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Available online at www.sciencedirect.com

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Food Science and Human Wellness 5 (2016) 177–185

Research and development of Cordyceps in Taiwan

Ching-Peng Chiu a,1, Tsong-Long Hwang b,c,d,1, You Chan e, Mohamed El-Shazly f,Tung-Ying Wu g, I-Wen Lo a, Yu-Ming Hsu a, Kuei-Hung Lai a, Ming-Feng Hou h,

Shyng-Shiou Yuan i, Fang-Rong Chang a,h,j,k,l,∗, Yang-Chang Wu a,g,m,n,o,∗∗a Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China

b Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, Chinac Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology,

Taoyuan 33302, Taiwan, Chinad Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 33302, Taiwan, China

e Department of Microbiology and Immunology, and Institute of Microbiology and Immunology, School of Medicine, Chung Shan Medical University, Taichung40201, Taiwan, China

f Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Cairo, Egyptg Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40402, Taiwan, China

h Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, Chinai Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China

j Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, Chinak Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China

l Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Chinam Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 40402, Taiwan, China

n School of Pharmacy, College of Pharmacy, China Medical University, Taichung 40402, Taiwan, Chinao Center of Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan, China

Received 2 May 2016; received in revised form 24 August 2016; accepted 30 August 2016Available online 21 September 2016

bstract

Cordyceps is treasured entomopathogenic fungi that have been used as antitumor, immunomodulating, antioxidant, and pro-sexual agent.ordyceps, also called DongChongXiaCao in Chinese, Yartsa Gunbu (Tibetan), means winter worm-summer grass. Natural Cordyceps sinensisith parasitic hosts is difficult to be collected and the recent findings on its potential pharmacological functions, resulted in skyrocketing prices.herefore, finding a mass-production method or an alternative for C. sinensis products is a top-priority task. In this review, we describe current

tatus of Cordyceps research and its recent developments in Taiwan. The content and pharmacological activities of four major industrial speciesf Cordyceps (C. sinensis, Cordyceps militaris, Cordyceps cicadae and Cordyceps sobolifera) used in Taiwan, were reviewed. Moreover, weighlighted the effect of using different methods of fermentation and production on the morphology and chemical content of Cordyceps sp. Finally,

ch asby Elsevier B.V. This is an open access article under the CC BY-NC-ND

. militaris; C. cicadae; C. sobolifera

Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, China.

e summarized the bottle-necks and challenges facing Cordyceps resear 2016 Beijing Academy of Food Sciences. Production and hosting

icense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

eywords: Entomopathogenic fungi; Biofunction; Cordyceps sp.; C. sinensis; C

∗ Corresponding author at: Graduate Institute of Natural Products, College of

ax: +886 7 3114773.

∗∗ Corresponding author at: Chinese Medicine Research and Development Center, Cax: +886 4 22060248.

E-mail addresses: aaronfrc@kmu.edu.tw (F.-R. Chang), yachwu@mail.cmu.edu.t1 These authors contributed equally to this work.

Peer review under responsibility of Beijing Academy of Food Sciences

ttp://dx.doi.org/10.1016/j.fshw.2016.08.001213-4530/© 2016 Beijing Academy of Food Sciences. Production and hosting by

http://creativecommons.org/licenses/by-nc-nd/4.0/).

well as we proposed future road map for Cordyceps industry in Taiwan.

hina Medical University Hospital, Taichung 40402, Taiwan, China.

w (Y.-C. Wu).

Elsevier B.V. This is an open access article under the CC BY-NC-ND license

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78 C.-P. Chiu et al. / Food Science a

. Introduction

Studies on medicinal mushrooms become a very impor-ant topic because of their potent pharmacological uses anduge global markets. Fungi form the second largest group afternsects, and it is believed that 1.5 million fungi exist in nature [1].hey have attracted researchers from different disciplines owing

o their fascinating nature and capability to survive in hostilenvironments and the midst of decay at the harshest layer of thecosystem [2]. Different mechanisms in producing secondaryetabolites have been developed in various fungi from ancient

imes till now. To human beings, these secondary metabolitesre not only hazardous materials but also biofunctional agentshich were evolved over centuries with amazing potential in

