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Cordycepin: A Cordyceps Metabolite with Promising Therapeutic Potential

For thousands of years, natural products from medicinal mushroom are being used for the cure of different lethal diseases. Among the huge category of medicinal herbs, the genus Cordyceps is gaining special attention due to its broad spectrum of biological activity. Cordycepin, a nucleoside analogue, is the main bioactive ingredient of Cordyceps and known to mediate a variety of pharmacological effects. Many chemically modified cordycepin derivatives

Have been reported which have shown more potential therapeutic effects. With the advancement in fermentation techniques, it has been possible to produce the higher cordycepin product. The modern techniques enabled the researchers for an easy detection and extraction of cordycepin from fermentation medium. Being a nucleoside analogue, cordycepin can interfere with the DNA/RNA biosynthesis and acts as a potential candidate for the treatment of the dreadful diseases such as cancer. Besides, cordycepin have also been known to modulate a variety of signaling pathways involved in apoptosis, proliferation, metastasis, angiogenesis, and inflammation. This chapter will describe the chemistry, production, detection, and extraction strategies of cordycepin. In addition, variety of therapeutic applications of cordycepin with all possible molecular mechanisms of actions have also been summarized.

Cordycepin: A Cordyceps Metabolite with Promising Therapeutic Potential

Although there is an availability of numerous resources to design new therapeutic tools, the natural products are still preferred over the synthetic as they do not have any side effects. About 50 % of prescribed drugs in the USA are either the natural products or their structurally modified compounds [1, 2], which further increases the curiosity about the importance of these natural compounds in medical biology. There have been limited studies about the phytochemistry of the medicinal plants/herbs and their pharmacological potential. Today, the advancement in the research facilities and medical field has enabled us to carry out production, isolation, and identification of bioactive molecules. The modern tools such as ultraviolet, infrared, nuclear magnetic resonance, and mass spectrometry can help to identify an individual compound in a very short period of time.
Medicinal mushrooms have been known for thousands of years to produce a variety of biometabolites, which are being used as a possible therapeutic tool for the treatment of different diseases [3]. Over two third of cancer-related deaths could be prevented or reduced by modifying our diet with eatable mushrooms, as they contain many antioxidants [4, 5]. Cordyceps militaris is one of the medicinally important mushrooms, which has remarkable biomedical and pharmacological activities. The name Cordyceps has been derived from two Latin words, i.e., cord and ceps meaning club and head, respectively. Cordyceps militaris belongs to the Phylum Ascomycota classified in the Order Hypocreales, as spores are produced internally in sacs called ascus [6, 7].
Cordyceps, especially its extract, contains many biologically active compounds, including cordycepin, cordycepic acid, adenosine, exopolysaccharides, vitamins, and enzymes. Among these, cordycepin or 3′-deoxyadenosine (9-(3-deoxy-p-D-ribofuranosyl) adenine), a nucleic acid antibiotic, is the main active constituent
which is most widely studied and have a broad spectrum of biological activity [8]. Cordycepin is known to interfere with various biochemical and molecular processes such as purine biosynthesis, DNA/RNA synthesis, and mTOR (mammalian target of rapamycin) signaling transduction [3, 9]. It is predominantly produced commercially via solid-state fermentation and submerged cultivation of Cordyceps. Considerable effort is currently focused on three aspects of cordycepin production: strain screening and improvement, additives, and optimizing fermentation. However, high-efficiency batch fermentation of C. militaris is carried out in static culture for more than 30 days, which is too long to achieve high production efficiency and low operational cost and energy consumption [10]. Therefore, various methods have been proposed to extract and analyze bioactive metabolite like cordycepin from liquid culture as well as the fruiting body of C. militaris. This chapter reveals about the various production and extraction strategies adopted by the researchers for maximum gain of cordycepin. Furthermore, this chapter will update us about the potential applications of cordycepin as a therapeutic agent.

