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171.
Varga A Flachner B Konarev P Gráczer E Szabó J Svergun D Závodszky P Vas M 《FEBS letters》2006,580(11):2698-2706
Closure of the two domains of 3-phosphoglycerate kinase, upon substrate binding, is essential for the enzyme function. The available crystal structures cannot provide sufficient information about the mechanism of substrate assisted domain closure and about the requirement of only one or both substrates, since lattice forces may hinder the large scale domain movements. In this study the known X-ray data, obtained for the open and closed conformations, were probed by solution small-angle X-ray scattering experiments. The results prove that binding of both substrates is essential for domain closure. Molecular graphical analysis, indeed, reveals formation of a double-sided H-bond network, which affects substantially the shape of the main molecular hinge at beta-strand L, under the concerted action of both substrates. 相似文献
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173.
Földi R Kovács R Gesztelyi R Kardos G Berényi R Juhász B Szilágyi J Mózes J Majoros L 《Mycopathologia》2012,174(4):311-318
Caspofungin activity was determined in vitro and in vivo against three Candida orthopsilosis, three C. metapsilosis, two C. parapsilosis sensu stricto and two C. albicans isolates. MIC values and killing activity were determined in RPMI-1640 plus 50?% human serum. Neutropenic (cyclophosphamide-treated) mice were infected intravenously. Five-day intraperitoneal treatment with caspofungin was started after 24?h postinfection. Kidney burden was analyzed using the Kruskal-Wallis test with Dunn's post-test. In killing studies, caspofungin was fungistatic and fungicidal against C. albicans at ≥0.25 and ≥2?μg/ml concentrations, respectively. Caspofungin was fungistatic at ≥8-16, ≥2-8 and at ≥2-8?μg/ml against C. parapsilosis, C. orthopsilosis and C. metapsilosis, respectively. In the murine model, C. albicans was inhibited by 1, 2 and 5 mg/kg of caspofungin (P?0.001 compared to the controls). Against C. parapsilosis, only 5?mg/kg caspofungin was effective against both isolates (P?0.05). Two and five mg/kg of caspofungin was effective against all C. orthopsilosis and C. metapsilosis isolates (P?0.05 to <0.001). Serum-based killing tests proved to be useful in predicting in vivo efficacy of caspofungin against four Candida species. Caspofungin at clinically attainable concentrations proved to be effective against all four species. 相似文献
174.
Li S Nagothu K Ranganathan G Ali SM Shank B Gokden N Ayyadevara S Megyesi J Olivecrona G Chugh SS Kersten S Portilla D 《American journal of physiology. Renal physiology》2012,303(3):F437-F448
Peroxisome proliferator-activated receptor-α (PPARα) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARα and CP on expression and enzyme activity of kidney lipoprotein lipase (LPL) as well as on expression of angiopoietin protein-like 4 (Angptl4), glycosylphosphatidylinositol-anchored-HDL-binding protein (GPIHBP1), and lipase maturation factor 1 (Lmf1), which are recognized as important proteins that modulate LPL activity. CP caused a 40% reduction in epididymal white adipose tissue (WAT) mass, with a reduction of LPL expression and activity. CP also reduced kidney LPL expression and activity. Angptl4 mRNA levels were increased by ninefold in liver and kidney tissue and by twofold in adipose tissue of CP-treated mice. Western blots of two-dimensional gel electrophoresis identified increased expression of a neutral pI Angptl4 protein in kidney tissue of CP-treated mice. Immunolocalization studies showed reduced staining of LPL and increased staining of Angptl4 primarily in proximal tubules of CP-treated mice. CP also increased TG accumulation in kidney tissue, which was ameliorated by PPARα ligand. In summary, a PPARα ligand ameliorates CP-mediated nephrotoxicity by increasing LPL activity via increased expression of GPHBP1 and Lmf1 and by reducing expression of Angptl4 protein in the proximal tubule. 相似文献
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177.
