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Enterovirus A71 (EV-A71) infection typically causes mild illnesses, such as hand-foot-and-mouth disease (HFMD), but occasionally leads to severe or fatal neurological complications in infants and young children. Currently, there is no specific antiviral treatment available for EV-A71 infection. Thus, the development of an effective anti-EV-A71 drug is required urgently. Cordycepin, a major bioactive compound found in Cordyceps fungus, has been reported to possess antiviral activity. However, its specific activity against EV-A71 is unknown. In this study, the potency and role of cordycepin treatment on EV-A71 infection were investigated. Results demonstrated that cordycepin treatment significantly reduced the viral load and viral ribonucleic acid (RNA) level in EV-A71-infected Vero cells. In addition, EV-A71-mediated cytotoxicity was significantly inhibited in the presence of cordycepin in a dose-dependent manner. The protective effect can also be extended to Caco-2 intestinal cells, as evidenced by the higher median tissue culture infectious dose (TCID 50 ) values in the cordycepin-treated groups. Furthermore, cordycepin inhibited EV-A71 replication by acting on the adenosine pathway at the post-infection stage. Taken together, our findings reveal that cordycepin could be a potential antiviral candidate for the treatment of EV-A71 infection.

Polyalthia belong to the Annonaceae family and are a type of evergreen tree distributed across many tropical and subtropical regions. Polyalthia species have been used long term as indigenous medicine to treat certain diseases, including fever, diabetes, infection, digestive disease, etc. Recent studies have demonstrated that not only crude extracts but also the isolated pure compounds exhibit various pharmacological activities, such as anti-oxidant, anti-microbial, anti-tumor, anti-cancer, etc. It is known that the initiation of cancer usually takes several years and is related to unhealthy lifestyle, as well as dietary and environmental factors, such as stress, toxins and smoking. In fact, natural or synthetic substances have been used as cancer chemoprevention to delay, impede, or even stop cancer growing. This review is an attempt to collect current available phytochemicals from Polyalthia species , which exhibit anti-cancer potentials for chemoprevention purposes, providing directions for further research on the interesting agents and possible clinical applications.

Cordycepin is an adenosine derivative isolated from Cordyceps sinensis , which has been used as an herbal complementary and alternative medicine with various biological activities. The general anti-cancer mechanisms of cordycepin are regulated by the adenosine A3 receptor, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), and glycogen synthase kinase (GSK)-3β, leading to cell cycle arrest or apoptosis. Notably, cordycepin also induces autophagy to trigger cell death, inhibits tumor metastasis, and modulates the immune system. Since the dysregulation of autophagy is associated with cancers and neuron, immune, and kidney diseases, cordycepin is considered an alternative treatment because of the involvement of cordycepin in autophagic signaling. However, the profound mechanism of autophagy induction by cordycepin has never been reviewed in detail. Therefore, in this article, we reviewed the anti-cancer and health-promoting effects of cordycepin in the neurons, kidneys, and the immune system through diverse mechanisms, including autophagy induction. We also suggest that formulation changes for cordycepin could enhance its bioactivity and bioavailability and lower its toxicity for future applications. A comprehensive understanding of the autophagy mechanism would provide novel mechanistic insight into the anti-cancer and health-promoting effects of cordycepin.

Midazolam (MDZ) could affect lymphocyte immune functions. However, the influence of MDZ on cell's K + currents has never been investigated. Thus, in the present study, the effects of MDZ on Jurkat T lymphocytes were studied using the patch-clamp technique. Results showed that MDZ suppressed the amplitude of delayed-rectifier K + current ( I K(DR) ) in concentration-, time-, and state-dependent manners. The IC 50 for MDZ-mediated reduction of I K(DR) density was 5.87 μM. Increasing MDZ concentration raised the rate of current-density inactivation and its inhibitory action on I K(DR) density was estimated with a dissociation constant of 5.14 μM. In addition, the inactivation curve of I K(DR) associated with MDZ was shifted to a hyperpolarized potential with no change on the slope factor. MDZ-induced inhibition of I K(DR) was not reversed by flumazenil. In addition, the activity of intermediate-conductance Ca 2+ -activated K + (IK Ca ) channels was suppressed by MDZ. Furthermore, inhibition by MDZ on both I K(DR) and IK Ca -channel activity appeared to be independent from GABAA receptors and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes. In conclusion, MDZ suppressed current density of I K(DR) in concentration-, time-, and state-dependent manners in Jurkat T-lymphocytes and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes.

