Abstract

1. Introduction

Cordyceps, derived from two Latin words “cord” and “ceps” representing ‘club’ and ‘head’ respectively, describing it as club fungi. It is an entomopathogenic fungus where extensions of the stroma and fruiting body arise from insect larvae carcasses [1]. Cordyceps predominantly lives on the head of larvae of a particular moth species, Hepialus armoricanus Oberthur (Lepidoptera). It belongs to the Ascomycetes family and has been a very well-known fungus in Chinese traditional medicine for the last 300 years. Cordyceps is also known as ‘Dong Chong Xia Cao’, which means ‘Worm in winter and grass in summer’ in China [2,3,4]. According to the previous reports, around 1200 types of entomopathogenic fungi are known, out of which, Cordyceps is considered as one of the largest genus containing approximately 500 species. Several species of Cordyceps have been cultivated for their therapeutic properties such as Cordyceps sinensis, Cordyceps sobolifera, Cordyceps cicadicola, Cordyceps liangshanesis, Cordyceps ophioglossoides and Cordyceps militaris [5]. On the other hand, keeping in mind the therapeutic value, its major distribution location at approximately 14,000 ft altitude in the Himalayan regions of China, Nepal, Tibet and India makes it very expensive at around USD ($) 12,000 kg⁻¹ [3,6,7]. Moreover, despite the harvesting difficulties and distribution, it is still considered a highly valued mushroom because of its abundant natural bioactive component resources with various potent biological activities and nutraceutical importance [2]. For hundreds of years, Cordyceps were used as a folk tonic food, but only in recent times, its potential pharmaceutical as well as nutraceutical application have been explored, which has attracted food scientists globally [8].

Currently, it has been observed that a majority of the population from developed as well as developing countries are suffering from chronic diseases, and the underlying causes are believed to be rapid urbanization and changes in eating and lifestyle behavior. Among the various underline causes, eating habits are considered one of the major risk factors for chronic diseases, such as obesity, diabetes, hypertension, hyperlipidemia and many more affecting both wellness and the wellbeing of mankind [9,10]. Therefore, the scientific community is working relentlessly to develop naturally occurring or naturally derived product, such as nutraceuticals, which could help in improving the human health status while not possessing harmful effects. Cordyceps are among the thousands of mushroom available containing various bioactive components with innumerable health benefits [11]. It has been used for its therapeutic values since long time and new promising features of cordycepin-based nutraceuticals are an advantage for the current population. There is a very well-known quote from Hippocrates stating that, “Let food be thy medicine and medicine be thy food”, describing the importance of nutrition for the prevention, treatment and management of diseases. Therefore, Cordyceps, as an edible mushroom, could be an ideal nutraceutical containing both nutritionally bioactive components as well as a source of various physiological benefits [12,13]. Moreover, based on our literature search, we found that researchers have majorly discussed cordycepin for its anticancer potential, but other therapeutic applications and potential nutraceutical approaches have either not been discussed in detail or ignored. The main objective of this review is to focus on the nutraceutical potential of cordycepin (the major bioactive component of Cordyceps), using a mechanistic approach to study its pharmacological functions as well as to demonstrate the benefit of commercial availability of cordycepin-based nutraceuticals.