2.Chemistry of Cordycepin
The chemical formula of cordycepin (9-(3-Deoxy-p-D-ribofuranosyl) adenine) is C1oH13N5O3 and its melting point is 228^231 °C. The structure of cordycepin shows that it has a molecular weight of 251.24 Da. Its UV spectrum reveals strong absorption bands at « 259.0 nm [11]. The NMR spectrum of cordycepin shows singlet at 3.4 ppm, which can be attributed to C-H proton. The -NH2 peak is found to present at 4.6 ppm, whereas the absorption peaks due to different -OH groups are found to be in the range of 8-8.5 ppm. The signals due to R3-CH and -N-C-H protons can be observed at 2.3 and 2.5 ppm, respectively [12]. The structure of cordycepin comprises a purine nucleoside molecule attached to a ribose sugar moiety via a p-N9-glycosidic bond (Fig. 1). Chemical synthesis of cordycepin is mainly achieved by the replacement of deoxyribose ring 3′ CO bond to form 2′, 3′-epoxy deoxyribose structure and region stereo-selective open-loop and direct synthesis of 3-deoxyribose derivatives. In a study, [13] investigated the synthesis of cordycepin monophosphate either via treatment of cordycepin with cyanoethyl phosphate in the presence of N, N-dicyclohexylcarbodiimide via enzymatic transference of phosphate from uridine 5′-phosphate to cordycepin [13]. Cordycepin analogue of 2-5A (2-5 linked oligoadenylate) has also been synthesized and found to be a potent antiviral agent with comparison to natural molecule [14, 15]. The synthesis of N-acyl-cordycepin derivatives using alkyl chain has also been prepared. The resultant derivatives were not only observed to protect fast oxidation of cordycepin but also enhance its bioavailability and bioactivity [16]. Also, there have been immense possibility toward the formation of cordycepin-based metal complexes due to the presences of electron-donating atoms (N and O) in its structure and can easily donate their lone pairs of electron to the empty d orbital of the metal atoms [11].

3.Fermentation Strategy for Cordycepin Production
The medicinal mushrooms are abundant sources of useful natural products with various biological activities. Therefore, the extensive research has been seen in the past few decades on isolation and characterization of bioactive molecules from medicinal mushrooms [17]. Evidences suggested that most of the active contents of the mushrooms are being extracted from their fruiting bodies while fewer parts are derived from mycelium culture [18]. Since there is a huge requirement of medicinal mushroom-based biometabolites, it is necessary to cultivate mycelium biomass artificially for which variety of methods for its cultivation have been proposed by many research groups [19-21]. The Cordyceps mycelium can grow on different nutrients containing media, but for commercial fermentation and cultivation, insect larvae (silkworm residue) and various cereal grains had been used in the past. It has been seen consistently that from both insect larvae and cereal grains, fruiting body of fungus can be obtained with almost comparable medicinal properties [22].
There are basically two fermentation techniques by which the cultivation of mycelium biomass of Cordyceps can be achieved including surface and submerged fermentation. In surface fermentation, the cultivation of microbial biomass occurs on the surface of liquid or solid substrate. While in submerged fermentation, microorganisms are cultivated in liquid medium aerobically with proper agitation to get the homogenous growth of cells and media components [23]. Some reports are mentioned below describing the cordycepin production using submerged and surface fermentations.
Mao et al. (2005) studied the effects of various carbon sources and carbon/ nitrogen ratios on production of cordycepin by submerged cultivation. The highest cordycepin production, i.e., 245.7 ± 4.4 mg L-1 on day 18, was obtained with
medium containing 40 g glucose L-1. Further, using central composite design and response surface analysis, cordycepin production and productivity was increased up to 345.4 ± 8.5 and 19.2 ± 0.5 mg L-1 day-1, respectively [24]. Similarly, the production conditions of cordycepin using surface culture technique were investigated by Masuda et al. [25]. They reported that under the optimal conditions, the maximum cordycepin concentration in the culture medium reached 640 mg L-1, and the maximum cordycepin productivity was 32 mg L-1 day-1. Further, Masuda et al. (2011) studied the effects of adenosine on cordycepin production in a surface liquid culture of the mutant and the wild-type strains [26]. For the mutant strain, the maximum levels of cordycepin production with and without adenosine were 8.6 and 6.7 g L-1, respectively. The effects of nitrogen sources (NH4+) on cell growth and cordycepin produced by submerged cultivation of Cordyceps militaris were studied by Mao et al. [27]. The authors found that by optimizing the feeding time and feeding amount of NH4+, a maximal cordycepin concentration of 420.5 ± 15.1 mg L-1 could be obtained. Similarly, [28] investigated the influence of initial pH value, various nitrogen sources, plant oils, and modes of propagation (shake flask and static culture) on the production of fungal biomass, exopolysaccharide (EPS), adenosine, and cordycepin using Cordyceps militaris CCRC 32219 [28]. They employed a Box-Behnken experimental design to optimize the production of cordycepin and achieved up to 2214.5 mg L-1 of cordycepin. Effect of ammonium feeding on cordycepin production was also investigated by Leung and Wu [29]. The authors reported that cordycepin production increases nearly fourfold (from 28.5 to 117 l ^g g-1) by the supplementation of 10 mM NH4Cl. However, at higher concentration, they found its negative effect on mycelium growth. In a study, Das et al. (2009) used mutant of the medicinal mushroom Cordyceps militaris for higher cordycepin production [30]. Among all the mutants, G81-3 had the highest cordycepin production of 6.84 g L-1 under optimized conditions compared to that of the control of 2.45 g L-1 (2.79 times higher). In addition, influences of different additives on the cordycepin production such as glycine and adenosine were also studied by the authors and found that cordycepin production can be increased up to 8.57 g L-1. Xie et al. (2009) optimized fermentation temperature, pH, and medium capacity using Box-Behnken design and showed that highest dry mycelium weight (19.1 g L-1) and cordycepin (1.8 mg g-1) can be obtained at temperature 28 °C, pH 6.2, and medium capacity 57 mL [31]. In another study, [32] explored the effect of inoculation on cordycepin production in surface fermentation using Cordyceps militaris [32]. Results showed that cordycepin production increases with increase in inoculum size. The effect of ferrous sulfate addition to production of cordycepin (3′-deoxyadenosine) has also been investigated in submerged cultures of Cordyceps militaris in shake flasks [33]. Researchers showed that at a concentration of 1 g L-1 of ferrous sulfate addition results in 70 % higher cordycepin production compared to control experiment. The effect of liquid culture conditions on extracellular secretion of cordycepin from C militaris was investigated in ref. [34]. They reported the optimal cultural conditions as follows: initial pH 7, cultivation temperature 24 °C, shaking

