Metabolites and Their Bioactivities from the Genus Cordyceps

The Cordyceps genus is a group of ascomycete parasitic fungi, and all known species of this genus are endoparasites; they mainly feed on insects or arthropods and a few feed on other fungi. Fungi of this genus have evolved highly specific and complex mechanisms to escape their host’s immune system and coordinate their life cycle coefficients with those of their hosts for survival and reproduction; this mechanism has led to the production of distinctive metabolites in response to the host’s defenses. Herein, we review approximately 131 metabolites discovered in the genus Cordyceps (including mycelium, fruiting bodies and fungal complexes) in the past 15 years, which can be used as an important source for new drug research and development. We summarize chemical structures, bioactivity and the potential application of these natural metabolites. We have excluded some reports that originally belonged to Cordyceps, but whose taxonomic attribution is no longer the Cordyceps genus. This can and will serve as a resource for drug discovery.


Introduction
Cordyceps sinensis is a renowned Chinese herbal medicine and has been widely used for medicinal treatment in China for over 300 years [1]. C. sinensis grows in very limited habitats, its yields decrease year by year, and its use is finite because of its high price and limited availability [2]. Researchers have been seeking substitute materials by investigating the fermentation and culture of fungi separated from C. sinensis and other Cordyceps species [3]. Cordyceps is the most numerous and diverse genus of the Clavellaceae family, of which 629 species have been identified, according to MycoBank (https://www.mycobank.org; accessed on 8 June 2022). It is a class of ascomycete parasitic fungi. All known species act as endoparasites, feeding mostly on insects and other arthropods and a little on other fungi. This survival mechanism of Cordyceps leads to the production of distinctive metabolites in response to host defenses, which is an important source for new drug research and development [4,5]. There are many species of Cordyceps. They are abundant in humid climates and tropical forests, widely distributed in North America; Europe; East and Southeast Asian countries, especially China, Japan, Nepal, Vietnam, Bhutan, Korea and Thailand, although some other species are also found in different habitats in other regions, indicating a global distribution. Species in the genus Cordyceps are widely accepted for using as food and medicine and good reviews have been published. For example, a review published by Zhou et al. reported on natural products, pharmacological functions, and novel products in Cordyceps sinensis [6]. Similarly, Olatunji et al. reviewed the advanced developments in traditional uses, phytochemistry and pharmacology of Cordyceps fungi, with a primary focus on C. sinensis and C. militaris [7]. On the other hand, Chen et al. provided an overview on the safety concerns of fungal fruiting bodies of several Cordyceps species in terms of their existence as food supplements or as animal feed by-products and analyzed the conservatism of gene clusters between Cordyceps and other fungi involved in toxin production [8]. In
Cordycepin is a vital active component of Cordyceps. During in-depth research on cordycepin, it was found that cordycepin has a wider range of biological activities, and many new mechanisms of action were discovered. Due to the emergence of mutant strains, the coronavirus disease 2019 (COVID-19) is ongoing globally, often causing severe acute respiratory syndrome and leading to the death of some patients. Using computational methods, researchers predicted a possible inhibitory affinity of cordycepin to the main SARS-CoV-2 protein target [17]. The latest research shows that cordycepin can effectively inhibit the reproduction of new SARS-CoV-2 drug-resistant strains, and its EC 50 was about 2 µM in in vitro anti-SARS-CoV-2 assays, which is superior to remdesivir and its active metabolite GS-441524 [18]. In addition, it was found that cordycepin can inhibit Dengue virus replication and significantly reduced DENV protein at EC 50 of 26.94 µM [19]. Other research on the activity of cordycepin found it could protect PC12 cells from the neurotoxicity induced by 6-hydroxydopamine through its powerful antioxidant activity [20]. Additionally, cordycepin modulated adenosine A1 receptors to increase long-term enhancementcapability formation and neuronal survival in the BCCAO model and glutamate-enticed HT22 neuronal cell death via the p38/JNK/ERK pathway [21,22]. In recent years, progress has been made in the study of the anti-cancer mechanisms of cordycepin, and many