• 【高度纯化的卵泡刺激素和人绒毛膜促性腺激素皮下自我给药治疗男性低促性腺激素性性腺功能减退。西班牙男性低促性腺激素性性腺功能减退合作小组。】 复制标题 收藏 收藏
    DOI:10.1093/humrep/12.5.980 复制DOI
    作者列表:Burgués S,Calderón MD
    BACKGROUND & AIMS: The efficacy and safety of highly purified follicle stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) was studied in 60 men with hypogonadotrophic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotrophic hypogonadism and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynaecomastia. No local reactions at injection site were observed. In conclusion, the s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.

    背景与目标: 在60名性腺功能减退的男性中研究了与人绒毛膜促性腺激素 (HCG) 相关的高纯度卵泡刺激素 (FSH) 的功效和安全性。在这些男性中,有16名患有Kallmann综合征,19名患有特发性促性腺激素性低性腺功能减退症,25名患有垂体机能减退症。发现基础睾丸激素浓度远低于正常范围。在基线时,有26例患者能够射精,所有患者均表现出无精子症,而其余患者则为aspermic。所有患者自我管理注射FSH (150 IU × 3/周) 和HCG (2500 IU × 2/周) 至少6个月,并定期评估睾丸功能。治疗期间睾丸激素浓度迅速增加,除一名患者外,所有患者均达到正常值。睾丸体积显示持续增加,几乎达到其基线值的3倍。在治疗结束时,48例患者 (80.0%) 的精子数量达到阳性。处理期间的最大精子浓度为24.5 +/- 8.1 × 10(6)/ml (平均值 +/- SEM)。诱导精子发生的中位时间为5个月。11例患者报告不良事件,一般与治疗无关。3例患者出现妇科乳房发育。在注射部位未观察到局部反应。总之,s.C.高度纯化的FSH HCG的自我管理具有良好的耐受性,并可有效刺激这些患者的精子发生和类固醇生成。
  • 【右精索静脉曲张和缺氧,男性不育的关键因素: 睾丸引流系统受损的流体力学分析。】 复制标题 收藏 收藏
    DOI:10.1016/s1472-6483(10)60638-4 复制DOI
    作者列表:Gat Y,Gornish M,Navon U,Chakraborty J,Bachar GN,Ben-Shlomo I
    BACKGROUND & AIMS: :Varicocele is considered a predominantly unilateral left-sided disease. However, since male fertility is preserved with only one healthy testis, infertility perforce represents bilateral testicular dysfunction. It was hypothesized that: (i) right varicocele cannot be diagnosed by palpation and therefore has not been treated in the past by the traditional treatment, and (ii) right varicocele causes impaired oxygen supply in the right testicular microcirculation, leading to germ cell degeneration. This study performed venographies of both right and left internal spermatic veins during the treatment of 840 infertile men with varicocele and analysed the results using tools of fluid mechanics. Histopathology of the right testis revealed stagnation of blood flow and degenerative changes attributed to lack of adequate oxygenation in all testicular cell types. Right varicocele was found in the vast majority of the patients. We found that due to the destruction of one-way valves, pathologic hydrostatic pressure is produced in the testicular venous microcirculatory system about five times higher than normal, exceeding arteriolar pressure. The pressure gradient between the arterioles and venules in the testicular tissue is therefore reversed, leading to persistent hypoxia. Right varicocele, although undetected, is prevalent in infertile men with varicocele, hence only bilateral occlusion of the internal spermatic veins, including the associated bypasses, eliminating the pathologic hydrostatic pressure will lead to resumption of arterial blood flow in the testicular microcirculation.
