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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 221-227

Cultivated cordyceps: A tale of two treasured mushrooms


1 GKT School of Medical Education, King's College London, London WC2R 2LS, UK
2 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai 201203, China
3 Renal Sciences and Integrative Chinese Medicine Laboratory, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, Weston Education Centre, King's College London, London SE5 9RJ, UK

Date of Submission16-Sep-2021
Date of Acceptance09-Dec-2021
Date of Web Publication28-Dec-2021

Correspondence Address:
Dr. Qi- He Xu
Renal Sciences and Integrative Chinese Medicine Laboratory, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, Weston Education Centre, King's College London, London SE5 9RJ
UK
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CMAC.CMAC_41_21

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  Abstract 


Ophiocordyceps sinensis and Cordyceps militaris both contain many bioactive compounds that confer potential therapeutic benefits. This review discusses the possible use of cultivated C. militaris as an effective substitute for native O. sinensis in the face of ever-increasing prices of O. sinensis because of its short supply. On the one hand, cultivated C. militaris contains higher levels of cordycepin when compared with that of wild-type O. sinensis and cultivation of C. militaris has been shown to be capable of reducing the risk of heavy metal contamination. On the other hand, there is a paucity of robust in vivo studies and randomized controlled tests comparing the pharmacology and use of C. militaris and O. sinensis. For extraction of cordycepin as western-style tablets, the use of cultivated C. militaris rather than O. sinensis represents the most appropriate future approach. For many other purposes, comparative pharmacology and clinical trials are in urgent needs.

Keywords: Cordycepin, cordyceps militaris, ophiocordyceps sinensis


How to cite this article:
Anyu AT, Zhang WH, Xu QH. Cultivated cordyceps: A tale of two treasured mushrooms. Chin Med Cult 2021;4:221-7

How to cite this URL:
Anyu AT, Zhang WH, Xu QH. Cultivated cordyceps: A tale of two treasured mushrooms. Chin Med Cult [serial online] 2021 [cited 2022 Jun 26];4:221-7. Available from: https://www.cmaconweb.org/text.asp?2021/4/4/221/334090




  Introduction Top


Dong Chong Xia Cao (冬虫夏草Cordyceps) is a genus of entomopathogenic ascomycetes, where entomopathogenic indicates that these species are parasites of insects, and ascomycetes indicate that this is a fungus that produces spores internally in sacs. The term “Cordyceps” has also been employed by the public to describe all of the commercial products that contain this fungus. Most notably, “Cordyceps” refers to Ophiocordyceps sinensis (O. sinensis), the most well-known and historically influential species, despite this fungus not falling into the Cordyceps subgenera according to a comprehensive phylogenetic analysis performed in 2007 to further categorize the Cordyceps genus into genera and subgenera through DNA sequencing.[1] In the previous studies, O. sinensis was named as Cordyceps sinensis, and the use of this term still prevails in some medical literature, for example, the latest edition of the Zhong Guo Yao Dian

(《中国药典》Chinese Pharmacopeia) published at the end of 2020.

Anti-cancer, anti-cirrhosis, disease-resisting, immunity-boosting, and life-prolonging are terms that have been associated with Cordyceps. As a medicinal mushroom that cures numerous diseases with few documented adverse effects,[2],[3] Cordyceps has unsurprisingly garnered worldwide popularity in recent years. Shortages of the naturally existent fungi have resulted in Cordyceps being commercially cultivated to meet consumer demand.


  History of Ophiocordyceps sinensis Top


Cordyceps as a health supplement has been used for many centuries. O. sinensis is a naturally existent fungus-caterpillar complex that has been used in Chinese and Tibetan traditional medicine since the 15th century.[3] O. sinensis is highly precious because it is harvested from remote locations of about 3800 m above sea level in Tibet, Qinghai, Yunnan, Sichuan, and Gansu provinces. Due to the limited quantity and high demand, O. sinensis was historically reserved for the most powerful and wealthiest people in society, such as members of the Emperor's Court in China.[4] In Tibet, this fungus was initially more known as a trade product than as a medicine. This is evident as the fungus has not been included in rGyud bzhi (《四部医典》The Four Tantras) and Shel gong shel phreng (《晶珠本草》The Crystal Rosary). The former is the fundamental treatise of Tibetan medicine dated between the 8th and the 12th century, while the latter is a highly comprehensive text devoted to Tibetan materia medica published in the 18th century.[5] Nonetheless, O. sinensis has long been included in Tibetan herbal preparations to improve energy levels and prolong lifespan. Since the 15th century, the fungus has been documented as a traditional Tibetan medicine to promote sexual virility.[5]

