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111.
Abstract: Activated microglia, often associated with neuritic amyloid plaques in the Alzheimer's disease brain, are likely to contribute to the progression of the disease process, e.g., by releasing neurotoxic reactive oxygen and/or nitrogen intermediates. In the present study, whether the amyloid β peptide (Aβ), the principal constituent of amyloid plaques, can stimulate microglial respiratory burst activity and/or microglial production of nitric oxide was examined. Using neonatal rat microglial cultures as a model, it was found that neither the spontaneous release of nitric oxide nor the lipopolysaccharide-induced production of nitric oxide was altered in cultures previously incubated with synthetic Aβ(1–40). for 24 h. In addition, no direct stimulatory effect of Aβ(1–40) on the respiratory burst activity was observed. Nevertheless, concomitant with an increase in the number of responsive cells, a profound priming of the phorbol 12-myristate 13-acetate-evoked production of superoxide anion was observed in Aβ(1–40)-treated cultures. Thus, both the maximal rate and the total phorbol 12-myristate 13-acetate-induced production of superoxide appeared to be statistically significantly higher as compared with untreated cultures. It is concluded that, as far as activation of the microglial respiratory burst is concerned, Aβ(1–40) may merely act as a priming rather than a triggering stimulus. 相似文献
112.
† Ken-ichiro Fukuchi †Tauni Ohman Nocthao Dang Anetta C. Smith ‡Clement E. Furlong George M. Martin 《Journal of neurochemistry》1996,66(5):2201-2204
Abstract: P19 is a C3H mouse-derived line of multipotent embryonic carcinoma cells that differentiate into neural cells. P19 cell clones overexpressing the three major forms of β-amyloid precursor protein from their cDNA constructs were established. Unlike a previous study in which P19-derived neurons had a limited α-secretase activity, all of these clones produced significant amounts of secreted β-amyloid precursor protein. When treated with retinoic acid, these transformed lines differentiated into neurons and survived better than did nontransformed parental P19 cells. Furthermore, P19-derived neurons survived better in medium conditioned by the transformed P19 line, and survival was reduced by immunoabsorption with an antibody to β-amyloid precursor protein. These results suggest neurotrophic effects of secreted β-amyloid precursor protein and contrast with a previous report in which overexpression of a full-length cDNA for β-amyloid precursor protein led to degeneration of P19-derived neurons. Western blot analysis suggested that this difference might result from different levels of expression of putative neurotoxic C-terminal fragments of β-amyloid precursor protein; moreover, P19-derived neurons differ from P19 stem cells in the processing of these C-terminal fragments. 相似文献
113.
†Kelly J. Conn Michael Pietropaolo ‡Shyr-Te Ju † Carmela R. Abraham 《Journal of neurochemistry》1996,66(5):2011-2018
Abstract: Alzheimer's disease is characterized neuropathologically by the presence of neuritic and amyloid plaques, vascular amyloid, and neurofibrillary tangles in specific brain areas. The main constituent of amyloid deposits is amyloid β protein, a 40–42 amino acid proteolytic product of the amyloid β-precursor protein. In our search for proteases that can generate the N-terminus of amyloid β protein (β-secretases), we discovered a thiol-dependent metalloprotease that was identified, by peptide sequencing, as metalloendopeptidase EC 3.4.24.15. In vitro, the metalloprotease cleaves the methionine-aspartic acid bond in a 10 amino acid synthetic peptide, indicating that it could generate the N-terminus of amyloid β protein, and generates amyloidogenic fragments from full-length recombinant amyloid β-precursor protein. Mouse monoclonal antibodies produced against a unique synthetic peptide from the metalloprotease labeled various monkey tissues as detected by western blots and immunohistochemistry. Unexpectedly, two monoclonal antibodies, IVD6 and IIIF3, immunolabeled strongly intracellular neurofibrillary tangles, neurites of senile plaques, and neuropil threads, but not "ghost" tangles or amyloid in sections taken from Alzheimer's disease brain. This finding provides further evidence for the metalloprotease's relevance to Alzheimer's disease pathology, although the connection between tangle staining and the formation of amyloid β protein remains to be elucidated. 相似文献
114.
115.
Mary Jeanne Kreek 《Neurochemical research》1996,21(11):1469-1488
The early history of research on the possible existence of specific opioid receptors and on developing a new form of pharmacotherapy
for the treatment of heroin addiction in New York City, from 1960–1973, along with the special relationships between two leading
scientists conducting these research efforts, Dr. Eric Simon and Dr. Vincent P. Dole Jr., are presented in a historical perspective.
