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321.
322.
Murias M Handler N Erker T Pleban K Ecker G Saiko P Szekeres T Jäger W 《Bioorganic & medicinal chemistry》2004,12(21):5571-5578
Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is found in grapes and various medical plants. Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The most potent resveratrol compounds were 3,3',4',5-tetra-trans-hydroxystilbene (COX-1: IC(50)=4.713, COX-2: IC(50)=0.0113 microM, selectivity index=417.08) and 3,3',4,4',5,5'-hexa-hydroxy-trans-stilbene (COX-1: IC(50)=0.748, COX-2: IC(50)=0.00104 microM, selectivity index=719.23). Their selectivity index was in part higher than celecoxib, a selective COX-2 inhibitor already established on the market (COX-1: IC(50)=19.026, COX-2: IC(50)=0.03482 microM, selectivity index=546.41). Effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure-activity relationship (QSAR) analysis and a high correlation was found with the topological surface area TPSA (r=0.93). Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes. Hydroxylated resveratrol analogues therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies. 相似文献
323.
The bioavailability of lipophilic substrates is critical for biotransformations with isolated enzymes as well as with whole cells. With the example of a series of lipophilic ketones the suitability of saccharides as potent solubilisers for highly lipophilic substrates was demonstrated. Best results were obtained for d-glucose, which increased substrate solubility up to 50 times. In whole-cell biocatalysis the sugar acts both as solubiliser and as carbon source for which reason this procedure does not impair cell physiology and is unique in being environmentally benign. The capability of saccharides to solubilise lipophilic compounds in aqueous media sources from their ability to form hydrophilic and lipophilic domains at hydrophobic interfaces, thus forming cyclodextrin-like structures around the lipophilic substrate. 相似文献
324.
Beta-1,3 glucan sulfate, but not beta-1,3 glucan, induces the salicylic acid signaling pathway in tobacco and Arabidopsis 下载免费PDF全文
Ménard R Alban S de Ruffray P Jamois F Franz G Fritig B Yvin JC Kauffmann S 《The Plant cell》2004,16(11):3020-3032
Sulfate substituents naturally occurring in biomolecules, such as oligosaccharides and polysaccharides, can play a critical role in major physiological functions in plants and animals. We show that laminarin, a beta-1,3 glucan with elicitor activity in tobacco (Nicotiana tabacum), becomes, after chemical sulfation, an inducer of the salicylic acid (SA) signaling pathway in tobacco and Arabidopsis thaliana. In tobacco cell suspensions, the oxidative burst induced by the laminarin sulfate PS3 was Ca2+ dependent but partially kinase independent, whereas laminarin triggered a strickly kinase-dependent oxidative burst. Cells treated with PS3 or laminarin remained fully responsive to a second application of laminarin or PS3, respectively, suggesting two distinct perception systems. In tobacco leaves, PS3, but not laminarin, caused electrolyte leakage and triggered scopoletin and SA accumulation. Expression of different families of Pathogenesis-Related (PR) proteins was analyzed in wild-type and mutant tobacco as well as in Arabidopsis. Laminarin induced expression of ethylene-dependent PR proteins, whereas PS3 triggered expression of ethylene- and SA-dependent PR proteins. In Arabidopsis, PS3-induced PR1 expression was also NPR1 (for nonexpressor of PR genes1) dependent. Structure-activity analysis revealed that (1) a minimum chain length is essential for biological activity of unsulfated as well as sulfated laminarin, (2) the sulfate residues are essential and cannot be replaced by other anionic groups, and (3) moderately sulfated beta-1,3 glucans are active. In tobacco, PS3 and curdlan sulfate induced immunity against Tobacco mosaic virus infection, whereas laminarin induced only a weak resistance. The results open new routes to work out new molecules suitable for crop protection. 相似文献
325.
Intermolecular recombination events were monitored in Arabidopsis thaliana lines using specially designed recombination traps consisting of tandem disrupted beta-glucuronidase or luciferase reporter genes in direct repeat orientation. Recombination frequencies (RFs) varied between the different lines, indicating possible position effects influencing intermolecular recombination processes. The RFs between sister chromatids and between homologous chromosomes were measured in plants either hemizygous or homozygous for a transgene locus. The RFs in homozygous plants exceeded those of hemizygous plants by a factor of >2, implying that in somatic plant cells both sister chromatid recombination and recombination between homologous chromosomes exist for recombinational DNA repair. In addition, different DNA-damaging agents stimulated recombination in homozygous and hemizygous plants to different extents in a manner dependent on the type of DNA damage and on the genomic region. The genetic and molecular analysis of recombination events showed that most of the somatic recombination events result from gene conversion, although a pop-out event has also been characterized. 相似文献
326.
