5.1. INTRODUCTION

Cordyceps is the composite of a genus of fungus that grows on the larva of insects. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. However, since 1964, only Cordyceps sinensis has been recorded officially as an herbal drug in Chinese pharmacopoeia. C. sinensis, known as Dongchongxiacao (winter-worm summer-grass) in Chinese, is one of the most famous traditional Chinese medicines and medicinal mushrooms. The fungus attacks the larva of some species of insects (Fam. Hepialidae), and converts each larva to a sclerotium, from which the fruiting body grows (Figure 5.1).

FIGURE 5.1

(See color insert.) (a) Cordyceps sinensis, illustrated in the book Ben Cao Bei Yao by Wang Ang, which was published in 1694; (b) C. sinensis found in the soil (arrowhead indicates C. sinensis); and (c) collected as raw materials.

According to the theory of Chinese medicine, C. sinensis is sweet in taste and neutral in nature, and it can replenish the kidney, soothe the lung, stop bleeding, and eliminate phlegm. The fungus C. sinensis has been used for the treatment of fatigue, cough, hyposexuality, asthenia after severe illness, renal dysfunction, and renal failure (State Pharmacopoeia Commission of PRC 2005). In China, it is found in the soil of prairies at elevations of 3500–5000 m, mainly in the provinces of Qinghai, Tibet, Sichuan, Yunnan, and Gansu. In China, C. sinensis has been known and used as a remedy for more than 300 years. It was first recorded in Ben Cao Bei Yao by Wang Ang in 1694, and the Italian scholar Saccardo named the Cordyceps found in China officially as Cordyceps sinensis (Berk.) Sacc. in 1878; this nomenclature has been used ever since.

The ecosystem of C. sinensis has been terribly affected by the restriction of habitat and over- exploration. Although the Ordinance of Resources Protection on Wild Herbal Medicine was issued in 1987, the yield of natural C. sinensis is still decreasing. It was reported based on a survey conducted during June–July 2007 that the yield of natural C. sinensis decreased by more than 90% in the last 25 years. The price rocketed to more than 200,000 Renminbi (RMB)/kg (approximately US$25,000) in 2007 (Feng, Yang, and Li 2008), and its usage was limited during the past decade by its limited supply.

Due to the rarity and outstanding curative effects of C. sinensis, some natural substitutes such as C. militaris, C. liangshanensis, C. gunnii, and C. cicadicola have been sold in markets (Yang et al. 2009). In addition, several cultured mycelia of C. sinensis and C. militaris fungi have become the main substitutes of the natural species as commercial products, and 50 medicines and two dietary supplements related to cultured Cordyceps have been approved by the State Food and Drug Administration of China since 2002 (Feng, Yang, and Li 2008). For example, JinShuiBao capsule, the commercial product of C_s-4 (Paecilomyces hepialid, a standardized mycelium of C. sinensis), has been used in clinics throughout China. This product generates several million U.S. dollars every year. Synnematum sinensis, Cephalosporium sinensis, Gliocladium roseum, and Mortierella hepialid, the fungus strains isolated from natural C. sinensis, have also been subjected to large- scale fermentation and are used as commercial products (Cheung, Li, and Tsim 2005). Therefore, much effort has been invested in studying the evaluation of the quality, pharmacological activities, and clinical efficacies of natural and cultured cordyceps. In this chapter, we focus on the bioactivities, action mechanisms, and active ingredients of cordyceps, both natural and cultured.

5.2. ANTITUMOR ACTIVITY

Cancer is the second leading cause of disease-related mortality throughout the world (Xiao and Zhong 2007). However, related therapy strategies are still limited to surgery, radiotherapy, and chemotherapy. Due to the limitations of surgery and radiotherapy and the side effects of chemotherapy, there is increasing interest in developing antitumor drugs from natural products. Studies have shown that cordyceps has antitumor activity in various cancers through several pathways. Both natural and cultured cordyceps have demonstrated antitumor effects (Feng, Yang, and Li 2008; Zhou et al. 2009a).

Studies in vivo showed cordyceps had an inhibitory effect on Ehrlich ascites carcinoma and meth-A fibrosarcoma (Ng and Wang 2005), EL-4 lymphoma (Yamaguchi et al. 1990), B16 melanoma (Wu, Zhang, and Leung 2007a), Lewis lung carcinoma (Nakamura et al. 1999), and H22 tumors (Chen et al. 2006) in mice. Furthermore, C. sinensis reversed the suppressive effect of Taxol-induced leukopenia in mice, which indicated that C. sinensis could be used with other chemotherapy methods for cancer treatment (Liu et al. 2008). Cordyceps exhibited direct cytotoxic activity against several kinds of tumor cells, including Lewis lung carcinoma, B16 melanoma, lymphocytic (Jurkat), prostate (PC3), breast (MCF7), hepatocellular (HepG2, Hep3B), colorectal (HT-29)and HCT 116), and HL-60 cells (Nakamura et al. 1999; Wang et al. 2005; Wu, Zhang, and Leung 2007a). Although cordyceps had a cytotoxic effect on tumor cells, it did not show any cytotoxicity against normal cells (Wu, Zhang, and Leung 2007a).

Several mechanisms contribute to the antitumor effect of cordyceps, such as direct cytotoxicity, immunopotentiation, apoptosis, selective inhibition of ribonucleic acid (RNA), and protein synthesis, as well as antioxidant, antiangiogenic, antimutagenic, antimetastatic, and antiviral activities (Xiao and Zhong 2007; Feng, Yang, and Li 2008; (Zhou et al. 2009a). Of them, the apoptotic homeostasis regulated by cordyceps might be the most important (Buenz et al. 2005; Feng, Yang, and Li 2008) mechanism. The apoptotic molecular mechanism of cordyceps includes the activation of Bax, caspase-3 and/or -9, -8; inhibition of cyclooxygenase-2 (COX-2); and nuclear factor κB (NF-κB) protein expression and downregulation of Bcl-2 level (Xiao and Zhong 2007; Feng, Yang, and Li 2008). Besides, apoptosis of MDA-MB-231 human breast carcinoma cells induced by C. militaris aqueous extract (0.8 mg/mL) was also associated with loss of mitochondrial membrane permeability. In addition, the extract decreased Akt activation and reversed PI3K/Akt-pathway-enhanced apoptosis (Jin, Kim, and Choi 2008). Furthermore, the apoptotic events induced by the extract were also mediated by diminished telomerase activity (Park et al. 2009).

5.3. IMMUNOMODULATING EFFECT

The immune system protects human beings from infection with layered defenses of increasing specificity. First, physical barriers prevent pathogens from entering the body. If a pathogen breaks these barriers, the innate immune system provides an immediate, but nonspecific response. The human body possesses a third layer of protection, that is, the adaptive immune system. The adaptive immune response is activated by the response of the innate immune system. Cells of the innate system include phagocytes (macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. In the adaptive system, B cells are involved in humoral immune response, whereas T cells contribute to cellular immune response. Immunopotentiating drugs are used to restore the immune system to normal and to reduce reoccurring and life-threatening infections. Immunosuppressive drugs are applied to control autoimmune disorders and inflammation when excessive tissue damage occurs, as well as to prevent transplant rejection after an organ transplant (Taylor, Watson, and Bradley 2005). Increasing evidence shows that cordyceps is a bidirectional modulator with both potentiating and suppressive effects on the immune system through regulating innate and adaptive immunity (Li and Tsim 2004; Ng and Wang 2005; Feng, Yang, and Li 2008; (Zhou et al. 2009a).

5.4. ANTIOXIDANT ACTIVITY

Reactive oxygen species (ROS), including molecular oxygen (O₂), superoxide anion (O₂^-), H₂O₂, hydroxyl radical (OH), peroxynitrite (ONOO^-), and hypochlorous acid (HOCl; Zhou, Mrowietz, and Rostami-Yazdi 2009b), are well recognized as playing a dual role in biological systems, since they can be either beneficial or harmful to living systems (Valko et al. 2004). Normally, ROS form the natural by-products of aerobic metabolism and play a physiological role in cell signaling. However, the concentration of ROS can increase dramatically during times of environmental stress such as exposure to ultraviolet (UV) radiation or heat, causing damage to the lipids, proteins, and nucleic acids of cells. This injury to cell structures leads to several diseases, such as senescence, cancer, atherosclerosis and cardiovascular diseases, inflammatory lung diseases, immune dysfunction, and neurodegenerative disorders (Rahman 2003; Zhong 2006; Valko et al. 2007).

