Medicinal Properties of Cordyceps Mushrooms: Comparison
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Mushrooms have also been known to exhibit medicinal properties, and as such, they have been used in traditional medicine worldwide. Recently, scientists have turned their attention to Cordyceps (C.) sp. mushrooms in search of a natural product with high medicinal value. The study of C. mushrooms has shown they have anti-oxidant, anti-inflammatory, hypoglycemic, and anti-tumoral effects. It has also been shown that they can help improve the gut microbiota.

  • Cordyceps
  • honey
  • antioxidants
  • polyphenols

1. General Aspects

The Cordyceps genus contains over 400 species, amongst which the best known are C. sinensis and C. militaris. C. sinensis grows at high altitudes, typically in pastures over 3000 m above sea level in the Himalaya region (Nepal and India) and the Tibetan plateau (China) [14][1].
Most of the Cordyceps genus members are endoparasites, using arthropods as hosts. C. sinensis starts growing inside a living host, then it kills and mummifies its host. The fruiting growths then grow outside of the host’s body. Recently, C. sinensis was renamed Ophiocordyceps sinensis [15][2]. For a very long time, this mushroom has been known to have medicinal properties. In the Tibet region, it is often known as “winter worm, summer grass” or “ caterpillar mushroom” [8,16][3][4].
The parasitic nature of Cordyceps is a really intriguing characteristic. These organisms can infect various insects and arthropods, resulting in elongated and thin protrusions from the host’s body. These protrusions serve as structures for producing fungal spores [17][5]. Parasitic Cordyceps have attracted considerable interest due to their possible therapeutic effects in traditional Chinese medicine and contemporary herbal supplements. In addition to their parasitic forms, certain species of Cordyceps also exhibit saprophytic growth, obtaining nutrients from decomposing organic material. The latest scientific investigations have revealed these organisms’ intricate chemical makeup, encompassing several bioactive substances such as cordycepin and polysaccharides [18][6]. These findings have generated considerable attention due to the possible health advantages associated with these compounds, which encompass a wide range of benefits, including bolstering the immune system and enhancing athletic performance. Due to their varied ecological functions and potential in pharmacology, Cordyceps species remain a topic of scientific investigation and cultural importance [19][7].
Because of the environmental limitations and their parasitic nature, significant amounts of Cordyceps mushrooms are rarely found in nature. To solve this issue, efforts are made to allow cultivation on artificial media or submerged fermentation [20][8].

2. Composition

Various constituents have been detected in Cordyceps sp. mushrooms, encompassing proteins, polyamines, peptides, polysaccharides, nucleosides, sterols, and fatty acids. Through gas chromatography–mass spectrometry analysis, four distinct free sterols have been identified: cholesterol, ergosterol, beta-sitosterol, and campesterol. While many bioactive compounds have been pinpointed, it is suggested that Cordyceps may contain other additional compounds [14][1]. In other investigations, researchers aimed to unravel the structural attributes of the polysaccharides present in C. sinensis, including parameters such as molecular mass, monosaccharide composition, glycosidic bond configuration, and molecular chain conformation. Employing techniques such as chromatography, mass spectrometry, infrared spectroscopy, and nuclear magnetic resonance, these studies delved into the intricate characteristics of the polysaccharides [21][9].
Cordyceps polysaccharides are typically large, complex molecules composed of multiple sugar units linked together. They often have branched structures, making them more intricate than simple sugars. Many of the polysaccharides in Cordyceps are beta-glucans. Beta-glucans are a type of polysaccharide known for their immunomodulatory properties and ability to support the immune system. Cordyceps polysaccharides can have a high molecular weight, which may contribute to their bioactivity and potential health benefits [22][10]. These polysaccharides comprise various monosaccharides, including glucose, mannose, and galactose. The specific composition can vary depending on the Cordyceps species and extraction methods. Researchers have investigated the glycosidic bond configuration within Cordyceps polysaccharides. The arrangement of these chemical bonds can influence their biological activity [23][11].