reviews show that cordycepin may facilitate tumor cell death via cysteine-aspartic proteases (caspases), mitogen-activated protein kinase (MAPK) and glycogen synthase kinase (GSK)-3β pathways mediated by putative adenosine receptors, death receptors and/or epidermal growth factor receptors (EGFR) [23,24]. In particular, cordycepin regulates the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibits cyclin-dependent kinase 2 (Cdk-2), extracellular signal-regulated kinase 1/2 (ERK1/2) and Rb/E2F1 and fibroblast growth factor receptors 1-4 (FGFR 1-4) regulate the cell cycle and further reduce the growth of testicular tumors, gastric cancer cells and cervical cancer cells [25,26]. In addition, cordycepin also regulates diverse signaling proteins, such as hedgehog, glioblastoma protein (GLI), DNA-dependent protein kinase (DNA-PK) and ERK, to induce cancer cell apoptosis [27,28]. from the neurotoxicity induced by 6-hydroxydopamine through its powerful antiox dant activity [20]. Additionally, cordycepin modulated adenosine A1 receptors to i crease long-term enhancement-capability formation and neuronal survival in th BCCAO model and glutamate-enticed HT22 neuronal cell death via the p38/JNK/ER pathway [21,22]. In recent years, progress has been made in the study of the anti-canc mechanisms of cordycepin, and many reviews show that cordycepin may facilitate t mor cell death via cysteine-aspartic proteases (caspases), mitogen-activated protein k nase (MAPK) and glycogen synthase kinase (GSK)-3β pathways mediated by putativ adenosine receptors, death receptors and/or epidermal growth factor receptors (EGFR [23,24]. In particular, cordycepin regulates the phosphoinositide 3-kinase/protein kina B (PI3K/AKT) signaling pathway and inhibits cyclin-dependent kinase 2 (Cdk-2), extr cellular signal-regulated kinase 1/2 (ERK1/2) and Rb/E2F1 and fibroblast growth fact receptors 1-4 (FGFR 1-4) regulate the cell cycle and further reduce the growth of testi ular tumors, gastric cancer cells and cervical cancer cells [25,26]. In addition, cordycep also regulates diverse signaling proteins, such as hedgehog, glioblastoma protein (GL DNA-dependent protein kinase (DNA-PK) and ERK, to induce cancer cell apoptos [27,28].
Cardinalisamides A-C (32-34) were separated from C. cardinalis NBRC 103832. Cardinalisamides A-C showed antitrypanosomal activity against Trypanosoma brucei and their IC50 were 8.56, 8.65 and 8.63 mg/mL, respectively, in vitro, and had IC50 values of 18.48, 14.00 and 23.84 mg/mL, respectively, against normal human diploid fibroblasts (MRC-5 cells) in cytotoxicity assays [36]. Cordycecin A (35) and two known compounds beauvericins E (36) and J (37) were separated from the ascocarps and insect-body tranches of C. cicadae. Beauvericin J (37) was cytotoxic against HepG2 and HepG2/ADM cells, whose IC50 values were in the range of 5.04 ± 0.20 μM and 2.67 ± 0.09 μM, respec-   14.00 and 23.84 mg/mL, respectively, against normal human diploid fibroblasts (MRC-5 cells) in cytotoxicity assays [36]. Cordycecin A (35) and two known compounds beauvericins E (36) and J (37) were separated from the ascocarps and insect-body tranches of C. cicadae. Beauvericin J (37) was cytotoxic against HepG2 and HepG2/ADM cells, whose IC 50 values were in the range of 5.04 ± 0.20 µM and 2.67 ± 0.09 µM, respectively; beauvericin E (36) revealed moderate inhibitory effects and its IC 50 value was in the range of 13.67 ± 2.59 µM and 14.48 ± 1.68 µM, respectively [37]. Cordycommunin (38) was separated from the Ophiocordyceps communis BCC 16475 and it had a growth inhibiting effect on Mycobacterium tuberculosis H37Ra and its MIC value was 15 µM. Compound 38 also exhibited slight cytotoxicity to KB cells and its IC 50 value was 45 µM [38]. Beauverolide J b (39) was obtained from C. javanica [39]. A tripeptide, arginylphenylalanyl-methionine (40), isolated from C. gunnii, with the molecular formula of C 20 H 32 N 6 O 4 S, is a sedative and hypnotic active substance [40]. Other polypeptide compounds have had less report published in recent years. However, recent studies have shown that cordyceps polypeptide complexes are helpful for improving learning and memory, but their mechanism of action needs further study [41]. The structures of 32-40 are shown in Figure 3.
Microorganisms 2022, 10, x FOR PEER REVIEW 6 of nyl-methionine (40), isolated from C. gunnii, with the molecular formula of C20H32N6O is a sedative and hypnotic active substance [40]. Other polypeptide compounds ha had less report published in recent years. However, recent studies have shown th cordyceps polypeptide complexes are helpful for improving learning and memory, b their mechanism of action needs further study [41]. The structures of 32-40 are shown Figure 3.

