Cordyceps is a genus of fungus which develops on larvae of insects. As of today there are more than 350 Cordyceps-related species have been identified all over the world based on fungus or insects as hosts. Since 1964 it is the only time that Cordyceps sinensis has been officially recorded as a herbal remedy in Chinese Pharmacopoeia. C. sinensis, also known by the name of Dongchongxiacao (winter-worm grass of summer) in Chinese is among the most well-known traditional Chinese medicinal and herbal mushrooms. The fungus eats the larvae of a few insect species (Fam. Hepialidae) and transforms each one of them into an sclerotium from which the fruiting body is created.
(a) Cordyceps sinensis shown in the work Ben Cao Bei Yao by Wang Ang, which was published in 1694. (b) C. sinensis that was discovered in soil (arrowhead denotes C. sinensis) as well as (c) harvested as raw material.
Based on the theories that is the basis of Chinese medicina, C. sinensis has a sweet taste and neutral in nature and it is able to restore kidney function, relax your lung, reduce bleeding and get rid of Phlegm. This fungus C. sinensis is used in the treatment of cough, fatigue hyposexuality, asthenia, severe disease, renal dysfunction and kidney failure (State Pharmacopoeia Commission of the PRC 2005). In China it is found in the prairie soil at an elevation of 3500-5000 m. It is found mainly located in provinces such as Qinghai, Tibet, Sichuan, Yunnan, and Gansu. In China, C. sinensis has been recognized and used to treat ailments for over 300 years. It was first documented as a remedy in Ben Cao Bei Yao by Wang Ang in 1694, and in 1694, the Italian scholar Saccardo identified this Cordyceps that were discovered throughout China legally to be Cordyceps sinensis (Berk.) Sacc. in 1878. The designation has been used since.
Its ecosystem C. sinensis is severely impacted by habitat restrictions and the over-exploration. While it was the Ordinance of Resources Protection on Wild Herbal Medicine was released in 1987 however, the yield of the natural C. sinensis is declining. The report was based on an investigation conducted in June and July 2007, that yields of the natural C. sinensis was reduced by over 90% over the past 25 years. The cost soared to over 100,000 Renminbi (RMB)/kg (approximately USD25,000) as of 2007. (Feng, Yang, and Li in 2008) and its use was restricted over the last decade because of its scarce quantity.
Due to the rareness and exceptional curative properties of C. sinensis, there are a number of natural substitutes include C. militaris C. liangshanensis, C. gunnii, and C. Cicadadicola have all been sold on markets (Yang and co. 2009). Additionally, there are several mycelia from cultured populations of C. sinensis, and C. militaris fungi have emerged as the most popular substitutes for natural species in commercial products. 50 drugs and two nutritional supplements that are related to the cultivated Cordyceps have been endorsed through the State Food and Drug Administration of China since 2002 (Feng, Yang, and Li 2008). For instance, JinShuiBao capsule, the commercial product of Cs-4 (Paecilomyces Hepialid), a standardized mycelium from C. sinensis) It has been utilized in clinics across China. The product is worth several million U.S. dollars every year. Synnematum sinensis Cephalosporium sinensis Gliocladium roseum and Mortierella Hepialid, fungus strains extracted from the natural C. sinensis, are also exposed to large-scale fermentation, and are now used in commercial applications (Cheung, Li, and Tsim 2005). This is why a great deal of effort has been put into researching the evaluation of quality, pharmacological properties and clinical efficacy of both cultured and natural cordyceps. This chapter will will focus on the bioactivities, actions mechanisms, and active components of the cordyceps, both naturally and cultured.
ANTITUMOR ACTIVITY
Cancer is the second most prevalent cause of death due to disease in the globe (Xiao as well as Zhong 2007). But, the treatment methods are limited to radiotherapy, surgery, and chemotherapy. Because of restrictions of surgeries as well as radiotherapy as well as the negative side consequences that chemotherapy can cause, there's an increasing desire to develop antitumor medicines using natural products. Studies have demonstrated that the power of cordyceps is antitumor across a range of cancers, via various routes. Both cultured and natural cordyceps show antitumor activity (Feng, Yang, and Li 2008; Zhou et al. 2009a).
In vivo studies showed that cordyceps acted as an inhibitor on Ehrlich ascites meth-A fibrosarcoma as well as cancer (Ng as well as Wang 2005) and lymphoma EL-4 (Yamaguchi and co. 1990), B16 melanoma (Wu, Zhang, and Leung 2007a), Lewis lung carcinoma (Nakamura et al. 1999) as well as H22 cancers (Chen and Leung. 2006.) within mice. Furthermore, C. sinensis was able to reverse the suppressive effect of leukopenia caused by Taxol in mice, which suggested that C. sinensis may be used in conjunction in conjunction with other chemotherapy strategies to treat cancer (Liu and colleagues. 2008). Cordyceps demonstrated cytotoxic activity direct against various types of tumor cells, such as Lewis lung cancer, B16 melanomas, lymphocytic (Jurkat) (PC3), prostate (PC3) and breast (MCF7) and hepatocellular (HepG2 Hep3B, HepG2) and the colorectal (HT-29)and the HCT116) in addition to HL-60 cells (Nakamura and co. 1999; Wang et al. 2005; Wu, Zhang, and Leung 2007a). While cordyceps showed cell-killing effect on cancer cells, it didn't exhibit any cytotoxicity to healthy cell lines (Wu, Zhang, and Leung 2007a).
