Cordyceps is a very studied genus of fungi in the Ascomycota phylum. The name Cordyceps comes from the Latin words "cord" and "ceps," meaning "club" and "head," respectively, about the shape of the fungal fruiting bodies. Cordyceps species are found in humid temperate and tropical regions of the world. In Asia, they are found in Korea, Japan, Nepal, and China [1]. In nature, Cordyceps species parasite insects and other arthropods. They evolved to evade insects’ immune systems to perform their life cycle, survive, and propagate by producing unique bioactive compounds that have been used in Chinese medicine for centuries [2].
In 2007, a phylogenetic analysis led to the division of the Cordyceps group into four distinct genera: Cordyceps, Elaphocordyceps, Metacordyceps, and Ophiocordyceps. As a consequence, Cordyceps sinensis, the most studied Cordyceps, was renamed Ophiocordyceps sinensis (O. sinensis) and reclassified as belonging to the Ophiocordyceps [3]. This nomenclature change greatly impacts current research on Cordyceps as the current misuse of Cordyceps sinensis for O. sinensis creates confusion in literature [4]. Most research has concentrated on O. sinensis; however, due to the challenges associated with its cultivation, Cordyceps militaris (C. militaris) has often been used as a substitute as both fungi share similar bioactive compounds. Notably, C. militaris, still classified within the Cordyceps genus, also produces unique compounds, such as pentostatin, which are absent in O. sinensis, distinguishing the two fungi in their chemical profiles [5,6].
In this article, we'll be delving into C. militaris and its role as a medicinal mushroom by delving into its bioactive compounds, pharmacological functions, and finally, current limitations in research.
Cordyceps as a source of bioactive compounds
Cordycepin, cordycepic acid, and pentostatin
In 1950, cordycepin, a derivative from the adenosine nucleoside, was first isolated from C. militaris [7]. It differs from adenosine by the lack of oxygen in its 3’ position of the ribose part [8] and is extracted from the fruiting bodies and the cultured Cordyceps mycelia. Cordycepic acid, a quinic acid isomer, is another of the main active compounds extracted from the fruiting bodies. It was first studied in 1957 [9] and was identified many years later as D-mannitol [10]. Finally, pentostatin, a purine analog found in C. militaris, functions as an antineoplastic antimetabolite and is approved for the treatment of various forms of leukemia [11,12].
Nucleotides, polysaccharides, and sterols
C. militaris contains many nucleotides, including adenosine, uridine, and guanosine [13]. It also contains polysaccharides in large amounts ranging between 3 and 8% of its total weight. These structurally diverse polysaccharide macromolecules in the mycelium and fruiting bodies of cultured Cordyceps exert many properties, including anti-tumor, anti-inflammatory, antioxidant, and immunomodulating effects [6,10]. Finally, ergosterol, one of the sterols found in fungal cell membranes, presents antimicrobial, antioxidant, and anti-neurodegenerative properties among others [14]. It is also a precursor of vitamin D2, which plays a crucial role in calcium and phosphorus metabolism and in maintaining skeletal and neuromuscular homeostasis [15].
Pharmacological effects and functions
C. militaris has been used in traditional Chinese herbal medicine for centuries due to its medicinal properties. Pharmacological studies have demonstrated that this fungus has anti-tumor [16], immunomodulatory [17], neuroprotective, antioxidant, hypoglycemic [18], hypolipidemic [19], and anti-inflammatory [20] properties.
Anti-tumor effects
The anti-tumor properties of Cordyceps may primarily be attributed to cordycepin, sterols, polysaccharides, and adenosine compounds. A study has investigated the effects of the extract of Cordyceps militaris on breast cancer and hepatocellular carcinoma cells. The findings showed that the co-culture of cancer cells with effector immune cells in the presence of C. militaris extract increased cancer cell death, demonstrating its potential to improve the efficacy of immunotherapy for breast cancer and hepatocellular carcinoma [21]. Another study investigated the effects of C. militaris extract on angiogenesis and tumor growth using different human cells in vitro and mice in vivo. The results showed that this extract had anti-angiogenic properties that may result from a reduced expression of basic fibroblast growth factor [22]. Finally, another study on lung metastatic melanoma cells showed that C. militaris extract demonstrated anti-tumor effects and inhibited tumor invasion, while also enhancing T cytotoxic cell activity by significantly increasing the number of CD8+ T cells [23]. These findings collectively highlight the potential of C. militaris as a promising adjunct in cancer therapies, particularly in enhancing immune responses and inhibiting tumor growth and invasion.