    背景与目标: : 精索静脉曲张被认为是一种主要的单侧左侧疾病。但是,由于只有一个健康的睾丸可以保留男性的生育能力,因此不育表现为双侧睾丸功能障碍。假设 :( i) 无法通过触诊来诊断右精索静脉曲张,因此过去没有通过传统疗法进行治疗,并且 (ii) 右精索静脉曲张会导致右睾丸微循环中的氧气供应受损,导致生殖细胞变性。这项研究在治疗840名患有精索静脉曲张的不育男性期间对左右精索内静脉进行了静脉造影,并使用流体力学工具分析了结果。右睾丸的组织病理学显示,由于所有睾丸细胞类型缺乏足够的氧合,导致血流停滞和退行性变化。在绝大多数患者中发现了右精索静脉曲张。我们发现,由于单向阀的破坏,睾丸静脉微循环系统中产生的病理性静水压力约为正常水平的五倍,超过了小动脉压力。因此,睾丸组织中小动脉和小静脉之间的压力梯度相反,导致持续的缺氧。右精索静脉曲张虽然未被发现,但在患有精索静脉曲张的不育男性中很普遍,因此只有双侧精索内静脉 (包括相关的旁路) 闭塞,消除病理性静水压将导致睾丸微循环中动脉血流的恢复。
  • 【欧洲男性和非洲女性对非裔美国人基因组的贡献增加。】 复制标题 收藏 收藏
    DOI:10.1007/s00439-006-0261-7 复制DOI
    作者列表:Lind JM,Hutcheson-Dilks HB,Williams SM,Moore JH,Essex M,Ruiz-Pesini E,Wallace DC,Tishkoff SA,O'Brien SJ,Smith MW
    BACKGROUND & AIMS: :The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis.
    背景与目标: : 非洲和欧洲的男性和女性对非裔美国人单个基因组的不同相对贡献与利用混合分析定位基因有关。在男性中,最容易解决祖先种群对四种类型的基因组DNA (常染色体,X和Y染色体以及线粒体) 及其不同遗传方式的贡献的评估。提出了对93名非洲裔美国男性的2,018个常染色体单核苷酸多态性 (SNP) 标记,121个X染色体SNP,10个由SNP指定的Y染色体单倍群以及6个定义mtDNA SNP的单倍群的全面评估。在X染色体和常染色体混合组分之间观察到的明显缺乏相关性支持在基于混合的基因作图应用中对这些染色体进行单独处理。欧洲对Y染色体的遗传贡献最高 (非洲最低) (28.46%),其次是常染色体 (19.99%),然后是X染色体 (12.11%) 和mtDNA (8.51%)。基因组区室中混合组分的相对顺序验证了先前的研究,这些研究表明,性别偏向的基因流具有较高的欧洲男性和非洲女性贡献。与欧洲女性相比,欧洲男性对非裔美国人个体基因组的贡献高出三倍 (Y染色体与mtDNA),这意味着基于混合物的基因发现将对常染色体具有最大的力量,并且对X染色体分析。
  • 【药物洞察: 男性激素避孕的最新进展。】 复制标题 收藏 收藏
    DOI:10.1038/ncpendmet0069 复制DOI
    作者列表:Amory JK,Page ST,Bremner WJ
    BACKGROUND & AIMS: :As there are limitations to current methods of male contraception, research has been undertaken to develop hormonal contraceptives for men, analogous to the methods for women based on estrogen and progestogens. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Since these hormones are the main stimulatory signals for spermatogenesis, low levels of LH and FSH markedly impair sperm production. After 3-4 months of testosterone treatment, 60-70% of men no longer have sperm in their ejaculate, and most other men exhibit markedly diminished sperm counts. Male hormonal contraception is well tolerated, free of serious adverse side effects, and 95% effective in the prevention of pregnancy. Importantly, male hormonal contraception is reversible, with sperm counts usually recovering within 4 months of the discontinuation of hormone treatment. Because exogenous testosterone administration alone does not completely suppress sperm production in all men, researchers have combined testosterone with second agents, such as progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Recent trials have used combinations of long-acting injectable or implantable forms of testosterone with progestogens, which can be administered orally, by injection or by a long-acting implant. Such combinations suppress spermatogenesis to zero without severe side effects in 80-90% of men, with near-complete suppression in the remainder of individuals. One of these testosterone and progestogen combination regimens might soon bring the promise of male hormonal contraception to fruition.