A variety of mechanisms contribute to the antitumor activity of cordyceps. These include the direct cytotoxicity, immunopotentiation the apoptosis process, and selective inhibition of the ribonucleic acid (RNA) and protein synthesis as well being antioxidants, antiangiogenic, an antimutagenic, antimetastatic and antiviral actions (Xiao Zhong 2007; Zhong 2007 ); Feng, Yang, and Li 2008; (Zhou et al. 2009a). Of these the apoptotic homeostasis that is controlled by cordyceps may be the most significant (Buenz and co. 2005; Feng, Yang, and Li 2008) mechanism. The molecular basis for apoptosis in cordyceps is based on activation of Bax, caspase-3 or -9 8 and -8; inhibition of the enzyme cyclooxygenase-2 (COX-2) and nuclear factor KB (NF-kB) expression and the reduction of Bcl-2 levels (Xiao as well as Zhong 2007; Feng, Yang, and Li 2008). In addition, MDA-MB-231 cells undergo apoptosis. human breast cancer cells stimulated by C. militaris extract aqueous (0.8 mg/mL) was in turn associated with the loss the permeability of mitochondrial membranes. In addition, the extract decreased Akt activation and reversed PI3K/Akt-pathway-enhanced apoptosis (Jin, Kim, and Choi 2008). Additionally, the apoptotic processes caused by the extract were additionally mediated by decreased the activity of telomerase (Park and co. 2009).
IMMUNOMODULATING EFFECT
The immune system shields humans from infections with multilayered defenses with increasing specificity. The first is physical barrier block pathogens from entering into the body. If pathogens breach this barrier, our body's innate immune system responds immediately with an non-specific, but immediate response. Humans have another layer of protection. This is an adaptive immune system. The adaptive immune system is activated by the the inborn immune system. The innate system's cells comprise the phagocytes (macrophages neutrophils, phagocytes, as well as dendritic cells) mast cells, eosinophils basophils, as well as naturally-killer cells. Within the adaptive system B cells play a role in the humoral immune system, while T cells are involved in the cellular immune response. Anti-immune drugs help bring the immune system back to its normal state and prevent recurring and life-threatening infections. The use of immunosuppressive medications is to manage autoimmune disorders and inflammation after tissues are damaged to the extent that they should and to avoid rejection of transplants following the transplantation of an organ (Taylor, Watson, and Bradley 2005). More evidence suggests that cordyceps functions as a bidirectional moderator, having the ability to suppress and enhance actions on our immune system via the regulation of adaptive and innate immune system (Li and Tsim 2004; Ng and Wang 2005; Feng, Yang, and Li 2008; (Zhou et al. 2009a).
Potentiation Activity
Natural C. sinensis has an extensive time of usage for treating cancer and respiratory infections. It has been suggested that the mechanism behind its use is related to activation of the immune system and, in particular, the enhancement of inborn immunity. Oral administration of C. sinensis extract improved the phagocytosis of macrophages in resting and cyclophosphamide-treated C57BL/6 mice implanted subcutaneously with syngeneic EL-4 lymphoma cells (Yamaguchi et al. 1990). Cultured C. sinensis stimulated the production of interleukin (IL)-1b as well as IL-6, ITN and tumor necrosis factors (TNF)-a and elevated phagocytosis in Human peripheral blood mononuclear cell (HPBMC) and increased macrophage phagocytosis as well as monocyte production of H2O2. However, it failed to trigger cytokine excess in mice (Ka and co. 2006). The study further revealed that aqueous extracts of mycelia from C. sinensis improved the levels of TNF-a, IL-6 and Nitric oxide (NO) release from murine macrophages that are primary by stimulating mitogen-activated proteinkinase (MAPK) pathways associated with the inflammatory stimulus. The extract also acted synergistically by interferon gamma (IFN-g) to increase the production of cytokine from macrophages and the spleens of mice that were treated with extract were less prone to bacterial burden when in comparison to the vehicle control. The results suggest that C. sinensis mycelia defended animals from the growth of bacteria, by activating macrophages (Jordan, Sullivan, and Lee 2008a). The C. sinensis may also boost the naturally occurring killer cells (Ng as well as Wang 2005). A C. militaris water extract caused functional and phenotypic maturation in dendritic cells. They was followed by T-cell activation against cancerous microbial pathogens as well as tumors (Kim and colleagues. 2006a).
