Cordycepin

The body of Cordyceps sienesis (Berkeley) Saccardo

Antifungal activity of 3'-deoxyadenosine (cordycepin).[Pubmed:9624488]

Antimicrob Agents Chemother. 1998 Jun;42(6):1424-7.

The antifungal activity of the nucleoside analog 3'-deoxyadenosine (Cordycepin) was studied in a murine model of invasive candidiasis. When protected from deamination by either deoxycoformycin or coformycin, both of which are adenosine deaminase inhibitors, Cordycepin exhibited potent antifungal efficacy, as demonstrated by prolongation of survival and a decrease in CFU in the kidneys of mice treated with Cordycepin plus an adenosine deaminase inhibitor. The antifungal effect was seen with three different Candida isolates: Candida albicans 64, a relatively fluconazole-resistant clinical isolate of C. albicans (MIC, 16 micrograms/ml), and the fluconazole-resistant Candida krusei. Cordycepin and related compounds may provide another avenue for the discovery of clinically useful antifungal drugs.

Cordycepin: selective growth inhibitor derived from liquid culture of Cordyceps militaris against Clostridium spp.[Pubmed:10898616]

J Agric Food Chem. 2000 Jul;48(7):2744-8.

The growth responses of nine human intestinal bacteria to liquid culture of Cordyceps militaris Link. Pt. (Ascomycotina: Clavicipitaceae) collected from a pupa of Bombyx mori L. (Lepidoptera: Bombycidae) were examined using spectrophotometric and impregnated paper disk methods and compared to those of tetracycline and chloramphenicol, as well as those of Coptis japonica root-derived berberine chloride. The biologically active constituent of the cultures was characterized as Cordycepin (3'-deoxyadenosine) by spectroscopic analysis. This compound revealed potent growth-inhibiting activity toward Clostridium paraputrificum and Clostridium perfringens at 10 microgram/disk without adverse effects on the growth of Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium adolescentis, Lactobacillus acidophilus, and Lactobacillus casei, whereas tetracycline and chloramphenicol inhibited the growth of these lactic acid-producing bacteria, clostridia and Escherichia coli. However, C. militaris-derived materials revealed no growth stimulation on the bifidobacteria and lactobacilli. These results may be an indication of at least one of the pharmacological actions of C. militaris. As a naturally occurring antibacterial agent, Cordycepin could be useful as a new preventive agent against various diseases caused by clostridia.

Cordycepin protects against cerebral ischemia/reperfusion injury in vivo and in vitro.[Pubmed:21554870]

Eur J Pharmacol. 2011 Aug 16;664(1-3):20-8.

Cordycepin, (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological actions, such as anti-inflammatory, antioxidative and anticancer activities. Little is known about the neuroprotective action of Cordycepin as well as its molecular mechanisms. In this study, Cordycepin was investigated for its neuroprotective potential in mice with ischemia following 15 min of the bilateral common carotid artery occlusion and 4h of reperfusion. The effect of Cordycepin was also studied in mice brain slices treated with oxygen-glucose deprivation (OGD) injury. Our results showed that Cordycepin was able to prevent postischemic neuronal degeneration and brain slice injury. Excitatory amino acids such as glutamate and aspartate in brain homogenized supernatant, which were increased in ischemia/reperfusion group, were detected by high performance liquid chromatography (HPLC). The results showed that Cordycepin was able to decrease the extracellular level of glutamate and aspartate significantly. Moreover, Cordycepin was able to increase the activity of superoxide dismutase (SOD) and decrease the level of malondialdehyde (MDA), ameliorating the extent of oxidation. Furthermore, matrix metalloproteinase-3(MMP-3), a key enzyme involved in inflammatory reactions, was markedly increased after ischemia reperfusion, whereas Cordycepin was able to inhibit its expression obviously. In conclusion, our in vivo and in vitro study showed that Cordycepin was able to exert a potent neuroprotective function after cerebral ischemia/reperfusion.

The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells.[Pubmed:24486958]

Neurotoxicology. 2014 Mar;41:102-11.