    背景与目标: : 由于目前男性避孕方法存在局限性,因此已经进行了研究以开发针对男性的激素避孕药,类似于基于雌激素和孕激素的女性避孕方法。当向男性施用睾丸激素时,它通过抑制垂体的促黄体激素 (LH) 和促卵泡激素 (FSH) 的分泌而起到避孕作用。由于这些激素是精子发生的主要刺激信号,因此低水平的LH和FSH明显损害了精子的产生。经过3-4个月的睾酮治疗后,60-70% 的男性射精中不再有精子,大多数其他男性的精子数量明显减少。男性激素避孕耐受性良好,无严重不良副作用,95% 有效预防妊娠。重要的是,男性激素避孕是可逆的,精子数量通常在停止激素治疗后4个月内恢复。由于单独使用外源性睾丸激素并不能完全抑制所有男性的精子产生,因此研究人员已将睾丸激素与第二种药物 (例如孕激素或促性腺激素释放激素拮抗剂) 结合使用,以进一步抑制LH和FSH的分泌并改善精子发生的抑制。最近的试验使用了长效可注射或可植入形式的睾丸激素与孕激素的组合,可以口服,注射或长效植入物给药。在80-90% 的男性中,这种组合将精子发生抑制为零,而没有严重的副作用,在其余个体中几乎完全抑制。这些睾丸激素和孕激素联合疗法之一可能很快就会实现男性激素避孕的希望。
  • 【热应激对雄性小鼠体内和体外生育力的影响。】 复制标题 收藏 收藏
    DOI:10.1071/rd05022 复制DOI
    作者列表:Yaeram J,Setchell BP,Maddocks S
    BACKGROUND & AIMS: :A study was conducted to determine whether following exposure of male mice to high temperatures, the ability of their spermatozoa to fertilise ova was reduced, especially during the period before the males became completely infertile. Male mice placed in a microclimate chamber at 36 degrees C for two periods, each of 12 h on successive days, were less able to fertilise control females in vivo when mated and, even in those females that became pregnant, litter size was reduced. However, these effects were associated with falls in testis weight and numbers of spermatozoa in the testis and epididymis. To determine whether the effect on fertility was a result of the decreased spermatozoa numbers, spermatozoa were collected from the epididymides of heated and control males. Equal numbers of motile spermatozoa from an unselected sample or those subjected to a swim-up procedure to separate those that were motile from the immotile ones in the sample were then mixed in vitro with oocytes from superovulated normal females. Similar numbers of spermatozoa from both control and heated males bound to the zona pellucida but smaller percentages of the oocytes were fertilised by spermatozoa from the heated males and fewer of these spermatozoa penetrated the ova. The effects were first seen 7 days after the heat exposure and became more obvious after 10 or 14 days.