3. Beneficial Effects, Pharmacological Properties and Bioactive Compounds

A large number of specialist studies described the pharmacological properties of Cordyceps mushrooms. The constituents of Cordyceps are associated with multiple pharmacological properties, such as anti-tumoral, anti-metastasis, immunomodulating, antioxidant, anti-inflammatory, hypoglycemic, hyperlipidemic, prebiotic, and anti-aging properties [21,24][9][12]. Cordyceps has also been effective in preventing viral infections [25][13].
Multiple studies have demonstrated the hypoglycemic effects of C. sinensis extracts, with a reduction of blood glucose concentration observed in vitro [26][14] and in vivo [27][15].
In traditional Chinese medicine, Cordyceps sp. mushrooms are used in preparing a natural medicine for multiple health problems such as lung or kidney dysfunction and generalized fatigue [28][16].
C. sinensis is used as an immunosuppressant in the maintenance treatment of kidney transplant recipients in China, but there is no consensus regarding its use [29][17].
Treatment with C. militaris extract inhibited metabolic disorders induced by obesity caused by fat-rich diets, mainly by improving metabolic parameters. As active constituents, pyrrolic alkaloids and nucleotide derivatives were characterized. These results suggest C. militaris could be used to treat obesity via the metabolic effects of its constituents [30][18].
In studies examining the properties of C. sinensis polysaccharides, the polysaccharide CS-F70 (composed of 62% galactose, 28% glucose, and 10% mannose), obtained from alkaline mycelium extract, was proven to have hypoglycemic effects. The extract showed powerful hypoglycemic activity in normal mice and those with induced diabetes. In parallel, the effects of the extract on cholesterol and triglycerides were also studied on the same two types of mice. The results showed a reduction in the triglycerides in both types of mice, which confirms the medicinal properties of the polysaccharide CS-F70 [31][19].
Mannitol and cordycepin are two of the most important pharmacologically active components of C. sinensis [32][20]. Mannitol has beneficial effects, such as diuretic or anti-coughing properties and inhibition of free radicals [33][21].
Cordycepin (3′-deoxyadenosine), one of the nucleosidic analogs, was first isolated from C. militaris. The difference between cordycepin and adenosine is the lack of the 3′-hydroxyl group in cordycepin [24][12].
Studies have shown that average levels of adenosine and cordycepin were significantly higher in cultivated Cordyceps compared to mushrooms harvested from wild flora. On the other hand, the levels of mannitol and polysaccharides were lower in the cultivated mushrooms [34][22].
Among the aspects studied was data regarding the effect of Cordyceps spp. and cordycepin in bones and associated processes. The impact of Cordyceps spp. and cordycepin on bones, teeth, and tooth pulp was described as the result of the interaction of AMPK (adenosine monophosphate-activated protein kinase) and ATP (adenosine-5′-triphosphate). This way, it is possible to obtain medicine with regenerative effects that can be used in trauma recovery or the terminal stages of some diseases [35][23].
Because it has been used for centuries in traditional Chinese medicine, C. sinensis was intensely studied for its anti-oxidative, anti-tumoral, anti-hyperglycemic, and immunomodulating properties [14][1].
In a study conducted by Cho et al. (2003), the researchers examined and evaluated the impacts of Cordyceps sp. extract (CME) and Sweet Potato Anthocyanin (SPA) on lipid peroxidation, DPPH radicals, and cognitive impairments. The two extracts exhibited comparable efficacy in their capacity to scavenge free radicals. The study’s results indicate that only SPA demonstrated the ability to suppress the process of lipid peroxidation, which was induced by the presence of Fe2+ ions and ascorbic acid in rat brain tissue samples. The administration of SPA was found to enhance cognitive performance in mice that were subjected to ethanol treatment. The combined effects of SPA and CME were statistically similar to those observed with SPA alone [36][24]. Polysaccharides represent the most important biologically active compound in C. sinensis and C. militaris. The components of these compounds include rhamnose, ribose, arabinose, xylose, mannose, glucose, galactose, mannitol, fructose, and sorbose. The exopolysaccharide fraction has pharmacological properties, the most important of which are the immunomodulatory and anti-tumoral effects. Mannoglucan is also among the polysaccharides found in Cordyceps, its notable effect being mild cytotoxic effects on the cancer lineage SPC-I1. Various nucleosides and their corresponding compounds, including adenine, adenosine, inosine, cytidine, cytosine, guanine, uridine, thymidine, uracil, hypoxanthine, and guanosine, have been extracted from C. sinensis. These compounds contain amino acids and polypeptides that positively affect the cardiovascular system. They also exhibit sedative and hypnotic effects, with tryptophane being the most effective component in this regard [37][25].
C. sinensis mycelium extract helps reduce the growth and dissemination of bacteria, increasing the survival rate in mice inoculated with streptococci. The macrophages’ phagocytosis activity was increased after the treatment with C. sinensis [38][26].

