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101.
In Vivo Reversal of Multidrug Resistance by Two New Dihydropyridine Derivatives, S16317 and S16324 总被引:3,自引:0,他引:3
Laurence Kraus-berthier Nicolas Guilbaud Jean-Louis Peglion Stephane Leonce Alain Lombet Alain Perre Ghanem Atassi 《Acta oncologica (Stockholm, Sweden)》1994,33(6):631-637
Two new dihydropyridine derivatives with low calcium channel affinity, S16317 and S16324, were found to fully overcome multidrug resistance in vitro. These two compounds increased doxorubicin cytotoxicity on the human COLO 320DM cell line and completely reversed the vincristine resistance of murine P388/VCR cells. In vivo, S16324 administered p.o. (200 mg/kg on days 1 to 4) or i.p. (50mg/kg on days 1, 5, 9) in combination with vincristine (i.p.) restored the antitumor activity of vincristine in P388/VCR-bearing mice. S16317 showed a reversing activity when administered p.o., i.v. (days 1 to 4) or i.p. (days 1, 5, 9) at the same dose (25 mg/kg), suggesting a remarkable bioavailability. Moreover, these two compounds potentiated the antitumor activity of vincristine in the sensitive P388 leukemia, increasing the number of long-term survivors. These results suggest that combination chemotherapy using S16317 or S16324 would be effective not only in circumventing multidrug resistance but also in preventing the emergency of a population of resistant tumor cells in sensitive tumors. 相似文献
102.
Lee SD Joseph M Lambert AS Mazer CD Hutchison SJ 《The Canadian journal of cardiology》2002,18(4):433-436
A 40-year-old man with Down syndrome presented with right heart failure. He was markedly obese and had severe developmental delay. There was marked edema and an early diastolic sound. Transthoracic echocardiography suggested a right heart mass. Transesophageal echocardiography revealed an unruptured balloon-like sinus of Valsalva aneurysm within the right atrium that obstructed the tricuspid orifice. The patient died in hospital of mixed obstructive and/or septic shock. 相似文献
103.
A noncognate aminoacyl-tRNA synthetase that may resolve a missing link in protein evolution
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Skouloubris S Ribas de Pouplana L De Reuse H Hendrickson TL 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(20):11297-11302
Efforts to delineate the advent of many enzymes essential to protein translation are often limited by the fact that the modern genetic code evolved before divergence of the tree of life. Glutaminyl-tRNA synthetase (GlnRS) is one noteworthy exception to the universality of the translation apparatus. In eukaryotes and some bacteria, this enzyme is essential for the biosynthesis of Gln-tRNAGln, an obligate intermediate in translation. GlnRS is absent, however, in archaea, and most bacteria, organelles, and chloroplasts. Phylogenetic analyses predict that GlnRS arose from glutamyl-tRNA synthetase (GluRS), via gene duplication with subsequent evolution of specificity. A pertinent question to ask is whether, in the advent of GlnRS, a transient GluRS-like intermediate could have been retained in an extant organism. Here, we report the discovery of an essential GluRS-like enzyme (GluRS2), which coexists with another GluRS (GluRS1) in Helicobacter pylori. We show that GluRS2's primary role is to generate Glu-tRNAGln, not Glu-tRNAGlu. Thus, GluRS2 appears to be a transient GluRS-like ancestor of GlnRS and can be defined as a GluGlnRS. 相似文献
104.