There is increasing evidence that cordyceps has antioxidant activity, which may be one of the mechanisms behind the antiaging, anticancer, anti-inflammatory, antiatherosclerosis, and immunomodulatory effects of cordyceps (Table 5.1). As far as different parts of C. sinensis are concerned, the fruiting bodies showed a similar potency with caterpillars in their antioxidant activities in xanthine oxidase assay, induction of hemolysis assay, and lipid-peroxidation assay (Li et al. 2002). The results also demonstrated that the caterpillar has a similar chemical composition to the fruiting body, which indicates that the function of the worm in cordyceps is to provide a growth medium for the fruiting body, and the caterpillar is eventually totally invaded by cordyceps mycelia (Li et al. 2002).

TABLE 5.1

Antioxidant Activity In Vitro and In Vivo of Cordyceps.

Both water (Li et al. 2001; Yu et al. 2006; Dong and Yao 2008) and ethanol (Wang et al. 2005; Won and Park 2005; Ra et al. 2008) extracts of cordyceps showed significant antioxidant activity in vitro. However, the water extract exhibited a stronger inhibitory effect on superoxide anions and hydroxyl radicals than the ethanol extract (Yamaguchi et al. 2000a). Furthermore, both natural C. sinensis and cultured cordyceps showed direct and potent antioxidant activities using in vitro assays, such as lipid-peroxidation assay, 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, and protein-peroxidation assay. Therefore, cultured cordyceps can be used for antioxidant activity, relieving human demands on natural C. sinensis, an endangered species (Li et al. 2001; Yu et al. 2006; Dong and Yao 2008).

5.5. ANTIHYPERGLYCEMIC ACTIVITY

Cordyceps has hypoglycemic activity in normal animals. The oral administration of a cordyceps carbohydrate extract “Cs-4” at 2 g/kg/day for 25 days increased insulin sensitivity, and the extract had potential beneficial effects by maintaining whole-body glucose disposal with a less-pronounced increase in insulin secretion after a carbohydrate challenge in rats (Balon, Jasman, and Zhu 2002). In another study, normal rats fed with Cs-4 at 250 or 500 mg/kg/day for 17 days showed significant decreases in fasting blood glucose level by 27% and 24%, respectively, and the fasting plasma insulin of rats in the 500-mg/kg group decreased by 37%. Furthermore, oral glucose tolerance tests demonstrated that the extract significantly improved glucose tolerance at 0.5, 1.0, and 2.0 hours after ingestion of glucose (Zhao et al. 2002).

Cordyceps also showed an antihyperglycemic effect in diabetic animals. Although fruiting bodies of natural C. sinensis (4 g/kg/day) had no effect on the fasting insulin level in diabetic rats (Lo et al. 2004), it improved the weight and attenuated water intake (day 15 to day 29), fasting blood glucose level (day 15 to day 26), and serum concentration of fructosamine (day 29) in diabetic rats. Fruiting bodies of C. sinensis also improved thymus weight and glucose tolerance (day 26; Lo et al. 2004 and 2006). However, in this experiment, C. sinensis had no effect on serum triglycerides and cholesterol concentrations of diabetic rats (Lo et al. 2004). Choi et al. (2004) also found that the aqueous extract of cultured C. militaris had no effect on fasting insulin level or glucose uptake in the gastrointestinal tract. However, the extract was found to lower fasting serum glucose level, reduce triglycerides level in soleus muscles, increase the whole-body glucose disposal rate, as well as enhance glucose transporter 4 (GLUT 4) content and fraction velocity of glycogen synthase in the soleus and quadriceps muscles in 90% pancreatectomized rats that were fed C. militaris extract at 500 mg/kg/day for 8 weeks (Choi et al. 2004).

Interestingly, fruiting bodies, not caterpillars, of C. sinensis had an effect on lowering the fasting blood glucose level and increasing the thymus weight (Lo et al. 2004). However, fermented mycelia and broth of C. sinensis had similar antihyperglycemic effect with fruiting bodies in nicotinamide and streptozotocin-induced diabetic rats (Lo et al. 2006). Therefore, the fermented products of cordyceps can be developed as potential antidiabetic agents or functional foods for persons with a high risk of diabetes mellitus.

5.6. SEXUAL AND REPRODUCTIVE FUNCTION ENHANCEMENT ACTIVITY

Testosterone is necessary for normal sperm development. It activates genes in Sertoli cells, which promote differentiation of spermatogonia. Cordyceps has traditionally been used for the enhancement of sexual function in human beings. Evidence shows that C. sinensis and C. militaris can improve reproductive activity and restore impaired reproductive function (Table 5.2). The administration of C. sinensis enhanced libido and sexual activity, and restored impaired reproductive function in both sexes in human (Zhu, Halpern, and Jones 1998). Such effects are related to the enhancement of testosterone release in plasma through cAMP (adenosine monophosphate)-protein kinase A signal pathway (Hsu et al. 2003a). Fractions of cultured mycelia of C. sinensis with water- soluble low-molecular-weight proteins and polysaccharides of relatively poor water solubility and protein, but not fractions with water-soluble low-molecular-weight polysaccharides, increased testosterone levels in mice (Hsu et al. 2003b; Huang et al. 2004). A protein in C. sinensis contributed to the observed hypotensive and vasorelaxant properties by improving the production of NO (Chiou et al. 2000); this protein might help the penis trap blood for erection, thereby improving sexual function (Drewes, George, and Khan 2003).

TABLE 5.2

Effect of C. sinensis and C. militaris on Sexual and Reproductive Function.

5.7. ANTIFATIGUE ACTIVITY

Fatigue is defined as difficulty in initiating or sustaining voluntary activity (Chaudhuri and Behan 2004), and can be classified into mental and physical fatigue (Mizuno et al. 2008). Fatigue is a common symptom in sickness and in health. Chronic fatigue can affect an individual’s performance. In addition, long-term accumulated fatigue can lead to karoshi (a Japanese word meaning death as a result of overwork). In China, cordyceps is used to restore health after various diseases and to hasten recovery from exhaustion because of its adaptogenic (antistress) properties and ability to enhance endurance and strength (Bucci 2000).

Oral administration of C. sinensis mycelia water extract at 150 mg/kg/day for 7 days (Koh et al. 2003b) or ingestion of fruiting bodies of C. militaris at 500 mg/kg/day for 4 weeks (Jung, Kim, and Han 2004) significantly prolonged the swimming time of mice by about 20 and 24 minutes, respectively. This effect was related to the enhancement of immunity. The administration of C. sinensis at 150 mg/kg/day for 8 days inhibited the increase of total cholesterol and the decrease of alkaline phosphatase in rats, as well as significantly reversed the decreased weight of liver, adrenal gland, thymus, and thyroid (Koh et al. 2003b). The involvement of cordyceps in adenosine triphosphate (ATP) production also accounts for a decrease in physical fatigue when it is administered. The oral administration of cultured C. sinensis extract (200 mg/kg/day, p.o.) not only improved hepatic energy metabolism and blood flow in dietary hypoferric anemic mice for 4 weeks (Manabe et al. 2000) but also increased significantly the ATP/inorganic phosphate ratio in the liver of normal mice for 3 weeks (Manabe et al. 1996) or for 7 days (Dai et al. 2001) with no steatosis, necrosis, inflammation, or fibrosis in the liver specimens (Manabe et al. 1996 and 2000). Treatment with natural or cultured cordyceps extracts (1 g/kg/day, p.o.) for 3 days enhanced myocardial ATP generation capacity ex vivo in mice by 29% and 32%, respectively, which might be mediated by the enhancement of mitochondrial electron transport (Siu et al. 2004).

Patients having chronic fatigue syndrome often have depression. Around 30–70% of such patients show the features of major depression (Adler 2004). Supercritical fluid extract (SCCS, 2.5–10 mL/kg, p.o.), other than hot water extract (500–2000 mg/kg, p.o.), of C. sinensis show significant antidepressant-like activity. After 5 days of administration, SCCS shortened immobility times in the mouse-tail suspension test, although it had no effect on locomotor activity in the mouse open field test. It was considered that SCCS played an antidepressant-like role by affecting the adrenergic and dopaminergic systems other than the serotonergic system (Nishizawa et al. 2007). In addition, cordyceps has a powerful antioxidant effect, which may eliminate the ROS produced in working muscles during exercise and help in relieving fatigue (Mizuno et al. 2008). Finally, C. sinensis induced a more efficient utilization and consumption of O₂, which resulted in a greater survival rate under a hypoxic environment (Lou, Liao, and Lu 1986) in mice. The results indicate a more efficient use of O₂ by cordyceps to support essential physiological activities of tissues and improve tolerance to hypoxia-induced acidosis. However, few clinical trials have been conducted on the antifatigue effect of cordyceps, and most of the conducted tests were methodologically flawed, especially in the inclusion of other drugs in the experiments. For instance, capsules containing Cs-4, Rhodiaola rosea, and other ingredients did not enhance muscle-tissue oxygen saturation (Colson et al. 2005) and cycling performance (Earnest et al. 2004) in healthy men. Similarly, ingestion of a supplement containing cultured C. sinensis, adenylpyrophosphoric acid, calcium pyruvate, and yohimbine hydrochloride once 1 hour before a sport activity showed no ergogenic effects in healthy men (Herda et al. 2008). One reason may be that the ingestion schema of C. sinensis was insufficient to elicit positive changes in humans. A 1-week loading phase followed by at least a 2–4-week maintenance phase may be needed to obtain the effect of promoting aerobic capacity and resistance to fatigue. Another reason may be that as these experiments were performed on healthy persons, there were fewer margins for physiological, health, and performance improvement than in diseased or elderly persons (Colson et al. 2005).

