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Secondary metabolites (SMs) of Isaria cicadae and Isaria tenuipes

Both Isaria cicadae and Isaria tenuipes are important entomopathogenic fungi used in health foods and traditional herbal medicines in East Asia. However, the safety concerns for both fungal species have been attracting significant attention. Thus, surveying their secondary metabolites (SMs) will be beneficial to improving the safety of their fungal products. In the case of I. cicadae, its SMs mainly include nucleosides, amino acids, beauvericins, myriocin, and oosporein. In contrast, trichothecene derivatives, isariotins, cyclopenta benzopyrans and PKs, are found in the case of I. tenuipes. Among them, beauvericins, myriocin, oosporein and many trichothecene derivatives are toxic compounds. The toxicity and side effects of the fungal products may be related to these SMs. Thus, to ensure the safety of fungal products, the residues standards of SMs need to be reported. Furthermore, methods for the detection of their SMs and biological identification of their strains must be considered. This review gives new insight into the secondary metabolites of medical and edible fungi.


Introduction
Isaria is an entomopathogenic fungal genus with more than 100 species (http://www.mycobank.org/), which plays important roles in biodiversity conservation and is utilized in medicines and agriculture. 1,2 Both I. cicadae and I. tenuipes (Fig. 1) belonging to the anamorph of Cordyceps genus, are popular mushrooms mostly infecting insects (in nature, oen the underground nymphs of cicadas), leading to their death, and then produces white fruit body from the dead insect, which releases white powdery spores. The fruit body is used in expensive traditional medicines and health products in East Asia. [2][3][4] I. cicadae, the asexual type of C. cicadae, is a famous mushroom. In nature, the fruiting bodies form uniquely on pupated cicadae (Platylomia spp.) and are referred to as "cicada ower" or the Chinese name "Jingchanhua" in China. In the laboratory, this fungus can be inoculated in the pupae of Chinese tussah silkworm (Antheraea pernyi). Interestingly, in contrast to other Cordyceps species that produce sexual fruiting bodies in nature, C. cicadae forms synnema-like asexual structures. 5 I. sinclairii was once known as C. cicadae, C. kobayasii, Paecilomyces cicadae, P. sinclairii and C. sinclairii. [6][7][8] However, it is considered as the synonym of I. cicadae. 9 This species is found in Asia (particularly China, Japan, and Korea) and New Zealand. It infects cicadas of the genera Amphipsalta and Melampsalta in nature, and in the lab it can be cultured on the bodies of silkworms, 10 which also shows potential as a biological control agent against the agricultural pest Plutella xylostella. 11 Its fruit body is used to treatment cancers and improve the eyesight and renal function and immunity of patients. 12 It also has anti-hypertensive effect in spontaneously hypertensive rats. 13 However, it was reported that it induced kidney toxicity in rats exposed to its fungus fruit bodies. 14,15 I. tenuipes is a common entomopathogenic fungus that usually infects Lepidopteran insects. 16 It has the synonymies of C. tenuipes and P. tenuipes, and it was also called Spicaria heliothis, C. concurrens, C. polyarthra, and C. subpolyarthra (http:// www.mycobank.org/). Moreover, it is considered as the anamorph of C. takaomontana 17 and synonymy I. japonica. 18 Its fruiting body is used in the production of health foods and traditional medicine with the functions of lowering bloodglucose, antitumor, antibacterial, anti-depression, antioxidation, and anti-aging activity, lowering blood fat and immunoregulation. 7,18,19 However, safety concerns of consuming these entomopathogenic fungi have been frequently raised due to the uncertainty of the fungal production of human-toxic mycotoxins. 20 In fact, Isaria fungi have rigorous secondary metabolisms through different pathways, including non-ribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and terpenoid synthetase (TS), which produce various secondary metabolites (SMs), such as ribosomal peptides (NRPs), polyketides (PKs), terpenoid and miscellaneous types. 5,21,22 According to the research (patents not included) published in the past forty years, it is estimated that more than 200 SMs have been isolated and identied from both Isaria fungi. Many SMs are the functional components with anti-virus, anti-bacteria, and anti-tumor activity and immunity regulation. 23,24 Interestingly, SMs are considered as important drug resources. For example, ngolimod, a novel type of immunosuppressive agent, is a new medicine derived from I. sinclairii, which is used for treating multiple sclerosis, renal cancer, and asthma. 25,26 However, many SMs belong to mycotoxins, which are toxic to humans and animals. Nevertheless, there are few documents reviewing the risks of Isaria fungi mycotoxins. Thus, the current review focuses on the mycotoxins of both Isaria fungi, including their structures, bioactivities and toxicities, as well as their risk evaluation.