Polyketides
Three new compounds, paecilomycones A-C (41-43), were identified from a met anol extract of C. gunnii. Paecilomycones A-C showed significant tyrosinase inhibito activity, and the IC50 values were 0.11 μM, 0.17 μM and 0.14 μM, respectively. Structu and activity research showed that the tyrosinase inhibition activity was connected to t amount of hydroxyl groups on the paecilomycones.
The structure of compound 41 is very similar to the anti-HIV target flurane (a ti-HIV, the IC50 value was 1.7 μM), while the compound 43 has a NH2 group in C-9 rath than the usual -OH group, which indicates that compounds 41 and 43 may be promisin

Polyketides
Three new compounds, paecilomycones A-C (41-43), were identified from a methanol extract of C. gunnii. Paecilomycones A-C showed significant tyrosinase inhibitory activity, and the IC 50 values were 0.11 µM, 0.17 µM and 0.14 µM, respectively. Structure and activity research showed that the tyrosinase inhibition activity was connected to the amount of hydroxyl groups on the paecilomycones.

Sterols and Terpenoids
It has been reported that sterols in C. sinensis have anti-tumor activity, immunosuppression, anti-arteriosclerosis and antibacterial activities. However, the active sterols in C. militaris are seldom reported.

Sterols and Terpenoids
It has been reported that sterols in C. sinensis have anti-tumor activity, immunosuppression, anti-arteriosclerosis and antibacterial activities. However, the active sterols in C. militaris are seldom reported.

Protein
There are also proteins in C. sinensis. As far as we know, these proteins have a variety of activities, such as antifungal, anticancer and antiviral activities, etc. These research results show that C. sinensis proteins also play an important role in biology. In recent years, studies on C. militaris proteins have also been gradually increasing. A new anti-tumor protein was separated from the seed entity of C. militaris, named CMIP (92). CMIP showed anti-metastasis activity by reducing the amount of tumor nodules in the lung of tumor-bearing mice and extended their lives on a mouse model of 4T1 breast cancer lung metastasis. The results showed that CMIP possessed immune regulatory activity [59].
In addition, a new protein with a molecular mass of 18.0 kDa was separated from C. militaris and named CMP (93); however, it is a nocuous protein that can cause cell apoptosis via a mitochondrion-dependent mechanism [60]. A glycopeptide (Cs-GP1) (94) was purified from the strain C. sinensis Cs-HK1, and its molecular weight was 6.0 kDa.

