A brief review on the medicinal uses of Cordyceps militaris

1. Introduction

Many acute and chronic disorders are treated with various drugs. The majority of allopathic medications are used to cure ailments in the modern world. Allopathic drugs have also been proven to be quite helpful for treating illnesses, but they also come with many drawbacks when treating chronic illnesses, thus they have both benefits and drawbacks. Toxic and tolerable side effects result from the continuous use of allopathic medications to treat chronic disorders. As a result of years of ongoing drug exposure, resistance evolves. Under certain circumstances, managing the tolerance by raising the drug dosage was possible, but after a while, it also lost its effectiveness. This results in poor disease management.

Additionally, because drug toxicity is dose-dependent, treating chronic conditions over a lengthy period of time with drug administration might have harmful side effects. In CNS-related illnesses and disorders, drug toxicity is frequent. Drug toxicity has a significant negative impact on the kidneys, liver, heart, skin, and other organs, which contributes to sepsis and finally results in patient mortality.

Alternative remedies are adopted as a result of the above-mentioned drawbacks of allopathic medications. Allopathic drug management has become more challenging in recent years as a result of adverse drug reactions from prolonged use. Studies that have reportedly been conducted have indicated that using alternative remedies is beneficial. Alternative and complementary medicines are used in alternative therapies. Allopathic medications are substituted with complementary ones. Allopathic treatments' effects are enhanced by complementary medicines. In comparison to allopathic medications, these are also less harmful.

2. Materials and methods

2.1. Types of alternative medicines

This includes a variety of medicine like,

I
Acupuncture
II
Ayurveda
III
Homeopathy
IV
Naturopathic medicines

2.2. Types of complementary medicines: -

I
Mind-Body Interventions
II
Biologically-Based Therapies
III
Manipulative and Body-Based Methods
IV
Energy Therapies

Naturopathic medicines are obtained from natural sources. It is beneficial in the prevention and treatment of many diseases. It also has fewer side effects compared to allopathic medicines. Naturopathic medicines were also used traditionally across the globe in the least encroaching yet effective manner. Its use deteriorated slowly after World War II when allopathic medicines became popular in North America and gradually covered the globe. These are obtained from many different natural sources like plant sources, animal sources, microbial sources, marine sources, etc. One such naturopathic agent is Cordyceps militaris. Throughout history, medicinal mushrooms have played a significant role in human society. With approximately 750 varieties and being among the largest genera in the Cordycipitaceae family, the genus Cordyceps is also one of the most diverse [1,2]. This diversity can be seen in the variety of species, their morphology, and their ability to adapt to a variety of hosts. The ethnomedicinal fungus C. militaris is widely used as a functional ingredient and a primitive food supplement in Asia [3]. It is significant in traditional Chinese medicine. In its genus, C. militaris is the second most often studied species. Blood glucose management, hypolipidemia, anti-tumor, anti-microbial, anti-viral, antiprotozoal, anti-inflammatory, neuroprotective, anti-oxidant, and immunoprotective actions of this species have all been reported [3,4]. As a result, the C. militaris may be regarded as a significant possibility for the treatment of many diseases.

2.3. Plant profile of Cordyceps militaris

Kingdom - Fungi

Division - Ascomycota

Class - Sordariomycetes

Order - Hypocreales

Family - Cordycipitaceae

Genus - Cordyceps

Species - C. militaris

Binomial name - Cordyceps militaris

2.4. Geographical source

These diversified species are primarily found in humid temperate and tropical settings throughout Asia (including Korea, Japan, Nepal, and China) and other regions of the world. The existence of several species in multiple ecological settings around the planet suggests its global dispersion [4,5]. The link between the Cordyceps species and associated hosts is mediated by unique and synchronized pathways. After eluding their immune systems and the subsequent synthesis of defensive secondary metabolites by the organisms, they sustain their life cycles in accordance with the features of the hosts for growth and survival, which can be viewed as promising sources of novel pharmaceuticals [5]. These species have grown significantly in value as a source of natural compounds with a variety of biological functions as a result of this feature [4]. Due to their rarity and high cost to acquire and process, Cordyceps species encountered in the wild have lately been overtaken by specimens grown in a lab [6].

