Cordyceps

Cordyceps sinensis
(from Medicinal Mushrooms – A Clinical Guide by Martin Powell)

Japanese name – Tochukas
Chinese name – Dong Chong Xia Cao
English name – Caterpillar fungus

Cordyceps is unique among the medicinal mushrooms in growing on an insect host rather than a plant host. To date over 700 species of Cordyceps have been identified worldwide. In most cases they grow parasitically on their insect hosts. However, it appears likely that in some cases a symbiotic relationship exists whereby the insect host derives a selective advantage from the fungal anamorph (the fungus growing in a single cell form), giving them a competitive advantage, especially in marginal environments where energy efficiency is at a premium, such as the high Tibetan plateau above 3,000m where the main species used traditionally, Cordyceps sinensis, occurs naturally 1.

Although traditionally harvested cordyceps is still available, the vast majority of cordyceps on the market today is cultivated on non-insect, grain-based substrates leading to improved quality control and affordability. Despite the commercially cultivated cordyceps being grown on a different substrate from the wild collected Cordyceps, HPLC analysis of both shows identical chemical profiles and the two are seen to be interchangeable clinically2.

As well as polysaccharides and lipids, Cordyceps species contain a large number of nucleoside analogues, prominent among which is cordycepin, 3-deoxyadenosine3. This molecule differs from adenosine in the absence of oxygen at the 3 position of its ribose part. Because it is similar to adenosine some enzymes cannot distinguish between the two and so it is able to participate in certain biochemical reactions, including RNA/DNA synthesis where its incorporation leads to the termination of the RNA molecule as there is no oxygen at the 3 position to bond with the next nucleotide4-7.

This ability to interrupt RNA synthesis has led to the use of such nucleoside analogues, termed reverse transcriptase inhibitors, in the treatment of viral infections, including HIV and Hepatitis, as well as cancer, under pharmaceutical names including AZT (Retrovir), Videx and Epivir. In normal healthy cells such reverse transcriptase inhibitors are out competed by the corresponding nucleoside but in rapidly dividing cancer cells and virally infected cells they are able to exert effective inhibition of replication.

Adenosine in the form of adenosine monophosphate and adenosine triphosphate also plays a central role in energy metabolism and cyclic nucleotides including cAMP play an important role in signal transduction and regulating hormone production, activities which correlate well with the observed activity of Cordyceps in these areas.

Anti-aging – C. sinensis has traditionally been used as a supplement for the elderly and those recovering from long illness and studies with the cordyceps Cs-4 strain in healthy elderly subjects showed significant increases in oxygen uptake, aerobic capacity and resistance to fatigue.

Experimental evidence based on polysaccharide extracts indicate that C. sinensis is also able to improve brain function and antioxidative enzyme activity (superoxide dismutase, glutathione peroxidase and catalase), which, together with its beneficial effect on cardiovascular function, make it an ideal supplement for the elderly8. Athletic performance – The use of C. sinensis, together with other supplements, by the record breaking Chinese athletes of the early 1990’s has attracted considerable interest in its potential to enhance athletic performance.

A 1996 study on long distance runners reported a significant improvement in 71% of participants and both C. sinensis and a closely related species, C. militaris, have been shown to increase endurance in animal models. Studies on sedentary humans also show a significant increase in energy output and oxygen capacity 9-12.

However, three subsequent human studies have failed to demonstrate any effect on performance in competitive cyclists or other professional athletes and it has been suggested that this may be because such athletes are already operating at or close to their maximum aerobic capacity 13,14. Sexual function – C. sinensis produces clear benefits for male sexual hypofunction when taken over a period of time. Anecdotal evidence and reports from China also indicate possible benefits for female libido.

Based on animal studies C. sinensis and related species have a clear effect on increasing levels of male sex hormones, improving testes morphology, sperm quantity and quality. In-vitro research indicates that Cordyceps affects the signal transduction pathway of steroidogenesis after the formation of cAMP 15-19.

Fertility – C.sinensis is increasingly being used by leading specialists in the field of infertility and clinical evidence suggests that cordyceps has a beneficial impact on female fertility and the success of IVF. In part this may be due to its ability to stimulate 17β-estradiol (oestrogen) production, through increased StAR (steroidogenic acute regulatory protein) and aromatase expression20. In common with other mushrooms, cordyceps’ ability to regulate immune function and in particular NK cell activity may also play a part.

The ability of C. sinensis to increase oestrogen production also has potential for the management of postmenopausal osteoporosis21.

Diabetes - Experimental evidence indicates that C.sinensis is able to:
    Trigger Release of Insulin Increase Hepatic Glucokinase Increase Sensitivity of Cells to Insulin

In one randomized trial 95% of patients treated with 3g/day C. sinensis biomass saw improvements in their blood sugar profile compared with 54% treated by other methods. In addition it has been reported that consumption of 4.5g/day C.sinensis biomass by patients with alcohol induced diabetes also produced a reduced desire for alcohol 2,22-25.

Recent evidence indicates that cordycepin and related nucleoside derivatives play an active role in the anti-diabetic action of C. sinensis26.