Protein
There are also proteins in C. sinensis. As far as we know, these proteins have a variety of activities, such as antifungal, anticancer and antiviral activities, etc. These research results show that C. sinensis proteins also play an important role in biology. In recent years, studies on C. militaris proteins have also been gradually increasing. A new antitumor protein was separated from the seed entity of C. militaris, named CMIP (92). CMIP showed anti-metastasis activity by reducing the amount of tumor nodules in the lung of tumor-bearing mice and extended their lives on a mouse model of 4T1 breast cancer lung metastasis. The results showed that CMIP possessed immune regulatory activity [59].
In addition, a new protein with a molecular mass of 18.0 kDa was separated from C. militaris and named CMP (93); however, it is a nocuous protein that can cause cell apoptosis via a mitochondrion-dependent mechanism [60]. A glycopeptide (Cs-GP1) (94) was purified from the strain C. sinensis Cs-HK1, and its molecular weight was 6.0 kDa. Furthermore, Cs-GP1, mostly consisting of glucose and mannose at 3.2:1.0 molar ratio, showed notable antioxidant activities (1183.8 µmol Trolox/g and 611.1 µmol Fe(II)/g) [61]. A protein designated the Cordyceps militaris protein (CMP I) (95) was the first protein from C. militaris; it is a 12 kDa protein in the form of dimers. CMP I exhibited powerful antifungal activities against the growth of the Fusarium oxysporum. In the CCK assays, CMP I (95) significantly inhibited the viability of MCF-7 cells, its IC 50 value was 9.3 µM and the IC 50 against 5637 cells was 8.1 mM. However, CMP I showed almost no inhibitory effect on A-549 cells [62]. Two peptides, named VPRKL(Se)M (Se-P1) (96) and RYNA(Se)MNDYT (Se-P2) (97), were purified from Se-enriched C. militaris and demonstrated neuroprotective effects, and compared to the damage group, Se-P1 and Se-P2 increased PC-12 cell viability by 30 and 33%, respectively. In addition, Se-Ps may moderate cognitive damage in LPSinjured mice (p < 0.05). Therefore, Se-Ps has the potential to be an alternative to drugs to prevent and/or treat AD (Alzheimer's disease) [63].
A fibrinolytic enzyme (98) was identified from C. militaris, and its enzyme activity was 1682 U/mg; its molecular weight and pI were 32 kDa and 9.3 ± 0.2, respectively; its first-rank pH and temperature were 7.4 and 37 • C, respectively. This fibrinolytic enzyme could hydrolyze fibrin(ogen) rapidly and cleave the α-chains more effectively than βand γ-chains, and it also could degrade thrombin. Therefore, it could be a potential natural agent for oral fibrinolytic medical treatment or to prevent the formation of blood clots [59]. An antifungal peptide, cordymin (99) with a unique N-terminal amino acid sequence was purified from the C. militaris; its molecular mass was 10,906 Da. Cordymin inhibited the mycelial growth of Bipolaris maydis, Rhizoctonia solani, Mycosphaerella arachidicola and Candida albicans and their IC 50 values were 50, 80, 10 and 0.75 µM, respectively. Cordymin also had an IC 50 of 55 µM for inhibiting HIV-1 reverse transcriptase [64]. A novel protease (100) was purified and characterised from the edible fungus C. sinensis; its molecular weight was approximately 43 kDa; and its first-rate pH and temperature were 9.5 and 30 • C, respectively [65]. A novel fibrinolytic enzyme named CMase (101) was purified from C. militaris for the first time; its molecular mass was approximated to be 27.3 kDa and its optimal pH and temperature were pH 6.0 and 25 • C, respectively [66]. These reports suggest that C. militaris represents a new source of proteins.

