Introduction
Chinese caterpillar fungus Ophiocordyceps sinensis (Berk.) is a well-known entomopathogenic fungus with high medicinal values.1 In China, it is colloquially known as Dong Chong Xia Cao, derived from the Tibetan name དབྱར་རྩྭ་དགུན་འབུ (Yartsa Gunbu), meaning “summer grass, winter worm”. The fungus is endemic to the Tibetan Plateau and its surroundings, including Tibet, Qinghai, Sichuan, and Yunnan provinces in China, as well as the Himalayas, such as Bhutan, India, and Nepal.2O. sinensis is an aggregation of larvae and parasitic fungi associated with lepidopteran hosts. More than 400 species of Ophiocordyceps spp. exist worldwide, and approximately 90 species of Ophiocordyceps spp. have been recorded in China.3,4 The most commonly used and extensively investigated species are O. sinensis and Cordyceps militaris (orange caterpillar fungus),5,6 with O. sinensis being more commonly used as a medicinal product. O. sinensis has been used as a traditional medicine in China for over 700 years.7 As a renowned traditional Chinese medicine, it has long been known to boost the human immune system. O. sinensis enhances the immune response by increasing the production of interleukin (IL) and tumor necrosis factor, inducing macrophage phagocytosis, and stimulating the inflammatory response through the mitogen-activated protein kinase pathway, playing a role in regulating the immune response and helping to resist bacterial infections.3 In addition, modern pharmacological research has revealed its therapeutic effects on various diseases and conditions, including respiratory, renal, liver, nervous system, and cardiovascular diseases.8 It has also shown potential as an anti-tumor, cholesterol-reducing, and antioxidant agent.9,10 The pharmacological effects are attributed to the active ingredients in O. sinensis.11 The chemical components of O. sinensis include polysaccharides, nucleosides, amino acids, sterols, alkaloids, and other nutrients and bioactive ingredients.12 It has been reported that changes in growth conditions and environmental factors may alter the composition of these components, leading to differences in their pharmacological effects.
O. sinensis has a restricted geographical distribution, with a preference for high altitudes. The long-term interaction between the fungus and the larvae has resulted in the complex composition of O. sinensis.13 Furthermore, the precious pharmacological effects of wild O. sinensis have led to increasing market demand and over-exploitation, which has severely endangered its wild population and jeopardized its sustainability. Therefore, artificially cultivated O. sinensis has been gradually developed as an alternative.14 Various methods have been introduced to understand the biological characteristics of natural and cultivated O. sinensis through component comparisons, including mass spectrometry-based metabolomics, transcriptomics, surface-enhanced Raman spectroscopy combined with machine learning algorithms, proteomics, and others.15–17 These methods have facilitated extensive research on the similarities and differences in pharmacologically active ingredients and functions between natural and cultivated O. sinensis, promoting the market application of the latter in artificial cultivation.18
In conclusion, a deeper understanding of the differences in the content of active ingredients between cultivated and wild O. sinensis is essential for clarifying its growth, development, and pharmacological activity. This review summarizes and explains in detail the differences in bioactive components and medicinal functions between natural and cultivated O. sinensis, aiming to facilitate the understanding of the alternative value of cultivated O. sinensis as a substitute for natural O. sinensis.