O. sinensis is “yartsu gambu” in Tibetan and “Dong Chong Xia Cao” in Chinese, which means “worm in the winter, herb in the summer.”[6] This expression is in reference to how the fungus infects the caterpillar in late October but only grows out of the soil and matures in summer. As is shown in [Figure 1], O. sinensis infects the underground larva of Hepialus Himalayan ghost moths and has the appearance of a silkworm. The exact mechanism that the fungus uses to plant its spores within the larvae is unknown.[3] Once inside the larvae, the fungus begins to consume the larvae and digests the inside of the larva, filling the larva with hyphae until only the exoskeleton remains. Hence, although the larva still appears intact in the caterpillar-fungus complex, its contents have already been entirely replaced by metabolites from the fungus. In spring, the fungus emerges from the fontanelle of the larva and grows out of the soil, this time with the ability to release ascospores that infect new larvae.[3] Thus, the fully mature form of O. sinensis can only be harvested from May to July.[6]
Figure 1: The life cycle of Ophiocordyceps sinensis in nature

Click here to view



  Current Usage of Ophiocordyceps sinensis Top


According to the Chinese Pharmacopeia (2020 Edition), O. sinensis is the sole legal source of Cordyceps for medicinal use. It is the main ingredient of the Bailing granule and Jinshuibao capsule sold in China. In traditional Chinese medicine (TCM) terminology, O. sinensis has the function to replenish the kidney, soothe the lung, stop blood bleeding and eliminate phlegm and is indicated for conditions with kidney deficiency, spinal and joint disorders, male sexual disorders, and respiratory diseases.[7] Consumed in its fermented or non-fermented state as a monotherapy or as part of a formulated therapy, O. sinensis is also used in clinical interventions for its immunomodulatory and apoptosis-modulating, anti-inflammatory, antioxidant, antitumor, as well as cardio-, reno-, osteo-protective and male sexual boosting effects in conventional medicine. These effects of O. sinensis have been reviewed by Xu et al.[8]

For example, Jinshuibao capsule alleviated early diabetic nephropathy when used in conjunction with angiotensin receptor blockers, according to a meta-analysis performed on 26 studies.[9] O. sinensis extracts, including Bailing granule, and O. sinensis containing herbal formulae have been reported to ameliorate acute kidney injury (AKI) induced by ischemia-reperfusion and nephrotoxic agents in animal models.[10] In randomized controlled trials, Bailing granule mitigated AKI in intensive care unit patients; Bailing granule, Jinshuibao capsule and Chongcao Shenkang capsule, an O. sinensis containing herbal formula prevented AKI induced by contrast medium, severe brain injury or epidemic hemorrhagic fever.[10] All these studies were conducted with the Chinese people as the target and with relatively small sample sizes. Thus, a larger treatment group and more diverse population samples are required to reach more definitive conclusions.

Another major area of current use of O. sinensis is oncology. The scientific evidence on the antitumor effect of O. sinensis has been previously reviewed, involving multiple mechanisms, for example, inducing apoptosis of cancer cells, promoting immune responses against cancer, and regulating signal pathways mediating cancer invasion and migration.[8]

Side effects from treatment with O. sinensis have not been documented in detail. In immature (5-week-old) and mature (10-week-old) male mice, O. sinensis extracts increased plasma testosterone levels.[11] This supports the traditional use of O. sinensis to improve male sexual function but also necessitates caution for O. sinensis use among children and females. There were two cases of lead poisoning caused by contamination of Cordyceps powder, with a high lead concentration of 20,000 ppm. However, the side effects began to cease once people stopped taking the Cordyceps powder.[12] Otherwise, adverse effects and toxicity related to O. sinensis have not been reported in humans. In a preclinical study, rabbits were fed with 10 g/kg daily of O. sinensis for 3 months and the normal blood reports and function tests of the liver and the kidney suggest that O. sinensis is a rather nontoxic medicinal mushroom.[13]

