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Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1 总被引:1,自引:0,他引:1 下载免费PDF全文
Dalle S Imamura T Rose DW Worrall DS Ugi S Hupfeld CJ Olefsky JM 《Molecular and cellular biology》2002,22(17):6272-6285
beta-Arrestin-1 mediates agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCRs) and is also essential for GPCR mitogenic signaling. In addition, insulin-like growth factor I receptor (IGF-IR) endocytosis is facilitated by beta-arrestin-1, and internalization is necessary for IGF-I-stimulated mitogen-activated protein (MAP) kinase activation. Here, we report that treatment of cells for 12 h with insulin (100 ng/ml) induces an approximately 50% decrease in cellular beta-arrestin-1 content due to ubiquitination of beta-arrestin-1 and proteosome-mediated degradation. This insulin-induced decrease in beta-arrestin-1 content was blocked by inhibition of phosphatidylinositol-3 kinase (PI-3 kinase) and MEK with wortmannin and PD98059, respectively. We also found a marked decrease in the association of beta-arrestin-1 with the IGF-IR and a 55% inhibition of IGF-I-stimulated MAP kinase phosphorylation. In insulin-treated, beta-arrestin-1-downregulated cells, there was complete inhibition of lysophosphatidic acid (LPA) or isoproterenol (ISO)-stimulated MAP kinase phosphorylation. This was associated with a decrease in beta-arrestin-1 association with the beta2-AR as well as a decrease in beta-arrestin-1-Src and Src-beta2-AR association. Ectopic expression of wild-type beta-arrestin-1 in insulin-treated cells in which endogenous beta-arrestin-1 had been downregulated rescued IGF-I- and LPA-stimulated MAP kinase phosphorylation. In conclusion, we found the following. (i) Chronic insulin treatment leads to enhanced beta-arrestin-1 degradation. (ii) This downregulation of endogenous beta-arrestin-1 is associated with decreased IGF-I-, LPA-, and ISO-mediated MAP kinase signaling, which can be rescued by ectopic expression of wild-type beta-arrestin-1. (iii) Finally, these results describe a novel mechanism for heterologous desensitization, whereby insulin treatment can impair GPCR signaling, and highlight the importance of beta-arrestin-1 as a target molecule for this desensitization mechanism. 相似文献
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Jean-Hugues Parmentier Pierre Kremers Luc Ferrari Anne-Marie Batt Jacques E. Gielen Gerard Siest 《Cell biology and toxicology》1993,9(3):307-313
Interleukin-1 is known to repress a number of hepatic drug-metabolizing enzymes in rats and humans. The effect of interleukin-1 on lauric acid 12-hydroxylase (CYP4A family) was studied in cultured fetal rat hepatocytes after clofibric acid induction. Dexamethasone was used as an agent promoting differentiation and long-term maintenance of active hepatocytes. Dexamethasone and clofibric acid in combination allowed maximal (13.5-fold) induction of CYP4A1. Lauric acid 12-hydroxylase activity was found to increase with time in culture. Interleukin-1 adversely affected P4504A clofibric acid-induced activity, totally eliminating the effect of induction at doses exceeding 5 ng/ml. This repression/inhibition was dose-dependent. The mechanism by which interleukin-1 prevents the development of cytochrome P4504A activity is unclear.Abbreviations CA
clofibric acid
- CM
culture medium
- d
day
- D
dexamethasone
- IL-1
interleukin-1
- LAH
lauric acid 12-hydroxylase
- PB
phenobarbital
- PPAR
phenobarbital
- PPAR
peroxisome proliferator activated receptor 相似文献
44.