mproving health and preventing diseases [3]. Currently, fungiaterials can be obtained from two main sources, natural wild

ollection as well as artificial culture mycelium/fruity bodies.ollection of fungi from the wild is difficult and it raises seri-us concerns regarding environment sustainability; therefore,ost industrial manufacturers and academic research groups use

rtificial fermentation technologies to obtain fungi material.Mushrooms have been used by humans since thousands of

ears as food, functional food and/or folk medicine. More than4,000 species of mushrooms are recognized, and among them,pproximately 2000 are identified as edible [4]. Other stud-es have suggested that many potential anticancer medicinalushrooms need to be developed, such as Agaricus, Antro-

ia, Albatrellus, Calvatia, Clitocybe, Cordyceps, Flammulina,omes, Funlia, Ganoderma, Inocybe, Inonotus, Lactarius,hellinus, Pleurotus, Russula, Schizophyllum, Suillus, Trametesnd Xerocomus, etc. [5]. The research evidences from variousesearch groups all over the world demonstrated the beneficialherapeutic effects of mushroom extracts, and thus unarguably

akes it a popular research area with mass attention. Certainly,tudying the rare and medicinally active mushroom, Cordycepsp., is included in this wave of research.

The entomogenous habit likely arose and spread concomi-antly with the diversification of phytophagous insects thatook place during the Cretaceous period [6]. Entomopathogenicungi produce a wide range of secondary metabolites duringheir infection and proliferation in insects [7]. Most ento-

opathogenic fungi belong to the orders Entomophthoralesnd Hypocreales. Currently, 51 entomopathogenic fungi generaere identified with over 9000 isolates belonging to dif-

erent species. These isolates are important and promisingio-control agents for controlling arthropod pests [8]. Amonghe entomopathogenic fungi is the caterpillar fungus “Dong-hongXiaCao”, which is an important Traditional Chineseedicine (TCM).The genus Cordyceps belongs to the Ascomycota, Pyreno-

ycetes, Hypocreales, Clavicipitaceae. Cordyceps sp. arenteresting macrofungi because of their characteristic parasiticabitat on larvae and pupae of insects, and even on perfect insects9]. Many natural Cordyceps sp. are used in traditional Chinese

edicines in China, Japan, Korea, Taiwan and other easternsian countries. In 2006, the imbalance between supply andemand of wild Cordyceps sinensis increased the price of the

uct[

man Wellness 5 (2016) 177–185

ushroom up to $32,000/kg justifying its name as “soft gold”n China [10]. Cordyceps capsules in functional foods reachedn average price of $5.8 per gram [11].

Due to collection difficulties, most researchers invested ineveloping fermentation technologies to harvest large amountsf biomass for functional foods [12]. Functional foods can offerealth benefits and nutrition especially to an intended popula-ion. In developed countries, chronic and age-related diseasesave turned into major causes of death. These kinds of foods,hich can protect or delay the onset of diseases such as cancer,iabetes mellitus, cardiovascular and obesity diseases, become

necessity rather than luxury [13].In Taiwan, the origin of functional foods began in 1970 with

aiwan Sugar Corporation, and has been developing over theast 40 years. People generally use functional foods to improveheir stamina as well as to protect them from diseases. Theotal global market value of functional food reached 896 billionTD (approximately 27 billion USD) in 2011 [14]. The mostopular functional foods sold in Taiwan are herbal products,unctional drinks, and medicinal mushroom such as Agaricuslazei, Antrodia cinnamomea, Cordyceps sp., and Ganodermaucidum. Additionally, dietary supplements such as multipleitamins, calcium tablets and glucosamine are widely used [15].

One of the most important features of functional foods econ-my is its resilience to economic recession. During 2008–2009conomic collapse, the sales of functional foods did not dropown but they increased due to high consumers’ satisfactionnd loyalty. Taiwanese consumers are interested in functionaloods targeting metabolic, liver, sexual, and bone/joint disorders15]. In this review, we focus on the Cordyceos sp. functionaloods in Taiwan, including origins, chemistry, and biofunctions.his review aims to guide researchers for a better utilization ofordyceos sp. in the development of new drugs and therapeutics

argeting various ailments.

