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991.
992.
Nuclear factor-kappaB (NF-kappaB) has been implicated in the development of drug resistance in cancer cells. We systematically examined the baseline levels of NF-kappaB activity of representative carcinoma cell lines, and the change of NF-kappaB activity in response to a challenge with four major anticancer drugs (doxorubicin, 5-fluorouracil, cisplatin, and paclitaxel). We found that the basal level of NF-kappaB activity was heterogeneous and roughly correlated with drug resistance. When challenged with various drugs, all the cell lines examined responded with a transient activation of NF-kappaB which then declined to basal level despite variation in the concentration of the agent and the timing of the treatment. In contrast to tumor necrosis factor-alpha (TNF-alpha), which activates NF-kappaB in minutes, NF-kappaB activation induced by anticancer drugs usually occurred more than 1hr after stimulation. A gradual increase of total NF-kappaB and its nuclear translocation, and cytoplasmic translocation of nuclear IkappaBalpha and its degradation were involved in this process. In particular, when cells were pretreated with common biologic modulators such as tamoxifen, dexamethasone, and curcumin, the doxorubicin-induced NF-kappaB activation was attenuated significantly. This inhibition may play a role in sensitizing cancer cells to chemotherapeutic drugs. This study has demonstrated that activation of NF-kappaB is a general cellular response to anticancer drugs, and the mechanism of activation appears to be distinct from that induced by TNF-alpha. These observations may have implications for improving the efficacy of systemic chemotherapy for cancer patients. 相似文献
993.
Singh J Van Vlijmen H Liao Y Lee WC Cornebise M Harris M Shu IH Gill A Cuervo JH Abraham WM Adams SP 《Journal of medicinal chemistry》2002,45(14):2988-2993
The antigen alpha4beta1 (very late antigen-4, VLA-4) plays an important role in the migration of white blood cells to sites of inflammation. It has been implicated in the pathology of a variety of diseases including asthma, multiple sclerosis, and rheumatoid arthritis. We describe a series of potent inhibitors of alpha4beta1 that were discovered using computational screening for replacements of the peptide region of an existing tetrapeptide-based alpha4beta1 inhibitor (1; 4-[N'-(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val) derived from fibronectin. The search query was constructed using a model of 1 that was based upon the X-ray conformation of the related integrin-binding region of vascular cell adhesion molecule-1 (VCAM-1). The 3D search query consisted of the N-terminal cap and the carboxyl side chain of 1 because, upon the basis of existing structure-activity data on this series, these were known to be critical for high-affinity binding to alpha4beta1. The computational screen identified 12 reagents from a virtual library of 8624 molecules as satisfying the model and our synthetic filters. All of the synthesized compounds tested inhibit alpha4beta1 association with VCAM-1, with the most potent compound having an IC(50) of 1 nM, comparable to the starting compound. Using CATALYST, a 3D QSAR was generated that rationalizes the variation in activities of these alpha4beta1 antagonists. The most potent compound was evaluated in a sheep model of asthma, and a 30 mg nebulized dose was able to inhibit early and late airway responses in allergic sheep following antigen challenge and prevented the development of nonspecific airway hyperresponsiveness to carbachol. Our results demonstrate that it is possible to rapidly identify nonpeptidic replacements of integrin peptide antagonists. This approach should be useful in identification of nonpeptidic alpha4beta1 inhibitors with improved pharmacokinetic properties relative to their peptidic counterparts. 相似文献
994.
Kim CY Whittington DA Chang JS Liao J May JA Christianson DW 《Journal of medicinal chemistry》2002,45(4):888-893
Carbonic anhydrase inhibitors are effective in lowering intraocular pressure, the primary indication of glaucoma. Human carbonic anhydrase II, and possibly carbonic anhydrase IV (CAII and CAIV, respectively), help regulate fluid secretion into the anterior chamber of the eye. Because inhibitors currently formulated as drugs to treat glaucoma were designed to target CAII, an understanding of the structural basis of CAII-CAIV discrimination by inhibitors would be useful for probing the role of each isozyme in the etiology of the disease. Here, we report the X-ray crystal structures of three novel thieno[3,2-e]-1,2-thiazine-6-sulfonamides complexed with CAII and the computationally predicted structures of the same compounds complexed with CAIV. All three compounds bind with similar affinity to CAII, but they bind with up to 100-fold lower affinities to CAIV. Comparisons of experimentally determined structures of CAII-inhibitor complexes and computationally predicted structures of CAIV-inhibitor complexes allow us to rationalize these affinity trends and outline molecular features that may contribute to high-affinity inhibitor binding to CAIV. This study demonstrates how experimental structure determination methods and computational structure prediction methods can be used together to answer questions that cannot be answered by either method alone. 相似文献
995.
996.