    背景与目标: : 进行了一项研究,以确定雄性小鼠暴露于高温后,其精子受精卵子的能力是否降低,尤其是在雄性完全不育之前。在36摄氏度的小气候室中放置两个周期的雄性小鼠,每次连续12小时,交配时在体内受精对照雌性的能力较小,即使在怀孕的雌性中,产仔数也减少了。然而,这些影响与睾丸重量下降以及睾丸和附睾中精子数量下降有关。为了确定对生育力的影响是否是精子数量减少的结果,从加热和对照男性的附睾中收集了精子。然后将来自未选择样品的等量运动精子或经过游泳程序以将样品中运动的精子与未运动的精子分开的精子与超排卵正常雌性的卵母细胞在体外混合。与透明带结合的对照雄性和受热雄性的精子数量相似,但受热雄性的精子受精的卵母细胞百分比较小,而这些精子穿透卵子的数量较少。这种影响首先在暴露于热后7天出现,并在10或14天后变得更加明显。
  • 【[非洲男性乳腺癌,与瓦加杜古大学教学医院 (布基纳法索) 的5例病例有关]。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Sano D,Dao B,Lankoandé J,Touré B,Sakandé B,Traoré SS,Wandaogo A,Dakouré R,Sanou A
    BACKGROUND & AIMS: :A retrospective study of male breast cancer was undertaken at Ouagadougou University Teaching Hospital over a 3 year period (1993-1996). Authors report 5 cases representing 4.16% of all breast cancers. The patients' mean age was 61 years. The average duration of signs and symptoms before the diagnosis was 13 months. Clinically all the 5 cases presented advanced cancers (4 T4N2M0, 1 T4N2M1 according to UICC TNM System) with size ranging from 5.5, to 11.5 cm. Histology found: 2 medullary infiltrating carcinoma, 1 canalar infiltrating carcinoma, 1 colloid mucous carcinoma and 1 lobular infiltrating carcinoma. All patients had mastectomy associated with axillary clearance in 4 cases. Radiotherapy, chemotherapy and hormonotherapy were not associated because unavailable in Burkina Faso. Three patients died: the first, 10 days after surgical treatment and the 2 others respectively after 14 and 17 months. We have lost sight 1 patients. The last one is still alive. Authors find that to get better prognosis, it is important to improve medical and technical means, to increase information and to promote early detection.
    背景与目标: : 在瓦加杜古大学教学医院进行了为期3年 (1993-1996年) 的男性乳腺癌回顾性研究。作者报告了5例代表所有乳腺癌4.16% 的病例。患者的平均年龄为61岁。诊断前症状和体征的平均持续时间为13个月。临床上所有5例均表现为晚期癌症 (根据UICC TNM系统,4个T4N2M0,1个T4N2M1),大小从5.5到11.5厘米。组织学发现: 髓质浸润性癌2例,管内浸润性癌1例,胶体粘液性癌1例,小叶浸润性癌1例。所有患者均行乳房切除术伴腋窝清除4例。放疗,化疗和激素治疗不相关,因为在布基纳法索不可用。3例患者死亡: 手术治疗后第1、10天,另外2例分别在14和17个月后死亡。我们已经看不见1个病人了。最后一个还活着。作者发现,要获得更好的预后,必须改善医疗和技术手段,增加信息并促进早期发现。
  • 【在台湾,替加环素与其他抗菌剂对肺炎链球菌,流感嗜血杆菌和卡他莫拉菌的体外活性比较。】 复制标题 收藏 收藏
    DOI:10.1089/mdr.2006.12.130 复制DOI
    作者列表:Lau YJ,Hsueh PR,Liu YC,Shyr JM,Huang WK,Teng LJ,Liu CY,Luh KT
    BACKGROUND & AIMS: :We compared the in vitro activities of tigecycline to those of other agents against 300 nonduplicate isolates of Streptococcus pneumoniae (194 isolates), Haemophilus influenzae (60 isolates), and Moraxella catarrhalis (46 isolates) recovered from patients treated in three major hospitals in Taiwan from August through December, 2003. All of these isolates were inhibited at 0.5 mg/L of tigecycline. For S. pneumoniae isolates, 72% were not susceptible to penicillin (69% intermediate and 3% resistant) and 96% were not susceptible to azithromycin. Among the 178 isolates resistant to azithromycin, 53 isolates (30%) had the M phenotype and 70% had the cMLSB phenotype. The rate of nonsusceptibility to ertapenem, telithromycin, moxifloxacin, and quinupristindalfopristin in S. pneumoniae was 3%, 2%, 1%, and 57%, respectively. For H. influenzae, 36 (60%) were not susceptible to ampicillin, among which 31 possessed beta-lactamase. A high rate (8.3%) of H. influenzae isolates with beta-lactamase-negative and ampicillin-resistant phenotype was found. All H. influenzae isolates were susceptible to azithromycin, but 40% of them were not susceptible to clarithromycin. Ninety-eight percent (44 isolates) of M. catarrhalis possessed beta-lactamase. All three fluoroquinolones tested were highly active (MIC90 < or =0.12 mg/L) against H. influenzae and M. catarrhalis.