Cordycepin, a bioactive constituent from the fungus Cordyceps sinensis , could inhibit cancer cell proliferation and promote cell death via induction of cell cycle arrest, apoptosis and autophagy. Our novel finding from microarray analysis of cordycepin-treated MA-10 mouse Leydig tumor cells is that cordycepin down-regulated the mRNA levels of FGF9, FGF18, FGFR2 and FGFR3 genes in MA-10 cells. Meanwhile, the IPA-MAP pathway prediction result showed that cordycepin inhibited MA-10 cell proliferation by suppressing FGFs/FGFRs pathways. The in vitro study further revealed that cordycepin decreased FGF9-induced MA-10 cell proliferation by inhibiting the expressions of p-ERK1/2, p-Rb and E2F1, and subsequently reducing the expressions of cyclins and CDKs. In addition, a mouse allograft model was performed by intratumoral injection of FGF9 and/or intraperitoneal injection of cordycepin to MA-10-tumor bearing C57BL/6J mice. Results showed that FGF9-induced tumor growth in cordycepin-treated mice was significantly smaller than that in a PBS-treated control group. Furthermore, cordycepin decreased FGF9-induced FGFR1-4 protein expressions in vitro and in vivo. In summary, cordycepin inhibited FGF9-induced testicular tumor growth by suppressing the ERK1/2, Rb/E2F1, cell cycle pathways, and the expressions of FGFR1-4 proteins, suggesting that cordycepin can be used as a novel anticancer drug for testicular cancers.

A clerodane diterpene compound 16-hydroxycleroda-3,13-dien-15,16-olide (CD) is considered a therapeutic agent with pharmacological activities. The present study investigated the mechanisms of CD-induced apoptosis in T24 human bladder cancer cells. CD inhibited cell proliferation in a concentration and time-dependent manner. CD-induced overproduction of reactive oxygen species and reduced mitochondrial membrane potential, associated with reduced expression of Bcl-2 and increased levels of cytosolic cytochrome c, cleaved PARP-1 and caspase-3. In addition, CD treatment led to cell cycle arrest at the G0/G1 phase and inhibited expression of cyclin D1 and cyclin-dependent kinases 2 and 4 and led to increased levels of p21, p27Kip1 and p53. All of these events were accompanied with a reduction of pEGFR, pMEK1/2, pERK1/2, pAkt, pmTOR, pP70S6K1, HIF-1α, c-Myc and VEGF. RNAseq-based analysis revealed that CD-induced cell death was characterised by an increased expression of stress and apoptotic-related genes as well as inhibition of the cell cycle-related genes. In summary, CD induces apoptosis in T24 bladder cancer cells through targeting multiple intracellular signaling pathways as a result of oxidative stress and cell cycle arrest.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and accounts for over 90% of malignant neoplasms of the oral cavity, with a 5-year survival rate of less than 50%. The long-term survival rate of OSCC patients has not markedly improved in recent decades due to its heterogeneous etiology and treatment outcomes. We investigated the anticancer effect of the combination of irradiation (IR) and cordycepin in the treatment of human OSCC cells in vitro. The type of cell death, especially autophagy and apoptosis, and the underlying mechanisms were examined. We found synergistic effects of cordycepin and IR on the viability of human oral cancer cells. The combination of cordycepin and IR treatment induced apoptosis, cell cycle arrest, and autophagic cell death. Furthermore, cordycepin induced S-phase arrest and prolonged G2/M arrest in the cells that received the combination treatment compared with those that received irradiation alone. Combined treatment induced the upregulation of ATG5 and p21 in an autophagy cascade-dependent manner, arrested the cell cycle in the G2/M phase, and repressed cell proliferation. Thus, we conclude that the combination of cordycepin and IR treatment could be a potential therapeutic strategy for OSCC., Competing Interests: The authors declare no conflict of interest.