methodson the quantification of nucleosides in natural and culturedCordycepsrdquo Journal of Pharmaceutical and Biomedical Analysisvol 48 no 1 pp 231ndash235 2008

[35] M Kitakaze and M Hori ldquoAdenosine therapy a new approachto chronic heart failurerdquo Expert Opinion on InvestigationalDrugs vol 9 no 11 pp 2519ndash2535 2000

[36] S Nakav C Chaimovitz Y Sufaro et al ldquoAnti-inflammatorypreconditioning by agonists of adenosine A1 receptorrdquo PLoSONE vol 3 no 5 Article ID e2107 2008

[37] J P Manfredi and H V Sparks Jr ldquoAdenosinersquos role in coronaryvasodilation induced by atrial pacing and norepinephrinerdquoThe American Journal of PhysiologymdashEndocrinology and Meta-bolism vol 243 no 4 pp H536ndashH545 1982

[38] J Ontyd and J Schrader ldquoMeasurement of adenosine inosineand hypoxanthine in human plasmardquo Journal of Chromatogra-phy vol 307 no 2 pp 404ndash409 1984

[39] Y-J Tsai L-C Lin and T-H Tsai ldquoPharmacokinetics of ade-nosine and cordycepin a bioactive constituent of Cordycepssinensis in ratrdquo Journal of Agricultural and Food Chemistry vol58 no 8 pp 4638ndash4643 2010

[40] DYang T YaguchiH Yamamoto andTNishizaki ldquoIntracellu-larly transported adenosine induces apoptosis inHuH-7 humanhepatoma cells by downregulating c-FLIP expression causingcaspase-3-8 activationrdquo Biochemical Pharmacology vol 73 no10 pp 1665ndash1675 2007

[41] D Yang T Yaguchi C-R Lim Y Ishizawa T Nakano and TNishizaki ldquoTuning of apoptosis-mediator gene transcription inHepG2 human hepatoma cells through an adenosine signalrdquoCancer Letters vol 291 no 2 pp 225ndash229 2010

[42] Y F Ma J Zhang Q Zhang et al ldquoAdenosine induces apop-tosis in human liver cancer cells through ROS productionand mitochondrial dysfunctionrdquo Biochemical and BiophysicalResearch Communications vol 448 no 1 pp 8ndash14 2014

[43] R Iannone L Miele P Maiolino A Pinto and S MorelloldquoAdenosine limits the therapeutic effectiveness of anti-CTLA4mAb in amousemelanomamodelrdquoAmerican Journal of CancerResearch vol 4 no 2 pp 172ndash181 2014

[44] S Gessi S Merighi and P A Borea ldquoTargeting adenosinereceptors to prevent inflammatory skin diseasesrdquo ExperimentalDermatology vol 23 no 8 pp 553ndash554 2014

[45] J E Coelho P Alves P M Canas et al ldquoOverexpression ofadenosine A

2A receptors in rats effects on depression locomo-

tion and anxietyrdquo Frontiers in Psychiatry vol 5 article 67 2014[46] H Fan F Q Yang and S P Li ldquoDetermination of purine

and pyrimidine bases in natural and cultured Cordyceps usingoptimum acid hydrolysis followed by high performance liquidchromatographyrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 45 no 1 pp 141ndash144 2007

[47] W Struck-Lewicka R Kaliszan andM JMarkuszewski ldquoAnal-ysis of urinary nucleosides as potential cancer markers deter-mined using LC-MS techniquerdquo Journal of Pharmaceutical andBiomedical Analysis vol 101 pp 50ndash57 2014

[48] S P Li ldquoThe nucleosides contents and their variation in naturalCordyceps sinensis and cultured Cordyceps myceliardquo Journal ofChinese Pharmaceutical Sciences vol 10 pp 175ndash179 2001

[49] X Zhou Z Gong Y Su J Lin and K Tang ldquoCordyceps funginatural products pharmacological functions and developmen-tal productsrdquo Journal of Pharmacy and Pharmacology vol 61no 3 pp 279ndash291 2009

