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排序方式: 共有107条查询结果,搜索用时 15 毫秒
21.
Uluçkan O Eagleton MC Floyd DH Morgan EA Hirbe AC Kramer M Dowland N Prior JL Piwnica-Worms D Jeong SS Chen R Weilbaecher K 《Journal of cellular biochemistry》2008,104(4):1311-1323
Platelets contribute to the development of metastasis, the most common cause of mortality in cancer patients, but the precise role that anti-platelet drugs play in cancer treatment is not defined. Metastatic tumor cells can produce platelet alphaIIb beta3 activators, such as ADP and thromboxane A(2) (TXA(2)). Inhibitors of platelet beta3 integrins decrease bone metastases in mice but are associated with significant bleeding. We examined the role of a novel soluble apyrase/ADPase, APT102, and an inhibitor of TXA(2) synthesis, acetylsalicylic acid (aspirin or ASA), in mouse models of experimental bone metastases. We found that treatment with ASA and APT102 in combination (ASA + APT102), but not either drug alone, significantly decreased breast cancer and melanoma bone metastases in mice with fewer bleeding complications than observed with alphaIIb beta3 inhibition. ASA + APT102 diminished tumor cell induced platelet aggregation but did not directly alter tumor cell viability. Notably, APT102 + ASA treatment did not affect initial tumor cell distribution and similar results were observed in beta3-/- mice. These results show that treatment with ASA + APT102 decreases bone metastases without significant bleeding complications. Anti-platelet drugs such as ASA + APT102 could be valuable experimental tools for studying the role of platelet activation in metastasis as well as a therapeutic option for the prevention of bone metastases. 相似文献
22.
Biosynthesis of 5,15-dihydroxyeicosatetraenoic acid (5,15-diHETE) in leukocytes involves consecutive oxygenation of arachidonic acid by 5-lipoxygenase (LOX) and 15-LOX in either order. Here, we analyzed the contribution of cyclooxygenase (COX)-2 to the biosynthesis of 5,15-diHETE and 5,11-diHETE in isolated human leukocytes activated with lipopolysaccharide and calcium ionophore A23187. Transformation of arachidonic acid was initiated by 5-LOX providing 5S-HETE as a substrate for COX-2 forming 5S,15S-diHETE, 5S,15R-diHETE, and 5S,11R-diHETE as shown by LC/MS and chiral phase HPLC analyses. The levels of 5,15-diHETE were 0.45 ± 0.2 ng/106 cells (mean ± SEM, n = 6), reaching about half the level of LTB4 (1.3 ± 0.5 ng/106 cells, n = 6). The COX-2 specific inhibitor NS-398 reduced the levels of 5,15-diHETE to below 0.02 ng/106 cells in four of six samples. Similar reduction was achieved by MK-886, an inhibitor of 5-LOX activating protein but the above differences were not statistically significant. Aspirin treatment of the activated cells allowed formation of 5,15-diHETE (0.1 ± 0.05 ng/106 cells, n = 6) but, as expected, abolished formation of 5,11-diHETE. The mixture of activated cells also produced 5S,12S-diHETE with the unusual 6E,8Z,10E double bond configuration, implicating biosynthesis by 5-LOX and 12-LOX activity rather than by hydrolysis of the leukotriene A4-epoxide. Exogenous octadeuterated 5S-HETE and 15S-HETE were converted to 5,15-diHETE, implicating that multiple oxygenation pathways of arachidonic acid occur in activated leukocytes. The contribution of COX-2 to the biosynthesis of dihydroxylated derivatives of arachidonic acid provides evidence for functional coupling with 5-LOX in activated human leukocytes. 相似文献
23.
阿司匹林,又称乙酰水杨酸,已证实有抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡和抑制血管生成等多种抗癌功能.除已知对环氧合酶COX-2的活性有抑制外,阿司匹林抗癌分子机制尚不十分清楚.已报道阿司匹林可以降低多种癌症发生风险,但应用于人类睾丸肿瘤治疗的研究报道很少.本文研究了阿司匹林对人恶性睾丸肿瘤NTera-2细胞凋亡的机制.通过MTT方法检测细胞活力,发现阿司匹林以时间和剂量依赖方式抑制NTera-2细胞增殖.不同浓度阿司匹林处理NTera-2细胞后,采用Hoechest 33258染色方法和Annexin V-FITC/PI流式法分别检测NTera-2细胞的形态学变化、凋亡小体形成、细胞凋亡水平;RT-PCR结果显示,NTera-2细胞中Fas和caspase-8的表达以阿司匹林剂量依赖性上升;蛋白印迹结果显示,FasL的蛋白表达水平下降并活化caspase-8、caspase-3蛋白表达,PARP出现剪切体. 进一步的实验证明,caspase广谱抑制剂Z-VAD-FMK能够减弱阿司匹林诱导NTera-2细胞凋亡. 结果显示,阿司匹林能明显抑制NTera-2细胞活力,并通过激活caspase 通路诱导NTera-2细胞的凋亡,为进一步利用阿司匹林治疗人类睾丸肿瘤的研究奠定基础. 相似文献
24.