5.8. PROTECTIVE EFFECT ON THE KIDNEY

C. sinensis has been used for the treatment of renal diseases, such as chronic nephritis, chronic pyelonephritis, chronic renal dysfunction or failure, and nephritic syndrome (Feng, Yang, and Li 2008). The C. sinensis extract significantly improved renal function via antiapoptotic and anti-inflammatory activity in rats subjected to 60 minutes of ischemia and following 3 days of reperfusion of the kidneys. Downregulation of the apoptotic gene of caspase-3 accompanied the decreases in inflammatory genes such as MCP-1, TNF-α, and iNOS. The result indicates that C. sinensis plays a potential therapeutic role in renal transplantation (Shahed, Kim, and Shoskes 2001).

Another mechanism by which cordyceps protects the kidney is its inhibitory effect on mesangial cell proliferation. It has been suggested that glomerular sclerosis is preceded by proliferation of mesangial cells that exhibit smooth muscle cell features and accumulation of mesangial extracellular matrix. Both C. sinensis and C. militaris, at a concentration of 100 mg/mL, significantly reversed the proliferation of human mesangial cell stimulated by low-density lipoprotein (LDL; Wu, Wang, and Cheng 2000). Moreover, C. sinensis could protect the kidney from cyclosporine A–induced chronic nephrotoxicity, with lower blood urea nitrogen (BUN), interstitial edema and fibrosis, and bulbular necrosis (Wojcikowski, Johnson, and Gobë 2006). Furthermore, administration of a water extract of cordyceps had a protective effect in rats with acute renal failure induced by gentamicin. The possible mechanisms include protection of sodium pump activity, lowering of lipoperoxidation in tubular cells, and attenuation of lysosomal overactivity in tubular cells (Ng and Wang 2005; Li and Yang 2008a). In addition, C. sinensis enhanced cellular immunity in rats with chronic renal failure (Cheng 1992).

Clinical trials have also shown some evidence for the use of cordyceps as a renoprotectant remedy (Wojcikowski, Johnson, and Gobë 2004 and 2006). For example, Bailing capsule, a preparation made from C. sinensis mycelia, ameliorated the rejection of renal transplant, improved renal and liver function, regulated hypoproteinemia and hyperlipidemia, stimulated hemopoietic function, and decreased the incidence of infections in patients after renal transplant (Sun et al. 2004; Li et al. 2009). In patients with chronic renal failure, ingestion of another cordyceps product Cs-4, called JinShuiBao, also significantly promoted renal function, which decreased serum urea and creatinine and increased total blood protein and calcium (Feng, Yang, and Li 2008).

5.9. EFFECT ON THE LIVER

Cordyceps has been used in clinical practice for the treatment of chronic hepatitis and related diseases (Zhao 2000). There are several ways in which it contributes to the treatment of and protection against liver disease. First, cordyceps has a potential enhancing effect on the immunological function of patients suffering from chronic hepatitis B (Gong, Wang, and Tang 2000) and from posthepatic cirrhosis (Zhu and Liu 1992). Second, cordyceps was shown to inhibit and reverse liver fibrosis via degradation of collagen in rats with liver cirrhosis induced by dimethylnitrosamine (Li et al. 2006a; Wang, Liu, and Tang 2008), inhibit proliferation of hepatic stellate cells in vitro (Chor et al. 2005), downregulate intercellular adhesion molecule-I (an index of liver fibrogenesis) and CD126 in human fibroblasts (Li and Tsim 2004), and decrease expression of transforming growth factor-β and platelet-driven growth factor (Liu and Shen 2003). Third, cordyceps decreased lipid peroxide levels in serum and hepatic tissue, and lowered serum TNF-α in bacillus calmette guerin plus LPS-induced liver injury in mice (Zeng, Tang, and Yuan 2001).

5.10. ACTIVE COMPONENTS

Many active ingredients, such as cordycepin, polysaccharides, and ergosterol, have been isolated from various Cordyceps species and account for a range of bioactivities (Table 5.3).

TABLE 5.3

Chemical Compounds in Cordyceps and Their Pharmacological Activities.

5.10.3. Free Fatty Acids and Their Activities

Ten free fatty acids (FFAs), that is, lauric acid, myristic acid, pentadecanoic acid, palmitoleic acid, palmitic acid, linoleic acid, oleic acid, stearic acid, docosanoic acid, and lignoceric acid, have been found in natural C. sinensis, C. liangshanensis, and C. gunnii, as well as in cultured C. sinensis and C. militaris. Among these FFAs, palmitic acid, linoleic acid, oleic acid, and stearic acid are the major components in natural and cultured cordyceps. Natural cordyceps contains more palmitic acid and oleic acid than cultured (Yang et al. 2009). The FFAs are not only essential nutritional compounds but also modulators of many cellular functions through their receptors. The FFA receptors are G-protein-coupled receptors, including G-protein receptor (GPR) 40, GPR41, GPR43, GPR120, and GPR84 (Rayasam et al. 2007; Hirasawa et al. 2008; Swaminath 2008). The activation of FFA receptors exhibits several physiological effects (Table 5.4); they, therefore, are purported to be novel therapeutic targets for diabetes, dyslipidemia, and immunomodulation, especially type 2 diabetes.

TABLE 5.4

Summary of Free Fatty Acid Receptor Ligands and Physiological Roles in Various Tissues.

Pentadecanoic acid (C15) and palmitic acid (C16) are the most potent FFAs on GPR40, and can activate the GPR40 receptor and stimulate calcium release (Briscoe et al. 2003). This, in turn, triggers insulin release from the β-cells of the pancreas, thus producing a hypoglycemic effect. Both these FFAs exist in both wild and cultured cordyceps, palmitic acid being a main ingredient, and palmitic acid may be one of the active hypoglycemic components in cordyceps. On the other hand, FFAs in cordyceps may also indirectly promote glucose-stimulated insulin secretion and then inhibit plasma glucose level by activation of GPR120 in the intestinal tract (Hirasawa et al. 2008). The receptors GPR41, GPR43, and GPR84 are expressed on immune cells. Activation of these receptors by FFAs induces an immunomodulatory effect (Swaminath 2008) and cordyceps contains FFAs and possesses significant relevant activity, indicating that the FFAs in the cordyceps contribute to its immunomodulatory mechanisms.

5.11. CONCLUSIONS

C. sinensis is a valued traditional Chinese medicine. Because it is rare and expensive, several other natural cordyceps, cultured mycelia, and fruiting bodies of cordyceps have become its main substitutes in commercial health food formulations. Experiments have shown that cordyceps has several bioactivities, such as antitumor, immunomodulatory, antioxidant, sexual and reproductive function enhancement, hypoglycemic, and antifatigue activities, and have a protective effect on the kidney and liver. Different compounds contribute to different bioactivities. Normally, the cultured mycelia of cordyceps are as effective as those found in natural cordyceps. Cordyceps is quite safe in the in vivo treatment of animals for up to 3 weeks. Fermented products of cordyceps, along with natural C. sinensis, could be potential agents or functional foods for maintaining human health.