[50] S P Li P Li T T X Dong and K W K Tsim ldquoAnti-oxidationactivity of different types of natural Cordyceps sinensis andcultured Cordyceps myceliardquo Phytomedicine vol 8 no 3 pp207ndash212 2001

[51] S P Li Z R Su T T X Dong and KW K Tsim ldquoThe fruitingbody and its caterpillar host of Cordyceps sinensis show closeresemblance in main constituents and anti-oxidation activityrdquoPhytomedicine vol 9 no 4 pp 319ndash324 2002

[52] Y-J Chen M-S Shiao S-S Lee and S-Y Wang ldquoEffect ofCordyceps sinensis on the proliferation and differentiation ofhuman leukemic U937 cellsrdquo Life Sciences vol 60 no 25 pp2349ndash2359 1997

[53] Y Ohta J-B Lee K Hayashi A Fujita K P Dong and T Hay-ashi ldquoIn vivo anti-influenza virus activity of an immunomo-dulatory acidic polysaccharide isolated fromCordycepsmilitarisgrown on germinated soybeansrdquo Journal of Agricultural andFood Chemistry vol 55 no 25 pp 10194ndash10199 2007

[54] K Nakamura Y Yamaguchi S Kagota K Shinozuka andM Kunitomo ldquoActivation of in vivo Kupffer cell function byoral administration of Cordyceps sinensis in ratsrdquo The JapaneseJournal of Pharmacology vol 79 no 4 pp 505ndash508 1999


[55] T Kiho K Ookubo S Usui S Ukai and K Hirano ldquoStruc-tural features and hypoglycemic activity of a polysaccharide(CS- F10) from the cultured mycelium of Cordyceps sinensisrdquoBiological and Pharmaceutical Bulletin vol 22 no 9 pp 966ndash970 1999

[56] J-H Koh J-M Kim U-J Chang and H-J Suh ldquoHypocholes-terolemic effect of hot-water extract from mycelia of Cordycepssinensisrdquo Biological and Pharmaceutical Bulletin vol 26 no 1pp 84ndash87 2003


[58] J Guan F-Q Yang and S-P Li ldquoEvaluation of carbohydrates innatural and cultured Cordyceps by pressurized liquid extractionand gas chromatography coupled with mass spectrometryrdquoMolecules vol 15 no 6 pp 4227ndash4241 2010

[59] J ChenW Zhang T Lu J Li Y Zheng and L Kong ldquoMorpho-logical and genetic characterization of a cultivated Cordycepssinensis fungus and its polysaccharide component possessingantioxidant property in H

22tumor-bearing micerdquo Life Sciences

vol 78 no 23 pp 2742ndash2748 2006[60] W Zhang J Li S Qiu J Chen and Y Zheng ldquoEffects of the

exopolysaccharide fraction (EPSF) from a cultivated Cordycepssinensis on immunocytes of H

22tumor bearing micerdquo Fitoter-

apia vol 79 no 3 pp 168ndash173 2008[61] L Sheng J Chen J Li and W Zhang ldquoAn exopolysaccha-

ride˜from cultivated Cordyceps sinensis and its effects on cyto-kine expressions of immunocytesrdquo Applied Biochemistry andBiotechnology vol 163 no 5 pp 669ndash678 2011

[62] M Movassagh A Spatz J Davoust et al ldquoSelective accumu-lation of mature DC-Lamp + dendritic cells in tumor sites isassociated with efficient T-cell-mediated antitumor responseand control of metastatic dissemination in melanomardquo CancerResearch vol 64 no 6 pp 2192ndash2198 2004

[63] D Song J Y Lin F J Yuan andW Zhang ldquoEx vivo stimulationof murine dendritic cells by an exopolysaccharide from oneof the anamorph of Cordyceps sinensisrdquo Cell Biochemistry andFunction vol 29 no 7 pp 555ndash561 2011

