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Various genotoxic agents cause monoubiquitination of NEMO/ IKK;-the regulatory subunit of IKB kinase (IKK) complexin the nucleus. Ubiquitinated NEMO exits from the nucleus and forms a complex with the IKK catalytic subunits IKKA and IKKB, resulting in IKK activation and, ultimately, nuclear factor-KB (NF-KB) activation. Thus, NEMO ubiquitination is a prerequisite for IKK-dependent activation of NF-KB. However, the IKK activation mechanism is unknown and the NEMOubiquitinating E3 enzyme has not been identified. We found that inhibitors of apoptosis protein (IAP) regulate genotoxic stress-induced NF-KB activation at different levels. XIAP mediates activation of the upstream IKK kinase, TAK1, and couples activated TAK1 to the IKK complex. This XIAPdependent event occurs in response to camptotechin or etoposide/VP16; however, XIAP is dispensable for activation of NF-KB by doxorubicin, which engages a MEK-ERK pathway to activate IKK. We also show that cIAP1 mediates NEMO ubiquitination and cIAP2 regulates an event downstream of NEMO ubiquitination. Our study highlights nonredundant cooperative contributions of IAPs to antiapoptotic NF-KB activation by genotoxic signals beyond their classic caspase inhibitory functions. [Cancer Res 2009;69(5):1782-91]

During the course of evolution, animals encountered the harmful effects of fungi, which are strong pathogens. Therefore, they have developed powerful mechanisms to protect themselves against these fungal invaders. β-Glucans are glucose polymers of a linear β(1,3)-glucan backbone with β(1,6)-linked side chains. The immunostimulatory and antitumor activities of β-glucans have been reported; however, their mechanisms have only begun to be elucidated. Fungal and particulate β-glucans, despite their large size, can be taken up by the M cells of Peyer's patches, and interact with macrophages or dendritic cells (DCs) and activate systemic immune responses to overcome the fungal infection. The sampled β-glucans function as pathogen-associated molecular patterns (PAMPs) and are recognized by pattern recognition receptors (PRRs) on innate immune cells. Dectin-1 receptor systems have been incorporated as the PRRs of β-glucans in the innate immune cells of higher animal systems, which function on the front line against fungal infection, and have been exploited in cancer treatments to enhance systemic immune function. Dectin-1 on macrophages and DCs performs dual functions: internalization of β-glucan-containing particles and transmittance of its signals into the nucleus. This review will depict in detail how the physicochemical nature of β-glucan contributes to its immunostimulating effect in hosts and the potential uses of β-glucan by elucidating the dectin-1 signal transduction pathway. The elucidation of β-glucan and its signaling pathway will undoubtedly open a new research area on its potential therapeutic applications, including as immunostimulants for antifungal and anti-cancer regimens.

The purpose of this study was to investigate the potential effectiveness of a surface-modified natural calcium carbonate, hen eggshell (ES) as a bone graft substitute. The surface characteristics, cell viability on, and osteoconductivity of, particulated ES with and without hydrothermal treatment in phosphate solutions were evaluated. Hydrothermal treatment partially converted ES to calcium-deficient hydroxyapatite (HA) with surface microstructure. MTT assay indicated higher osteoblast viability on surface-modified ES compared with a commercially available bone substitute, anorganic bovine bone (Bio-Oss, BO) (p < 0.001). Histological and histomorphometric analysis showed significantly greater new bone formation and mineralized bone-to-graft contact of surface-modified ES, especially with hydrothermally treated ES, compared with BO in 5-mm diameter calvarial defects in rats at 4 and 8 weeks of healing (p < 0.01). Complete bony bridging was more frequently found with hydrothermally treated ES. The results of this pilot study indicate the potential efficacy of surface-modified particulated hen eggshell as an osteoconductive bone substitute in a rat calvarial defect model.