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The GABAA Receptor Complex as a Target for Fluoxetine Action 总被引:3,自引:0,他引:3
Tunnicliff G. Schindler N. L. Crites G. J. Goldenberg R. Yochum A. Malatynska E. 《Neurochemical research》1999,24(10):1271-1276
The clinically important antidepressant fluoxetine is established as a selective serotonin reuptake inhibitor. This study demonstrates that fluoxetine also interacts with the GABAA receptor complex. At concentrations above 10 M fluoxetine inhibited the binding of both [3H]GABA (IC50 = 2 mM) and [3H]flunitrazepam (IC50 = 132 M ) to the GABAA receptor complex in brain cortical membranes. Low fluoxetine concentrations (1 nM) enhanced GABA-stimulated Cl– uptake by a rat cerebral cortical vesicular preparation. At higher concentrations (100 M and 1 mM), however, fluoxetine inhibited GABA-stimulated Cl– uptake, an effect related to a reduction in Emax. These observations might assist in an explanation of the basis of the antidepressant action of fluoxetine. 相似文献
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In vivo CD4+ T cell tolerance induction versus priming is independent of the rate and number of cell divisions 总被引:6,自引:0,他引:6
Adler AJ Huang CT Yochum GS Marsh DW Pardoll DM 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(2):649-655
In vitro studies have suggested that tolerance induction (i.e., anergy) is associated with an inability of T cells to proliferate vigorously upon Ag recognition. In vivo, the relationship between T cell proliferation and tolerance induction is less clear. To clarify this issue, we have been studying a model system in which naive CD4+ T cells specific for the model Ag hemagluttinin (HA) are adoptively transferred into different transgenic founder lines of mice expressing HA as a peripheral self-Ag. When transferred into two lines whose HA expression differs by at least 1000-fold, HA-specific T cells undergo multiple rounds of cell division before reaching a nonresponsive (i.e., tolerant) state. While the proliferative response is more rapid in mice expressing higher levels of HA, the T cells become tolerant regardless of the level of peripheral HA expression. When the T cells encounter HA expressed as a viral Ag, they proliferate at a similar rate and undergo the same number of divisions as with self-HA, but they do not become tolerant. These results indicate that a tolerizing stimulus can induce similar T cell mitotic rates as a priming stimulus. Therefore, CD4+ T cell tolerance induction in vivo is not the result of an insufficient proliferative response elicited upon TCR engagement. 相似文献
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Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex rela tionship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts. 相似文献