2.5. Cultivation procedure

The stock culture was kept alive on potato-dextrose-agar (PDA) slants that contained 20.0 grammes of glucose per liter of medium, 3.0 grammes of potassium hydroxide per liter of medium, and 1.5 grammes of magnesium sulfate per liter of medium. Using PDA media, the seed culture obtained from a viable slant was cultivated in a Petri plate for 13 days at 25 °C before being stored at 4 °C for subculture [7]. One centimeter of PDA plate culture was sliced off with a sterilized cylindrical cutter to serve as the inoculum. To start the surface culture, the seed culture was injected into a 500 mL culture container with an 8.5 cm diameter and a 14.0 cm height. The six bug species were put in polypropylene containers and autoclaved for 30 min at 121 °C to disinfect them. After reaching room temperature, each polypropylene vial was infected with the same amount of inoculum (v/w 1:2). Inocula were grown with edible insects (or brown rice as a reference) in 250-mL polypropylene containers at 25 °C in darkness, 70% humidity for 5–7 days. Following the coating of the substrates with white mycelium, the culture was maintained for an additional 49 days in an atmosphere including light, maintaining a temperature of 20 °Celsius and a relative humidity of 90%. The sclerotium containing fruiting bodies was then pulverized into a powder form in a laboratory blender after air drying at 60 °C for 48 h. The specimens were either kept in a freezer at a temperature of −80 °Celsius or were utilized straight away for studies including gas chromatography–mass spectrometry (GC–MS), gene expression analysis, and assessment of the amount of cordycepin present [8,9].

2.6. Microscopic characters

Both dried and moist conserved specimens [10] were employed for the microscopic analyses that were carried out. The cured specimen portions were placed in water after being placed for a short time in 95% ethyl alcohol (to remove the air). By chopping free-hand portions of the material, the anatomical aspects of the specimen were worked out. With the use of a research microscope, microscopic particulars of the object were determined in the laboratory setting. Mycelium and spores were both subjects of this investigation. In order to better see the sections, they were stained with cotton blue solution (1%), followed by lactophenol. Under a microscope, the segments were studied.

2.7. Macroscopic characters

Club- or clavate-shaped stroma that are separated into fertile and sterile segments. Fertile portion, measuring 10–30 × 5–12 mm, is reddish to darker orange and is abraded by ostioles from the orange perithecia. Yellow, pale or crimson orange, occasionally mottled with orange; sterile portion 30–4 × 5–10 mm in size. Semi-submerged, ovoid perithecia measure 550–700 × 250–400 μm in size. Asci 350–400 × 3∼4 μm, barely cylindrical, eight-spored, splitting up into numerous separate spores [11].

2.8. Chemical constituents

In light of the findings of the scientific research, it is feasible to gather information on bioactive compounds from the group of nucleosides and polysaccharides that are present in C. militaris. These chemicals can be found in the plant. It has been established that C. militaris contains the nucleosides cordycepin and adenosine, and the amount of these components that can be found in C. militaris is significantly greater than what can be found in C. sinensis. -aminobutyric acid (GABA) and ergothioneine were found to be present in C. militaris, as were the following biologically active substances: glycolipids (cerebrosides), glycoproteins (lectins), D-mannitol (referred to as cordycepic acid), xanthophylls including carotenoids (lutein and zeaxanthin), sterols (ergosterol), statins (lovastatin), phenolic compounds (including phenolic acids and flavonoids), vitamins and biominerals/bioelements (magnesium, potassium, selenium, and sulfur) [12], [13], [14]. The drying temperature of 60 °C. is ideal for C. militaris. When the temperature is increased, the amount of cordycepin and phenolic chemicals that are present decreases [15].