Research progress on natural and cultivated O. sinensis
The fungus O. sinensis has been regarded as a highly valuable traditional Chinese medicine for centuries, as documented in numerous ancient texts. According to reports, this distinctive and precious fungus is predominantly found in alpine meadows situated at elevations ranging from 3,000 to 5,000 meters across the Qinghai-Tibetan Plateau in southwest China, as well as in the Himalayas of Bhutan and Nepal.7 These regions experience extremely low temperatures and significant fluctuations between day and night, creating particularly challenging conditions.19 Additionally, O. sinensis fungus is a fascinating organism that grows parasitically on the larvae of specific ghost moth species, Thitarodes spp. This entomopathogenic fungus continues multiplying within the larvae until the entire worm is digested and filled with fungal hyphae.6 When the nutrition in the infected larvae is exhausted, the worm dies during winter but remains intact and is known as a “winter worm”. In the following year, as the weather warms during late spring and early summer, the fruiting body of O. sinensis grows out from the head of the dead worm, resembling the appearance of summer grass.20Figure 1 illustrates the distinct steps involved in the formation of the Chinese caterpillar fungus. O. sinensis comprises two parts: the fruiting body and the dead larva. The fruiting body is the part above the head of the insect that grows out of the body of the larva parasitized by the fungus, while the dead larva is the body of the insect larva that died after being parasitized. There are clear and visible rings on the surface of the larva’s body, as well as eight pairs of feet under the abdomen of the dead larva. Terrain, climate, soil, and other factors restrict the distribution and formation of O. sinensis, which is why its availability is limited. Its reliance on specific moth species as hosts, as well as its long growth cycle and restricted geographical range, contribute to this scarcity.
The unique bioactive metabolites and components with medicinal values in natural O. sinensis have undoubtedly increased its demand in the commercial market, leading to its high price and overharvesting. Research has shown that techniques have been developed to cultivate and feiment O. sinensis mycelium products, such as the cultivation of asexual mycelium from O. sinensis harvested in nature, the asexual reproduction of O. sinensis, and the growth of mycelium in culture media.21,22 Currently, the culture medium temperature is maintained at 16–25°C, and large-scale cultivation takes only about 30 days to obtain Cordyceps militaris.23,24 Significant progress has also been made in isolating the fungus and rearing the cultured larvae. The isolated spores are injected into the parasitic larvae, enabling large-scale cultivation of artificially cultivated Cordyceps sinensis under controlled conditions. The fungi have been identified as O. sinensis and Hepialus xiaojinensis Y.Q.25 It is worth noting that the fungus can be isolated from various tissues and organs at different developmental stages of O. sinensis, such as fruiting bodies, dead caterpillars, living larvae, and ascospores.21 Although natural and cultivated O. sinensis are similar in appearance, the composition and content of cultivated O. sinensis may differ from those of natural O. sinensis due to the lack of multiple environmental factors. This discrepancy may lead to a preference for natural O. sinensis in terms of medicinal value and health functions. Additionally, consumers are concerned about whether cultivated and natural O. sinensis have the same medicinal effects. Therefore, a comprehensive understanding of the pharmacological components and functional similarities and differences between natural and cultivated O. sinensis is essential, providing a theoretical basis for using cultivated O. sinensis as a reliable Chinese medicinal.
Composition of natural and cultivated Ophiocordyceps sinensis
Natural and cultivated O. sinensis have a unique combination of metabolites, including polysaccharides, nucleosides, sterols, alkaloids, and amino acids. In addition, they also contain a variety of minerals, vitamins, and other nutrients (Fig. 2).26 Comparison of natural O. sinensis with cultivated O. sinensis showed that the metabolite compositions of these two are similar.27 Similarly, the Nuclear Magnetic Resonance (NMR) fingerprint of natural O. sinensis is consistent with that of cultivated O. sinensis.27 However, there are still some differences in the content of certain ingredients. For example, during the cultivation process, carbon sources are usually added as nutrients, so the carbohydrate content in natural O. sinensis is slightly lower than that in cultivated O. sinensis.28 In addition, the nucleoside content in natural O. sinensis is increased to cope with the harsh growth environment, as the accumulation of nucleosides is essential for enhancing the stress resistance of plants during growth.29 Therefore, we summarized the similarities and differences in the contents of active compounds in natural and cultivated O. sinensis, providing a basis for determining whether cultivated O. sinensis can be used as an alternative.
