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S Shimuzu S Shiozawa K Shiozawa S Imura H Ishikawa K Hirohata T Fujita 《Virchows Archiv. B, Cell pathology including molecular pathology》1988,54(6):350-356
The ability of enzyme-dissociated synovial adherent cells (SAC) obtained from patients with active rheumatoid arthritis to restore the proliferation and differention of peripheral blood mononuclear non-adherent cells (NAC) into immunoglobulin-secreting cells (ISC) was investigated. Autologous combinations of cells were used in this study to eliminate allogeneic reactions. Peripheral blood NAC, prepared by glass adherence and leucine methylester treatment to remove monocytes, almost completely lost their capacity to proliferate and differentiate into ISC in response to pokeweed mitogen. The response of NAC was restored by adding 12.5% of 'fresh SAC', which was obtained by glass-adherence after an overnight culture of non-rosette forming, enzyme-dissociated rheumatoid synovial cells. Although the response was also restorable by adding more than 25% fresh SAC, this was less satisfactory than adding 12.5% SAC. 'Old SAC', obtained by glass-adherence after 7 days culture of enzyme-dissociated synovial cells, did not restore the response of NAC. Immunohistochemical studies showed that 55% of fresh SAC and 3% of old SAC expressed HLA-DR antigens. When 100 units/ml of interferon gamma was present, 25% of old SAC remained HLA-DR-positive and some of these cells retained a dendritic morphology after 7 days culture. The results indicate that rheumatoid synovia contain macrophage-like cells that can effectively support the ultimate differentiation of lymphocytes to ISC. 相似文献
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Human induced pluripotent stem cell (iPSC)-derived neurons have been proposed to be a highly valuable cellular model for studying the pathomechanisms of Alzheimer''s disease (AD). Studies employing patient-specific human iPSCs as models of familial and sporadic forms of AD described elevated levels of AD-related amyloid-β (Aβ). However, none of the present AD iPSC studies could recapitulate the synaptotoxic actions of Aβ, which are crucial early events in a cascade that eventually leads to vast brain degeneration. Here we established highly reproducible, human iPSC-derived cortical cultures as a cellular model to study the synaptotoxic effects of Aβ. We developed a highly efficient immunopurification procedure yielding immature neurons that express markers of deep layer cortical pyramidal neurons and GABAergic interneurons. Upon long-term cultivation, purified cells differentiated into mature neurons exhibiting the generation of action potentials and excitatory glutamatergic and inhibitory GABAergic synapses. Most interestingly, these iPSC-derived human neurons were strongly susceptible to the synaptotoxic actions of Aβ. Application of Aβ for 8 days led to a reduction in the overall FM4–64 and vGlut1 staining of vesicles in neurites, indicating a loss of vesicle clusters. A selective analysis of presynaptic vesicle clusters on dendrites did not reveal a significant change, thus suggesting that Aβ impaired axonal vesicle clusters. In addition, electrophysiological patch-clamp recordings of AMPA receptor-mediated miniature EPSCs revealed an Aβ-induced reduction in amplitudes, indicating an impairment of postsynaptic AMPA receptors. A loss of postsynaptic AMPA receptor clusters was confirmed by immunocytochemical stainings for GluA1. Incubation with Aβ for 8 days did not result in a significant loss of neurites or cell death. In summary, we describe a highly reproducible cellular AD model based on human iPSC-derived cortical neurons that enables the mechanistic analysis of Aβ-induced synaptic pathomechanisms and the development of novel therapeutic approaches.In Alzheimer''s disease (AD), synapse damage and synapse loss are thought to underlie cognitive deficits.1 Oligomers of the amyloid-β (Aβ) peptide appear to induce synaptic failure as an early event in the etiology of AD.2, 3, 4 However, despite its well-established synapse-impairing effects in rodent models,5, 6, 7 the synaptotoxic actions of Aβ most relevant for the human disease have not been identified in a human model system. Several studies have investigated the synaptotoxic effects of Aβ in cultured rodent neurons and in transgenic mouse models revealing a multitude of potential mechanisms affecting synapses. Postsynaptic Aβ actions result in the loss of functional (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type) glutamate receptors,8, 9, 10 involve long-term depression-like mechanisms,9, 11, 12 and lead to the degradation of the entire postsynapse (dendritic spines).9, 11, 13 In addition, several distinct presynaptic Aβ actions on the synaptic vesicle cycle have been described.10, 14 Furthermore, Aβ-induced impairments of axonal transport regulation and Aβ-induced axon degeneration have been found in rodent neurons.15, 16, 17 This puzzling diversity of Aβ-induced synapse-related defects raises the question whether all of them are involved in the early pathomechanisms of human AD.In addition to well-established animal systems, the modelling of human neurological disease pathologies by human induced pluripotent stem cell (hiPSC) technology18 has been proposed as an innovative approach.19, 20, 21 The in vitro differentiation of hiPSCs to excitable neurons has been reported using a variety of protocols.22, 23, 24 However, quantitative analysis of both functional glutamatergic and GABAergic synapses has been difficult to achieve.19, 25, 26 In addition to studying the functional properties of iPSC-derived human neurons from healthy individuals, the in vitro differentiation of patient-derived iPSCs has been used to model complex neurodevelopmental and neurodegenerative diseases.19, 27, 28 Recently, iPSCs derived from AD patients have been reported to exhibit increased secretion of Aβ upon in vitro neuronal differentiation; however, neither a loss of synapses nor an impairment of synapse function was detected.21, 29, 30, 31, 32, 33 Here we describe a hiPSC-based, carefully optimized in vitro differentiation protocol, including a novel immunopanning step, which enabled us to study the deleterious effects of application of Aβ on human cortical neurons and on human synapses. 相似文献
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Yash Agarwal Stefan Doebele Markus Windolf Thomas Shiozawa Boyko Gueorguiev Fabian M. Stuby 《Journal of biomechanics》2014
The dorsal component of the pelvic ring is considered to be the most essential element for the stability of the pelvic ring. None of the current biomechanical set-ups include the effect of shear stresses by alternating loads that the pelvic ring has to withstand during walking. We hypothesize that a biomechanical test set-up with two-leg alternate loading will lead to stress imitation at the pubic symphysis that are more similar to existing strains than other test set-ups, and would, therefore, be more adequate for biomechanical testing of fixation methods. 相似文献
58.