Cordyceps can also boost its adaptive immune system including humoral and cellular immunity. Even though both the natural and cultured C. sinensis extracts were not able to have an impact on the growth of splenocytes or cytokine release like IL-2 in the splenocytes of mice in the laboratory (Siu and colleagues. 2004) or in BALB/c mice in vivo (Ka et al. 2006) The extracts boosted concanavalin A-stimulated proliferative capacity and the IL-2 levels of splenocytes from mice within the laboratory with 200 mg/mL (Siu and co. 2004) or ovalbumin-induced splenocyte growth and the serum immuneglobulin (Ig) G and IgG1 and IgG2b levels in the mice with ovalbumin-immunized (Wu and colleagues. 2006). Cultured C. sinensis raised CD25 expression in lymphocytes in the laboratory (Ka and co. 2006) and increased numbers of CD4+ and CD8+ cells, enhanced the ratio of CD4+/CD8+, and decreased IgA as well as IgG amounts in those suffering from posthepatic liver cirrhosis (Ng as well as Wang 2005). Additionally, cordyceps showed the ability to regulate bronchoalveolar saline liquids (BALF) cell lines. The C. sinensis extract from ethanol could boost Th1 immunity, including IFN-g production and IL-12 production which can then block the release of IL-10 by Th2 cells, and then decrease IgE production by B lymphocytes. A reduced production of IgE could reduce the frequency in asthma attack (Kuo and co. 2001). The fruiting body of C. militaris water extract dramatically increased the expression of IL-18, as well as triggering IFN-g in T cells as well as NK cells in the C57BL/6 mouse brain as well as liver in vivo, as well as within RAW264.7 cells in the laboratory (Kim and colleagues. 2008). Fruiting bodies, not caterpillars of C. Cicadae methanol extract increased growth and IL-2 and IFN-g production by phytohemagglutinin (PHA)-stimulated HPBMC (Weng et al. 2002).
Suppressive Effect
Because of its inhibitory effects in the body's immune system cordyceps is a good choice to treat autoimmune disorders as well as for the treatment of immunosuppression following organ transplants. A short-term treatment with C. sinensis (2.4 mg/g/day) resulted in the redistribution HPBMC with lower percentages of T cell CD4+ (P .05) and reduced the severity of lupus (NZB/NZW) F1 mouse, with an increase in survival, a decrease in proteinuria and lower the titers of anti-double-strandedDNA antibody (Chen and co. 2009). Administration of C. sinensis can enhance the effect of blocking the cyclosporin A compound on allogeneic graft rejection, by decreasing mononuclear cell enlargement into kidney grafts. It also reduces the number of C4+ T cells within blood vessels in the peripheral region, serum IL-2 and IFN-g production in the allograft kidney transplantation model in rats (Ding and colleagues. 2009). Mycelia of C. sinensis water extract and subtherapeutic cyclosporin B also reduced acute rejection in rats who had received a heart transplant. completely abrogated acute vasculopathy in mice at a dosage of 50 mg/kg and reduced the release of IFN-g from mouse splenocytes as well as T cells that are CD8+ at 3.4 mg/mL in the laboratory (Jordan, Hirsch, and Lee 2008b).
In addition, the cordyceps had anti-inflammatory effects. The fruiting body of C. sinensis Methanol extract reduced PHA-stimulated lymphoproliferation and NK cell activity as well as IL-2 and TNF release from HPBMC (Kuo and co. 1996). Chloroform and n-butanol fractions from the bodies that produce fruit of C. sinensis methanol extract inhibited the elevation of NO, inducible nitric oxide synthase (iNOS), TNF-a, and IL-12 in lipopolysaccharide (LPS)/IFN-g-activated murine peritoneal macrophages in a dose-dependent manner in vitro (Rao, Fang, and Tzeng 2007). Administration of C. militaris reduced airway inflammation in mice that were induced by ovalbumin (Hsu and co. 2008) and also had anti-inflammatory effects on croton oils-induced mouse ear edema due to topical and carrageenan-induced hind chronic edema of the hind (Won and Park 2005). In the administration C. pruinosa extract to methanol inhibited production of IL-b, TNF a NO, IL-b and PGE2 when stimulated by LPS macrophages with 10 mg/mL in the laboratory and in mice administered with LPS at 5 mg/kg intra-vivo, through the inhibition of activation of the NF-kB (Kim and colleagues. 2003). Methanol extracts of caterpillars, but not the fruiting bodies of C. Cicadae led to the reduction of the proliferation that PHA induces in HPBMC and the reduction of the levels of IL-2, IL-4 IFN-g, and the IL-12 released from the PHA stimulated HPBMC (Weng and colleagues. 2002). Thus, different parts of cordyceps can have distinct effects on immune responses.
Effect on Gut Immune System
The gastrointestinal tract performs an important role in the human physiology. That is, digestion and the uptake of nutrients, as well as the maintaining immune homeostasis. The gastrointestinal-associated lymphoid tissue (GALT) is composed of Peyer's patches and other GALT such as lymphoid aggregates in the appendix, large intestine, and esophagus, tonsils, and adenoids. There are macrophages, dendritic cell B lymphocytes, T lymphocytes found in GALT. Both adaptive and innate reactions are involved in sustaining GALT's immune balance (Huffnagle as well as Noverr 2008). Although C. sinensis hot-water extract had an insignificant effect on the spread of Salmonella sp. Escherichia Coli, as well as Lactocbacillus sp. It could, however, substantially reduce the harmful bacteria population (Salmonella sp. and E. coli. ) and increases beneficial number of bacteria (Lactocbacillus species.) in the intestines of broiler chicks given 600 mg/kg/day for a period of 35 days (Koh, Suh, and Ahn 2003a). The results show that C. sinensis regulates intestinal microbes by increasing GALT as well as systemic immunity or both. Ingestion of oral the mycelia from C. sinensis hot water extract at 1 g/kg/day for 7 days stimulated the activation of peritoneal macrophages and Peyer's patch cells with increase in granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6 levels in ICR mice (Koh et al. 2002). Macrophages within GALT serve as antibacterial guards by killing and phagocytosing any microbes that get into the lamina propria (Macpherson Marrinic, Macpherson as well as Harris 2002). Therefore, C. sinensis is believed to increase the macrophages' activities in GALT. The evidence that cytokines, such as GM-CSF and IL-6 are important in immune system cells indicates that C. sinensis regulates the immune system. process through a mechanism that is controlled by the Peyer's patches cell (Koh and co. 2002). in mesenteric lymphoma (MLN) lymphocytes C. sinensis extracts aqueous boosted the release of IL-2 and IFN-g by Th1 cells. In addition, the extract enhanced IgA release from concanavalin A-stimulated and resting lymphocytes of MLN, while the it increased the production of IgA on mucosal surface could create an anti-inflammatory milieu by neutralizing antigens (Park and colleagues. 2008). Furthermore, C. sinensis as well as C. scarabaecola demonstrated the intestinal immune system modulating its activity through the stimulation of lymphocytes within Peyer's patch (Koh and co. 2002; Yu, Kim, and Suh 2003).