Carbohydrates
The carbohydrates in O. sinensis consist of free saccharides, polymerized saccharides, sugar alcohols, and sugar acids, which are important compounds with multiple pharmacological activities.30 Polysaccharides are a group of essential ingredients with biological activities in O. sinensis,13,31 and the content of polysaccharides is approximately 3–8% of the total weight.32 Polysaccharides might be used as markers for the quality evaluation of O. sinensis. Previous studies have shown that the polysaccharides in O. sinensis exhibit antioxidant, anti-cancer, immune-enhancing, and liver-protective biological activities.33–36 At the same time, structural studies show a close relationship between the structure of O. sinensis polysaccharides and their pharmacological activities.37 Currently, polysaccharides with different molecular weights have been discovered in O. sinensis. However, due to the structural diversity and complexity of polysaccharide molecules, variations in monosaccharide composition, molecular weight, and configuration may be key factors affecting their pharmacological activities.
The carbohydrate compounds in natural Cordyceps are mainly α-1,4, α-1,3, and α-1,6 linked glucans, with small amounts of galactose, arabinose, mannose, and galacturonic acid. The structural composition of carbohydrate compounds is complex, and different monosaccharide compositions, glycosidic bond connection methods, and the presence of straight chains and branches may result in different biological activities.
In recent years, studies have extracted four types of polysaccharides from both natural O. sinensis and artificially cultivated O. sinensis, indicating that the main chain of polysaccharides in natural O. sinensis is composed mainly of α-1,4, α-1,3, and α-1,6 linked glucans, with small amounts of galactose, arabinose, mannose, and galacturonic acid.38 In contrast, the polysaccharide structure in cultivated O. sinensis is very complex, mainly composed of glucose, galactose, and mannose, with 1,4-glucose and 1,4-galactose as the main chains, and the average molecular weight is much lower than that of natural cordyceps.39 Studies have shown that mannitol has a content more than twice that of natural O. sinensis compared to cultivated O. sinensis.40 In addition, studies have demonstrated that the content of trehalose is higher in natural O. sinensis, while the content of D-arabitol, D-xylitol, D-xylose, gluconic acid, and 6-phosphogluconic acid is higher in cultivated O. sinensis.15
In general, O. sinensis polysaccharides can be divided into two types based on their location: intracellular polysaccharides (IPSs) and extracellular polysaccharides (EPSs). IPSs are mainly extracted from the fruiting bodies (or worms) and mycelium by heating.41 To extract EPS, they are obtained by concentration followed by ethanol precipitation.31 Previous research on the polysaccharide structure in O. sinensis found that IPSs in O. sinensis are usually composed of glucose, mannose, and galactose with 1-4(6)-glucopyranosyl, 1-6-mannopyranosyl, and 1-4(6)-galactopyranosyl,42 indicating that IPS has a multi-branched chain structure, consisting of small rings and helical structures, while EPS is prone to forming large interaction networks in aqueous solutions.31 It should be noted that the pharmacological activity of polysaccharide molecules is related to their molecular weight, chemical structure, and conformation. For example, the higher the content of high molecular weight IPS, the higher the anti-tumor activity,43 only polysaccharides with a molecular weight greater than 16,000 have effective anti-tumor activity.44 Therefore, the relationship between the structure of polysaccharides and the pharmacological effects of O. sinensis deserves further research. In a recent study, Liu et al.45 isolated and purified biological macromolecular glycogen from O. sinensis using the sucrose gradient method for the first time and characterized the particle size distribution and chain length distribution of glycogen particles, providing a new direction for the subsequent exploration of the biological activity of polysaccharides in O. sinensis.