speed 180 rpm, and cultivation period 9 days. They observed that these culture conditions led to reach cordycepin content of up to 0.537 gL-1 in the culture fluid. In another study, Zhang et al. (2013) applied response surface methodology (RSM) to optimize the medium components for the cordycepin production by submerged liquid culture [35]. They also suggested that repeated batch operation could be an efficient method to increase the cordycepin yield. Recently, Kang et al. (2014) studied single-factor design, using Plackett-Burman and central composite design to establish the key factors responsible for cordycepin production. They reported that maximum cordycepin up to 2 g L-1 could be achieved with working volume of 700 mL in the 1000 mL glass jar [36]. Similarly, Jiapeng et al. (2014) carried out fermentation to optimize maximum production of cordycepin in static culture using single-factor experiments with Placket-Burman and a central composite design. They demonstrated a maximum cordycepin yield of 7.35 g L-1 that can be achieved in a 5 L fermenter under the optimized conditions [37].

4.Analysis Tool for Cordycepin Detection
Nowadays different products of Cordyceps are available in the market, as health supplement or neutraceuticals. Hence, it is very important to analyze the presence of cordycepin for its quantitative as well as qualitative analysis [38]. Several techniques such as thin layer chromatography, high performance liquid chromatography (HPLC), and capillary electrophoresis have been reported in the analysis of the cordycepin present in medicinal herb Cordyceps. Herein, the development in biochemical analysis of cordycepin is reviewed and discussed.

5.Thin Layer Chromatographic Analysis
Thin layer chromatography (TLC) is known to be an easy and versatile method for separation of mixture of chemical components. Kim et al. (2006) developed TLC plates in chloroform/ methanol/water (64:14:1). The spots of separated molecules were stained with 10% sulfuric acid solution (in ethanol) for visualization [39]. Ma and Wang (2008) established a dual wavelength TLC-scanning method for the determination of nucleosides in the preparation of Cordyceps sinensis and analyzed the samples on silica GF254 thin layer plate using 1 % CMC-Na (carboxyl-methyl-cellulose) as adhesive and chloroform-ethyl acetate-isopropanol-water-ammonia (8:2:6:0.5:0.12) as developing agent [40]. Hu and Fang (2008) compared the similarity between chemical components of Cordyceps sinensis and solid fermentation of Cordyceps militaris by TLC. They showed that solid fermentation of Cordyceps militaris and Cordyceps sinensis were basically similar in terms of their TLC spots occurred at the corresponding place except for a slight difference in size [41].