Glutamate toxicity increases the formation of reactive oxygen species (ROS) and intracellular calcium levels, resulting in neuronal dysfunction, neurodegenerative disorders, and death. Cordycepin is a derivative of the nucleoside adenosine, and is believed to exert neuroprotective effects against glutamate-induced oxidative toxicity in HT22 neuronal cells. Excessive glutamate induces oxidative and endoplasmic reticulum (ER) stress, gradually increasing ER-related pro-apoptotic transcription factor C/EBP homologous protein (CHOP) expression, and eventually up-regulating expression of the pro-apoptotic factor Bax. Cordycepin inhibits CHOP and Bax expressions, as well as p-ERK, p-JNK, and p-p38, all of which are involved in oxidative or ER stress-induced apoptosis. In addition, the increased production of ROS from excessive glutamate leads to elevation of mitochondrial membrane potential (MMP), a hallmark of mitochondrial dysfunction. Cordycepin retains MMP and reduces the elevated levels of ROS and Ca(2+) induced by glutamate. Caspases are crucial mediators involved in mitochondrial apoptosis, and while glutamate disrupts mitochondrial function, it does not change expression levels of caspase 3 and caspase 9. Similarly, Cordycepin has no effect on caspase 3 and caspase 9 expressions; however, it decreases the expression of ER stress-specific caspase 12, which plays a key role in the initiation of ER stress-induced apoptosis. Finally, we found that the anti-apoptotic effects of Cordycepin are partially dependent on activation of the adenosine A1 receptor, whereas an antagonist selectively attenuated the neuroprotective effects of Cordycepin. Collectively, these results suggest that Cordycepin could be a potential future therapeutic agent for neuronal disorders.

Cordycepin inhibits lipopolysaccharide-induced inflammation by the suppression of NF-kappaB through Akt and p38 inhibition in RAW 264.7 macrophage cells.[Pubmed:16899239]

Eur J Pharmacol. 2006 Sep 18;545(2-3):192-9.

Cordyceps militaris, a caterpillar-grown traditional medicinal mushroom, produces an important bioactive compound, Cordycepin (3'-deoxyadenosine). Cordycepin is reported to possess many pharmacological activities including immunological stimulating, anti-cancer, anti-virus and anti-infection activities. The molecular mechanisms of Cordycepin on pharmacological and biochemical actions of macrophages in inflammation have not been clearly elucidated yet. In the present study, we tested the role of Cordycepin on the anti-inflammation cascades in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. In LPS-activated macrophage, nitric oxide (NO) production was inhibited by butanol fraction of C. militaris and the major component of C. militaris butanol faction was identified as Cordycepin by high performance liquid chromatography. To investigate the mechanism by which Cordycepin inhibits NO production and inducible nitric oxide synthase (iNOS) expression, we examined the activation of Akt and MAP kinases in LPS-activated macrophage. Cordycepin markedly inhibited the phosphorylation of Akt and p38 in dose-dependent manners in LPS-activated macrophage. Moreover, Cordycepin suppressed tumor necrosis factor (TNF-alpha) expression, IkappaB alpha phosphorylation, and translocation of nuclear factor-kappaB (NF-kappaB). The expressions of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were significantly decreased in RAW 264.7 cell by Cordycepin. Taken together, these results suggest that Cordycepin inhibits the production of NO production by down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB activation, Akt and p38 phosphorylation. Thus, Cordycepin may provide a potential therapeutic approach for inflammation-associated disorders.

Cordycepin (3'-deoxyadenosine) suppressed HMGA2, Twist1 and ZEB1-dependent melanoma invasion and metastasis by targeting miR-33b.[Pubmed:25868853]

Oncotarget. 2015;6(12):9834-53.