Nucleosides
Nucleosides are the principal components in O. sinensis, playing a key role in regulating various physiological processes in the body and exhibiting effective anti-viral, anti-inflammatory, antioxidant activities, as well as neuroprotective functions.46 Currently, more than ten nucleosides, nucleobases, and related compounds have been isolated and identified from O. sinensis through various analytical methods (Fig. 1). Nucleosides are the principal components that ensure the authenticity of O. sinensis. Cordycepin and adenosine are important nucleosides in O. sinensis.4,47 As early as the 1950s, cordycepin was first isolated from Cordyceps militaris, with the structural formula determined as 3′-deoxyadenosine. The content of cordycepin in cultivated O. sinensis is higher than that in natural O. sinensis.48 Additionally, adenosine is the main nucleoside in O. sinensis and has been used as a quality control indicator. It is also the main bioactive component in O. sinensis and plays multiple roles in regulating inflammation and tissue remodeling.44,49–52 Research has confirmed that the adenosine content in cultivated O. sinensis is much higher than that in natural O. sinensis. O. sinensis also contains many other adenosine analogs, such as 2′-deoxyadenosine, 2′,3′-dideoxyadenosine, cordycepin triphosphate, and 3′-amino-3′-deoxyadenosine. So far, six nucleobases have been identified from natural and cultivated O. sinensis, including cytosine, guanine, uracil, thymine, hypoxanthine, and adenine.53 Additionally, four nucleotides were isolated by reverse-phase liquid chromatography-mass spectrometry, including uridine 5′-monophosphate, adenosine 5′-monophosphate, guanosine 5′-monophosphate, and cytidine 5′-monophosphate. Among these, guanosine and uridine were found to be high in content, and there was no significant difference in guanosine content between cultivated and natural O. sinensis, as reported in previous studies.40O. sinensis also contains many specific nucleotides, such as adenosine, 2′,3′-dideoxyadenosine, hydroxyethyl adenosine, cordycepin triphosphate, guanidine, and deoxyguanidine. Adenosine and cordycepin (3′-deoxyadenosine), have several different deoxyguanosine structures.46 Non-targeted UPLC-MS-based metabolomics identified that the contents of 11 nucleotides were higher in natural O. sinensis, about 2.22–104.36 times that of cultivated samples.15 Currently, the identification and detection of nucleoside components in O. sinensis is a hot research topic, aiming to develop a fast, sensitive, and selective method for the quality evaluation of O. sinensis.
Proteins and nitrogenous compounds
Amino acids play an important role in maintaining internal balance and are key precursors for synthesizing plant hormones, as well as acting as amino group donors to form nitrogen-containing compounds.54 It has been proven that O. sinensis contains all essential amino acids and some non-essential amino acids (including pyroglutamic acid, glutamic acid, histidine, arginine, and tyrosine), as well as abundant and vital peptides, proteins, and polyamines.3,40 In a comparative analysis, Wang and his colleagues examined the amino acid composition of cultivated and natural O. sinensis.39 The results demonstrated a marked increase in the total amino acid content in cultivated samples. Specifically, compared to cultivated O. sinensis, natural O. sinensis contains higher levels of glutamic acid, arginine, pyroglutamic acid, valine, histidine, phenylalanine, and tyrosine, while the content of leucine and aspartic acid is lower.40,55,56 Glutamic acid was the most dominant amino acid across all samples. However, arginine was the second most prevalent amino acid in natural samples, while cultivated samples had a higher concentration of aspartic acid and leucine.40 Additionally, O. sinensis contains several rare cyclic dipeptides, including cyclo-[Gly-Pro], cyclo-[Leu-Pro], cyclo-[Val-Pro], cyclo-[Ala-Leu], and cyclo-[Thr-Leu]. Significant quantities of polyamines, such as 1,3-diamino propane, cadaverine, spermidine, spermine, and putrescine, were also detected. Other nitrogenous compounds, like putrescine, were also identified.
