Cordycepin reverses cisplatin resistance in human bladder cancer cells via the PTEN/PI3K/AKt pathway

Purpose: To study the influence of cordycepin (Cor) on cisplatin insensitivity in bladder carcinoma, and its underlying mechanism of action.Methods: The effects of cisplatin and Cor treatments on the viability of T24-sensitive and T24/DDPinsensitive bladder carcinoma cells were investigated by using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method to assess selectivity index. Flow cytometry was employed to evaluate the apoptosis of T24/DDP-resistant bladder cancer cells treated with cisplatin and Cor. The concentrations of PTEN, p-AKt and Akt in T24/DDP-resistant bladder cancer cells treated with cisplatin and Cor were determined by western blot assay.Results: Compared with T24-sensitive cells, the sensitivity of T24/DDP-resistant bladder cancer cells to cisplatin was significantly decreased, along with significant increase in half-inhibitory concentration (IC50) value, resulting in 10.56-fold increase in resistance (p < 0.05). The median effective concentration (EC50) value of Cor for DDP reversal was 1.03 ± 0.15 μM, and it had a high selectivity index for normal cells (> 48.5). The results from flow cytometry showed that Cor significantly enhanced the apoptosisinducing capacity of DDP in T24/DDP-resistant cells (p < 0.05), while Western blot data indicate that PTEN protein expression increased and phosphorylated Akt protein expression decreased in T24/DDPresistantcells after Cor treatment when compared with control group (p < 0.05).Conclusion: Cordycepin significantly improves the sensitivity of T24/ DDP-resistant bladder cancer cells to cisplatin via a mechanism related to the activation of PTEN/AKt signaling pathway, thus indicating that it is a potential candidate reversing DDP-resistance in bladder cancer. Keywords: Bladder cancer, Cordycepin, Cisplatin resistance, PTEN/Akt signaling pathwa

Pharmacological isolation of postsynaptic currents mediated by NR2A- and NR2B-containing NMDA receptors in the anterior cingulate cortex

NMDA receptors (NMDARs) are involved in excitatory synaptic transmission and plasticity associated with a variety of brain functions, from memory formation to chronic pain. Subunit-selective antagonists for NMDARs provide powerful tools to dissect NMDAR functions in neuronal activities. Recently developed antagonist for NR2A-containing receptors, NVP-AAM007, triggered debates on its selectivity and involvement of the NMDAR subunits in bi-directional synaptic plasticity. Here, we re-examined the pharmacological properties of NMDARs in the anterior cingulate cortex (ACC) using NVP-AAM007 as well as ifenprodil, a selective antagonist for NR2B-containing NMDARs. By alternating sequence of drug application and examining different concentrations of NVP-AAM007, we found that the presence of NVP-AAM007 did not significantly affect the effect of ifenprodil on NMDAR-mediated EPSCs. These results suggest that NVP-AAM007 shows great preference for NR2A subunit and could be used as a selective antagonist for NR2A-containing NMDARs in the ACC

CD73 promotes proliferation and migration of human cervical cancer cells independent of its enzyme activity

100 ΟM Adenosine treatment did not change the expression of EGFR, VEGF and Akt. (JPG 335 kb

Age Differences of Salivary Alpha-Amylase Levels of Basal and Acute Responses to Citric Acid Stimulation Between Chinese Children and Adults

It remains unclear how salivary alpha-amylase (sAA) levels respond to mechanical stimuli in different age groups. In addition, the role played by the sAA gene (AMY1) copy number and protein expression (glycosylated and non-glycosylated) in sAA activity has also been rarely reported. In this study, we analyzed saliva samples collected before and after citric acid stimulation from 47 child and 47 adult Chinese subjects. We observed that adults had higher sAA activity and sAA glycosylated levels (glycosylated sAA amount/total sAA amount) in basal and stimulated saliva when compared with children, while no differences were found in total or glycosylated sAA amount between them. Interestingly, adults showed attenuated sAA activity levels increase over those of children after stimulation. Correlation analysis showed that total sAA amount, glycosylated sAA amount, and AMY1 copy number×total sAA amount were all positively correlated with sAA activity before and after stimulation in both groups. Interestingly, correlation r between sAA levels (glycosylated sAA amount and total sAA amount) and sAA activity decreased after stimulation in children, while adults showed an increase in correlation r. In addition, the correlation r between AMY1 copy number×total sAA amount and sAA activity was higher than that between AMY1 copy number, total sAA amount and sAA activity, respectively. Taken together, our results suggest that total sAA amount, glycosylated sAA amount, and the positive interaction between AMY1 copy number and total sAA amount are crucial in influencing sAA activity before and after stimulation in children and adults

Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex

Long-term potentiation (LTP) in the anterior cingulate cortex (ACC) is believed to be critical for higher brain functions including emotion, learning, memory and chronic pain. N-methyl-D-aspartate (NMDA) receptor-dependent LTP is well studied and is thought to be important for learning and memory in mammalian brains. As the downstream target of NMDA receptors, the extracellular signal-regulated kinase (ERK) in the mitogen-activated protein kinase (MAPK) cascade has been extensively studied for its involvement in synaptic plasticity, learning and memory in hippocampus. By contrast, the role of ERK in cingulate LTP has not been investigated. In this study, we examined whether LTP in ACC requires the activation of ERK. We found that P42/P44 MAPK inhibitors, PD98059 and U0126, suppressed the induction of cingulate LTP that was induced by presynaptic stimulation with postsynaptic depolarization (the pairing protocol). We also showed that cingulate LTP induced by two other different protocols was also blocked by PD98059. Moreover, we found that these two inhibitors had no effect on the maintenance of cingulate LTP. Inhibitors of c-Jun N-terminal kinase (JNK) and p38, other members of MAPK family, SP600125 and SB203850, suppressed the induction of cingulate LTP generated by the pairing protocol. Thus, our study suggests that the MAPK signaling pathway is involved in the induction of cingulate LTP and plays a critical role in physiological conditions

Effect of reaction atmosphere on catalytic CO oxidation over Cu-based bimetallic nanoclusters on a CeO2 support

Understanding the nature of active sites and the catalytic properties of oxide-supported bimetallic clusters under reaction conditions remains challenging. In this study, we combine first-principles calculations with genetic algorithm and grand canonical Monte Carlo methods to reveal the structures and compositions of CeO2-supported Cu-based bimetallic clusters in an oxygen-rich environment. Oxidized Cu4X4 (X = Pd, Pt, and Rh) bimetallic clusters on CeO2(111) are stable and exhibit different catalytic properties during CO oxidation compared with the pristine bimetallic clusters. Microkinetic simulations predict that CeO2(111)-supported Cu4Pd4O10, Cu4Pt4O11, and Cu4Rh4O14 clusters have much higher CO oxidation activity than the supported Cu4Pd4, Cu4Pt4, and Cu4Rh4 clusters; this is ascribed to the moderate CO adsorption strength and active oxygen on oxidized alloy clusters. A mechanistic study suggests that CO oxidation occurs via the O2 associative reaction mechanism on the Cu4Pd4O10 and Cu4Pt4O11 clusters, while it proceeds through the O2 dissociative reaction mechanism on the Cu4Rh4O14 cluster. Our calculations further predict that CO oxidation on the Cu4Rh4O14 cluster exhibits a low apparent activation energy, indicating that the oxidized cluster possesses excellent CO oxidation activity. This work demonstrates that the catalytic activity and reaction mechanism vary with the composition and oxidation state of the alloy nanocluster under the reaction conditions and emphasizes the influence of the reaction atmosphere on the reaction mechanisms and catalytic activity of oxide-supported alloy catalysts