. Studies on origins, chemistry and biofunctions

.1. Cordyceps sinensis

C. sinensis (Berk.) Sacc. is an entomopathogenic fungus thatas long been used as a Chinese medicine and tonic foods. Theatural C. sinensis herbal product is composed of the fruitingody and its host larva. This species endophytically parasitizesn dead caterpillars of the moth Hepilus spp. Spores of C. sinen-is geminate inside the caterpillars, filling the caterpillars withyphae, and produce a stalked fruiting body [16]. C. sinensisxists in two stages: sexual stage (teleomorph) and asexual stageanamorph). Generally, C. sinensis is similar to the sexual stageteleomorph) with a caterpillar and fruiting body. In the past fewears, due to the high demand on C. sinensis, the collection of theungus from its natural habitat has been insufficient, and so cul-uring C. sinensis as a conidial form (anamorphic stage) has been

sed as a substitute for the natural fruiting bodies [17]. However,ulturing C. sinensis does not produce a uniform mycelium andhe produced anamorphic type was named Hirsutella sinensis18]. Genetic analysis of H. sinensis and C. sinensis proved that

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C.-P. Chiu et al. / Food Science a

oth fungi are the same species but H. sinensis is the asexualhase of the C. sinensis.

Many compounds were purified from C. sinensis and theirtructures were elucidated using different spectroscopic tech-iques. The isolated major compounds (Fig. 1) were cordycepin3′-deoxyadenosine, C10H13N5O3), adenosine (C10H13N5O4),rgosterol (C28H44O), nucleosides and nucleobases [19–21].denosine containing extract from C. sinensis contributes to

he fungus hypotensive and vasorelaxant activities [22]. In ordero explore chemical components and biofunction of C. sinensis

ycelia, the crude extract and partially purified fractions werexamined for their inhibition ability of superoxide anion gen-ration and elastase release. Furthermore, five new compound,ordysinins A–E were reported [23]. The sterol type compoundsre important group in C. sinensis. Sterols H1-A from C. sinensisere isolated and purified by silica gel column chromatography

nd high-performance liquid chromatography. They were foundo suppress the active HMC (human mesangial cell) and alleviategAN (Berger’s disease) with clinical and histologic improve-ent [24]. The study revealed that the pure compound H1-A may

e potentially useful for treating systemic lupus erythematosusn patients [25]. It was suggested that H1-A might be effective inhe management of autoimmune disorders, apoptosis, and mod-lation of signal transduction proteins, Bcl-2 and Bcl-XL [26].. sinensis contains a large amount of polysaccharides, whichan be in the range of 3%–8% of the total weight and usuallyomes from the fruiting bodies, the mycelium of solid fermen-ation submerged cultures and the broth [27]. PolysaccharidesME-1 exhibited highly potent antiplatelet activity that might

nvolve in the activation of adenylate cyclase/cyclic AMP andubsequently the inhibition of intracellular signals such as Aktnd MAPK resulting in the inhibition of platelet activation [28].

The ancient herbal pharmacopoeia (Ben Cao Cong Xin)ecorded the activity of the mushroom in protecting “lung-idney, resolving phlegm, hemostasis and improve erectileysfunction”. According to the theory of TCM, the main effectf C. sinensis is enriching the lung yin and yang, which includesreating chronic lower back pain, sensitivity to cold, overabun-ance of mucus and tears, chronic cough and wheezing, blood inhlegm from consumption of kidney yang (shenyangxu) [27]. C.inensis also exhibited antibacterial function, reduced asthma,owered blood pressure, and strengthened the heartbeat [27].s highlighted in relevant citations, most reported bioactivitiesere immunomodulatory, antiinflammatory, apoptotic (antitu-

or), and organ protective (lung and kidney) effects (Table 1).

n most studies, the treatment with C. sinensis water extractsrought immunomodulatory effect. On the other hand, organic

ig. 1. Major chemical structures purified from Cordyceps sinensis. (A) Cordy-epin, (B) adenosine and (C) ergosterol.

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man Wellness 5 (2016) 177–185 179

olvent extracts of C. sinensis, containing nucleosides, sterols,atty acids, etc., showed apoptotic and organ protective func-ions.