Polysaccharide
Cordyceps polysaccharide is the important bioactive component in C. sinensis, which has demonstrated anti-cancer, anti-oxidant, anti-viral, immunomodulation properties and the improvement of liver function [67]. Furthermore, studies have shown that the sulfated exosaccharide of C. sinensis can enhance its antioxidant activity [68].
A polysaccharide (SDQCP-1) (102) was separated from C. militaris that was cultivated on hull-less barley; it mainly consisted of mannose, glucose and galactose at 13.3:1.0:9.7 molar ratio; its average molecular weight was 19.3 kDa. The antioxidant and immunomodulatory activities showed that SDQCP-1 had great antioxidant capacity, its ORACFL value was 24.7 mmol Trolox/g and TEAC value was 202.4 µmol Trolox/g. SDQCP-1 also motivated macrophages to liberate NO, IL-6, TNF-α and IL-10 and mostly facilitated the M1 polarization of macrophages. The findings suggest that SDQCP-1 has potential as a natural antioxidant and immunomodulator in functional foods or drugs [69].
A novel polysaccharide CMP-1 (103), with an average molecular weight of 4.3 kDa, was isolated from the fruit body of cultured C. militaris with antioxidant, immune stimulatory and anti-tumor activity. CMP-1 showed free radical-scavenging effects, ferrous-ion chelating ability and reducing power in antioxidant assays. Furthermore, CMP-1 considerably encouraged mouse splenocyte proliferation in vitro. It also inhibited the proliferation of HepG2, HeLa, HT-29 and K562 cells and the IC 50 values were 176.29, 162.59, 137.66 and 364.01 µg/mL, respectively, in cytotoxicity assays [70]. A novel polysaccharide CM3-SII (104) was isolated from C. militaris with potential hypolipidemic effect; it consisted of mannose, glucose and galactose at a 10.6:1.0:3.7 molar ratio. The interference of CM3-SII considerably increased the protein expression of LDLR and intracellular levels of PCSK9 at the concentration of 100 and 200 µg/mL [71]. A homogeneous exopolysaccharide (EPS-III) (105) was obtained from C. militaris with hypoglycemic activity; its average molecular weight was 1.56 × 10 3 kDa. In a hypoglycemic experiment of EPS-III in vivo, the inhibition rate of α-glucosidase was considerably enhanced when the concentration of EPS-III was increased, and at a concentration of 3 mg/mL the inhibition rate reached 55.94 ± 1.34%. In addition, studies showed that EPS-III moderated weight loss, decreased plasma glucose concentration, promoted glucose tolerance, secured immune organs and repaired dyslipidemia to moderate diabetes in STZ-induced diabetic mice [72]. An alkaline-extracted polysaccharide (CM3II) (106) was purified from C. militaris with anti-atherosclerotic effects; it was mainly composed of mannose, glucose and galactose at a 1.4:1.0:1.2 molar ratio. In experimental mice with atherosclerosis induced by a high-fat diet, Oil Red O staining results showed that simvastatin and CM3II interference decreased the atherosclerotic lesion/lumen ratio by 6.1% and 17.8% (p < 0.05), respectively. Moreover, CM3II increasingly decreased the TC and TG standards [73]. Two new polysaccharides, SCP II-1 (107) and SCP II-2 (108), were purified from silkworm Cordyceps and demonstrated antioxidant and antitumor activity; the molecular weight of SCP II-1 was 35.2 kDa and SCP II-2 was 23.4 kDa; they consisted of ribose, mannose, glucose and galactose in a molar ratio of 1.0:27.38:8.52:17.99 and 1.0:21.21:1.95:14.28, respectively. In the DPPH radical scavenging activity assays, the DPPH radical removal degrees of SCP II-1 and SCP II-2 were 88.328% and 75.028%, respectively. The DPPH radical removal IC 50 values were less than 0.5 mg/mL. In the antitumor activity experiment, SCP II-1 had an IC 50 value of 119.34 ± 1.76 µg/mL against HepG2 cell proliferation [74]. A polysaccharide (CMP-III) (109) was isolated from C. militaris; its average molecular weight was 4.796 × 10 4 kDa; it was composed of glucose, mannose and galactose at an 8.09:1.00:0.25 molar ratio. Moreover, the studies of immunomodulatory functions showed that CMP-III could enhance macrophage phagocytosis and the release of NO, TNF-α and IL-6 at a concentration of 25-200 µg/mL [75]. An acidic exopolysaccharide (AESP-II) (110) was purified from C. militaris that demonstrated immunological activity. AESP-II consisted of mannose, glucuronic acid, rhamnose, galactose acid, N-acetylgalactosamine, glucose, galactose and arabinose at a 1.07:5.38:1:3.14:2.23:15:6.09:4.04 molar ratio, and its molecular weight was 61.52 kDa. In addition, AESP-II considerably increased the proliferation of B lymphocytes in a dose-dependent manner and significantly increased the proliferation of T lymphocytes at a low dose (25 mg/kg body weight) in an animal experiment [76]. A poly-N-acetylhexosamine (polyhexNAc) (111) with an average molecular weight of about 6 kDa was isolated from C. sinensis Cs-HK1; its molecular structure is a [-4-β-D-ManNAc-(1 → 3)-β-D-GalNAc-(1 →] disaccharide repeating unit in the chief chain. It exhibited remarkable antioxidant activities (330 µmol Trolox/g and 45.7 µmol Fe(II)/g) and showed meaningful cytoprotective activity at a concentration of 10-200 mg/mL [77]. A novel polysaccharide (CMPA90-1) (112) with antioxidant and anti-tumor activity was isolated from C. militaris. CMPA90-1 consisted of arabinose, mannose and galactose at a 1.00:2.89:2.03 molar ratio; it exhibited inhibitory activity against A549 cells and its IC 50 value was 39.08 µg/mL in the cytotoxicity assay [78].
A polysaccharide CP2-S (129) was purified from C. militaris, with a molecular weight of 5.938 × 10 3 kDa and consisted of glucose. CP2-S significantly stimulated macrophages to take up neutral red, produce NO and increased the excretion of the cytokines IL-1β and IL-6 (50-500 µg/mL) [92]. A protein-polysaccharide HS002-II (130) was fractionated from Hirsutella sinensis and its average molecular weight was 44 kDa. HS002-II was composed of 57.9% polysaccharide and 42.1% protein and was linked by N-type carbohydrate-protein linkages. It consisted of (1 → 3)-linked α-D-ribofuranosyl units, (1 → 4)-linked α-D-xylopyranosyl units and (1 → 4)-linked β-D-glucopyranosyl units. Furthermore, HS002-II induced the expression of pro-inflammatory cytokines TNF-α in the upper clear liquid and IL-1β, NF-κB, TNF-α and iNOS in the transcription level in a concentration-dependent manner (0-2.2 µM) [93]. A new polysaccharide (CM-S) (131) was extracted from the fruiting bodies of C. militaris. Its molecular weight was 134,631 Da. CM-S consisted of galactose, glucose and xylose at a 3:2:1 molar ratio and its main chain was (1 → 6)-α-d-galactose. In addition, CM-S considerably increased the proliferation of T cells in contrast to the blank control group at 5, 10 and 20 µg/mL [94]. The information of polysaccharides from Cordyceps fungi was shown in Table 1.  The fungi of Cordyceps taii [95], Cordyceps gracilioides [96] and Cordyceps indigotica [97,98] taxonomically belonged to Cordyceps previously; however, they have now been classified into other genera. Therefore, its metabolites and its metabolites' biological activities are not described here.