Hepatoprotective – Animal studies have shown the ability of C. sinensis to inhibit hepatic fibrosis and help restore liver function. One clinical study using 3g/day C. sinensis biomass to treat alcohol-induced liver steatosis in 14 patients showed reductions of 70% in AST levels, 63% in ALT levels and 64% in GGT levels over a 90 day period 27,28.

Kidney Protective – C. sinensis has traditionally been considered to possess the ability to support the kidneys and 3.5g/day has been shown to both improve kidney function in patients with chronic renal failure and speed recovery in patients with gentamycin induced kidney damage2.

Respiratory Disease
– C. sinensis has traditionally been used to treat respiratory ailments and is reported to be beneficial clinically, especially for asthma and COPD2.

Anti-viral – As mentioned above, the nucleoside analogues present in cordyceps species are able to inhibit viral replication. At the same time the polysaccharides in cordyceps modulate the immune response to viral infections. This combination of enhanced immune response and interrupted viral replication make cordyceps one of the most effective mushrooms for tackling chronic viral infections 5,6.

Anti-cancer - C. sinensis also shows promise for cancer treatment and a growing body of in-vitro evidence supports the ability of the nucleoside derivatives, particularly cordycepin, to induce apoptosis, inhibit nuclear factor kappaB (NF-κB) and activator protein-1 (AP-1) production and increase levels of Th1 promoting cytokines 29-33.

CLINICAL SUMMARY

Main Therapeutic Applications – Fertility and sexual function, Energy, Diabetes, Lung Function, Kidney Support, Liver Disorders
Key Component – Nucleoside derivatives
Dose – Cordyceps’ unique properties are principally those of its nucleoside derivatives and as these are largely excreted (research on C. militaris shows that 98% of cordycepin is secreted into the growth medium34) biomass products offer the natural dosage format for Cordyceps. 3-6g/day biomass is used in most cases while doses of up to 50g/day Cordyceps biomass have been reported to give good results in a range of cancers2.
The finding that other species of Cordyceps produce higher levels of nucleoside derivatives than C. sinensis has also led to the development of hybrid strains and the use of growing conditions that replicate those in the natural environment in order to maximise their production 35,36.

Caution – Hormone dependent cancers (prostate and breast) due to increased levels of oestrogen and testosterone. C. sinensis’ hypoglycemic properties indicate desirability of glucose monitoring in patients using insulin.