3. Biological activities

Since prehistoric days, the C. militaris medicinal mushroom has had a significant role in China's healthcare system and has been frequently consumed therein (3000 years). As a clinical intervention, it is utilized for the treatment of lung and renal dysfunction, hyperglycemia and hyperlipidemia, respiratory problems, fatigue, treatment of nocturnal sweating, fertility concerns, cardiac arrhythmias, and other heart ailments. C. militaris possesses a wide variety of pharmacological qualities, including the ability to decrease inflammation, as well as antioxidant, anticancer, antimetastatic, immunomodulatory, hypoglycemic, and steroidogenic effects as shown (Fig. 1) below [3,16,17].

3.1. Anti -cancer activity

There is still a need for a capable and effective treatment for cancer, which is currently the leading cause of mortality worldwide. The chemical Cordycepin (3′-deoxyadenosine) from C. militaris has an anti-tumor or anti-cancer action. Insights from research on this specific chemical component of the disease's treatment seem promising. C. militaris aqueous extract suppresses proliferation and triggers apoptosis in human lung cancer cells, according to research by Park et al. [18]. Increased caspase-3, caspase-8, and caspase-9 enzymatic activity as well as telomerase enzyme suppression were linked to C. militaris' anticancer effects as demonstrated below in Fig. 2. The Fas protein, which is linked to the "death receptor" of cancer cells, was found to be present in higher concentrations, according to the analysis.

A mechanistic investigation that was carried out by Chou et al. found that the anticancer effects of C. militaris on leukemia cell lines might be due to amplification of AKT and p38 mitogen activated protein kinase (MAPK), throughout the course of apoptosis induction, implying the probable use of its extracts against leukemia by engaging the p38 MAPK cascade [19].

A more recent investigation revealed that cordycepin inhibited the development of human liver cancer cells. The mechanism of cordycepin's anticancer effect has been attributed to a decrease in the production of the chemokine CxCR4, which encourages liver cancer cells' invasion and migration [20]. In non-small cell lung cancer, C. militaris has been demonstrated to cause cancer cells to undergo apoptosis. The tectonic-3 protein (TCTN3) expression is what causes apoptotic activity to occur. The reduction of many signaling pathways, including the Smoothened (SMO), Patched1 (PTCH1), and Glioma-Associated (GLI1) pathways, was connected with a decrease in TCTN3 expression. The aforesaid mechanisms are correlated with elevated Bak, cleaved caspase-3, and caspase-9 levels, as well as decreased Bcl-2 and BclxL levels [21].

3.2. Anti-oxidant activity

The polysaccharides found in C. militaris were the primary source of the antioxidant activity affirmation. The antioxidant abilities of cordycepin have not been extensively studied [22]. Other chemical elements that are present in the fruiting bodies of C. militaris, such as ergothioneine, phenolic compounds, carotenoids, and selenium, may also have an effect on the antioxidant activity of the species [12], [13], [14].

The antioxidant capability of C. militaris is greater than that of C. sinensis with regard to its ability to suppress lipid peroxidation. The antioxidant potential of C. militaris fruiting bodies was shown to be proportional to the amount of polysaccharides and phenolic compounds that were present in those bodies [23]. Previous research has demonstrated that the polysaccharides P70–1 and CBP-1 derived from C. militaris have the capability of neutralizing hydroxyl radicals [24]. It has been demonstrated that the polysaccharide known as CM-hs-CPS2 possesses both the ability to chelate ions (Fe²⁺) as well as the antioxidant activity [25]. Antioxidant capacity of the polysaccharide segments was reported for the components WCBP50, CMP, CMP-1, and SeCSP-I in a number of in vitro tests [26], [27], [28], [29]. It was discovered that increasing the amount of selenium present in the medium of C. militaris resulted in an increase in the antioxidant properties of the polysaccharide fractions [30].

A polysaccharide CM-hsCPS2 isolated from the fruiting bodies of C. militaris showed in vitro anti-oxidant activity to testify the hydroxyl radical scavenging potential. Thus, the result suggested that the extracts of cultured Cordyceps militaris own powerful anti-oxidant and anti‐lipid peroxidation activities and inhibit the buildup of cholesteryl ester in macrophages through suppression of low-density lipoprotein oxidation as shown in the Fig. 3 below. Superoxide dismutase (SOD), catalase, and GPX enzymes with antioxidant potential were found to be more active in experiments on mice fed C. militaris containing polysaccharides, and malondialdehyde (MDA) levels were also reduced [17,31]. A correlation between antioxidant activity and neuroprotective or hepatoprotective properties was also seen in additional rodent investigations.