2. Nutritional Value of Cordyceps

Nutrition is considered as a fundamental pillar of human beings for maintaining health or in development across the entire life span. Moreover, it is very important to have a proper diet and enough nutrition for survival, physical growth, mental development, performance and productivity, health and well-being [14]. One often quoted phrase, “medicines and foods have a common origin” and based upon this idea, Cordyceps could be considered as one of the most significant mushrooms, enriched with various nutrients with possible nutraceutical value [12]. Abundant amounts of bioactive components are present in Cordyceps such as proteins, fats, essential amino acids, volatile oils, carotenoids, phenolic compounds, flavonoids, minerals (Fe, Ca, Mg, Ni, Sr, Na, Ti, Pi, Se, Mn, Zn, Al, Si, K, Cr, Ga, V and Zr), vitamins (B1, B2, B12, E and K) as well as various types carbohydrates like monosaccharides, oligosaccharides, polysaccharides, sterols, nucleosides, etc. [15,16,17,18,19]. Proximate analysis of some of the Cordyceps species have reported that moisture, total ash, crude protein, fat, crude fibre and carbohydrate content are 7.18%, 7.48%, 21.46%, 1.80%, 6.40% and 55.68%, respectively [20]. Many authors have also reported proximate analyses of Cordyceps fruiting bodies and mycelial biomass. The protein, moisture, ash, fat, and carbohydrate compositions of Cordyceps fruiting bodies were reported as 59.8%, 5.7%, 5.1%, 8.8% and 29.1%, whereas, mycelial biomass contains 39.5%, 13.1%, 5.7%, 2.2% and 39.6% of protein, moisture, ash, fat and carbohydrates, respectively [21]. On the other hand, the amino acid contents of the corpus as well as fruiting bodies of Cordyceps militaris (C. militaris) were reported to be 14.03 mg/g and 69.32, respectively. Additional amino acid analysis indicates that the fruiting bodies contains abundant amounts of proline, lysine, threonine and glutamic acid. Moreover, fatty acid profiling indicates almost 70% of unsaturated fatty acids out of the total fat percentage. Importantly, the amount of cordycepin and adenosine in both corpus and fruit bodies was reported to be (0.97 and 0.36%) and (0.18 and 0.06%), respectively [17,22]. With the increasing interest in Cordyceps in recent times for pharmaceutical, nutraceutical or food biotechnological purposes, further research is necessary to obtain an overview of the potential of this medicinal mushroom [2].

3. Bioactive Components of Cordyceps

The significance of bioactive components present in foods has been gaining interest recently due to public health concerns. Moreover, with rising consumer awareness regarding promotion, prevention as well as maintenance of health, bioactive components present in food could play a very important role [23,24]. Bioactive compounds can be described as molecules present in food derived of plant or animal sources consumed to have a regular energy intake along with various therapeutic activities such as against metabolic disorders, anti-inflammatory, chronic diseases and many more [25]. The presence of these bioactive components, even in minute quantities, not only meets the basic nutritional needs, but also confers numerous health benefits. Epidemiological studies indicate that high consumption of foods rich in bioactive compounds with different phytochemicals such as antioxidants, vitamins, flavonoids and carotenoids has a positive effect on human health [26]. Mushrooms have been known and used for centuries for food and medicinal use. Among various mushrooms, very well-known medicinal mushrooms like Cordyceps producing bioactive metabolites are used or studied for the possible treatment of several diseases [15]. The presence of antioxidants acquired by modifying our diet with mushrooms could play an important role in the prevention of diseases. Cordyceps have a history of medicinal use spanning millennia in parts of Asia, but they can also be potentially used for their nutraceutical values [22,27]. Cordyceps have been reported to contain various bioactive components such as proteins, fat, carbohydrates, exopolysaccharides, cordycepin, phenolic compounds, polysaccharides, cordycepic acid, adenosine, proteoglucans, terpenoids, amphinol, steroids, ergosterol, lectins, etc. A detailed list of bioactive components present in Cordyceps is presented in Table 1 along with the chemical structures of some potent identified bioactive molecules (Figure 1 and Figure 2). Out of these, cordycepin is the main active constituent which is most widely studied for its medicinal value along with its nutraceutical potential [2,8,22,28,29]. Moreover, various mechanisms have been reported for the pharmacological actions of cordycepin such as inhibition of DNA and RNA synthesis, post-transcriptional processing of hnRNA and activation of adenylate cyclase, inhibition of chemotaxis and particular protein synthesis of macrophage cell lines, anti-tumorigenic activity on some cell lines, enhancement of cell differentiation etc. [1].

Figure 1

Chemical structures of some known and potent bioactive compounds in Cordyceps. (A) Cordycepin (B) Adenosine (C) Cordycepic acid (D) Ergosterol (E) Structure of (a) and (b). (a) Cordyceamides A (b) Cordyceamides B (F) Linoleic acid (G) Oleic acid (H) Palmitic acid.