The demand for O. sinensis has increased only because of the rising affluence of middle-class Chinese households who can now afford this fungus and the media coverage in the Western world. This growing demand, combined with the scarce supply, has resulted in the extremely high prices. In 2013, the annual harvest of O. sinensis was valued at 5–11 billion USD.[14] Harvesting O. sinensis has enabled rural Tibetan people to earn three times the average annual income of the region, leading to more collectors every year.[15] In a bid to harvest as many of the fungi as possible, O. sinensis are gathered even before they are sexually mature and have reproduced. The destruction of habitats caused by overharvesting has caused a decline in the quantity of O. sinensis collected. In a survey questionnaire given to harvesters in the Tibetan Autonomous Region, it was found that 95.1% believed the availability of O. sinensis in the pastures was declining, and 67.0% felt that the harvesting practices were not sustainable.[14]

Since the early 1980s, several scientific organizations have attempted to artificially culture the species to increase the availability and affordability of O. sinensis.[6] O. sinensis has both a sexual stage (teleomorph) and an asexual stage (anamorph). Commercially attempts to develop an efficient technology for the cultivation of fruiting bodies have yet to succeed. Anamorphic mycelia produced by fermentation thus was widely used as the alternative of natural O. sinensis. Industrial cultured mycelial products of O. sinensis claimed to have similar pharmacological activities to wild O. sinensis, although the cultured mycelial samples have higher contents of polysaccharides, adenine, and adenosine but much lower mannitol when compared with natural samples.[8] In China, research on cultivation of O. sinensis has made some progressions, including in the artificial feeding and reproduction of moth larvae of the genus Hepialus, the generation and isolation of O. sinensis, and the mechanism of fungal spores to attack the moth larvae.[16] Companies such as Aloha Medicinals based in the USA have filed patents for O. sinensis cultivation methods. However, there is conflicting literature on whether these companies have successfully cultivated O. sinensis. Some difficulties encountered during large-scale production attempts, for example, the cultivation of mycelia required a significant amount of energy as they needed a fixed temperature range for the incubation phase (15–20 °C) and larval phase (10–18 °C) of the host insect. Temperatures that were too high resulted in the death of the fungus. When the temperatures were too low, slow growth was observed. Humidity and soil moisture content had to be maintained over a narrow range. Furthermore, O. sinensis requires a lengthy production phase and is prone to contamination.[17] Nonetheless, the lack of data describing the production process may also be out of the reason that no official scientific report detailing the successes and specific cultivation methods has been published by any companies for fear that other institutions will capitalize on this lucrative industry.[6]


  Advantages of Cultivated Cordyceps militaris as an Alternative Top


The economic production value and high content of bioactive compounds of Cordyceps militaris (C. militaris) make it the highest-selling cultivated species of Cordyceps, with an estimated annual revenue of 3 billion USD in China.[18] C. militaris is commercially cultivated because this fungus has a shorter life cycle than O. sinensis, and the production costs are relatively less expensive. Unlike O. sinensis, there is no well-documented history recording the use of C. militaris as herbal medicine because it is comparatively scarcer in the wild than that of O. sinensis. While O. sinensis takes 1–2 years to fulfill its life cycle, C. militaris takes only 4–6 weeks as it does not require a host insect because it fruits readily in culture. Furthermore, the humidity and oxygen levels do not need to be controlled as strictly as the cultivated O. sinensis, making the production of this fungus economical. There are at least 36 approved supplements on the market made from C. militaris. This fungus can be consumed directly in its mushroom stage, in capsule form or as a mycelia powder, with all three forms approved by the Ministry of Health in China.[19] Official certification and improved availability of these products on the market should protect consumers from purchasing counterfeit and contaminated C. militaris products.

In contrast, counterfeit O. sinensis and related products remain a problem. To address this issue, a duplex polymerase chain reaction (PCR) method has recently been devised that uses primer pairs specific to naturally existent O. sinensis to successfully distinguish this fungus from artificial mimics and other Cordyceps species, including C. militaris and even its pure fermented mycelial form, which lacks the host species.[20] As this duplex PCR method can be quickly and inexpensively replicated in any molecular biology laboratory, authentication and certification by health authorities of O. sinensis should improve, which will quell the fear consumers have about unwittingly purchasing counterfeit O. sinensis products.