3.3. Anti-inflammatory activity

Inflammation plays a crucial role in biological processes that are triggered by a variety of stimuli and unpleasant elements, including UV radiation, allergens, pathogens, and cell damage. Redness, a high body temperature, discomfort, and changes in physiological processes at infected locations are the major characteristics of inflammation [32,33]. Inflammation, which can be acute or chronic, is typically thought of as a protective mechanism against pathogen-induced tissue damage. In order to sustain the undesirable immune response, neutrophils, natural killer cells, mast cells, and T and B cells are involved [32]. Diseases caused by chronic inflammation are characterized by terrible consequences. Inflammation can be brought on by a variety of sources, including toxins, physical injury, contagious diseases, immunological reactions, and metabolic abnormalities. Due to their ability to suppress both acute and chronic inflammatory reactions, medicinal fungi like C. militaris or their component cordycepin are currently being studied as anti-inflammatory therapeutic medicines. Antioxidant activity, transcription factors, matrix metalloproteinases, complement cascade characteristics, and adhesion molecules like intercellular adhesion molecule-1 (ICAM-1), selectin, and vascular cell adhesion molecule-1 are the actual mechanisms behind anti-inflammatory reactions (VCAM-1). Additionally, C. militaris and its components control the expression of inflammatory genes as well as the actions of pro-inflammatory enzymes. Recent studies showed that COX-2 and iNOS gene expressions were suppressed by cordycepin, one of the major components of C. militaris [34]. C. militaris has been shown to have significant promise as an antioxidant in a number of different investigations. Zhang et al. [35] provided evidence that the polysaccharide-iron (III) has a significant radical scavenging ability on DPPH, hydroxyl ABTS, and superoxide species. In a different piece of research, the ability of neutral polysaccharide to act as an antioxidant was determined by testing its degradation efficiency, ABTS radical scavenging activity, oxygen radical absorbance capacity (ORAC-fluorescein), and hydroxyl radical scavenging activity [36]. In vitro, C. militaris ethanol extracts inhibited DPPH, superoxide, hydroxyl radicals, and low-density lipoproteins. In addition, treatment with C. militaris was found to be an effective therapy for inflammation-related neurodegenerative effects [37]. Cordycepin was able to reduce the amount of MDA that was induced by LPS as well as the production of inflammatory cytokines (IL-1β, TNF-α) as demonstrated below in Fig. 4 [38].

3.4. Ergogenic and anti-fatigue activity

There is a correlation between the activity of lowering the sense of tiredness and the reinforcing and ergogenic effect, which may be defined as an improvement in a person's physical efficiency. Cordycepin is the primary bioactive component in C. militaris that has the potential to induce ergogenic effects. Cordycepin's ergogenic effect can be traced back to its physiological role as an indirect antecedent of ATP and NO [16,39]. In a manner analogous to that of creatine, cordycepin functions as an indirect precursor of ATP. The hypothesis that creatine has an ergogenic effect is backed up by a significant amount of scientific research. Creatine has been shown to boost a person's physical capacity in many bursts of high-intensity, high-volume exercise [40]. The ability of C. militaris to prevent rodents from becoming fatigued was established in a series of studies using the organism. The amount of time it took mice to become fatigued during the swimming test was significantly increased. The reduction in burnout that was prompted by C. militaris in animal experiments was due to an improvement in the concentration of ATP and antioxidant enzymes, a decline in the intensity of lactate and ROS, and activation of AMPK and AKT/mTOR paths [41], [42], [43].Mice that were given an extract of C. militaris with cordycepin had improved exercise performance when they were put through a test measuring their grip strength [44]. Dudgeon et al. [45] showed that healthy young adults (ages 19–34) who consumed a mushroom blend including C. militaris had greater athletic endurance, a longer time to fatigue, a higher VO₂max, and a lower blood lactate percentage.

