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Tamoxifen inhibits nitrotyrosine formation after reversible middle cerebral artery occlusion in the rat 总被引:9,自引:0,他引:9
Osuka K Feustel PJ Mongin AA Tranmer BI Kimelberg HK 《Journal of neurochemistry》2001,76(6):1842-1850
Tamoxifen (TAM), a widely used non-steroidal anti-estrogen, has recently been shown to be neuroprotective in a rat model of reversible middle cerebral artery occlusion (rMCAo). Tamoxifen has several potential mechanisms of action including inhibition of the release of excitatory amino acids (EAA) and nitric oxide synthase (NOS) activity. The question addressed in this study was whether TAM reduces ischemia-induced production of nitrotyrosine, considered as a footprint of the product of nitric oxide and superoxide, peroxynitrite. In rat brain, 2 h rMCAo produced a time-dependent increase in nitrotyrosine content in the cerebral cortex, as measured by Western blot analysis. Compared with vehicle, TAM significantly reduced nitrotyrosine levels in the ischemic cortex at 24 h. The neuronal (n)NOS inhibitor, 7-nitroindazole also tended to reduce nitrotyrosine, but this reduction was not statistically significant. Immunostaining for nitrotyrosine was seen in cortical neurons in the MCA territory and this immunostaining was reduced by TAM. In vitro, TAM and the calmodulin inhibitor trifluoperazine inhibited, with similar EC(50) values, the activity of recombinant nNOS as well as NOS activity in brain homogenates, measured by conversion of [(3)H]arginine to [(3)H]citrulline. There was marginal inhibition of recombinant inducible (i)NOS activity up to 100 microM TAM. These data suggest that TAM is an effective inhibitor of Ca(2+)/calmodulin-dependent NOS and the derived peroxynitrite production in transient focal cerebral ischemia and this may be one mechanism for its neuroprotective effect following rMCAo. 相似文献
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Ishiguro M Puryear CB Bisson E Saundry CM Nathan DJ Russell SR Tranmer BI Wellman GC 《American journal of physiology. Heart and circulatory physiology》2002,283(6):H2217-H2225
Cerebral artery vasospasm is a major cause of death and disability in patients experiencing subarachnoid hemorrhage (SAH). Currently, little is known regarding the impact of SAH on small diameter (100-200 microm) cerebral arteries, which play an important role in the autoregulation of cerebral blood flow. With the use of a rabbit SAH model and in vitro video microscopy, cerebral artery diameter was measured in response to elevations in intravascular pressure. Cerebral arteries from SAH animals constricted more (approximately twofold) to pressure within the physiological range of 60-100 mmHg compared with control or sham-operated animals. Pressure-induced constriction (myogenic tone) was also enhanced in arteries from control animals organ cultured in the presence of oxyhemoglobin, an effect independent of the vascular endothelium or nitric oxide synthesis. Finally, arteries from both control and SAH animals dilated as intravascular pressure was elevated above 140 mmHg. This study provides evidence for a role of oxyhemoglobin in impaired autoregulation (i.e., enhanced myogenic tone) in small diameter cerebral arteries during SAH. Furthermore, therapeutic strategies that improve clinical outcome in SAH patients (e.g., supraphysiological intravascular pressure) are effective in dilating small diameter cerebral arteries isolated from SAH animals. 相似文献
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Stuart A Suttie Alan GK Li Martha Quinn Kenneth GM Park 《World journal of surgical oncology》2007,5(1):1-9
Background
Caveolin-1 is thought to have an important impact on both signal transduction and mediation of intracellular processes. Furthermore, it has been suggested that Caveolin-1 may contribute to certain steps of carcinogenesis in various types of cancer. We examined the potential clinical relevance of Caveolin-1 in normal, benign and malignant breast tissue specimens.Methods
Using tissue microarray (TMA) technology cases of invasive breast cancer, DCIS, benign breast disease (i.e. fibroadenoma, sclerosing adenosis, ductal hyperplasia and radial scar) and normal breast tissue were evaluated for Caveolin-1 expression. Immunohistochemical staining with an anti-Caveolin-1-antibody was performed. Staining intensity was quantified semiquantitatively. In invasive lesions staining results were correlated with clinical and pathological data.Results
No Caveolin-1 expression was observed in epithelial cells of normal breast tissue (n = 5), benign breast disease (n = 295) and DCIS (n = 108). However, Caveolin-1 expression was found in 32 of 109 cases of invasive breast carcinomas (29.4%). Caveolin-1 expression in invasive breast cancer could neither be correlated with survival parameters such as overall or disease-free survival nor with established clinical and pathological markers.Conclusion
In this study we demonstrated expression of Caveolin-1 in one third of invasive breast cancers. A significant increase in Caveolin-1 expression was observed comparing invasive breast cancer to both benign breast tissue and non-invasive breast cancer. Since inhibitors of Caveolin-1 signalling are available, targeting Caveolin-1 in breast cancer may represent a potential option for future breast cancer treatment. 相似文献16.
