Bone-resorbing osteoclasts are of hemopoietic cell origin, probably of the CFU-M-derived monocytemacrophage family (1). Osteoclasts are large multinucleated giant cells that express tartrate-resistant acid phosphatase (TRAP) activity and calcitonin receptors and have the ability to form resorption pits on dentine slices (2-4). In the process of osteoclast differentiation, there is an absolute requirement for cell-cell contact between osteoclast progenitors and bone marrow stromal cells or calvaria-derived osteoblasts (5-8).We developed a mouse coculture system of hemopoietic cells and primary osteoblasts to investigate osteoclast formation in vitro. In this coculture system, several systemic and local factors were capable of inducing osteoclast-like multinucleated cell (OCL) formation (6-9). These boneresorbing factors were classified into 3 categories according to their signal transduction pathways: (a) 1α,25-dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] induced OCL formation via 1α,25(OH) 2 D 3 receptors (VDR) present in the nuclei; (b) parathyroid hormone (PTH), PTH-related protein (PTHrP), prostaglandin E 2 (PGE 2 ), and IL-1 induced OCL formation via the A kinase system; and (c) IL-11, oncostatin M, leukemia inhibitory factor, and IL-6 in the presence of soluble IL-6 receptors, all of which transduce their signals through a signal-transducing gp130 protein, also induced OCL formation in vitro. We reported previously that the target cells of IL-6 are osteoblasts/stromal cells but that they are not osteoclast precursors in inducing osteoclast differentiation (10). Similarly, coculture experiments using VDR knockout mice and PTH/PTHrP receptor knockout mice have indicated that the signals mediated by 1α,25(OH) 2 D 3 and PTH, respectively, are also transduced into osteoblasts/stromal cells, but not into osteoclast precursors, to induce osteoclast formation (11,12). Thus, it is concluded that the signals induced by all bone-resorbing factors are transduced into osteo-blasts/stromal cells to induce osteoclast formation. Our hypothesis proposes that osteoblasts/stromal cells express a critical common mediator named osteoclast differentiation factor (ODF), a membrane-bound factor that promotes differentiation of osteoclast progenitors into osteoclasts in response to various bone-resorbing factors through a mechanism involving cell-cell contact (6, 8). IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 incre...

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Spinal cord injury after stented elephant trunk deployment might be related to occlusion of the excessive intercostal arteries or thromboembolism. Patients with a history of abdominal aortic aneurysm repair who require extensive deployment of the stented elephant trunk seem to be at a higher risk for spinal cord injury.

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Increasing evidence suggests that the elevation of ␤-amyloid (A␤) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signalregulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates A␤-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble A␤ 1-40 and A␤ 1-42 in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-A␤ antibody, it was evidently shown that the administration of nobiletin decreased the A␤ burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.

Docosahexaenoic acid (DHA, C22:6, x-3) is a highly polyunsaturated omega-3 fatty acid. It is concentrated in neuronal brain membranes, for which reason it is also referred to as a ''brain food''. DHA is essential for brain development and function. It plays an important role in improving antioxidant and cognitive activities of the brain. DHA deficiency occurs during aging and dementia, impairs memory and learning, and promotes age-related neurodegenerative diseases, including Alzheimer's disease (AD). For about two decades, we have reported that oral administration of DHA increases spatial memory acquisition, stimulates neurogenesis, and protects against and reverses memory impairment in amyloid b peptide-infused AD rat models by decreasing amyloidogenesis and protects against age-related cognitive decline in the elderly. These results demonstrate a robust link between DHA and cognitive health. Rodents that were fed a diet low in x-3 polyunsaturated fatty acids, particularly those that were DHA-deficient, frequently suffered from anxiety, depression and memory impairment. Although the exact mechanisms of action of DHA in brain functions are still elusive, a host of mechanisms have been proposed. For example, DHA, which inherently has a characteristic three-dimensional structure, increases membrane fluidity, strengthens antioxidant activity and enhances the expression of several proteins that act as substrates for improving memory functions. It reduces the brain amyloid burden and inhibits in vitro fibrillation and amyloid-induced neurotoxicity in cell-culture model. In this review, we discuss how DHA acts as a molecule with diverse functions. ARTICLE HISTORY

Ubiquitin ligases define the substrate specificity of protein ubiquitination and subsequent proteosomal degradation. The catalytic sequence was first characterized in the C terminus of E6-associated protein (E6AP) and referred to as the HECT (homologous to E6AP C terminus) domain. The human homologue of the regulator of cell proliferation hyperplastic discs in Drosophila, designated hHYD, is a HECT-domain ubiquitin ligase. Here we show that hHYD provides a ubiquitin system for a cellular response to DNA damage. A yeast twohybrid screen showed that DNA topoisomerase II␤-binding protein 1 (TopBP1) interacted with hHYD. Endogenous hHYD bound the BRCA1 C-terminus domains of TopBP1 that are highlighted in DNA damage checkpoint proteins and cell cycle regulators. Using an in vitro reconstitution, specific E2 (ubiquitin-conjugating) enzymes (human UbcH4, UbcH5B, and UbcH5C) transferred ubiquitin molecules to hHYD, leading to the ubiquitination of TopBP1. TopBP1 was usually ubiquitinated and degraded by the proteosome, whereas X-irradiation diminished the ubiquitination of TopBP1 probably via the phosphorylation, resulting in the stable colocalization of up-regulated TopBP1 with ␥-H2AX nuclear foci in DNA breaks. These results demonstrated that hHYD coordinated TopBP1 in the DNA damage response.The ubiquitin-proteosome proteolytic system is involved in a variety of fundamental cell regulations including gene expression, stress response, DNA repair, and cell cycles (1-6). Ubiquitination includes a cascade of three classes of enzymes, the ubiquitin-activating enzyme E1, 1 the ubiquitin-conjugating enzyme Ubc or E2, and the ubiquitin ligase E3. After activation of a ubiquitin by E1, E2 and E3 cooperate to catalyze the formation of a multiubiquitin chain on a protein substrate. The E3 enzymes or the protein complexes with a ligase activity are believed to target the substrate for selective ubiquitination and a subsequent turnover by a large protease complex, the 26 S proteosome. There are two distinct groups of human ubiquitin ligases, the HECT domain E3 enzymes, including E6-associated protein (E6AP) and NEDD4, and the RING finger E3 enzymes, including SCF (Skp1-cullin-F box), VBC (VHL-Elongin B-Elongin C), APC (anaphase-promoting complex) and other single RING finger proteins such as c-Cbl and MDM2 (7). The HECT sequence of ϳ200 amino acids is highly conserved in the C-terminal catalytic domain of family members from yeast to mammals. The HECT-domain protein forms a thiol ester bond with a ubiquitin at the active cysteine residue and transfers the ubiquitin directly to the substrate (8 -10), whereas RING finger proteins form complexes containing an E2 enzyme, which facilitate ubiquitination of the substrate. However, the overall mechanisms by which these ubiquitin ligases recognize the target proteins remain to be elucidated.In the present study, we focused on characterizing the human HECT-domain protein, a counterpart of the regulator of cell proliferation and the putative tumor suppressor hyperplastic discs in Drosophil...