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 approximately 1.3 million people die every year from diabetes. According to International Diabetes Federation (IDF), it is estimated that around 629 million people will have diabetes around the globe by 2045.

However, as per the recommendation from dieticians or physicians, a healthy lifestyle and healthy food habits could be one of the key answers to this problem. It has also been observed that, in most diabetic patients, several other complications also arise, such as cardiovascular diseases, retinopathy, nephropathy, hyperlipidemia, and neuropathy.

Various studies also suggest that no single treatment can treat diabetes, although most treatments achieve normal blood glucose levels or improve microcirculation. 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 Cordyceps showed a significant decrease in blood glucose levels by increasing glucose metabolism and protection against diabetic nephropathy.

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. It reduced the expression of type 2 diabetes-regulating genes (11β-HSD1 and PPARλ). The expression of co-stimulatory molecules such as ICAM-1 and B7-1/-2 was also decreased with the increase in cordycepin concentration, as presented. Furthermore, cordycepin has been found to suppress the expression of diabetes-regulating genes by inactivating NF-κb-dependent inflammatory responses. Another study reported cordycepin’s antidiabetic activity in an alloxan-induced diabetic mouse model.

The results suggested a significant improvement in glucose tolerance tests after administering an effective dose of cordycepin. 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. Several reports suggest that cordycepin has excellent potential for being a safe antidiabetic pharmaceutical agent.

  1. Cordycepin and Cardiovascular Diseases (Hyperlipidemia)

Cardiovascular diseases have become one of the major causes of death worldwide, and it has been assumed that there are various factors (excessive tobacco, alcoholism, sedentary lifestyle, unhealthy eating habits, etc.) related to it. Among the various risk factors, rises in lipid levels are believed to be one of the main ones causing this chronic disease. Hyperlipidemia is caused by the number of fatty acids present in lipids, low-density lipoprotein cholesterol, trans fats, and triglycerides accumulated in human bodies causing cardiovascular diseases such as atherosclerosis and coronary heart disease.

Moreover, a mechanistic approach involved in regulating fat metabolism is due to AMP-activated protein kinase (AMPK), a main cell electricity sensor.

In addition, activation of AMPK causes a decline in levels of fatty acids through phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), which helps regulate fatty acid biosynthesis and oxidation. AMPK activation was also reported to decrease total cholesterol and triglycerides by inhibiting the activity of glycerol-3-phosphate acyltransferase (GPAT) and HMG CoA reductase rate-limiting enzymes in TC and TG synthesis, respectively. Cordycepin could also prevent intracellular lipid accumulation by activating AMPK interplay.

Thus, it was found that regulating AMPK would provide a solution for overweight and obese people causing hyperlipidemia. According to previous reports, cordycepin has been found very effective in lipid reduction due to its chemical structural similarity with adenosine (an activator of AMPK). Similarly, the administration of cordycepin effectively reduced the accumulation of low-density lipoprotein cholesterol, total cholesterol, and triglycerides. It could be a potent nutraceutical agent for reducing hyperlipidemia caused by high-fat diets.

On the other hand, cordycepin was evaluated for regulating autophagy and lipid metabolism. It has been found that cordycepin was effective against hepatic lipid accumulation induced by PA through autophagy induction, and PKA/mTOR pathway could be the possible mechanism behind its efficacy. More importantly, it was observed that cordycepin was largely effective in reducing the intracellular levels of total lipids, total cholesterol, C and TG, LDL-C, VLDL-C, and LDL-C/HDL-C and TC/HDL-C ratios. Therefore, the feature of lipid-lowering in cordycepin could be potentially used in the treatment of hyperlipidemia.

  1. Cordycepin and Anti-Inflammatory Effects

Inflammation, a natural response to injury, occurs in our body to eliminate harmful elements such as damaged cells, irritants, and pathogens by initiating the healing system. Acute and chronic pulmonary inflammations have been reported in various respiratory diseases such as asthma, acute respiratory distress syndrome, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD).

Cordycepin has been reported to suppress intestinal irritation in an acute colitis mouse model and microglia by inhibiting pro-inflammatory mediators such as TNFα. It has been found that cordycepin is effective in a mouse version of bronchial asthma. It also improves mucus clearance and airway surface hydration, as it is hyper-secreted in various respiratory problems, like COPD and asthma.

In addition, cordycepin has also been reported to attenuate airway remodeling in rats with COPD by preventing airway inflammation and the TGF-β1/Smad signaling pathway. According to this report, cordycepin could be helpful in the case of COPD. Cordycepin extracts were reported to relieve fibrosis in the lung by inhibiting TGF-b1 expression and promoting collagen degradation.

Therefore, based on these collective reports and data, it could be summarized that cordycepin has all the potential to become a very potent bioactive anti-inflammatory component.