Malignant melanoma, the most deadly form of skin cancer, has a high propensity for metastatic spread and is notoriously chemotherapy-resistant. Cordycepin, the active component of Cordyceps spp., has been identified to have anti-metastatic effect on tumor progression and thus possesses pharmacological and therapeutic potentials. However, the mechanisms of anti-metastatic effects of Cordycepin at cellular levels remain elusive. We analyzed the effect of Cordycepin on human melanoma miRNA expression profiles by miRNAarray and found that miR-33b was upregulated in highly-metastatic melanoma cell lines following Cordycepin exposure. Cordycepin-mediated miR-33b expression was dependent on LXR-RXR heterodimer activation. miR-33b directly binds to HMGA2, Twist1 and ZEB1 3'-UTR to suppress their expression. The negative correlations between miR-33b levels and HMGA2, Twist1 or ZEB1 expression were detected in 72 patient melanoma tissue samples. By targeting HMGA2 and Twist1, miR-33b attenuated melanoma migration and invasiveness upon Cordycepin exposure. miR-33b knockdown or ZEB1 overexpression reverted Cordycepin-mediated mesenchymal-epithelial transition (MET), triggering the expression of N-cadherin. In spontaneous metastasis models, Cordycepin suppressed tumor metastasis without altering primary tumor growth. We showed for the first time that targeting miRNA by Cordycepin indicates a new mechanism of Cordycepin-induced suppression of tumor metastasis and miR-33b/HMGA2/Twist1/ZEB1 axis plays critical roles in regulating melanoma dissemination.

Cordyceps militaris mushroom and cordycepin inhibit RANKL-induced osteoclast differentiation.[Pubmed:25789604]

J Med Food. 2015 Apr;18(4):446-52.

Cordyceps militaris is a medicinal mushroom and its bioactive compound, Cordycepin, is reported to have many pharmacological activities. The goal of this study was to investigate the effects of C. militaris extract (CME) and Cordycepin on osteoclast differentiation in vitro and on an inflammatory bone loss in vivo. In RAW 264.7 cells, CME and Cordycepin showed dose-dependent inhibition of receptor activator of the nuclear factor kappa B (NF-kappaB) ligand (RANKL)-induced osteoclast differentiation by TRAP (tartrate-resistant acid phosphatase) staining. Moreover, the mRNA expression of osteoclastogenesis-related genes (TRAP, cathepsin K, MMP-9, and NFATc1) was also inhibited by CME and Cordycepin. Also, Cordycepin significantly inhibited RANKL-induced phosphorylation of p38 and NF-kappaB, but not that of other members of mitogen-activated protein kinase families. To examine the effect of CME on bone loss in vivo, we used a mouse model of lipopolysaccharide (LPS)-mediated bone loss. Micro-CT analysis of the femurs showed that LPS treatment caused bone loss. However, bone loss was significantly attenuated in mice treated with CME. These results suggest that Cordycepin or/and CME have inhibitory effects on osteoclast differentiation in vitro and that they suppress inflammatory bone loss in vivo.

[Mechanisms of cordycepin on improving renal interstitial fibrosis via regulating eIF2alpha/TGF-beta/Smad signaling pathway].[Pubmed:25775775]

Zhongguo Zhong Yao Za Zhi. 2014 Nov;39(21):4096-101.

OBJECTIVE: To investigate the effects and mechanisms of Cordycepin,an effective component of cordyceps militaris, on renal interstitial fibrosis (RIF) and its related eIF2alpha/TGF-beta/Smad signaling pathway. METHOD: Firstly, 15 C57BL/6 mice were randomly divided into 3 groups,the control group (Group A), the model group (Group B) and the Cordycepin-treated group (Group C). After renal interstitial fibrotic model was successfully established by unilateral ureteral obstruction (UUO), the mice in Group C were intraperitoneally administrated with Cordycepin(5 mg x kg(-1) d(-1)) and the ones in Group A and B were administrated with physiological saline for 5 days. At the end of the study, the obstructed kidneys were collected and detected for the pathological changes of RIF, and the mRNA expressions of collagen type I (Col I) and alpha-smooth muscle actin (alpha-SMA) in the kidney by Northern blot. Secondly, after renal tubular epithelial (NRK-52E) cells cultured in vitro were exposed to transforming growth factor (TGF) -beta with or without Cordycepin, the mRNA expressions of Col I and collagen type IV( Col IV) by Northern blot, and the protein expressions of eukaryotic initiation factor 2alpha (eIF2alpha), phosphorylated eIF2alpha ( p-eIF2alpha), Smad2/3 and phosphorylated Smad2/3 (p-Smad2/3) were tested by Western blot. RESULT: In vivo, Cordycepin alleviated RIF in model mice, including improving fibrotic pathological characteristics and mRNA expressions of Col I and alpha-SMA. In vitro, Cordycepin induced the high expression of p-elF2alpha, and inhibited the expressions of p-Smad2/3, Col I and Col IV induced by TGF-beta in NRK-52E cells. CONCLUSION: Cordycepin attenuates RIF in vivo and in vitro, probably by inducing the phosphorylation of eIF2alpha, suppressing the expression of p-Smad2/3, a key signaling molecule in TGF-beta/Smad signaling pathway, and reducing the expressions of collagens and alpha-SMA in the kidney.