Sterol
Furthermore, the steroids in O. sinensis have critical physiological functions. They exist in two forms: free ergosterol and esterified ergosterol. Various sterols have been isolated from O. sinensis, including ergosterol and four ergosterol derivatives (ergosteryl-3-O-β-D-glucopyranoside, 22,23-dihydroergosteryl-3-O-β-D-glucopyranoside, 5α, 8α-epidioxy-24(R)-methylcholesta-6,22-dien-3β-D-glucopyranoside, 5α, 6α-epoxy-24(R)-methylcholesta-7,22-dien-3β-ol).57 Studies have shown that the ergosterol content in different natural O. sinensis samples varies and is higher than that in cultivated O. sinensis.11 Different sterol compounds are involved in various physiological processes. Among the four ergosterol derivatives, a large number of experiments have confirmed that the latter two have anticancer activity, while the first two do not.58 Studies have determined the sterols in O. sinensis fruiting bodies (CsA) and parasitic caterpillars (CsB) separately and found that CsA and CsB have similar ergosterol compositions, but the content of ergosterol in CsA is much higher than that in CsB, indicating that CsA and CsB may be in different growth stages or have different physiological functions related to ergosterol growth and reproduction.59
For example, anti-tumor compounds and ergosterol derivatives can induce apoptosis in human liver cancer HepG2 cells,60 while ergosterol compounds have significant cytotoxic activity.58,61
Alkaloids
Alkaloids can improve blood circulation and regulate endocrine functions.621H-NMR identification of O. sinensis metabolites revealed that the betaine content in cultivated O. sinensis is relatively high. Two new pyrrole alkaloid derivatives, 2-carboxaldehyde-1-(4-aminobutyl)-5-(methoxymethyl)-1H-pyrrole (14) and 2-carboxaldehyde-5-(methoxymethyl)-1-(2-oxo-3-piperidinyl)-1H-pyrrole (15), were isolated from O. sinensis, and the anti-inflammatory results showed no significant inhibitory activity.55 Recently, in the study of the chemical components of O. sinensis, a thiazole alkaloid was isolated and identified, which has glucosidase inhibitory activity and is a potential anti-diabetes compound.63
Other components
In addition, three different lipid metabolites, namely linolenic acid, linoleic acid, and oleic acid, were isolated from O. sinensis.55 Among them, linolenic acid was only detected in natural O. sinensis. O. sinensis is rich in minerals, with five macro-elements and eighteen trace minerals detected (Table 1).15,40,48,53,55,57,64–66 The contents of K and P among the five macro-elements are significantly higher in cultivated O. sinensis. The Se, Zn, Cu, and Co contents in natural O. sinensis are higher than those in cultivated samples, while the Ni content is three to five times higher than that in natural O. sinensis samples. Interestingly, as natural O. sinensis grows at higher altitudes, the content of toxic elements Ni, Pb, Hg, and As decreases.40 At the same time, O. sinensis is also rich in vitamins B1 and B2, which help promote blood circulation and primary metabolism in the human body. Taken together, the rich active ingredients in O. sinensis determine its important pharmacological activity. Therefore, more in-depth research is needed on the biological components and content of O. sinensis to cultivate more effective alternatives to it.