    背景与目标: : 我们比较了替加环素与其他药物对300种非重复肺炎链球菌分离株 (194株),流感嗜血杆菌 (60株) 和卡他莫拉菌 (46株) 的体外活性,这些分离株是从8月到2003年12月在台湾的三家主要医院中康复的。在0.5 mg/L替加环素的浓度下,所有这些分离株均被抑制。对于肺炎链球菌分离株,72% 对青霉素不敏感 (69% 中间体和3% 耐药),96% 对阿奇霉素不敏感。在对阿奇霉素耐药的178株中,53株 (30% 株) 具有M表型,70% 株具有cMLSB表型。肺炎链球菌对厄他培南,泰利霉素,莫西沙星和奎奴普汀的不敏感性分别为3%,2%,1% 和57%。对于流感嗜血杆菌,36 (60%) 对氨苄青霉素不敏感,其中31具有 β-内酰胺酶。发现具有 β-内酰胺酶阴性和氨苄青霉素抗性表型的流感嗜血杆菌分离株率高 (8.3%)。所有流感嗜血杆菌分离株对阿奇霉素敏感,但其中40% 对克拉霉素不敏感。卡他氏杆菌的百分之九十八 (44个分离株) 具有 β-内酰胺酶。测试的所有三种氟喹诺酮类药物对流感嗜血杆菌和卡他氏杆菌具有高度活性 (MIC90 <或 = 0.12 mg/L)。
  • 【关系质量,激素避孕选择和青少年妇女不使用避孕套的发展关联。】 复制标题 收藏 收藏
    DOI:10.1016/j.jadohealth.2005.12.027 复制DOI
    作者列表:Sayegh MA,Fortenberry JD,Shew M,Orr DP
    BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.
    背景与目标:
  • 【氟化分子作为中枢神经系统中的药物和显像剂。】 复制标题 收藏 收藏
    DOI:10.2174/156802606777951046 复制DOI
    作者列表:Sun S,Adejare A
    BACKGROUND & AIMS: :The strategic use of fluorine substitution in drug discovery and drug development is well documented. The small size and high electronegativity of fluorine are among properties of this element that lend special advantages. Applications in drugs targeted to the central nervous system (CNS) have been particularly fruitful in addition to favorable properties seen in many peripherally acting drugs. Fluorine substitution can be used to solve problems unique to the CNS, such as blood brain barrier (BBB) penetration. Likewise, use of the positron emitting isotope, (18)F, provides a unique tool for non-invasive imaging and diagnoses in the CNS. In this review, fluorine in CNS drugs and drug discovery are discussed.
    背景与目标: : 氟替代在药物发现和药物开发中的战略用途已得到充分证明。氟的小尺寸和高电负性是该元素的特殊优点之一。除了在许多外周作用药物中看到的有利特性外,针对中枢神经系统 (CNS) 的药物中的应用特别富有成效。氟替代可用于解决CNS特有的问题,例如血脑屏障 (BBB) 渗透。同样,使用正电子发射同位素 (18)F为CNS中的非侵入性成像和诊断提供了独特的工具。本文对中枢神经系统药物中的氟和药物发现进行了讨论。
  • 【一些腙衍生物作为新型抗癌剂和抗癌剂的合成和生物学评价。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejmech.2012.10.011 复制DOI
    作者列表:Altıntop MD,Özdemir A,Turan-Zitouni G,Ilgın S,Atlı Ö,İşcan G,Kaplancıklı ZA
    BACKGROUND & AIMS: :New hydrazone derivatives were synthesized via the nucleophilic addition-elimination reaction of 2-[(1-methyl-1H-tetrazol-5-yl)thio)]acetohydrazide with aromatic aldehydes/ketones. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Genotoxicity of the most effective anticandidal compounds was evaluated by umuC and Ames assays. All compounds were also investigated for their cytotoxic effects on NIH3T3 and A549 cell lines. Compound 8 was the most effective antifungal derivative against C. albicans (ATCC-90028) with a MIC value of 0.05 mg/mL. Compound 5 can be identified as the most promising anticancer agent against A549 cancer cell lines due to its inhibitory effect on A549 cell lines and low toxicity to NIH3T3 cells.