REFERENCES

1. Adler R. H. Chronic fatigue syndrome (cfs). Swiss Med Wkly. 2004;134:268–76. [PubMed]
2. Ahn Y. J, Park S. J, Lee S. G, Shin S. C, Choi D. H. Cordycepin: Selective growth inhibitor derived from liquid culture of Cordyceps militaris against Clostridium spp. J Agric Food Chem. 2000;48:2744–8. [PubMed]
3. Anderson S. D, Charlton B, Weiler J. M, et al., editors. Comparison of mannitol and methacholine to predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma. Respir Res. 2009;10:4. [PMC free article] [PubMed]
4. Awad A. B, Chan K. C, Downie A. C, Fink C. S. Peanuts as a source of beta-sitosterol, a sterol with anticancer properties. Nutr Cancer. 2000;36:238–41. [PubMed]
5. Balon T. W, Jasman A. P, Zhu J. S. A fermentation product of Cordyceps sinensis increases whole-body insulin sensitivity in rats. J Altern Complement Med. 2002;8:315–23. [PubMed]
6. Bok J. W, Lermer L, Chilton J, Klingeman H. G, Towers G. H. Antitumor sterols from the mycelia of Cordyceps sinensis. Phytochemistry. 1999;51:891–8. [PubMed]
7. Briscoe C. P, Tadayyon M, Andrews J. L, et al., editors. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem. 2003;278:11303–11. [PubMed]
8. Bucci L. R. Selected herbals and human exercise performance. Am J Clin Nutr. 2000;72:624S–36S. [PubMed]
9. Buenz E. J, Bauer B. A, Osmundson T. W, Motley T. J. The traditional Chinese medicine Cordyceps sinensis and its effects on apoptotic homeostasis. J Ethnopharmacol. 2005;96:19–29. [PubMed]
10. Bunyapaiboonsri T, Yoiprommarat S, Intereya K, Kocharin K. New diphenyl ethers from the insect pathogenic fungus Cordyceps sp. BCC 1861. Chem Pharm Bull. 2007;55:304–7. [PubMed]
11. Calò L, Fornelli F, Ramires R, et al., editors. Cytotoxic effects of the mycotoxin beauvericin to human cell lines of myeloid origin. Pharmacol Res. 2004;49:73–7. [PubMed]
12. Chang Y, Jeng K. C, Huang K. F, et al., editors. Effect of Cordyceps militaris supplementation on sperm production, sperm motility and hormones in Sprague-Dawley rats. Am J Chin Med. 2008a;36:849–59. [PubMed]
13. Chang W, Lim S, Song H, et al., editors. Cordycepin inhibits vascular smooth muscle cell proliferation. Eur J Pharmacol. 2008b;597:64–9. [PubMed]
14. Chaudhuri A, Behan P. O. Fatigue in neurological disorders. Lancet. 2004;363:978–88. [PubMed]
15. Chen J. L, Chen Y. C, Yang S. H, Ko Y. F, Chen S. Y. Immunological alterations in lupus-prone autoimmune (NZB/NZW) F1 mice by mycelia Chinese medicinal fungus Cordyceps sinensisinduced redistributions of peripheral mononuclear T lymphocytes. Clin Exp Med. 2009;9(4):277–84. [PubMed]
16. Chen L. S, Stellrecht C. M, Gandhi V. RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells. Br J Haematol. 2008;140:682–91. [PubMed]
17. Chen J, Zhang W, Lu T, et al., editors. Morphological and genetic characterization of a cultivated Cordyceps sinensis fungus and itspolysaccharide component possessing antioxidant property in H22 tumor-bearing mice. Life Sci. 2006;78:2742–8. [PubMed]
18. Cheng Q. 1992Effect of Cordyceps sinensis on cellular immunity in rats with chronic renal insufficiency Zhonghua Yi Xue Za Zhi 7227–9.,63. [PubMed]
19. Cheng Y, Schneider B, Riese U, Schubert B, Li Z, Hamburger M. Farinosones A-C, neurotrophic alkaloidal metabolites from the entomogenous deuteromycete Paecilomyces farinosus. J Nat Prod. 2004;67:1854–8. [PubMed]
20. Cheng Y, Schneider B, Riese U, Schubert B, Li Z, Hamburger M. (+)-N-Deoxymilitarinone A, a neuritogenic pyridone alkaloid from the insect pathogenic fungus Paecilomyces farinosus. J Nat Prod. 2006;69:436–8. [PubMed]
21. Cheung J. K. H, Li J, Cheung A. W. H, et al., editors. Cordysinocan, a polysaccharide isolated from cultured Cordyceps, activates immune responses in cultured T-lymphocytes and macrophages: Signaling cascade and induction of cytokines. J Ethnopharmacol. 2009;124(1):61–8. [PubMed]
22. Cheung J. K. H, Li S. P, Tsim K. W. K. Authentication and qualitycontrol of Cordyceps sinensis, a traditional Chinese medicine known as winter-worm summer-grass. Orient Pharm Exp Med. 2005;5:262–71.
23. Chiou W. F, Chang P. C, Chou C. J, Chen C. F. Protein constituent contributes to the hypotensive and vasorelaxant activities of Cordyceps sinensis. Life Sci. 2000;66:1369–76. [PubMed]
24. Cho H. J, Cho J. Y, Rhee M. H, Kim H. S, Lee H. S, Park H. J. Inhibitory effects of cordycepin (3'-deoxyadenosine), a component of Cordyceps militaris, on human platelet aggregation induced by thapsigargin. J Microbiol Biotechnol. 2007a;17:1134–8. [PubMed]
25. Cho H. J, Cho J. Y, Rhee M. H, Lim C. R, Park H. J. Cordycepin (3'-deoxyadenosine) inhibits human platelet aggregation induced by U46619, a TXA2 analogue. J Pharm Pharmacol. 2006;58:1677–82. [PubMed]
26. Cho H. J, Cho J. Y, Rhee M. H, Park H. J. Cordycepin (3'-deoxyadenosine) inhibits human platelet aggregation in a cyclic AMP- and cyclic GMP-dependent manner. Eur J Pharmacol. 2007b;558:43–51. [PubMed]
27. Choi S. B, Park C. H, Choi M. K, Jun D. W, Park S. Improvement of insulin resistance and insulin secretion by water extracts of Cordyceps militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats. Biosci Biotechnol Biochem. 2004;68:2257–64. [PubMed]
28. Chor S. Y, Hui A. Y, To K. F, et al., editors. Anti-proliferative and pro-apoptotic effects of herbal medicine on hepatic stellate cell. J Ethnopharmacol. 2005;100:180–6. [PubMed]
29. Colson S. N, Wyatt F. B, Johnston D. L, Autrey L. D, FitzGerald Y. L, Earnest C. P. Cordyceps sinensis- and Rhodiola rosea-based supplementation in male cyclists and its effect on muscle tissue oxygen saturation. J Strength Cond Res. 2005;19:358–63. [PubMed]
30. Cunningham K. G, Mason W, Spring F. S, Hutchinson S. A. Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.). Nature. 1950;166:949. [PubMed]
31. Dai G, Bao T, Xu C, Cooper R, Zhu J. S. CordyMax Cs-4 improves steady-state bioenergy status in mouse liver. J Altern Complement Med. 2001;7:231–40. [PubMed]
32. Ding C, Tian P, Jia L, et al., editors. The synergistic effects of C. Sinensis with CsA in preventing allograft rejection. Front Biosci. 2009;14:3864–71. [PubMed]
33. Dong C. H, Yao Y. J. In vitro evaluation of antioxidant activities of aqueous extracts from natural and cultured mycelia of Cordyceps sinensis. LWT-Food Sci Technol. 2008;41:669–77. [PMC free article] [PubMed]
34. Drewes S. E, George J, Khan F. Recent findings on natural products with erectile-dysfunction activity. Phytochemical. 2003;62:1019–25. [PubMed]
35. Earnest C. P, Morss G. M, Wyatt F, et al., editors. Effects of a commercial herbal-based formula on exercise performance in cyclists. Med Sci Sports Exerc. 2004;36:504–9. [PubMed]
36. Feng K, Yang Y. Q, Li S. P. Renggongchongcao. In: Li S. P, Wang Y. T, editors. Pharmacological Activity-Based Quality Control of Chinese Herbs. New York: Nova Science Publisher, Inc.; 2008. pp. 155–78.
37. Gong H. Y, Wang K. Q, Tang S. G. Effects of Cordyceps sinensis on T lymphocyte subsets and hepatofibrosis in patients with chronic hepatitis B. Hunan Yi Ke Da Xue Xue Bao. 2000;25:248–50. [PubMed]
38. Guo H, Hu H, Liu S, Liu X, Zhou Y, Che Y. Bioactive p-terphenyl derivatives from a Cordyceps- colonizing isolate of Gliocladium sp. J Nat Prod. 2007;70:1519–21. [PubMed]