[64] J Yang W Zhang P Shi J Chen X Han and YWang ldquoEffectsof exopolysaccharide fraction (EPSF) from a cultivated Cordy-ceps sinensis fungus on c-Myc c-Fos and VEGF expression inB16 melanoma-bearing micerdquo Pathology Research and Practicevol 201 no 11 pp 745ndash750 2005

[65] J K Yan W Q Wang H L Ma and J Y Wu ldquoSulfation andenhanced antioxidant capacity of an exopolysaccharide pro-duced by the medicinal fungus Cordyceps sinensisrdquo Moleculesvol 18 no 1 pp 167ndash177 2013

[66] W B Shen D Song J Y Wu and W Zhang ldquoProtective effectof a polysaccharide isolated from a cultivatedCordycepsmyceliaon hydrogen peroxide-induced oxidative damage in PC12 cellsrdquoPhytotherapy Research vol 25 no 5 pp 675ndash680 2011

[67] S P Li K J Zhao Z N Ji et al ldquoA polysaccharide isolated fromCordyceps sinensis a traditional Chinese medicine protectsPC12 cells against hydrogen peroxide-induced injuryrdquo LifeSciences vol 73 no 19 pp 2503ndash2513 2003

[68] W Chen W Zhang W Shen and K Wang ldquoEffects of the acidpolysaccharide fraction isolated from a cultivated Cordycepssinensis on macrophages in vitrordquo Cellular Immunology vol262 no 1 pp 69ndash74 2010

[69] W Chen F Yuan K Wang D Song and W Zhang ldquoMod-ulatory effects of the acid polysaccharide fraction from oneof anamorph of Cordyceps sinensis on Ana-1 cellsrdquo Journal ofEthnopharmacology vol 142 no 3 pp 739ndash745 2012

[70] Y Wang M Wang Y Ling W Fan and H Yin ldquoStructuraldetermination and antioxidant activity of a polysaccharidefrom the fruiting bodies of cultured Cordyceps sinensisrdquo TheAmerican Journal of Chinese Medicine vol 37 no 5 pp 977ndash989 2009

[71] S P Li G H Zhang Q Zeng et al ldquoHypoglycemic activity ofpolysaccharide with antioxidation isolated from cultured Cor-dycepsmyceliardquo Phytomedicine vol 13 no 6 pp 428ndash433 2006

[72] Y Wang H Yin X Lv H Gao and M Wang ldquoProtectionof chronic renal failure by a polysaccharide from Cordycepssinensisrdquo Fitoterapia vol 81 no 5 pp 397ndash402 2010

[73] Y Wang D Liu H Zhao et al ldquoCordyceps sinensis polysac-charide CPS-2 protects human mesangial cells from PDGF-BB-induced proliferation through the PDGFERK and TGF-1205731Smad pathwaysrdquoMolecular and Cellular Endocrinology vol382 no 2 pp 979ndash988 2014

[74] Y L Wu N Hu Y J Pan L Zhou and X Zhou ldquoIsolationand characterization of a mannoglucan from edible Cordycepssinensis myceliumrdquo Carbohydrate Research vol 342 no 6 pp870ndash875 2007

[75] S-H Wang W-B Yang Y-C Liu et al ldquoA potent sphin-gomyelinase inhibitor from Cordyceps mycelia contributes itscytoprotective effect against oxidative stress in macrophagesrdquoJournal of Lipid Research vol 52 no 3 pp 471ndash479 2011

[76] W Yalin O Ishurd S Cuirong and P Yuanjiang ldquoStructureanalysis and antitumor activity of (1rarr 3)-120573-D-glucans (cordy-glucans) from themycelia ofCordyceps sinensisrdquo PlantaMedicavol 71 no 4 pp 381ndash384 2005