Polarized membrane traffic and cell polarity development is dependent on dihydroceramide synthase-regulated sphinganine turnover 下载免费PDF全文
Van IJzendoorn SC Van Der Wouden JM Liebisch G Schmitz G Hoekstra D 《Molecular biology of the cell》2004,15(9):4115-4124
Sphingoid bases have been implicated in various cellular processes including cell growth, apoptosis and cell differentiation. Here, we show that the regulated turnover of sphingoid bases is crucial for cell polarity development, i.e., the biogenesis of apical plasma membrane domains, in well-differentiated hepatic cells. Thus, inhibition of dihydroceramide synthase or sphinganine kinase activity with fumonisin B1 or N,N-dimethylsphingosine, respectively, dramatically perturbs cell polarity development, which is due to increased levels of sphinganine. Consistently, reduction of free sphinganine levels stimulates cell polarity development. Moreover, dihydroceramide synthase, the predominant enzyme responsible for sphinganine turnover, is a target for cell polarity stimulating cAMP/protein kinase A (PKA) signaling cascades. Indeed, electrospray ionization tandem mass spectrometry analyses revealed a significant reduction in sphinganine levels in cAMP/PKA-stimulated cells. These data suggest that sphinganine turnover is critical for and is actively regulated during HepG2 cell polarity development. Previously, we have identified an apical plasma membrane-directed trafficking pathway from the subapical compartment. This transport pathway, which is part of the basolateral-to-apical transcytotic itinerary, plays a crucial role in apical plasma membrane biogenesis. Here, we show that, as a part of the underlying mechanism, the inhibition of dihydroceramide synthase activity and ensuing increased sphinganine levels specifically perturb the activation of this particular pathway in the de novo apical membrane biogenesis. 相似文献
327.
328.
Sorrentino D Faller G DeVita S Avellini C Labombarda A Ferraccioli G Kahlow-Toussaint S 《Helicobacter》2004,9(1):46-53
Background. Previous studies have shown that Helicobacter pylori seroprevalence in Sjögren's syndrome is comparable with that of the general population. However, the origin of the chronic gastropathy associated with this syndrome and the role of local autoimmunity – possibly triggered by bacterial infection – in its pathogenesis remain unclear. Materials and Methods. We initially determined the prevalence of IgG anti H. pylori in dyspeptic subjects with and without Sjögren's syndrome. In subsets of both groups we then determined anti CagA and human tissue‐tested anticanalicular/antifoveolar autoantibodies. We also compared activity, atrophy and Mucosa Associated Lymphoid Tissue (MALT) scores, as well as symptoms, before and after bacterial eradication. Results. Prevalence of H. pylori in Sjögren's syndrome patients was similar to controls: 31/54 (57%) vs. 93/150 (62%). Anti CagA prevalence was also similar in the two groups. Twenty weeks after H. pylori eradication, histological activity decreased in both groups, however, atrophy and MALT decreased significantly only in controls. Sixteen months after H. pylori eradication, 75% of Sjögren's syndrome patients still complained of dyspepsia compared with 13% of controls. Finally, antigastric autoantibodies were present in 29% of tested Sjögren's syndrome patients vs. 28% of controls. Conclusions. H. pylori infection was equally prevalent among dyspeptic Sjögren's syndrome patients and dyspeptic controls. Likewise, there were no differences regarding anti CagA prevalence or antigastric autoantibodies among the two groups. The persistence of symptoms as well as of the lymphocytic infiltration and atrophy after H. pylori eradication in Sjögren's syndrome may underlie the ‘endogenous’ and still unknown nature of the gastropathy in this condition. 相似文献
329.
Dorner GT Garhofer G Kiss B Polska E Polak K Riva CE Schmetterer L 《American journal of physiology. Heart and circulatory physiology》2003,285(2):H631-H636
The purpose of the present study was to investigate the contribution of basal nitric oxide (NO) on retinal vascular tone in humans. In addition, we set out to elucidate the role of NO in flicker-induced retinal vasodilation in humans. Twelve healthy young subjects were studied in a three-way crossover design. Subjects received an intravenous infusion of either placebo or NG-monomethyl-L-arginine (L-NMMA; 3 or 6 mg/kg over 5 min), an inhibitor of NO synthase. Thereafter, diffuse luminance flicker was consecutively performed for 16, 32, and 64 s at a frequency of 8 Hz. The effect of L-NMMA on retinal arterial and venous diameter was assessed under resting conditions and during the hyperemic flicker response. Retinal vessel diameter was measured with a Zeiss retinal vessel analyzer. L-NMMA significantly reduced arterial diameter (3 mg/kg: -2%; 6 mg/kg: -4%, P < 0.001) and venous diameter (3 mg/kg: -5%; 6 mg/kg: -8%, P < 0.001). After placebo infusion, flicker induced a significant increase in retinal vessel diameter (P < 0.001). At a flicker duration of 64 s, arterial diameter increased by 4% and venous diameter increased by 3%. L-NMMA did not abolish these hyperemic responses but blunted venous vasodilation (P = 0.017) and arterial vasodilation (P = 0.02) in response to flicker stimulation. Our data indicate that NO contributes to basal retinal vascular tone in humans. In addition, NO appears to play a role in flicker-induced vasodilation of the human retinal vasculature. 相似文献
330.
Büttelmann B Alanine A Bourson A Gill R Heitz MP Mutel V Pinard E Trube G Wyler R 《Bioorganic & medicinal chemistry letters》2003,13(10):1759-1762
A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo. 相似文献