Picherit C Dalle M Néliat G Lebecque P Davicco MJ Barlet JP Coxam V 《The Journal of steroid biochemistry and molecular biology》2000,75(2-3):201-208
The present study investigated the effect of genistein, daidzein and estradiol on in vitro rat uterine responsiveness to oxytocin (OT) and PGF(2)alpha or luprostiol (L). In a first experiment, animals were either sham-operated (SH; n=5), or ovariectomized (OVX; n=20) and orally treated for three months with either genistein (G; n=5; 10 microg/g BW/d) or daidzein (D; n=5; 10 microg/g BW/d) or 17 alpha-ethinylestradiol (E; n=5; 23 microg/kg BW/d) or untreated (OVX; n=5). At necropsy, the basal uterine tension was lower in OVX, G and D than in SH, the highest value being measured in E. Oxytocin (10(-12); 10(-11) M) or PGF(2)alpha (10(-12); 10(-9) M) induced an increase in SH, but not in OVX, E and G. In D, only the highest doses were efficient. In a second experiment, 20 intact animals were s.c. injected with either genistein (G; n=5; 10 microg/g BW) or daidzein (D; n=5; 10 microg/g BW) or estradiol benzoate (E; n=5; 23 microg/kg BW) or vehicle (C: controls; n=5), and killed 24 h later. In C and E, OT (10(-15) to 10(-10) M) or L (10(-12) to 10(-7) M) stimulated uterine contractile activity in a dose-dependent manner until a maximal level. On the opposite, in G and D, contractile agents (except the highest luprostiol doses) did not stimulate myometrium contractions. Moreover, radioligand binding assays showed that genistein or daidzein inhibited the specific binding of [(3)H] estradiol to the calf uterus estrogen receptor (ER). Therefore, it could be postulated that both genistein and daidzein might bind to the rat uterus ER, inducing either anti-estrogenic or very weak estrogenic effects (depending on the experimental conditions) on in vitro uterine responsiveness to OT and PGF(2)alpha or luprostiol. 相似文献
45.
Metal ions modulate the effect of doxorubicin on actin assembly 总被引:1,自引:0,他引:1
Doxorubicin (DXR) exhibits a significant activity in many human malignant neoplasms but, unfortunately, produces many undesirable cellular troubles which mainly lead to a severe dose-dependent cardiomyopathy. Many Authors had suggested that doxorubicin interacts with actin and affects the intracellular ion composition; following this reasoning, we studied the effect of doxorubicin on actin polymerization in vitro induced by different metal ions. In this paper we show that the negative action of doxorubicin on actin polymerization (inhibition of filament growth, reduction of polymer amount and polymer size at steady-state) is strongly ion-dependent. With this finding, we suggest that the direct action of antibiotic on actin assembly, in the presence of the drug-related changes in cytoplasmic electrolyte pattern, could become predominant in vivo. 相似文献
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47.
Jean-Hugues Dalle 《Comptes rendus biologies》2013,336(3):148-151
Hematopoietic stem cell transplantation (HSCT) is the one and only curative therapy available for patient with severe sickle cell disease (SCD). Until today, several hundreds of patients have undergone geno-identical HSCT. More than 200 patients were transplanted in France. The first indication was cerebral vasculopathy. Among both malignant and non-malignant diseases treated with HSCT, the success rate obtained in SCD patients appears as the best one. From the year 2000, more than 95% of transplanted patients survived the HSCT procedure and more than 90% are completely cured and experience a very satisfying health condition post-transplantation. However, the current standard procedure includes a myeloablative conditioning regimen for warranting engraftment. Such regime is linked to severe long-term side effects such as hypofertility. Due to the excellent obtained results, we have to think about a possible widening of indications, a decrease of conditioning intensity and toxicity, and about HSCT from alternative stem cell sources, such as mismatch family donor, unrelated volunteer donor or unrelated cord blood. 相似文献
48.
Marta Hlad Barbara Veselka Dawnie Wolfe Steadman Baptiste Herregods Marc Elskens Rica Annaert Mathieu Boudin Giacomo Capuzzo Sarah Dalle Guy De Mulder Charlotte Sabaux Kevin Salesse Amanda Sengeløv Elisavet Stamataki Martine Vercauteren Eugène Warmenbol Dries Tys Christophe Snoeck 《American journal of physical anthropology》2021,175(4):777-793
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