Moinard C Caldefie-Chezet F Walrand S Vasson MP Cynober L 《The British journal of nutrition》2002,88(6):689-695
Glutamine (GLN) and arginine (ARG) are recognized for their ability to modulate immune cell function. However, the metabolic pathways involved in their action remain unclear. It was recently shown that GLN- or ARG-enriched diets increased radical oxygen species (ROS) production by neutrophils from stressed rats. Since these two amino acids have a tied metabolism, we hypothesized that conversion between GLN and ARG (and its active metabolites NO* and polyamines) might be involved. To test this hypothesis male Sprague-Dawley rats (n 117) were randomized into thirteen groups: rats in eleven groups were rendered catabolic by dexamethasone injection (1.5 mg/kg per d for 5 d) and 6.8 mmol either GLN, ARG or non-essential amino acids (NEAA; glycine, alanine and histidine)/kg per d were given by the enteral route; one group was pair-fed to the treated groups. The regimens of all the groups were rendered isonitrogenous by the addition of NEAA. The last group was not treated and was fed ad libitum. For each supplementation three subgroups were formed, each of which received a specific inhibitor: methionine sulfoximine (inhibitor of GLN synthase; 100 mg/kg per d), S-methylthiourea (inhibitor of inducible NO* synthase (iNOS); 50 mg/kg per d) and difluoromethylornithine (inhibitor of ornithine decarboxylase (ODC); 50 mg/kg per d). Oxidative metabolism, intracellular H2O2, and extracellular O2*- production were measured in unstimulated and phorbol myristate acetate-stimulated polymorphonuclear neutrophils. GLN- and ARG-enriched diets increased respiratory burst by neutrophils (oxidative metabolism of 152 (sem 24) and 138 (sem 45) v. 57 (sem 18) mV for GLN-, ARG- and NEAA-enriched diets respectively, P<0.05). In vivo inhibition of iNOS or ODC decreased ROS production induced by GLN and ARG. In vivo inhibition of GLN synthase did not modify the effect of ARG on ROS production. In conclusion, GLN and ARG modulate ROS production in neutrophils from stressed rats by the same pathway involving polyamine and NO* synthesis. 相似文献
105.
Schneider SM Al-Jaouni R Pivot X Braulio VB Rampal P Hebuterne X 《Clinical nutrition (Edinburgh, Scotland)》2002,21(6):499-504
BACKGROUND & AIMS: Sarcopenia is a common feature in the healthy elderly. However, little is known on age-related modifications of body composition in malnourished patients. The aims of this cross-sectional study were to evaluate the effects of aging per se on body composition and resting energy expenditure (REE) in malnourished patients. METHODS: Ninety-seven non-stressed patients referred for chronic malnutrition (C-reactive protein <5 mg/l) were separated into two groups: middle-aged (26 female, 19 male, 48+/-15 yr), and elderly (26 female, 26 male, 79+/-6 yr). Body composition was assessed by bioelectrical impedance analysis and REE by indirect calorimetry. RESULTS: In middle-aged patients, body composition remained stable between moderate (body-mass index [BMI; in kg/m(2)] 16-18.5) and severe (BMI < 16) malnutrition, with similar values of fat-free mass (FFM), body cell mass (BCM) and fat mass (FM) as percentages of body weight, whereas in elderly patients malnutrition occurred at the expense of FFM and BCM, with unchanged FM absolute values. REE/FFM values remained stable in middle-aged patients at every stage of malnutrition, whereas they increased in elderly patients along with their degree of malnutrition. In multivariate analysis, both body composition and REE/FFM were influenced by sex, age, BMI and mid-arm circumference. CONCLUSION: Compared to younger patients, weight loss in the elderly leads to cachexia, with a preferential loss of FFM and BCM that may participate in the more severe outcomes observed in these patients. They also show elevated REE/FFM values that induce higher energy needs. 相似文献
106.
The multidrug transporter,P-glycoprotein,actively mediates cholesterol redistribution in the cell membrane 总被引:13,自引:0,他引:13
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Garrigues A Escargueil AE Orlowski S 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(16):10347-10352
P-glycoprotein (P-gp) is a plasma membrane ATP-binding cassette transporter, responsible for multidrug resistance in tumor cells. P-gp catalyzes the ATP hydrolysis-dependent efflux of numerous amphiphilic compounds of unrelated chemical structures. In the absence of any identified substrate, P-gp exhibits an apparently futile, basal ATPase activity. By using native membrane vesicles containing high amounts of P-gp, we show here that (i) this basal ATPase activity is tightly dependent on the presence of cholesterol in the membrane; (ii) the stimulation of P-gp ATPase activity by drugs transported by P-gp is higher in the absence than in the presence of cholesterol and, conversely, the stimulation of P-gp ATPase activity by cholesterol is higher in the absence than in the presence of known P-gp substrates; (iii) P-gp mediates the ATP-dependent relocation of cholesterol from the cytosolic leaflet to the exoplasmic leaflet of the plasma membrane; and (iv) the decrease of the cholesterol dependence of P-gp ATPase activity induced by known P-gp substrates is correlated with the inhibition of the ATP-dependent cholesterol redistribution within the membrane. These data are highly evocative of a coupling between the basal ATPase activity of P-gp and its intramembrane cholesterol-redistribution function, and they are fully consistent with the possibility that P-gp may actively translocate cholesterol in the membrane. Finally, this P-gp-mediated cholesterol redistribution in the cell membrane makes it likely that P-gp contributes in stabilizing the cholesterol-rich microdomains, rafts and caveolae, and that it is involved in the regulation of cholesterol trafficking in cells. 相似文献
107.