  1. Cordycepin and Immunomodulatory Effects

Immunomodulation is usually defined as the modulation of the immune system. It can be done by any chemical agent that modifies the immune response or the functioning of the immune system via the stimulation of antibody formation or the inhibition of white blood cell activity. Cordycepin has been reported to stimulate cytokine release of resting peripheral blood mononuclear cells (PBMCs) and influence PBMCs proliferation and transcription factors in a human acute monocytic leukemia cell line (THP-1).

Moreover, cordycepin regulated human immune cell functions in vitro. It has also been observed that the antitumor activity of cordycepin is associated with its immunomodulatory effects.

Additionally, pure bioactive components extracted from C. militaris are reported to have good immunomodulatory effects by increasing the survival rate of lupus mice and reducing anti-ds-DNA production. C. sinensis behaves like an immunosuppressant in a heterotopic heart allograft model in rats and increases the survival period.

Therefore, cordycepin has been proven a potentially effective immunomodulator, and it is even specifically used to control autoimmune disorders and transplant rejections after an organ transplant. An increasing number of studies indicate that cordycepin is a bi-directional modulator with suppressive and influencing effects on the immune system by regulating adaptive and innate immunity.

Immunomodulation is usually defined as the modulation of the immune system. It can be done by any chemical agent that modifies the immune response or the functioning of the immune system via the stimulation of antibody formation or the inhibition of white blood cell activity.

Cordycepin has been reported to stimulate cytokine release of resting peripheral blood mononuclear cells (PBMCs) and influence PBMCs proliferation and transcription factors in a human acute monocytic leukemia cell line (THP-1).

Moreover, cordycepin was found to regulate human immune cell functions in vitro. It has also been observed that the antitumor activity of cordycepin is associated with its immunomodulatory effects.

Additionally, pure bioactive components extracted from C. militaris are reported to have good immunomodulatory effects by increasing the survival rate of lupus mice and reducing anti-ds-DNA production. C. sinensis behaves like an immunosuppressant in a heterotopic heart allograft model in rats and increases the survival period.

Therefore, cordycepin has been proven a potentially effective immunomodulator, and it is even specifically used to control autoimmune disorders and transplant rejections after an organ transplant. An increasing number of studies indicate that cordycepin is a bi-directional modulator with suppressive and influencing effects on the immune system by regulating adaptive and innate immunity.

  1. Cordycepin and Anti-Osteoporosis Effect

Osteoporosis is a condition of low bone mineral density (BMD) and loss of bones’ structural and biomechanical properties. It increases the fracture risk as bones become more porous and fragile. Osteoporosis mainly occurs in people aged, specifically post-menopausal women and patients who had long-term steroid therapy treatment.

Anti-osteoporotic effect of cordycepin was studied in ovariectomized osteopenic rats; it was found that cordycepin could counteract the loss of bone in the experimental model. The mechanical approach in this study showed the decline in the activity of tartrate-resistant acid phosphatase and alkaline phosphatase enzymes both in vitro and in vivo.

Moreover, the results showed that oral intake of cordycepin could increase the level of osteocalcin (OC), a marker of bone formation, and decrease C-terminal cross-linked telopeptide of type I collagen (CTX) level, a marker of bone resorption, as well as restore oxidative stress levels in ovariectomized rats.

These results suggest that cordycepin can be a valuable bioactive compound for osteoporosis treatment and can prevent bone loss caused by estrogen deficiency. Cordycepin was also reported to inhibit RANKL-induced osteoclast differentiation (RANKL), receptor activator of nuclear factor-kappa-Β ligand, and down-regulate the mRNA expressions of osteoclastogenesis-related genes such as matrix metalloproteinase (MMP)-9, cathepsin K, tartrate-resistant alkaline phosphatase (TRAP) and nuclear factor of activated T-cells, cytoplasmic 1.

  1. Cordycepin and Anti-Arthritic Effect

Arthritis, an autoimmune disease affecting bone joints, is mainly characterized by joint stiffness and joint pain, among other symptoms such as swelling, warmth, redness, and reduction in joint mobility. There is no known effective treatment for arthritis.

However, many drugs such as glucocorticosteroids, non-steroidal anti-inflammatory drugs, and other biological agents are used to improve the symptoms, such as pain, fatigue, and disability. Long-term usage of these drugs decreases their effectiveness and increases side effects.

Recently, studies were conducted looking for effective anti-arthritic drugs with increased therapeutic and fewer side effects. Traditional herbal medicine, which is shown to be more effective, safer, and economical, has attracted more attention in arthritis treatment.

Moreover, cordycepin has been found to modulate glycosaminoglycan (GAG) release by suppressing the stimulation of IL-1β. In addition, levels of proteases that have been reported in cartilage matrix degradation, such as MMP-13, cathepsin K, MMP-1, cathepsin S, ADAMTS-5, and ADAMTS-4, were decreased by cordycepin in a dose-dependent manner.

