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51.
Contribution of redox-active iron and copper to oxidative damage in Alzheimer disease 总被引:1,自引:0,他引:1
Castellani RJ Honda K Zhu X Cash AD Nunomura A Perry G Smith MA 《Ageing research reviews》2004,3(3):319-326
Metal-catalyzed hydroxyl radicals are potent mediators of cellular injury, affecting every category of macromolecule, and are central to the oxidative injury hypothesis of Alzheimer disease (AD) pathogenesis. Studies on redox-competent copper and iron indicate that redox activity in AD resides exclusively within the neuronal cytosol and that chelation with deferoxamine, DTPA, or, more recently, iodochlorhydroxyquin, removes this activity. We have also found that while proteins that accumulate in AD possess metal-binding sites, metal-associated cellular redox activity is primarily dependent on metals associated with nucleic acid, specifically cytoplasmic RNA. These findings indicate aberrations in iron homeostasis that, we suspect, arise primarily from heme, since heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in AD, and mitochondria, since mitochondria turnover, mitochondrial DNA, and cytochrome C oxidative activity are all increased in AD. These findings, as well as studies demonstrating a reduction in microtubule density in AD neurons, suggest that mitochondrial dysfunction, acting in concert with cytoskeletal pathology, serves to increase redox-active heavy metals and initiates a cascade of abnormal events culminating in AD pathology. 相似文献
52.
Endo K 《Rinsho byori. The Japanese journal of clinical pathology》2004,52(9):759-766
The recent methodological advances in molecular biology, immunology, and genetics have clarified neuroimmunological problems in axonal Guillain-Barré syndrome, seronegative myasthenia gravis, paraneoplastic neurologic syndromes and many others. In addition to clinical and serological studies in peripheral neuropathies, the origins and measurement of anti-ganglioside antibodies and relationships to similar carbohydrate structures on infectious organisms are discussed in the context of molecular mimicry hypothesis, especially related with both the localization of relevant gangliosides in the nerve and clinical phenotypes. Major advances have been made in animal modeling of anti-ganglioside antibody-associated disease. An explanation for muscular weakness in 10-15% of patients with seronegative myasthenia gravis who lack autoantibodies to acetylcholine receptors(AchRs) appears to be the autoantibodies to muscle-specific receptor tyrosine kinase (MuSK). MuSK mediates agrin-induced clustering of AchRs during synapse formation. These autoantibodies to the extracellular domain of MuSK inhibit its function in tissue culture. Isoelectric focusing (IEF) and agar gel electrophoresis (AGE) are used to examine cerebrospinal fluid (CSF) and sera from patients with multiple sclerosis (MS). The CSF oligoclonal IgG bands (OB) are less frequently observed in Japanese MS patients compared with Caucasian patients. Few optic-spinal form of MS (OS-MS) was positive for OB by agarose gel electrophoresis, but IEF is more sensitive than AGE. Recent IEF data revealed some OS-MS patients were positive for OB. The neuroimmunological advances revealed the relationship between the neuroimmunological diseases and the putative autoantibodies as diagnostic markers, for example, HAM and hnRNP-A1, MSand anti-hnRNP-B1 antibody, opsoclonus-myoclonus syndrome and anti-GluRdelta2 antibody, Rasmussen encephalitis and anti-GluR3 antibody, paraneoplastic brainstem encephalitis and anti-Ma2 antibody, and so on. 相似文献
53.
Suzuki A Nozawa-Inoue K Ikeda N Amizuka N Ono K Takagi R Maeda T 《The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology》2005,286(2):908-916
Previous developmental studies on the temporomandibular joint (TMJ) have proposed several hypotheses on the formation of its articular cavity. However, detailed information is meager. The present study examined the formation process of the articular cavity in the rat TMJ by immunocytochemistry for CD31, RECA-1, and ED1, which are useful cellular markers for endothelial cells and monocyte/macrophage lineages, respectively. The upper articular cavity formation had begun by embryonic day 21 (E21) and was completed at postnatal day 1 (P1) in advance of the lower cavitation; the latter took place from P1 to P3. The occurrence and distribution pattern of the CD31-, RECA-1-, and ED1-positive cells differed between the upper and lower articular cavity-forming areas: the ED1-positive cells exclusively occurred in the area of the prospective upper articular cavity prior to its formation, while no ED1-positive cell appeared in the lower cavity-forming area. In contrast, the CD31- and RECA-1-positive endothelial cells were restricted to the lower cavity-forming area (never the prospective upper cavity) at E19 and diminished thereafter. Throughout the cavity formation, we failed to find any apoptotic cells in the cavity formation area, indicating no involvement of apoptosis in the cavity formation in TMJ. The present findings on the behaviors of endothelial cells and ED1-positive cells show a possibility of different mechanism in the cavity formation between the upper and lower articular cavities in the rat TMJ. The appearance of ED1-reactive cells and temporal vascularization may play crucial roles in the upper and lower articular cavity formation, respectively. 相似文献
54.
Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable,epigenetic gene silencing: a mammalian cell culture model of gene variegation 总被引:18,自引:2,他引:18
Ayyanathan K Lechner MS Bell P Maul GG Schultz DC Yamada Y Tanaka K Torigoe K Rauscher FJ 《Genes & development》2003,17(15):1855-1869
Heterochromatin protein 1 (HP1) is a key component of constitutive heterochromatin in Drosophila and is required for stable epigenetic gene silencing classically observed as position effect variegation. Less is known of the family of mammalian HP1 proteins, which may be euchromatic, targeted to expressed loci by repressor-corepressor complexes, and retained there by Lys 9-methylated histone H3 (H3-MeK9). To characterize the physical properties of euchromatic loci bound by HP1, we developed a strategy for regulated recruitment of HP1 to an expressed transgene in mammalian cells by using a synthetic, hormone-regulated KRAB repression domain. We show that its obligate corepressor, KAP1, can coordinate all the machinery required for stable gene silencing. In the presence of hormone, the transgene is rapidly silenced, spatially recruited to HP1-rich nuclear regions, assumes a compact chromatin structure, and is physically associated with KAP1, HP1, and the H3 Lys 9-specific methyltransferase, SETDB1, over a highly localized region centered around the promoter. Remarkably, silencing established by a short pulse of hormone is stably maintained for >50 population doublings in the absence of hormone in clonal-cell populations, and the silent transgenes in these clones show promoter hypermethylation. Thus, like variegation in Drosophila, recruitment of mammalian HP1 to a euchromatic promoter can establish a silenced state that is epigenetically heritable. 相似文献
55.
Ryoki Ishikawa Tsuyoshi Okagaki Kazuhiro Kohama 《Journal of muscle research and cell motility》1992,13(3):321-328
Summary From the plasmodia of a lower eukaryote,Physarum polycephalum, we have previously purified a 210-kDa protein that showed similar properties to those of smooth muscle caldesmon. Further characterization of the 210-kDa protein revealed that it bundled actin filaments. This bundling activity was inhibited by calmodulin in the presence of Ca2+. Unlike smooth muscle caldesmon, the 210-kDa protein bundled actin filaments whether or not a reducing agent, such as dithiothreitol, was present. The protein was shown to have two (or more) different actin-binding sites which were classified into salt-sensitive and salt-insensitive sites. Electron microscopy revealed that the 210-kDa protein was an elongated molecule (mean length, 97 ± 25 nm) which was bent in the middle. The Stokes radius and sedimentation coefficient of the 210-kDa protein were 130 Å and 2.9 S, respectively. An immunofluorescence study revealed that the 210-kDa protein colocalized with the bundles of actin filaments in thin-spread preparations ofPhysarum plasmodia, suggesting that the 210-kDa protein was regulating the appearance and disappearance of the actin bundles that are associated with the contraction-relaxation cycle of the plasmodia. 相似文献
56.
Expression cloning of gamma interferon-inducing antigens of Mycobacterium avium subsp. paratuberculosis
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Three recombinant proteins, Map10, Map39, and Map41, produced based on nucleotide sequences obtained from the screening of Mycobacterium avium subsp. paratuberculosis genomic library expressed in Escherichia coli significantly elicited gamma interferon production in peripheral blood mononuclear cells from infected cattle. Two of these proteins were members of the PPE protein family. 相似文献
57.