    背景与目标: : 通过2-[(1-甲基-1h-四唑-5-基) 硫代)] 乙酰酰肼与芳族醛/酮的亲核加成消除反应合成了新的腙衍生物。对化合物进行了针对各种念珠菌的体外测试,并与酮康唑进行了比较。通过umuC和Ames分析评估了最有效的抗癌症化合物的遗传毒性。还研究了所有化合物对NIH3T3和A549细胞系的细胞毒性作用。化合物8是对白色念珠菌 (ATCC-90028) 最有效的抗真菌衍生物,MIC值为0.05 mg/ml。化合物5由于对A549细胞系的抑制作用和对NIH3T3细胞的低毒性,可被确定为最有前途的抗A549癌细胞系的抗癌剂。
  • 【发现链烯基硼酸作为神经保护剂,影响与阿尔茨海默氏病有关的多个生物靶标。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.11.068 复制DOI
    作者列表:Jiménez-Aligaga K,Bermejo-Bescós P,Martín-Aragón S,Csákÿ AG
    BACKGROUND & AIMS: :Alkenylboronic acids have shown important biological activities that contribute to neuroprotection. We have determined their influence on the β-amyloid (βA) aggregation process, β-secretase and acethylcholinesterase activities on cell-free systems, on the redox and lipid peroxidation status, and on the vulnerability to apoptotic death in an APPswe neuroblastoma cell line, before and after hydrogen peroxide treatment. We have discovered that 2-arylvinylboronic acids and some of their esters possess a set of properties which makes them highly useful as neuroprotective agents affecting multiple biological targets involved in AD. These properties are not paralleled by the related 2-arylboronic acids.
    背景与目标: : 烯基硼酸显示出重要的生物活性,有助于神经保护。我们已经确定了它们对 β-淀粉样蛋白 (β a) 聚集过程,β-分泌酶和乙胆碱酯酶在无细胞系统上的活性,对氧化还原和脂质过氧化状态以及对APPswe神经母细胞瘤细胞凋亡死亡的脆弱性的影响过氧化氢治疗之前和之后。我们发现2-芳基乙烯基硼酸及其某些酯具有一系列特性,这使它们作为影响AD中涉及的多个生物靶标的神经保护剂非常有用。这些性质与相关的2-芳基硼酸不平行。
  • 【白藜芦醇衍生物的设计,合成和评估,如a ß (派-) 聚集抑制剂,抗氧化剂和神经保护剂。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmcl.2012.09.105 复制DOI
    作者列表:Lu C,Guo Y,Li J,Yao M,Liao Q,Xie Z,Li X
    BACKGROUND & AIMS: :A series of novel resveratrol derivatives were designed, synthesised and evaluated as potential therapeutic agents for the treatment of Alzheimer's disease. Among these compounds, compound 7l, (E)-5-(4-(isopropylamino)styryl)benzene-1,3-diol, exhibited potent ß-amyloid aggregation inhibition activity, which was confirmed by a ThT fluorescence assay (71.65% at 20 μM) and transmission electron microscopy (TEM). Compound 7l also exhibited good antioxidant activity (4.12 Trolox equivalents in an oxygen radical absorbance capacity assay and a 37% reduction in reactive oxygen species in cells at 10 μM). The cytotoxicity analysis of compounds 7f, 7i, 7j and 7l indicated that these compounds have lower toxicities than resveratrol at 60 μM.
