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91.
We previously developed a preliminary 3-D QSAR model for the binding of 14 hydantoins to the neuronal voltage-gated sodium channel; this model was successful in designing an effective non-hydantoin ligand. To further understand structural features that result in optimum binding, here we synthesized a variety of compound classes and evaluated their binding affinities to the neuronal voltage-gated sodium channel using the [3H]-batrachotoxinin A 20-alpha-benzoate ([3H]BTX-B) binding assay. In order to understand the importance of the hydantoin ring for good sodium channel binding, related non-hydantoins such as hydroxy amides, oxazolidinediones, hydroxy acids, and amino acids were included. Two major conclusions were drawn: (1) The hydantoin ring is not critical for compounds with long alkyl side chains, but it is important for compounds with shorter side chains. (2) Relative to Khodorov's pharmacophore, which contains two hydrophobic regions, a third hydrophobic region may enhance binding to provide nanomolar inhibitors. 相似文献
92.
Cyclooxygenases in cancer: progress and perspective 总被引:20,自引:0,他引:20
Aspirin has been used to control pain and inflammation for over a century. Epidemiological studies first associated a decreased incidence of colorectal cancer with the long-term use of aspirin in the early 1980s. Near the same time the first reports showing regression of colorectal adenomas in response to the non-steroidal anti-inflammatory drug (NSAID) sulindac were reported. In subsequent years, the use of other NSAIDs, which inhibit cyclooxygenase (COX) enzymes, was linked to reduced cancer risk in multiple tissues including those of the breast, prostate, and lung. Together these studies resulted in the identification of a new cancer preventive and/or therapeutic target-COX enzymes, especially COX-2. Meanwhile, the overexpression of COX-2, and less consistently, the upstream and downstream enzymes of the prostaglandin synthesis pathway, was demonstrated in multiple cancer types and some pre-neoplastic lesions. Direct interactions of prostaglandins with their receptors through autocrine or paracrine pathways to enhance cellular survival or stimulate angiogenesis have been proposed as the molecular mechanisms underlying the pro-carcinogenic functions of COX-2. The rapid development of safe and effective inhibitors targeting individual COX enzymes not only dramatically improved our understanding of the function of COX-2, but also resulted in discovery of COX independent functions of NSAIDs, providing important hints for future drug design. Here we review the fundamental features of COX enzymes, especially as related to carcinogenesis, their expression and function in both animal tumor models and clinical cancers and the proposed mechanisms behind their roles in cancer. 相似文献
93.
Alpha-methylacyl-CoA racemase as an androgen-independent growth modifier in prostate cancer 总被引:11,自引:0,他引:11
Zha S Ferdinandusse S Denis S Wanders RJ Ewing CM Luo J De Marzo AM Isaacs WB 《Cancer research》2003,63(21):7365-7376
Alpha-methylacyl-CoA racemase (AMACR) is an enzyme involved in beta-oxidation of branched-chain fatty acids and bile acid intermediates. Recent work has identified AMACR as a new diagnostic marker for prostate cancer (PCa). The data from the present study suggest that AMACR is also functionally important for the growth of PCa cells. Overexpressed AMACR from both clinical tissues and PCa cell lines is wild type by sequence analysis and functionally active by enzymatic assay. Correspondingly, enzyme activity of AMACR increases approximately 4-fold in PCa in comparison with adjacent normal prostate. Small interference RNA (siRNA) against AMACR, but not the control inverted siRNA, reduced the expression of AMACR and significantly impaired proliferation of the androgen-responsive PCa cell line LAPC-4. No effect was observed in HeLaS3 cells, which express AMACR at a low level. Cell cycle analyses revealed a G(2)-M cell cycle arrest in LAPC-4 cells treated with siRNA compared with mock treatment or control inverted siRNA. Expression of a siRNA-resistant form of AMACR in LAPC-4 cells protects the cells from growth arrest after AMACR-specific siRNA treatment. Data from Western blotting and luciferase-based reporter assays suggest that the function and expression of AMACR are independent of androgen receptor-mediated signaling. Moreover, simultaneous inhibition of both the AMACR pathway by siRNA and androgen signaling by means of androgen withdrawal or antiandrogen suppressed the growth of LAPC-4 cells to a greater extent than either treatment alone. Taken together, these data suggest that AMACR is essential for optimal growth of PCa cells in vitro and that this enzyme has the potential to be a complementary target with androgen ablation in PCa treatment. 相似文献
94.
目的:了解湖州市食品中单增李斯特菌、肠出血性大肠埃希菌、沙门菌、金黄色葡萄球菌、副溶血性弧菌、空肠弯曲菌的污染状况,为食物中毒监测提供科学依据。方法:按国标方法,对6类食品进行单增李斯特菌、肠出血性大肠埃希菌、沙门菌、金黄色葡萄球菌、副溶血性弧菌和空肠弯曲菌分离、生化及血清型鉴定。结果:192份样品中共检出致病菌28株,总检出率为14.6%。其中单增李斯特菌检出10株,检出率为5.2%;沙门菌检出12株,检出率为6.3%;副溶血性弧菌检出6株,检出率为3.1%;未检出金黄色葡萄球菌、肠出血性大肠埃希菌、空肠弯曲菌。结论:湖州市食品中存在食源性致病菌的污染,其中生肉制品和水产品受到的污染最为严重,卫生监督部门应加强对生肉制品和水产品的监督管理,防止食源性疾病的发生。 相似文献
95.