Shinichiro Izuta Masaaki Ueki Masaki Ueno Kahoru Nishina Shunichi Shiozawa Nobuhiro Maekawa 《Biotechnology letters》2012,34(12):2175-2182
The effect of T-5224, a selective inhibitor of c-Fos/activator protein (AP)-1, on lipopolysaccharide (LPS) induced liver injury was examined in mice. Administration of LPS (10?mg?kg?1, i.p.) markedly increased serum levels of tumor necrosis factor-alpha (TNFα), high mobility group box 1 (HMGB1), alanine aminotransferase/aspartate aminotransferase (ALT/AST), liver tissue levels of macrophage-inflammatory protein-1 alpha (MIP-1α) and monocyte chemoattractant protein-1 (MCP-1), as well as hepatic necrosis and inflammation, leading to 67?% lethality. Administration of T-5224 (300?mg?kg?1, p.o.) after intraperitoneal injection of LPS imparted appreciable protection against acute elevations in serum levels of TNFα, HMGB1, ALT/AST as well as in liver tissue levels of MIP-1α and MCP-1, and reduced the lethality (27?%). These data indicate that T-5224 ameliorates liver injury and improves survival through decreasing production of proinflammatory cytokines and chemokines in endotoxemic mice. 相似文献
59.
The relict dace (Relictus solitarius) is an endemic minnow restricted to isolated spring systems within Butte, Goshute, Ruby and Steptoe valleys in the eastern
Nevada portion of the Great Basin. It is the only native fish in these basins, but speckled dace (Rhinichthys osculus) have been introduced into some localities in Ruby Valley and, based on morphology, the two species are believed to have
hybridized in those areas. We used DNA sequence data from one mitochondrial gene (cytochrome b) and one nuclear intron (S7) to determine if putative relict dace populations in Ruby Valley share mtDNA haplotypes with
speckled dace, or show signs of hybridization. Results of our analyses show that 11 of 16 Ruby Valley populations sampled
contain only speckled dace, and one speckled dace population exhibited signs of limited introgressive hybridization. The remaining
five Ruby Valley populations that were sampled contain relict dace that remain genetically distinct from speckled dace. The
integrity of the Ruby Valley relict dace populations should be actively protected, particularly in the area surrounding Ruby
Lake where speckled dace have been widely introduced. 相似文献
60.
Shiozawa Y Havens AM Jung Y Ziegler AM Pedersen EA Wang J Wang J Lu G Roodman GD Loberg RD Pienta KJ Taichman RS 《Journal of cellular biochemistry》2008,105(2):370-380
One of the most life-threatening complications of prostate cancer is skeletal metastasis. In order to develop treatment for metastasis, it is important to understand its molecular mechanisms. Our work in this field has drawn parallels between hematopoietic stem cell and prostate cancer homing to the marrow. Our recent work demonstrated that annexin II expressed by osteoblasts and endothelial cells plays a critical role in niche selection. In this study, we demonstrate that annexin II and its receptor play a crucial role in establishing metastasis of prostate cancer. Prostate cancer cell lines migrate toward annexin II and the adhesion of prostate cancer to osteoblasts and endothelial cells was inhibited by annexin II. By blocking annexin II or its receptor in animal models, short-term and long-term localization of prostate cancers are limited. Annexin II may also facilitate the growth of prostate cancer in vitro and in vivo by the MAPK pathway. These data strongly suggest that annexin II and its receptor axis plays a central role in prostate cancer metastasis, and that prostate cancer utilize the hematopoietic stem cell homing mechanisms to gain access to the niche. 相似文献