    背景与目标: : 设计,合成和评估了一系列新型白藜芦醇衍生物,可作为治疗阿尔茨海默氏病的潜在治疗剂。在这些化合物中,化合物7l,(E)-5-(4-(异丙基氨基) 苯乙烯基) 苯-1,3-二醇表现出有效的 β-淀粉样蛋白聚集抑制活性,通过ThT荧光分析 (71.65% 在20μm) 和透射电子显微镜 (TEM) 证实了这一点。化合物7l也显示出良好的抗氧化活性 (在氧自由基吸收能力分析中4.12的Trolox当量和10μm细胞中活性氧的37% 减少)。化合物的细胞毒性分析7f,7i,7j和7l表明这些化合物在60μm时的毒性比白藜芦醇低。
  • 【八氢吡嗪 [2,1-a:5,4-a '] 二异喹啉衍生物作为有效抗癌剂的生物学评价。】 复制标题 收藏 收藏
    DOI:10.1177/1010428317701641 复制DOI
    作者列表:Gornowicz A,Pawłowska N,Czajkowska A,Czarnomysy R,Bielawska A,Bielawski K,Michalak O,Staszewska-Krajewska O,Kałuża Z
    BACKGROUND & AIMS: :In this study, we evaluated the cytotoxic activity and antiproliferative potency of novel octahydropyrazin[2,1-a:5,4-a']diisoquinoline derivatives (1-7) in MCF-7 and MDA-MB-231 breast cancer cell lines. Annexin V binding assay and disruption of the mitochondrial potential were performed to determine apoptosis. The activity of caspases 3, 8, 9, and 10 was measured after 24 h of incubation with tested compounds to explain detailed molecular mechanism of induction of apoptosis. The results from experiments were compared with effects obtained after incubation in the presence of camptothecin and etoposide. Our study demonstrated that the most active compounds in both analyzed breast cancer cell lines were compounds 3 and 4. We also observed that all compounds induced apoptosis. We demonstrated the higher activity of caspases 3, 8, 9, and 10, which confirmed that induction of apoptosis is associated with external and internal cell death pathway. Our study revealed that the novel compounds in group of diisoquinoline derivatives are promising candidates in anticancer treatment by activation of both extrinsic and intrinsic apoptotic pathways.
    背景与目标: : 在这项研究中,我们评估了新型八氢吡嗪 [2,1-a:5,4-a '] 二异喹啉衍生物 (1-7) 在MCF-7和MDA-MB-231乳腺癌细胞系中的细胞毒性和抗增殖能力。进行膜联蛋白V结合测定和线粒体电位破坏以确定细胞凋亡。与测试化合物孵育24小时后,测量了胱天蛋白酶3、8、9和10的活性,以解释诱导凋亡的详细分子机制。将实验结果与在喜树碱和依托泊苷存在下孵育后获得的效果进行了比较。我们的研究表明,在两种分析的乳腺癌细胞系中最具活性的化合物是化合物3和4。我们还观察到所有化合物均诱导细胞凋亡。我们证明了caspases 3、8、9和10的较高活性,这证实了凋亡的诱导与外部和内部细胞死亡途径有关。我们的研究表明,二异喹啉衍生物组中的新型化合物通过激活外在和内在凋亡途径在抗癌治疗中是有希望的候选者。
  • 【2-取代-4-(3 ',4',5 '-三甲氧基苯基)-5-芳基噻唑类抗癌剂的合成及生物学评价。】 复制标题 收藏 收藏
    DOI:10.1016/j.bmc.2012.10.001 复制DOI
    作者列表:Romagnoli R,Baraldi PG,Salvador MK,Camacho ME,Preti D,Tabrizi MA,Bassetto M,Brancale A,Hamel E,Bortolozzi R,Basso G,Viola G
    BACKGROUND & AIMS: :Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH(3) > Me > N(CH(3))(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N,N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC(50) values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization.