.2. Cordyceps militaris

Cordyceps militaris (bei-chong-cao, northern worm grass)s a valuable source of a useful natural components possessingiverse biological activities. Despite some similarities between. militaris and C. sinensis they differ in their color and host.he host of C. militaris is Lepidopteran pupa and the color of

ts fruiting bodies is yellow or orange, while C. sinensis host isepialu larva, and the color of its fruiting bodies is dark brown.cientists used electron microscopic tools such as TEM andEM to elucidate anamorph–teleomorph relationships of C. mil-

taris [29]. The examination indicated that providing a distinctaxonomic name for the anamorph of C. militaris was unneces-ary for the practical purposes because this fungus is normallyominant in nature as a teleomorph [30]. The fruiting bodies ofild C. militaris are extremely expensive because of host speci-city and rarity in nature. Also, they grow extremely slowly,

heir growth is restricted to specific areas and their sizes areery small. Consequently, the solid culture of C. militaris takes

long time to provide fruiting bodies. Many attempts have beenade to extract useful substances from the submerged mycelial

ultures to be incorporated in nutraceuticals and functional foods31]. Therefore, the collection of this fungus in large and suf-cient quantities for the use as a drug remedy and in scientificesearch is an urgent priority. Many researchers tuned condi-ions to culture this fungus, such as culture chemical components32], illumination [33], gene expression [34] and traditional cul-ure condition [35]. Batch to batch variations in fruiting bodiesultured products obtained under optimized conditions can beonitored by a simple and rapid method using capillary elec-

rophoresis (CE) and high-performance liquid chromatographyHPLC) [36]. Deep ocean water (DOW) was applied to culti-ate C. militaris in submerged and solid culture, and the effectf DOW on the production of C. militaris fermentative productsas investigated. The results showed that it could significantly

ncrease the production of cordycepin [37]. In addition, the solidaste medium of C. militaris had been used for the prepara-

ion of cordycepin with high extraction efficiency and minimumolvent usage [38]. The cultured and amplified fruiting bodiesechnologies applied to cultivate C. militaris were extremelynvestigated and developed. The results of these investigationsre summarized in Table 2 showing their different morphologicalharacteristics.

Different chemical constituents from C. militaris were iso-ated including polysaccharides, sugars, cerebroside derivatives,terols, nucleotides, nucleosides, proteins (cyclic dipeptides andmino acid) and essential oils. In one report, authors demon-trated the isolation of ten pure compounds from C. militarislong with the evaluation of their biological activities by deter-

ining their effect on free radical NO and cytokines (TNF-� and

L-12) production [39]. Among the isolated compounds cordy-epin, ergosterol, 3,4-O-isopropylidene-d-mannitol, d-mannitolnd ergosterol peroxide showed the most potent activity through

180 C.-P. Chiu et al. / Food Science and Human Wellness 5 (2016) 177–185

Table 1Biological activities of C. sinensis extracts.

No. Extract orcompound

Material source Biological activity Mechanism pathway References

1 Bailing capsule C. sinensis mycelium Renal protective Influenced SDF-1�, CXCR4,CXCL12

[48]

2 Extract C. sinensis mycelium Hepatoprotective Reduced AST, TNF-�,NO thenincreased IL-10 and SOD

[49]

3 Water extract Natural C. sinensis Hepatoprotective N/A [50]

4 Water extract C. sinensis mycelium Induce steroidogenesis Activated PKC [51]

5 Polysaccharide C. sinensis fruiting bodies Anti-tumor (U937) N/A [52]

6 Water extract C. sinensis mycelium Improve fertilization Increased P450 side chain cleavageenzyme, 3�- hydroxysteroiddehydrogenase and aromatase.

[53]

7 Supercriticalcarbon dioxideextract

C. sinensis mycelium Free radical scavenging andapoptotic (Hep 3B, Hep G2, HT-29and HCT-116)

N/A [54]

8 Supplementation C. sinensis mycelium Improve ergogenic value N/A [55]

9 95% alcoholextract

C. sinensis mycelium Antidiabetic N/A [56]

10. Water extract C. sinensis mycelium Antibacterial Increased IFN-�, IL-12, p35, p40 andTNF-�, but did not increase IL-1�,IL-6 or IL-8

[57]

11. Water extract C. sinensis mycelium Antibacterial Increased IL-12, TNF-�andmacrophage phagocytic activity

[58]

12 Methanol extract C. sinensis mycelium Radiation protective N/A [59]

13 Methanol extract C. sinensis fruiting bodies Immunomodulatory Suppressed IL-�, IL-6, TNF-� andIL-8

[60]

14 Water extract C. sinensis mycelium Antiinflammatory Directed dendritic cells driven Th1response toward a Th2 response.

