Cordyceps militaris (C. militaris) is a fungal traditional medicine that has been used for centuries, especially in Tibetan and Chinese cultures, for its pretended ability to enhance vitality and longevity. C. militaris belongs to the Clavicipitaceae family within the Ascomycota phylum and is found in various regions around the world, especially in humid temperate and tropical forests.
During its teleomorphic (or sexual) reproduction, this fungus infects and parasitizes various insects (i.e. Lepidoptera, Coleoptera, Diptera, and Hymenoptera) in their larva, pupa, or adult stages [1] to kill them and produce its orange fruiting bodies within their host.
In its anamorphic (or mitotic) reproduction, C. militaris mycelia rapidly grows in an artificial medium within bioreactors [1]. Once produced, the fruiting bodies serve as a source to extract numerous bioactive compounds, such as cordycepin, D-mannitol, cordyceps polysaccharides, GABA, ergothioneine, lovastatin, and vitamins (A, E, B2, B3, and C) among others. C. militaris has received increasing attention due to the long list of therapeutic effects of its compounds. Indeed, its extracts showed antitumor, anti-diabetic, antioxidant, anti-inflammatory, antihyperlipidemic, antibacterial, antiviral, and immunomodulatory activities [2-5].
Due to these numerous properties, the literature on C. militaris is rapidly expanding, but some studies lack rigor while others are unconvincing [5]. The perceived miraculous efficacy of C. militaris was originally attributed to the Chinese philosophical concept of yin and yang rather than a meticulous scientific methodology. Nevertheless, substantial pharmacological data, particularly concerning apoptosis, are available, and many of its properties have been subject to thorough scientific review.
Cordycepin
Cordycepin, or 3′-deoxyadenosine, is one of the most characteristic bioactive compounds of C. militaris and was first isolated and characterized in 1950 [6]. It is a nucleoside analog, structurally very close to adenosine. Adenosine is a key molecule within the human body, contributing to energy metabolism, nucleic acid structure, cellular signaling, neurotransmission, and immunomodulation. Compared to adenosine, cordycepin lacks a hydroxyl group in the 3’ position of its ribose moiety, which greatly increases its potency [7].
Radhi and colleagues performed a systematic review of its biological effects, compiling information from nearly 200 scientific articles published before 2021, and cordycepin demonstrated clear beneficial effects in vitro and in many animal models with diverse disease-related symptoms [5]. Their analysis of the literature clearly shows that cordycepin has strong anti-inflammatory activity in vitro and in vivo, and published data suggest that cordycepin can inhibit TGF-β activity by diminishing activation and blocking the cellular response.
Cordycepin is also an inhibitor of cell migration (anti-metastasis effect), affects cell division, and promotes apoptosis, which directly relates to its anti-tumor properties [7]. Although cordycepin-binding target molecules and mechanisms of action for these therapeutic effects are not fully elucidated, the literature suggests that cordycepin affects the MAPK signaling pathway by reducing phosphorylation of ERK by MEK, thus inhibiting the ERK pathway. It also unequivocally indicates that cordycepin activates the AMPK pathway, and affects the PI3K/mTOR/Akt pathway by repressing Akt phosphorylation by mTOR [5].
Cordycepin exhibits potent therapeutic activity against cancer, hyperlipidemia, and diabetes, and is also a strong immunomodulator [8]. While cordycepin and derived molecules are being tested in clinical trials in oncology [5], this compound shows potential as a therapeutic agent for metabolic disorders such as diabetes or non-alcoholic fatty liver disease. Both disorders are of critical importance due to their significant impact on public health, given their prevalence and associations with other conditions such as obesity or cardiovascular diseases.
Metabolic disorders
Diabetes
Diabetes mellitus is a disease characterized by chronic hyperglycemia that affected about 537 million adults worldwide in 2021 [9]. Two different forms of the disease exist.
Type 1 diabetes mellitus is an autoimmune disease that leads to the destruction of insulin-producing pancreatic β-cells and results in insulin deficiency; while type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, or reduced responsiveness of the body to insulin. T2DM is the most prevalent type and represents 90% of diabetic patients. Although hyperglycemia is asymptomatic in the first stage of the disease, it can lead to severe complications if not correctly controlled, such as nephropathy, neuropathy, retinopathy, or cardiovascular diseases.
Recent research highlights the significant potential of cordycepin in the context of T2DM, as evidenced in studies conducted on mice or rats, in vitro and in vivo. Cordycepin demonstrates promising effects in regulating glycemia and alleviating associated cardiovascular complications.
The potential of cordycepin in modulating glycemia via gut microbiota and their metabolites was recently shown in mice [10]. Liu and colleagues studied the effects of cordycepin on a high-fat diet in streptozotocin-induced T2DM mice. They demonstrated that cordycepin significantly lowered (p-value < 0.01) fasting blood glucose after 4 weeks of a high-fat diet compared to T2DM mice without treatment. Metabolic parameters were also measured and triglycerides, total cholesterol, and LDL lowered while HDL increased compared to untreated mice. Cordycepin also significantly reduced the levels of oxidative factors (p-value < 0.01) measured in mice serum (i.e., superoxide dismutase, and catalase) and decreased alanine transaminases, indicating reduced liver damage. Finally, the inflammatory response, as measured by TNF-α and IL-6 serum concentrations, significantly decreased (p-value < 0.01) in cordycepin-treated T2DM mice compared to the untreated mice.