    背景与目标: : 与微管蛋白结合并破坏微管动力学的抗肿瘤剂在过去几年中引起了极大的关注。为了扩展我们对噻唑环作为combretastatin A-4中存在的顺式烯烃的合适模拟物的了解,我们将3,4,5-三甲氧基苯基固定在噻唑核的C4-position。我们发现C2-和C5-positions的取代基对抗增殖活性具有深远的影响。比较噻唑环C5-position具有相同取代基的化合物,C2-position部分影响抗增殖活性,效力顺序为NHCH(3)> Me> N(CH(3))(2)。相对于C2-amino对应物,N-甲基氨基取代基显着提高了MCF-7细胞的抗增殖活性。从N-甲基氨基到N,N-二甲基氨基C2-position的空间体积增加导致活性降低1-2对数。2-n-甲基氨基噻唑衍生物3b,3d和3e是作为抗增殖剂的最具活性的化合物,其IC(50) 值从低微摩尔到个位数纳摩尔,此外,它们在多药耐药细胞系中也具有活性过表达P-糖蛋白。抗增殖活性可能是由化合物与微管蛋白聚合的秋水仙碱位点结合并破坏微管动力学引起的。此外,活性最高的化合物3e通过激活caspase-2,-3和-8诱导细胞凋亡,但3e并未引起线粒体去极化。
  • 【植物心理药物的临床试验。】 复制标题 收藏 收藏
    DOI:10.1016/S0944-7113(97)80050-5 复制DOI
    作者列表:Schulz V,Hübner WD,Ploch M
    BACKGROUND & AIMS: :Phyto-psychopharmacological agents are extracts of plants with stimulating or calming effects on the central nervous system. Phyto-psycho-pharmacological agents are among the most commonly prescribed herbal medicines in Germany. The efficacy and harmlessness of some of the preparations have been established by high quality clinical trials. Between 1975 and 1992, a total of 34 clinical studies involving some 2326 patients were published on the effects of Ginkgo special extract EGb 761 and LI 1370; to date, 28 clinical trials in 2120 patients have been under-taken with alcoholic extracts of St. John's Wort. The therapeutic efficacy of kava and valerian extracts has been investigated in six and four controlled studies, respectively. In general, a high placebo effect is likely, which is why it is essential to include control groups in these studies. A considerable advantage over synthetic psychopharmacological agents is the low incidence of side effects, which in safety assessment studies is below 3%. The sharp increase in quality standards for clinical trials has meant that only a few preparations have undergone large scale testing programs in accordance with international guidelines. For other phyto-psychopharmacological agents, there is the danger that no further clinical trials will be undertaken due to the excessively high standards now demanded.
    背景与目标: : 植物心理药物是对中枢神经系统具有刺激或镇静作用的植物提取物。植物心理药物是德国最常用的草药之一。一些制剂的疗效和无害化已通过高质量的临床试验确定。在1975年至1992年之间,共发表了34项临床研究,涉及约2326名患者,涉及银杏特殊提取物EGb 761和LI 1370的影响; 迄今为止,已对2120名患者进行了28项临床试验,其中包括圣约翰草的酒精提取物。卡瓦和缬草提取物的治疗功效已分别在六个和四个对照研究中进行了研究。一般来说,安慰剂效应可能很高,这就是为什么在这些研究中包括对照组是必不可少的。与合成精神药物相比,相当大的优势是副作用的发生率低,在安全性评估研究中,副作用的发生率低于3%。临床试验质量标准的急剧提高意味着只有少数制剂按照国际指南进行了大规模的测试计划。对于其他植物心理药物,由于现在要求的标准过高,因此存在无法进行进一步临床试验的危险。

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