Table 1Comparison of the bioactive compound composition of natural and cultivated O. sinensis
| Chemical name | Chemical formula | Classification | Change direction | Reference |
|---|
| 6-phosphogluconic acid | C6H13O10P | Carbohydrates | ↓ | 15 |
| D-arabitol | C5H12O5 | | ↓ | 15 |
| D-xylitol | C5H12O5 | | ↓ | 15 |
| D-xylose | C5H10O5 | | ↓ | 15 |
| Gluconic acid | C6H12O7 | | ↓ | 15 |
| Mannitol | C6H14O6 | | ↑ | 40 |
| Trehalose | C12H22O11 | | ↑ | 64 |
| 2′-deoxyadenosine | C9H15N3O5 | Nucleoside | ↑ | 15 |
| 2′,3′-dideoxyadenosine | C10H13N5O2 | | – | 53 |
| 3′-amino-3′- deoxyadenosine | C10H14N6O3 | | – | 53 |
| Adenosine | C10H13N5O4 | | ↑ | 65 |
| Adenine | C5H5N5 | | ↑ | 15 |
| Cordycepic acid | C6H14O6 | | ↓ | 40 |
| Cordycepin | C10H13N5O3 | | ↓ | 48 |
| Cordycepin triphosphate | C10H16N5O12P3 | | – | 53 |
| Cytidine | C9H13N3O5 | | – | 53 |
| Cytosine | C4H5N3O | | – | 53 |
| Guanosine | C10H13N5O5 | | NS | 40 |
| Guanine | C5H5N5O | | ↑ | 15 |
| Hypoxanthine | C5H4N4O | | ↑ | 15 |
| Thymine | C5H6N2O2 | | ↑ | 15 |
| Xanthine | C5H4N4O2 | | ↑ | 15 |
| Uracil | C4H4N2O2 | | ↑ | 15 |
| Uridine | C9H12N2O6 | | ↑ | 15 |
| Alanine | C3H7NO2 | Amino acids | ↓ | 40 |
| Arginine | C6H14N4O2 | | ↑ | 40 |
| Aspartic acid | C4H7NO4 | | ↓ | 40 |
| Cysteine | C3H7NO2S | | NS | 40 |
| Glycine | C2H5NO2 | | ↓ | 66 |
| Glutamic acid | C5H9NO4 | | ↑ | 40 |
| Histidine | C6H9N3O2 | | ↑ | 40 |
| Isoleucine | C6H13NO2 | | ↓ | 40 |
| Leucine | C6H13NO2 | | ↓ | 40 |
| Lysine | C6H14N2O2 | | ↓ | 66 |
| Methionine | C5H11NO2S | | ↓ | 40 |
| Phenylalanine | C9H11NO2 | | ↑ | 40 |
| Proline | C5H9NO2 | | ↓ | 40 |
| Pyroglutamic acid | C5H7NO3 | | ↑ | 55 |
| Serine | C3H7NO3 | | NS | 40 |
| Threonine | C4H9NO3 | | NS | 40 |
| Tryptophan | C11H12N2O2 | | – | 40 |
| Tyrosine | C9H11NO3 | | ↑ | 40 |
| Valine | C5H11NO2 | | ↑ | 40 |
| Ergosterol | C28H44O | Sterol | ↑ | 57 |
| Ergosteryl-3-O-β-D-glucopyranoside | C34H54O6 | | – | 57 |
| 22,23-dihydroergosteryl-3-O- β- D-glucopyranoside | C34H54O8 | | – | 57 |
| 5α, 8α- Epidioxy-24 (R) - methylcholesta-6,22 dien-3β- D-glucopyranoside | C28H44O3 | | – | 57 |
| 5α, 6α- Epoxy 24 (R) - methylcholesta-7,22 dien-3β-ol | C28H44O2 | | – | 57 |
| Betaine | C5HNO2 | Alkaloids | ↓ | 64 |
| Linoleic acid | C18H32O2 | Other components (fatty acid) | – | 55 |
| Linolenic acid | C18H30O2 | | ↑ | 55 |
| Oleic acid | C18H34O2 | | – | 55 |
| Aluminum | Al | Other components (mineral) | ↑ | 40 |
| Arsenic | As | | ↑ | 40 |
| Barium | Ba | | ↑ | 40 |
| Cadmium | Cd | | NS | 40 |
| Calcium | Ca | | ↑ | 40 |
| Chromium | Cr | | NS | 40 |
| Cobalt | Co | | ↑ | 40 |
| Copper | Cu | | ↑ | 40 |
| Hydrargyrum | Hg | | NS | 40 |
| Iron | Fe | | ↑ | 40 |
| Lead | Pb | | ↑ | 40 |
| Magnesium | Mg | | ↑ | 40 |
| Manganese | Mn | | ↑ | 40 |
| Molybdenum | Mo | | NS | 40 |
| Niccolum | Ni | | ↓ | 40 |
| Phosphorusb | P | | ↓ | 40 |
| Potassium | K | | ↓ | 40 |
| Selenium | Se | | ↑ | 40 |
| Sodium | Na | | ↑ | 40 |
| Stannum | Sn | | ↑ | 40 |
| Strontium | Sr | | ↓ | 40 |
| Vanadium | V | | NS | 40 |
| Zinc | Zn | | ↑ | 40 |
Medicinal functions of Ophiocordyceps sinensis
Current research has confirmed the pharmacological effects of O. sinensis in anti-diabetes, antioxidants, anti-inflammatory, immunomodulatory, liver protection, and anti-atherosclerosis (Fig. 2).65 Diabetes is a metabolic disease characterized by hyperglycemia, and persistent hyperglycemia has become an increasingly serious public health problem. Previous studies have found that a variety of traditional Chinese medicines have been used to lower blood glucose, such as berberine, astragalus, Panax notoginseng, and Pueraria lobata.67–70 At the same time, polysaccharides extracted from O. sinensis have been shown to alleviate diabetic metabolic disorders by regulating glucose metabolism and modulating intestinal flora and metabolites.71 The mycelium of