[77] J K H Cheung J Li A W H Cheung et al ldquoCordysinocan apolysaccharide isolated from cultured Cordyceps activatesimmune responses in cultured T-lymphocytes and macro-phages signaling cascade and induction of cytokinesrdquo Journalof Ethnopharmacology vol 124 no 1 pp 61ndash68 2009

[78] L M Seitz ldquoErgosterol as a measure of fungal growthrdquo Phy-topathology vol 69 no 11 pp 1202ndash1206 1979

[79] W F Osswald W Holl and E F Elstner ldquoErgosterol as a bio-chemical indicator of fungal infection in spruce and fir needlesfrom different sourcesrdquo Zeitschrift fur Naturforschung vol 41pp 542ndash544 1986

[80] Y H Li and X L Li ldquoDetermination of ergosterol in Cordycepssinensis and Cordycepsblack-bone chicken capsules by HPLCrdquoActa Pharmaceutica Sinica vol 26 no 10 pp 768ndash771 1991

[81] S Kitchawalit K Kanokmedhakul S Kanokmedhakul and KSoytong ldquoA new benzyl ester and ergosterol derivatives fromthe fungus Gymnoascus reessiirdquo Natural Product Research vol28 no 14 pp 1045ndash1051 2014

[82] J Zheng Y Wang J F Wang P Liu J Li and W Zhu ldquoAnti-microbial ergosteroids and pyrrole derivatives from halotol-erant Aspergillus flocculosus PT05-1 cultured in a hypersalinemediumrdquo Extremophiles vol 17 no 6 pp 963ndash971 2013

[83] S B Rajput and S M Karuppayil ldquoSmall molecules inhibitgrowth viability and ergosterol biosynthesis in Candida albi-cansrdquo SpringerPlus vol 2 article 26 no 1 2013


[84] L-Y Yang W J Huang H-G Hsieh and C-Y Lin ldquoH1-Aextracted from Cordyceps sinensis suppresses the proliferationof human mesangial cells and promotes apoptosis probably byinhibiting the tyrosine phosphorylation of Bcl-2 and Bcl-XLrdquoJournal of Laboratory and Clinical Medicine vol 141 no 1 pp74ndash83 2003

[85] L-Y Yang A Chen Y-C Kuo and C-Y Lin ldquoEfficacy ofa pure compound H1-A extracted from Cordyceps sinensis onautoimmunedisease ofMRL lprlprmicerdquo Journal of Laboratoryand Clinical Medicine vol 134 no 5 pp 492ndash500 1999

[86] C-Y Lin F-M Ku Y-C Kuo et al ldquoInhibition of activatedhuman mesangial cell proliferation by the natural product ofCordyceps sinensis (H1-A) an implication for treatment of IgAmesangial nephropathyrdquo Journal of Laboratory and ClinicalMedicine vol 133 no 1 pp 55ndash63 1999

[87] J W Bok L Lermer J Chilton H G Klingeman and G HN Towers ldquoAntitumor sterols from the mycelia of Cordycepssinensisrdquo Phytochemistry vol 51 no 7 pp 891ndash898 1999

[88] H Matsuda J Akaki S Nakamura et al ldquoApoptosis-inducingeffects of sterols from the dried powder of culturedmycelium ofCordyceps sinensisrdquo Chemical and Pharmaceutical Bulletin vol57 no 4 pp 411ndash414 2009

[89] G Bernardi E Appella and R Zito ldquoStudies on acid deoxyri-bonuclease III Physical and chemical properties of hog spleenacid deoxyribonucleaserdquo Biochemistry vol 4 no 9 pp 1725ndash1729 1965

[90] M Q Ye Z Hu Y Fan L He F Xia and G Zou ldquoPurificationand characterization of an acid deoxyribonuclease from thecultured mycelia of Cordyceps sinensisrdquo Journal of Biochemistryand Molecular Biology vol 37 no 4 pp 466ndash473 2004

[91] H-P Li Z Hu J-L Yuan et al ldquoA novel extracellular proteasewith fibrinolytic activity from the culture supernatant of Cordy-ceps sinensis purification and characterizationrdquo PhytotherapyResearch vol 21 no 12 pp 1234ndash1241 2007