As microbiota imbalance can affect glucose and lipid metabolism, and thereby promote T2DM development [11], Liu and colleagues analyzed mice microbiota to detect changes in the intestinal microflora. Cordycepin influenced the gut microbiota composition by promoting the growth of beneficial bacteria, such as firmicutes and bacteroidetes. It also positively influenced microbiota metabolites by increasing phenols, fatty acids, and phenylacetones among others. Metabolite variations between cordycepin-treated and untreated T2DM mice revealed several favored metabolic pathways in the treated group, such as the PI3K/Akt/PPAR, PI3K/Akt/mTOR, PI3K/Akt/FOXO, and phenylalanine metabolism pathways. These data suggest that the therapeutic impact of cordycepin may be primarily associated with the PI3K/Akt/mTOR signaling cascade, a pathway known to be a major effector of metabolic insulin action that regulates glucose homeostasis [12,13].
As indicated earlier, T2DM is a major risk factor for cardiovascular diseases. As seen in T2DM, insulin resistance is associated with endothelial dysfunction leading to critical cardiovascular alterations [14]. Cordycepin showed a promising protective effect over vascular function impairment in T2DM [15]. Xue and colleagues tested the effects of a four-week treatment of cordycepin on streptozotocin-induced T2DM rats fed with a high-fat diet. They observed that the endothelium-dependent relaxation of the thoracic aorta ring, which decreased in T2DM rats, could be rescued by cordycepin in a dose-dependent manner. Moreover, cordycepin increased both the expression and activation of SIRT3 (a sirtuin protein located in the mitochondria and closely related to T2DM [16] and cardiovascular diseases [17]), alleviating the endothelial mitochondrial dysfunction induced by hyperglycemia and advanced glycation end products. After observing that the protective mitochondrial effect of cordycepin was blocked in SIRT3 knockdown cells, they concluded that its protective effect over T2DM-impaired vascular function may involve the SIRT3 pathway [15].
The protective effects of cordycepin, identified in vitro and in vivo, highlight the therapeutic potential of this molecule in the management of T2DM.
Non-alcoholic fatty liver disease
The Western diet and a sedentary lifestyle greatly favor the development of chronic metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) refers to a wide range of diseases. It encompasses simple steatosis (accumulation of hepatic triglycerides), non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and cirrhosis [18]. NASH is clinically more relevant than NAFL due to its increased risk of progression to more severe liver-related complications. In NASH, the presence of hepatic steatosis, inflammation, and hepatocellular injury with different degrees of liver fibrosis can lead to cirrhosis, liver failure, or hepatocellular carcinoma. Worldwide, NASH prevalence is rising and is estimated to be between 1.5% and 6.5% in the US [19], 2.4% and 6.1% in China [20], 1% and 3% in Japan, and around 3% in Europe [19]. Notably, there is currently no approved treatment for this disease [21].
Cordycepin has shown beneficial effects preventing hyperlipidemia and hepatotoxicity in hamsters fed with a high-fat diet [22], reducing the weight of rats fed with a high-fat diet to induce obesity [23], and preventing liver injury in mice fed with D-galactosamine/lipopolysaccharide [24]. As such, it may also be beneficial for NASH.
Lan and colleagues used mice fed with high-fat or high-fat/high-cholesterol diets as murine models for NASH to evaluate the effects of cordycepin [25]. Comparing cordycepin-treated with untreated mice, they observed that cordycepin significantly lowered hepatic and serum lipid (triglycerides and total cholesterol) levels. Treatment also slowed the hepatic lipid droplet accumulation typically observed in NASH. To investigate the effects of cordycepin on lipid accumulation and inflammation in hepatocytes under metabolic stress, human hepatocyte L02 cells were either treated or left untreated with cordycepin in the presence or absence of palmitic and oleic acids. Treatment with cordycepin lowered the hepatic expression of genes related to fatty acid synthesis and uptake (i.e., HMGCR, FASN, SCD1, PPARγ, CD36, and FABP1), and repressed inflammatory genes such as IL1B, CXCL2, CXCL10, CCL2, and CCL5. A gene set enrichment analysis revealed that cordycepin treatment affected various signaling pathways related to metabolism, inflammation, and fibrosis, both in vitro (L02 cells) and in vivo (mice), and particularly the AMPK signaling cascade, the most altered pathway.
The AMPK signaling pathway is central to the energy management of the cells. It gets activated in response to low adenosine triphosphate (ATP) levels, and increased adenosine diphosphate (ADP) and adenosine monophosphate (AMP) levels. As a result, it activates pathways that produce ATP to increase ATP levels [5]. Thus, AMPK has a significant impact on lipid metabolism. When activated, it inhibits fatty acid synthesis and promotes fatty acid oxidation. In the liver, this helps reduce the accumulation of triglycerides and lipids, which is a key aspect in the prevention and management of NASH [26]. In vitro, Lan and colleagues showed that cordycepin was able to induce the AMPK autophosphorylation of Thr172 [25], which in turn inhibited acetyl-CoA carboxylase (ACC) leading to an increase in fatty acid oxidation [5]. Finally, the use of Compound C, an AMPK inhibitor preventing AMPK phosphorylation and its downstream target ACC repression, clearly demonstrated that AMPK pathway activation is required for cordycepin-mediated improvement of hepatic steatosis and inflammation. Thus, as a natural activator of AMPK, cordycepin can mitigate NASH by preventing hepatic steatosis, inflammation, and fibrosis.
Conclusion
Cordycepin shows promising therapeutic effects in the context of T2DM and NASH in animal models and cell cultures. These properties may also apply to humans, though further research is needed to verify this, including the identification of target molecules binding to cordycepin and the clear establishment of links between binding and therapeutic effects.
While the AMPK and PI3K/mTOR/Akt pathways are recognized as crucial in the intricate T2DM and NASH diseases [27], they are very complex pathways participating in various essential cellular processes, such as cell proliferation and survival.
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References
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