Figure 2

Chemical structures of some known and potent bioactive compounds in Cordyceps. (A) Stearic acid (B) N-acetyl muramic acid (C) Hypoxanthine (D) Nephthaquinone (E) Dipliconic acid (F) Myriocin (G) Cordyheptapeptide A (H) Cicadapeptin 1.

4. Cordycepin and Its Chemical Features

Cordycepin (C₁₀H₁₃N₅O₃, molecular weight 251.24 Da, melting point 228–231 °C) is chemically (9-(3-deoxy-β-D-ribofuranosyl) adenine), 3’–deoxyadenosine [5,47]. The structure of cordycepin consists of a purine molecule attached to one ribose sugar moiety [48]. The NMR spectrum of cordycepin shows a singlet at 3.4 ppm, attributed to the C-H proton and a -NH₂ peak reported to be present at 4.6 ppm, whereas, the peaks due to the different -OH groups are found to in the 8–8.5 ppm range [47]. The concentration of cordycepin in C. militaris, i.e., around 2–3 mg/kg, is very low compared to the needs of the commercial market, therefore various synthetic and semi-synthetic methods have been reported for the preparation of cordycepin [49]. Cordycepin can be synthesized chemically by replacing an OH group with an H group at the 3′-position of the ribofuranosyl moiety to produce an adenosine analogue [50]. Cordycepin is found to be structurally very similar to adenosine except for the lack of a 3′-hydroxyl group [49,51] Due to its very close structural similarity with adenosine, it is considered to be a very potent bioactive component with essential properties for its nutraceutical applications. There are various reports suggesting that cordycepin competitively inhibits the courses of synthesis and metabolism of DNA and RNA, as well as it affects the activity of adenosine deaminase and the mTOR signaling pathway [52]. Therefore, cordycepin has been reported to have a wide variety of pharmacological actions such as antioxidant, immunological, hypolipidemic, anti-inflammatory, anticancer, antimicrobial, antiviral, and hypoglycemic properties [49].

5. Cordycepin as a Nutraceutical and Its Role in Human Health

The concept of “nutraceutical” was first introduced in the survey study conducted in France, United Kingdom and Germany, where they found that rating of diet by the consumers was much higher compared to the other factors such as exercise or hereditary to achieve a good health [53]. DeFelice was the first to introduce the word “nutraceutical” by coalescing the two words “nutrition” and “pharmaceutical” and define it as “food or a part of food which not only impart health benefits but also contributes in preventing or treating various diseases”. Moreover, in broad terms nutraceuticals can be summarized as bioactive components which play a vital role in human beings by maintaining their normal physiological functions and well-being [10,54]. Notably, nutraceuticals have been designed in such a way, that it could be useful for the betterment and maintenance of human health without causing any harm due to their natural occurrence [55,56]. Nutraceuticals of plant, animal origin or live microorganisms offer great opportunities for food scientists and food industries to produce novel foods or food components for the future needs of human beings to stay healthy [57,58]. Nutraceuticals have been classified in various ways based upon their understanding and applications. Naturally available food sources are considered for their nutraceutical values. They can be characterized as antioxidants, dietary fibre, prebiotics, polyunsaturated fatty acids, probiotics, vitamins, polyphenols and spices [9,53]. The sudden rise in demand of nutraceutical products is mainly due to their therapeutic properties in various ailments such as the common cold, hypertension, heart disease, arthritis, dyslipidemia, diabetes, cancer, depression, inflammatory bowel disease, and increased life span by postponing aging, integrity of the body and support of smooth normal functioning. Therefore, nutraceuticals could play an important role in the improvement of health as well in chronic disease prevention [58]. Nutritionally potent Cordyceps are considered a powerhouse of energy, because of their ability to revitalize several organ systems. Moreover, according to various scientific reports, the Cordyceps active component cordycepin is considered very useful due to its potential application in various ailments (Figure 3). Several pharmaceutical as well as nutraceutical preparations made from Cordyceps dry powder (Table 2) are marketed and reported to protect renal and hepatic functions, improve intracellular energy exchange, increases oxygenation and natural endurance, remove toxins from the body, control blood glucose level and lipid profile, delays the aging process, stimulates the natural metabolism of energy and nourishes the body’s immune system [59].