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3. Analysis of the main nucleosides in Cordyceps sinensis by LC/ESI-MS. Xie J.W, Huang L.F, Hu W, He Y.B, Wong K.P. Molecules. 2010;15(1):305-14.
4. Some biologically active substances from a mycelial biomass of medicinal ‘Caterpillar fungus’ Cordyceps sinensis (Berk.) Sacc. (Ascomycetes). Smirnov D.A, Babitskaya V.G, Puchkova T.A, Shcherba V.V, Bisko N.A, Poyedinok N.L. Int J Med Mushr. 2009;11(1):80
5. Effect of Cordycepin Triphosphate on in vitro RNA synthesis by plant viral replicases. White J.L, Dawson W.O. J Virol. 1979;29(2):811-814.
6. Cordycepin interferes with 3′ end formation in yeast independently of its potential to terminate RNA chain elongation. RNA. 2009;15(5):837-49.
7. Cordycepin inhibits (collagen induced) human platelet platelet aggregation in a cAMP- and cGMP-dependent manner. Eur J Pharmacol. 2007;558:43-51.
8. Antiaging effect of Cordyceps sinensis extract. Ji D.B, Ye J, Li C.L, Wang Y.H, Zhao J, Cai S.Q. Phytother Res. 2009;23(1):116-22.
9. Increased aerobic capacity in healthy elderly humans given a fermentation product of Cordyceps CS-4. Xiao, Y.; Huang, X. Z.; Chen, G.; Wang, M. B.; Zhu, J. S.; Cooper, C. B. FACSM Medicine & Science in Sports & Exercise: May 1999 – Volume 31 – Issue 5 – p S174
10. Randomized double-blind placebo-controlled clinical trial and assessment of fermentation product of Cordyceps sinensis (Cs-4) in enhancing aerobic capacity and respiratory function of the healthy elderly volunteers. Xiao Y, Huang X.Z and Zhu J.S. Chinese Journal of Integrative Medicine. 2004;10,3:187-192
11. Effect of medicinal plant extracts on forced swimming capacity in mice. Jung K, Kim IH, Han D. J Ethnopharmacol. 2004 Jul;93(1):75-81.
12. CordyMax enhances aerobic capability, endurance performance, and exercise metabolism in healthy, mid-age to elderly sedentary humans. JS Zhu, JM Rippe – Gerontology, 2001
13. Cordyceps Sinensis Supplementation Does Not Improve Endurance Performance in Competitive Cyclists. Parcell A.C, Smith J.M, Schulthies S.S, Myrer J.W, Fellingham G. Medicine & Science in Sports & Exercise: 2002;34(5):231
14. Does Cordyceps sinensis Ingestion Aid Athletic Performance? TB Walker. Strength and Conditioning Journal, 2006
15. Effect of Cordyceps militaris supplementation on sperm production, sperm motility and hormones in Sprague-Dawley rats. Am J Chin Med. 2008;36(5):849-59.
16. In vivo and in vitro stimulatory effects of Cordyceps sinensis on testosterone production in mouse Leydig cells. Life Sci. 2003 Sep 5;73(16):2127-36.
17. Influence of Cordyceps Sinensis on Reproduction and Testis Morphology in Mice. Shenzhen Journal of Integrated Chinese and Western Medicine. 2005-6
18. Improvement of sperm production in subfertile boars by Cordyceps militaris supplement. Am J Chin Med. 2007;35(4):631-41.
19. Estrogenic Substances from the Mycelia of Medicinal Fungus Cordyceps ophioglossoides (Ehrh.) Fr. (Ascomycetes). Hirokazu Kawagishi, Kentaro Okamura, Fumio Kobayashi, Noriko Kinjo. IntJMedMushr.v6.i3.40 2004
20. Upregulation of Steroidogenic Enzymes and Ovarian 17β-Estradiol in Human Granulosa-Lutein Cells by Cordyceps sinensis Mycelium. Biology of Reproduction May 1, 2004 vol. 70 no. 5 1358-1364
21. The Co-effect of Cordyceps sinensis and Strontium on Osteoporosis in Ovariectomized Osteopenic Rats. Qi W, Yan YB, Wang PJ, Lei W. Biol Trace Elem Res. 2010 May 5.
22. Hypoglycemic Activity of a Polysaccharide (CS-F30) from the Cultural Mycelium of Cordyceps sinensis and Its Effect on Glucose Metabolism in Mouse Liver. Kiho T, et al. Biol Pharm Bull. Feb1996;19(2):294-96.
23. Structural Features and Hypoglycemic Activity of a Polysaccharide (CS-F10) from the Cultured Mycelium of Cordyceps sinensis. Kiho T, Ookubo K, Usui S, et al. Biol Pharm Bull. Sep1999;22(9):966-70.
24. Anti-hyperglycemic activity of natural and fermented in rats with diabetes induced by nicotinamide and streptozotocin. Lo HC, Hsu TH, Tu ST, Lin KC. Am J Chin Med. 2006;34(5):819-32.
25. Hypoglycemic activity of polysaccharide, with antioxidation, isolated from cultured Cordyceps mycelia. Li SP, Zhang GH, Zeng Q, Huang ZG, Wang YT, Dong TT, Tsim KW. Phytomedicine. 2006 Jun;13(6):428-33.
26. Cordycepin Suppresses Expression of Diabetes Regulating Genes by Inhibition of Lipopolysaccharide-induced Inflammation in Macrophages. Shin S, Lee S, Kwon J, Moon S, Lee S, Lee CK, Cho K, Ha NJ, Kim K. Immune Netw. 2009 Jun;9(3):98-105.
27. Inhibitive Effect of Cordyceps sinensis on Experimental Hepatic Fibrosis and its Possible Mechanism- Liu YK, Shen W. Department of Gastrointerology, the Second Affiliated Hosptial, Chongqing University of Medicial Sciences, Chongqing 400010, Chinga World J Gastroenterol. 2003. 2003 Mar;9(3):529-33.
28. Dynamical Influence of Cordyceps sinensis on the Activity of Hepatic Insulinase of Experiemental Liver Cirrhosis-Zhang X, Liu YK, Shen W, Shen DM. Hepatobiliary Pancreat Dis Int. 2004 Beb;3(1):99-101.
29. RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells. Chen LS, Stellrecht CM, Gandhi V. Br J Haematol. 2008 Mar;140(6):682-391. 30. Antitumor activity of Cordycepin in mice. Clin Exp Pharmacol Physiol. 31, S51-S53. 2004
30. Cordycepin inhibits protein synthesis and cell adhesion through effects on signal transduction. J Biol Chem. 2010 Jan 22;285(4):2610-21.
31. Effect of cordycepin on interleukin-10 production of human peripheral blood mononuclear cells. European Journal of Pharmacology, volume 453, Issues 2-3, 25 October 2002, Pages 309-317
32. Cordycepin suppresses TNF-alpha-induced invasion, migration and matrix metalloproteinase-9 expression in human bladder cancer cells. Lee EJ, Kim WJ, Moon SK. Phytother Res. 2010 Jun 17.
33. Role of Cordycepin and Adenosine on the Phenotypic Switch of Macrophages via Induced Anti-inflammatory Cytokines. Shin S, Moon S, Park Y, Kwon J, Lee S, Lee CK, Cho K, Ha NJ, Kim K.Immune Netw. 2009 Dec;9(6):255-64.
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36. Determination of nucleosides and nucleobases in different species of Cordyceps by capillary electrophoresis-mass spectrometry. Yang FQ, Ge L, Yong JW, Tan SN, Li SP. J Pharm Biomed Anal. 2009 Oct 15;50(3):307-14.

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