Conclusions
Cordyceps sinensis, a famous and precious traditional Chinese medicine, has various activities, including antitussive, asthma-relieving, immune regulation, antibacterial and antitumor, and has a medicinal history of more than 200 years [1]. Cordycepin, isolated and purified from Cordyceps, has also become a focus of research because of its various biological activities. The present review summarizes compounds obtained from Cordyceps with new structures or new activities reported from 2007 to 2022. These compounds include nucleosides, non-ribosomal peptides and alkaloids, polyketides and polysaccharides, among others, which show antitumor, antioxidant, antibacterial, hypoglycemic and immune regulation enhancement activities. Furthermore, researchers have also obtained metabolites from Cordyceps fungi in different manners.  (52) were obtained from C. militaris grown on germinated soybeans [46]; two new polyketides cordypyrones A (68) and B (69) were obtained by the heterologous expression of the gene cluster in Aspergillus nidulans [53]; and an acidic exopolysaccharide AESP-II (110) was isolated on the basis of the immune activity of the fermentation broth of C. militaris [76]. In addition, the paper briefly concludes new activities or new mechanisms of cordycepin that have been reported in recent years. By summarizing the compounds with the new structures and new activities of the known metabolites obtained from the genus Cordyceps in the past 15 years, this paper provides a theoretical basis for research on the active compounds of the genus Cordyceps.

Prospects
Cordyceps fungi have always attracted scientific attention due to their various biological activities; however, effectively isolating active monomer compounds from them has been challenging. Under laboratory conditions, fungi produce far fewer compounds than they do under natural conditions [99], and through the analysis of fungal genome data and bioinformatics, fungi have a number of biosynthetic gene clusters of active natural products; however, more than 90% are silent [100]. Cordyceps A (68) and B (69) are novel compounds obtained by heterologously expressing the gene cluster of C. militaris in Aspergillus nidulans. Therefore, by the method of heterologous expression, the biosynthetic gene cluster of Cordyceps fungi can be activated and expressed in filamentous fungi, which can also be used as a potential method for obtaining active compounds in Cordyceps fungi. In addition, in recent years some important molecular technologies have been developed in the deep mining of fungal natural products, such as obtaining specific or non-specific target products through molecular genetic manipulation and directly reconstituting the biosynthesis pathway of target compounds in engineered strains to obtain target compounds. The progress of these methods provides technical support for the research of natural products of Cordyceps fungi [101]. The research on the metabolites and their activities of Cordyceps fungi has been ongoing, and the most in-depth research on the activity and action mechanism has been carried out on cordycepin. In particular, important progress has been made in research on the mechanism of the anti-tumor, immunosuppression and neuroprotective effects of cordycepin [21][22][23]28]. Cordycepin has been clinically studied in multiple clinical settings worldwide as a potential antileukemia/anti-cancer chemotherapeutic agent and has passed clinical phase 1 and 2 (clinical trials NCT00003005 (https://clinicaltrials.gov/ct2/show/NCT00003005, accessed on 3 September 2004) and NCT00709215 (https://clinicaltrials.gov/ct2/show/NCT00709215, accessed on 3 July 2008)). Therefore, there is still great research potential and mining value for other active compounds of Cordyceps fungi.