4. Effects on the Microbiota

The research targeted to evaluate the impact of Cordyceps militaris on the function of the intestinal barrier and the composition of the gut intestinal microbiota in a porcine model. Usage of C. militaris improved the number of goblet cells, increased the lymphocyte number, and improved intestinal morphology. Cordyceps militaris was found to downregulate pro-inflammatory cytokines and upregulate anti-inflammatory cytokines at the mucosal level. The use of Cordyceps can potentially achieve the modulation of intestinal microbiota and the intestinal barrier, hence offering potential avenues for the enhancement of intestinal health. [11,13,39,40][27][28][29][30].
The low molecular weight exopolysaccharides of C. militaris have an antioxidant effect. They are observed to be excellent prebiotics, which increases the proliferation of the probiotics and the increase of phenolic acid [9,10][31][32].
After elucidating the structural characteristics of the alkali-extracted polysaccharide CM3-SII obtained from C. militaris, the amelioration of hyperlipemia in hamsters with a heterozygous model of hyperlipidemia with low-density lipoprotein receptor (LDLR) deficiency was studied using this polysaccharide. The study demonstrated that CM3-SII significantly decreased plasma total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels in LDLR-deficient heterozygous hamsters. Increased plasma concentration of polylipoprotein A1, abundance of Actinobacteria, and Bacteroidetes/Firmicutes ratio were observed [41][33].
A similar study was conducted on mice fed a high-fat, high-sucrose diet. Polysaccharides derived from C. militaris decreased blood sugar and serum lipid levels in these mice. In addition, C. militaris polysaccharide treatment ameliorated intestinal dysbiosis by promoting the next-generation probiotic Akkermansia muciniphila population in the intestine of mice fed the high-fat, high-sucrose diet. Polysaccharides derived from C. militaris have the potential to alter gut microbiota to increase metabolic syndrome. The cordycepin-rich solution obtained from C. militaris had different efficacies in regulating hyperglycemia and gut microbiota in studied mice [42][34]. Polysaccharides from C. militaris may be a potential prebiotic agent to modulate specific gut microbes [43,44][35][36].
Modulation of gut microbiota dysbiosis was studied in rats with diabetic nephropathy. The health benefits of C. cicadae polysaccharides (CCP) on renal injury and renal interstitial fibrosis in rats with induced diabetic nephropathy were studied. Rats that received CCP showed improved insulin resistance and glucose tolerance. It has also been observed to suppress inflammation and renal dysfunction, slowing the progression of renal intestinal fibrosis and modulating gut microbiota dysbiosis [40,45][30][37].
The theoretical background of the hypoglycemic effect of C. cicadae research was described in 2023. Bacterium substance polysaccharides (BSP), spore powder polysaccharides (SPP), and pure powder polysaccharides (PPP) were separated, purified, and collected from sclerotia, spores and fruiting bodies of C. cicadae, respectively, and chosen as study material. The basis of the hypoglycemic effect of SPP is the mechanism that regulates the mRNA expression of key PI3K/Akt genes involved in the insulin signaling pathway to alleviate insulin resistance, contributing to the development of functional products [46][38].
The protective efficacy of extracellular polysaccharides from C. militaris against toxicity and their regulatory effect on gut microbiota against Pb2+-induced toxicity in vivo was demonstrated in lead-poisoned mice [39][29].
Special attention is paid to the relationship between the gut microbiota and type 2 diabetes. The hypoglycemic activity of the purified fraction obtained from the polysaccharides of C. militaris was investigated, together with its mechanisms, in mice with induced type 2 diabetes. The results indicated that the symptomatic improvement of diabetes could be related to the polysaccharide extracted from C. militaris, which regulates the intestinal microbiota against the TLR4/NF-κB pathway to protect the intestinal barrier [12,47][39][40].
The activity of cordycepin extracted from C. militaris was described in a study on mice, which demonstrated its influence on type 2 diabetes, improving the abundance of Firmicutes/Bacteroides that promote the growth of beneficial bacteria by regulation of the intestinal flora, enhancing the metabolites and metabolic pathways associated with the diabetes type 2 modifications [7][41].
Until now, the study’s results have revealed the mechanisms involved in the reduction of blood sugar and lipids using Cordyceps and the way forward for the establishment of new anti-obesity and anti-inflammatory therapies would involve Enterococcus cecorum along with Cordyceps [47][40].
Considering the need to bring solutions as effective as possible and with as few side effects, polysaccharides from C. cicadae were studied for cervical cancer. There are few studies on the anti-cancer activity of C. cicadae artificially cultivated by the bionic method. Several studies have shown that the appearance and development of cervical cancer are linked to abnormal cell proliferation and differentiation alongside abnormal cell apoptosis [48][42]. This study provides the necessary support for further clinical applications, which observed polysaccharides on cell proliferation and apoptosis and the molecular mechanism [49,50][43][44].

5. Side Effects

There needs to be more information regarding the long-term effects of Cordyceps mushrooms, as severe side effects have yet to be reported. Despite this, one case of excessive bleeding has been documented in a patient after a dental intervention. Patients who require insulin must be aware of the hypoglycemic effects of Cordyceps sp. mushrooms and derivate products. Women are not recommended to consume Cordyceps products during pregnancy or breastfeeding as the effects on the newborn are not yet known. As a blood-diluting agent and immunostimulant, care must be taken when administering alongside immunosuppressants, blood dilutants, or coagulants [25][13].

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