Antileukemic activity and mechanism of action of cordycepin against terminal deoxynucleotidyl transferase-positive (TdT+) leukemic cells.[Pubmed:10609556]

Biochem Pharmacol. 2000 Feb 1;59(3):273-81.

The nucleoside analogue Cordycepin (3'-deoxyadenosine, 3'-dA) is substantially more cytotoxic to terminal deoxynucleotidyl transferase positive (TdT+) leukemic cells than to TdT leukemic cells in vitro in the presence of an adenosine deaminase inhibitor, deoxycoformycin (dCF), and has been considered as a therapeutic agent for TdT+ leukemia. The intracellular metabolism of 3'-dA was examined with HPLC, and the mechanism of its anti-TdT+ leukemic activity was analyzed. In the presence of dCF (2.5 microM), TdT+ leukemic cells (N = 5) were sensitive to the cytotoxic effect of 3'-dA, whereas TdT (N = 6) cells were not. A high level of 3'-dA-5'-triphosphate (3'-dATP) formation was detected in TdT+ NALM-6 cells (67 pmol/10(6) cells) and TdT- K562 cells (49 pmol/10(6) cells) when cultured with 1 microM [3'-3H]-labeled 3'-dA. A substantial level of 3'-dATP was detected in TdT HUT-102 cells (27 pmol/10(6) cells), whereas the level of 3'-dATP in TdT+ MOLT-4 cells was low (0.3 pmol/10(6) cells). The mean IC50 values of 3'-dA against phytohemagglutinin (PHA)-activated and resting peripheral blood mononuclear cells (PBM) (N = 5) were 8 and 32 microM, respectively. There was a modest level of 3'-dATP (7 pmol/10(6) cells) in PHA-PBM, whereas a lower level of 3'-dATP was detected in resting PBM (2.5 pmol/10(6) cells). These data suggest that the presence of 3'-dATP is not sufficient for the antileukemic effect of 3'-dA, but that TdT positivity is essential, and that PBM are significantly less sensitive to the cytotoxicity of 3'-dA in vitro. Further development of 3'-dA as a potential antileukemic agent to treat patients with TdT+ leukemia is warranted.

The synthesis of 3'-dATP and its use as an inhibitor of ATP-dependent DNA synthesis in toluene-treated Escherichia coli.[Pubmed:779831]

Biochemistry. 1976 Jun 29;15(13):2804-9.

A structural analogue of ATP, 3'-deoxyadenosine triphosphate (3'-dATP), has been synthesized from Cordycepin (3'-deoxyadenosine), characterized, and determined to be an inhibitor of ATP-dependent DNA synthesis in Escherichia coli cells which have been reduced permeable to nucleoside triphosphates by treatment with toluene. The analogue is a competitive inhibitor of ATP and it inhibits replicative DNA synthesis 50% at concentrations of ca. 0.15 mM in the presence of 1.0 mM ATP and 4 x 10(8) cells/ml. The degree of inhibition of a given amount of 3'-dATP is inversely related to the cell concentration in the reaction mixture. The analogue interferes with some function of ATP which is continuously required during the course of the reaction and does not irreversibly inactivate the cells' DNA synthesis apparatus. 3'-Deoxyadenosine triphosphate may prove useful in elucidating the roles of ATP in DNA synthesis in more purified replicating systems.

Cordycepin (3'-Deoxyadenosine) is a nucleoside derivative isolated from Cordyceps and inhibits IL-1β-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts (RASFs) in a dose-dependent manner. Cordycepin kills Mycobacterium tuberculosis through hijacking the bacterial adenosine kinase.

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