CTSL is expressed by cancerous tissues and encodes a lysosomal cysteine proteinase that regulates cancer progression and SARS-CoV-2 entry. Therefore, it is critical to predict the susceptibility of ...cancer patients for SARS-CoV-2 and evaluate the correlation between disease outcomes and the expression of CTSL in malignant cancer tissues. In the current study, we analyzed CTSL expression, mutation rate, survival and COVID-19 disease outcomes in cancer and normal tissues, using online databases. We also performed immunohistochemistry (IHC) to test CTSL expression and western blot to monitor its regulation by cordycepin (CD), and N6, N6-dimethyladenosine (m
A), respectively. We found that
is conserved across different species, and highly expressed in both normal and cancer tissues from human, as compared to ACE2 or other proteinases/proteases. Additionally, the expression of CTSL protein was the highest in the lung tissue. We show that the mRNA expression of
is 66.4-fold higher in normal lungs and 54.8-fold higher in cancer tissues, as compared to
mRNA expression in the respective tissues. Compared to other proteases/proteinases/convertases such as TMPRSS2 and FURIN, the expression of CTSL was higher in both normal lungs and lung cancer samples. All these data indicate that
might play an important role in COVID-19 pathogenesis in normal and cancer tissues of the lungs. Additionally, the CTSL-002 isoform containing both the inhibitor_I29 and Peptidase_C1 domains was highly prevalent in all cancers, suggesting its potential role in tumor progression and SARS-CoV-2 entry in multiple types of cancers. Further analysis of the expression of CTSL mutant showed a correlation with FURIN and TMPRSS2, suggesting a potential role of CTSL mutations in modulating SARS-CoV-2 entry in cancers. Moreover, high expression of
significantly correlated with a short overall survival (OS) in lung cancer and glioma. Thus, CTSL might play a major role in the susceptibility of lung cancer and glioma patients to SARS-CoV-2 uptake and COVID-19 severity. Furthermore, CD or m
A inhibited CTSL expression in the cancer cell lines A549, MDA-MB-231, and/or PC3 in a dose dependent manner. In conclusion, we show that CTSL is highly expressed in normal tissues and increased in most cancers, and CD or m
A could inhibit its expression, suggesting the therapeutic potential of targeting CTSL for cancer and COVID-19 treatment.
COVID-19 is an acute respiratory disease caused by SARS-CoV-2 that has spawned a worldwide pandemic. ADAM17 is a sheddase associated with the modulation of the receptor ACE2 of SARS-CoV-2. Studies ...have revealed that malignant phenotypes of several cancer types are closely relevant to highly expressed ADAM17. However, ADAM17 regulation in SARS-CoV-2 invasion and its role on small molecules are unclear. Here, we evaluated the ADAM17 inhibitory effects of cordycepin (CD), thymoquinone (TQ), and N6, N6-dimethyladenosine (m
A), on cancer cells and predicted the anti-COVID-19 potential of the three compounds and their underlying signaling pathways by network pharmacology. It was found that CD, TQ, and m
A repressed the ADAM17 expression upon different cancer cells remarkably. Moreover, CD inhibited GFP-positive syncytia formation significantly, suggesting its potential against SARS-CoV-2. Pharmacological analysis by constructing CD-, TQ-, and m
A-based drug-target COVID-19 networks further indicated that ADAM17 is a potential target for anti-COVID-19 therapy with these compounds, and the mechanism might be relevant to viral infection and transmembrane receptors-mediated signal transduction. These findings imply that ADAM17 is of potentially medical significance for cancer patients infected with SARS-CoV-2, which provides potential new targets and insights for developing innovative drugs against COVID-19.
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•Cordycepin is a major active compound found in most Cordyceps.•Considerable efforts have been put on the improvement of cordycepin content.•Genetical engineering and synthetic ...biology will be the great potential strategies.
Cordyceps genus, such as C. militaris and C. kyushuensis, is a source of a rare traditional Chinese medicine that has been used for the treatment of numerous chronic and malignant diseases. Cordycepin, 3′-deoxyadenosine, is a major active compound found in most Cordyceps. Cordycepin exhibits a variety of biological activities, including anti-tumor, immunomodulation, antioxidant, and anti-aging, among others, which could be applied in health products, medicine, cosmeceutical etc. fields. This review focuses on the synthesis methods for cordycepin. The current methods for cordycepin synthesis involve chemical synthesis, microbial fermentation, in vitro synthesis and biosynthesis; however, some defects are unavoidable and the production is still far from the demand of cordycepin. For the future study of cordycepin synthesis, based on the illumination of cordycepin biosynthesis pathway, genetical engineering of the Cordyceps strain or introducing microbes by virtue of synthetic biology will be the great potential strategies for cordycepin synthesis. This review will aid the future synthesis of the valuable cordycepin.