抗生育中草药的抗HIV研究现状和展望 总被引:1,自引:0,他引:1
近年来,抗HIV药物的研究有了很大的发展,目前美国食品及药品管理局(FDA)已经批准了至少29种用于治疗HIV感染的抗病毒药物,主要包括3大类:核苷类逆转录酶抑制剂(NRTIs),非核苷类逆转录酶抑制剂(NNRTIs)及蛋白酶抑制剂(PIs),它们通过抑制HIV病毒的逆转录酶和蛋白酶发挥抗HIV活性。然而,目前HIV对临床使用的上述抗HIV药物均产生耐药性,因此围绕耐药性问题进行了大量的分子机制研究。与此同时,抗HIV天然药物因其专一性、毒副反应少、方便有效等原因得到了越来越多的重视和研究,包括生物碱类、香豆素类、黄酮类、木脂素类和酚类等化合物。研究发现,在天然药物中,有很多抗生育中草药同时具有抗HIV活性,由于抗生育与抗HIV在免疫机制、基因表达、信号转导和促进细胞凋亡方面的机理具有一定的相关性,同时艾滋病又是一种性传播疾病,因此抗生育与抗HIV结合可能成为临床基础研究的新热点。 相似文献
96.
97.
目的:探讨EAP/LF交替方案进展胃癌的疗效。方法:自1994年10月至1999年12月,124例经病理确诊的有可测量病灶的进展期胃癌患者被随机分入EAP/LF组(研究组)和EAP组(对照组),研究组用药为:足叶乙甙(Vp-16)70mg/m^2,静滴,d4-6;阿霉素(ADM)15mg/m^2,静注d1.7;顺铂(DDP)20mg/m^2,静滴,d2.8,醛氢叶酸(CF)70mg/m^2,静滴,d29-33,5-氟尿嘧啶(5-FU)325mg/m^2,静滴,d29-33,每8周重复,。结果:研究组客观有效率为62.1%,明显优于对照组的48.3%(P=0.032);研究组有效者中位生存期、无进展生存时间分别为20个月、13个月,均明显优于对照组13个月(P=0.037)、7个月(P=0.007)。两组不良反应主要有白细胞减少、口腔粘膜炎、脱发、结论:调整剂量的EAP/LF交替方案是一疗效确切,安全、对生存有益处的治疗进展期胃癌的优势方案,值得临床进一步研究。 相似文献
98.
西藏自治区精神障碍流行病学调查I:重型精神障碍 总被引:6,自引:2,他引:4
WEI Geng LIU Shanming ZHANG Wei XIANG Yun HUANG Xiaoqi YANG Chuang HUANG Wenjun XIE Weijue HE Xia SU Xiaofan Wang Jia Ciren Pingcuo Baima Zuoga Ci Pu Zha Sang LIU Xiehe 《中国神经精神疾病杂志》2008,(10)
目的调查西藏精神障碍患病率,为政府制订西藏卫生工作规划提供科学依据。方法参考两次全国精神障碍流行病学调查的方法,使用美国精神障碍诊断与统计手册轴I障碍用临床定式检查执行手册/研究版(SCID-I)作为定式检查工具,并以美国精神障碍诊断与统计手册-第四版(DSM-IV)为诊断标准,对西藏具有代表性的4个地市进行精神障碍流行病学抽样调查。结果在西藏≥15岁人口中实际调查5375人,心境障碍、精神分裂症、器质性精神障碍和急性短暂精神病性障碍的时点患病率分别为0.48%,0.34%,0.17%和0.037%;终生患病率分别为0.56%,0.37%,0.17%和0.037%。结论西藏4类重型精神障碍总的终生患病率为1.14%,如何妥善解决全自治区1%人口中重型精神障碍患者的诊治问题,在政府制订卫生工作规划时有必要特别加以关注。 相似文献
99.
100.
目的研究胸水细胞端粒酶活性对良恶性胸水的鉴别价值.方法采用TRAP-Hyb法直接检测并在去除胸水淋细胞后再检测胸水细胞端粒酶活性,将检测结果和临床诊断进行比较.结果直接检测胸水细胞端粒酶活性显示54例良性胸水有4例阳性、33例恶性胸水有26例阳性(P<0.01),去除胸水淋巴细胞后胸水细胞端粒酶活性显示良性组有1例阳性、恶性组有23例阳性(P<0.01).去除胸水淋巴细胞前后胸水细胞端粒酶活性诊断效能分别如下:诊断灵敏度0.788和0.697、特异度为0.926和0.982、阳性预示值0.867和0.958、阳性似然比10.636和37.636.结论胸水细胞端粒酶活性的检测有助于鉴别良恶性胸水,去除淋巴细胞后胸水细胞端粒酶活性较直接检测胸水细胞端粒酶活性诊断效能优越. 相似文献