108.
Markus Zollinger Felix Waldmeier Stefan Hartmann Gerhard Zenke Alfred G Zimmerlin Ulrike Glaenzel Jean-Pierre Baldeck Alain Schweitzer Stephane Berthier Thomas Moenius Maximilian A Grassberger 《Drug metabolism and disposition》2006,34(5):765-774
The absorption and disposition of pimecrolimus, a calcineurin inhibitor developed for the treatment of inflammatory skin diseases, was investigated in four healthy volunteers after a single oral dose of 15 mg of [(3)H]pimecrolimus. Supplementary information was obtained from in vitro experiments. Pimecrolimus was rapidly absorbed. After t(max) (1-3 h), its blood concentrations fell quickly to 3% of C(max) at 24 h, followed by a slow terminal elimination phase (average t(1/2) 62 h). Radioactivity in blood decreased more slowly (8% of C(max) at 24 h). The tissue and blood cell distribution of pimecrolimus was high. The metabolism of pimecrolimus in vivo, which could be well reproduced in vitro (human liver microsomes), was highly complex and involved multiple oxidative O-demethylations and hydroxylations. In blood, pimecrolimus was the major radiolabeled component up to 24 h (49% of radioactivity area under the concentration-time curve(0-24) h), accompanied by a large number of minor metabolites. The average fecal excretion of radioactivity between 0 and 240 h amounted to 78% of dose and represented predominantly a complex mixture of metabolites. In urine, 0 to 240 h, only about 2.5% of the dose and no parent drug was excreted. Hence, pimecrolimus was eliminated almost exclusively by oxidative metabolism. The biotransformation of pimecrolimus was largely catalyzed by CYP3A4/5. Metabolite pools generated in vitro showed low activity in a calcineurin-dependent T-cell activation assay. Hence, metabolites do not seem to contribute significantly to the pharmacological activity of pimecrolimus. 相似文献
109.
We determined changes in functional feeding skills and growth after one year of intraoral appliance therapy in dysphagic children. Twenty children, 4.2-13.1 years of age (average 8.3 +/- 0.9 years), participated in this study. Children wore the appliance daily. Phase I of treatment (6 months) aimed primarily at stabilizing the mandible and phase II aimed at facilitating ingestive skills. A control period of 6 months preceded treatment. Functional feeding skills improved significantly during phase I beyond changes seen during the control period. Further significant improvement occurred in chewing during phase II. All children significantly gained weight (kg) during the control period, as well as during the two treatment phases. This weight gain was sufficient for children to maintain their growth trajectory. There was also significant growth in height (cm). This growth spurt was characterized by marginal catch-up. Jaw stabilization was a major contributor to the significant improvement in functional feeding skills. Weight gain cannot be attributed to intervention because it occurred during the control period and was the same in magnitude through both treatment phases. However, it permitted a period of growth in stature which previously had been described only after tube feeding. 相似文献
110.
The Peripheral Benzodiazepine Receptors: A Review 总被引:6,自引:0,他引:6
Beurdeley-Thomas A Miccoli L Oudard S Dutrillaux B Poupon MF 《Journal of neuro-oncology》2000,46(1):45-56
Peripheral benzodiazepine receptors (PBRs) have been identified in various peripheral tissues as well as in glial cells in the brain. This review describes the tissue and subcellular distribution of the PBR in mammalian tissues and analyzes its many putative endogenous ligands. It deals with the pharmacological, structural and molecular characterization of the PBR, the proteins associated with the receptor (VDAC, ANC, PRAX-1) and their roles in cell growth and differentiation, cancer, steroid biosynthesis, and other physiological roles. 相似文献