3.5. Immunomodulatory activity

The immunomodulatory potency of extracts derived from fresh C. militaris fruiting bodies, both in vitro and in animal models, is significantly higher than that of extracts obtained from dried C. militaris fruiting bodies. It was discovered that the quantity of cordycepin and adenosine did not vary significantly among freshly harvested and dried raw material, however the concentration of polysaccharides, polyphenols, and flavonoids was higher in fresh C. militaris [46].

Edible fungi, especially mushrooms, contains a variety of immunomodulatory proteins, such as lectins, ribosome inactivating proteins, ribonucleases, laccases, and fungal immunomodulatory protein (FIP). By regulating immune cell mitosis, proliferation, differentiation, and maturation, these proteins can improve immunity. These immunomodulatory proteins mostly consist of FIP, which has been the focus of the most study. A brand-new FIP called Cordyceps militaris immunomodulatory protein (CMIMP) has been identified as a cytokine inducer whose mechanism of action is demonstrated in the Fig. 5 below [47].

In experiments with rodents, there was a discernible rise in both the rate of phagocytosis and the generation of lymphocytes in the spleen cells. The immunostimulatory activity could be accounted by the action of polysaccharides that were contained in the material that was examined from the mushroom [17]. The polysaccharide component obtained from the fruiting bodies of C. militaris was shown to have immunostimulatory potential [48], which was demonstrated through the stimulation of macrophages.

Cordycepin-rich extract of C. militaris has immunostimulatory effects on murine macrophages. The mechanism of C. militaris and cordycepin's immunostimulatory ability is centered on macrophage activation to create NO and proinflammatory cytokines IL-1, IL-6, TNF-α, and prostaglandin-2 (PGE2), as well as an enhancement in the functioning of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). The nuclear transcription factor (NF-B) was activated by C. militaris/cordycepin, which caused macrophages to generate proinflammatory mediator [16,39].

3.6. Anti-microbial activity

The peptide known as cordymin was extracted from C. militaris. In experiments carried out in vitro, its antiviral and antifungal properties were demonstrated. Cordymin was able to stop the growth of a number of different kinds of fungi, such as Bipolaris maydis and Candida albicans. Additionally, the reverse transcriptase of the HIV was suppressed. The effectiveness of cordymin as both an anti-inflammatory and an antinociceptive agent has been demonstrated in a number of different research studies [49].

The isolated lyophilized specimen (1 g) was then screened through Whatman No. 4 paper after being stirred with 40 ml of methanol for an hour. Following that, the remnant was extracted using 20 ml of methanol for 1 h. The consolidated methanolic extracts were evaporated to dryness at 40ᵒc (rotary evaporator Büchi R-210) before being redissolved in (a) methanol for antioxidant activity assays (20 mg/ml), (b) 5% DMSO in distilled water for antimicrobial activity assays (100 mg/ml), and (c) distillated water for anti-proliferative activity assays (8 mg/ml) [50]. The methanolic extract also showed potent antifungal and antibacterial properties. Henceforth, the methanolic extracts from fruiting bodies and fermented mycelia of C. militaris have strong and direct antioxidant and antimicrobial activities.

Research conducted in vitro have shown that cordycepin and its analogues have an antiviral effect on several virus strains. Antiviral action was demonstrated for multiple viruses, including HIV, herpes simplex virus (HSV), Epstein–Barr virus (EBV), and influenza virus. Cordycepin's antiviral efficacy is connected to its capability of inhibiting the virus's RNA polymerase and reverse transcriptase [51], [52], [53]. In an in-silico analysis, cordycepin was found to have significant molecular interaction with SARS-CoV-2. Specifically, it interacted with the receptor-binding domain (RBD) of the spike protein (S) and the major protease (Mpro) of the virus. Cordycepin's ability to limit viral replication was found to coincide with its anti-SARS-CoV-2 modes of action [54]. Another in silico investigation employing pharmacologic and molecular modeling, simulation, and estimation found that cordycepin has the capacity to block RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 [55].

