A JNK-Dependent Pathway Is Required for TNFα-Induced Apoptosis

AbstractTumor necrosis factor (TNFα) receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-κB and the kinase, JNK. While activation of caspase 8 is required for TNFα-induced apoptosis, and induction of NF-κB inhibits cell death, the precise function of JNK activation in TNFα signaling is not clearly understood. Here, we report that TNFα-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP1 complex. We propose that the JNK pathway described here is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. Further, our findings define a mechanism for crosstalk between intrinsic and extrinsic cell death pathways

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National Research Foundation (NRF) Singapore; AXA Research Fun

Role for PKC δ in Fenretinide-Mediated Apoptosis in Lymphoid Leukemia Cells

The synthetic Vitamin A analog fenretinide is a promising chemotherapeutic agent. In the current paper, the role of PKC δ was examined in fenretinide-induced apoptosis in lymphoid leukemia cells. Levels of proapoptotic cleaved PKC δ positively correlated with drug sensitivity. Fenretinide promoted reactive oxygen species (ROS) generation. The antioxidant Vitamin C prevented fenretinide-induced PKC δ cleavage and protected cells from fenretinide. Suppression of PKC δ expression by shRNA sensitized cells to fenretinide-induced apoptosis possibly by a mechanism involving ROS production. A previous study demonstrated that fenretinide promotes degradation of antiapoptotic MCL-1 in ALL cells via JNK. Now we have found that fenretinide-induced MCL-1 degradation may involve PKC δ as cleavage of the kinase correlated with loss of MCL-1 even in cells when JNK was not activated. These results suggest that PKC δ may play a complex role in fenretinide-induced apoptosis and may be targeted in antileukemia strategies that utilize fenretinide

Shock control of a low-sweep transonic laminar flow wing

This paper presents a combined experimental and computational study of a low-sweep transonic natural laminar flow (NLF) wing with shock-control bumps (SCBs). A transonic NLF wing with a relatively low sweep angle of 20 deg was chosen for this study. To avoid the complexity of the flow introduced by perforated/slotted walls commonly used for transonic wind-tunnel tests for reducing the wall interference, both experimental tests and computational simulations were conducted with solid wind-tunnel wall conditions. This allows for like-to-like validation of the computational simulation. Optimization of the shock-control bumps was first conducted to design the wind-tunnel test model with bumps. Two critical parameters of the three-dimensional SCBs for shock control (i.e., bump crest position and bump height) were optimized in terms of total drag reduction at the given design point in the wind tunnel. We show that the strong shock wave on the low-sweep NLF wing can be effective controlled by well-designed SCBs deployed along the wing span. The optimized SCBs result in 18.5% pressure drag reduction with 5% viscous drag penalty, and the SCBs also bring some benefits at off-design conditions. The wind-tunnel tests include pressure measurement, particle image velocimetry, and temperature-sensitive paint to provide detailed insight into the shock-control flowfield and to validate the computational simulations. Comparisons include surface pressure profile, velocity distribution, and transition location

Advances of the small molecule drugs regulating fibroblast-like synovial proliferation for rheumatoid arthritis

Rheumatoid arthritis (RA) is a type of chronic autoimmune and inflammatory disease. In the pathological process of RA, the alteration of fibroblast-like synoviocyte (FLS) and its related factors is the main influence in the clinic and fundamental research. In RA, FLS exhibits a uniquely aggressive phenotype, leading to synovial hyperplasia, destruction of the cartilage and bone, and a pro-inflammatory environment in the synovial tissue for perpetuation and progression. Evidently, it is a highly promising way to target the pathological function of FLS for new anti-RA drugs. Based on this, we summed up the pathological mechanism of RA-FLS and reviewed the recent progress of small molecule drugs, including the synthetic small molecule compounds and natural products targeting RA-FLS. In the end, there were some views for further action. Compared with MAPK and NF-κB signaling pathways, the JAK/STAT signaling pathway has great potential for research as targets. A small number of synthetic small molecule compounds have entered the clinic to treat RA and are often used in combination with other drugs. Meanwhile, most natural products are currently in the experimental stage, not the clinical trial stage, such as triptolide. There is an urgent need to unremittingly develop new agents for RA