39. Herda T. J, Ryan E. D, Stout J. R, Cramer J. T. Effects of a supplement designed to increase ATP levels on muscle strength, power output, and endurance. J Int Soc Sports Nutr. 2008;5:3. [PMC free article] [PubMed]
40. Hirasawa A, Hara T, Katsuma S, Adachi T, Tsujimoto G. Free fatty acid receptors and drug dis-covery. Biol Pharm Bull. 2008;31:1847–51. [PubMed]
41. Hsu C. C, Huang Y. L, Tsai S. J, Sheu C. C, Huang B. M. In vivo and in vitro stimulatory effects of Cordyceps sinensis on testosterone production in mouse Leydig cells. Life Sci. 2003b;73:2127–36. [PubMed]
42. Hsu C. H, Sun H. L, Sheu J. N, et al., editors. Effects of the immunomodulatory agent Cordyceps militaris on airway inflammation in a mouse asthma model. Pediatr Neonatol. 2008;49:171–8. [PubMed]
43. Hsu C. C, Tsai S. J, Huang Y. L, Huang B. M. Regulatory mechanism of Cordyceps sinensis mycelium on mouse Leydig cell steroidogenesis. FEBS Lett. 2003a;543:140–3. [PubMed]
44. Huang B. M, Hsu C. C, Tsai S. J, Sheu C. C, Leu S. F. Effects of Cordyceps sinensis on testosterone production in normal mouse Leydig cells. Life Sci. 2001b;69:2593–602. [PubMed]
45. Huang B. M, Ju S. Y, Wu C. S, Chuang W. J, Sheu C. C, Leu S. F. Cordyceps sinensis and its fractions stimulated MA-10 mouse Leydig tumor cell steroidogenesis. J Androl. 2001a;22:831–7. [PubMed]
46. Huang Y. L, Leu S. F, Liu B. C, Sheu C. C, Huang B. M. In vivo stimulatory effect of Cordyceps sinensis mycelium and its fractions on reproductive functions in male mouse. Life Sci. 2004;75:1051–62. [PubMed]
47. Huffnagle G. B, Noverr M. C. GI Microbiota and Regulation of the Immune System. Vol. 635. New York: Springer Science+Business Media, LLC; 2008. [PubMed]
48. Hwang K, Lim S. S, Yoo K. Y, et al., editors. A phytochemically characterized extract of Cordyceps militaris and cordycepin protect hippocampal neurons from ischemic injury in berbils. Planta Med. 2008;74:114–9. [PubMed]
49. Ikeda M, Tsuru S, Ohmori T, Kitahara S, Inouye T, Healy G. B. CO-N reaction-a new serologi- cal activity index-on Wegener’s granulomatosis. J Laryngol Otol. 1993;107:607–10. [PubMed]
50. Ilowite J, Spiegler P, Chawla S. Bronchiectasis: New findings in the pathogenesis and treatment of this disease. Curr Opin Infect Dis. 2008;21:163–7. [PubMed]
51. Isaka M, Boonkhao B, Rachtawee P, Auncharoen P. Axanthocillin-like alkaloid from the insect pathogenic fungus Cordyceps brunnearubra BCC 1395. J Nat Prod. 2007;70:656–8. [PubMed]
52. Isaka M, Tanticharoen M, Kongsaeree P, Thebtaranonth Y. Structures of cordypyridones A-D, antimalarial Nhydroxy- and N-methoxy-2-pyridones from the insect pathogenic fungus Cordyceps nipponica. J Org Chem. 2001;66:4803–8. [PubMed]
53. Jaques A, Daviskas E, Turton J. A, et al., editors. Inhaled mannitol improves lung function in cystic fibrosis. Chest. 2008;133:1388–96. [PubMed]
54. Jen C. Y, Lin C. Y, Leu S. F, Huang B. M. Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis through caspase-9 pathway. Evid Based Complement Alternat Med. 2009;6:1–10. [PMC free article] [PubMed]
55. Ji D. B, Ye J, Li C. L, Wang Y. H, Zhao J, Cai S. Q. Antiaging effect of Cordyceps sinensis extract. PhytotherRes. 2009;23:116–22. [PubMed]
56. Jia J. M, Ma X. C, Wu C. F, Wu L. J, Hu G. S. Cordycedipeptide A, a new cyclodipeptide from the culture liquid of Cordyceps sinensis (Berk.). 2005;53:582–3. Sacc. Chem Pharm Bull (Tokyo) [PubMed]
57. Jin C. Y, Kim G. Y, Choi Y. H. Induction of apoptosis by aqueous extract of Cordyceps milita- ris through activation of caspases and inactivation of Akt in human breast cancer MDA-MB-231 cells. J Microbiol Biotechnol. 2008;18:1997–2003. [PubMed]
58. Jin D. Q, Park B. C, Lee J. S, et al., editors. Mycelial extract of Cordyceps ophioglossoides prevents neuronalcell death and ameliorates ?-amyloid peptide-induced memory deficits in rats. Biol Pharm Bull. 2004;27:1126–9. [PubMed]
59. Jordan J. L, Hirsch G. M, Lee T. D. C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A. Transpl Immunol. 2008b;19:159–66. [PubMed]
60. Jordan J. L, Sullivan A. M, Lee T. D. G. Immune activation by a sterile aqueous extract of Cordyceps sinensis: Mechanism of action. Immunopharmacol Immunotoxicol. 2008a;30:53–70. [PubMed]
61. Jung E. C, Kim K. D, Bae C. H, Kim J. C, Kim D. K, Kim H. H. A mushroom lectin from ascomycete Cordyceps militaris. Biochem Biophys Acta. 2007;1770:833–8. [PubMed]
62. Jung K, Kim I. H, Han D. Effect of medicinal plant extracts on forced swimming capacity in mice. J Ethnopharmacol. 2004;93:75–81. [PubMed]
63. Ka W. L. S, Kwok W.C, Kai K. S, Nam L. K, Wai K. L. C. Immunomodulatory activities of HERBSnSENSES Cordyceps -in vitro and in vivo studies. Immunopharmacol Immunotoxicol. 2006;28:341–60. [PubMed]
64. Kaczka E. A, Trenner N. R, Arison B, Walker R. W, Folkers K. Identification of cordycepin, a metabolite of Cordyceps militaris, as 3'-deoxyadenosine. Biochem Biophys Res Commun. 1964;14:456–7. [PubMed]
65. Kiho T, Hui J, Yamane A, Ukai S. Polysaccharides in fungi. XXXII. Hypoglycemic activity and chemical properties of a polysaccharide from the cultural mycelium of Cordyceps sinensis. Biol Pharm Bull. 1993;16:1291–3. [PubMed]
66. Kiho T, Nagai K, Miyamoto I, Watanabe T, Ukai S. Polysaccharides in fungi. XXV. Biological activities of two galactomannans from the insect-bodyportion of Chán hua (fungus: Cordyceps cicadae). Yakugaku Zasshi. 1990;110:286–8. [PubMed]
67. Kiho T, Ookubo K, Usui S, Ukai S, Hirano K. Structural features and hypoglycemic activity of a polysaccharide (CS-F10) from the cultured mycelium of Cordyceps sinensis. Biol Pharm Bull. 1999;22:966–70. [PubMed]
68. Kiho T, Yamane A, Hui J, Usui S, Ukai S. Polysaccharides in fungi. XXXVI. Hypoglycemic activity of a polysaccharide (CS-F30) from the cultural mycelium of Cordyceps sinensis and its effect on glucose metabolism in mouse liver. Biol Pharm Bull. 1996;19:294–6. [PubMed]
69. Kim G. Y, Ko W. S, Lee J. Y, et al., editors. Water extract of Cordyceps militaris enhances maturation of murine bone marrow-derived dendritic cells in vitro. Biol Pharm Bull. 2006a;29:354–60. [PubMed]
70. Kim K. M, Kwon Y. G, Chung H. T, et al., editors. Methanol extract of Cordyceps pruinosa inhibits in vitro and in vivo inflammatory mediators by suppressing NF-kappaB activation. Toxicol Appl Pharmacol. 2003;190:1–8. [PubMed]
71. Kim C. S, Lee S. Y, Cho S. H, et al., editors. Cordyceps militaris induces the IL-18 expression via its promoter activation for IFN-gamma production. J Ethnopharmacol. 2008;120:366–71. [PubMed]
72. Kim J. S, Sapkota K, Park S. E, et al., editors. A fibrinolytic enzyme from the medicinal mushroom Cordyceps militaris. J Microbiol. 2006;44:622–31. [PubMed]
73. Kim H. G, Shrestha B, Lim S. Y, et al., editors. Cordycepin inhibits lipopolysaccharide-induced inflammation by the suppression of NF-kappaB through Akt and p38 inhibition in RAW 264.7 macrophage cells. Eur J Pharmacol. 2006b;545:192–9. [PubMed]
74. Kim J. R, Yeon S. H, Kim H. S, Ahn Y. J. Larvicidal activity against Plutella xylostella of cordycepin from the fruiting body of Cordyceps militaris. Pest Manag Sci. 2002;58:713–7. [PubMed]
75. Kittakoop P, Punya J, Kongsaeree P, et al., editors. Bioactive naphthoquinones from Cordyceps unilateralis. Phytochemical. 1999;52:453–7.
76. Kneifel H, Konig W. A, Loeffler W, Muller R. Ophiocordin, an antifungal antibiotic of Cordyceps ophioglossoides. Arch Microbiol. 1977;113:121–30. [PubMed]
