Autophagy prevents autophagic cell death in Tetrahymena in response to oxidative stress

Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species（ROS） generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membranebound vacuoles characteristic of autophagy followed by autophagic cell death（referred to as cell death with autophagy） after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3-methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena.

Dynamic control of the terahertz rainbow trapping effect based on a silicon-filled graded grating

We theoretically propose a scheme to realize the dynamic control of the properties of the terahertz（THz） rainbow trapping effect（RTE） based on a silicon-filled graded grating（SFGG） in a relatively broad band via optical pumping.Through the theoretical analysis and finite-element method simulations, it is conceptually demonstrated that the band of the RTE can be dynamically tuned in a range of -0.06 THz. Furthermore, the SFGG can also be optically switched between a device for the RTE and a waveguide for releasing the trapped waves. The results obtained here may imply applications for the tunable THz plasmonic devices, such as on-chip optical buffers, broad band slow-light systems, and integrated optical filters.

Targeting apoptosis is the major battle field for killing cancers

Targeting apoptosis is one of the major strategies for cancer therapy. Essentially, most of the conventional cancer therapeutic drugs that are in the clinical use induce apoptosis and in part necrosis of malignant cells and therefore prevent cancer progression and metastasis. Although these cytotoxic anticancer drugs are important weapons for killing cancers, their toxic side effects limited their application. The molecularly targeted therapeutics that are based on the deeper understanding of the defects in the apoptotic signaling in cancers are emerging and have shown promising anticancer activity in selectively killing cancers but not normal cells. The examples of molecular targets that are under exploration for cancer therapy include the cell surface receptors such as TNFR family death receptors, the intrinsic Bcl-2 family members and some other intracellular molecules like p53, MDM2, IAP, and Smac. The advance in the high-throughput bio-technologies has greatly accelerated the progress of cancer drug discovery.

Discovery of novel inhibitors of anti-apoptotic Bcl-2 proteins derived from Bim BH3 domain

The BH3 mimetics targeting the interaction between the BH3-only proteins and their prosurvival Bcl-2family proteins have shown enormous potential as cancer therapeutics. Herein, seven analogues targeting anti-apoptotic Bcl-2 proteins derived from the Bim BH3 domain via sequence simplification and/or modification are described. The in vitro binding affinity on anti-apoptotic Bcl-2 proteins and cell killing activity were evaluated. The results showed that analogues could significantly bind to target proteins and exhibited anti-cancer effect against three cancer cell lines. Of particular interest were the analogue SM-5（KD= 9.48 nmol/L for Bcl-2） and SM-6（KD= 0.08 nmol/L for Bcl-xL）, which exhibited improved binding affinity compared with the lead Bim（KD= 16.90 nmol/L for Bcl-2 and 22.2 nmol/L for Bcl-xL, respectively）. These results indicated that the peptide sequence containing the four hydrophobic side chains occupying pockets within the BH3-recognition cleft of anti-apoptotic Bcl-2 proteins might be the minimum sequence required for the bioactivity and the active core region of Bim. Promising inhibitors of anti-apoptotic Bcl-2 proteins with high bioactivity might be designed based on the active core.