6.Spectrometry Analysis of Cordycepin
The spectrophotometric detection of cordycepin is based on its color reaction with anthrone. It has been reported that cordycepin reacts with a slightly modified anthrone (0.2 g anthrone in 100 mL 90 % H2SO4) reagents at high temperature, which results in the production of a cherry-red color [42]. The reaction was reported negative with adenine.

7.HPLC Analysis of Cordycepin
A simple high performance liquid chromatography (HPLC) with UV detection (HPLC-UV) method was proposed for the detection of cordycepin [43-46]. Chang et al. (2005) determined the concentrations of adenosine and cordycepin, 3′ deoxyadenosine in the hot water extract of a cultivated Antrodia camphorate by HPLC method. The procedure was carried out on a reversed-phase C-18 column [47]. Meena et al. (2010) compared the cordycepin content in natural and artificial cultured mycelium of Cordyceps using reverse phase HPLC [48]. In addition, though UV detection is widely used for chromatographic analysis, MS detection allows more definite identification and quantitative determination of compounds which may not be fully separated. ESI-MS in positive mode is most commonly used in the analysis of nucleosides in Cordyceps

8.Capillary Electrophoresis
Ling et al. (2002) determined the content of cordycepin by capillary zone electrophoresis in ultrasonic extracted Cordyceps for the first time [51]. Similarly, Rao et al. (2006) investigated a modified capillary electrophoresis (CE) procedure with UV detection at 254 nm for determination of cordycepin. They found 20 mM sodium borate buffer with 28.6 % methanol, pH 9.5, separation voltage 20 kV, hydrodynamic injection time 10 s, and temperature 25 °C were the optimal conditions for cordycepin detection [52]. Furthermore, Yang et al. (2009) developed capillary electrophoresis-mass spectrometry (CE-MS) method for the simultaneous analysis of 12 nucleosides and nucleobases including cytosine, adenine, guanine, cytidine, cordycepin, adenosine, hypoxanthine, guanosine, inosine, 2′-deoxyuridine, uridine, and thymidine in natural and cultured Cordyceps using 5-chlorocytosine arabinoside as an internal standard (IS). They optimized systematically for achieving good CE resolution and MS response tested compounds and found optimum parameters as follows: 75 % (v/v) methanol containing 0.3 % formic acid with a flow rate of 3 pL min-1 as the sheath liquid; the flow rate and temperature of drying gas were 6 L min-1 and 350 °C, respectively

9.Extraction Strategy for Cordycepin
Being a biologically active molecule, a large quantity of pure cordycepin is urgently needed for further studies. Several extraction methods have been developed to extract cordycepin from the fermentative fluid and fruiting bodies of C. militaris, including ultrasound- or microwave-assisted extraction, pressurized extraction, soxhlet extraction, and reflux extraction. Some of them are discussed as follows.