In conclusion, research has shown that cordyceps can affect both adaptive and innate immunity. In addition, it also plays a role in modulating the gut immune system that could enhance the systemic immune function.
ANTIOXIDANT ACTIVITY
The reactive oxygen species (ROS) comprise molecular oxygen (O2) superoxide anion (O2-) H2O2, the hydroxyl radical (OH) and peroxynitrite (ONOO-) and hypochlorous acid (HOCl; Zhou, Mrowietz and Rostami-Yazdi 2009b) These are all well-known for their dual roles in the biological system, as they may be beneficial or detrimental in living systems (Valko and co. 2004). ROS are normally the naturally occurring by-products of aerobic metabolism. They also perform a physiological function in cell signaling. However, the amount of ROS may increase significantly in times of stress like the exposure of ultraviolet (UV) and heat radiation, which causes damage to the proteins, lipids and nucleic acids in cells. The damage to cell structures causes numerous diseases, like atherosclerosis, cancer, senescence and the cardiovascular disease and inflammatory lung diseases. the neurodegenerative diseases (Rahman 2003; Zhong 2006; Valko and others. 2007).
There is increasing evidence to suggest that cordyceps may have antioxidant properties and could constitute one of the underlying mechanisms that are responsible for the anti-aging cancer, anti-inflammatory, the anti-atherosclerosis and immunomodulatory properties of cordyceps. Concerning the various aspects of C. sinensis are concerned fruiting bodies demonstrated the same potency as caterpillars' antioxidant capabilities in xanthine Oxase assay, the hemolysis induction assay and lipid peroxidation assay (Li and co. 2002). The results also showed that the caterpillar shares an identical chemical composition to the fruiting body. This implies that the primary function of the worm in cordyceps to serve as a growth medium to the body that produces fruit and that the caterpillar eventually completely engulfed by the mycelia of the cordyceps (Li and co. 2002).
Both water (Li and al. 2001; Yu et al. (2006); Dong as well as Yao 2007) as well as ethanol (Wang and Wong. 2005; Won and Park 2005; Ra et al. 2008) extracts of cordyceps displayed significant antioxidant action in the laboratory. However, the extract from water showed a stronger inhibitory effect on superoxide anions as well as radicals hydroxyl than the extract of ethanol (Yamaguchi and co. 2000a). Additionally, both the natural C. sinensis and cultured cordyceps showed direct and potent antioxidant activities using in vitro assays, such as lipid-peroxidation assay, 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, and protein-peroxidation assay. Thus, cultured cordyceps may be used to boost antioxidants to reduce human demands on the natural C. sinensis, an endangered species (Li et al. 2001; Yu et al. 2006; Dong and Yao 2008).
ANTIHYPERGLYCEMIC ACTIVITY
Cordyceps is hypoglycemic in animals that are normal. The administration of an oral dose of Cs-4 extract of cordyceps “Cs-4” with 2 g/kg/day over a period of 25 days improved insulin sensitivity. The extract may have positive effects due to the fact that it maintained whole-body glucose metabolism, albeit with a less noticeable rise in insulin production after the challenge of carbohydrate in rodents (Balon, Jasman, and Zhu 2002). In a different study in which normal rats were fed Cs-4 at 250 and 500 mg/kg/day over 17 days observed significant decreases in blood glucose levels at the time of fasting by 27 percent and 24%, respectively, while the insulin levels in the plasma of rats in the 500 mg/kg group reduced by 37 percent. In addition tests on oral glucose tolerance showed that the extract significantly enhanced tolerance to glucose levels when it was 0.5, 1.0, and 2.0 hours following consumption of glucose (Zhao and colleagues. 2002).