(
) is a fungus with a long history of widespread use in folk medicine, and its biological and medicinal functions are well studied. A crucial pharmacological effect of
is immunomodulation. In this ...review, we catalog the immunomodulatory effects of different extracts of
, namely total extracts, polysaccharides and cordycepin
Total extracts obtained using water or 50% ethyl alcohol and polysaccharides from
were discovered to tend to promote type 1 immunity, whereas total extracts obtained using 70-80% ethyl alcohol and cordycepin from
were more likely to promote type 2 immunity. This article is the first to classify the immunomodulatory effects of different extracts of
. In addition, we discovered a relationship between different segments or extracts and differing types of immunity. This review can provide the readers a comprehensive understanding on the immunomodulatory effects of the precious folk medicine and guidance on its use for both health people and those with an immunodeficiency.
Free radical-induced oxidative damage is considered to be the most important consequence of the aging process. The activities and capacities of antioxidant systems of cells decline with increased ...age, leading to the gradual loss of pro-oxidant/antioxidant balance and resulting in increased oxidative stress. Our investigation was focused on the effects of cordycepin (3′-deoxyadenosine) on lipid peroxidation and antioxidation in aged rats. Age-associated decline in the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), reduced glutathione (GSH), vitamin C and vitamin E, and elevated levels of malondialdehyde (MDA) were observed in the liver, kidneys, heart and lungs of aged rats, when compared to young rats. Furthermore, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine were found to be significantly elevated in aged rats compared to young rats. Aged rats receiving cordycepin treatment show increased activity of SOD, CAT, GPx, GR and GST, and elevated levels of GSH, and vitamins C and E such that the values of most of these parameters did not differ significantly from those found in young rats. In addition, the levels of MDA, AST, ALT, urea and creatinine became reduced upon administration of cordycepin to aged rats. These results suggest that cordycepin is effective for restoring antioxidant status and decreasing lipid peroxidation in aged rats.
► Aging leads to the gradual loss of pro-oxidant/antioxidant balance and increase oxidative stress. ► Cordycepin treatment decreases oxidative stress and increases antioxidant status. ► Cordycepin treatment can ameliorate antioxidants during aging and it might attenuate the age-associated disorders.
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•C. militaris strain 147 displayed a strong xylose utilisation capability.•Xylose metabolism enhanced the cordycepin synthesis in the fungus.•The cordycepin yield reached 6.54 g/L by ...optimising medium components.•Xylose altered the expression of genes involving purine and amino acid metabolisms.
Cordycepin is an important active metabolite of Cordyceps militaris. Xylose, an attractive feedstock for producing chemicals through microbial fermentation, cannot be effectively utilised by many reported C. militaris strains. Herein, a xylose-utilising C. militaris strain 147 produced the highest level of cordycepin (3.03 g/L) in xylose culture. Xylose, alanine, and ammonium citrate were determined as the main affecting factors on the cordycepin production using a Plackett-Burman design. The combination of these factors was optimised using response surface methodology, and the maximal 6.54 g/L of cordycepin was produced by the fungus in the optimal medium. Transcriptome analysis revealed that xylose utilisation upregulated the transcriptional levels of genes participating in purine and energy metabolisms in the fungus, which may facilitate the formation of precursors for cordycepin biosynthesis. This investigation provides new insights into the efficient production of cordycepin and is conducive to the valorisation of biomass rich in xylose.
The responsive mechanism of C. militaris TBRC7358 on xylose utilization was investigated by comparative analysis of transcriptomes, growth kinetics and cordycepin productions. The result showed that ...the culture grown on xylose exhibited high production yield of cordycepin on dry biomass. Comparing xylose to other carbon sources, a set of significantly up-regulated genes in xylose were enriched in pentose and glucuronate interconversion, and cordycepin biosynthesis. After validating up-regulated genes using quantitative real-time PCR, interestingly, putative alternative 3′-AMP-associated metabolic route on cordycepin biosynthesis was identified. Through reporter metabolites analysis of C. militaris, significant metabolites (e.g., AMP, glycine and L-glutamate) were identified guiding involvement of growth and cordycepin production. These findings suggested that there was a cooperative mechanism in transcriptional control of the supplying precursors pool directed towards the cordycepin biosynthesis through main and putative alternative metabolic routes for leverage of cell growth and cordycepin production on xylose of C. militaris strain TBRC7358.