3.7. Effect on respiratory system

Cordycepin from C. militaris has been shown to alter the mobility of Na⁺, K⁺, Cl⁻ions in the epithelial cells lining the respiratory tract, according to in vitro investigations [56]. Preliminary studies revealed that prednisolone and montelukast, the standard drugs, are more efficient at reducing inflammation in a murine model of asthma than preparations from the fruiting bodies of C. militaris. The decline in IgE content, eosinophilia, and suppression of leukotriene production were all hardly affected by C. militaris extracts [57]. Subsequent scientific research, meanwhile, revealed that cordycepin ameliorates airway hypersensitivity, reduces inflammation, and lowers IgE and eosinophil levels in a mouse asthma model. It was found that the expression of IL-4, IL-5, IL-13, and NF-κB decreased [39]. In a rat model of asthma, cordycepin was found to lessen the amount of airway remodeling that occurred. There was also a reduction in the quantities of IgE, eosinophils, and neutrophils, as well as a reduction in the expression of TNF-α, TGF-β1, IL-5 and IL-13 [58]. Cai et al. and Gai et al. [59] conducted research on humans and established that C. militaris may be effective in the treatment of chronic bronchitis. An immunostimulatory impact was detected in the study that was conducted by Jung and colleagues [60], despite the fact that C. militaris did not have a great influence on the progression of an upper respiratory tract infection in the volunteers who participated in the study.

3.8. As anti-hyperlipidemic or cardiovascular agent

Given its beneficial effects on vascular reactions in smooth muscle cells, cordycepin may be a promising target for future anti-atherosclerotic drug development [61]. Hyperlipidemia persists in cases of serious cardiovascular diseases. The use of synthetic drugs to decrease the lipid content in blood has been found to induce frequent and serious side effects. In rat studies using an animal model of hyperlipidemia, cordycepin from C. militaris has been shown reduce triglycerides, total cholesterol, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) levels. Inhibitors of hepatic lipase and lipoproteins as well as an AMPK activator were characteristics of cordycepin [62,63]. In vitro tests on adipocytes showed that cordycepin suppressed adipogenesis and lipid deposition. The repression of the C/EBP, PPAR, and mTORC1 pathways and activation of AMPK were discovered to be related to the biological activity of cordycepin [64]. In vitro experiments further supported cordycepin's hypolipidemic action and its capacity to activate AMPK and the γ1 region [65]. The hypolipidemic efficacy of the polysaccharide fractions extracted from C. militaris was further validated by an in vitro experiment and an in vivo examination in rodents [66,67]. The hypolipidemic action of intracellular (IPCM) and extracellular polysaccharides (EPCM) from C. militaris was also established by Huang et al. [68] in mice given a high-fat diet.

3.9. Hypoglycemic activity

Type 1 diabetes is caused by abnormalities in insulin production, while type 2 diabetes is caused by either enhanced cell resistance to insulin or a combination of the two. Hyperglycemia, or an unusually elevated blood glucose content, is the result of this condition and causes extensive organ failure [69]. As of present, a variety of therapeutic drug alternatives for DM are offered. Several different classes of oral antidiabetic agents fall within this category, including sulfonylureas, biguanides, glinides, tolbutamide, phenformin, rosiglitazone, and repaglinide. Despite the fact that there are lot of treatments out there, the vast majority of them are harmful and expensive. They are therefore unable to prevent or delay the progression of diabetes problems. Some of these medications may elevate the risk of developing kidney tumor's, liver damage, or acute hepatitis. Most present antidiabetic research is directed toward creating antihyperglycemic therapies without the potentially harmful side effects of the currently available drugs [70]. The anti-diabetic properties of crude extracts derived from the fruiting bodies and mycelia of a variety of medicinal fungus were evaluated and compared by Zhang et al. [71] These medicinal fungi included C. militaris, C. sinensis, Omphalia lapidescens, and Tricholoma mongolicum. In a study conducted by Dong et al. [72], diabetic Sprague-Dawley rats were given either a water extract or an alcohol extract of Cordyceps militaris. The investigators came to the conclusion that the extract induced a considerable drop in blood glucose levels by increasing glucose metabolism. Additionally, the extract substantially lowered the amount of total cholesterol and triglycerides. The anti-diabetic efficacy of C. militaris fractions was demonstrated by De Silva et al. [73], who observed decreased blood glucose levels in streptozotocin-induced diabetic mice. They found that C. militaris water extract contains a chemical that enhanced insulin production and reduced insulin tolerance in rats with type II diabetes. Cordycepin, which is isolated from C. militaris, was hypothesized to inhibit inflammatory reactions by blocking the NF-Kb pathway by Patel and Ingalhalli [74]. Some studies have linked the hormonal and neurochemical alterations that occur in people with diabetes mellitus to feelings of depression and anxiety. Vanadium complex of vanadium-enriched C. militaris (VECM) has been proposed as a means of averting depression in people with diabetes, as well as influencing insulin's activity and emulating its positive effects on patients' satisfaction with treatment and their disposition. Antidepressant-like activity in C. militaris has been reported, and it reduces the rise in blood sugar that occurs as a result of diabetes.