NaCl-preferring NZB/B1NJ mice and NaCl-avoiding CBA/J mice have similar amiloride inhibition of chorda tympani responses to NaCl 总被引:1,自引:1,他引:0
Integrated chorda tympani nerve responses to NaCl were studied in two mouse
strains, an NaCl-preferring NZB/B1NJ and an NaCl-avoiding CBA/J. The NaCl
responses of both strains had similar magnitude and were suppressed by
amiloride to a similar extent. This suggests that peripheral gustatory
responsiveness to NaCl is not the only mechanism underlying mouse strain
variation in NaCl acceptance.
相似文献
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Guay D Beaulieu C Belley M Crane SN DeLuca J Gareau Y Hamel M Henault M Hyjazie H Kargman S Chan CC Xu L Gordon R Li L Mamane Y Morin N Mancini J Thérien M Tranmer G Truong VL Wang Z Black WC 《Bioorganic & medicinal chemistry letters》2011,21(10):2832-2835
A weak antagonist of the pyrimidinergic receptor P2Y14 containing a dihydropyridopyrimidine core was identified through high-throughput screening. Subsequent optimization led to potent, non-UTP competitive antagonists and represent the first reported non-nucleotide antagonists of this receptor. Compound 18q was identified as a 10 nM P2Y14 antagonist with good oral bioavailability and provided sufficient exposure in mice to be used as a tool for future in vivo studies. 相似文献
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Lachance N Gareau Y Guiral S Huang Z Isabel E Leclerc JP Léger S Martins E Nadeau C Oballa RM Ouellet SG Powell DA Ramtohul YK Tranmer GK Trinh T Wang H Zhang L 《Bioorganic & medicinal chemistry letters》2012,22(2):980-984
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model. 相似文献
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The secondary intracellular target of human neutrophil peptide-1 has been examined in M. tuberculosis H37Ra. Binding studies with radioiodinated HNP-1 revealed biphasic equilibrium binding kinetics with respect to time. The major
site of HNP-1 binding was found to be plasma membrane/cell wall whereas the cytosol appears to be a secondary site. Among
the different macromolecules examined, maximum inhibition (75%) was observed in DNA biosynthesis during treatment with HNP-1.
The interaction of HNP-1 with mycobacterial genomic DNA on the basis of gel retardation assay revealed HNP-1 binding to DNA.
These results indicate that HNP-1 has DNA as the secondary intracellular target for antibacterial action against mycobacteria.
Received: 25 October 2000/Accepted: 10 January 2001 相似文献
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To evaluate breastfed infants' responses to scented objects, we videotaped
the facial and bodily reactions of sixty-three infants as they explored, in
succession, three toys that were identical in appearance but different in
their characteristic odor. Two of the toys were scented with odorants
previously shown to be transmitted to human milk, one with ethanol and the
other with vanilla, whereas the third toy was unscented. Each videotape was
subjected to frame-by-frame analysis to measure a variety of behaviors that
are considered either to be exploratory in nature in that they lead to
perceptual information about the object or to reflect the infants' hedonic
reaction. Analyses of these behaviors revealed that the infants looked more
and vocalized less in the presence of the vanilla-scented toy and spent
less time manipulating the ethanol-scented toy when compared with the
unscented toy. Moreover, differential exposure to the odors of ethanol and
vanilla, as indicated by differential consumption of alcohol by a parent or
use of vanilla-scented product by the mother, was related to differential
responses to these odors. These findings suggest that human infants are
able to detect and retain information about the chemical features of their
environment.
相似文献