•Responsive mechanism of C. militaris strain TBRC7358 on xylose utilization was investigated by comparative transcriptomics.•Significant metabolites involved in growth and cordycepin production of C. militaris strain TBRC7358 were identified.•Putative 3’-AMP-associated route on cordycepin production of C. militaris strain TBRC7358 was identified in xylose culture.
Hematological malignancies(HMs) are highly heterogeneous diseases with globally rising incidence. Despite major improvements in the management of HMs, conventional therapies have limited efficacy, ...and relapses with high mortality rates are still frequent. Cordycepin, a nucleoside analog extracted from Cordyceps species, represents a wide range of therapeutic effects, including anti-inflammatory, anti-tumor, and anti-metastatic activities. Cordycepin induces apoptosis in different subtypes of HMs by triggering adenosine receptors, death receptors, and several vital signaling pathways such as MAPK, ERK, PI3K, AKT, and GSK-3β/β-catenin. This review article summarizes the impact of utilizing cordycepin on HMs, and highlights its potential as a promising avenue for future cancer research based on evidence from in vitro and in vivo studies, as well as clinical trials.
•Hematological malignancies (HMs) are heterogeneous blood and lymphatic system cancers with high relapse and mortality rates.•Cordycepin, a fungi-derived 3′-deoxyadenosine, induces anti-cancer effects by repression of cell migration, induction of autophagy, and augmentation of the effectiveness of chemotherapy.•Utilizing Nano carries of cordycepin can be a way to improve its anti-tumor activity.
Cordycepin (known as 3-deoxyadenosine, CRD), a natural product from the valuable traditional Chinese medicine Cordyceps militaris, has been reported to improve cognitive function and modulate ...neuroprotective effects on the central nervous system (CNS). However, the modulating mechanisms of cordycepin on information processing in hippocampal CA1 pyramidal neurons are not fully understood. To clarify how cordycepin modulates synaptic responses of pyramidal neurons in rat hippocampal CA1 region, we conducted an electrophysiological experiment using whole-cell patch-clamp technique. The spontaneous and miniature excitatory postsynaptic currents (sEPSCs and mEPSCs, respectively) and the spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) recorded by this technique evaluated pure single or multi-synapse responses and enabled us to accurately quantify how cordycepin influenced the pre and postsynaptic aspects of synaptic transmission. The present results showed that cordycepin significantly decreased the frequency of both glutamatergic and GABAergic postsynaptic currents without affecting the amplitude, while these inhibitory effects were antagonized by the A1 adenosine receptor antagonist (DPCPX), but not the A2A (ZM 241385), A2B (MRS1754) and A3 (MRS1191) adenosine receptor antagonists. Taken together, our results suggested that cordycepin had a clear presynaptic effect on glutamatergic and GABAergic transmission, and provided novel evidence that cordycepin suppresses the synaptic transmission through the activation of A1AR.
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•Cordycepin decreased the frequency of glutamatergic postsynaptic currents.•Cordycepin decreased the frequency of GABAergic postsynaptic currents.•Cordycepin suppressed the synaptic transmission through the activation of A1AR.
Recent research emphasizes the central role of neuroinflammation in complex neurological disorders such as Alzheimer's disease, Parkinson's disease, depression, multiple sclerosis, and traumatic ...brain injury. Multiple pathological variables with identical molecular mechanisms have been implicated in the development of CNS inflammatory diseases. Therefore, one of the most crucial tasks in the management of CNS disorders is the alleviation of neuroinflammation. However, there are many drawbacks of new pharmacological drugs used in the management of CNS disorders, including medication side effects, and treatment complications. There is a growing inclination towards bioactive constituents of natural origin to unearth the potential remedies. Cordycepin, an adenosine analogue, is one such bioactive constituent with multiple actions, viz., anticancer, anti-inflammatory, hepato-protective, antidepressant, anti-Alzheimer's, anti-Parkinsonian and immunomodulatory effects, along with the promotion of remyelination. This review highlights the converging neuroinflammatory targets of cordycepin in Alzheimer's disease, Parkinson's disease, and depression, to substantiate its anti-neuroinflammatory property. Cordycepin acts by downregulation of adenosine A2 receptor, inhibition of microglial activation, and subsequent inhibition of several neuroinflammatory markers (NF-κB, NLRP3 inflammasome, IL-1β, iNOS, COX-2, TNF-α, and HMGB1). Cordycepin mitigates LPS-mediated toll-like receptor activation by activating adenosine receptor A1, thereby improving antioxidant enzymes (superoxide dismutase, glutathione peroxidase) levels. These pieces of evidence point to the probable anti-neuroinflammatory mechanisms of cordycepin, which could facilitate the development of new remedies against neuroinflammation-associated CNS disorders.
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