77. Koh J. H, Kim K. M, Kim J. M, Song J. C, Suh H. J. Antifatigue and antistress effect of the hot-water fraction from mycelia of Cordyceps sinensis. Biol Pharm Bull. 2003b;26:691–4. [PubMed]
78. Koh J. H, Suh H. J, Ahn T. S. Hot-water extract from mycelia of Cordyceps sinensis as a substitute for antibiotic growth promoters. Biotechnol Lett. 2003a;25:585–90. [PubMed]
79. Koh J. H, Yu K. W, Suh H. J, Choi Y. M, Ahn T. S. Activation of macrophages and the intestinal immune system by an orally administered decoction from cultured mycelia of Cordyceps sinensis. BiosciBiotechnol Biochem. 2002;66:407–11. [PubMed]
80. Kumar V, Sharma A. Adenosine: An endogenous modulator of innate immune system with therapeutic potential. Eur J Pharmacol. 2009;616(1-3):7–15. [PubMed]
81. Kuo M. C, Chang C. Y, Cheng T. L, Wu M. J. Immunomodulatory effect of exo-polysaccharides from submerged cultured Cordyceps sinensis: Enhancement of cytokine synthesis, CD11b expression, and phagocytosis. Appl Microbiol Biotechnol. 2007;75:769–75. [PubMed]
82. Kuo Y. C, Tsai W. J, Shiao M. S, Chen C. F, Lin C. Y. Cordyceps sinensis as an immunomodula- tory agent. Am J Chin Med. 1996;24:111–25. [PubMed]
83. Kuo Y. C, Tsai W. J, Wang J. Y, Chang S. C, Lin C. Y, Shiao M. S. Regulation of bronchoalveolar lavage fluids cell function by the immunomodulatory agents from Cordyceps sinensis. Life Sci. 2001;68:1067–82. [PubMed]
84. Kuo Y. C, Weng S. C, Chou C. J, Chang T. T, Tsai W. J. Activation and proliferation signals in primary human T lymphocytes inhibited by ergosterol peroxide isolated from Cordyceps cicadae. Br J Pharmacol. 2003;140:895–906. [PMC free article] [PubMed]
85. Lameire N. H, De Vriese A. S, Vanholder R. Prevention and nondialytic treatment of acute renal failure. Curr Opin Crit Care. 2003;9:481–90. [PubMed]
86. Li H. P, Hu Z, Yuan J. L, et al., editors. A novel extracellular protease with fibrinolytic activity from the culture supernatant of Cordyceps sinensis: Purification and characterization. Phytother Res. 2007;21:1234–41. [PubMed]
87. Li S. P, Li P, Dong T. T, Tsim K. W. Anti-oxidation activity of different types of natural Cordyceps sinensis and cultured Cordyceps mycelia. Phytomedicine. 2001;8:207–12. [PubMed]
88. Li F. H, Liu P, Xiong W. G, Xu G. F. Effects of Cordyceps sinensis on dimethylnitrosamine- induced liver fibrosis in rats. Zhong Xi Yi Jie He Xue Bao. 2006a;4:514–7. [PubMed]
89. Li F. H, Liu P, Xiong W. G, Xu G. F. Effects of Cordyceps polysaccharide on liver fibrosis induced by DMN in rats. Zhongguo Zhong Yao Za Zhi. 2006c;31:1968–71. [PubMed]
90. Li S. P, Su Z. R, Dong T. T, Tsim K. W. The fruiting body and its caterpillar host of Cordyceps sinensis show close resemblance in main constituents and anti-oxidation activity. Phytomedicine. 2002;9:319–24. [PubMed]
91. Li S. P, Tsim K. W. The biological and pharmacological properties of Cordyceps sinensis, a traditional Chinese medicine that has broad clinical applications. In: Herbal and Traditional Medicine. New York: Marcel Dekker; 2004. pp. 657–82.
92. Li Y, Xue W. J, Tian P. X, et al., editors. Clinical application of Cordyceps sinensis on immunosuppressive therapy in renal transplantation. Transplant Proc. 2009;41:1565–9. [PubMed]
93. Li S. P, Yang Y. Q. Dongchongxiacao. In: Pharmacological Activity-Based Quality Control of Chinese Herbs. New York: Nova Science Publisher, Inc.; 2008a. pp. 139–56.
94. Li S. P, Yang F. Q. Mixture of nucleosides with immune enhancing effect. 2008b China Patent. CP: 200810124405.0.
95. Li S. P, Yang F. Q. Mixture of nucleosides with immune suppressing effect. 2008c China Patent. CP: 200810128420.2.
96. Li S. P, Zhang G. H, Zeng Q, et al., editors. Hypoglycemic activity of polysaccharide, with antioxidation, isolated from cultured Cordyceps mycelia. Phytomedicine. 2006b;13:428–33. [PubMed]
97. Li S. P, Zhao K. J, Ji Z. N, et al., editors. A polysaccharide isolated from Cordyceps sinensis, a traditional Chinese medicine, protects PC12 cells against hydrogen peroxide-induced injury. Life Sci. 2003;73:2503–13. [PubMed]
98. Lin C. Y, Ku F. M, Kuo Y. C, et al., editors. Inhibition of activated human mesangial cell proliferation by the natural product of Cordyceps sinensis (H1-A): An implication for treatment of IgA mesangial nephropathy. J Lab Clin Med. 1999;133:55–63. [PubMed]
99. Lin W. H, Tsai M. T, Chen Y. S, et al., editors. Improvement of sperm production in subfertile boars by Cordyceps militaris supplement. Am J Chin Med. 2007;35:631–41. [PubMed]
100. Liu W. C, Chuang W. L, Tsai M. L, Hong J. H, McBride W. H, Chiang C. S. Cordyceps sinensis health supplement enhances recovery from taxol-induced leucopenia. Exp Biol Med (Maywood). 2008;233:447–55. [PMC free article] [PubMed]
101. Liu Y. K, Shen W. Inhibitive effect of Cordyceps sinensis on experimental hepatic fibrosis and its possible mechanism. World J Gastroenterol. 2003;9:529–33. [PMC free article] [PubMed]
102. Liu W. C, Wang S. C, Tsai M. L, et al., editors. Protection against radiation-induced bone marrow and intestinal injuries by Cordyceps sinensis, a Chinese herbal medicine. Radiat Res. 2006;166:900–7. [PubMed]
103. Lo H. C, Hsu T. H, Tu S. T, Lin K. C. Anti-hyperglycemic activity of natural and fermented Cordyceps sinensis in rats with diabetes induced by nicotinamide and streptozotocin. Am J Chin Med. 2006;34:819–32. [PubMed]
104. Lo H. C, Tu S. T, Lin K. C, Lin S. C. The anti-hyperglycemic activity of the fruiting body of Cordyceps in diabetic rats induced by nicotinamide and streptozotocin. Life Sci. 2004;74:2897–908. [PubMed]
105. Lou Y, Liao X, Lu Y. Cardiovascular pharmacological studies of ethanol extracts of Cordyceps mycelia and Cordyceps fermentation solution. Chin Tradit Herb Drug. 1986;17:209–13.
106. Lv X. B, Yin H. P, Li H. T, Chen X. Therapeutic effects of Cordyceps polysaccharide on freezing- kidney-induced chronic renal failure in rats. Yao Xue Jin Zhan. 2007;31:314–9.
107. Macpherson A. J, Marrinic M. M, Harris N. The functions of mucosal T-cells in containing the indigenous commensal flora of the intestine. Cell Mol Life Sci. 2002;59:2088–96. [PubMed]
108. Manabe N, Azuma Y, Sugimoto M, et al., editors. Effects of the mycelial extract of cultured Cordyceps sinensis on in vivo hepatic energy metabolism and blood flow in dietary hypoferric anaemic mice. Br J Nutr. 2000;83:197–204. [PubMed]
109. Manabe N, Sugimoto M, Azuma Y, et al., editors. Effects of the mycelial extract of cultured Cordyceps sinensis on in vivo hepatic energy metabolism in the mouse. Jpn J Pharmacol. 1996;70:85–8. [PubMed]
110. Matsuda H, Akaki J, Nakamura S, et al., editors. Apoptosis-inducing effects of sterols from the dried powder of cultured mycelium of Cordyceps sinensis. Chem Pharm Bull (Tokyo). 2009;57:411–4. [PubMed]
111. Mizuno K, Tanaka M, Nozaki S, et al., editors. Antifatigue effects of coenzyme Q10 during physical fatigue. Nutrition. 2008;24:293–9. [PubMed]
112. Nakamura K, Konoha K, Yoshikawa N, et al., editors. Effect of cordycepin (3'-deoxyadenosine) on hematogenic lung metastatic model mice. Vivo. 2005;19:137–42. [PubMed]
113. Nakamura K, Yamaguchi Y, Kagota S, Kwon Y. M, Shinozuka K, Kunitomo M. Inhibitory effect of Cordyceps sinensis on spontaneous liver metastasis of Lewis lung carcinoma and B16 melanoma cells in syngeneic mice. Jpn J Pharmacol. 1999;79:335–41. [PubMed]