Cordyceps also proved to have an antihyperglycemic impact on diabetics. While the fruiting bodies of natural C. sinensis (4 grams/kg/day) did not affect the insulin levels in fasting diabetic rats (Lo and co. 2004) It improved the weight and reduced water intake (day 15 to 29) and the blood glucose levels in the fasting phase (day 15 to 26) and the serum concentration of fructosamine (day 29) in diabetic rats. The fruiting body of C. sinensis have also increased thymus weight and tolerance to glucose (day 26, Lo in et al. 2004 and 2006). However, in this research, C. sinensis didn't have any effect on the cholesterol levels and serum triglycerides of rats suffering from diabetes (Lo and co. 2004). Choi et al. (2004) found out an aqueous extract from C. militaris that was cultured C. militaris did not affect the level of insulin in the fasting state or glucose absorption in the digestive tract. The extract was shown to reduce the serum glucose levels of fasting and reduce the amount of triglycerides in soleus muscles, boost the rate of glucose elimination throughout the body and also increase the glucose transporter 4 (GLUT 4) levels and the speed of glycogen synthase within the quadriceps and soleus muscles of 90% pancreatomized rats that received C. militaris extract at 500 mg/kg/day for 8 weeks (Choi et al. 2004).
Incredibly, fruiting bodies, and not caterpillars, from C. sinensis acted on decreasing the blood glucose level, and also increasing the thymus ‘ weight (Lo and co. 2004). However, mycelia fermented with fermentation and the broth of C. sinensis had similar antihyperglycemic effect with fruiting bodies in nicotinamide and streptozotocin-induced diabetic rats (Lo et al. 2006). So, the products of fermentation of cordyceps may be utilized as possible anti-diabetic substances or as functional food for people who are at risk of developing diabetes mellitus.
SEXUAL AND REPRODUCTIVE FUNCTION ENHANCEMENT ACTIVITY
Testosterone is a necessary ingredient for the normal development of sperm. It triggers genes within Sertoli cells that aid in the the differentiation of the spermatogonia. Cordyceps is traditionally used to enhance sexual function in humans. Research has proven that C. sinensis, as well as C. militaris may improve reproduction and repair the function of reproduction that is impaired. In the administration process, C. sinensis increased sexual libido and activity, and also restored impaired reproduction in both genders in humans (Zhu Halpern, Xu as well as Jones 1998). Such effects are related to the enhancement of testosterone release in plasma through cAMP (adenosine monophosphate)-protein kinase A signal pathway (Hsu et al. 2003a). Mycelia from cultured cultures of C. sinensis containing water-soluble low-molecular-weight proteins as well as polysaccharides with low water solubility and protein, but not the fractions with low-molecular weight polysaccharides that are water-soluble and testosterone levels that were higher in mice (Hsu and colleagues. 2003b; Huang et al. 2004). A protein in C. sinensis was responsible for the observed vasorelaxant and hypotensive effects by enhancing the creation of NO (Chiou and colleagues. 2000) The protein may assist in capturing blood from the penis to erection, which could improve sexual performance (Drewes, George, and Khan 2003).
ANTIFATIGUE ACTIVITY
Fatigue is defined as a difficulty in establishing or maintaining a the activity that is voluntary (Chaudhuri and Behan 2004) It can also be classified into physical and mental fatigue (Mizuno and colleagues. 2008). The symptom of fatigue is common of illness and health. Chronic fatigue can impact the performance of an individual. Additionally, over time, accumulated fatigue may lead to the term karoshi (a Japanese word meaning death due to the overwork). In China the use of cordyceps is to restore health after a variety of illnesses and speed up recuperation from exhaustion thanks to the adaptogenic (antistress) characteristics and capacity to increase the endurance and increase strength (Bucci 2000).
Ingestion of C. sinensis mycelia extract, 150 mg/kg/day over 7 days (Koh and colleagues. 2003b) or the ingestion of the fruiting bodies of C. militaris, at a dosage of 500 mg/kg/day for four months (Jung, Kim, and Han 2004) significantly extended the time spent swimming by mice by around two and twenty minutes in each case. This was due to an increase in immunity. In treating C. sinensis, 150 mg/kg/day, for 8 days prevented the rise of total cholesterol and the diminution of alkaline-phosphatase rats. In addition, it dramatically reversing the decrease in weight of the adrenal gland, liver as well as thyroid, thymus, and the liver (Koh and colleagues. 2003b). The role of cordyceps in adenosine-triphosphate (ATP) production is also responsible for a reduction in physical fatigue when administered. Oral administration the cultured C. sinensis extract (200 mg/kg/day, p.o.) not only increased the hepatic energy metabolism as well as blood flow in hypoferric mice for 4 weeks (Manabe and colleagues. 2000) but also significantly increased the ratio of ATP/inorganic phosphate in the livers that normal mice have for three weeks (Manabe and co. 1996) or for 7 days (Dai et al. 2001) without any steatosis necrosis or inflammation in liver specimens (Manabe and colleagues. 1996 and 2000). Treatment with either cultured or natural cordyceps extracts (1 grams/kg/day p.o.) for 3 days increased the ATP production capacity of myocardial cells ex live on mice by 29 percentage and 32% according to studies, and could be due to the increase the mitochondrial electron transportation (Siu and co. 2004).