丙丁酚抑制体外氧化低密度脂蛋白诱导的单核细胞对内皮细胞的粘附 总被引:13,自引:0,他引:13
目的:研究丙丁酚抑制体外氧化低密度脂蛋白诱导的单核细胞对内皮细胞的粘附机制.方法:采用酶联免疫法检测丙丁酚对内皮细胞粘附分子、细胞间粘附分子1(ICAM-1)、血管细胞粘附分子1 (VCAM-1)、P-选择素和E-选择素表达的影响,对比分析丙丁酚和上述粘附分子单克隆抗体抑制氧化低密度脂蛋白诱导的单核细胞对内皮细胞的粘附作用.结果:丙丁酚呈浓度依赖性抑制氧化低密度脂蛋白诱导的单核细胞对内皮细胞的粘附,丙丁酚浓度从10μmol/L增加到80μmol/L,单核细胞对内皮细胞的粘附从16.7%降低至7.0%(P<0.01),同时ICAM-1和P-选择素表达分别被抑制75%和72%(P相似文献
997.
非融合重组人碱性成纤维细胞生长因子在大肠杆菌中的克隆及高效表达 总被引:2,自引:0,他引:2
Chen XJ Sun FY Xie QL Liao MD Zhang L Li ZY Hong A Lin J 《Acta pharmacologica Sinica》2002,23(9):782-786
目的:获得大肠杆菌中高效表达的非融合重组人碱性成纤维细胞生长因子(rhbFGF).方法:采用RT-PCR技术,以人胎儿脑组织的总RNA克隆出hbFGF基因,再以此为模板,设计引物,对hbFGF的TIR(翻译起始区)部分碱基进行改造和降低G C含量,最后将该新基因克隆于质粒载体pET-3C,转化于大肠杆菌中表达.结果:非融合rhbFGF在大肠杆菌中高效表达,占总蛋白量的30%以上.采用离子交换和亲和层析方法纯化后,生物活性与标准蛋白一致.结论:非融合rhbFGF及调整TIR区域的碱基序列能有效提高重组蛋白的表达效率. 相似文献
998.
Sex differences in risk for coronary heart disease mortality associated with diabetes and established coronary heart disease 总被引:7,自引:0,他引:7
BACKGROUND: The sex-specific independent effect of diabetes mellitus and established coronary heart disease (CHD) on subsequent CHD mortality is not known. METHODS: This is an analysis of pooled data (n = 5243) from the Framingham Heart Study and the Framingham Offspring Study with follow-up of 20 years. At baseline (1971-1975), 134 men and 95 women had diabetes, while 222 men and 129 women had CHD. Risk for CHD death was analyzed by proportional hazards models, adjusting for age, hypertension, serum cholesterol levels, smoking, and body mass index. The comparative effect of established CHD vs diabetes on the risk of CHD mortality was tested by testing the difference in log hazards. RESULTS: The adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for death from CHD were 2.1 (95% CI, 1.3-3.3) in men with diabetes only, and 4.2 (95% CI, 3.2-5.6) in men with CHD only compared with men without diabetes or CHD. The HR for CHD death was 3.8 (95% CI, 2.2-6.6) in women with diabetes, and 1.9 (95% CI, 1.1-3.4) in women with CHD. The difference between the CHD and the diabetes log hazards was +0.73 (95% CI, 0.72-0.75) in men and -0.65 (95% CI, -0.68 to -0.63) in women. CONCLUSIONS: In men, established CHD signifies a higher risk for CHD mortality than diabetes. This is reversed in women, with diabetes being associated with greater risk for CHD mortality. Current treatment recommendations for women with diabetes may need to be more aggressive to match CHD mortality risk. 相似文献
999.
OBJECTIVES: Dural metastasis associated with chronic subdural hematoma (CSH) is rare in patients with malignant neoplasm. In this study, biopsy of the dura and cytological examination of the subdural hematoma was performed for patients with malignant neoplasm and chronic subdural hematoma to investigate the association of dural metastasis and CSH. MATERIALS AND METHODS: Four patients with malignant neoplasm (one breast, one lung, and one colon cancers, and one lymphoma) were diagnosed with CSH. Biopsy of the dura and cytological examination of the subdural fluid were performed for each of these patients. RESULTS: Pathological examination of the dura revealed metastasis for two patients (one lymphoma and one breast cancer), with no specific change except neomembrane formation revealed for the dura of the other two patients. The cytology study was negative for all four patients. All these four patients died within 10 days of the operation; one from recurrent subdural hematoma, and three from infection. CONCLUSION: The results suggest that dural metastasis should be considered in patients with malignant neoplasm and CSH. Further, the prognosis for patients with malignant neoplasm and CSH may be poor because of systemic metastasis and the side-effects of chemotherapy. 相似文献
1000.
Statistical parametric mapping of brain SPECT perfusion abnormalities in patients with Alzheimer's disease 总被引:3,自引:0,他引:3
Brain perfusion in 20 patients with mild Alzheimer's disease (AD), 20 patients with moderate AD and 20 control subjects (matched for age, gender and education) were assessed by single photon emission computed tomography (SPECT) using technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO). SPECT images were transformed to a standard size and shape for group comparisons by the voxel-based t test of the statistical parametric mapping techniques. Cerebral hypoperfusion in the left lower parietal area was found in mild AD patients. In moderate AD patients, significant cerebral hypoperfusion was located in bilateral posterior parietotemporal cortices, contiguous anterior occipital lobes, posterior cingulate gyri and, to a lesser extent, in frontal areas. 相似文献