114. Ng T. B, Wang H. X. Pharmacological actions of Cordyceps, a prized folk medicine. J Pharm Pharmacol. 2005;57:1509–19. [PubMed]
115. Nishizawa K, Torii K, Kawasaki A, et al., editors. Antidepressant-like effect of Cordyceps sinensis in the mouse tail suspension test. Biol Pharm Bull. 2007;30:1758–62. [PubMed]
116. Noh E. M, Kim J. S, Hur H, et al., editors. Cordycepin inhibits IL-1beta-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts. Rheumatology (Oxford). 2009;48:45–8. [PubMed]
117. Oh J. Y, Baek Y. M, Kim S. W, et al., editors. Apoptosis of human hepatocarcinoma (HepG2) and neuroblastoma (SKN-SH) cells induced by polysaccharides-peptide complexes produced by submerged mycelial culture of an entomopathogenic fungus Cordyceps sphecocephala. J Microbiol Biotechnol. 2008;18:512–9. [PubMed]
118. Oh H, Kim T, Oh G. S, et al., editors. (3R,6R)-4-methyl-6-(1-methylethyl)-3-phenylmethyl-perhydro-1, 4-oxazine-2,5-dione: An apoptosis-inducer from the fruiting bodies of Isaria japonica. Planta Med. 2002;68:345–8. [PubMed]
119. Ohmori T, Tamura K, Fukui K, et al., editors. Isolation of galactosaminoglycan moiety (CO-N) from protein-bound polysaccharide of Cordyceps ophioglossoides and its effects against murine tumors. Chem Pharm Bull (Tokyo). 1989;37:1019–22. [PubMed]
120. Ohta Y, Lee J. B, Hayashi K, Fujita A, Park D. K, Hayashi T. In vivo anti-influenza virus activity of an immunomodulatory acidicpolysaccharide isolated from Cordyceps militaris grown on germinated soybeans. J Agric Food Chem. 2007;55:10194–9. [PubMed]
121. Ostlund Jr., R. E. Phytosterols, cholesterol absorption and healthy diets. Lipids. 2007;42:41–5. [PubMed]
122. Park D. K, Choi W. S, Park P. J, et al., editors. Immunoglobulin and cytokine production from mesenteric lymph node lymphocytes is regulated by extracts of Cordyceps sinensis in C57Bl/6N mice. J Med Food. 2008;11:784–8. [PubMed]
123. Park S. E, Yoo H. S, Jin C. Y, et al., editors. Induction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militaris. Food Chem Toxicol. 2009;47(7):1667–75. [PubMed]
124. Ra Y. M, Hyun N. S, Young K. M. Antioxidative and antimutagenic activities of 70% ethanolic extracts from four fungal mycelia-fermented specialty rices. J Clin Biochem Nutr. 2008;43:118–25. [PMC free article] [PubMed]
125. Rahman I. Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol. 2003;36:95–109. [PubMed]
126. Rangel-Castilla L, Gopinath S, Robertson C. S. Management of intracranial hypertension. Neurol Clin. 2008;26:521–41. [PMC free article] [PubMed]
127. Rao Y. K, Fang S. H, Tzeng Y. M. Evaluation of the anti-inflammatory and anti-proliferation tumoral cells activities of Antrodia camporata, Cordyceps sinensis, and Cinnamomum osmophloeum bark extracts. J Ethnopharmacol. 2007;114:78–85. [PubMed]
128. Rayasam G. V, Tulasi V. K, Davis J. A, Bansal V. S. Fatty acid receptors as new therapeutic targets for diabetes. Expert Opin Ther Targets. 2007;11:661–71. [PubMed]
129. Rottenberg M. E, Masocha W, Ferella M, et al., editors. Treatment of African trypanosomiasis with cordycepin and adenosine deaminase inhibitors in a mouse model. J Infect Dis. 2005;192:1658–65. [PubMed]
130. Rukachaisirikul V, Chantaruk S, Tansakul C, et al., editors. A cyclopeptide from the insect pathogenic fungus Cordyceps sp. BCC 1788. J Nat Prod. 2006;69:305–7. [PubMed]
131. Schmidt K, Günther W, Stoyanova S, Schubert B, Li Z, Hamburger M. Militarinone A, a neu- rotrophic pyridone alkaloid from Paecilomyces militaris. Org Lett. 2002;4:197–9. [PubMed]
132. Schmidt K, Riese U, Li Z, Hamburger M. Novel tetramic acids and pyridone alkaloids, militarinones B, C, and D, from the insect pathogenic fungus Paecilomyces militaris. J NatProd. 2003;66:378–83. [PubMed]
133. Shahed A. R, Kim S. I, Shoskes D. A. Down-regulation of apoptotic and inflammatory genes by Cordyceps sinensis extract in rat kidney following ischemia/reperfusion. Transplant Proc. 2001;33:2986–7. [PubMed]
134. Shi P, Huang Z, Tan X, Chen G. Proteomic detection of changes in protein expression induced by cordycepin in human hepatocellular carcinoma BEL-7402 cells. Methods Find Exp Clin Pharmacol. 2008;30:347–53. [PubMed]
135. Siu K. M, Mak D. H, Chiu P. Y, Poon M. K, Du Y, Ko K. M. Pharmacological basis of “Yin-nourishing” and “Yang-invigorating” actions of Cordyceps, a Chinese tonifying herb. Life Sci. 2004;76:385–95. [PubMed]
136. State Pharmacopoeia Commission of PRC. Pharmacopoeia of the People’s Republic of China. Vol.1. Beijing: Chemical Industry Publishing House; 2005.
137. Sun M, Yang Y. R, Lu Y. P, et al., editors. Clinical study on application of bailing capsule after renal transplanta-tion. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004;24:808–10. [PubMed]
138. Swaminath G. Fatty acid binding receptors and their physiological role in type 2 diabetes. Arch Pharm Chem Life Sci. 2008;341:753–61. [PubMed]
139. Taylor A. L, Watson C. J, Bradley J. A. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol. 2005;56:23–46. [PubMed]
140. Thomadaki H, Tsiapalis C. M, Scorilas A. Polyadenylate polymerase modulations in human epithelioid cervix and breast cancer cell lines, treated with etoposide or cordycepin, follow cell cycle rather than apoptosis induction. Biol Chem. 2005;386:471–80. [PubMed]
141. Thomadaki H, Tsiapalis C. M, Scorilas A. The effect of the polyadenylation inhibitor cordycepin on human Molt-4 and Daudi leukaemia and lymphoma cell lines. Cancer Chemother Pharmacol. 2008;61:703–11. [PubMed]
142. Valko M, Izakovic M, Mazur M, Rhodes C. J, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. 2004;266:37–56. [PubMed]
143. Valko M, Leibfritz D, Moncol J, Cronin M. T, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39:44–84. [PubMed]
144. Wang X. B, Liu P, Tang Z. P. Intervening and therapeutic effect of Cordyceps mycelia extract on liver cirrhosis induced by dimethylnitrosamine in rats. Zhongguo Zhong Xi Yi JieHe Za Zhi. 2008;28:617–22. [PubMed]
145. Wang B. J, Won S. J, Yu Z. R, Su C. L. Free radical scavenging and apoptotic effects of Cordyceps sinensis fractionated by supercritical carbon dioxide. Food Chem Toxicol. 2005;43:543–52. [PubMed]
146. Weng S. C, Chou C. J, Lin L. C, Tsai W. J, Kuo Y. C. Immunomodulatory functions of extracts from the Chinese medicinal fungus Cordyceps cicadae. J Ethnopharmacol. 2002;83:79–85. [PubMed]
147. Wilt T, Ishani A, MacDonald R, Stark G, Mulrow C, Lau J. Beta-sitosterols for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2000;2 CD001043. [PMC free article] [PubMed]
148. Wojcikowski K, Johnson D. W, Gobë G. Medicinal herbal extracts-renal friend or foe? Part two: Herbal extracts with potential renal benefits. Nephrology (Carlton). 2004;9:400–5. [PubMed]
149. Wojcikowski K, Johnson D. W, Gobë G. Herbs or natural substances as complementary therapies for chronic kidney disease: Ideas for future studies. J Lab Clin Med. 2006;147:160–6. [PubMed]
150. Won K. J, Lee S. C, Lee C. K, et al., editors. Cordycepin attenuates neointimal formation by inhibiting reactive oxygen species-mediated responses in vascular smooth muscle cells in rats. J Pharmacol Sci. 2009;109:403–12. [PubMed]
151. Won S. Y, Park E. H. Anti-inflammatory and related pharmacological activities of cultured mycelia and fruitingbodies of Cordyceps militaris. J Ethnopharmacol. 2005;96:555–61. [PubMed]