2 SMs from I. cicadae I. cicadae produces numerous SMs (Table 1 and Fig. 2). Using metabolism omics analysis, Lu et al. reported that more than 110 compounds were detected in the mycelia, primordia and stroma stages of the fungus. 5 While eight compounds were found in C. cicadae sporoderm-broken spore powders (CCBSP) using UPLC-ESI-Q-TOF-MS, and forty-nine volatile molecules representing 99.56% of CCBSP were clearly identied by GC-MS. 27 Moreover, another experiment reported that 60 metabolites including amino acids and their derivatives, saccharides, organic acids and fatty acids were identied in the methanol extract of the complex of the cicadae body and I. cicadae stroma, while inositol, gamma-aminobutyric acid, ornithine and threonine were the most abundant compounds. 28 Based on their molecular structures, I. cicadae SMs are mainly categorized as organic acids, amino acids, lipids and phospholipids, nucleosides, carbohydrates and their derivatives. Among them, some compounds are functional or bioactive components, for example, cordycepin (1) and cordycepic acid (3) are considered as the bioactive components of I. cicadae, similar with Cordyceps spp. 29 Furthermore, many other compounds such as adenosine, guanosine, uridine, inosine and thymidine and other nucleosides, ergosterol and its peroxide, and D-mannitol benecial for pharmacological functions. 30,31 However, some of the SMs are toxic to humans and animals, while probably most SMs are unknown, and their molecular structures and biological functions have not been elucidated. 5 The main nucleoside of this fungus is cordycepin (1), 3 0 -deoxyadenosine, which was isolated from the sporoderm-broken spore powders and fruit bodies of C. cicadae. 27,32 As an adenosine derivative, it is an important parameter for quality control in medicines, referring to Dongchongxiacao CORDYCEPS, Cordyceps sinensis (BerK.) Sacc. in the Chinese Pharmacopoeia, 2015. Since cordycepin (1) is similar to adenosine, it can participate in certain biochemical reactions (for example, be incorporated into an RNA molecule, thus causing the premature termination of its synthesis) 33 and has multiple bioactivities such as anti-cancer, antimetastatic, antioxidant, antidepressant and immunoregulation properties. [34][35][36][37] It also enhances male reproduction by stimulating in vitro and in vivo steroidogenesis in mouse Leydig cells by activating the PKA pathway. 38 In 2007, the US Food and Drug Administration (FDA) granted cordycepin orphan drug designation for the treatment of TdT-positive acute lymphocytic leukemia (https://www.fda.gov/). Cordycepin plus pentostatin was subjected to a clinic trail of phase 1/phase 2 in patients with refractory TdT-positive leukemia in 2008-2010 (https://www.clinicaltrials.gov/). In China, it was reported that cordycepin was used for clinic adjuvant treatment of non-small cell lung cancer 39 and nephropathy of type 2 diabetes mellitus. 40 However, the main fungal species used to produce cordycepin in industry is C. militaris. 41 Another adenosine derivative, N-(2-hydroxyethyl) adenosine (2) was isolated and proven to exhibit antioxidant activity by measuring its radical scavenging effect on 1,1-diphenyl-2picrylhydrazyl (DPPH) radicals. 42  Bactericidal and insecticidal activities, as well as growthinhibitory effects on some pathogenic fungi Cycloheximide acid A (19) 1610848-67-3 Mycelia, cultivated complex of fruit body of C. cicadae CCAD02 and Antheraea pernyi 2-(3-Carboxy-2-hydroxypropyl)-3methyl-2-cyclopentenone (20) 1019196-  Cultivated mycelia of C. cicadae (21) 1018901-08-0 Cultivated mycelia of C. cicadae Cordycepic acid (3) (D-mannitol), an isomer of quinic acid with a polyol structure, was isolated from sporoderm-broken spore powders. 27 It is believed to be another active ingredient and is used as an important index of quality control for C. sinensis products. It exhibits diuretic action and prophylaxis against postoperative acute renal failure, relieving cough and asthma, and anti-free radical activities. Specically, it can be used to provide effective protection or treatment for patients aer cerebral ischemia and trauma, such as improving cerebral microcirculation and cerebral blood ow. 43 The amino derivative betaine (4) (N,N,N-trimethylglycine), which was rst found in sugar beet in the nineteenth century, was detected in the mycelia, primordia and stroma of C. cicadae. 