O. sinensis and the polysaccharide components in the extract exhibit strong antioxidant activity. For example, previous studies have reported that water-soluble polysaccharides isolated from O. sinensis demonstrate effective in vitro antioxidant activity, including scavenging hydroxyl and superoxide radicals and inhibiting hemolysis caused by hydrogen peroxide.72 Studies have shown that the monosaccharide composition of polysaccharides can significantly influence their antioxidant activity. It has been reported that a higher glucose content in the monosaccharide composition correlates with stronger antioxidant activity.73 Moreover, acidic polysaccharides mainly composed of glucose (88.4%) not only exhibit free radical scavenging effects in vitro but also enhance antioxidant enzyme activity in type 2 diabetic mice.74
Xu et al.75 first described the enhancement of natural killer cell activity in vivo and in vitro by the ethanol extract of O. sinensis, as well as the reduction of melanoma formation in the lungs of mice, suggesting the immune-enhancing effect of O. sinensis on immune-deficient organisms. Currently, several compounds with immunomodulatory activity have been isolated from O. sinensis, among which polysaccharides are the main component. O. sinensis polysaccharides induces T lymphocyte proliferation and secretion of IL-β and IL-6. In addition, they can enhance the phagocytosis of macrophages, demonstrating their important role in immune response, and can be used as a natural immune regulator.76 Bi et al.77 reported that low molecular weight polysaccharides obtained from cultivated O. sinensis fruiting bodies exerted immunostimulatory effects. Inflammation is a protective mechanism that defends against tissue damage caused by various stimuli and harmful factors, such as ultraviolet radiation, infection, and cell damage. Studies have shown that O. sinensis polysaccharides enhance the immunity of mice exposed to ionizing radiation by reducing oxidative damage and regulating the secretion of cytokines (IL-4, IL-5, and IL-17).78 Recent studies have shown that O. sinensis polysaccharides can alleviate acute liver injury by upregulating vascular endothelial growth factor, stromal cell-derived factor-1α, proliferating cell nuclear antigen, and downregulating IL-12 and caspase-1 to promote hepatocyte proliferation and liver tissue repair.79 Notably, O. sinensis polysaccharides can increase the abundance of Akkermansia and Lachnospiraceae, reduce the abundance of Bacteroides, Parabacteroides, and Blautiae, improve intestinal barrier function, and inhibit intestinal inflammation.80 In addition, many studies have demonstrated the potential of cordycepin from Cordyceps militaris in anti-inflammatory treatment. For example, cordycepin effectively alleviates lipopolysaccharide induced acute lung injury by inhibiting inflammation and oxidative stress.81 Cordycepin significantly decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase in RAW 264.7 cells.82
Compounds in O. sinensis, including polysaccharides, sterols, and adenosine, have been shown to inhibit tumor cell growth and metastasis by inducing tumor cell apoptosis, cell cycle arrest, and inhibiting angiogenesis.83 Previous studies have found that O. sinensis polysaccharides have a strong regulatory effect on mouse liver cancer.84 Ergosterol can reduce the proliferation of various tumor cells, and cordycepin inhibits the proliferation of cancer cells by triggering the Wnt signaling pathway. For example, in human colon cancer cells, it induces apoptosis by increasing pro-apoptotic molecules.85 Additionally, it could enhance exercise and improve memory and learning ability, as supported by various clinical studies.86 It has also shown reliable results in improving organ malfunctioning by regulating cytokines, chemokines, and oxidative stress-induced protein changes.