3.10. Neuroprotective action

Through an in vitro investigation conducted on murine microglia cells, the neuroprotective potential of cordycepin was demonstrated and verified in Fig. 6. The anti-inflammatory property [75] or the antioxidant activity [76] of cordycepin was essential for the protective effect that cordycepin had on neurons.

In cerebral ischemia, there is insufficient flow of blood to the brain cells to meet their metabolic requirements. The major reason for the condition is cerebral hypoxia or deficiency in the supply of oxygen to the cells leading to the death of cells and ultimately cerebral infarction or ischemic stroke in the brain cells. This irreversible damage in the brain cells and functional loss of neurons was reported in past studies. This leads to temporary amnesia involving permanently impaired learning and memory, dementias, memory loss, involving attention deficits, and judgment disorders. The chief reason behind Vascular Dementia is a poor supply of blood to the brain cells, typically bought about by a series of minor strokes, significantly leading to worsening cognitive decline. Normally it co-exists with Alzheimer's disease, vascular dementia, and mixed neurodegenerative disorder involved in age-related cognitive impairment [77].

Lee et al. [78] demonstrated that effects of scopolamine-induced cognitive impairment in experimental rats could be prevented by administering C. militaris. In a murine model of dementia and ischemic brain injury, the protective activity of C. militaris was also established [77]. Cognition in mice was improved by the use of a polypeptide that was obtained from C. militaris, according to Yuan et al. [79]. A decline in the function of acetylcholinesterase (AChE) as well as an increase in the neurotransmission of GABA were found.

3.11. Pro-sexual or fertility enhancer

Infertility is a widespread issue that impacts a large number of people, the vast majority of whom nowadays seek medical attention for the condition [80]. According to Dada and Ajilore [81], there has been a shift in focus away from synthetic medications toward traditional herbal products. As a result, there has been an increase in the utilization of herbal extracts as fertility enhancers in animals. Chang et al. [82] provided an explanation for the influence of the role that cordycepin from C. militaris plays in enhancing the quality and quantity of sperm. It was found that supplementing with C. militaris resulted in a rise in serum cordycepin concentration, which concurrently augmented testosterone and estradiol-17 levels, resulting in a boost in the percentage of motile sperm cells. Cordycepin was hypothesized by Patel and Ingalhalli [74] to be the factor that led to enhanced sperm quality and quantity in wild pigs, as well as enhanced semen output. The anabolic influence of C. militaris on testosterone synthesis in male mice was demonstrated and recorded by Hong et al. [83]. The findings of this investigation showed that the rats did not experience any changes in their body weight, their consumption of food and water, or their water intake; however, the content of testosterone in the serum of the rats was considerably enhanced by C. militaris (p<0.05). Therefore, fruiting bodies of C. militaris cultivated on the drone bee platform have the potential to function as an integrated medication for the treatment of reproductive issues in human males resulting from inadequate amounts of testosterone.