People suffering from chronic fatigue syndrome are often diagnosed with depression. Between 30 and 70% of these patients have symptoms for major depression (Adler 2004). Extract of supercritical fluid (SCCS, 2.5-10 mL/kg, p.o. ) in addition to the hot water extract (500-2000 mg/kg p.o. ), of C. sinensis have shown significant antidepressant activity. After five days of administration, SCCS shortened immobility times in the test for mouse tail suspension but it had no impact on locomotor activity during the open field test of mice. It was concluded that SCCS had an antidepressant-like effect through its effects on the adrenergic and dopaminergic systems in addition to that of the serotonergic mechanism (Nishizawa and co. 2007). Additionally, the cordyceps muscle has an antioxidant powerhouse which can help eliminate ROS produced by working muscles during exercise. It can also aid in reducing fatigue (Mizuno and co. 2008). Finally, C. sinensis led to a greater efficient usage and use of O2 which led to an increased survival rate in an environment that was hypoxic (Lou, Liao, and Lu 1986) in mice. The results show the more effective use of O2 by cordyceps in order to enhance vital physiological functions of tissues as well as improve resistance to acidosis caused by hypoxia. However, only a few clinical studies have been conducted to determine the effects of cordyceps on fatigue as well as the majority of tested tests were not methodologically sound particularly in the addition of other medications in the studies. For instance, the capsules that contained Cs-4 Rosea rhodiaola as well as other ingredients did not increase oxygen saturation (Colson and co. 2005) and the performance of cyclists (Earnest et al. 2004) in healthy men. In addition, the consumption of a supplement with the cultured C. sinensis, adenylpyrophosphoric acid calcium pyruvate, as well as Yohimbine hydrochloride for 1 hour prior to a sporting event did not show any ergogenic effects on healthy males (Herda and colleagues. 2008). One possible reason is the fact that the ingestion mechanism of C. sinensis was not sufficient to trigger favorable changes within humans. A one-week loading phase, that was followed by two weeks of maintenance could be required to achieve the benefits of promoting endurance and resistance to fatigue. Another explanation could be the fact that since these studies were conducted on healthy individuals and there was less room in terms of health, physiological and performance improvement that in older or ill individuals (Colson and colleagues. 2005).
PROTECTIVE EFFECT ON THE KIDNEY
sinensis is used in the treatment of kidney diseases including chronic pyelonephritis, chronic nephritis chronic renal dysfunction or failing, as well as nephritic disease (Feng, Yang, and Li 2008). The C. sinensis extract significantly enhanced kidney function through antiapoptotic and anti-inflammatory properties in rats exposed to ischemia for 60 minutes and 3 days after rehabilitation of kidneys. The downregulation of the apoptotic gene of caspase-3 was associated with reductions in inflammation genes, such as MCP-1 TNF-a, as well as iNOS. The results suggest that C. sinensis may play a therapeutic role in kidney transplantation (Shahed, Kim, and Shoskes 2001).
Another way that cordyceps shields kidneys is through its inhibition of mesangial cell growth. Glomerular degeneration is believed to be triggered by the proliferation of mesangial cells that display characteristics of smooth muscle cells and the accumulation of the mesangial matrix extracellular. Both C. sinensis as well as C. militaris, in a dose of 100 mg/mL, dramatically stopped the growth of mesangial cells from humans activated by low density lipoprotein (LDL; Wu, Wang, and Cheng 2000). Moreover, C. sinensis may help protect kidneys from cyclosporine A-induced chronic nephrotoxicity. This is due to lower BUN (blood Urea Nitrogen (BUN) as well as interstitial edema and fibrosis as well as bulbsular necrosis (Wojcikowski, Johnson, and Gobe 2006). Additionally, administering the water extract of cordyceps showed an anti-inflammatory effect on rats suffering from acute renal failure, caused by gentamicin. The potential mechanisms are protection against sodium pump activity and a reduction in lipoperoxidation within tubular cells, as well as the reduction of lysosomal activity inside tubular cells (Ng and Wang 2005; Li and Yang 2008). Additionally, C. sinensis improved the cellular immune system in rats suffering from persistent renal impairment (Cheng 1992).
Clinical studies have also provided some evidence of using cordyceps in an renoprotectant (Wojcikowski, Johnson, and Gobe 2004 and 2006). For instance, Bailing capsule, a product made from C. sinensis mycelia has helped in reducing the rejection of renal transplants and improved liver and renal function, controlled hyperlipidemia and hypoproteinemia, boosted the function of hemopoietic cells, and lowered the risk of infection among patients who had received a renal transplantation (Sun and Li. 2004; Li et al. 2009). For patients suffering from chronic renal failure, the consumption of a different product from the cordyceps family Cs-4 also known as JinShuiBao has also been shown to significantly improve kidney function, which reduced serum urea and creatinine levels and increased total blood proteins and calcium (Feng, Yang, and Li 2008).
EFFECT ON THE LIVER
Cordyceps is used in clinical practice to aid in the treatment of chronic hepatitis as well as related illnesses (Zhao 2000). There are many ways how it can aid in the treatment and protection from liver disease. The first is that it has an increased potential for enhancing the immune system function of those who suffer from chronic liver disease B (Gong, Wang, and Tang 2000) as well as posthepatic liver chronic cirrhosis (Zhu as well as Liu 1992). The second reason is that it was found to block and reverse the process of liver fibrosis through destruction of collagen in rodents who suffer from liver cirrhosis caused by dimethylnitrosamine (Li and Tang. 2006a and Wang, Liu, and Tang 2008) and inhibit the growth of hepatic stellate cells in the laboratory (Chor and co. 2005) and downregulate intercellular adhesion molecule I (an indicator of fibrogenesis in the liver) in addition to CD126 from human fibroblasts (Li and Tsim 2004) and reduce the levels of the transforming growth factors-b and platelet-driven growth factors (Liu as well as Shen 2003). Thirdly, cordyceps reduced levels of lipid peroxides in the tissues of the liver and serum and decreased TNF-a levels in the serum of bacillus calmette guerin and LPS-induced liver injury within rodents (Zeng, Tang, and Yuan 2001).