[61]

15 Water extract C. sinensis mycelium Antiinflammatory N/A [62]

16 Methanol extract C. sinensis fruiting bodies Antiinflammatory andantiproliferative

Inhibited NO, TNF-� and IL-12 [63]

17 Water extract C. sinensis powder Immunosuppressant with C. sinensis N/A [64]

18 Freeze-driedpowder

C. sinensis fruiting bodies Antidiabetic N/A [65]

19 Water extract C. sinensis mycelium Health supplement N/A [66]

20 Fraction of extract(F3)

C. sinensis mycelium Increase steroid production N/A [67]

21 Fraction of extract C. sinensis mycelium Stimulate in vivo testosteroneproduction

N/A [68]

22 Protein of C.sinensis

C. sinensis mycelium Stimulate the cAMP-PKA signaltransduction (regulate testosteroneproduction)

Activated cAMP-orotein kinase Asignal pathway, but did not activateprotein kinase C

[69]

23 Fraction of extract C. sinensis mycelium Stimulate in vivo and in vitrotestosterone secretion.

N/A [70]

24 C. sinensis C. sinensis mycelium Affect transcription and translation N/A [71]

25 C. sinensis C. sinensis mycelium Activate PKA and PKC signal tostimulate steroidogenesis

Activated PKA and PKC signaltransduction pathway

[72]

26 C. sinensis C. sinensis mycelium Affect testosterone production N/A [73]

27 C. sinensis extract C. sinensis mycelium Does not induce StAR protein and/orother protein expressions to stimulatesteroidogenesis

N/A [74]

28 Water extract C. sinensis mycelium Does not induce in vivoroduc

N/A [75]

N

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/A: not be mentioned in this article.

nhibiting inflammatory mediators production and human cancerell proliferation. Our group reported the purification of cere-roside, nucleotides and sterols from C. militaris fruiting bodies

[wo

tion

40]. The antiinflammatory activity of the isolated compoundsas demonstrated by their inhibitory effect on the accumulationf pro-inflammatory iNOS protein and the reduction of COX-2

C.-P. Chiu et al. / Food Science and Human Wellness 5 (2016) 177–185 181

Table 2Compare different characteristic of C. militaris and C. sinensis.

Properties Cordyceps militaris Cordyceps sinensis

Type

Stroma Plural SingularHost Lepidopteran pupa Hepialus larvaAnamorphic Paecilomyces militaris Hirsutella sinensisDistribute location Northeast of China Southwest of ChinaArtificial cultured Fruiting body & mycelium Mainly myceliumMycelium color White or yellow WhiteFruiting body spores color Yellow or orange Dark brownM

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ajor compound Cordycepin

rotein expression in LPS-stimulated RAW264.7 cells. This washe first study reporting the isolation of cerebrosides with antiin-ammatory activity from this TCM. Another study reported the

dentification of nonvolatile components of C. militaris fruitingodies and mycelia [41]. The concentrations of the free aminocids in C. militaris fruiting bodies differed from mycelia. In aescending order, glutamic acid, cysteine, lysine, arginine andyrosine were the major amino acids in the fruiting bodies. Therder differed in mycelia with tyrosine as the major amino acidollowed by lysine, cysteine and arginine. In general, these pre-ious reports revealed that the chemical content and biologicalctivities of C. militaris cultured products differed with the cul-ure conditions suggesting that uniform conditions are essentialor stable products profile.

C. sinensis was used more extensively than C. militaris, nev-rtheless their clinical applications were similar. A number ofaluable biological activities have been collected for C. mili-aris by several teams (Table 3). It was revealed that C. militarisiological activities focused on antitumor, antidiabetic, anti-nflammatory and improving sperm effects. These biologicalctivities are similar to those of C. sinensis rendering C. mil-taris as interesting alternative for the expensive and rare C.inensis.