5 Betaine (4) is a methyl donor of increasingly recognized signicance in biology, and serves as an organic osmolyte, which is a substance synthesized or taken up from the environment by cells for protection against osmotic stress, drought, high salinity, and high temperature. 44 Hercynine (5), a derivative of histidine, was detected in the mycelia, primordia and stroma of C. cicadae. 5 However, ergothioneine (6) was identied in its fruit body and mycelia. 45 Hercynine (5) is considered as the primer for ergothioneine biosynthesis, which is a secreted antioxidant that protects cells from oxidative stress. 46 Fumimycin (7), an unusual metabolite incorporating an unusual alanine unit linked to a phenyl group at the alpha-carbon with both lactone and amide moieties, was rst isolated from Aspergillus fumisynnematus, and it was detected in the mycelia, primordia and stroma of C. cicadae. 5 It showed antibacterial activity against Staphylococcus aureus with an IC 50 value of 4.1 mM, inhibiting peptide deformylase. 47 Cordysinin A (8), a diketopiperazine rst identied from C. sinensis, 48,49 was detected in the mycelia of C. cicadae. 5 It shows activity in inhibiting the proliferation of human glioma U87-MG and U251 cells. 50 It has anti-inammatory activity in human neutrophils, which was assessed by its inhibition of FMLP/CBinduced superoxide anion generation (https:// pubchem.ncbi.nlm.nih.gov).

57-87-4
A strain of cell fusion from C. cicadae and C. militaris 3-Benzyl-6-isopropyl-2,5piperazinedione (31) 14474-71-6 A strain of cell fusion from C. cicadae and C. militaris acute toxicity of myriocin is too high for therapeutic purposes. It had intraperitoneal toxicity with an LD 50 of 5-10 and 2-5 mg kg À1 for mice and rats, respectively, and resulted in the death of dogs 48-72 hours aer they were treated by subcutaneous injection of 0.25 mg kg À1 . 63 Therefore, myriocin did not attract more attention until it was found in the culture broth of the strain CTCC 24400 of I. sinclairii and exhibited 10-to 100-fold more potency than cyclosporin A as an immunosuppressive agent of the immune response in vitro and in vivo. 64 In 1995, a novel immunosuppressant, FTY720 (ngolimod), was rst synthesized and screened based on the knowledge that 2substituted 2-aminoethanol is the minimum essential structure for the immunosuppression activity of myriocin. 65,66 Different from the action mechanism of myriocin, which inhibits serine palmitoyl transferase, FTY720 is a sphingosine 1-phosphate (S1P) receptor modulator, which is mainly phosphorylated by sphingosine kinase 2 in vivo. The phosphorylated drug (-P) acts as a potent agonist of four of the ve G protein-coupled receptors for S1P: S1P(1), S1P (3), S1P(4), and S1P(5). 67 FTY720 is now used worldwide for the treatment of multiple sclerosis. 68 Phytosphingosine (16), a myriocin-like long-chain compound, was also found in the mycelia, primordia and stroma of C. cicadae. 5 In the budding yeast Saccharomyces cerevisiae, the endoplasmic reticulum stress surveillance pathway is activated by phytosphingosine, which ensures that daughter cells inherit a functional ER. 69 Oosporein (17), an important dibenzoquinone pigment identied early, 70 was also detected in the mycelia, primordia and stroma of C. cicadae. 5 It exhibited median oral toxicity to 1 day-old cockerels. 71 Oosporein inhibits total erythrocyte membrane ATPase activity in a dose-dependent manner due to alterations in erythrocyte morphology and promotes varying degrees of cell lysis. 72 Oosporein also exhibits broad spectrum in vitro antimicrobial, antioxidant and cytotoxic activities. 73 Oosporein is a rather strong organic acid and can hardly be adsorbed by organisms; thus, oosporein is unlikely to enter the food chain and inuence human health. 74 Also, this fungus produces other pigments and is considered as a resource of natural color materials for the food industry. 75,76 However, the exact components in its pigments are not clear.