ACTIVE COMPONENTS
A number of active ingredients, including polysaccharides, cordycepin and ergosterol have been isolated from a variety of Cordyceps varieties and contribute to a wide range of bioactive substances.
Nucleosides and Their Activities
Nucleosides are among the main ingredients in cordyceps. To date, more than 10 nucleosides and their related components, including adenine, adenosine, cytidine, cytosine, guanine, guanosine, uracil, uridine, hypoxanthine, inosine, thymine, thymidine, 2′-deoxyuridine, 2′-deoxyadenosine, cordycepin, N6-methyladenosine, and 6-hydroxyethyl-adenosine, have been isolated and/or identified in cordyceps (Feng, Yang, and Li 2008). Adenosine A1, A2A, A2B, and A3 receptors can be found throughout the lung, brain and heart, liver and kidneys, and have been implicated in central nerve system (CNS)-mediated activities like sleep, immune response and the regulation of respiratory function, cardiovascular functions and kidney and liver activity (Li as well as Yang 2008a.). Incredibly, the pharmacological actions of cordyceps correspond well to the roles and distribution of adenosine receptors. These include antithrombosis, anticancer, antiaging as well as antiarrhythmias and antihypertension, as well as immunomodulatory activities and protection effects for the liver, kidneys, as well as the the lung (Li and Yang 2008a).).
Macrophages contain Adenosine A2A, A2B, and A3 receptors. In the case of activation of these receptors, it leads to the increase in the IL-10 gene; a decrease in TNF-a and IL-12, and an increases in vascular endothelial factor (VEGF) and macrophage inflammatory proteins (MIP)-1a and NO and NO, respectively (Kumar and Sharma 2009). The ratio of uridine:inosine:guanosine at 8:11:5, which is the ratio of natural C. sinensis showed an enhanced impact on the release of NO, TNF-a and the IL-1 released from primary mouse macrophages. It did not affect cell lines stimulated with LPS (Li Yang 2008b and Yang 2008b). However, uridine:adenosine:guanosine at a ratio of 11:7:9, the ratio found in cultured C. sinensis, enhanced NO, TNF-a and IL-1 production by resting macrophages while reducing production of cytokine in cells stimulated by LPS (Li as well as Yang in 2008a). The results suggest that various components interact with various subreceptors. Therefore that different ratios of these nucleosides trigger different immune responses of macrophages.
Cordycepin has been isolated from the cultured C. militaris in 1950 (Cunningham et al. 1950) and was later identified as 3′-deoxyadenosine by 1964 (Kaczka and colleagues. 1964). It is mostly found in C. militaris that is cultured C. militaris, but there is a small amount in the natural, and no in the cultured C. sinensis (Feng, Yang, and Li 2008). Cordycepin has anticancer, antioxidant and immunomodulating capabilities. In the midst of phase I/II clinical trials, researchers are studying the use of cordycepin for treatment of chronic lymphocytic leukemia. A study showed that the drug had cytotoxic effects on cancer cells. The B16 cell growth was slowed by 60 mM of the drug by 70.1 percent after 72 hours. The result was stimulated by stimulating the adenosine A3 receptors, followed by the GSK-3b pathway that signals activation, and cyclin D1 suppression (Yoshikawa and colleagues. 2008). Furthermore, Won et al. discovered that cordycepin reduced ROS production (O2 H2O2) in platelet-derived growth factor BB (PDGF- BB)-induced smooth muscle cells of the vascular system in vitro, which served to in preventing the formation of neointima and the outgrowth of vascular sprouts due to the PDGF-BB. The A1/A2 adenosine-receptor antagonist dipropyl-8-sulphophenylxanthine (DPSPX; 10 nM, 60 minutes) reversed the inhibition of PDGF-BB-induced migration evoked by cordycepin. The A1/A2 receptors can be found present in vascular cells and have cardioprotective properties. Thus, cordycepin may act as an antiatherosclerotic medication by stimulating the receptor A1/A2 (Won and co. 2009).
Sterols and Their Activities
Several sterols, including ergosterol, H1-A, D3ergosterol, ergosterol peroxide, ergosteryl-3-0-b- D-glucopyranoside, cereisterol, b-sitosterol, daucosterol, cholesterol, 22, 23-dihydroergosteryl-3– O-b-D-glucopyranoside, cholesteryl palmitate, campesterol, and dihydrobrassicasterol, have been identified in cordyceps (Feng, Yang, and Li 2008). Ergosterol is found as free or mixed forms in cordyceps. Furthermore, the amount from the pure form are high in both cultured and natural cordyceps (Yang and Li. 2009). Ergosterol is a precursor in the biological process of vitamin D2 that is required to develop bone in humans. The sterol b-sitosterol can be found predominantly in natural cordyceps and commercially cultivated C. sinensis. It is absent in commercial cultured C. militaris and in cultured C. sinensis found in Yang's lab (Yang and co. 2009). In Europe P-sitosterol is a significant role in treating benign prostatic hypertrophy (Wilt and co. 2000). Phytosterols, particularly b-sitosterol have a protective effect against prostate, colon as well as breast cancer (Awad and co. 2000). Furthermore, phytosterols such as campesterol, b'sitosterol, and stigmasterol, reduce cholesterol absorption, while being poorly absorbable in and of themselves (Ostlund 2007). The bioactivities of sterols can be useful in understanding the therapeutic potential of cordyceps like cancer and hyperlipidemia.