.3. Cordyceps cicadae and Cordyceps soboliferaChan-hua)

Cordyceps cicadae and Cordyceps sobolifera are otherxamples of entomogenous fungi belonging to the familylavicipitaceae and the genus Cordyceps. They are considered

wo treasured traditional Chinese medicinal mushrooms knowns Chan-hua, Sandwhe, and cicadae flower. They are rigorously

arasitic on wingless Cicada nymphs or larva [42,43]. The mush-ooms absorb nutrition from larva and become a clover larva ofycelium. The few fruiting bodies come out from the head,outh and bottom of the larva.

swp

Adenosine

An ergosterol proxide, 3�-hydroxy-5,8-epidioxyergosta-,22-diene (C28H44O3), from the Chan-hua exhibiteduppressant effects on T-cell proliferation, activated by PHA44]. Cordycepin was also reported to suppress NF-�B throughkt and p38 inhibition in RAW264.7 macrophage cells. A

imilar cordycepin derivative, N6-(2-hydroxyethyl)adenosine,emonstrated antiinflammatory activity by suppressingLR4-mediated NF-�B signaling pathways [45]. In onerevious report, myriocin, adenosine, cordycepin, N6-(2-ydroxyethyl)adenosine, ergosterol, ergosterol peroxides,yclic heptapeptides and polysaccharides were isolated fromhan-hua [43]. Based on Chan-hua literature, the mushroom isasy to be cultured and its chemical constituents are similar tohose of C. sinensis. Therefore, it became another interestinglternative for C. sinensis.

The ancient herbal pharmacopoeia (Ben Cao Gang Mu) statedhat Chan-hua can be used to treat “infantile convulsions and

orbid night crying of babies, palpitation and malaria”. Theompendium of Materia Medica showed that C. cicadae relievedonvulsion, dispelled wind and heat, promoted eruption andmproved eyesight, and removed eye. It also mentioned that C.icadae was primarily used in the treatment of infantile con-ulsions and morbid night crying of babies, palpitation andalaria [43]. Literature had indicated that the two different

pecies of Cordyceps, C. sobolifera and C. cicadae, possess sim-lar bioactivity. It is worth noting that three species (C. sinensis,. sobolifera and C. cicadae) have a common characteristic in

enal protection effects [46]. Three different Cordyceps sp. wereisted in the articles indicating the extent of the possible diver-ity involved in the biology and activity. According to relevanteferences, the bioactivities of Chan-hua were described as anti-nflammatory and renal protective effects (Table 4). In one recenteport, the possible health hazards arising from repeated expo-

ure to submerged mycelial culture of C. cicadae over 90 daysas investigated [47]. In general, Chan-hua possesses multi-le pharmacological activities that provide featured advantages

182 C.-P. Chiu et al. / Food Science and Human Wellness 5 (2016) 177–185

Table 3Biological activities of C. militaris extracts.

No. Extract orcompound

Material source Biological activity Mechanism pathway References

1 Water extract C. militaris Antidiabetic Reduced the caspase-3 [76]

2 Water extract C. militaris fruiting body Antidiabetic Increased the IRS-1 and GLUT-4 [77]

3 C. militaris C. militaris fruiting bodyand mycelium

Antidiabetic Increased IRS-1, pIRS-1, AKT,pAKT and GLUT-4

[78]

4 Methanol extract C. militaris fruiting body Antiinflammatory and anti-tumor Inhibited NO, TNF-� and IL-12 [79]

5 Water extract C. militaris mycelium Apoptotic (HL-60) N/A [80]

6 Fermentationbroth

C. militaris mycelium Anti-tumor N/A [81]

7 Fermentationbroth

C. militaris mycelium Apoptotic (GBM8401) Involved to PI3K/Akt and MEK1 [82]

8 Water extract C. militaris fruiting body Anti-asthma N/A [83]

9 Water extract C. militaris mycelium Anti-oxidative N/A [84]

10. Water extract C. militaris mycelium Hepatoprotective N/A [50]

11. C. militarissupplement

C. militaris mycelium Improve hormones and spermmotility

Increased serum testosterone andestradiol-17

[85]

12 C. militarissupplement

C. militaris mycelium Improve sperm production N/A [86]

13 Fermentationproduction

C. militaris mycelium Improve growth and mineralization N/A [87]

N/A: not be mentioned in this article.