AbstractCyclooxygenases are encoded by COX-1 and COX-2. They share over sixty percent sequence identity in human and are similar to each other in their crystallographic structures. One major difference in the primary structure of these two isozymes is the presence of eight amino acids in the amino-terminal region of COX-1 that are not present in COX-2. The function of this amino acid sequence is unknown. In this study, a human COX-1 mutant (Δ7aa) with this sequence removed was studied in parallel with COX-1. Signal peptide cleavage, N-linked glycosylation, protein expression, distribution and dimerization were not affected by the mutation. The mutant was enzymati-cally active and showed the same sensitivity toward aspirin. The KM for the enzyme remained the same as COX-1. However, the Vmax of the COX-1 mutant decreased by 3.3-fold. We conclude that the COX-1 specific amino-terminal sequence has a subtle but detectable effect on COX-1 catalysis. 相似文献
25.
26.
Crisanti P Laplace O Lecain E Jonet L Jeanny JC Omri B 《Apoptosis : an international journal on programmed cell death》2006,11(6):983-991
Intravitreal NMDA injection has been shown to induce the excitotoxic loss of retinal cells. The retinal ganglion cell apoptosis
induced by NMDA is thought to play an important role in retinal ischemia injury and NMDA-injected rat has been used as a model
of neuronal loss in diseases such as glaucoma. In this experimental model, we studied the early effects of NMDA leading to
the degeneration of retinal ganglion cells. PKCζ regulates the NF-κB pathway in cellular responses to various stresses and
we have shown that aspirin inhibits purified human PKCζ. We therefore investigated the molecular mechanism by which retinal
cells limit ocular injury following NMDA treatment. We found that the NMDA-induced apoptosis of ganglion cells was mediated,
at least partly, by PKCζ. This enzyme was activated early in the cellular response to NMDA. Prolonged activation was followed
by PKCζ cleavage, and nuclear translocation of the C-terminal region of this protein—a critical event for the survival of
retinal cells. We also found that pretreatment with aspirin or the coinjection of NMDA with a specific PKCζ inhibitor counteracted
the effects of NMDA. These findings provide new insight into the role played by PKCζ in neuronal loss in glaucoma. 相似文献
27.
Ibrić S Jovanović M Djurić Z Parojcić J Petrović SD Solomun L Stupar B 《AAPS PharmSciTech》2003,4(1):62-70
The purpose of the present study was to model the effects of the concentration of Eudragit L 100 and compression pressure
as the most important process and formulation variables on the in vitro release profile of aspirin from matrix tables formulated
with Eudragit L 100 as matrix substance and to optimize the formulation by artificial neural network. As model formulations,
10 kinds of aspirin matrix tablets were prepared. The amount of Eudragit L 100 and the compression pressure were selected
as causal factors. In vitro dissolution time profiles at 4 different sampling times were chosen as responses. A set of release
parameters and causal factors were used as tutorial data for the generalized regression neural, network (GRNN) and analyzed
using a computer. Observed results of drug release studies indicate that drug release rates vary widely between investigated
formulations, with a range of 5 hours to more than 10 hours to complete dissolution. The GRNN model was optimized. The root
mean square value for the trained network was 1.12%, which indicated that the optimal GRNN model was reached. Applying the
generalized distance function method, the optimal tablet formulation predicted by GRNN was with 5% of Eudragit L 100 and tablet
hardness 60N. Calculated difference (f
1 2.465) and similarity (f
2 85.61) factors indicate that there is no difference between predicted and experimentally observed drug release profiles for
the optimal formulation. This work illustrates the potential for an artificial neural network, GRNN, to assist in development
of extended release dosage forms. 相似文献
28.
阿斯匹林对大鼠在低O2高CO2下肺动脉高压的作用 总被引:1,自引:0,他引:1
目的:研究阿斯匹林(ASA)对慢性低O2高CO2性肺动脉高压的抑制作用。方法:将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2 阿斯匹林组。用光镜、放射免疫等方法,观察各组大鼠肺动脉平均压(mPAP)、颈动脉平均压(mCAP)、肺细小动脉显微结构、血浆和肺匀浆TXB2及6-keto-PGF1α含量的变化。结果:①低O2高CO2组mPAP比正常组显著增高,ASA组的mPAP比低O2高CO2组显著降低,3组间mCAP比较差异无显著性。②光镜下低O2高CO2组与正常组相比,肺细小动脉管壁面积/管总面积(WA/TA)和肺细小动脉中膜厚度(PAMT)均显著增高。ASA组WA/TA和PAMT显著降低。③低O2高CO2组血浆和肺匀浆TXB2、6-keto-PGF1α浓度以及TXB2/6-keto-PGF1α比正常组显著增高,而ASA组与低O2高CO2组相比显著降低。结论:ASA有抑制慢性低O2高CO2性肺动脉高压和肺血管重构的作用。 相似文献
29.
30.
Functionality comparison of 3 classes of superdisintegrants in promoting aspirin tablet disintegration and dissolution 总被引:1,自引:0,他引:1
The aims of this study are (1) to compare the disintegration efficiency, and (2) to develop a discriminating test model for
the 3 classes of superdisintegrants represented by Ac-Di-Sol, Primojel, and Polyplasdone XL10. Using a digital video camera
to examine the disintegration process of tablets containing the same wt/wt percentage concentration of the disintegrants,
Ac-Di-Sol was found to disintegrate tablets rapidly into apparently primary particles; Primojel also apparently disintegrated
tablets into primary particles but more slowly; Polyplasdone XL10 disintegrated tablets rapidly but into larger masses of
aggregated particles. The differences in the size distribution generated in the disintegrated tablets likely contribute to
the drug dissolution rate differences found for aspirin tablets with similar disintegration rates. The aspirin tablet matrix
is proposed as a model formulation for disintegrant efficiency comparison and performance consistency testing for quality
control purposes.
Published: December 12, 2005 相似文献