The linkage of these early efforts and the subsequent identification and the elucidation of the effects of exogenous opiates
acting at specific opiate receptors in human physiology, including some findings from perspective studies of heroin addicts
at time of entry to and during methadone maintenance treatment, are presented in the context of the important clues which
thereby were provided concerning the possible roles of the endogenous opioids in normal mammalian physiology. From many of
these early clinical research findings and studies in animal models, the hypothesis that the endogenous opioids system may
play an important role in stress responsivity was formulated along with the related hypothesis, first presented in the early
1970s, that an atypical responsivity to stress and stressors might be involved in the acquisition and persistence of, and
relapse to specific addictive diseases, including heroin addiction, cocaine dependency and alcoholism. More recent studies
of the possible involvement of the specific opioid receptors in these three addictive diseases—heroin addiction, cocaine addiction
and alcoholism—from our laboratory are discussed in a historical perspective of the development of these ideas from the early
research findings of not only Dr. Eric Simon, but his numerous colleagues in opioid research in the United States and throughout
the world.
Special issue dedicated to Dr. Eric J. Simon. 相似文献
116.
Cholinesterase activities in rat forebrain, erythrocytes, and plasma were assessed after a single oral administration of metrifonate
or dichlorvos. In 3-month-old rats, the dichlorvos (10 mg/kg p.o.)-induced inhibition of cholinesterase reached its peak in
brain after 15–45 min and after 10–30 min in erythrocytes and plasma. Cholinesterase activity recovered rapidly after the
peak of inhibition, but did not reach control values in brain and erythrocytes within 24 h after drug administration. The
recovery of plasma cholinesterase activity, in contrast, was already complete 12 h after dichlorvos treatment. Metrifonate
(100 mg/kg p.o.) had qualitatively similar inhibition kinetics as dichlorvos, albeit with a slightly delayed onset. Peak values
were attained 45–60 min (brain) and 20–45 min (blood), after drug administration. Apparently complete recovery of cholinesterase
activity was noted in both tissues 24 h after treatment. The dose-dependence of drug-induced inhibition of cholinesterase
in rat blood and brain was determined at the time of maximal inhibition, i.e., 30 min after dichlorvos treatment and 45 min
after metrifonate treatment. The oral ED50 values obtained for dichlorvos were 8 mg/kg for brain and 6 mg/kg for both erythrocyte and plasma cholinesterase. The corresponding
oral ED50 values for metrifonate were 10 to 15 times higher, i.e., 90 mg/kg in brain and 80 mg/kg in erythrocytes and plasma. In rats
deprived of food for 18 h before drug treatment, the corresponding ED50 values for metrifonate were 60 and 45 mg/kg, respectively, indicating an about two-fold higher sensitivity of fasted rats
to metrifonate-induced cholinesterase inhibition compared to non-fasted rats. Compared to 3-month-old rats, 19-month-old rats
showed a higher sensitivity towards metrifonate and dichlorvos. At the time of maximal inhibition, there was a strong correlation
between the degree of cholinesterase inhibition in brain and blood. These results demonstrate that single oral administration
of metrifonate and dichlorvos induces an inhibition of blood and brain cholinesterase in the conscious rat in a dose-dependent
and apparently fully reversible manner. While the efficiency of a given dose of inhibitor may vary with the satiety status
or age of the animal, the extent of brain ChE inhibition can be estimated from the level of blood ChE activity. 相似文献
117.
Human evolution began in East Africa four million years ago, with a transition from an arboreal state to a more terrestrial
one. This evolution seems to be correlated with a large environmental change in East Africa around 2.5 m.y. due to a major
climatic change leading to drier and cooler conditions.
Cenogram analysis (a graphical representation of community structure) can be used to reconstruct the vegetation cover at a
regional scale, and to infer the changing climatic conditions. Using cenogram sequences of different sites along the Rift
Valley, we were able to determine the regional ecological context in which mammals and hominids have evolved in East Africa
during the last 3 million years.
Between 3.5 and 2 m.y., during a general climatic change, successive faunas of South Tanzania reflect the progressive opening
of their environment. In contrast around Lake Turkana a mosaic of isolated dry and wet habitats were present throughout this
period. At this time, the Rift seems to have been spatially structured in several basins isolated from one other, and isolated
faunas experienced separate speciation events (particularly with the appearance ofHomo genus).