4. Evaluation of hazards and toxicology

In experiments conducted with living animals, it was found that a high-dose treatment of C. militaris (4.9 × 10⁸ spores/mouse) for a period of seven days did not produce any adverse effects in the rodents. With regards to body weight, blood hematological parameters, and the amount of food and water consumed, there were no substantial variations seen between both the experimental and control groups treated with C. militaris [84]. In the sub-acute oral toxicity test, C. militaris at a concentration of 3000 mg/kg/day did not produce any hazardous effects in the rats that were used in the research. There was no evidence of genotoxicity or teratogenic consequences. During the sub-chronic toxicity studies that lasted for ninety days, the clinical, histological, and hematological characteristics of the experimental rats that were given C. militaris did not show any signs of alteration. The no-observed-adverse-effect level (NOAEL) for C. militaris mycelium was estimated to be 4000 mg per kilograms per day in experimental rats [85]. In mice, the greatest cordycepin dose that may be tolerated without producing any negative effects was determined to be 3600 mg/kg per day [86].

5. Challenges and possibilities for the future

The naturally occurring form of C. militaris commands an extremely high price due to its scarcity, host specificity, and environment requirements. In addition, the manufacture of cordycepin from this therapeutic fungus is indeed not expected to reach quantities that are commercially viable owing to the many practical limitations that exist, such as stringent farming practices. It is essential to emphasize that the yield of cordycepin through chemical processes is a time-consuming operation that not only results in a reduction in productivity but also results in the release of a sizeable quantity of organic solvents that are hazardous to our environment. For these reasons it is critical to stress these facts. Cultivating this fungus also results in the natural synthesis of considerably essential elements of C. militaris, such as cordycepin, which can be utilized on a commercial scale.

Despite the fact that large-scale cultivation raises some concerns, a number of studies have found that the quantities and compositions of chemical constituents in cultivated and naturally occurring C. militaris are very similar.

As a potential therapeutic agent, C. militaris has a slew of drawbacks, the most notable of which are negligence, a lack of appropriate comprehensive information, poor in-depth study, and consciousness. In the past, only members of a specific group of individuals were permitted to make use of it; however, as more time has passed, it has been accessible to everyone. Manufacturers, as well as the functional food, pharmaceutical, and other businesses, should emphasize C. militaris research into its medicinal efficacy, detrimental impact, biosafety, and suitable standardization.

The state of nature provides the raw materials that are processed into natural medicines. The vast majority of pharmaceuticals have their roots in the plant world. People choose these treatments for a multitude of reasons, one of which is the possibility that chemically produced pharmaceuticals might well end up causing patients to become vulnerable to diseases, whereas natural measures, such as medicinal mushrooms, could battle life-threatening ailments with fewer adverse effects on human health. In order to sustain robust growth, the pharmaceutical sector must embrace innovation that results in the production of materials at lower costs while maintaining sufficient levels of health safety. It is possible that edible mushroom-based medications will undergo a revolutionary change as a result of the coupling of chemistry and biotechnology with organic starting materials, such as secondary metabolites. Therefore, cordycepin, peptides, polysaccharides, and other active ingredients produced from C. militaris will play a pivotal role in advancing eco-friendly pharmacognosy and pharmacology.

6. Conclusion

In recent years, there has been an increase in the use of natural/herbal medications instead of synthetic ones. Because of its untapped potentials obtained through various culture techniques and being a great source of bioactive metabolites with even more than 21 clinically approved benefits on human health, including anti-tumor, anti-diabetic, anti-oxidative, immunomodulatory, sexual potentiator, antimicrobials, insecticidal, and immunosuppressive effects, cordyceps, a traditional medicinal mushroom used as a crude drug for the mankind's well-being in ancient civilization, is now a cause. Since cordycepin has been extensively studied for its anti-cancer and anti-oxidant properties, it has the pharmacological and therapeutic potential to one day treat a wide range of debilitating disorders. The fascinating potential of this therapeutic mushroom on human health has to be further investigated, and growing methods need to be promoted for ethno-pharmacological and commercialization uses of this amazing plant. It's conceivable that Cordyceps has unidentified pharmacological effects. In the future, it would be beneficial to evaluate the potencies of the different Cordyceps species in various bioassays.

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