The chondroprotective effect of cordycepin by preventing cartilage denegation and interfering with an inflammatory response in osteoarthritis pathogenesis has also been reported. Cordycepin has been reported to reduce excessive inflammatory cell infiltration via down-regulation of macrophages, interferon gamma-induced protein 10 (IP-10), and Mig expressions through terminating protein-coding gene (STAT1) phosphorylation.

Some reports suggest that T-cell infiltration inflammation could be inhibited by using a cordycepin concentration of 10 mg/kg. According to that report, cordycepin can regulate the T-cell receptor, a protein complex found on the T-cell surface, that signals to suppress excessive T-cell activation in inflammation. Therefore, based on these reports, it can be concluded that cordycepin has therapeutic potential in anti-catabolic and anti-inflammatory actions against arthritic diseases.

  1. Cordycepin and Antioxidant Effect

Antioxidants are compounds that can prevent or slow down oxidation reactions producing free radicals that ultimately cause cell damage in organisms. Oxidative stress, related to an increased formation of oxidizing species or a significant reduction of natural antioxidant levels, is involved in different human diseases (cellular necrosis, cardiovascular disease, cancer, neurological disorder, aging). Non-toxic antioxidants from natural sources, particularly medicinal plants, prevent oxidative damage due to their richness in polyphenolics and bioactive compounds.

Female scientist working in the CDC laboratory.

Various authors have reported the antioxidant activity of Cordyceps. Cordycepin has been reported to significantly increase antioxidant enzymes such as superoxide dismutase and glutathione peroxidase activities in 6-OHDA-treated cells.

Moreover, the results showed that cordycepin prevents 6-OHDA-induced neurotoxicity in adrenal pheochromocytoma cells (PC12 cells) via its potent antioxidant action.

In addition, cordycepin containing protein-bound polysaccharides causes a reduction in lipid peroxidation and increases the activity of antioxidant enzymes in the liver like catalase and superoxide dismutase. Other authors have suggested the potential of cordycepin in reducing lipid peroxidation in mouse liver.

Therefore, cordycepin could be considered a potential antioxidant. A few studies have even suggested that the antioxidant potential of Cordyceps is close to that of ascorbic acid.

  1. Cordycepin and Anti-Malarial Effect

Malaria, a widespread disease globally with a high mortality rate, is caused by Plasmodium, a parasitic organism. The parasite gets into the human body through the bites of infected mosquitoes. It is one of the deadliest diseases in the world, as it is estimated that every 2 min, a child dies of malaria, and each year more than two hundred million new cases of the disease are reported. Most people who die from the disease are young children in Africa.

The growth of the malaria parasite is affected by cordycepin which affects the parasite’s nucleic acid and protein synthesis. It makes cordycepin a possible molecule that can be explored further as a probable anti-malarial agent.

  1. Cordycepin and Other Diseases

Hyperuricemia is a long-time purine metabolic disorder recognized as a result of excessive serum uric acid status in the blood and associated with gout, renal sicknesses, hypertension, hyperlipidemia, and atherosclerosis. C. militaris has been reported for its anti-hyperuricemic effect in hyperuricemic mice at different doses, reaching the levels of normal mice.

Another study showed the cordycepin’s potential as an anti-hyperuricemic in hyperuricemic mice. Infertility can be described as a disease condition where females cannot become pregnant despite having frequent, unprotected sex for at least a year for most couples. According to the reports, cordycepin has been proven potent in increasing sperm quality and quantity. C. militaris supplementation has been stated to increase serum cordycepin concentration, which concurrently enhances testosterone and estradiol-17 levels, ultimately increasing the percentage of motile sperm cells.

In addition, Cordycepin is also reported to increase semen production as well as sperm quality in boars. The effect of cordycepin on testosterone levels in male rats was reported. It was found that the concentration of testosterone in the serum of the rats was significantly increased by C. militaris.

Therefore, fruiting bodies of C. militaris grown on the drone bee medium could act as an integrative medicine for treating reproductive problems caused by insufficient testosterone levels in human males.

On the other hand, chronic kidney disease (CKD) is a condition where the condition of the kidneys deteriorates steadily and has been related to non-communicable diseases, e.g., diabetes and hypertension, and infectious diseases like hepatitis B, malaria, and HIV. Clinical research exploring the possible cordycepin application has confirmed the beneficial effects in decreasing the progression of end-stage kidney disease in CKD patients.

Moreover, other pharmaceutical applications of cordycepin are also recommended, such as increasing creatinine clearance, serum albumin, and hemoglobin, lowering serum creatinine levels, and improving lipid metabolism.