[92] W-F Chiou P-C Chang C-J Chou and C-F Chen ldquoProteinconstituent contributes to the hypotensive and vasorelaxantactivities of Cordyceps sinensisrdquo Life Sciences vol 66 no 14 pp1369ndash1376 2000

[93] P Vestergaard L Rejnmark and L Mosekilde ldquoDiabetes andits complications and their relationship with risk of fractures intype 1 and 2 diabetesrdquo Calcified Tissue International vol 84 no1 pp 45ndash55 2009

[94] L A Ahmed RM Joakimsen G K Berntsen V Foslashnneboslash andH Schirmer ldquoDiabetes mellitus and the risk of non-vertebralfractures the Tromsoslash studyrdquo Osteoporosis International vol 17no 4 pp 495ndash500 2006

[95] W Qi Y Zhang Y-B Yan et al ldquoThe protective effect ofcordymin a peptide purified from the medicinal mushroomCordyceps sinensis on diabetic osteopenia in alloxan-induceddiabetic ratsrdquo Evidence-based Complementary and AlternativeMedicine vol 2013 Article ID 985636 6 pages 2013

[96] J-M Jia X-C Ma C-F Wu L-J Wu and G-S Hu ldquoCordy-cedipeptide A a new cyclodipeptide from the culture liquid ofCordyceps sinensis (BERK) SACCrdquo Chemical and Pharmaceuti-cal Bulletin vol 53 no 5 pp 582ndash583 2005

[97] J-M Jia H-H Tao and B-M Feng ldquoCordyceamides A andB from the culture liquid of Cordyceps sinensis (Berk) saccrdquoChemical and Pharmaceutical Bulletin vol 57 no 1 pp 99ndash1012009

[98] S S Zhang D S Zhang T J Zhu and X Y Chen ldquoA pharmac-ological analysis of the amino acid components of Cordycepssinensis SACCrdquo Acta Pharmaceutica Sinica vol 26 no 5 pp326ndash330 1991

[99] R Chatterjee K S Srinivasan andPCMaiti ldquoCordyceps sinesis(Berkeley) Saccardo structure of cordycepic acidrdquo Journal of theAmerican Pharmaceutical Association vol 46 no 2 pp 114ndash1181957

[100] J Guo and S L Friedman ldquoHepatic fibrogenesisrdquo Seminars inLiver Disease vol 27 no 4 pp 413ndash426 2007

[101] Y Y Ouyang Z Zhang Y R Cao et al ldquoEffect of cordyceps acidand cordycepin on the inflammatory and fibrogenic response ofhepatic stellate cellsrdquo Chinese Journal of Hepatology vol 21 no4 pp 275ndash278 2013

[102] A ZNomani ZNabiH Rashid et al ldquoOsmotic nephrosiswithmannitol review articlerdquo Renal Failure vol 36 no 7 pp 1169ndash1176 2014

[103] M A Sahmeddini S Zahiri M B Khosravi S GhaffaripourM H Eghbal and S Shokrizadeh ldquoEffect of mannitol onpostreperfusion cardiac output and central venous oxygensaturation during orthotopic liver transplant a double-blindrandomized clinical trialrdquo Progress in Transplantation vol 24no 2 pp 121ndash125 2014

[104] Z-Y Zhu Q Yao Y Liu et al ldquoHighly efficient synthesisand antitumor activity of monosaccharide saponins mimickingcomponents of Chinese folk medicine Cordyceps sinensisrdquoJournal of Asian Natural Products Research vol 14 no 5 pp429ndash435 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