Immunomodulating effects
C. militaris has attracted attention for its immunomodulating effects, which may enhance its potential as a therapeutic agent in various health conditions. A randomized controlled clinical trial recently investigated the immunomodulating effects of a beverage made from C. militaris in 20 healthy volunteers from Thailand. Participants received the C. militaris beverage or placebo for eight weeks. Immune cell markers, immunoglobulins, and safety parameters were measured at baseline, at 4 and 8 weeks. The results showed that the C. militaris beverage was able to stimulate the volunteers’ immune response by activating natural killer cells, increasing monocytes, and reducing inflammatory cytokines without toxicity. These results suggest that C. militaris beverages may be beneficial as a natural immunostimulatory supplement [24]. Another randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of Cordyceps as adjuvant therapy in 65 patients with mild-to-moderate symptoms of COVID-19 infection. Overall, there was no statistically significant difference between the Cordyceps group compared and the placebo group [25]. Further research involving a larger sample size is needed to shed more light on C. militaris' immunomodulating effects and elucidate its mechanisms of action.
Neuroprotective effects
C. militaris also exerts neuroprotective properties as evidenced in mice and rats in numerous studies. For example, C. militaris was able to improve memory impairments resulting from global cerebral ischemia and scopolamine-induced memory deterioration in rats [26,27]. Another study on mice suggests that Cordyceps polysaccharides, previously shown to improve learning and memory in mice with exercise fatigue [28], exert their effects by reducing oxidative stress, thus preventing oxidative damage [29]. These findings in rodents suggest that C. militaris may have therapeutic potential in vascular dementia and neuroinflammatory disorders.
Hypoglycemic effects
In traditional Chinese medicine, C. militaris is believed to have hypoglycemic properties, and several studies have reported this effect in rats [30,31]. Recent work identified a novel exopolysaccharide isolated from this fungus with hypoglycemic properties observed in vitro and in vivo. This exopolysaccharide was able to inhibit the α-glucosidase, an enzyme responsible for the absorption of glucose in the intestines, with a dose-effect relationship. In vivo experiments in a streptozotocin-induced diabetic mice model showed that this compound reduced plasma glucose concentration, improved glucose tolerance, and repaired dyslipidemia [32]. As such, C. militaris polysaccharides have been shown to alleviate diabetic symptoms by regulating gut microbiota against the TLR4/NF-κB pathway [33]. C. militaris can lower glycemia in rodents, though further studies are needed to assess its therapeutic potential in humans.
Hypolipidemic effects
Several studies showed that cordycepin and polysaccharides extracted from C. militaris were able to prevent hyperlipidemia in mice, rats, and hamsters fed with a high-fat diet. Cordycepin or polysaccharide treatments effectively reduced total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum by activating phospho-AMP-activated protein kinase, and possibly, through upregulation of serum lipoprotein lipase expression [19,34-36]. These findings suggest that cordycepin and polysaccharides from C. militaris hold promise for managing hyperlipidemia and improving lipid profiles in individuals at risk of cardiovascular diseases.
Current limitations in Cordyceps research
Although numerous studies have explored the therapeutic potential of Cordyceps in animal models, the findings are currently constrained by several methodological limitations. For example, standardization of Cordyceps extracts is urgently needed to make reproducibility and comparison between studies possible. Indeed, variation in fungal growth protocols combined with multiple lab extraction methods leads to variation in the contents of extracts. Bioactive compounds from extracts should be systematically identified and isolated to evaluate their activities and unravel their mechanisms of action. Finally, doses used in animal studies may not be directly translatable to humans without causing undesirable toxic side effects [2].
Conclusion
Cordyceps fungi have been used for centuries in traditional Chinese medicine and are believed to treat many diseases. Numerous scientific studies have evaluated the properties of Cordyceps extracts, a rich source of bioactive compounds, containing cordycepin, cordycepic acid, pentostatin, nucleotides, polysaccharides, and sterols. They have shown promising properties in animal models, including immunomodulation, neuroprotection, hypoglycemic and hypolipidemic effects, and anti-tumor activity. Future efforts should focus on standardizing Cordyceps extracts and using their promising potential as sources of new medicines.
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