Figure 3

Pictorial representation of Cordyceps therapeutic potential in general.

6. Mechanism of Action and Pharmacological Implications of Cordycepin

6.1. Cordycepin and Diabetes

Diabetes has recently become one of the most prevalent epidemics worldwide, affecting almost 382 million people. According to the reports, it is believed that every year approximately 1.3 million people die from diabetes. According to International Diabetes Federation (IDF), it is estimated that around 629 million people will be diabetic around the globe by 2045. However, as per the recommendation from dieticians or physicians, a healthy life style and healthy food habits, could be one of the key answers to this problem [60,61]. It has also been observed that, in most diabetic patients, several other complications also arise, such as cardiovascular diseases, retinopathy, nephropathy, hyperlipidemia and neuropathy [62]. Of note, it is also suggested by various studies, that no single treatment programme can treat diabetes, although most of the treatments achieve normal blood glucose levels or improve microcirculation [63]. Currently, pharmaceutical products used for the management or therapeutic purposes against diabetes are sulfonylureas, biguanides, thiazolidinedione, α-glucosidase inhibitors or insulin injections. However, pharmaceutical products available for the treatment of diabetes have several adverse effects and their potency is sometimes controversial. Other non-medicinal strategies used in diabetes are exercise, weight loss plans and changes in food habits. Occasionally, complications of diabetes can cause morbidity because of pathophysiology flaws. Therefore, consumer interest has currently moved towards alternative medicinal approaches such as nutraceutical food products containing bioactive antidiabetic components. Some studies have reported that extract of C. militaris showed a significant decrease in blood glucose levels by virtue of increasing glucose metabolism as well as protection against diabetic nephropathy [64].

The mechanism of cordycepin’s antidiabetic activity is not fully understood, but a few studies have explained a possible pathway. They found that cordycepin prevents the production of NO and pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 in LPS activated macrophages by inhibiting the protein expression of pro-inflammatory mediators. By virtue of this the expression of type 2 diabetes-regulating genes (11β-HSD1 and PPARλ) was reduced. Expression of co-stimulatory molecules such as ICAM-1 and B7-1/-2 was also decreased with the increase in cordycepin concentration as presented in Figure 4A [65]. Furthermore, cordycepin has been found to suppress the expression of diabetes-regulating genes through the inactivation of NF-κb-dependent inflammatory responses [66,67]. In another study, cordycepin’s antidiabetic activity was reported in an alloxan-induced diabetic mouse model. The results suggested a significant improvement in glucose tolerance tests after administration of an effective dose of cordycepin [68]. Additionally, an effect of cordycepin on diabetic nephropathy by suppressing cell apoptosis, renal fibrosis and rescued cell autophagy in the diabetic nephropathy rat model was also reported [69]. There are several reports which suggest that cordycepin has very good potential for being a safe anti-diabetic pharmaceutical agent [64,65,70].

Figure 4

(A) Possible mechanism of cordycepin for its anti-diabetic activity (B) Possible mechanism of cordycepin in regulation of fat metabolism in hyperlipidemia [47].