N

N

N

N

O

OH

HO

NH2

Figure 1 Chemical structure of cordycepin

an important role in the drug development of cancer andinfectious diseases andnucleosides and their derivatives havebeen widely used in anticancer and antiviral therapies Since31015840-deoxyadenosine namely cordycepin was isolated fromcultured Cordyceps militaris nucleosides in Cordyceps havebecome a focus [1] In succession more than ten nucleosidesand their related compounds including adenine adeno-sine inosine cytidine cytosine guanine uridine thymidineuracil hypoxanthine and guanosine have been isolatedfrom Cordyceps sinensis Almost all of the nucleotides andnucleosides in C sinensis can be transformed reciprocally[17] Furthermore many scholars began to study its phar-macological effects and had a lot of achievements [18 19]An UPLC method for fast simultaneous determination ofseveral nucleosides was developed this year and was alsoapplied for the determination of the analytes in culturedCordyceps sinensis [19 20] Then a series of researches aboutnucleosides was carried out quickly For example nucleosidescan adjust and control the human body physiological activ-ities through purinergic andor pyrimidine receptors [17]Therefore determination of nucleosides and their relatedcompounds is extremely important for the pharmacologicalstudy and quality control of C sinensis and its products

211 Cordycepin Early in 1950 cordycepin was first isolatedfrom C militaris and its structural formula was confirmed as31015840-deoxyadenosine but it is only found in natural C sinensiswith very low content and cannot be detected in the culturedones [17] Cordycepin is the most considerable adenosineanalogue from some Cordyceps [21] which is a derivative ofthe nucleoside adenosine differing from the latter by theabsence of oxygen in the 31015840 position of its ribose entity (Fig-ure 1) Cordycepin was separated with a mixture of acetoni-trile and water (5 95 vv) at a flow rate of 10mLmin whichis the commonly used method to extract the composition[22]

Cordycepin is a category of compounds that exhibitssignificant therapeutic potential and has many intracellulartargets including nucleic acid apoptosis and cell cycle Tuliet al researched the variety of molecular mechanisms thatmediate the pharmacological effects of cordycepin Besidesthey deem that cordycepin can participate in various molec-ular processes in cells because of its similarity with adenosine

[7] Wang et al investigated the effects of cordycepin inprevention of focal cerebral ischemicreperfusion (IR) injuryand suggested that cordycepin has a neuroprotective effect inthe ischemic brain which is due to the inhibition of inflam-mation and increase of antioxidants activity related to lesionpathogenesis [23 24] So cordycepin could be an attractivetherapeutic candidatewith oral activity against IR-associatedheart diseases such as myocardial infarction [25] Besidescordycepin showed the obvious analgesic effect throughacetic acid-induced abdominal constrictions hot-plate testand neurolysin inhibition assay in mice [26] Qian et alconsidered that cordycepin is a potent anti-inflammatory andanalgesic medicine There are several studies demonstratingthat C sinensis stimulates steroidogenesis in primary mouseLeydig cell and activates apoptosis in MA-10 mouse Leydigtumor cells in dose- and time-dependent manners [27 28]The steroidogenic and apoptotic mechanism of cordycepin isalso clearmdashcordycepin stimulated intracellular PLCPKCandMAPK signal transduction pathways to induce steroidogene-sis and cell death inMA-10 mouse Leydig tumor cells [29] Inaddition cordycepin stimulated the release of some cytokinesof resting PBMCs and influenced proliferation of PBMCsand transcription factors in THP-1 cell line Accordinglycordycepin can intensively regulate the functions of humanimmune cells in vitro [30] Besides cordycepin is a broadspectrum biocidal compound possessing not only antitumoractivity but also antibacteria antivirus and insecticidal activ-ities [2] To sum up cordycepin was confirmed as a markerfor C militaris within the content profiles of nucleosides inCordyceps product [1]