The richness of bioactive compounds in C. militaris and the associated pharmacological effects are substantial. For example, C. militaris was found to have an even higher cordycepin concentration than O. sinensis.[18],[21] Cordycepin is a type of nucleoside, 3-deoxyadenosine, with a wide array of properties, such as anti-tumor activity [Table 1].[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37] As shown in [Figure 2], cordycepin has a similar structure to adenosine and thus functions as a nucleoside analog. This structural semblance enables cordycepin to be incorporated into DNA and RNA during the synthesis of nucleic acids instead of adenosine. However, the missing 3' hydroxyl group, which is present in adenosine, leads to premature transcription termination when cordycepin is added to the growing RNA chain because further bases cannot be added to the RNA chain.[38] This incorporation of cordycepin into nucleic acids can be helpful in cancer therapy, as it can stop the proliferation of tumor cells by terminating the cell cycle. In 1961, it was first shown that administering cordycepin over 7 days increased the survival time of mice with Ehrlich ascites carcinoma.[39]
Table 1: Summary of the anti-tumor effects of cordycepin

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Figure 2: Chemical structures of bioactive compounds cordycepin (isolated from Cordyceps militaris) and adenosine

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Cordycepin also demonstrates anti-tumor properties by causing tumor apoptosis via caspase-dependent pathways. This anti-tumor activity has been shown to be effective for human liver cancer cells (HepG2), human bladder carcinoma cells (T24 cells), human breast cancer cells (MCF-7 and MDA-MB-231), human renal cancer cells, and human non-small cell lung cancer.[40] Hence, the consumption of C. militaris should have a more potent anti-tumor effect than O. sinensis when administered at the same dose level.

In addition, the C. militaris protein (CMP), a cytotoxic antifungal protease, was identified in C. militaris. CMP was found to be effective against the fungus Fusarium oxysporum in vitro. Furthermore, CMP was cytotoxic against pure isolated human breast cancer MCF-7 and bladder cancer (5637) cell lines. These functions of CMP suggest that C. militaris might be an anti-fungal agent and could be used to treat cancer.[41] However, the experiment was not carried out in vivo and thus, potential interactions with other cells and substances within the body may affect CMP activity. In addition, CMP functions optimally at 37 °C and pH 7.0–9.0. Operating under nonoptimal conditions probably reduces the activity of CMP.

The anti-inflammatory activity of Cordyceps is also of interest. In lipopolysaccharides (LPS)-induced RAW264.7 cells, a C. militaris extract-mediated nano-emulsion exerted inhibitory effects on nitric oxide production and downregulated proinflammatory gene expression.[42] The biological activity of C. militaris was attributed to the saccharide and nucleoside contents. Chiu et al. isolated cerebrosides and nucleosides from the C. militaris extract and demonstrated the anti-inflammatory activity in vitro.[43] C. militaris contains β-(1R3)-D-glucan, an anti-inflammatory compound, which induces immune response by binding pattern recognition receptors (PRR) of cells similar to what pathogen-like molecules do and activating immune cells such as macrophages and dendritic cells. In an experiment, β-glucans were extracted from C. militaris and given to mice with peritonitis induced by LPS. The β-glucans inhibited the effects of IL-1β, TNF-α and COX-2 in a macrophage cell line in vitro, with β-(1R3)-D-glucan being the most potent. Furthermore, localized inflammatory pain both from peritonitis and induced by local tissue damage through injecting formalin into the paws of mice was reduced by β-glucans, suggesting that β-glucans from C. militaris could be used as a potential non-steroidal anti-inflammatory drug.[44] However, no consensus has been reached on what moiety of β-glucans binds to PRR, and the anti-inflammatory mechanism remains poorly understood. Additionally, although β-glucans found in C. militaris may demonstrate these effects, this does not guarantee that C. militaris would exert the same effects because of possible interactions with other substances.

There is no study that has demonstrated the anti-inflammatory effects of C. militaris in humans. A topical anti-inflammatory effect on mice with crouton-oil-induced ear edema has been examined. In this experiment, the mice had crouton oil injected into both ears. Acetonic solutions containing cultivated mycelia or fruiting bodies of C. militaris were applied to the right ear, whereas the left ear was left untreated. The difference in weight between the right and left ears was 51.8% for the cultivated mycelia and 58.7% for the fruiting bodies, thereby showing a strong inhibitory activity of edema and possibly inflammation.[45] In another study, the potential anti-inflammatory effect of an extract of C. militaris grown on germinated Rhynchosia nulubilis (GRC) fermented with Pediococcus pentosaceus ON89A (GRC-ON89A) was demonstrated in a mouse model of 1-fluoro-2,4-dinitrofluorobenzene-induced allergic contact dermatitis, in which GRC-ON89A reduced ear swelling and thickness.[46]