An increasing number of studies have concentrated on the pharmacological activities of cultivated O. sinensis, including antioxidant, anti-inflammatory, anticancer, immunomodulatory, hypoglycemic, and the ability to delay the progression of kidney disease.87–89 Dong et al.90 evaluated the in vitro antioxidant activity of aqueous extracts of natural and cultivated O. sinensis mycelium and confirmed that both had effective antioxidant activity. Wang et al.91 compared the protective effects of natural and cultivated O. sinensis against hepatotoxicity. The results showed that both play a liver-protective role by preventing liver cells from oxidative damage. Therefore, the pharmacological functions of natural and cultivated O. sinensis are similar, and there is no significant difference in pharmacological activity.
Despite these advances, there remains a need for further research to comprehensively understand the molecular mechanisms underlying these effects and to explore the full spectrum of pharmacological activities. Similarly, new drug delivery systems should be developed to enhance the effects of O. sinensis active ingredients, compensating for the limitations of traditional drug delivery methods and better elucidating the bioactive compounds of O. sinensis and their therapeutic potential.
Conclusions
The chemical composition and bioactive compounds of O. sinensis have been increasingly elucidated, with key components such as cordycepin, adenosine, polysaccharides, and sterols recognized for their pharmacological properties. These compounds have demonstrated a range of health benefits, including immunomodulatory, anti-inflammatory, antioxidant, and antitumor activities. Beyond the traditional harvesting of wild O. sinensis from their native, harsh environments, significant advancements have been made in the large-scale artificial cultivation of O. sinensis. This method is particularly advantageous as it allows for more sustainable production while mitigating the environmental impact associated with wild harvesting. However, the market is currently flooded with numerous low-quality substitutes, which may not only fail to deliver the therapeutic benefits associated with genuine O. sinensis but may also pose safety risks. To ensure clarity, precision, and a deeper understanding of the medicinal potential of O. sinensis, a multifaceted approach to its production and quality control is imperative. Thus, it is essential to establish rigorous identification and standardization protocols. These should include a detailed analysis of morphological characteristics and comprehensive profiling of active ingredients to distinguish between natural O. sinensis, its fermented counterparts, and inferior substitutes. Current research is mainly through comparative analysis of natural and cultivated O. sinensis metabolites. It is generally believed that the components and pharmacological activities of the two are similar, but there are differences in the content of some specific components. Accurate identification and quality control are crucial to ensuring that the therapeutic potential of O. sinensis is fully harnessed. Therefore, a more profound and systematic understanding of the health benefits and therapeutic potential of O. sinensis will significantly contribute to its future medicinal applications. Such knowledge will not only enhance its utilization in traditional medicine but also pave the way for its integration into modern therapeutic practices, potentially leading to the development of novel drugs and health supplements derived from this precious fungus.
Declarations
Acknowledgement
We thank the anonymous reviewers for their constructive comments, which greatly improved the quality of the manuscript.
Funding
No funding was received for the study.
Conflict of interest
LW has been an editorial board member of Future Integrative Medicine since October 2021. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors’ contributions
Topic conception, logical framework, student supervision, project administration (LW), discussions (YRT), investigation, image visualization (ZWM), writing of the original draft, and performing the literature review (ZWM, QHL, YXH, JC, JWT). All the authors approved the final version and publication of the manuscript.