Free Fatty Acids and Their Activities
Ten free fat acids (FFAs) which is lauric acid and myristic acid pentadecanoic acid palmitic acid, palmitoleic acid, linoleic acid Oleic acid, stearic acids docosanoic acids, and lignoceric acid are found in the natural C. sinensis C. Lingshanensis as well as C. gunnii, and in the cultured C. sinensis, and C. militaris. It is among these FFAs palmitic acid, the linoleic acid and oleic acid and stearic acid are the most important components found in the natural and cultured varieties of cordyceps. Natural cordyceps contain more than oleic acid and palmitic acid than those grown in culture (Yang and co. 2009). The FFAs are not just essential nutritional compounds but also regulate many of the functions of cells by their receptors. These FFA receptors include G-protein-coupled receptors, such as G-protein receptor (GPR) 40 GPR41, GPR43 the GPR120 and GPR84 (Rayasam and others. 2007; Hirasawa et al. 2008; Swaminath 2008). FFA receptors are associated with a myriad of physiological effects in the activation process. They, consequently, could be a new therapeutic target for dyslipidemia, diabetes and immunomodulation, specifically type 2 diabetes.
Pentadecanoic Acid (C15) along with palmitic acids (C16) can be the potentest FFAs that interact with GPR40 which can trigger GPR40. GPR40 receptor and trigger the release of calcium (Briscoe and co. 2003). This will trigger an insulin response from b cells of the pancreas and triggers the hypoglycemic effect. Both of these FFAs occur in natural and cultured cordyceps with palmitic acid being the main ingredient. In addition, palmitic acid could be one of the key hypoglycemic ingredients in cordyceps. On the other hand FFAs in cordyceps could indirectly increase insulin secretion stimulated by glucose and, in turn, reduce the the level of glucose in plasma through activation of GPR120 within the intestinal tract (Hirasawa and co. 2008). GPR84, GPR41, GPR43 and GPR84 are present by immune cells. The activation of these receptors through FFAs triggers an immune-modulatory result (Swaminath 2008) and cordyceps is a source of FFAs and has significant activities, suggesting that FFAs found in the cordyceps are a contributor to its immunomodulatory functions.
Carbohydrates and Their Activities
Cordyceps is not just an abundance of polysaccharides ranging between 3 and 8% of the dry mass, it it also is a rich source of D-mannitol. D-mannitol is also known as cordycepic acid, was discovered from C. sinensis in the year 1957. It is among the most important compounds found in both cultured and natural cordyceps. It contributes more than 3.4 percent (Li Yang 2008a and Li Yang in 2008a) and 2.4 percentage (Feng, Yang, and Li 2008) of the dry weight and 2.4% (Feng, Yang, and Li 2008) of total dry weight. Due to its osmotic function D-mannitol has been utilized to treat cerebral edema as well as chronic intracranial hypertension after the aftermath of brain trauma or subarachnoid hemorrhage as well as stroke (Rangel-Castilla, Gopinath, and Robertson 2008) and when there is acute renal impairment (Lameire and De Vriese 2003). as well as Vanholder 2003). Inhaling dry mannitol powder is an effective therapeutic option for those suffering from cystic fibrosis (Jaques and co. (2008)) or asthmatic bronchiectasis (Ilowite, Spiegler, and Chawla 2008) The inhaled powder enhances mucociliary clearance by making the airway more hydrated. Mannitol can also be employed for diagnostic purposes to detect airway hyper-responsiveness to aid in diagnosing asthma (Anderson and colleagues. 2009). These pharmacological benefits of D-mannitol may be the main reason behind the use of cordyceps in treating certain respiratory disorders like asthma, chronic bronchitis kidney failure and renal dysfunction and hypertension.
CONCLUSIONS
C. sinensis is one of the most sought-after traditional Chinese medicine that is highly valued in traditional Chinese. Since it is scarce and costly, a variety of natural cordyceps, mycelia cultured and the fruiting bodies of Cordyceps are now the main alternatives in health food commercial formulations. Research has shown that the cordyceps is a bioactive plant with a variety of benefits, like immunomodulation, antitumor antioxidant sexual and reproductive improvement, hypoglycemic, as well as antifatigue functions, as well as an effect of protection on the liver and kidneys. Different compounds contribute to different bioactivities. In general, the mycelia grown in culture of cordyceps are just as efficient as the natural cordyceps. Cordyceps is highly safe for the treatment in vivo of animals for up to three weeks. Cordyceps-fermented products, together with natural C. sinensis, may be potent ingredients or functional food items that help maintain health.