Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell apoptosis-inducing factor that can induce apoptosis in a variety of cancer cells. However, resistance to TRAIL in cancer cells is a huge obstacle in creating effective TRAIL-targeted clinical therapies. Thus, agents that can either enhance the effect of TRAIL or overcome its resistance are needed. In this study, we combined TRAIL with SNX-2112, an Hsp90 inhibitor we previously developed, to explore the effect and mechanism that SNX-2112 enhanced TRAIL-induced apoptosis in cervical cancer cells. Our results showed that SNX-2112 markedly enhanced TRAIL-induced cytotoxicity in HeLa cells, and this combination was found to be synergistic. Additionally, we found that SNX-2112 sensitized TRAIL-mediated apoptosis caspase-dependently in TRAIL-resistant HeLa cells. Mechanismly, SNX-2112 downregulated antiapoptosis proteins, including Bcl-2, Bcl-XL, and FLIP, promoted the accumulation of reactive oxygen species (ROS), and increased the expression levels of p-JNK and p53. ROS scavenger NAC rescued SNX-2112/TRAIL-induced apoptosis and suppressed SNX-2112-induced p-JNK and p53. Moreover, SNX-2112 induced the upregulation of death-receptor DR5 in HeLa cells. The silencing of DR5 by siRNA significantly decreased cell apoptosis by the combined effect of SNX-2112 and TRAIL. In addition, SNX-2112 inhibited the Akt/mTOR signaling pathway and induced autophagy in HeLa cells. The blockage of autophagy by bafilomycin A1 or Atg7 siRNA abolished SNX-2112-induced upregulation of DR5. Meanwhile, ROS scavenger NAC, JNK inhibitor SP600125, and p53 inhibitor PFTα were used to verify that autophagy-mediated upregulation of DR5 was regulated by the SNX-2112-stimulated activation of the ROS-JNK-p53 signaling pathway. Thus, the combination of SNX-2112 and TRAIL may provide a novel strategy for the treatment of human cervical cancer by overcoming cellular mechanisms of apoptosis resistance.
This paper applies Pirson and Malhotra's (2011) framework for organizational trust to data reuse in an educational context. Their framework delineates stakeholders along two axes: depth of the interactions (e.g., shallow or deep) and the locus of the relationship (e.g., internal or external). We analyzed 139 survey responses and 44 in-depth interviews with users of repositories holding video records of practice. We found that factors such as data quality, co-production of data between the repository and data producer, responsiveness of staff, and transparency of curation processes influenced trust, and that responsiveness and transparency were of particular importance for trust development for users with deeper interactions and a more internal loci of relationships to repositories.
Tin anode has great potential for sodium-ion batteries owing to its high theoretical capacity, but its tremendous volume expansion during the sodium (de)alloying processes leads to the structural degradation and cycling instability. Herein, we report a new design strategy by using low-cost enzymatic hydrolysis lignin-derived hard carbon as an ideal support for Sn particles dispersion. Sn can be uniformly anchored on the robust carbon substrate, to efficiently relieve Sn volume expansion upon cycling. In addition, conductive hard carbon support can facilitate electrons to transfer and further enhance Na + storage capacity and accelerate facile Na + diffusion in the Sn/C hybrid anodes. The resultant Sn/C hybrids as anodes deliver high-rate performance as well as distinguished cycling stability in view of high reversible capacity of 374 mAh g À1 at 20 mA g À1 and capacity retention of 91% at 1000 mA g À1 after 1000 cycles, benefiting from high electrical conductivity, highly dispersed Sn particles and suitable pore structure. This work is expected to provide fresh insight into cost-effective Sn-based anodes for sodium ion batteries.
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