The trichothecene derivative, 4-b-acetoxyscirpendiol (4-ASD) (39) was isolated from the fruit body in 2001, which induced apoptosis in human leukemia cells (HL-60). 83 It lowered the blood sugar levels in the circulatory system by inhibiting Na + / glucose transporter-1 (SGLT-1) 84 and also showed signicant apoptosis-inducing activity in various human cancer cell lines. 85 Tenuipesine A (40) and paecilomycines A-C (41-43) were isolated from the cultivated fruiting bodies also, but only paecilomycine A (41) exhibited activity in neurotrophic factor biosynthesis in glial cells. 86,87 The spirocyclic trichothecanes, spirotenuipesines A (44) and B (45), were isolated from fruiting body grown in barley grain. The two compounds had the potent activity in neurotrophic factor biosynthesis in glial cells. 88 As is known, trichothecenes are very important mycotoxins with multiple toxicities including carcinogenic, teratogenic and mutagenic effects. 89 Cyclopenta benzopyran and penostatins A-C (46-48) and J (49) were isolated in 2014 by Chen et al. All of them are protein tyrosine phosphatase 1B (PTP1B) inhibitors. 90 In fact, penostatins A-C were identied in a strain of Penicillium sp. originally separated from the marine alga Enteromorpha intestinalis. They exhibited signicant cytotoxicity against cultured P388 cells. 91 I. tenuipes produces isariotins, which are alkaloids probably biosynthesized through the hybrid NRPS-PKS pathway. Isariotins A-D (50-53) were isolated from the culture broth of I. tenuipes   (62), were isolated from the fruiting bodies of I. japonica cultivated on silkworm pupae. 96,97 Hanasanagin (61) exhibited antioxidant activity, but 3,4-diguanidinobutanoyltyrosine (62) showed no antioxidant activity. 96,97 In addition, I. tenuipes produces the depsipeptide beauvericin (9). It was conrmed that beauvericin is one of the active principles of three strains of I. tenuipes, which strongly inhibited mycelial growth of the two phytopathogens Phytophthora sojae and Aphanomyces cochlioides. 98

Problems and perspectives
In recent years, the concerns about the safety risks of medical and edible Isaria fungi have been attracting the attention of researchers and consumers. In fact, several research reports about the biosafety analysis of both fungi were published.
For I. cicadae, there were four reports indicating its safety to humans, but one report demonstrated its toxicity to the kidneys ( Table 3). The possible toxicity arising from repeated exposure to freeze-dried submerged mycelial culture of C. cicadae for 90 days was evaluated. The results indicated that there were no adverse effects to male and female Sprague Dawley rats by gavage >2000 mg kg À1 C. cicadae whole broth. 99 Also, toxicological effects were not recorded in the adult Sprague Dawley rats administered orally with a complex powder suspension of P. sinclairii and larvae of Bombyx mori at doses ranging from 0.008 to 5 g kg À1 body weight for 2 weeks, except for a decline in the weight of the thymus in males. 100 The extract of wild C. cicadae fruit bodies was not toxic to mice even at a dosage of 80 g kg À1 , which was 444 times the clinical daily dosage. 101 Moreover, the genotoxicity of the fruiting bodies of I. sinclairii together with its parasitic host larva was evaluated by using short-term genotoxicity tests, namely, the Ames, chromosome aberration (CA), and micronuclei (MN) tests. The results indicated that this complex has no mutagenic potential in the in vitro and in vivo systems. 102 However, concerns about the nephrotoxicity of the complex of P. sinclairii and its host insect (Bombyx mori) have been raised. Kidney toxicity was investigated aer 13 weeks of administering the complex orally to rats. Dosedependent kidney cell karyomegaly and tubular hypertrophy were observed. There was a dose-dependent increase in kidney injury molecule 1 (KIM-1) and matrix metalloproteinase 1 (TIMP-1) levels in the kidney and urinary KIM-1, cystatin C, beta-2-microglobulin, and osteopontin levels. KIM-1 and TIMP-1 increased in the male kidneys, and they did not recover 2 weeks aer stopping exposure. Cystatin C in the kidney was signicantly lowered in all treatment groups at 13 weeks of administration. All the changes were more noticeable in males. 14 In addition, some clinical cases of poisoning by eating wild the complex of C. cicadae and the host insect (Cicadae ammata) were reported in China. 103 For I. tenuipes, there were two different research reports about its biosafety (Table 3). In the rst report, the genotoxicity, acute and subchronic toxicity of the water-macerated extracts of its fungus fruiting bodies were evaluated in Korea. 104 The acute oral LD 50 to rats was >2000 mg kg À1 of body weight. In the subchronic test, the oral treatment of rats with 500, 1000 or 2000 mg kg À1 extract daily for 13 weeks did not induce any doserelated changes (body weight, food consumption, clinical observation, urinalysis, hematology, clinical chemistry and organ weight). However, histopathological observation revealed that the I. tenuipes extract induced karyomegaly in the outer medulla of the kidneys of all the treated rats. Importantly, the I. tenuipes extract exerted mutagenic potential in the Ames assay.