152. Wong J. H, Wang H, Ng T. B. A hemagglutinin from the medicinal fungus Cordyceps militaris. Biosci Rep. 2009;29:321–7. [PubMed]
153. Wu W. C, Hsiao J. R, Lian Y. Y, Lin C. Y, Huang B. M. The apoptotic effect of cordycepin on human OEC-M1 oral cancer cell line. Cancer Chemother Pharmacol. 2007b;60:103–11. [PubMed]
154. Wu Y, Hu N, Pan Y, Zhou L, Zhou X. Isolation and characterization of a mannoglucan from edible Cordyceps sinensis mycelium. CarbohydrRes. 2007c;342:870–5. [PubMed]
155. Wu Y, Sun H, Qin F, Pan Y, Sun C. Effect of various extracts and a polysaccharide from the edible mycelia of Cordyceps sinensis on cellular and humoral immune response against ovalbumin in mice. PhytotherRes. 2006;20:646–52. [PubMed]
156. Wu Z. L, Wang X. X, Cheng W. Y. Inhibitory effect of Cordyceps sinensis and Cordyceps militaris on human glomerular mesangial cell proliferation induced by native LDL. Cell Biochem Funct. 2000;18:93–7. [PubMed]
157. Wu J. Y, Zhang Q. X, Leung P. H. Inhibitory effects of ethyl acetate extract of Cordyceps sinensis mycelium on various cancer cells in culture and B16 melanoma in C57BL/6 mice. Phytomedicine. 2007a;14:43–9. [PubMed]
158. Xiao J, Liang Z, Liu A, Wan W, Xiao Y, Liu J. The effect of ultrasonication on immuno- modulating activity of mycelial polysaccharide from Cordyceps gunnii. Zhong Yao Cai. 2004;27:747–50. [PubMed]
159. Xiao J. H, Zhong J. J. Secondary metabolites from Cordyceps species and their antitumor activity studies. Recent Pat Biotechnol. 2007;1:123–37. [PubMed]
160. Yamaguchi Y, Kagota S, Nakamura K, Shinozuka K, Kunitomo M. Antioxidant activity of the extracts from fruiting bodies of cultured Cordyceps sinensis. Phytother Res. 2000a;14:647–9. [PubMed]
161. Yamaguchi Y, Kagota S, Nakamura K, Shinozuka K, Kunitomo M. Inhibitory effects of water extracts from fruiting bodies of cultured Cordyceps sinensis on raised serum lipid peroxide levels and aortic cholesterol deposition in atherosclerotic mice. Phytother Res. 2000b;14:650–2. [PubMed]
162. Yamaguchi N, Yoshida J, Ren L. J, et al., editors. Augmentation of various immune reactivities of tumor-bearing hosts with extract of Cordyceps sinensis. Biotherapy. 1990;2:199–205. [PubMed]
163. Yang L. Y, Chen A, Kuo Y. C, Lin C. Y. Efficacy of a pure compound H1-A extracted from Cordyceps sinensis on autoimmune disease of MRL lpr/lpr mice. J Lab Clin Med. 1999;134:492–500. [PubMed]
164. Yang F. Q, Feng K, Zhao J, Li S. P. Analysis of sterols and fatty acids in natural and cultured Cordyceps by one-step derivatization followed with gas chromatography-mass spectrometry. J Pharm Biomed Anal. 2009;49:1172–8. [PubMed]
165. Yang L. Y, Huang W. J, Hsieh H. G, Lin C. Y. H1-A extracted from Cordyceps sinensis suppresses the proliferation of human mesangial cells and promotes apoptosis, probably by inhibiting the tyrosine phosphorylation of Bcl-2 and Bcl-XL. J Lab Clin Med. 2003;141:74–83. [PubMed]
166. Yang J, Zhang W, Shi P, Chen J, Han X, Wang Y. Effects of exopolysaccharide fraction (EPSF) from a cultivated Cordyceps sinensis fungus on c-Myc, c-Fos, and VEGF expression in B16 melanoma- bearing mice. Pathol Res Pract. 2005;201:745–50. [PubMed]
167. Yoo O, Lee D. H. Inhibition of sodium glucose cotransporter-I expressed in Xenopus laevis oocytes by 4-acetoxyscirpendiol from Cordyceps takaomantana (anamorph = Paecilomyces tenuipes). Med Mycol. 2006;44:79–85. [PubMed]
168. Yoshikawa N, Nakamura K, Yamaguchi Y, Kagota S, Shinozuka K, Kunitomo M. Antitumour activity of cordycepin in mice. Clin Exp Pharmacol Physiol. 2004;31:S51–3. [PubMed]
169. Yoshikawa N, Yamada S, Takeuchi C, et al., editors. Cordycepin (3'-deoxyadenosine) inhibits the growth of B16-BL6 mouse melanoma cells through the stimulation of adenosine A3 receptor followed by glycogen synthase kinase-3 beta activation and cyclin D1 suppression. Naunyn Schmiedebergs Arch Pharmacol. 2008;377:591–5. [PubMed]
170. Yu K. W, Kim K. M, Suh J. J. Pharmacological activities of stromata of Cordyceps scarabaecola. Phytother Res. 2003;17:244–9. [PubMed]
171. Yu R, Song L, Zhao Y, et al., editors. Isolation and biological properties of polysaccharide CPS-1 from cultured Cordyceps militaris. Fitoterapia. 2004;75:465–72. [PubMed]
172. Yu H. M, Wang B. S, Huang S. C, Duh P. D. Comparison of protective effects between cultured Cordyceps militaris and natural Cordyceps sinensis against oxidative damage. J Agric Food Chem. 2006;54:3132–8. [PubMed]
173. Yu R, Yin Y, Yang W, et al., editors. Structural elucidation and biological activity of a novel polysaccharide by alkaline extraction from cultured Cordyceps militaris. Carbohydr Polym. 2009;75:166–71.
174. Yu L, Zhao J, Zhu Q, Li S. P. Macrophage biospecific extraction and high performance liquid chromatography for hypothesis of immunological active components in Cordyceps sinensis. J Pharm Biomed Anal. 2007;44:439–43. [PubMed]
175. Zeng X. K, Tang Y, Yuan S. R. The protective effects of CS and CN80-2 against the immunological liver injury in mice. Zhongguo Yao Xue Za Zhi. 2001;36:161–4.
176. Zhang G. Q, Huang Y. D, Bian Y, Wong J. H, Ng T. B, Wang H. X. Hypoglycemic activity of the fungi Cordyceps militaris, Cordyceps sinensis, Tricholoma mongolicum, and Ompalia lapidescens in streptozotocin-induced diabetic rats. Appl Microbiol Biotechnol. 2006;72:1152–6. [PubMed]
177. Zhang W, Li J, Qiu S, Chen J, Zheng Y. Effects of the exopolysaccharide fraction (EPSF) from a cultivated Cordyceps sinensis on immunocytes of H22 tumor-bearing mice. Fitoterapia. 2008;79:168–73. [PubMed]
178. Zhang W, Yang J, Chen J, Hou Y, Han X. Immunomodulatory and antitumour effects of an exopoly- saccharide fraction from cultivated Cordyceps sinensis (Chinese caterpillar fungus) on tumour-bearing mice. Biotechnol Appl Biochem. 2005;42:9–15. [PubMed]
179. Zhao S. L. Advance of treatment for Cordyceps on chronic hepatic diseases. Shanxi Zhong Yi. 2000;16:59–60.
180. Zhao C. S, Yin W. T, Wang J. Y, et al., editors. CordyMax Cs-4 improves glucose metabolism and increases insulin sensitivity in normal rats. J Altern Complement Med. 2002;8:309–14. [PubMed]
181. Zhong X. Q. Oxygen free radicals and disease. J Shaoguan Univ Nat Sci. 2006;27:87–90.
182. Zhou X, Gong Z, Su Y, Lin J, Tang K. Cordyceps fungi: Natural products, pharmacological functions and developmental products. J Pharm Pharmacol. 2009a;61:279–91. [PubMed]
183. Zhou X, Luo L, Dressel W, et al., editors. Cordycepin is an immunoregulatory active ingredient of Cordyceps sinensis. Am J Chin Med. 2008;36:967–80. [PubMed]
184. Zhou X, Meyer C. U, Schmidtke P, Zepp F. Effect of cordycepin on interleukin-10 production of human peripheral blood mononuclear cells. Eur J Pharmacol. 2002;453:309–17. [PubMed]
185. Zhou Q, Mrowietz U, Rostami-Yazdi M. Oxidative stress in the pathogenesis of psoriasis. Free Radic Biol Med. 2009b;47(7):891–905. [PubMed]
186. Zhu J. S, Halpern G. M, Jones K. The scientific rediscovery of a precious ancient Chinese herbal regimen: Cordyceps sinensis. Part I. J Altern Complement Med. 1998;4:289–303. [PubMed]
187. Zhu J. L, Liu C. Modulating effects of extractum semen Persicae and cultivated Cordyceps hyphae on immuno-dysfunction of inpatients with posthepatitic cirrhosis. Zhongguo Zhong Xi Yi Jie He Za Zhi. 12(195):207–9. [PubMed]