Cultivated C. militaris may be produced following good agricultural and manufacture practices, thus may be better positioned to avoid heavy metal poisoning, which can be hard to avoid from harvested native O. sinensis. In 2008, 13 out of 14 batches of native O. sinensis contained levels of arsenic, lead, mercury, cadmium, and copper that exceeded the green industry standard for medicinal plants, thereby posing a threat to humans if ingested. Under artificial cultivation, heavy metals can be monitored and kept at safe levels, hence avoiding poisoning.[47] However, mineral medicines containing mercury and arsenic, for example, An Gong Niu Huang Pill (安宫牛黄丸), is sometimes purposely added to preexisting formulations in TCM because of their sedative effects and they have been proven to have neuroprotective properties against cerebral ischemia-reperfusion injury with no hepatotoxic or nephrotoxic effects when administered over 7 days.[48]


  Disadvantages of Cordyceps militaris as an Alternative Top


Native O. sinensis was found to have an inosine level higher than that of cultured C. militaris and O. sinensis. Inosine stimulates the growth of axons in vitro and the adult central nervous system.[49] Thus, native O. sinensis is a better source when using inosine as a marker of quality. Furthermore, for nerve damage treatment, native O. sinensis may represent the best option. In ddition, the level of D-mannitol, previously known as cordycepic acid before its identification in other species, was higher in native O. sinensis when compared with the levels in C. militaris. D-mannitol exhibits diuretic, cough relieving and anti-free radical activities. However, D-mannitol is found significantly higher in concentrations in fruits such as cranberries. Consequently, Cordyceps are not the best source of this compound.[50] Furthermore, consumers may be doubtful about whether cultivated and wild-type Cordyceps have uniform medical applications. A comparison of wild-type and cultivated O. sinensis indicated that the metabolites and protein compositions were similar, but the caterpillar bodies differed from the stromata. Proteomic results also showed that artificial cultivation influenced the metabolism and amino acid synthesis pathways. The levels of four amino acids, lysine, threonine, serine and arginine, differed between wild-type and cultivated O. sinensis.[51] A study to identify a rapid and precise peptide marker to distinguish between native and cultivated O. sinensis through chemometrics and mass spectrometry found that native O. sinensis fruiting body, fermented O. sinensis mycelia powder and cultivated O. sinensis mycelia powder all had different marker peptides.[52] Hence, although the chemical components may be broadly similar, their pharmacological activities may vary because of differences in various peptides and cellular pathways. C. militaris has been artificially cultivated, but the development of the cultivation industry is slow, with the degradation of the fungus being the primary problem limiting the development of this industry. In addition, the unique climatic conditions of Xinjiang lead to unstable yields of fruiting bodies. The lack of effective scientific guidance can also lead to significant economic losses.


  Conclusions Top


There is the evidence that novel compounds in cultivated Cordyceps can be used as potential medicinal or health products. These active compounds that may have therapeutic properties still require rigorous pharmacological and chemical testing and safety assessment through placebo-controlled trials. Furthermore, the pharmacological activities of cultivated Cordyceps have also not been compared in detail with their native species. Thus, it is difficult to confirm the therapeutic benefits of cultivated Cordyceps. Cultivation of Cordyceps should meet the current demand of this desirable resource, thereby ensuring a more sustainable harvesting practice and less environmental damage. However, the lack of quality control may be detrimental. Thus, a synchronized effort between the cultivated Cordyceps industry and scientific research communities is needed to future-proof this important industry.

Finally, although this paper primarily focuses on O. sinensis and C. militaris, other members of the megagenus Cordyceps may also have important roles to play in replacing O. sinensis in certain clinical applications. For example, in a recent report from China, ethyl acetate fractions of O. xuefengensis and O. sinensis both have in vitro anticancer activity. Eighty-two and 101 compounds were identified from the O. xuefengensis and O. sinensis extracts, respectively. Among these compounds, 68 existed in both O. xuefengensis and O. sinensis.[53] Thus, in addition to cultured C. militaris and mycelial products of O. sinensis, native and cultivated O. xuefengensis may also have its role to play in substituting O. sinensis in Cordyceps-based therapeutics.

Funding

None.

Ethical approval

This article does not contain any studies with human or animal subjects performed by either of the authors.

Author contributions

Anawinla Ta Anyu conceptualized this project, conducted initial literature retrieval and analysis, and wrote the first draft. Wen-Hui Zhang led the revision to the first draft, including amendments to the figures, as well as added more contents to the manuscript. Qi-He Xu supervised the whole process of this project and led the revision process before and after peer review. All authors agreed to the contents of the whole manuscript.

Conflict of interest



 
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