7. Global Nutraceutical Market of Cordycepin: Current and Future Trend

Nutraceuticals are developed from foods or food derived components due to their health promoting properties to establish a clear link between ‘nutrients’ and ‘pharmaceuticals’ [9]. The health promoting effects of nutraceuticals have led to substantial increases in their market predominantly since the 1990s. Nutraceutical products have shown hope for various chronic diseases (diabetes, cancer, heart disease, hypertension, common cold, dyslipidemia, arthritis and many more) as well as help in delaying aging and eventually increasing life span [58]. Health awareness in consumers, caloric intake and weight management in countries like US, China and India, have already endorsed various applications of nutraceuticals, causing a significant impact on the industry growth. According to the data published online by the Grand View research team, the global nutraceutical market size could reach USD 722.49 billion by 2027, and is expected to expand at a CAGR of 8.3% over the forecast period [141]. Major key companies such as Abbott, Amway, Danone S.A., Nestle S.A., Glanbia Nutritionals, Herbalife International of America, Inc., The Archer Daniels Midland Company, BASF SE, PepsiCo, Inc., General Mills, Inc. are involved in the research & development of nutraceutical production [142]. On the other hand, the global cordycepin market is predicted to surpass US$ 1 billion by 2026. Asia Pacific (mainly China) is considered as the global leader in the production or extraction of cordycepin from C. sinensis and C. militaris, with an expected 47% of global nutraceutical market (Figure 5) [143].

Figure 5

Expected global nutraceutical market by 2025 with China, India, Tibet and Nepal as global leaders for production and extraction of cordycepin [144].

8. Safety and Efficacy

Cordyceps, a well-known traditional Chinese medicine is also called a miracle mushroom because of its exceptional health benefits. Due to its natural occurrence, it is considered pharmacologically safe for human consumption. However, in some cases it has been reported to cause dry mouth, nausea, abdominal distension, throat discomfort, headache and diarrhea as well as allergic reactions [22,34,145]. It is recommended to avoid its consumption in the case of patients suffering from systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. Moreover, there are a few reports indicating that Cordyceps intake can cause lead poisoning in some cases. Considering the potential for toxicity, resistance and its efficiency, potential drug derivatives designed from the natural products for the adenosine deaminase-resistant properties and low-toxicity causing effects of cordycepin, as well as organ-targeted nanoparticles for cordycepin delivery for in vivo therapy, are also needed [146]. Further clinical, experimental as well as epidemiological data are required for identification of other molecular targets to see the correlation between Cordyceps and other diseases like cancers and to estimate the validation of optimum dosing for its safety and efficacy [28]. The mechanism of action of cordycepin still needs further detailed scientific studies along with exploration of the various biochemical pathways involved. Thereby, its pharmacological and mechanism of actions will help in scientific scrutiny to answer every aspect of cordycepin [34]. Aside from some negative reports and clinical data, Cordyceps is still relatively considered safe and non-toxic for human consumption [22].

9. Conclusions and Future Perspectives

Over the past few years, people have shown confidence and trust in naturally occurring food-based products such as nutraceuticals for the treatment or management of various chronic diseases. Medicinal mushrooms have been proved to be very effective against numerous serious ailments. Cordyceps, some of the most important medicinal mushrooms, have been in use in the traditional Chinese medicine system since a long time ago. They are considered an excellent reservoir of various bioactive components, of which cordycepin is believed to have the most nutraceutical potential. Based on several research reports, cordycepin indicates its nutraceutical values by showing possible therapeutic activity against various diseases by modulating a number of cellular signaling pathways due to its redox behavior. In future, it would be important to uncover other unknown molecules present in Cordyceps and to understand their therapeutic potential. Likewise, it is equally important for the scientific community to explore the possibilities of nano-biotechnology-mediated targeted drug delivery systems for cordycepin and how to enhance its bioavailability. Further experimental and clinical studies are required to identify the exact mechanism behind the role of cordycepin, as well as its efficacy and safety alone and in combination. Since Cordyceps are edible, they will play a key role in the prevention and cure of various ailments caused by metabolic disorders or infections.

Author Contributions

Conceptualization, S.A.A., A.E.O.E., M.A., and S.H.; resources, A.E.O.E., A.M.A., M.S.A., and A.J.S.; data curation, A.J.S., M.P., A.E.O.E., A.M. and M.S.; visualization, M.S.A., M.A. and M.P.; writing—initial draft, S.A.A., M.P., M.S., A.M.A. and A.J.S.; writing—review and final editing, S.A.A., M.A., and M.S.; supervision, M.A. and S.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References