212Adenosine Adenosine (Figure 2) which plays an impor-tant role in biochemical process in the organism is a majornucleoside in Cordyceps spp [31] The content of adenosineis much higher in cultured Cordyceps sinensis than in thenatural one Among them cultured C sinensis has a largenumber of adenosines which are much higher than those incultured C militaris [20 31] Nucleotide named AMP can bedegraded to adenosine and the source of inosine in natural Csinensismay be the oxidative deamination of adenosine [17]Many other adenosine analogues such as 21015840-deoxyadenosine2101584031015840-dideoxyadenosine cordycepin triphosphate and 31015840-amino-31015840-deoxyadenosine have also been found inCordycepssinensis [1] Yang and Li introduced three methods to extractadenosine organic solvent pressurized liquid extractionboiling water extraction and ambient temperature waterextraction They found that the extraction ratio of adenosineis much affected by extracting time and natural Cordycepssinensis may contain some enzymes which can decomposeadenosine [32ndash34]

Also adenosine is an energy transfer and signal trans-ductant in cells and can still exert a wide spectrum of cyto-protection or prevent tissue damage such as treating chronicheart failure anti-inflammatory properties and anticonvul-sant activity [35ndash38] In addition adenosine is reported tosuppress cell growth via diverse extrinsic and intrinsic sig-naling pathways In both pathways adenosine activates cas-pases in a mitochondria-dependent andor -independentmanner [39ndash41] For example Ma et al first observed that


N

N

N

N

O

OH OH

HO

NH2



1 A2A A2B






Cytosine

NH

N

O

NH2

Uracil

NH

O

O

NH

Thymine

NH

O

O

NH

Adenine

NH

NN

N

NH2

Guanine

NN H

NHN

O

H2N

Hypoxanthine

NN H

NHN

O















12cells against H



2macrophages to







O

O

O

O

OO

O

O

O

O

O

O

OH

OH

OH

OH

OH OH

OH

OH

OHOH

HO

HOHO

HO

HOHO

HO

HO

39



16- and C





2[78]


H H

H

HO





HO

H1-A

O






4)2SO4









Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)


H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2




R2

R1

OO

O

O

HN

NH






Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















N

N

N

N

O

OH OH

HO

NH2



1 A2A A2B






Cytosine

NH

N

O

NH2

Uracil

NH

O

O

NH

Thymine

NH

O

O

NH

Adenine

NH

NN

N

NH2

Guanine

NN H

NHN

O

H2N

Hypoxanthine

NN H

NHN

O















12cells against H



2macrophages to







O

O

O

O

OO

O

O

O

O

O

O

OH

OH

OH

OH

OH OH

OH

OH

OHOH

HO

HOHO

HO

HOHO

HO

HO

39



16- and C





2[78]


H H

H

HO





HO

H1-A

O






4)2SO4









Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)


H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2




R2

R1

OO

O

O

HN

NH






Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























12cells against H



2macrophages to







O

O

O

O

OO

O

O

O

O

O

O

OH

OH

OH

OH

OH OH

OH

OH

OHOH

HO

HOHO

HO

HOHO

HO

HO

39



16- and C





2[78]


H H

H

HO





HO

H1-A

O






4)2SO4









Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)


H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2




R2

R1

OO

O

O

HN

NH






Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















O

O

O

O

OO

O

O

O

O

O

O

OH

OH

OH

OH

OH OH

OH

OH

OHOH

HO

HOHO

HO

HOHO

HO

HO

39



16- and C





2[78]


H H

H

HO





HO

H1-A

O






4)2SO4









Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)


H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2




R2

R1

OO

O

O

HN

NH






Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















HO

H1-A

O






4)2SO4









Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)


H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2




R2

R1

OO

O

O

HN

NH






Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















Glu O

(a)

Glu O

(b)

OOO

Glu

1

2

3

4

5

6

7

8

9

10

12

13

14 15

16

17

18

19

11

2021

22

23

2425

26

27

28

(c)

OHO

(d)


H3C

H3C

H2C

HN

CHNH

R

HH

O

O

1 2

3

4

5

678

9

10

11 12 13

O

C NH2R=CH2




R2

R1

OO

O

O

HN

NH






Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















Cordycepin


[17 21ndash30]




















3 Conclusion






Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Acknowledgments


References























































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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