Table 4Biological activities of C. sobolifera and C. cicadae (Chan-hua) extracts.

No. Extract or compound Material source Biological activity Mechanism pathway References

1 Lipopolysaccharide C. sobolifera mycelium Improvement of renal function N/A [88]

2 Glycoprotein C. sobolifera mycelium Improvement of renal tubule function Increased the TRMP6 and TRMP7channels

[89]

3 Polysaccharide C. sobolifera mycelium Improvement of renal function N/A [90]

4 Ergosterol peroxide C. cicadae fruiting body Antiinflammatory Suppressed T cell, cyclin E, IL-2,IL-4, IL-10, IFN-�, c-Fos, c-Jun

[91]

5 N6-(2-Hydroxyethyl)-adensione(HEA)

C. cicadae fruiting body Antiinflammatory Suppressed TLR4-mediated NF-�Bsignaling pathways

[92]

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Methanol extract C. cicadae fruiting body Immunomodu

/A: Not be mentioned in this article.

ncluding low toxicity and the availability of inexpensive rawaterials from artificial cultivation.

. Conclusion

In this review, we selected four species of Cordyceps includ-ng C. sinensis, C. militaris, C. sobolifera and C. cicadaeChan-hua), which possess potent pharmacological activitiesnd marketing potential. Literature indicated that these speciesxhibited potent antitumor, antiinflammatory, lung-kidney pro-ective effects. Interestingly, the major drive behind the use ofhese species is to improve stamina.

Literature reported approximately 500 species of medicinalushrooms in use. Among the most important genera are Antro-

ia, Cordyceps Ganoderma and Phellinus, which are popular inhe Taiwanese markets. Currently, four Cordyceps sp., C. sinen-

Co

Suppressed IL-2; IFN-� [93]

is, C. militaris, C. sobolifera and C. cicadae (Chan-hua), haveeen developed as functional foods with profitable economicalue. Major active compounds of Cordyceps sp. were cordy-epin and adenosine; however, the rest of potential compoundseed to be further investigated. Recently, we identified cerebro-ides as key components with potent anti-inflammatory activity40]. So far, nucleosides, sterols, sugars, fatty acids and polysac-harides were more often to be analyzed as quality markers ofordyceps. Among nucleosides, cordycepin and adenosine wereonsidered as important indicators in the chemical profiling ofordyceps sp. Furthermore, the Taiwanese traditional Chineseedicine of pharmacopoeia indicated that adenosine was used

n quality control protocols.

Moreover, different morphological or strain materials of

ordyceps genus are worthy of further development. Studiesn Cordyceps sp. should focus on developing this mushroom

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s functional food and potential drug. Researchers should adoptegulations, standards, and practices from Western and Easternedicine that have proven to be the most valuable in the quest

or health benefits.

cknowledgments

This work was supported by grants from ministry ofcience and technology of Taiwan (NSC 102-2628-B-037-003-Y3, MOST 103-2320-B-037-005-MY2, awarded to F.-R.C.).

his study is also supported partially by Kaohsiung Med-cal University (Aim for the Top Universities Grant, granto. KMU-TP104E39, KMU-TP104A26) Ministry of Health

nd Welfare of Taiwan (MOHW105-TDU-B-212-134007), andealth and welfare surcharge of tobacco products. This workas supported by grants from the Ministry of Science andechnology of Taiwan (MOST 105-2911-I-002-302, 103-2911--002-303, 103-2325-B-039-008, 103-2325-B-039-007-CC1,nd 102-2320-B-037-012-MY2, awarded to Y.-C.W.), theational Health Research Institutes (NHRI-EX103-10241BI),

nd in part by a grant from the Chinese Medicine Researchenter, China Medical University (Ministry of Education, Aim

or the Top University Plan). Chang Gung Memorial Hospi-al (CMRPD1B0481∼3, CMRPD1D0281∼3, and BMRP450 to.-L. Hwang).

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