Kredich and Guarino (1960) gave the first report on cordycepin extraction from liquid culture of Cordyceps militaris. They concentrated the fermented broth in an evaporator at 50 °C followed by cold precipitation and removal of impurities. Further, the obtained sample was passed through a column packed with Dowex-I-chloride of 200-400 mesh size [42]. In another study, Wang et al. (2004) compared supersonic water extraction, supersonic ethanol extraction, hydrothermal refluxing extraction, and ethanol thermal refluxing extraction for cordycepin and polysaccharide extraction using an orthogonal design experiment. They showed that hydrothermal refluxing extraction was the best extraction method of cordycepin and polysaccharide and its optimal technological conditions were optimized [54]. Rukachaisirikul et al. (2004) isolated and analyzed nine compounds from fungal mycelium as well as from liquid culture of Cordyceps militaris. Out of these, three were 10-membered macrolides, two were cepharosporolides, 2-carboxymethyl-4-(3′-hydroxybutyl) one was, furan, one was cordycepin, and one was pyridine-2, 6-dicarboxylic acid [55]. From dried fruiting bodies of Cordyceps militaris, Kim et al. (2006) extracted cordycepin using solvent-solvent extraction method. They extracted aqueous layer of crude fermented broth with hexane, butanol, and ethyl acetate [39]. Similarly, Rao et al. (2010) extracted and purified ten pure compounds, including cordycepin from the fruiting body of Cordyceps militaris [56]. Still, all these methods need optimization and were unsuitable for industrial applications. Jiansheng (2008) extracted and purified cordycepin from Cordyceps militaris using ion-exchange resin and silica gel column chromatography. They detected cordycepin on HPLC, LC/MS, and CE [57]. In a study, Wei et al. (2009) presented an efficient method of extracting and purifying cordycepin from the waste of the fruiting body production medium. This method included continuous counter-current extraction followed by column chromatography using 732 cation exchange resins. They found under optimized conditions cordycepin extraction yield reached up to 66.0 % [16]. Ni et al. (2009) developed column chromatography extraction (CCE) method for the extraction of cordycepin from the solid waste medium of Cordyceps militaris. The dried waste material was imbibed in water for 6 h and transferred to the columns and eluted with water. Eluates were directly separated with macroporous resin DM130 columns followed by purification steps with more than 95 % extraction yield [23]. Song et al. (2007) investigated optimization of cordycepin extraction from cultured Cordyceps militaris by HPLC-DAD coupled method. They reported that cordycepin extraction yield reached a peak with ethanol concentration 20.21 %, extraction time 101.88 min, and volume ratio of solvent to sample 33.13 g mL-1 [58]. The supercritical fluid extraction (SFE) method was purposed to extract cordycepin and

adenosine from the Cordyceps kyushuensis by Ling et al. (2009). They applied orthogonal array design (OAD) test, L9 (3)4 followed by preparative SFE extraction using high-speed counter-current chromatography (HSCCC). Their results yielded 8.92 mg of cordycepin and 5.94 mg of adenosine with purities of 98.5 % and 99.2 % from 400 mg SFE crude extraction, respectively [59]. Yong et al. (2010) compared six kinds of cordycepin extraction method from Cordyceps militaris medium. The authors got a higher extraction rate of cordycepin using microwave extraction method [60]. Zhang and his colleagues (2012) optimized the cordycepin extraction from the fruiting body of Cordyceps militaris YCC-01 using water, ethanol, ultrasonic, and synergistic approaches. They found that a synergistic approach was more efficient with cordycepin content of 9.559 mg g_1. Results suggested that the yield was 66.2 % higher than the control group [61]. The microwave-assisted extraction of cordycepin from the cultured mycelium of Cordyceps militaris was investigated by Chen et al. (2012). The prepared extract was purified using a cation exchange resin (CER) of LSD-001. They found optimal desorption conditions as follows: 0.2 M of NH3 combined with 80 % ethanol (v/v), desorption time – 2 h, temperature – 25 °C, and pH – 14 [62]. Yu et al. (2013) investigated the optimal conditions for cordycepin extraction from the waste medium of Cordyceps militaris using column chromatography. Initially, they did hot water leaching of Cordyceps waste at 70 °C for 8 h with dried feed and water ratio of 1 g: 20 ml followed by separation of cordycepin on macroporus resin XAD16 and polyamide column chromatography

10. Therapeutic Potential of Cordycepin
Our society is facing heavy health burden due to increasing incidences of cancer-related morbidity and mortality. Therefore, to come up with an effective therapeutic strategy to combat cancer is being considered an essential focus of the research and medical field. Among the natural anticancer compounds, cordycepin is considered to be an important molecule in terms of its potent anticancer activity without any potential side effects [64, 65]. The anticancer role of cordycepin has been intensively investigated in a variety of cancers, including glioma and cancers of oral, breast, lung, hepatocellular, bladder, colorectal, testicular, prostate, melanoma, and blood cell. Previous studies demonstrated that cordycepin has potential to modulate multiple signaling pathways involved in cancer cell proliferation, apoptosis, invasion, metastasis, angiogenesis, and cancer immunity (Fig. 2). The reports of anticancer activity and other therapeutic effects of cordycepin along with the molecular mechanisms of actions are summarized in the Tables 1 and 2, respectively.