Masaharu Muranaka Shuji Suzuki Kazuhiro Koizumi Hiroshi Igarashi Hiroshi Okumura Koyo Takeda Kenji Tadokoro Yoshihiko Horiuchi 《The Journal of allergy and clinical immunology》1978,62(5):276-282
All of the five commercially available benzylpenicillin preparations obtained from different sources and a PcG preparation prepared by filtration of a commercial PcG on Sephadex G10 elicited the systemic anaphylactic reactions in guinea pigs which had been immunized with benzylpenicilloyl (BPO)-Ascaris extract conjugate (BPO-As) mixed with aluminum hydroxide gel. These preparations could evoke no such reactions in guinea pigs immunized with BPO-bovine gamma globulin conjugate (BPO-BGG) emulsified with complete Freund's adjuvant. The severity of the systemic anaphylactic reactions correlated significantly with the titers of either 8-day passive cutaneous anaphylactic (8-day PCA) reactions or 4-hr PCA reactions evoked with the same benzylpenicillin preparations. In vitro benzylpenicillin preparation contracted the tracheas of the guinea pigs immunized with BPO-As. These results indicated that the commercially available benzylpenicillin preparations have enough antigenicity to evoke systemic anaphylactic reactions in guinea pigs immunized with BPO-As mixed with aluminum hydroxide gel. Such guinea pigs represent an animal model for investigation of penicillin allergy. 相似文献
58.
Izawa I Nishizawa M Tomono Y Ohtakara K Takahashi T Inagaki M 《Genes to cells : devoted to molecular & cellular mechanisms》2002,7(5):475-485
BACKGROUND: ERBIN, an ErbB2 receptor-interacting protein, belongs to a recently described family of proteins termed the LAP [leucine-rich repeats and PSD-95/dLg-A/ZO-1 (PDZ) domains] family which has essential roles in establishment of cell polarity. RESULTS: To identify new ERBIN-binding proteins, we screened a yeast two-hybrid library, using the carboxyl-terminal fragment of ERBIN containing PDZ domain as the bait, and we isolated p0071 (also called plakophilin-4) as an ERBIN-interacting protein. p0071 is a member of the p120 catenin family, which are defined as proteins with 10 armadillo repeats, and localizes along the cell-cell border. The ERBIN PDZ domain binds the COOH-terminus of p0071 containing the PDZ domain-binding sequence. Endogenous ERBIN was co-immunoprecipitated with p0071. In fully polarized Madin-Darby canine kidney (MDCK) cells, ERBIN co-localized largely with beta-catenin and partly with desmoplakin along the lateral plasma membrane domain. At these cell-cell contact regions, ERBIN co-localizes with p0071. Over-expression of the dominant active forms of Cdc42, Rac1 or RhoA, Rho family small GTPases, resulted in a marked accumulation of ERBIN at the cell-cell contacts of MDCK and HeLa cells. CONCLUSION: These results show that ERBIN interacts in vivo with p0071 and that it may be involved in the organization of adherens junctions and the desmosomes of epithelia. In addition, we demonstrated that the subcellular localization of ERBIN might be regulated by Rho family small GTPases. 相似文献
59.
Kazuhiro Tsukamoto Ikuyo Watanabe Tadayoshi Shiba M. Emi 《Journal of human genetics》1998,43(4):287-288
We isolated a polymorphic dinucleotide (CA) repeat sequence from a genomic clone containing the human progesterone receptor
(PGR) gene. This polymorphism will be a useful marker in the genetic study of disorders affecting female endocrine systems,
such as progesterone resistance and breast, uterine, and ovarian cancers.
Received: July 27, 1998 / Accepted: July 29, 1998 相似文献
60.
Kouroku Y Fujita E Jimbo A Kikuchi T Yamagata T Momoi MY Kominami E Kuida K Sakamaki K Yonehara S Momoi T 《Human molecular genetics》2002,11(13):1505-1515
Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)72 repeats [poly(Q)(72)] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D(318) (anti-m12D318), and showed that poly(Q)(72) with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)(72) with dispersed aggregates and small nuclear aggregates showed a significantly less effect. Poly(Q)(72) and poly(Q)(11) dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)(72) aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8(-/-) and caspase-3(-/-) mouse embryonic fibroblasts expressing poly(Q)(72) aggregates. Thus, caspase-12 was activated by poly(Q)(72) aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion. 相似文献