Introduction: β-Amyloid protein (Aβ) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aβ, it is known that Aβ oligomers (AβOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AβOs have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which AβOs attach.Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which AβOs specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of AβOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AβOs was developed and used to block the toxicity of AβOs. The data were analyzed with one-way analysis of variance.Results: AβOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of Aβ inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aβ. α3-Na/K-ATPase protein and synaptic β-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by Aβ oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3.Conclusion: We identified three AβO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aβ oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

Six new dihydrochalcones, 3-hydroxyasebotin (5), asebogenin 2'-O-beta-D-ribohexo-3-ulopyranoside (6), 2' '-acetylasebotin (7), 3',4,5'-trihydroxy-4'-methoxydihydrochalcone 3',5'-di-O-beta-D-glucopyranoside (8), and pierotins A (9) and B (10), along with four known dihydrochalcones, phloretin (1), phlorizin (2), asebogenin (3), and asebotin (4), were isolated from the leaves of Pieris japonica. Their structures were elucidated on the basis of spectroscopic analysis including HMQC, HMBC, NOESY, and X-ray crystal diffraction. Compounds 1, 3-5, and 7-10 inhibited the proliferation of murine B cells and compounds 5 and 10 inhibited the proliferation of murine T cells in vitro significantly.

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Background and purpose:The C-C chemokine receptor CCR5, and the C-X-C chemokine receptor CXCR3 are involved in the regulation of T cell-mediated immune responses, and in the migration and activation of these cells. To determine whether blockade of these chemokine receptors modulated inflammatory responses in the central nervous sytem (CNS), we investigated the effect of a non-peptide chemokine receptor antagonist, TAK-779, in mice with experimental autoimmune encephalomyelitis (EAE). Experimental approach: EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) 35-55. TAK-779 was injected s.c. once a day after immunization. Disease incidence and severity (over 3 weeks) were monitored by histopathological evaluation and FACS assay of inflammatory cells infiltrating into the spinal cord, polymerase chain reaction quantification of mRNA expression, assay of T cell proliferation, by [

Bicyclic titanacycles 2 generated with the Cp 2 TiCl 2 -Mg-P(OEt) 3 system can be trapped with bis-(trichloromethyl) carbonate (BTC) to give bicyclic cyclopentenones 3 in good yields. The titanacycle 2m was isolated and well-identified. Bicyclization of enynes containing 1,2-disubstituted olefin by this method gave good results with excellent stereoselectivity.a Method A: CO, M ) Ti, Zr. Method B: R3SiCN, then HOAc or CuSO4, M ) Ti.

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Three new polyoxygenated steroids, muricesteroid (1), and menellsteroids A (2) and B (3), were isolated from two species of the South China Sea gorgonian Muricella flexuosa and Menella verrucosa BRUNDIN, respectively. The structures of these new compounds were elucidated on the basis of extensive spectroscopic analysis, chemical methods and comparison with known related compounds. Introduction. -Gorgonians of the genera Muricella and Menella (both of them belong to the family Paramuriceidae, order Gorgonacea, class Anthozoa) is prolific in the South China Sea. A literature survey revealed that the chemical constituents of the gorgonians of the genus Muricella have been intensively investigated. A variety of secondary metabolites with different C-skeletons such as eunicellane diterpenoids [1 -3], 9,11-secosteroids [4] [5], and a carotenoid [6] were reported from various species of this genus, and some of them exhibited potent cytotoxic activities against several tumor cell lines [2] [3] [5], and toxic effects to brine-shrimp as well [2 -6]. In contrast, chemical studies on the genus Menella were relatively rare. In particular, no chemical study has been done on the Hainan gorgonian Menella verrucosa BRUNDIN, except for our recent work [7c] reporting five new uncommon guaiane lactones from the species. Recently, in the course of our systematic studies on the chemical constituents of the South China Sea gorgonians [7], we have made a collection of Muricella flexuosa off Sanya, Hainan Province, China. Chemical investigation of the Et 2 Menella verrucosa, allowed to isolate two new polyhydroxylated steroids, named menellsteroids A (2) and B (3), respectively. Herein, we describe the isolation and structural elucidation of these new metabolites. Results and Discussion. -Both gorgonians were collected off the coast of Xiaodong Hai, Hainan Province, China, in December 2001, at a depth of 20 m. The animals were immediately put at À 208 and kept frozen until extraction. Frozen materials of Muricella

BackgroundThe pathogenesis of traumatic TMJ ankylosis remains unclear. This study aimed to verify the role of the lateral pterygoid muscle in the pathogenesis of traumatic temporomandibular joint (TMJ) bony ankylosis.MethodsEight 6-month-old male sheep were used in this study. Bilateral TMJ osteotomies were performed to induce sagittal fractures of the mandibular condyle. The lateral one-fourth segment of the disc was removed to establish a model of TMJ bony ankylosis. Subsequently, the function of the left and right lateral pterygoid muscles was blocked (experimental group) or maintained (control group), respectively. At 12 weeks postoperatively, animals were sacrificed and TMJ complex samples were evaluated by gross observation, spiral computed tomography (CT), micro-CT, and histological examinations.ResultsGross observation revealed bony ankylosis in the control TMJs and fibrous adhesions in the experimental TMJs. Spiral CT and micro-CT demonstrated that, compared to the experimental group, the control group showed calcified callus formation in the joint space and roughened articular surfaces after new bone formation, which protruded into the joint space. Maximum mediolateral and anteroposterior condylar diameters were significantly larger in the control group than in the experimental group. Micro-CT also showed that the primary growth orientation of new trabeculae was consistent with the direction of lateral pterygoid traction in the control group, but not in the experimental group. Histological examination showed fibro-osseous ankylosis in the control group, but not in the experimental group.ConclusionsThe lateral pterygoid simulates the effects of distraction osteogenesis, which is an important factor in the pathogenesis of TMJ bony ankylosis during the healing of sagittal condylar fractures.