Exogenous and endogenous cannabinoids play an important role in modulating the release of neurotransmitters in hippocampal excitatory and inhibitory networks, thus having profound effect on higher cognitive and emotional functions such as learning and memory. In this study we have studied the effect of cannabinoid agonists on the potassium depolarization-evoked [(3)H]GABA release from hippocampal synaptosomes in the wild-type (WT) and cannabinoid 1 receptor (CB(1)R)-null mutant mice. All tested cannabinoid agonists (WIN55,212-2, CP55,940, HU-210, 2-arachidonoyl-glycerol, 2-AG; delta-9-tetra-hydrocannabinol, THC) inhibited [(3)H]GABA release in WT mice with the following rank order of agonist potency: HU-210>CP55,490>WIN55,212-2>2-AG>THC. By contrast, 2-AG and THC displayed the greatest efficacy eliciting almost complete inhibition of evoked [(3)H]GABA efflux, whereas the maximal inhibition obtained by HU-210, CP55,490, and WIN55,212-2 were less, eliciting not more than 40% inhibition. The inhibitory effect of WIN55,212-2, THC and 2-AG on evoked [(3)H]GABA efflux was antagonized by the CB(1) receptor inverse agonist AM251 (0.5 μM) in the WT mice. In the CB(1)R knockout mice the inhibitory effects of all three agonists were attenuated. In these mice, AM251 did not antagonize, but further reduced the [(3)H]GABA release in the presence of the synthetic agonist WIN55,212-2. By contrast, the concentration-dependent inhibitory effects of THC and 2-AG were partially antagonized by AM251 in the absence of CB(1) receptors. Finally, the inhibition of evoked [(3)H]GABA efflux by THC and 2-AG was also partially attenuated by AM630 (1 μM), the CB(2) receptor-selective antagonist, both in WT and CB(1) knockout mice. Our data prove the involvement of CB(1) receptors in the effect of exo- and endocannabinoids on GABA efflux from hippocampal nerve terminals. In addition, in the effect of the exocannabinoid THC and the endocannabinoid 2-AG, non-CB(1), probably CB(2)-like receptors are also involved. 相似文献
178.
Nyírő G Inczédy-Farkas G Reményi V Gál A Pál Z Molnár MJ 《Acta physiologica Hungarica》2012,99(1):33-39
Clopidogrel is an inhibitor of platelet-aggregation used in the prevention of secondary stroke. The molecule is activated by the cytochrome P450 2C19 (CYP2C19) enzyme. The frequent CYP2C19*2 point mutation causes loss of enzyme function, a decreased (heterozygous form) or blocked (homozygous form) formation of the active molecule. Thus, for a patient harboring a mutated allele, clopidogrel does not provide effective protection against stroke. Multiple drugs inhibit the CYP2C19 enzyme and their simultaneous use with clopidogrel is especially hazardous for patients with genetically decreased enzyme activity. Frequency of the CYP2C19*2 is variable in different populations, highest rates were detected in some Asian groups. In our study the CYP2C19 genotype was determined in one Hungarian sample of 354 stroke patients and 221 healthy controls. Frequency of the minor allele was found to be 12.87% (12.85% in stroke patients, 12.89% in healthy controls). The proportion of the homozygous CYP2C19*2 variant causing total loss of gene function was 1.74%, rate of the heterozygous allele causing reduced enzyme activity was 22.26% in the total population. Our results for the allele frequencies of the CYP2C19*2 gene are similar to those found in other Caucasian populations. In conclusion, the homozygous mutation, causing ineffectiveness of clopidogrel is relatively rare. However, the heterozygous form in which interaction of CYP2C19 inhibitors causes further decrease in the genetically impaired enzyme activity is present in every fifth drug-taking patient. Based on our findings, we would like to emphasize that it is important to adjust individually antiplatelet treatment in ischemic stroke patients and to take into consideration genetic factors as well as drugs taken for comorbid conditions. 相似文献
179.
Farkas Z Márki-Zay J Kucsera J Vágvölgyi C Golubev WI Pfeiffer I 《Acta biologica Hungarica》2012,63(2):277-287
Wickerhamomyces anomalus VKM Y-159 strain produces two types of toxin designated as WAKT a and WAKT b, encoded by chromosomal genes. The WAKT a toxin is heat-labile, pronase sensitive acting in pH range 3-4 affecting on several yeasts including pathogenic Candida species while the WAKT b toxin is protease- and thermo-resistant, acting in pH range 3-7 on two species, Candida alai and Candida norvegica. The rapid decrease of the number of viable cells after toxin treatment demonstrates that both toxins have cytocidic effect. 相似文献
180.
Horváth G Molnár P Radó-Turcsi E Deli J Kawase M Satoh K Tanaka T Tani S Sakagami H Gyémánt N Molnár J 《Acta biochimica Polonica》2012,59(1):129-132
The aim of the present study was to compare carotenoid extracts of Rose hips (Rosa canina L.) with regard to their phytochemical profiles and their in vitro anti-Helicobacter pylori (H. pylori), cytotoxic, multidrug resistance (MDR) reversal and radical scavenging activity. Carotenoid composition was investigated in the different fractionation of rose hips, using extraction methods. Six main carotenoids - epimers of neochrome, lutein, zeaxanthin, rubixanthin, lycopene, β,β-carotene - were identified from Rose hips by their chromatographic behavior and UV-visible spectra, which is in accordance with other studies on carotenoids in this plant material. The active principles in the carotenoid extract might differ, depending upon the extraction procedures. 相似文献