Since karyomegalic alterations are known to be associated with carcinogenicity, I. tenuipes probably has the risk of carcinogenicity. 104 In the second experiment, the aqueous and ethanol extracts of I. tenuipes N45 caused neither mortality nor toxicological signs in mice and rats with the maximum tolerance dose of 15 g kg À1 . No mortality or adverse effects was observed in the subchronic toxicity tests, in which no signicant difference in bodyweight, relative organ weight or hematological parameters, and no abnormality of internal organs were found between the treatment and control groups. This suggests that the fungus extract is safe. 105 Obviously, there are contradictions in these research reports, but some safety risks indeed exist in the both fungi. Of course, the toxicity is based on the substances in the fungus or the complex of the fungus and its insect hosts. Thus, from rational deduction, the toxicities of both Isaria fungi to humans may be related to the toxic MSs described above; however, this needs to be further validated because other toxic substances including mycotoxins and macro biological molecules in both fungi may not have been discovered yet. Also, their toxicity is related to the genetic backgrounds of the fungal strains and the hosts, and their growing environment and culture conditions. 106 In fact, different fungal strains under the same culture conditions or the same strain under different culture conditions, usually produce different toxic substances. 107,108 Therefore, controlling the culturing conditions and growth environments of Isaria fungi is very important for the quality and safety management of their fungal products.
To date, the products of I. cicadae and I. tenuipes have no standards for quality and safety control. Referring to C. sinensis in the Chinese Pharmacopoeia, 2015, the adenosine marker is the key parameter for quality control. Cordycepin and No acute toxicity to mice even at a dosage 80 g kg À1 for 7 days, which was 444 times the clinical daily dosage Water extract from the powder of P. sinclairii from the National Institute of Agricultural Science and Technology (Suwon, Korea) No toxicological effects to the adult Sprague Dawley rats orally treated at doses of 0.008-5 g kg À1 body weight for 2 weeks, except for a decline in the weight of the thymus in the males Extract of phosphate buffered saline (PBS) from the complex of the fruiting bodies of I. sinclairii and its parasitic host larva (Rural Development Administration, Korea) In the Ames test, no mutagenic response in the absence or presence of 59 mix with TA98, TA100, TA1535, and TA1537. In the chromosome aberration (CA) test, no signicant effect on Chinese hamster ovary (CHO) cells. In the micronuclei (MN) test, no signicant change in the occurrence of micronucleated polychromatic erythrocytes in male ICR mice intraperitoneally administered at doses of 15, 150, or 1500 mg kg À1 Powder of the cultured fruiting bodies of P. sinclairii (isolated from parasitizing dead or living Cicadae subspecies) and its silk worm larvae hosts (Rural Development Administration, Korea) Kidney toxicity was investigated aer 13 weeks of administering the complex orally to Sprague Dawley rats at doses of 0, 5000, 10 000, and 50 000 ppm. Dose-dependent kidney cell karyomegaly and tubular hypertrophy were observed, with higher severity in males. There was a dose-dependent increase in kidney injury molecule 1 (KIM-1) and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) levels in the kidney and urinary KIM-1, cystatin C, b2m, and osteopontin levels. KIM-1 and TIMP-1 increased in the male kidneys, and they did not recover 2 weeks aer stopping exposure. Cystatin C in the kidney was signicantly lowered in all treatment groups at 13 weeks of administration. All the changes were more noticeable in males. These data indicate that the complex damages renal tubule cells with histopathological lesions and changes in biomarker levels. Kidney and urinary KIM-1 and cystatin C were the most markedly affected and early increased indicators among the biomarkers tested; whereas, blood urea nitrogen (BUN) and creatinine were not affected