After 2 m.y., the disappearance of the isolating barriers on one hand, and a regional increase in aridity, on the other hand,
led to more homogenous faunas arising throughout the region. Replacements of mammal species occurred (especiallyHomo erectus replacingHomo habilis) and several others mammal species, including australopithecines, disappeared during this same period. 相似文献
118.
Twenty out of 33 Actinobacillus actinomycetemcomitans strains formed hemolytic colonies on horse blood agar plates under anaerobic conditions. The hemolytic activity found in A. actinomycetemcomitans strain 137HE was examined. This activity was detected in the late exponential to early stationary phases of growth. Human erythrocytes were the most susceptible, followed by rabbit, sheep, horse and swine red blood cells. The majority of activity was detected in the cell-associated vesicle fraction. Zwitterionic detergent 3-[(3-cholamidopropyl)-dimethyl-ammonio]-1-propanesulfonate (CHAPS) extract from whole cells was semipurified by ammonium sulfate precipitation, preparative isoelectric focusing (IEF) and gel-filtration chromatography to yield a major band on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) with a molecular mass of 12 kDa. Heating at 80 C for 30 min and treatment with proteinase K or trypsin resulted in complete disappearance of the hemolytic activity. Sulphydryl reagents enhanced activity and small amounts of cholesterol inhibited it. In summary, we demonstrated the presence of hemolysin in A. actinomycetemcomitans, and examined and characterized it. 相似文献
119.
Comparison of OspA Serotypes for Borrelia burgdorferi Sensu Lato from Japan,Europe and North America
Toshiyuki Masuzawa Bettina Wilske Tetsuro Komikado Hiroyuki Suzuki Hiroki Kawabata Nanao Sato Koichi Muramatsu Nobutake Sato Emiko Isogai Hiroshi Isogai Russell C. Johnson Yasutake Yanagihara 《Microbiology and immunology》1996,40(8):539-545
Sixty-one Borrelia burgdorferi sensu lato strains from various sources (ticks, human, and wild animals) in Japan and two strains from ticks in Far Eastern Russia were classified on the basis of reactivity with 16 monoclonal antibodies (mAb) to outer surface protein A (OspA) and by DNA-DNA hybridization assay. Eleven OspA serotypes (J1 to J11) were recognized among the Japanese and the Far East Russian isolates (serotypes J1 to J9 were identified as B. garinii, serotype J10 was identified as B. afzelii, and serotype J11 corresponded to B. japonica), whereas 7 OspA serotypes for North American and European isolates previously reported (Bettina Wilske et al, J. Clin. Microbiol. 31:340-350, 1993) were not observed except for OspA serotype 2 which showed identical reactivity with OspA serotype J10. This finding provides helpful information for understanding the geographical distribution of Lyme disease borrelia and the development of vaccine and diagnostic tests. In conclusion: 1. B. burgdorferi sensu stricto has not been observed in Japan, 2. Japanese B. afzelii isolates are closely related to those from Europe, 3. B. garinii isolates from Japan are highly heterogeneous and apparently different from European B. garinii isolates. 相似文献
120.
Treatment of Gaucher disease with an enzyme inhibitor 总被引:5,自引:0,他引:5
Norman S. Radin 《Glycoconjugate journal》1996,13(2):153-157
The hypothesis is offered predicting that Caucher patients could be treated with a drug that slows the synthesis of glucosylceramide, the lipid that accumulates in this disorder. The present therapeutic approach involves augmenting the defective enzyme, glucosylceramide -glucosidase, with exogenous -glucosidase isolated from human tissue. This spectacularly expensive mode of treatment should be replaceable with a suitable enzyme inhibitor that simply slows formation of the lipid and matches the rate of synthesis with the rate of the defective, slowly working -glucosidase. Several drugs that possess this ability are available, the best known of which is 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a designer inhibitor that resembles the synthase's substrate and product. PDMP has been found to be effective in mice, rats, fish, and a wide variety of cultured cells. Its use, at suitable dosages, seems to be harmless, although long-term tests have not been made. The lack of suitable animal models of Gaucher disease has made it difficult to test the hypothesis adequately, but PDMP does rapidly lower the levels of glucosylceramide in normal animal tissues and the animals evidently do well with the lowered levels of glucosylceramide and its more complex glycolipid metabolites.Abbreviations PDMP
1-phenyl-2-decanoylamino-3-morpholino-1-propanol
- GlcCer
glucosylceramide
- i.p.
intraperitoneal 相似文献