11.Bioactivity of Some Other Cordyceps Constituents
Besides cordycepin, a number of other bioactive compounds including cordycepic acid, ergosterol, and polysaccharides have also been identified from Cordyceps. Cordycepic acid, an isomer of quinic acid, is considered to be an active medicinal

component with potent anti-inflammatory activity [3]. Polysaccharides are other class of bioactive molecules which vary in the range 3-8 % of the total weight of Cordyceps. The exopolysaccharide fraction (EPSF) of Cordyceps on the hepatoma (H22) tumor-bearing mice not only inhibited the cancer growth but also significantly improved the immunocytic activity [116-118]. Similarly, a polysaccharide of 210-kDa from C. sinensis mycelia has been reported to protect pheochromocytoma (PC12) cells against H2O2-induced injuries [119]. A polysaccharide fraction from C. sinensis significantly inhibited proliferation of U937 cells by upregulating the levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1 [120]. In other study, Zhang et al. (2005) demonstrated that exopolysaccharide fraction of C. sinensis inhibits the metastasis of melanoma cells and also downregulates the antiapoptotic protein level Bcl-2 into B16 melanomabearing mice [121]. The moieties such as glucan and galactosaminoglycan have also been identified from Cordyceps and found to suppress the growth of sarcoma 180 solid-type tumors in mice [122]. In addition to antitumor activity, polysaccharides from Cordyceps have shown potent hypoglycemic activity in diabetic mice [123, 124]. An antimalarial metabolite, i.e., cordyformamide, a xanthocillin like precursor, was extracted from Cordyceps which was found to exhibit toxicity against Plasmodium falciparum [125]. Kneifel and his colleagues extracted ophiocordin, an antifungal from submerged cultures of C. ophioglossoides [126]. Antifibrotic effects of extracellular biopolymer of C. militaris on fibrotic rats were observed by.

Lipopolysaccharide (LPS), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), vitamin C and vitamin E, and elevated levels of malondialdehyde (MDA), serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine, inflammation-induced osteoporosis (IMO), serum osteocalcin (OC), homocysteine (HCY), C-terminal cross-linked telopeptides of collagen type I (CTX), RA synovial fibroblasts (RASFs), maleic dialdehyde (MDA), polymorphonuclear cells (PMN), interleukin-1p (IL-1p), and tumor necrosis factor- a (TNF-a), rheumatoid arthritis synovial fibroblasts (RASVs), osteoarthritis (OA), human African trypanosomiasis (HAT), oxygen-glucose deprivation (OGD), malondialdehyde (MDA), superoxide dismutase (SOD), matrix metalloproteinase-3 (MMP-3), amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), N-methyl-D-aspartic acid (NMDA), cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c), levels of phospho-AMP-activated protein kinase (AMPK) and phospho-acetyl-CoA carboxylase (phospho-ACC) phospho-acetyl-CoA carboxylase (phospho-ACC), rat renal interstitial fibroblast (NRK-49 F) cells
significant reduction in aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) along with bilirubin and hydroxyproline content [127]. The vasorelaxant activity of some protein constituents of Cordyceps has been found and could play an important role in cardiovascular diseases [12

12.Conclusions and Future Perspectives
In the last few decades, people have shown faith on mushroom-based products for the treatment of various dreadful diseases. The fruiting body of Cordyceps is an excellent reservoir of the therapeutic bio-agents with multidisciplinary mechanism of action. The availability of sophisticated instrumentation has made possible the higher rate of production as well extraction of these bioactive metabolites. Due to the redox behavior, cordycepin can modulate a number of cellular signaling pathways associated with various malignancies. A number of chemical modifications can be
made in the internal structure of the cordycepin to counter drug resistance development and to increase its pharmaceutical potential. The therapeutic potential of cordycepin may be increased using synergistic approaches with the multiple chemotherapeutic agents [129]. In future, it is essential to characterize the other unknown molecules of Cordyceps to understand their structure-function relationship. The scientific community should also focus on nano-biotechnology-mediated targeted drug delivery system not only to reduce the requirement of active doses of drug but also to enhance its bioavailability.

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