Aqueous and ethanol extracts of I. tenuipes N45 (CCTCC M2011145) (P. tenuipes RCEF 4339, Anhui Agricultural University, China) In acute toxicity, neither mortality nor toxicological signs were found in mice and rats with the maximum tolerance dose of 15 g kg À1 . No mortality or adverse effects was observed in the subchronic toxicity studies, in which no signicant difference in bodyweight, relative organ weight or hematological parameters, and no abnormality of internal organs were found between the treatment and control groups Water extract from the powder of fruiting bodies of P. tenuipes (Korea Food Research Institute, Seongnam, Korea) The acute oral LD 50 to Sprague Dawley rats was estimated to be greater than 2000 mg kg À1 of body weight. In the subchronic study, the oral treatment of rats with 500, 1000 or 2000 mg kg À1 daily for 13 weeks did not induce any dose-related changes (body weight, food consumption, clinical observation, urinalysis, hematology, clinical chemistry and organ weight). In contrast, histopathological observation revealed that the extract induced karyomegaly in the outer medulla of the kidney in all the treated rats. In the Ames tests, the extract signicantly produced His + mutants at the highest concentration of 5000 lg per plate in S. typhimurium TA102 and 1535 without S9 mix. In the presence of S9 mix, it also signicantly produced His + mutants in TA98, 100 and 102 at 5000 lg per plate of the extract. The increase in His + mutants was dosedependent although it was less than 2-fold in comparison to that of the control group cordycepic acid are considered as the bioactive components. 29 Their other functional compounds such as nucleosides, amino acids, fatty acids and carbohydrates are attracting researchers attention and certain detection methods have been developed. 31,109 However, to absolutely ensure the safety of the products of both fungi, only detecting their functional components is not sufficient. Two other aspects must be emphasized. First, identication standards for both fungi and hosts must be developed. As it is known, distinguishing fungal species based on their morphological features is very difficult, especially in commercially processed products. A good choice is may be methods based on DNA. In fact, DNA barcode-based species-specic sequence characterized amplied region (SCAR) markers to discriminate authentic herbal Cordyceps medicines and Cordyceps-derived dietary supplements from related but inauthentic species were recently reported. The ITS-based SCAR markers and the real-time PCR assay constitute a useful genetic tool for preventing the adulteration of Cordyceps and Cordycepsrelated dietary supplements. 110 Second, the accurate detection and differentiation of toxic components (mycotoxins) in the products of both fungi must be established. Furthermore, residue standards of their toxic components should be developed. In recent years, metabonomics based on GC/HPLC-MS has been used for the analysis of Cordyceps compounds 5,28,111 and other effective methods such as HPLC ngerprint for functional substances have also been developed. 31,109,112 These technologies will support the detection and identication of SMs in the both Isaria fungi and their products.
In conclusion, both I. cicadae and I. tenuipes are important edible and medicinal fungal species with multiple pharmacological functions. They produce various SMs that affect the quality and safety of their fungal products. For I. cicadae, its SMs include nucleosides, amino acids, beauvericins, and myriocin, oosporein. For I. tenuipes, trichothecene derivatives, isariotins, cyclopenta benzopyrans and PKs were found. Among them, beauvericins, myriocin, oosporein and many trichothecene derivatives are toxic compounds. Thus, the toxicity and sideeffects of the fungal products of I. cicadae and I. tenuipes may be related to these SMs. To ensure the quality and safety of their fungal products, residues standards for their SMs must be developed. Furthermore, methods for SM detection and strain biological identication must be give attention.

Conflicts of interest
The authors declare no conict of interests.